# Foods and IBS



## eric (Jul 8, 1999)

FYI http://www.ibshealth.com/ibs_foods_2.htm


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## SteveE (Jan 7, 1999)

This is why Dr. D is da man! Those words were so well put together, they should be tatooed on every IBSer, so they don't forget!


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## eric (Jul 8, 1999)

FYIAmerican College of Gastroenterology 67th Annual Scientific Meeting | IBS/ Functional Dyspepsia & Pancreatic DiseaseNew and Important Insights Into IBS: From Epidemiology to Treatment"PathophysiologyAltered Serotonin Signaling?The pathogenesis of IBS remains obscure, and in particular, an explanation for alternating diarrhea and constipation has been elusive. In arguably one of the most important papers presented during this year's meeting, Moses and colleagues 21 studied potential deregulation of the gut's serotonin transporter in IBS.It is known that serotonin 5-hydroxytryptamine or 5HT is released from enteroendocrine or enterochromaffin cells in response to either chemical or mechanical stimulation of the gut mucosa. Serotonin in turn initiates peristalsis, and then the serotonin released is taken up in health by a highly selective serotonin transporter SERT. One potential mechanism that could explain altered bowel function in IBS is an abnormality in the serotonin transporter itself. The study authors evaluated this hypothesis in patients with IBS with constipation and IBS with diarrhea compared with patients with ulcerative colitis and healthy controls. They were able to convincing show on blinded review that SERT immunoreactivity was less intense in patients with IBS with constipation and patients with ulcerative colitis.If these findings are indeed correct, they represent a landmark observation. The findings suggest that patients with constipation and IBS may have a reduced capacity to reuptake serotonin, leading to excess free serotonin and then desensitization of these receptors, thus reducing motor function. In contrast, in the setting of diarrhea, serotonin uptake was normal. If the underlying abnormality in serotonin transporter function alternated, then this would in turn explain alternating constipation and diarrhea.These data strongly suggest that IBS is a "real" gut disease and a potential diagnostic disease marker. They also suggest that it is valid to subdivide IBS into constipation and diarrhea symptom subgroups. This study also provides additional rationale for the use of serotonin-modulating agents in IBS and provides a new target for drug modulation. Confirmation of these very exciting initial findings in larger patient samples is awaited with great interest." http://www.medscape.com/viewarticle/444514


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## Mike NoLomotil (Jun 6, 2000)

The problem that a number of other physicians would point out with the nminal referecne to food intolerance within Dr. Drossman's posted tutorial on the website in question, which includes the following statments, is that a. It is not wholly accurate based upon how IBS is presently diagnosed andb. It is not inclusive of a large body of knowledge as regards the physiologic mechanisms of food intolerance and hypersensitivity.There are other investigators and clinicians expert in this area who would respectfulyl expand upon some of the rudimentary concepts quickly set fiorth in the paragraph in question.Let us consider the perspective of immunologists and allergists whose life work is investigating this aspect of physioology, not psychoneurogastroenterology which is a distinctly different area of expertise. First, the premise of the work of others with a different approach, perspective, and board certification credentials can be summarized by one of them... ______________________________ï¿½Considerable confusion is now arising over the relationship between food intolerance and the Irritable Bowel Syndrome (IBS). Although the name has been hallowed by long usage, IBS is not a distinct entity but merely a collection of disorders which are characterized by abdominal symptoms but no obvious organic pathology. G.W. Thompson forecast in 1985: ï¿½the IBS is organic; that is all sufferers will eventually be found to have measurable, unique pathologic defects.ï¿½ When that happy day arrives, the term ï¿½IBSï¿½ will no longer be used, and each patient will receive a more precise diagnosis. Until then it is sufficient to appreciate that food intolerance represents an important proportion of the conditions which together make up IBS.ï¿½John Hunter, MD, FCRPDirector or Gastroenterology and Consultant PhysicianAddenbrookeï¿½s HospitalCambridge, United KingdomFromï¿½Food Allergy and Food Intoleranceï¿½ Second Edition 2002J. Brostoff, MDS. Challacombe, MDSaunders ___________________________Indeed, the one specific statement set forth by Dr. Drossman in the post above which no one does or would disagree with, is that food intolerance is no more the causal basis of the pathogenesis of the group of conditions currently called 'IBS" than chronic stress is.It is, however, known by many and is the basis for effective treatment of many IBS patients, to be a major set of symptom-generating mechanisms among the subpopulation of diarrheic-prone people diagnosed with "IBS".There is ample evidence of this in the literature, sufficent even to result in inclusion of it in the Merck Manual of Diagnosis and Therapy: ________________________________"Page 1051 of the hard copy of the Merck Manual, and online Merck Manual at http://www.merck.com/pubs/mmanual/section1...ter148/148b.htm "Recently Food Intolerance was found to be responsible for symptoms of some patients with the IRRITABLE BOWEL SYNDROME, confirmed by double-blind food challenge.An increase in rectal prostaglandin levels was noted when a reaction occurred.Preliminary information suggests the same phenomenon may take place in patients with chronic ulcerative colitis.ï¿½ ___________________________In actuality the discovery of this mechanism is not all that recent....it sates back over 23 years to when it was first obserevd nad has been studied in vivo with invasive jejunal segmantal isolation studies which quantifiy inflammatory mediator release in the isolated small bowel of patients with so called "IBS" per the Rome criterai (food allergy ruled out) since about 1994. It can also be duplicated in vitro since about 1997.If one is seeking the most experienced and qualified experts on pscyhophysiology as it mat realte to IBS one should look to UNC and their work.If one is seeking expertise in fod allergy and intolerance one must begin at the top of the order, with Professors Brostoff, Challacombe and perhaps the 100 authors whoc contributed to the following new medical text on the subject...and for in vivo assays of immune response in food intolerance induce GI and systemic symptoms Prof Ulf Bengtsson has donw the most work to date in that area... ____________________________Books written edited or contributed by Professor Jonathan Brostoff:FOOD ALLERGY AND INTOLERANCE, Professor Jonathan Brostoff, MD, Stephen Challacombe, MD (NEW 2002) http://www.amazon.com/exec/obidos/ASIN/070...product-details http://www.greenleaves.com/bookcat/by_brostoff_jonathan.html Asthma: The Complete Guide to Integrative Therapies- by Jonathan Brostoff, Linda GamlinThe Complete Guide to Food Allergy and Intolerance- by Jonathan Brostoff, Linda GamlinFood Allergies and Food Intolerance : The Complete Guide to Their Identification and Treatment- by Jonathan Brostoff, Linda GamlinImmunology- by Ivan Roitt(Editor), Brostoff et alThe Allergy Bible : Understanding, Diagnosing, Treating, Allergies and Intolerances- by Reader's Digest(Editor), et alAutoimmune Disease : Aetiopathogenesis, Diagnosis and Treatment : Essays in Honour of the Retirement of Professor Ivan Roitt Frs- by Peter M. Lydyard(Editor), Jonathan Brostoff(Editor)Case Studies in Immunology- by Jonathan Brostoff, et alCase Studies in Immunology: Companion to Immunology, Fifth Edition- by Jonathan Brostoff, et alClinical Immunology- by Jonathan BrostoffClinical Immunology : An Illustrated Outline- by Jonathan Brostoff, David K. MaleImmunology- by Ivan M. Roitt, et alImmunology : Interactive 2.1- by David Male, et alThe Complete Guide to Hay Fever : The Latest Research & Techniques for Coping With Hayfever- by Jonathan BrostoffFood Allergy and Intolerance- by Jonathan Brostoff, Stephen J. ChallacombeImmunology- by Ivan Maurice Roitt, et alInmunologia Clinica- by Jonathan Brostoff, et alIntroducing Immunology- by Norman A. Staines, et al __________________________Also, a good tutorial on the mechanisms (multiple) of food reactivity and how they marshall IBS symptoms in the food intlerant patients would be this one:Alimentary Pharmacology and Therapeutics Vol. 15 Issue 4 Page 439 April 2001 Food hypersensitivity and irritable bowel syndrome S. Zar, D. Kumar, M. J. Benson http://www.blackwell-synergy.com/servlet/u...36.2001.00951.x To gain some eprspective into the effectiveness of isolating and prophylactically treating food and chemical intolerance in IBS and related conditions these discussions would also be useful: http://www.ibsgroup.org/cgi-local/ubbcgi/u...t=000407#000002 http://www.ibsgroup.org/ubb/ultimatebb.php...=4;t=000286;p=4 http://www.ibsgroup.org/cgi-local/ubbcgi/u...0286;p=3#000106 http://www.ibsgroup.org/ubb/ultimatebb.php...ic;f=4;t=000364 http://www.ibsgroup.org/cgi-local/ubbcgi/u...=4&DaysPrune=30 http://www.ibsgroup.org/ubb/ultimatebb.php...ic;f=4;t=000286 http://www.ibsgroup.org/ubb/ultimatebb.php...ic;f=4;t=000285 http://www.ibsgroup.org/cgi-local/ubbcgi/u...t=000331#000001 http://www.ibsgroup.org/ubb/ultimatebb.php...ic;f=4;t=000302 http://www.ibsgroup.org/ubb/ultimatebb.php...ic;f=4;t=000287 http://www.ibsgroup.org/ubb/ultimatebb.php...ic;f=4;t=000364 http://www.ibsgroup.org/cgi-local/ubbcgi/u...f=5&t=000313&p= http://www.ibsgroup.org/cgi-local/ubbcgi/u...0293;p=2#000069 http://www.ibsgroup.org/ubb/ultimatebb.php...ic;f=4;t=000276 http://www.ibsgroup.org/ubb/ultimatebb.php...ic;f=5;t=000073 http://www.ibsgroup.org/cgi-local/ubbcgi/u...f=5&t=000356&p= http://www.ibsgroup.org/cgi-local/ubbcgi/u...t=000320#000016 http://www.ibsgroup.org/cgi-local/ubbcgi/u...t=000383#000010 http://www.ibsgroup.org/cgi-local/ubbcgi/u...f=5&t=000126&p= http://www.ibsgroup.org/ubb/ultimatebb.php...c;f=17;t=000033 http://www.ibsgroup.org/cgi-local/ubbcgi/u...t=000363#000002 http://www.ibsgroup.org/cgi-local/ubbcgi/u...t=028290#000001 http://www.ibsgroup.org/cgi-local/ubbcgi/u...t=000335#000009 http://www.ibsgroup.org/cgi-local/ubbcgi/u...f=1&t=028290&p= http://www.ibsgroup.org/ubb/ultimatebb.php...ic;f=4;t=000353 http://www.ibsgroup.org/ubb/ultimatebb.php...ic;f=4;t=000389 http://www.ibsgroup.org/cgi-local/ubbcgi/u...t=000427#000006 http://www.ibsgroup.org/ubb/ultimatebb.php...ic;f=4;t=000421 http://www.ibsgroup.org/cgi-local/ubbcgi/u...t=000427#000015 http://www.ibsgroup.org/cgi-local/ubbcgi/u...t=030178#000003 http://www.ibsgroup.org/ubb/ultimatebb.php...ic;f=4;t=000476 http://www.ibsgroup.org/cgi-local/ubbcgi/u...t=029840#000027 http://www.ibsgroup.org/ubb/ultimatebb.php...ic;f=4;t=000478 (NEW testimonial by Bobbyï¿½good) http://www.ibsgroup.org/ubb/ultimatebb.php...ic;f=4;t=000488 (OHNOMETOO One year anniversary) http://www.ibsgroup.org/ubb/ultimatebb.php...ic;f=4;t=000478 In general this is like any other area of medicine...everyuone posesses some information in any given area, and the most specialzied information will be found among those whsoe specialty area is devoted to a particular area. There are many centers of excellence on the subject of food and chemical intolerance mechansism and therapy which go beyond the common boundaries simply due to the fact that it is their focus, so it is usually helpful to seek out specialized information at the acknoweldged source of the specialty.I do beleive that the 2002 edition of Brostoff 7 Challacome remains the ONLY medical textbook yet published on the subject of this particular thread.The more patient-specific one can make the assessment of any patients food and chemical tolerance, or lack thereof, the greater the degree of remission one can achieve. This is not easily done in most centers, as most centers do not make use of the most current methodologies in this specialized area, or do not approach the issue from the perspective that a specialist in that area would.But a study of broader information would make it apprant that there is broader informatio available upon which to base treatment.







MNL


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## Mike NoLomotil (Jun 6, 2000)

Post script....on another IF-THEN hypothesis which we need be careful not to stretch into more than it is at present: ____________________________"One potential mechanism that could explain altered bowel function in IBS is an abnormality in the serotonin transporter itself." ____________________________Indeed among the myriad biochemical activities which govern overall gut function and motility this is indeed as the authors state ONE of the many and indeed COULD be ONE mechanism. _____________________________"If the underlying abnormality in serotonin transporter function alternated, then this would in turn explain alternating constipation and diarrhea." __________________________IF-THEN, but of, of course, it would. But what we have at present is the careful presentation of a postulate. While a specific observed abnormality indeed is quantitifed, the basis for it (the pathogenesis and mechanism whereby the observed abnormality occurred in the patients selected) is not quantitifed and there are multiple mechanisms which can lead to the quntified activity. These needs to be further elucidated, and then of course one must show the mechanism "cycles" which again as yet is not shown. There are, however, mechanisms quantitied in specific IBS patients which do already account for the observed diarrheaic and constipation cycles seen in so called IBS victims, and while 5HT[x] receptors may be involved, other mediators and/or hormones with the same effects on gut function have already been quantified, and protocols which lead to the cessation of this cyclic phenomena are in clinical use.So inded this may end up being a mechanism but as yet it remains a postulatem while other mechanisms have already been quantified.Which of course the investigators make clear in the summary...as well as the fact that the objective,as is the objective of all investigations into the role of 5HT and 5HT[x} receptors in IBS is to try to find new drugs which can be used for treatment...hence the targeting of individual neurotransmitters among the many different types of receptors which affect gut function.So yes indeed, as it says this would, if it had been done, but it has not, yet there remain other biochemical markers which have been quantified and which can be addressed which already resut in cessation of cyclic diiarhea and constipation without the need for drug therapy. _________________________________"These data strongly suggest that IBS is a "real" gut disease and a potential diagnostic disease marker." _______________________________There are many who would agree with this, and who have since about 1980, who also have observed other potential "markers" among gut mediatros which appear that they may characterize certain subpulations. This might be one more. ________________________________"They also suggest that it is valid to subdivide IBS into constipation and diarrhea symptom subgroups." ________________________________This would be a good step forward as physicians who are advocates of not stopping at symptom absed diagnosis, rather continuing the pursuit of the causal basis for the patients symptoms, have long contended that this is an appropriate protocol. Nice to see that view becoming more widely espoused. Anything which will move the practcie towards causal based investigation is a good thing. __________________________"This study also provides additional rationale for the use of serotonin-modulating agents in IBS and provides a new target for drug modulation." ____________________________But of course, this is the basis of most such investigations...seeking modulatable targets for pharmaceutical intervention in a pill-therapy oriented society, not prophylactic solutions. ___________________________"Confirmation of these very exciting initial findings in larger patient samples is awaited with great interest." _____________________________Indeed like many existing postulates, one more which has potential merit among many....all of which, if they were integrated, could help assemble the puzzle that is the multiple mechanism syndrome of IBS.MNL


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## eric (Jul 8, 1999)

Mike, why don't you come to the next UNC chat and tell them this, that they don't know about the role of foods in IBS???


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## Mike NoLomotil (Jun 6, 2000)

Also posted at the other location of this duplicate thread: http://www.ibsgroup.org/cgi-local/ubbcgi/u...t=032173#000009 LOL...an intriguing possibility set forth in the form of an intentionally doomed challenge: _____________________________________"Mike, why don't you come to the next UNC chat and tell them this, about how they don't know about the role of foods in IBS??" ____________________________________Sure and you go on line with Brostoff and a bunch of sick people who trust his views and convince him that his books and his lifes work are all BS.That is the same type of challenge as you have set forth is it not?You crack me up, first how you misquote and morph what I say constantly, and second the naivete you exhibit as regards the profession of clinical and investigative medicine never ceases to amaze me."...tell them how they don't know the role of foods in IBS..."







Rarely have I seen anyone as pugnacious as you! Surer thats exactly what I said...







HOWEVER you do set forth the basis for some more appropriate activity along those lines which may be possible...but first that being said Perhaps a reality check is in order first...and then perhaps there is a more appropriate matchup we can arrange for such a discussion. You know, doctor to doctor.If you have a smoking engine, the guy certified in fuel systems will investigate and interpret the findings in the context of the hierarchy of possible causes of smoking which originate within the fuel system.However the very same engine, viewed from the perspective of the EEC IV guy will be out through a diagnostic hierarchy consistent with what he knows will elicit smoking from the perspective of the EEC and ignition systems.Sometimes the final causal basis will prove-out to be fuel system dysfunction. Sometimes it will be within the EEC or ignition subsystems.Sometimes there will be a combination of malfunctions, which could have originated in either system and then produced secondary malfunction in the other co-dependent system. And it could be either system which is primary and the other secondary.Clinical medicine and medical research are little different. Hierarchies and probabilities and postulates and interpretations are always colored by the perspective and specific area of specialization and expertise of the physician(s) involved.A good example was observed at a very tender age early in my career as an R.R.T. I would go on grand rounds with the pulomonary specialists at the Cleveland Clinic when I worked there every Friday morning. Oftentimes a case would be presented of, say, an asthmatic. The pulmonologist would present the data, provide and interpretation and at times make reference to the fact the patient was also seen by an allergist. The allergist findings would be quoted, for example, especially if the recommendations or interpretations or treatment regimen recommended were in contrast to that of the pulomonologist in attendance. This discussion was invariably punctuated by, at a minimum, shaking heads (tsk tsk tsk) and ï¿½knowing looks and bobbing headsï¿½ all around, to as much as guffaws and even squeals of delight at the clearly ill-informed recommendations.Then of course you might have a ventilator case who had been visited, say, last night by the thoracic surgeon who had performed an intervention and some orders had been left or an interpretation of something was entered in the chart, and the same sequence of fevents would occur.It was also of interest that, if one were clever enough to carefully read what was scheduled to be presented at each specialties rounds in any given week, that one could see some cases which were being presented twiceï¿½once by SPECIALISTS A and at another grand rounds from SPECIALISTS B. if you were really lucky they were not at the same time so you could go to bothï¿½and observe the same cases but viewed through the eyes of the OTHER specialists (like ï¿½opposing counselï¿½ I guess) and observe the same behaviors.The years working with various research and product development projects were no different when it cam to the halls of medical academeï¿½.THE difference, though, was that many times (most times) the caregivers, while taking some pleasure in their obvious expertise which was clearly lacking in their esteemed colleagues not of the same board certification, was usually set aside when the good of the patient was at stake. Usually. Not always. Why? Ethics and professionalism and a recognition that no one, not even themselves, holds an exclusive on all that is correct and all that is wise nor exclusive understanding of the single proper treatment protocol for any given patient. Most recognize in the end that their information if integrated with that of another specialist combined could lead to better care and outcomes many times than either could achieve alone.However, due to the nature of these professional paradigms, rarely does one see such things as Pulmonologist A engage Allergist B in a debate before any audience other than their peers unless they are of a certain ilk which is inlcined to debate in front of patients.Anyone who is a healthcare professional of any kind who cannot accept the validity of, and adopt, this objective and respectful behavior of differences over data rather than personalities not only does dissservice to the sick but violates the oath that all caregivers are ethically obligated to abide by. If one aspires to be, or acclaims themselves to be, a caregiver, then one is morally obligated to adapt as fully as all caregivers with specialty knowledge are obligated to adapt.It is far easier to be on the side, Armchair Quarterbacking, than actually being in the game. If you are in the game you have to follow the rules whereas the Armchair Quartberback can make up his own rules, or follow none at all, when holding forth one whatever subject he or she chooses to act upon in this capacity.So, first, your premise is flawed in that you misstate again what I have said, and second that I should appear and attempt to pursuade a group of psychogastroenterologists to alter their perspective, which would also suggest they alter their business mission. This is not mission for a therapist who is a student of the subject any more than it would be a mission for you to try to pursuade Professor Brostoff or Bengtsson or Stefanini that "food intolerance is a myth". It is as doomed from the start as was the Bay of Pigs invasion.The likelihood of any physician who already has assumed the position we have seen set forth being open to other information is reflected in whether such physicians have considered reading the book on the subject first. The proposition is not one that will be well received from a lowly lay person no matter how well read he might be.However, what is possible, what might be a discussion which a physician might be more open to suggestion, would be a discussion with another physician who is himself the source of much of the information available about food and chemical intolerance.I will extend your invitation first to Professor Brostoff and see if he, or one of his associates with similar credentials, would be able to schedule some time to participate in such a chat in spite of the innate juxtaposition of their specialties and perspectives. If he is unavailable there are some other physicians, including gastroenterologists, who might be willing to discuss their experiences with food intolerance and hypersensitivity and their IBS patients and how it does go beyond that which is commonly believed to be the limit of contribution.When are these chats scheduled? (what days of the week at what times and at what URL) so that I may see if I can obtain one or more physicians experienced in thee matters to participate. This ensures that the discussions are more likely to be on level ground.Let me know an I will see what I can do!







MNL


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## Julia37 (May 9, 2001)

Mike,I'm on the UNC mailing list. Here is the most recent:--------------------------------------You are receiving this email from the UNC Center for Functional GI & Motility disorders because, at one time, you requested information from the Center. The reason for this email is to remind you of the Center's monthly on-line "Chat with the "Experts." This month's topic is "Diagnostic Approach for IBS: How Much Testing is Necessary" If you have an interest in this topic, the link to the chat room is on the Center's home page www.med.unc.edu/ibs. The chat room will open on February 11th at 7:45, there will be a brief 10-15 minute overview beginning at 8PM Eastern Standard Time, highlighting what is known about the topic in the field. Following this introduction, you will be able to join the discussion on the topic with the presenters until 10PM Eastern Standard Time. We hope that you will join us this month at 7:45 and take this excellent opportunity to learn more about: "Diagnostic Approach for IBS: How Much Testing is Necessary." Dr. Albena Halpert will be presenting the overview on this on this month's topic, and Dr. Yehuda Ringel will join her for the discussion . On Feb. 11th, enter the chat room from our Center's web page: www.med.unc.edu/ibs. If you do not wish to be notified of Center activities through email, or if you would like to de removed from the mailing list, please email Donna###med.unc.edu and your name will be promptly removed from the appropriate lists.Donna SwantkowskiCenter CoordinatorDonna Swantkowski, MEdCenter CoordinatorUNC Center Functional GI & Motility Disorders---------------------------------------I've noticed in their print newsletters they do tend to ignore the possibility of food intolerance generating symptoms. I remember a few months ago a discussion of IBS in teenagers that didn't even mention it. I was thinking of writing them about this but haven't found the time yet.


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## eric (Jul 8, 1999)

serotonin and they believe previous enteric infection or shock to the cells or perhaps a congential defect.Gastrointestinal Disorders of Function: Into the Next MillenniumRecent advances in our understanding of the neurophysiology of the gastrointestinal GI system have uncovered many of the receptors and signaling pathways involved in Irritable Bowel Syndrome IBS, Gastroesophageal Reflux Disease GERD, and Functional Dyspepsia FD. This knowledge suggests new targets for pharmacotherapy, some of which are already being investigated, that treat the aberrant GI motor function and altered visceral hypersensitivity from which these disorders arise. In a session organized by The Johns Hopkins University Office of Continuing Medical Education, three sets of presentations explored the scientific advances and the potential clinical applications.This symposium program was supported by an unrestricted educational grant from Novartis Pharmaceuticals Corporation.Overlapping Symposiums of GI Disorders of FunctionG. Richard Locke III, MD Mayo Foundation reported that the prevalence of IBS in the United States and Western European is approximately 10 percent. It is estimated that 20 percent of the population experiences heartburn on at least a weekly basis. Recent studies show the prevalence of functional dyspepsia to be approximately 19 percent when patients with heartburn are excluded.Overlapping symptoms of IBS, GERD, and FD are frequently manifested. Among individuals with IBS, 42 percent have reflux symptoms and 45 percent have dyspepsia; among those with heartburn, 38 percent have dyspepsia and 25 percent have IBS; and for those with dyspepsia, 55 percent have reflux symptoms and 38 percent have IBS. Symptoms come and go. Approximately 70 percent of adult Americans have intermittent symptoms. Transitions between disorders have been shown to occur wherein symptoms of one disorder may be replaced by those of another years later. Agreus et al. Gastroenterol. 1995;3:671. Overlapping symptoms and transition over time suggest that there are common physiologic and pathologic components of these disorders.That these disorders have so many common features may be related to intrinsic properties of the enteric nervous system-particularly of enteric ganglia neurons and interstitial cells which, together, pace the bowel by modulating smooth muscle cells. In his presentation, Joseph H. Szurszewski, PhD Mayo Medical School focused on the inhibitory motoneurons that use nitric oxide as their primary neurotransmitter and on the interstitial cells of Cajal ICC.Normal human intestine produces more than enough inhibitory neurons to achieve complete relaxation of the visceral musculature. Motility disorders occur when these neurons are reduced below a critical number in the diseased bowel. Nitric oxide-containing nerve fibers run parallel to circular and longitudinal muscle fibers and provide inhibitory innervation to the neuromuscular apparatus of the gastrointestinal tract. It is now thought that up-regulation of these neurons by production of nitric oxide can lead to gastric dilatation, ileus, and toxic megacolon; and neurodegeneration from decreased production of nitric oxide may be involved in achalasia, gastric stasis, hypertrophic pyloric stenosis, chronic pseudo-obstruction, slow transit constipation, and Hirschsprung's megacolon.There are two ICC networks in the human intestine, one in the myenteric plexus ICC-MY and one in the circular muscle layer called the deep muscle plexus ICC-DMP. The pacing site of the stomach and small bowel is located in the ICC-MY. It establishes the frequency, duration, and direction of the contractile wave. The ICC-DMP is responsible for neurotransmission between enteric neurons and smooth muscle fibers. These apparently modulate and amplify nerve signals. Sharp reductions in the ICC-MY have profound effects on the ability of the muscle layers to contract and generate motor patterns. Hypertrophic pyloric stenosis, gastric and intestinal arrhythmias, and paraneoplastic intestinal dysmotilities have all been reported to involve ICC disorder.Scientists have identified genes that regulate smooth muscle contractile proteins, genes that regulate differentiation and proliferation of interstitial cells, and a number of genes that are responsible for the migration, development, maturation, and proliferation of enteric ganglia neurons. These discoveries open the way to improved understanding of the cellular and molecular biochemical bases of interstitial cell and enteric neuronal function as they relate to disorders of function in the GI tract. They also offer new targets for drug development.GI Disorders of Function:One Disease or Many* Overlap among symptoms* Transition over time* Common pathophysiology* Motor, sensory* Management similaritiesOverlapping Epidemiology* Symptoms of each disorder are common* People frequently have multiple symptoms* Symptoms come and go transitions over timeSerotonin: A Mediator of the Brain-Gut AxisJackie D. Wood, PhD Ohio State University characterized the enteric nervous system as "the little brain in the gut" and as the lower end-point of the hierarchical innervation of the GI tract. The other components are prevertebral sympathetic ganglia, central sympathetic centers in the brainstem, central parasympathetics the dorsal-vagal complex where the vagus nerve and the descending pathways of the spinal cord originate, and higher brain centers e.g., prefrontal cortex, amygdala, parabrachial nucleus, and hypothalamus. The sympathetics and parasympathetics are descending pathways to the gut. The higher brain centers interact with the autonomic centers by sharing information on perceptions of GI sensations and mani- festations of psychogenic factors such as physical and emotional stress.The chemical transfer of information within this circuitry is the work of serotonin 5-hydroxytryptamine, or 5-HT, 95 percent of which is localized in the GI tract and the remainder in the brain and enteric nervous system. In the first, an action potential traveling along an axon triggers release of the neurotransmitter neurocrine signaling 5-HT, carrying the signal to the post-synaptic neuron. In the second, 5-HT is released by either an enteric mast cell or an enterochromaffin cell paracrine signaling. This affects neurons by extracellular diffusion. Whether by neurocrine or paracrine release, 5-HT excites neurons by inducing rapidly activating depolarization or slowly activating depolarization of the membrane potential.The 5-HT3 receptor is involved in rapidly activating depolarization. These receptors are located on the terminals of vagal afferent sensory neurons. They are activated by triggering the release of 5-HT. The activated vagal afferent transmits information in the form of action potential codes to the central nervous system. This mechanism is the peripheral basis of nausea and vomiting and the reason for using 5-HT3 antagonists as antiemetic drugs. Similarly, 5-HT3 receptors located in spinal splanchnic afferents are involved in signaling the central nervous system with information on the state of the gut. If these become sensitized during inflammation, elevated postprandial 5-HT serum levels may induce an exaggerated sensory code that goes into spinal integrated circuits and may reach the level of consciousness as discomfort or pain. Mast cells execute sensitization reactions to food or infection by releasing 5-HT and other mediators such as histamine. The 5-H1P and 5-HT4 receptors modulate hypersensitivity reactions of the gut such as hypersecretion and propulsive motor events. Presynaptic inhibition possibly through 5-HT4 receptors at a nicotinic synapse is an important mechanism by which 5-HT affects enteric function. In addition, the 5-HT4 receptor facilitates release of acetylcholine at nicotinic synapses. This underlies the augmented intestinal propulsion seen with some prokinetic drugs.In general, motor, sensory, and chemical stimuli precipitate the release of 5-HT, which binds with sub-types of 5-HT receptors in the vagal sensory and splanchnic nerves, producing a variety of effects on the peristaltic reflex, colonic tone 5-HT3, acceleration of pan-gut transit 5-HT4, and gastric accommodation 5-HT4 and 5-HT1A. New 5-HT agents are being used experimentally to determine the roles of 5-HT receptor sub-types in motor and sensory function in the GI tract. Tegaserod and prucalopride are 5-HT4 agonists that appear to affect propulsion, and cisapride is simultaneously a 5-HT4 agonist and 5-HT3 antagonist that improves gastric accommodation.Dogiel type II myenteric neurons have a special gating function in the enteric nervous system. Unless stimulated by 5-HT, these multipolar neurons maintain a state of low excitability. But both neurocrine and paracrine release of 5-HT transforms them to a state of high excitability. Stimulation of the 5-HT receptors on their mucosal processes spreads action potentials up toward the cell body in the myenteric plexus. Once the cell body is activated, it gates the activity to other places in the enteric nervous system setting off a variety of secretory and motor events.Like enterochromaffin cells, intestinal mast cells are a source of 5-HT. These become sensitized in food allergies and infections by specific antibodies that adhere to receptors on their cell surfaces. Reappearance of the antigen cross-links the antibodies, causing degranulation of the mast cells and release of 5-HT and a variety of other mediators. The result is a form of gut behavior that includes hypersecretion and very strong propulsive contractions with attendant symptoms of diarrhea and abdominal discomfort. This behavior is programmed by the enteric nervous system and organized to eliminate threatening agents from the bowel lumen rapidly.Involvement of 5-HT1 and 5-HT2 receptors in the dorsal vagal complex has an apparent role in the brain-gut axis and psychogenic elements of bowel disorders of function. Laboratory experiments have shown that injection of spinal fluid into the fourth ventricle to influence the dorsal vagal complex produces no motility response. Injection of 5-HT alone stimulates motility minimally. But microinjection of thyrotrophin-releasing hormone followed by 5-HT generates an accentuated motility effect and acid secretion.Michael Camilleri, MD, FACG Mayo Medical School and Clinic dealt with the clinical importance of serotonin in IBS and carcinoid diarrhea. He also noted that blocking 5-HT sensory reception in the vagal afferents and in the chemoreceptor trigger zone of the fourth ventricle has revolutionized the treatment of chemo- therapy- and radiotherapy-induced emesis. He also emphasized the potential need for new therapies to modulate the 5-HT4 receptor involved in peristaltic and motor function of the gut.Carcinoid diarrhea is associated with overproduction of serotonin, as well as with accelerated small bowel transit, accelerated emptying of the proximal colon, and a reduction of the volume measurement of the ascending colon due to increased colonic tone. In a clinical study, treatment in the proximal colon of a carcinoid diarrhea patient was shown to traverse content around to the rectosigmoid area in just two hours -a trip that normally takes 15 to 18 hours. This suggests that 5-HT is an important mediator of postprandial colonic tone and transit of colonic residue. Clinically administerable doses of the 5-HT3 antagonist ondansetron restores normal tone.The 5-HT3 antagonists also appear to elevate the threshold for both perception of distension and pain, probably by relaxation of the colon. Study data do not suggest an anti-nociceptive effect.Tegaserod, a 5-HT4 receptor partial agonist, has been shown to increase contractile activity along the small bowel and colon of canines. In humans with constipation-predominant IBS, ororectal transit time is significantly accelerated in response to oral administration of tegaserod compared with placebo. In addition, tegaserod enhances colonic emptying.Serotonin Pharmocology: Therapeutic Potential in GI Disorders of FunctionThe third set of paired presentations was made by James J. Galligan, PhD Michigan State University and Nicholas J. Talley, MD, PhD, FACG University of Sydney, Australia. Dr. Galligan opened with a discussion of the 5-HT4, 5-HT3, and 5-HT1 receptors as drug targets.Enteric 5-HT4 receptors are localized to distal nerve endings of neurons within the gut wall at four specific places. The first are intrinsic primary afferent neurons, the cell bodies of which are in the myenteric plexus. They activate when mucosal stimulation e.g., bile, small changes in pH, glucose releases 5-HT from enterochromaffin cells. The afferent neurons make excitatory connections with other myenteric neurons and are the first link of a reflex arc that is likely to mediate a variety of motor reflexes such as peristalsis.The second are excitatory neurons that terminate in the longitudinal and circular muscle layers. These receptors are localized to nerve endings that release acetycholine (ACh), so that 5-HT4 receptor agonists will facilitate the release of ACh and enhance motor activity.The third category consists of cholinergic interneurons that pass excitatory information up and down the length of the gut. Receptor agonists applied here stimulate the nerve endings to release additional ACh, thereby potentiating reflex activity that is mediated by the ascending and descending interneurons.The fourth category of enteric 5-HT4 receptor is localized to nerve endings of secretomotor neurons in the submucosal plexus. Either 5-HT or 5-HT4 receptor agonists enhance secretomotor function of the mucosal epithelium in response to stimulation of these receptors.5-HT4 receptors are G-protein-coupled receptors. Categories two and three, by inducing the release of ACh, participate in smooth muscle contraction which, in turn, lowers the peristaltic threshold and enhances peristaltic efficiency. Cisapride, prucalopride, and tegaserod are all 5-HT4 receptor agonists, although their pharmachologic properties differ. Cisapride, which is also a 5-HT3 antagonist, is efficacious in treating such proximal GI disorders as functional dyspepsia and GERD, but is less effective in IBS. Furthermore, there is experimental evidence that cisapride can prolong the Q-T interval, and clinical evidence on its adverse drug interactions indicates an increase its circuating concentration and prolongation of the Q-T interval. Tegaserod and mosapride are not known to present this problem.The 5-HT3 receptors are also localized to the nerve endings of four specific neuronal populations in the gut wall. The first location is on the peripheral endings of the extrinsic primary afferent neurons whose cell bodies are in either the nodose ganglion or the spinal sensory ganglia. Paracrines excite these nerve endings to carry information toward the central nervous system. Information can relate to pain or distension of the bowel, or it can be sensory information used by the CNS to mediate GI motor reflexes.5-HT3 receptors are also located on the peripheral endings of intrinsic intestinal primary afferent neurons. When stimulated by 5-HT released from enterochromaffin cells, these intrinsic primary afferent neurons initiate intestinal motor reflexes by subsequent excitation of myenteric interneurons and motoneurons. 5-HT3 receptors located on a subpopulation of descending interneurons mediate descending excitatory ne


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## eric (Jul 8, 1999)

Brostoff diagnoses food sensitivitiesDrossman diagnoses IBSDifferent conditionsmisdiagnosespeople can have bothbut you can't call them the same


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## eric (Jul 8, 1999)

what about the IBSers misdignosed with food sensitivites?


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## Mike NoLomotil (Jun 6, 2000)

This was discussed at great length on several threads on the main board,







so what neeeds to be done is not what time rewriting and repsonding to obviously rhetorical questions over and over.When I get a chance later I will find those threads where this material was discussed in detail and simply refer the readers over there.One place of silly vitriol over the self-evident is enough time wasting on the scotoma-afflicted.Observers stand by...when I have a chance to find the threads where we wnet through this already on another discussion board I will bring them over.







MNLPSOH MY Julia....I am already wondering how I am going to Get Brostoff to come to a chat at 12:45 am London time that runs past 3 am London time....







uh ohNeed to work on that.


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## Mike NoLomotil (Jun 6, 2000)

Hey wait a minute...







I thought you already made your "Grand Exit" over here last evening: http://www.ibsgroup.org/ubb/ultimatebb.php...ic;f=1;t=032211







Aha! Maybe just "last minute housekeeping" I guess...like "oh my I left the iron on..." and then "did I leave the water running in the bathroom?"...etcDid ya get in all yer "parting shots" now, Roy?







MNL


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## Mike NoLomotil (Jun 6, 2000)

QUOTE: ____________________________"Brostoff diagnoses food sensitivitiesDrossman diagnoses IBSDifferent conditionsmisdiagnosespeople can have bothbut you can't call them the same" ___________________________Sure ya can. Shouldn't but they do....it is done a thousand times a day based upon current diagnostic criteria which are universally applied.I Can't find the right thread quickly....too many...so here let us summarize the same way.1. IBS is typically a symptom based diagnosis in the USA...many in Europe do not diagnose the patient with IBS symptoms proven provoked by food or chemicals as "IBS"...they diagnose them with "food intolerance". This is not so common in the USA as the subject is far less widely understood. Most patients just get told they have IBS.2. Patients with IBS symptoms provoked by one or more of the various mechanisms which are classifoed as non-allergic food or chemical sensitivity are routinely diagnosed as having "IBS" so they are called, treated, and classified as IBS patients henceforth clinically in the the investigative realm as well.3. This population, defined in this way by the Merck Manual of Diagnosis and Therapy among other places, is large and pervasive and ever present including large numbers of symptomatic people in this online community and others.4. Nobody has yet defined a single quantified pathogenesis for IBS which is exclusive of other possible pathogenesis and/or symptom generating mechanisms, therefore there is no current definition set forth by anyone, including the ROME II Committeee, for what so called IBS is other than a symptom set.5. Therefore, until this happens patients whose symptoms are provoked by various forms of food intolerance will continue to be diagnosed as having IBS in spite of the fact they should (probably) be considered a seprate population which would thus reduce dramatically the so called "IBS" population via their rediagnosis.6. Since this has not happened yet, they are all out there awaiting help and come seeking help. 7. When determining treatment protocols the mechanisms of symptom generation are what is clinically important to the patients quality of life as it determines the treatment plan, NOT what LABEL you hang on any given patient so8. As long as the disease management program used is patient specific and includes lifestyle modification, with as patient-specific the dietary therapy as possible, combined where needed with anxiety and stress-response reduction or other psychosocial behaviorol therapies(CBT or HT are the predominant modalites) and then pharmacotherapy is used PRN based upon the results of diet and stress reduction modalilities, then the practitioner has done everything that can and should be done for the patient at this stage of the game.Quibbling over what to call him/her will make little differece in the therapeutic outcomes if the protocol followed includes these elements.Ya cannot make it any plainer, nor factual, than that.







MNL


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## eric (Jul 8, 1999)

They do that in europe you say, yet England and Germany and Japan use the rome criteria and I am sure many other countries do also, I bet Rome does since they meet there.







I find it interesting that Mike always says thousands of people have been helped by eliminating food sensititivites via leap bood work in IBS, when thousands of patients with IBS have also been helped by Heathers diet cookbook with out sensitivities testing who have IBS.Things that make you go Hmmmmmmmmm.Just for the thought.The immune system activated without a pathogen which is connected to serotonin.The Fight or Flight Response in Irritable Bowel SyndromeOveractivation Linked to Predominance of Diarrhea SymptomsAn intense, powerful "fight-or-flight" response comes in handy when you're running away from a hungry tiger, but it could be the source of misery for people with certain digestive disorders.The chronic gastrointestinal distress of Irritable Bowel Syndrome IBS has been linked to "miscommunication" between the gut and the brain. Although it's still unclear just exactly how a glitch in gut-brain interaction sparks specific symptoms, a recent study has uncovered one important potential mechanism in a subgroup of patients.In patients with IBS who regularly experience diarrhea, pain, and other symptoms soon after eating, an "overdominant" sympatheti nervous system - signaled in part by the heightened release of the stres hormone cortisol after eating - may play a key role in triggering their symptoms. Researchers evaluated a group of 24 patients with IBS and a group of healthy controls, measuring their salivary cortisol levels, their heart rates, and their heart rate variabilities at different times of the day.Compared to the controls and to IBS patients with constipation, IBS patients with chronic food-induced diarrhea "demonstrated a significant increase in cortisol" soon after eating - with levels nearly doubling. This subset of patients also showed a more dominant sympathetic nervous system response, as evidenced by their heart rate variability ratios.The sympathetic nervous system tends to mobilize the body's stimulatory "fight-or-flight" response. Normally it's kept in check by the dampening effects of the parasympathetic nervous system. In patients with IBS with diarrhea, however, this muting response mediated by the vagus nerve appears weaker - a condition called "vagal withdrawal." "Notably, this vagal withdrawal was significantly associated with patients' reports of gastrointestinal symptoms," the researchers pointed out. These included bloating, abdominal pain, indigestion, and heartburn.A heightened, stimulatory stress response, characterized by overactivation of both the HPA-axis and sympathetic nervous system, may be triggered by "abnormal ascending feedback from the gut," the researchers speculated.NOTE: Two functional assessments help evaluate important dynamics of the gut-brain connection in stress-related gastrointestinal disorders."Source: Elsenbruch S, Orr WC. Diarrhea- and constipation-predominant IBS patients differ in postprandial autonomic and cortisol responses. Am J Gastroenterol 2001;96 2:460-466.


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## Mike NoLomotil (Jun 6, 2000)

Quote: _________________________________"They do that in europe you say, yet England and Germany and Japan use the rome criteria and I am sure many other countries do also, I bet Rome does since they meet there" ________________________________Of course they do...many do...this is the problem. the Rome Criteria cannot discriminate, cannot isolate, the patient whose symptoms are precipitated by an abnormal reaction, loss of oral tolerance, too something in the diet from subjects who may not have this as a symptom generating mechanism.The promulgators of the Rome Criteria recommend that "testing" looking for a causal basis of symptoms be "limited", and rather an early symptom based diagnosis made. treatment then can be "empirical".Therein lies the rub which is self evident...Bengtsson proved this when he begaun doing jejunal isolation investigations on patients who had IBS symptoms according to the Rome Criteria, and atopy and food allergy were then ruled out.The subjects were then shown to react positively to double blind oral challenge (the jejunum was isolated so no one could know what the food challenge was or whether it was a placebo challenge). A wide array of inflammtory mediators were then obsevred being released INTO the gut from the immunocytes within the gu wall (several classes including mast cells and lymphocytes as the markers retrieved in repsonse to oral challenge are specific to specific cells).You canot be any more obvious and clear than that...the symptoms were provoked by oral challenge so we have food intolerance being diagnosed as IBS according to the Rome Criteria.This is why it is advisable to look deeper into the symptom generating mechanisms of these patients as the removal of the test-positive "antigens" then cause there to be no provocation thus no symptoms. ______________________________" find it interesting that Mike always says thousands of people have been helped by eliminating food sensititivites via leap bood work in IBS, when thousands of patients with IBS have also been helped by Heathers diet cookbook with out sensitivities testing who have IBS."Things that make you go Hmmmmmmmmm. ____________________________You make thaT sound due to a lack of understanding...so you interpet things in the context of that lack of underStanding, form conclusions based on inadeQuate information, and then set them forth in manNer designed to create suspicion and bias. The buzzing sound often accompanies faulty conclusions and biased reasoning. But there is help. Education. Pay attention closely. MABE you will learn IF you want to. I will make it easy.One will also note without fail any time reference is made to other IBS diets or dietary instruction inclduing Hetahers books that the laws of probabilities are what defines ant set of dietary instructions applied to any given population.Data collection and obsrvtions of response over a large enough population leads to trends and probabilities.For example, studies on oligoantigenic diets typically show remission rates on such diets in excess of 90%. Then one does a frequency analysis of perhaps the 10 foods which were most frequently reactive within that population.So you then set up a protocol that simply removes the ten most frequently reactive foods for EVERYONE and then implement it and montor the outcomes.One will then find symptom reduction within the population BUT at a somehwat lower frewuency and at a lower degree of symptom reduction.Some people, in whom the foods are not reactive, will get no relief.Some people where these ars oem oftheir reactie foods, but not all, will get some relief but still have some symptoms as they are still consuming some offending foodsA few people may have all their foods covered by this diet and get complete remission BUT needlessly exclude foods fro their diet that coudl eat.In each case the diet would work better if it were patient specific so efforts have been made for years to find a means to do this. So it is available.However, this same methodology applies to any set of dietary instructions for IBS...it is based on probabilities so the betetr the study of probbailities and the more willing the person is to meticulously work their way through all the permutations and instructions the better the chance they will find relief. On the other hand some will find none as they either canot work the dietray instructions as they are too complex for the patients degree of committment to lifestyle change, or the probbailities work agains them and the diet ends up feeding them foods that were fine for other people but wrong for them.that is the problem...the phenomenon of lost oral tolerance is opatient specific...so even if you remove all sources of possible pseudoallergy or presumes enzyme deficiency or presume chemotoxicity the outcomes are alwsys compromised to some degeree in any given population.This has been explaioned many times and no one on this end has ever sued those limitations to either derogte that book, or the author, rather simply to note that one mand meat is anothers poison and no single set of dietary instructions is universla for all IBS victims.Things that make you go OOOOH!







________________________"Just for the thought." _______________________Good. Nice start. Now keep it up.But it appears that you do not understand what you are posting. At all. There is a great depth and range of immunohistochmeistry and immunoneuroendocrine investigation linked to such observations as ahve been made from such things as you posted like salivary cortisol, sympathetic activation, endocrine aberrations (regulatory hormones) inflammatiogenic resposes to food challenge of the gut-syst emic immune interface and the range of biochemical origins of such actions as sympathetic activation or any of the branches of autonimic nervous system (peripheral and central) in food intolerance. It is clear from what you posted an the context in which you post it that you do not have much of a grasp of the subject matter as a whole. It is very very difficult to interpret even when you have been tutored in it by immunologists and allergiss for 10 years. One must go through a lot of branching logic and integrative analysis of OTHER phsycials finiodngs in postive-challenge subjets to know where any specific selected sub-group of observations may fit into the mechanisms as a whole.It is not, you would see, possible to assess the realtive valeu of any ONE of the multitudinous findings or mechanisms anf force fit it into a given paradigm, as there may be other findiongs which would conflict with that paradigm. One cannot presume any one mechanism to be "the" sole mechanism. The authors here, for example, are very clear in what they are saying about this finding...for example: ______________________________"Although it's still unclear just exactly how a glitch in gut-brain interaction sparks specific symptoms, a recent study has uncovered one important potential mechanism in a subgroup of patients."and further on..."this muting response mediated by the vagus nerve appears weaker - a condition called "vagal withdrawal." ETC _________________________________Do you even know what this actually means in the ocntext of OTHER findings in the same type of population, much less the qualifiers of the hypotheses? Such asunlearglitchonepotentialDoes one comprehend the mutiple mechanisms of these observatins are, and how many variables and biochemical combinations and precuros events can elicit what appeared to the investigators?Of course not..in fact this is one of many such investigations into these pheneomena each of which sheds a bit of light upon the mechanisms of food intoerance and how symptoms are generated.There is a lot of reading and study to be done to catch up with 25 years of work that is out there to study and try to learn from, and then assess objectively... at least you oicked out one or two here and there in recent days so, that's a start anyway. Just be sure to remember what "qualifiers" are when investigators postulate about what their findings might mean..or might not for that matter.This is a good place to start if you want to become familiar with the subject:ï¿½FOOD ALLERGIES AND FOOD INTOLERANCE: THE COMPLETE GUIDE TO THEIR IDENTIFICTION AND TREATMENTï¿½, Professor Jonathan Brostoff , M.D.. Allergy, Immunology and Environmental Medicine, Kingsï¿½ College, London http://www.amazon.com/exec/obidos/ASIN/089...6487508-3420903 FOOD ALLERGY AND INTOLERANCE, Professor Jonathan Brostoff, MD, Stephen Challacombe, MD (NEW 2002) http://www.amazon.com/exec/obidos/ASIN/070...product-details Read those books cover to cover, and the bibliographies, then come back and I will as I have said before, provide a seprate bibliogpraphy of related studies that must be read and integrated into the information set which supplement or even update, what is in those books. At that time we can then talk further in a meaningful way as it is not possible to tutor effectively on the 2,000 pages of content that need to be read to come to a broad-based view of the subject, plus maybe 100 key inveatigations selected out of the universe of investigatiosn which are related, in the time and space available here.







MNL


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## eric (Jul 8, 1999)

GI Consult: Irritable Bowel SyndromeTwo specialists discuss the pathophysiology, clinical characteristics, and management of this common ailment.By Christine L. Frissora, MD, and Lucinda A. Harris, MD http://www.emedmag.com/html/pre/gic/consults/041501.asp


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## Mike NoLomotil (Jun 6, 2000)

I posted this on one of Toms threads I think. It fits here too pretty well. ____________________________"What always puzzles me whenever the topic of the psychoneuroimmune mechanisms related to the "IBS phenomenon" is broached is that at some point hypotheses become facts, or facts disappear, even from hypotheses.It is literally impossible to assemble and post all the material that has been published on the subjects of the mechanisms and pathogenesis (possible, probable, or actual) to date of the syndrome now dogmatically labelled as IBS.But if one looks at it all, inclusively, certain things are self evident.There are mechanisms whereby the symptoms doctors diagnose clinically via accepted symptom-based standards can be sourced to a clear psychosocial origin in some population. Consequential mechanisms then serve as symptom amplifiers when they are activated by various events.AND the complete polar opposite is true. There are mechanisms whereby the symptoms doctors diagnose clinically via accepted symptom-based standards can be sourced clearly to origins which are not of a primary psychosocial nature. And then the psychosocial consequences act through mechanisms which are thus secondary...and thus become amplifiers of symptoms.And then there is a population wherein so far neither description can be made to fit.This is the innate limitation of the existing symptom-based diagnosis approach to IBS: it cannot discriminate in and of itself the primary mechanisms one from another. You have to go further, deeper, into a vast array of physiologic assessments to be able to discriminate one population from the other by isolating the separate mechanisms and then observing their interdependency.It is at times almost amusing to see the difficulty even the scientific community can have in recognizing these self-evident truths. Thus they (and we in turn) assemble into groups based upon belief-systems, sometimes populated by persons overly eager to claim the high-ground as possessors of the One True Faith.







It is so counterproductive to argue, to attempt to assert, that which cannot possible be asserted under the present circumstances. That "this is IBS and this is not" when IBS is said to be a symptom-set and the symptoms do not clinically discriminate one potential causal basis from another. The literature inclusively make it self evident that based upon the tenets of symptom-based siagnosis and "empirical management" that the syndromes population is comprised of subpopulations wherein several models of symptom generating mechanisms exist and quite probably several models of pathogenesis exist.So until everyone decides which is to be inlcuded and called IBS and which is not and is to be called something else, they all remain clinically diagnosed as IBS, the patients all walk arounf wearing virtual "I HAVE IBS" T-Shirts, and any argument which asserts a single pathway to the symptoms is not possible to assert. Yet it happens. That is the aspect of the discussion which amuses me as a person with some modicum experience in healthcare delivery and R & D.In the same manner it is asserted there is some debate over the efficacy of specific modalities...be it CBT, HT or dietary therapy. There is more than ample proof in the literature that each modality alone is potentially beneficial, and that the outcomes of any single modality are dependent upon how patient-specific the modality is, and how well the patients follow the protocol for its use (thsu minimizing recidivism rates).It follows on that any time you can make a single modality more patient specific the better the outcomes, and the effort to COMBINE MODALITIES will also enhance therapeutic outcomes. But somehow this proposition, which no physician or therapist could or would legitimately take issue with, when set forth often metamorphoses magically before our very eyes into a supposed derogation of behavioral modalities or even of mind-body medicine itself...why?







Frankly, there is no basis for either assertion of a single-model of so called "IBS" pathoghenesis as it is presently defined, nor to argue against any of those modalities as the literature already provides sufficient proofs so that discussion should move beyond that level.Yet the collective "we" often somehow get stuck on that merry-goround. As we go around and around the sick people we are supposedly here to help get flung-off the subject like kids trying to hold onto a merry go round that the biggest kid keeps spinning faster and faster so that no one can possibly hold on for the ride excpet those who are as big and strong as him. In which case what has the merrygo-round become...certainly not what it was intended to be.Anyway...just musing.MNL" __________________________Res Ipsa Loquitur.MNL


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## eric (Jul 8, 1999)

FYI"It is literally impossible to assemble and post all the material that has been published on the subjects of the mechanisms and pathogenesis possible, probable, or actual to date of the syndrome now dogmatically labelled as IBS."They did a damn good job of this here.Everybody on the bb here who HAS IBS should log into medscape which requires a password, but it is TOTALLY FREE,They do not spam email you and they send IBS and gastroenterology updates in the email and have an IBS resource center with all new current IBS information.Its really easy to get into it and way worth the valid and important information on IBS!Irritable Bowel Syndrome: Taking Concepts Into Clinical Practice CMEChairperson: Michael D. Gershon, MD; Faculty: Kevin W. Olden, MD; Walter L. Peterson, MD; Nicholas J. Talley, MD, PhD; Gervais Tougas, MD, CM, FRCPC http://www.medscape.com/viewprogram/1985


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## Mike NoLomotil (Jun 6, 2000)

The recommended additional reading below is based upon the following additional propositions...how to create the most effective dietary prophylaxis for the population of IBS victoms whose symptoms are provoked by mechanisms not discussed in the short tutorial posted: ________________________________Page 1051 of the hard copy of Merck Manual of Diagnosis and Therapy, and the online Merck Manual at http://www.merck.com/pubs/mmanual/section1...ter148/148b.htm Points out the following oft-misunderstood mechanism of symptom generation in patients diagnsoed with IBS:"Recently Food Intolerance was found to be responsible for symptoms of some patients with the IRRITABLE BOWEL SYNDROME, confirmed by double-blind food challenge. An increase in rectal prostaglandin levels was noted when a reaction occurred. Preliminary information suggests the same phenomenon may take place in patients with chronic ulcerative colitis.ï¿½ ___________________________A brief explanation of how this fits into the clinical diagnosis and management of IBS follows: ____________________________"ï¿½Considerable confusion is now arising over the relationship between food intolerance and the Irritable Bowel Syndrome (IBS). Although the name has been hallowed by long usage, IBS is not a distinct entity but merely a collection of disorders which are characterized by abdominal symptoms but no obvious organic pathology. G.W. Thompson forecast in 1985: ï¿½the IBS is organic; that is all sufferers will eventually be found to have measurable, unique pathologic defects.ï¿½ When that happy day arrives, the term ï¿½IBSï¿½ will no longer be used, and each patient will receive a more precise diagnosis. Until then it is sufficient to appreciate that food intolerance represents an important proportion of the conditions which together make up IBS.ï¿½John Hunter, MD, FCRPDirector or Gastroenterology and Consultant PhysicianAddenbrookeï¿½s HospitalCambridge, United KingdomFromï¿½Food Allergy and Food Intoleranceï¿½ Second Edition 2002J. Brostoff, MDS. Challacombe, MDSaunders _________________________________Because there are multiple possible mechanisms by which a patients dietary elements can provoke symptomology, and can do this through direct biochemical effects upon the various neuromuscular and endocrine functions of the entire integrated brian-gut axis, it can b very difficult for practitioners to contrive patient specific diet unless extensive understanding is acqauired of these mechanisms and methods of isolating them. But there are methodologies now available.As noted in the literature with great consistency, the best outcomes will be achieved by an integrated approach to care including, as stated in the aforementioned article posted above, and most tutorials:1. dietary therapy2. behavioral therapy (HT or CBT)3. pharmacotherapy as required.Thus any approach which can assist the practitioner in developing a protocol which is highly patient specific and includes all these elements will improve outcomesAdditional recomended textbook self-study references which can enhance the outcomes of the element of dietary treatment of the IBS patient include:IBS: A DOCTORS PLAN FOR CHRONIC DIGESTIVE TROUBLESBy Gerard Guillory, M.D.; Vanessa Ameen, M.D.; Paul Donovan, M.D.; Jack Martin, Ph.D. http://www.amazon.com/exec/obidos/ASIN/088...3369143-6824157 ï¿½FOOD ALLERGIES AND FOOD INTOLERANCE: THE COMPLETE GUIDE TO THEIR IDENTIFICTION AND TREATMENTï¿½, Professor Jonathan Brostoff , M.D.. Allergy, Immunology and Environmental Medicine, Kingsï¿½ College, London http://www.amazon.com/exec/obidos/ASIN/089...6487508-3420903 for physicians:FOOD ALLERGY AND INTOLERANCE, Professor Jonathan Brostoff, MD, Stephen Challacombe, MD (NEW 2002) http://www.amazon.com/exec/obidos/ASIN/070...product-details _______________________There are several underlying precursor mechanisms which may account for the primary loss of oraltolerance too foods seen in many IBS victims, which are promising for further investigation. Untl then it is welle stablished that a properly constructed exclusion diet is highlty beneficial. Intestinal dysbiosis, if present, can alter digestion of foddstuff susfficiently to alter apparent antigenicity of some foods from non-antigenic to antigenic, which may be reversible with probiotic therapy...an interesting line of study needing more work as described here: ________________________________Britsh Journal of Nutrtion 2002 Sep;88 Suppl 1:67-72A Review of the Role of the Gut Microflora in Irritable Bowel Syndrome and the Effects of Probiotics.Hunter JO, Madden JA, Hunter JO.Gastroenterology Research Unit, Unit E7, Box 201 A, Addenbrookes NHS Trust, Hill's Road, CB2 2QQ.Irritable bowel syndrome (IBS) is a multi-factorial gastrointestinal condition affecting 8-22 % of the population with a higher prevalence in women and accounting for 20-50 % of referrals to gastroenterology clinics. It is characterised by abdominal pain, excessive flatus, variable bowel habit and abdominal bloating for which there is no evidence of detectable organic disease. Suggested aetiologies include gut motility and psychological disorders, psychophysiological phenomena and colonic malfermentation. The faecal microflora in IBS has been shown to be abnormal with higher numbers of facultative organisms and low numbers of lactobacilli and bifidobacteria. Although there is no evidence of food allergy in IBS, food intolerance has been identified and exclusion diets are beneficial to many IBS patients. Food intolerance may be due to abnormal fermentation of food residues in the colon, as a result of disruption of the normal flora. The role of probiotics in IBS has not been clearly defined. Some studies have shown improvements in pain and flatulence in response to probiotic administration, whilst others have shown no symptomatic improvement. It is possible that the future role of probiotics in IBS will lie in prevention, rather than cure." ________________________What will be interesting is the ability to assess the role of flora in the aberrant food provoked immune (inflammatogenic) responses isolated in the UPPER bowel (jejunal isolation and provocation) as well by researchers at Sahlgrens University in Sweden....excerpted from recent discussions of findings:"We studied allergy-like inflammation in a closed segment in jejunum. When challenged with different staple foods and could show high levels of inflammatory mediators suggesting allergy-like inflammation...we can show an allergy-Like inflammation during challenges with parameters like Il-4, IFN-gamma, CD3, CD4, CD8 and IgE."These patients had IBS in accordance with Rome Criteria BUT were negative for any circulating antibodies to the reaction-provoking foods (negative atopy, Ig[x] RAST and even SPT].This in general is what makes the food-intolerant IBS patient very difficult to assess for dietary therapy as these repsosnes are delayed-onset and does dependend tsince they do not involve food allergy mechanisms and can be difficult for the practitioner to isolate with available methods.Success in doing so, however, leads to much improved outcomes form dietary therapy implemented which will enhance further the effectiveness other adjunct therapies.MNL


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## eric (Jul 8, 1999)

Dr Grant Thomson,from the above qoute now knows of the "ORGANIC role of serotonin in IBS and that IBS is a brain gut dysfunction.The information above is more up to date then then any information on this thread.Dr Michael D. Gershon, MD is the worlds leading authority on the enteric nervous system and the person directly responsible for the role of serotonin in the enteric nervous sytem. http://www.hosppract.com/issues/1999/07/gershon.htm Quotes from the Medscape information."Return to Irritable Bowel Syndrome: Taking Concepts Into Clinical Practice Integrating Current Concepts of Causality: Towards a Unifying HypothesisGervals Tougas, MDPhenomenology, Pathophysiology, and Symptomatology of Irritable Bowel SyndromeSlide 1. Integrating Current Concepts of Causality: Towards a Unifying HypothesisSlide 2. OutlineMy brief is to review 6 main points:Look at how a phenomenon, a set of symptoms, relates to, or at least begins to relate to, a definable pathophysiologyTry to see to some extent how and why patients with irritable bowel syndrome (IBS) experience visceral painGet back to this area of mind and gut, and how events that seem to influence primarily psychological constraints, such as stress and psychological factors, will play a role in the perception of symptoms originating from the gutRemind us that in addition to these factors, primarily luminal and enteric factors, such as certain food types, infection, or inflammation, can also interact with these central nervous system (CNS) factors to produce painBegin to look at the role and the place of serotoninergic mechanisms in the modulation of these thingsLook at this in the broader sense of IBSSlide 3. Phenomenology and PathophysiologyWe know that in terms of its phenomenology, IBS is a condition that's associated with altered brain-gut communication. Pain plays a major role so that we have alterations, or at least generation of abnormal sensation within the gut. Emotions can modulate these symptoms to a large extent, but at the end they also have alterations of function characterized in general by either constipation or diarrhea. This is largely due to alterations of neuromodulation at the level of the enteric neurons and also at the level of central and autonomic pathways.""Return to Irritable Bowel Syndrome: Taking Concepts Into Clinical Practice Integrating Current Concepts of Causality: Towards a Unifying HypothesisGervals Tougas, MDPhenomenology, Pathophysiology, and Symptomatology of Irritable Bowel SyndromeSlide 1. Integrating Current Concepts of Causality: Towards a Unifying HypothesisSlide 2. OutlineMy brief is to review 6 main points:Look at how a phenomenon, a set of symptoms, relates to, or at least begins to relate to, a definable pathophysiologyTry to see to some extent how and why patients with irritable bowel syndrome (IBS) experience visceral painGet back to this area of mind and gut, and how events that seem to influence primarily psychological constraints, such as stress and psychological factors, will play a role in the perception of symptoms originating from the gutRemind us that in addition to these factors, primarily luminal and enteric factors, such as certain food types, infection, or inflammation, can also interact with these central nervous system (CNS) factors to produce painBegin to look at the role and the place of serotoninergic mechanisms in the modulation of these thingsLook at this in the broader sense of IBSSlide 3. Phenomenology and PathophysiologyWe know that in terms of its phenomenology, IBS is a condition that's associated with altered brain-gut communication. Pain plays a major role so that we have alterations, or at least generation of abnormal sensation within the gut. Emotions can modulate these symptoms to a large extent, but at the end they also have alterations of function characterized in general by either constipation or diarrhea. This is largely due to alterations of neuromodulation at the level of the enteric neurons and also at the level of central and autonomic pathways.Slide 4. The Many Facets of IBSIBS has many dimensions. The symptom complex itself is characterized by abdominal discomfort associated with altered bowel habits. In addition to these, though, there is a substantial psychological comorbidity in many patients. At the same time, we have frequent extraintestinal manifestations associated with poor sleep, fatigue, changes in libido, and loss of energy, and a number of other symptoms, that often overlap with symptoms in the gut, outside of the colon, such as dyspeptic symptoms or noncardiac chest pain.We also know from increasing literature that many of these patients have other symptoms including irritable bladder, chronic fatigue, fibromyalgia, headaches, and a number of other symptoms. This is related to a number of abnormalities, some of them having to do with autonomic dysregulation and visceral hypersensitivity, altered pain modulation, abnormal health-seeking behavior and, to some degree, iatrogenesis.""Slide 5. Symptoms, Pathophysiology, and Pathogenesis in IBSIf we try to integrate this into a coherent map, we have symptoms that are subjectively definable, which then are associated with a series of complaints, either diarrhea, constipation, or abdominal pain, the whole spectrum of IBS. There is a pathophysiological basis to these symptoms that will vary in individual patients but seems to involve abnormalities of perception, epithelial function, and in some patients, motility, which then leads to symptom generation, and involves both external stressors, psychological stress, as well as genetic abnormalities and inflammation at the peripheral level.""Return to Irritable Bowel Syndrome: Taking Concepts Into Clinical Practice Integrating Current Concepts of Causality: Towards a Unifying HypothesisGervals Tougas, MDPhenomenology, Pathophysiology, and Symptomatology of Irritable Bowel SyndromeSlide 1. Integrating Current Concepts of Causality: Towards a Unifying HypothesisSlide 2. OutlineMy brief is to review 6 main points:Look at how a phenomenon, a set of symptoms, relates to, or at least begins to relate to, a definable pathophysiologyTry to see to some extent how and why patients with irritable bowel syndrome (IBS) experience visceral painGet back to this area of mind and gut, and how events that seem to influence primarily psychological constraints, such as stress and psychological factors, will play a role in the perception of symptoms originating from the gutRemind us that in addition to these factors, primarily luminal and enteric factors, such as certain food types, infection, or inflammation, can also interact with these central nervous system (CNS) factors to produce painBegin to look at the role and the place of serotoninergic mechanisms in the modulation of these thingsLook at this in the broader sense of IBSSlide 3. Phenomenology and PathophysiologyWe know that in terms of its phenomenology, IBS is a condition that's associated with altered brain-gut communication. Pain plays a major role so that we have alterations, or at least generation of abnormal sensation within the gut. Emotions can modulate these symptoms to a large extent, but at the end they also have alterations of function characterized in general by either constipation or diarrhea. This is largely due to alterations of neuromodulation at the level of the enteric neurons and also at the level of central and autonomic pathways.Slide 4. The Many Facets of IBSIBS has many dimensions. The symptom complex itself is characterized by abdominal discomfort associated with altered bowel habits. In addition to these, though, there is a substantial psychological comorbidity in many patients. At the same time, we have frequent extraintestinal manifestations associated with poor sleep, fatigue, changes in libido, and loss of energy, and a number of other symptoms, that often overlap with symptoms in the gut, outside of the colon, such as dyspeptic symptoms or noncardiac chest pain.We also know from increasing literature that many of these patients have other symptoms including irritable bladder, chronic fatigue, fibromyalgia, headaches, and a number of other symptoms. This is related to a number of abnormalities, some of them having to do with autonomic dysregulation and visceral hypersensitivity, altered pain modulation, abnormal health-seeking behavior and, to some degree, iatrogenesis.Slide 5. Symptoms, Pathophysiology, and Pathogenesis in IBSIf we try to integrate this into a coherent map, we have symptoms that are subjectively definable, which then are associated with a series of complaints, either diarrhea, constipation, or abdominal pain, the whole spectrum of IBS. There is a pathophysiological basis to these symptoms that will vary in individual patients but seems to involve abnormalities of perception, epithelial function, and in some patients, motility, which then leads to symptom generation, and involves both external stressors, psychological stress, as well as genetic abnormalities and inflammation at the peripheral level.Slide 6. Visceral Pain in IBS"To summarize, we know that there is alteration of visceral perception. There are good data to that effect and increasingly sophisticated ways to measure this, but in most patients, visceral hypersensitivity seems to play a role. In a substantial group of patients, luminal events, in particular infection and some degree of mild irritation, can alter visceral perception and lead to symptoms. Psychological factors also play a role in altering visceral perception and the vigilance to symptoms originating from the gut.""Slide 7. Increased Sensitivity to Balloon Distention in IBS PatientsOne of the most convincing studies was done by Bradette and coworkers. This was a simple study that looked at differences in visceral perception to balloon distension in patients with IBS and compared it to healthy subjects. Both the threshold to discomfort and the threshold to pain were much lower in patients with IBS than in healthy controls, suggesting that, in fact, there was visceral hypersensitivity in those patients.""Slide 8. fMRI Imaging With Rectal Distension in IBSThings have progressed a fair bit since then and we can demonstrate that, in addition to symptomatic abnormalities, there are significant differences that we can see between IBS patients and control subjects using functional magnetic resonance imaging fMRI, brain imaging, during colonic distension. These abnormalities are in 2 main parts. One is the somatosensory areas of the brain and the other is the prefrontal cortex region of the brain, each of which deals with different aspects of pain symptomatology.""Slide 9. Altered Pain Perception in IBSUp to 95% of patients with IBS will have altered pain perception. They will have lower thresholds, so they experience symptoms at much lower volumes than healthy controls. They also have an increased intensity of the sensation elicited by distension at a given volume, and they have increased referral of these sensory perceptions in response to rectal distension when compared with healthy patients.This is not something that we see very often in normal subjects and there's also different somatic pain perception in a subset of IBS patients, but by no means all.""Slide 10. Different Sensations, Different DestinationsWhy would that be? There are 2 regions in the brain that are involved with the perception of visceral sensation. The first one is the somatosensory cortex that is associated with the perception of noxious stimulation and painful stimuli. This region closely interacts with the limbic system, which is the part of the brain that is involved with the neuroendocrine and autonomic responses associated with the perception of pain. This is more of a hard-wired reflex area, but it plays a very important role in modulating responses in areas involved more directly with pain perception. These areas are also associated with aspects such as mood, hedonic behavior, and motivation, which play a very important role in the psychological make-up and modulation of these visceral sensations.""Slide 11. Visceral Pain and the Autonomic PathwayA lot of this is mediated through autonomic responses, and the important aspect here is that perception of pain in itself elicits responses that will then, in turn, alter the response and the reactivity of the gut. Eliciting painful visceral sensation will involve activation of sympathetic spinal afferents that, in turn, will lead to homeostatic visceral responses that will be associated with vagal afferent responses leading to symptoms such as satiety, nausea, and even bloating. These afferent pathways will then lead to efferent responses that are associated with visceral perception. And this is important because these pathways can in turn modulate the intensity of the afferent input.""Slide 12. Key ConceptsTo summarize, IBS patients display evidence of a central hyperresponsiveness to visceral stimuli and events, and this occurs at the level of the brain. In response to these pain stimuli, IBS patients have a visceral hyperresponsiveness to luminal events and also to central, more psychologically derived events, and this is occurring at the level of the gut. The understanding of these mechanisms is still evolving and begins to explain the 2 dimensions that we see with IBS patients, pain and altered bowel function.""Slide 13. Emotions and Visceral PerceptionEmotions modulate pain perception by several dimensions. One of them is that if you've experienced unpleasant or uncomfortable symptoms, you will have an increased vigilance to these visceral stimuli. And to some degree, the same seems to be occurring at the level of visceral pain. This involves both cortical and brain stem nuclei and a large degree of autonomic modulation. The central nervous system increases the perception of symptoms at the level of the gut. There is a clear presence of visceral hyperalgesia that can be related in many situations and experimental paradigms to very early trauma during childhood or infancy, and also seems to be associated with very stressful, psychological events, such as abuse or posttraumatic stress disorder. This raises the issue of whether there is an element of neuroplasticity involving altered perception in addition to the cortical activation that comes from altered symptoms.Furthermore, a number of studies have shown that patients with IBS have altered autonomic activity. While this is not completely described yet, it is associated with an increase or altered visceral responsiveness in many of these patients. A final aspect is that these symptoms lead to increased health-seeking behavior and use of healthcare.""Slide 14. Auditory Stress Alters Perceptual and Emotional Ratings of Visceral StimuliOne of the best studies looking at this is a study that looked at auditory stress and showed that an unpleasant external stressor, a noise in this case, altered both the perceptual and emotional rating that you experience in response to a visceral stimulus. In this study published a year ago, a control subject had responses that were measured in response to either a relaxing stimulus or a stressful stimulus, a conflicting sound in both ears. In patients with IBS, the same stimulus led to an increased degree of unpleasantness at set pressure distension. Similarly, it had the same effect on the anger rating, a psychological measure of psychological stress.""Slide 16. Enteric Factors and IBS SymptomsWhen we look at the other dimension, enteric factors, many patients tell us that certain foods will produce symptoms. It is difficult to determine whether this is a pharmacological, a chemical, or even an immune mechanism. Also, low-grade inflammation is present in a small subset of patients with functional symptoms. There is increasing awareness that in the substantial group of patients, although the proportion remains to be determined, infectious events seem to lead to the subsequent development of IBS. Sometimes this occurs as a single precipitant, but in many studies the biggest predictor of the subsequent development of symptoms following an enteric infection is other factors, such as psychological stress or an adverse life event a few weeks or a few months preceding the infection. Clearly, there is a role for infections but this is in association with central factors.Slide 16. Enteric Factors and IBS SymptomsWhen we look at the other dimension, enteric factors, many patients tell us that certain foods will produce symptoms. It is difficult to determine whether this is a pharmacological, a chemical, or even an immune mechanism. Also, low-grade inflammation is present in a small subset of patients with functional symptoms. There is increasing awareness that in the substantial group of patients, although the proportion remains to be determined, infectious events seem to lead to the subsequent development of IBS. Sometimes this occurs as a single precipitant, but in many studies the biggest predictor of the subsequent development of symptoms following an enteric infection is other factors, such as psychological stress or an adverse life event a few weeks or a few months preceding the infection. Clearly, there is a role for infections but this is in association with central factors.""Slide 17. Pathophysiology of Postinfectious IBSIn postinfectious IBS patients, there is accelerated gut transit in many patients, increased visceral sensitivity, and evidence for alteration of intestinal permeability, something very relevant to chronic diarrhea in these patients. There's clear evidence in many patients of increased presence of enterochromaffin EC cells in the colon. Therefore, there is the possibility of increased release of serotonin 5-HT in these patients.""Slide 18. Serotonin and the Neural Control of Digestive FunctionsSerotonin is involved at just about every level of the communication between gut and brain, both going from gut to brain and then from brain to gut. One appealing therapeutic avenue is to focus on the site where most of the 5-HT is being released and try to affect outcome and symptoms by modulating symptoms at the level of the gut trying to avoid the possible side effects that may come with more central modulation of serotoninergic pathways.""Slide 19. Plasma 5-HT Levels in IBS vs ControlsWe know that 5-HT release is actually increased in IBS patients with the diarrhea-dominant component, suggesting that, again, 5-HT may play a role in subsets of patients with IBS.""Slide 20. Serotonin and EC Cells in Altered GI MotilityThis may be further demonstrated in the sense that there is increased circulating 5-HT in patients with diarrhea-dominant IBS and increased EC cell population in the gut, whereas in some subgroup of patients with chronic constipation, there appears to be a decreased number of EC cells suggesting that, if we stimulate serotoninergic pathways, we might be able to improve symptoms in these patients.""Slide 21. SummaryIn summary, IBS is affected and modulated by many factors. Some of them have to do with emotional dimensions, others are more related to visceral function and sensation. This is probably, to some extent, associated with a dysfunction or a disorder of gut-brain communication involving both afferent and efferent pathways going to and from the gut. There is good evidence to suggest that 5-HT is a central mediator in the regulation of these visceral functions, and its modulation may provide an appealing form of therapy for a proportion of patients with IBS."


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## Mike NoLomotil (Jun 6, 2000)

Comment: ______________________________ï¿½They did a damn good job of this here.ï¿½ ______________________________That does not mean there are not still some holes in it. It is unfortubate that it offends some so much to objectively point out mssing or overly-interpreted data but it is necessary when it happens. Even the above tutorail. I posted this on another thread where this "be all end all" CME is referred to and I kind of figured It would be needed to eb said elsewhere as well.On another thread itr is prefaced with:________________________________"Anyone who wants to get serious and read some serious IBS information and take there IBS seriously and see the BIG picture should read this. It is also in audio with text or in flash."_________________________________HERE it is prefaced with:_________________________________"The information above is more up to date then then any information on this thread."_________________________________Up to date does not automatically denote completeness nor proper interpretaton by the reader.I would agree, having read thus CME program several times, that this particular CME program has a vast amount of content which can help individuals who understand some of the physiology underlying the discussions to gain insights into a number of aspects of current theory and investigation into certain aspects of the diagnosis, treatment, possible pathogenesis, and multiple possible causal basis of the so called IBS.It also is exquisitely illustrative of the current approach to IBS pathogenesis from the direction of psychobiosocial modeling of the entity, and targeting investigation that is self-declared to be solely driven by the seeking of better targets for pharmacotherapy. "BIG" dose not denote "WHOLE" as of yet an not in the context of this CME program.first, the caveats that any reader, physician or layperson alike, needs to keep in mind when studying the material is to be able to carefully read the material in the exact context of that which each author prepared his presentation, so that THEORY and SUPPOSITION and POSULATES are read as such, and learned as such when you come away from the CME program. There is much of that, and some of it clearly is very close to being moved from theory to fact. However, the CME is just as rich with material that is not only not close to that transition, but if viewed in the context of some other findings not included therein might cause the theory stated to be modified to be inclusive of the other information missing. This will depend upon the paradigm of the person evaluating the information and the beleif system employed.So the reader must be cautious to discern that which is a FACTUAL OBSERVED EVENT and FACTUAL QUANTIFIED MECHANISM so that the reader is not CONFUSEING them with theory, postulate, supposition. This can lead people down the wrong path, away from further study and possibly away from other efficacious therapies.Keep in mind, and no on should suggest I am saying otherwise, that when it comes to tutorials on conditions still under active investigation it is rarely possible, and often impossible, for any one set of authors to create a program which is wholly inclusive of all information and all perspectives and all paradigms from which information can be viewed. This qualification must always be kept in mind, as even you will see the authors keep it in mind and select what they say with care so as to seprate evne enthusiastic speculation as clearly speculation.In that context I repeat that as another ï¿½studentï¿½ of the subject it is truly a wonderful tutorial as far as it goes. And it does go pretty far but not all the way by any means.A long as one is not seeking any information relative to those primary immunologic events and mechanisms of IBS symptom generation which have been identified and quantified elsewhere which the authors do not include in their program. By their deletion it leaves the program devoid of any basis for any effective patient-specific dietary therapy methodology beyond those already known to priduce equivocal outcomes at best as they do not address the actual underlying mechanisms which cause the outcomes to be equivocal. So this aspect is not imparted to physicians, dieticians, patients or readers to any degree, no protocols on how patient-specific dietary therapy can be developed which is related to patient specific cell-mediated or mucosal-mediated aberrant immune response to oral provocation. There are key words present which allude to the existence of the mechanisms but they are outside the scope of practice of the authors of this particular CME, as indeed much of the information remains outside the scope fo practice of many physicians as of yet, who have no means of addressing fundamental food or chemical intolerance in patients diagnosed with IBS via generally accepted symptom based standards.Indeed that entire realm of investigation and clinical findings which included but is not limited to in vivo jejunal isolation and provocation, global symptomology secondary to aberrant immune provocation as an aspect of symptom generation, and all matters appurtenant thereunto are pretty much not addressed. Many observations of altered biochemistry in IBS or altered phsyioliogic responses are denoted but not viewed in buit one context or in relation to a single mechanisms or mediator when there are other mechanisms to be explored, and which have been to some extent, which can provide alternative explanations for the events witnessed and postulated about.It is a comprehensive and very good CME but it needs to be made clear it is by no means wholly inclusive as to all known aspects of investigation into the condition nor therapeutics. There are things that can be fielld in with further study form other sources.At some point I hope to have time to finish an active review (it is underway but incompleteï¿½a little time here and there to work on it) of some of the areas where the authors stopped-short when approaching a given observation, postulate, or therapeutic modality in the tutorial and then insert references to other information which could be inserted at that point for the reader to refer-out to which would fill the hole left at each point by the authors...but this is not completed yet. It is time consuming as it is a somewhat lengthy tutorial and even though written in plainer english than most, to illustrate a branching of the thought process at certain points requires more than simply inserting an abstract which would "fill the hole"...many readers who are patients being referred to this for information would not comprehend the relationships.I do expect, though, that within a week to be able to assemble some interesting information which supplements and expands upon many of the areas addressed in this CME from other investigators whose work was not included, for the reader to consider when studying the subject.MNL--------------------Eat Well. Think Well. Be Well. http://www.nowleap.com


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## Mike NoLomotil (Jun 6, 2000)

Having had a few minutes now to review the material posted following this declarationï¿½..________________ï¿½posted 03-09-2003 01:54 PM Dr Grant Thomson,from the above qoute now knows of the "ORGANIC role of serotonin in IBS and that IBS is a brain gut dysfunction.The information above is more up to date then then any information on this thread. Etcï¿½.ï¿½ï¿½it is great to see that a lot of the heavy lifting has already been done for me in extracting much of exactly what I am talking about which makes my very point aboutinterpretationperspectiveobservation of event vs pathogenesis of eventmorphing postulate into fact.This allows me to drop what I was trying to construct and simply make a few key points in an effort to instill the proper objectivity into these discussions. ________________________________________ï¿½ï¿½. at least begins to relate toï¿½.ï¿½ ___________________________________________Please take note of what the phrase ï¿½begins to relate toï¿½ means when it is used to preface something. ___________________________________________ï¿½ï¿½ Try to see to some extentï¿½ï¿½ ___________________________________________Please consider what it means to ï¿½Try to see to some extentï¿½ï¿½means when the author prefaces something with that disclaimer. __________________________________________ï¿½ï¿½ how events that seem to influenceï¿½ï¿½ __________________________________________Please take note of explicitly what it means to observe or describe ï¿½how events seem to influenceï¿½ something I some way. __________________________________________ï¿½ï¿½ Remind us that in addition to these factors, .. ____________________________________________Please take note that this means ï¿½in addition to the factors I just described what I am about so say must be added to what I just said so add it on pleaseï¿½ ______________________________________________ ï¿½ï¿½primarily luminal and enteric factors, such as certain food types, infection, or inflammation, can also interact with these central nervous system (CNS) factors to produce painï¿½.ï¿½ ________________________________________________Primary lumenal events means events which occur within the lument of the GI tract first bedofre anything else and ï¿½enteric factorsï¿½ means just that avery borad term describing almost countless possibilities of things which can occur within the enteric systemï¿½and it includes things related to each of the items listed therafter ï¿½will INTERRACT with the aforementioned CNS factors (of which there is also a wide range) to produce pain.For example, consider that there are numerous neurochemical, immunochemical endocrine and exocrine factors and chemical mediators which are known each in its own way to effect various aspects of gut motor and sensory function. ONE mere example example as follows as regards factors which ï¿½produce painï¿½: _______________________________________From:Neurogastroenterologic Motility 2002 Oct;14(5):459-75Sensory Neurone Responses to Mucosal Noxae in the Upper Gut: Relevance to Mucosal Integrity and Gastrointestinal Pain.Holzer P.Department of Experimental and Clinical Pharmacology, University of Graz, Graz, Austria.The digestive tract is supplied by extrinsic and intrinsic sensory neurones that, together with endocrine and immune cells, form a surveillance network that is essential to gut function. This article focuses on the responses of extrinsic afferent neurones to chemical insults of the gastrointestinal mucosa and their pathophysiological relevance to mucosal integrity and abdominal pain. Within the gastroduodenal region, spinal afferents subserve an emergency function because, in case of insult by influxing acid, they stimulate mechanisms of mucosal protection via an efferent-like release of transmitters. Other sensory neurones signal chemical noxae to the brain, a task that is not confined to spinal afferents because vagal afferents communicate gastric acid and peripheral immune challenges to the brainstem and in this way elicit autonomic, endocrine, affective and behavioural reactions. Emerging evidence indicates that hypersensitivity of extrinsic afferent pathways to mechanical and chemical stimuli makes an important contribution to the abdominal hyperalgesia seen in functional dyspepsia and Irritable Bowel Syndrome. Sensitization may be brought about by inflammatory processes that lead to up-regulation and functional alterations of receptors and ion channels on sensory neurones. Such sensory neurone-specific molecules, which include vanilloid (capsaicin) receptors, may represent important targets for novel drugs to treat abdominal pain. ________________________________________________If one understands the physiology to which the author refers one understands how the author elucidates in the article the many enteric and lumenal factors including primary insult to the proximal bowel immunoprotective systems which will result in the system wide upregulation of sensory and motor function observed. Once cannot isolate or pick out one event, one mechanism, one mediator, from all that has been observed in mechanisms of symptom generation in IBSï¿½even just the symptom of heightened pain perception, and attribute it to a single pathway or single mediator. It is not possibleï¿½though as we see later it is convenient as if you can isolate one pathway which has broad influence over the behavior of the brain-gut axis (as opposed to perhaps other mediators whose influence is local, or specific to only other certain tissue or organs) then one can probably arrive more quickly at a drug which will be specific to that portion of the symptom which may have wider ranging effect than other mediators within the system. Since as many as 100 may be involved, as you se later in the tutorial it is explained what there is so much focus on 5HT and 5HT[x] receptors. It is not the sole mediator of the integrated B-G/HPA systems (however you choose to list them) or even the sole universal (global) mediator. It is easier to work with, investigate and hopefully manipulate as source of possible pharmacologic treatments than other mediators within the system.This distinction is important to keep in mind, and tutorials (including these posted) point that outï¿½that is the perspective and rationale for the perspective.Lets continue onï¿½sidetracked abit _____________________________________ï¿½ï¿½ Begin to look at the role and the place of serotoninergic mechanismsï¿½ï¿½ _________________________________________This is keyï¿½what does ï¿½begin to look at the role and place of..ï¿½ï¿½5HT and 5ht[X] receptors play a particular part but it is nowhere near a solo act. So the authors examine the apparent role of this mediator and its receptors as one of the more wide-ranging mediatorsï¿½.For example, a brief delineation of the range of biochemicals which can and do regulate the functions we are constantly referring to in ISB patients: ______________________________________________Effects of Inflammatory Mediators on Gut Sensitivity. Canadian Journal of Gastroenterology 1999 Mar;13 Suppl A:42A-46ABueno L, Fioramonti J Department of Pharmacology, INRA, Toulouse, France. Over the past decade, attention has been paid to the role of visceral sensitivity in the pathophysiology of functional bowel disorders, especially irritable bowel syndrome, and visceral hypersensitivity is the most widely accepted mechanism responsible for both motor alterations and abdominal pain. INFLAMMATORY MEDIATORS sensitize primary afferents, especially C-fibre polymodal nociceptors, favouring the recruitment of silent nociceptors that give rise to secondary spinal sensitization. After local tissue injury, the release of chemical mediators such as potassium ions, ATP, bradykinin and prostaglandin E2 directly activate nerve endings and indirectly trigger the release of algesic mediators such as histamine, 5-hydroxytryptamine and nerve growth factor from other cells, which, in turn, stimulate proximal afferent nerve endings and silent nociceptors. Among the intermediary structures activated by inflammatory mediators and susceptible to the release of proalgesic substances, mast cells and platelets play a crucial role; however, immunocytes such as macrophages and neutrophils or sympathetic nerve terminals are also candidates. Moreover, events likely to activate synthesis of mediators by mast cells, such as stress and septic shock, also trigger colonic hypersensitivity. Prolonged visceral hyperalgesia may also depend on spinal sensitization. A number of substances are candidates to play a role at the spinal cord level in mediating painful and nonpainful sensations. Among them, substance P, dynorphins and glutamate play a pivotal role in postsynaptic sensitization, particularly during and after gut inflammation. Finally, despite the complexity of the relationship between inflammatory mediators and gut hypersensitivity, numerous results strongly suggest that alteration in neuroimmune communications at the gut level may trigger a series of events that give rise to chronic changes in visceral sensitivity.Once one has some concept of the intricate system of communication between the brain, the gut, the immune system and the endocrine system and what buzzwords like ï¿½visceral hypersensitivityï¿½ actually mean (its an observed physical event which can have multiple causal bases biochemically) then one can appreciate in total ALL of the various physical events that have been observed in various subclasses of IBS patients, and thus what all the possible known mechanisms of ï¿½sensitizationï¿½ are to date and which are implicated under different conditions so as not to exclude any mechanism by being to selective in what data one considers. _________________________________________ï¿½ï¿½ IBS is a condition that's associated with altered brain-gut communicationï¿½.ï¿½ ______________________________________________Indeed every possible mechanism that has been observed which elicits IBS symptoms does so by altering the nature of or information relayed during ï¿½brain-gut communicationï¿½. This term does not denote some mysterious endogenous event of indeterminate mechanism. If one isolates, for example, the release of mediators as a consequence of a provoking event one can observe the pathway of those mediators in altering the behaviors of the brain-gut axis from the point of effect of that or those mediators. And there are many that can be isolated, each of which has its effect. The term does not denote iatrogenic brain dysfunction as is sometimes taught to IBS patientsï¿½rather it denotes dysfunction in known physical systems which communicate and co-regulate by known biochemical means. ___________________________________________ï¿½ï¿½ Emotions can modulate these symptoms to a large extent, but at the end they also have alterations of function characterized in general by either constipation or diarrheaï¿½ï¿½ _____________________________________________This is a key point always made by the educators and misinterpreted and repeated by those trying to be educated. Emotions modulate symptoms. Modulate. Indeed they can modulate many bodily functions through direct and indirect biochemical pathways which are legion in their number and effect.The key is isolating which ones are activated in given IBS victims, or their subpopulations, as this can discriminate one symptom set from another. Those in turn may discriminate one pathogenesis from another .Or to quote: _________________________________________________ Nicholas Talley, MD from ï¿½Irritable Bowel Syndrome: Physiology and Managementï¿½ presented at Digestive Disease Week 2002 ï¿½Dunlop and colleagues[4] also evaluated 76 patients with IBS and 40 healthy controls, applying immunohistochemical staining for lamina propria and intraepithelial lymphocytes, enteroendocrine (serotonin-containing) cells, and mast cells. They subdivided their patients into 3 groups, those with: (1)	postinfectious IBS; (2)	(2) constipation-predominant IBS; and, (3)	(3) nonconstipated, non-postinfectious IBS. (4)	These investigators found that cell counts in constipation-predominant IBS were not significantly different from that of controls. In contrast, patients with diarrhea, but without a postinfectious history, showed increased CD3 and lamina propria lymphocytes, in addition to mast cells, whereas patients with postinfectious IBS had increased enteroendocrine cells, CD3, and lamina propria lymphocytes. These findings suggest that subgrouping of IBS by bowel symptoms may identify distinct histomorphic phenotypes within IBS, which in turn suggests that treatment may need to be tailored to symptom subgroups. Mast Cells Park and colleagues[5] applied electron microscopy and found that mast cell counts were significantly higher in the cecum among patients with IBS, and that the number of activated mast cells close to nerves was increased in IBS patients vs controls. Similarly, Barbara and coworkers[6] employed immunofluorescence and found that tryptase-containing mast cells were increased 3-fold in IBS patients compared with controls. They also found evidence of mast cell degranulation. ______________________________________________This is the entire thrust of the historical investigations by physicians seeking the causal basis for IBS symptoms, and corresponds directly with the findings of investigators who have reported many times since 1994 the response of the small bowel immune system to direct food challenge in the isolated jejunum of subjects with diet-induced IBS symptoms but no food allergy.When you challenge the jejunum with foods which provoke IBS symptoms in the diarrheal subgroups you find in the wall and in the lumenal secretions a wide array of inflammatory mediators from lymphocytes and mast cells, not only EC cells, as well as markers of antigen presentation to lymphocytes as noted above ï¿½as reported by Bengtsson et al these include but are not limited to ï¿½ï¿½Il-4, IFN-gamma, CD3, CD4, CD8ï¿½ï¿½. ..there is an array, it just depends how many you want to test for at any given time as up to 100 are possible to appear.Also, the findings of increased mast cell density at the ileocecal junction, a sign of chronic insult at the outflow tract of the small bowel (mast cells concentrte at sites where the immune system perceives the need for their immunoprotective functionï¿½sites of chronic provocation), as I recall was first reported at least 10 years agoï¿½along wit many reports of mast cell mediator elease in response to oral challenge. There is wide ranging information showing the activation of humoral and cellular immune functions in the diarrheic subpopulations whether or not infection was a precursor event. This includes patients where atopy was ruled out and systemic food allergy (IgE antibodies) is absent. _________________________________ï¿½ï¿½ IBS has many dimensionsï¿½.ï¿½ ___________________________________Precisely, in fact this is the only point I have ever tried to make. _____________________________ï¿½ï¿½ there is a substantial psychological comorbidity in many patientsï¿½.ï¿½ ______________________________I do not think this self-evident fact, that this comorbidity is common and that psychological comorbidities contribute not only to behaviors but to symptoms as well, is argued by anyone. It is however not the source of the pathogenesis of the disease as is sometimes misunderstood by patients when they try to understand what experts are saying. _________________________________________ï¿½ï¿½ At the same time, we have frequent extraintestinal manifestations associated with poor sleep, fatigue, changes in libido, and loss of energy, and a number of other symptoms, that often overlap with symptoms in the gut, outside of the colon, such as dyspeptic symptoms or noncardiac chest painï¿½.ï¿½ ___________________________________________None of those symptoms are surprising when either a primary or secondary activation of the immunoprotective mechanisms of the gut are clearly seenï¿½consider these too before finishingï¿½. _____________________________________________ï¿½ï¿½ many of these patients have other symptoms including irritable bladder, chronic fatigue, fibromyalgia, headaches, and a number of other symptoms.ï¿½ ______________________________________________I one only examines extra-intestinal symptoms from the immunologic viewpoint, and one si able to observe and quantify the activation of immunoprotective mechanisms that have been seen In IBS patients, especially diarrheics, and one understands what the array of mediators is that is released locally In the gut and then systemically in the plasma it is an easy matter to comprehend one source of systemic symptoms.This is about the easiest way to describe it in the population of IBS patients where local and systemic abnormal immune response (inflammatory repsnse) can be observed: ___________________________________________Lancet 2000 Jul 29;356(9227):400-1Relation Between Food Provocation and Systemic Immune Activation in Patients with Food Intolerance.Jacobsen MB, Aukrust P, Kittang E, Muller F, Ueland T, Bratlie J, Bjerkeli V, Vatn MH.We found that food provocation in food intolerant patients was characterised by a general and systemic immune activation accompanied by an increase in systemic symptoms. Our findings might be important for the understanding of the mechanisms involved in the pathogenesis of food intolerance. _______________________________________Indeed the systemic effects of inflammatory mediator release can be startling. AND as I have tried to explain many times, ï¿½the knife can cut both waysï¿½ depending upon the patient. This is the value of the diagrams seen in Zars papers on the subject. Cytokines are among the several classes of numerous specific proinflmmatory mediators that have been found to be liberated in inflammatogenic responses in the diarrheic populations, be they acute pathogenic processes of reactions induced by oral challenge. Knowing theor effects it must give pause for one to consider those effects and integrate them into the postulates concerning the various global symptoms and behaviors manifest in so called IBS patients.Just a few examples of published discussions on how there may be seen primary infllammatory responses precipitating secondary central responses, or vice versa as has been discussed, how central stress responses and other behaviors can elicit inflammatory activationï¿½it is an undividable 2 way street. Further it sereves to better illuminate and put into perspective the relationships between serotonin and other proinflammatory mediators which are all neuromusculoendocrine activatorsï¿½.as well as activators of various portions of the central nervous system. _________________________________________ J Am Geriatr Soc 2002 Dec;50(12):2041-56Cytokines and Cognition--The Case for a Head-to-Toe Inflammatory Paradigm.Wilson CJ, Finch CE, Cohen HJ.St. Vincent Institute on Aging, St. Vincent Hospitals and Health Services, Indianapolis, Indiana 46260, USA.The brain is not only immunologically active of its own accord, but also has complex peripheral immune interactions. Given the central role of cytokines in neuroimmmunoendocrine processes, it is hypothesized that these molecules influence cognition via diverse mechanisms. Peripheral cytokines penetrate the blood-brain barrier directly via active transport mechanisms or indirectly via vagal nerve stimulation. Peripheral administration of certain cytokines as biological response modifiers produces adverse cognitive effects in animals and humans. There is abundant evidence that inflammatory mechanisms within the central nervous system (CNS) contribute to cognitive impairment via cytokine-mediated interactions between neurons and glial cells. Cytokines mediate cellular mechanisms subserving cognition (e.g., cholinergic and dopaminergic pathways) and can modulate neuronal and glial cell function to facilitate neuronal regeneration or neurodegeneration. As such, there is a growing appreciation of the role of cytokine-mediated inflammatory processes in neurodegenerative diseases such as Alzheimer's disease and vascular dementia. Consistent with their involvement as mediators of bidirectional communication between the CNS and the peripheral immune system, cytokines play a key role in the hypothalamic-pituitary-adrenal axis activation seen in stress and depression. In addition, complex cognitive systems such as those that underlie religious beliefs, can modulate the effects of stress on the immune system. Indirect means by which peripheral or central cytokine dysregulation could affect cognition include impaired sleep regulation, micronutrient deficiency induced by appetite suppression, and an array of endocrine interactions. Int J Neuropsychopharmacol 2002 Dec;5(4):375-88The Psychoneuroimmuno-Pathophysiology of Cytokine-Induced Depression in Humans.Wichers M, Maes M.Department of Psychiatry and Neuropsychology, Maastricht University, 6200 MD Maastricht, The Netherlands.Administration of the cytokines interferon-alpha and interleukin-2 is used for the treatment of various disorders, such as hepatitis C and various forms of cancer. The most serious side-effects are symptoms associated with depression, including fatigue, increased sleepiness, irritability, loss of appetite as well as cognitive changes. However, great differences exist in the prevalence of the development of depressive symptoms across studies. Differences in doses and duration of therapy may be sources of variation as well as individual differences of patients, such as a history of psychiatric illness. In addition, sensitization effects may contribute to differential responses of patients to the administration of cytokines. In animals administration of pro-inflammatory cytokines induces a pattern of behavioural alterations called 'sickness behaviour' which resembles the vegetative symptoms of depression in humans. Changes in serotonin (5-HT) receptors and in levels of 5-HT and its precursor tryptophan in depressed people support a role for 5-HT in the development of depression. In addition, evidence exists for a dysregulation of the noradrenergic system and a hyperactive hypothalamic-pituitary-adrenal (HPA) axis in depression. Some mechanisms exist which make it possible for cytokines to cross the blood-brain barrier. Pro-inflammatory cytokines such as IL-1beta, IFN-alpha, IFN-gamma and TNF-alpha affect the 5-HT metabolism directly and/or indirectly by stimulating the enzyme indoleamine 2,3-dioxygenase which leads to a peripheral depletion of tryptophan. IL-1, IL-2 and TNF-alpha influence noradrenergic activity and IL-1, IL-6 and TNF-alpha are found to be potent stimulators of the HPA axis. Altogether, administration of cytokines may induce alterations in the brain resembling those found in depressed patients, which leads to the hypothesis that cytokines induce depression by their influence on the 5-HT, noradrenergic and HPA system.________________________________________Neuroendocrinol Lett 1999;20(1-2):11-17Activation of the Inflammatory Response System: A new look at the Etiopathogenesis of Major Depression.van West D, Maes M.Clinical Research Center for Mental Health (CRC-MH), Antwerp, Belgium.Major depression is accompanied by various direct and indirect indicators of a moderate activation of the inflammatory response system (IRS). Increased production of proinflammatory cytokines, such as interleukin-1 (IL-1), IL-6 and interferon (IFNgamma), may play a crucial role in the immune and acute phase response in depression. Lower serum zinc and changes in the erythron are indirect indicators of IRS activation in depression. The reciprocal relationships between IRS activation and hypothalamic-pituitary-adrenal (HPA)-axis hyperactivity, alterations in HP thyroid (HPT)-axis function and the availability of tryptophan to the brain led us to hypothesize that these neuroendocrine changes in depression are indicators of IRS activation and that a combined dysregulation of the IRS, the turnover of serotonin (5-HT) and the HPA-axis is an integral component of depression. The IRS activation model of depression provides an explanation for the psycho-social (external stress) as well as organic (internal stress) etiology of major depression. Antidepressive treatments with various antidepressive agents, including SSRIs, tricyclic and heterocyclic antidepressants, have in vivo and in vitro negative immunoregulatory effects, suggesting that their antidepressant efficacy may be attributed, in part, to their immune effects._________________________________________________ ï¿½This is related to a number of abnormalities, some of them having to do with autonomic dysregulation and visceral hypersensitivity, altered pain modulation, abnormal health-seeking behavior and, to some degree, iatrogenesis."ï¿½ï¿½ _______________________________________________Indeed the more one studies from a broader perspective inclusive of other information where ï¿½the word IBS is not necessarily in the title, rather the patient selection is related to or includes persons who would be diagnosed with IBS, the more obvious that these general terms ï¿½dysregulationï¿½ and ï¿½visceral hypersensitivityï¿½ are names of CONDITIONS but shed no light on which specific mechanism is responsible for that condition, each of which is associated with the many observable conditions in IBS patients. On the other hand, each passing day there is less and less basis for interpreting anything seen as solely iatrogenic as there is not a condition observed so far in IBS patients which does not have at least one known mechanism which would explain it and which could be and should be examined more closely. ___________________________________________ï¿½ï¿½ There is a pathophysiological basis to these symptoms that will vary in individual patients ï¿½etcï¿½ _______________________________________________This is exactly what I have contended since day 1, as it is what I have learned from study, what I have been taught by physicians with this perspective, and which I have been privileged to see with my own eyes! Indeed its true and this the basis for this statement which I have been known to quote, as it summarizes the whole issue of what is known about IBS as set forth in these types of tutorials: _______________________________________________ï¿½ï¿½Considerable confusion is now arising over the relationship between food intolerance and the Irritable Bowel Syndrome (IBS). Although the name has been hallowed by long usage, IBS is not a distinct entity but merely a collection of disorders which are characterized by abdominal symptoms but no obvious organic pathology. G.W. Thompson forecast in 1985: ï¿½the IBS is organic; that is all sufferers will eventually be found to have measurable, unique pathologic defects.ï¿½ When that happy day arrives, the term ï¿½IBSï¿½ will no longer be used, and each patient will receive a more precise diagnosis. Until then it is sufficient to appreciate that food intolerance represents an important proportion of the conditions which together make up IBS.ï¿½John Hunter, MD, FCRPDirector or Gastroenterology and Consultant PhysicianAddenbrookeï¿½s HospitalCambridge, United KingdomFromï¿½Food Allergy and Food Intoleranceï¿½ Second Edition 2002J. Brostoff, MDS. Challacombe, MDSaunders ______________________________________________________At the root of all discussions if one pays close attention everyone is in fundamental agreement that there are distinct pathogenesis involved in distinct populations. Yet somehow people end up debating something that there is no debate about. ___________________________________________________Much of everything else quoted from the tutorial is simply restating all that has gone beforeï¿½with a few additional aspects noted hereafter ____________________________________________________ï¿½ï¿½ One of the most convincing studies was done by Bradette and coworkers. This was a simple study that looked at differences in visceral perception to balloon distension in patients with IBS and compared it to healthy subjects. Both the threshold to discomfort and the threshold to pain were much lower in patients with IBS than in healthy controls, suggesting that, in fact, there was visceral hypersensitivity in those patients."ï¿½ï¿½ _____________________________________________________At this point I do not think there has been any debate about the existence of visceral hypersensivity in IBS for some time. The task now is describing the mechanisms of it. Since they are known (all the various mediators of various types which can alter visceral sensitivity, and the cell types which express them have all been seen, and much of what provokes them is known, it does not seem that this phenomenon should be much of a mhystery.. Just look at what the known effects are of the mediators expressed by the various cell types, from EC to Mast to T cells, and one gets a pretty clear idea why there is visceral hypersensitivity, Then, sicne we also cans ee what provokes the expression of these mediators and it has been outlined, what remains is WHY does this process occur in patients and not in normal controls. Why do the abnormal reactions, provocations, exist in these people? This si what everyone I think is ultimately drilling down on. ____________________________________________ï¿½ï¿½ there are significant differences that we can see between IBS patients and control subjects using functional magnetic resonance imaging fMRI, brain imaging, during colonic distension. These abnormalities are in 2 main parts. One is the somatosensory areas of the brain and the other is the prefrontal cortex region of the brain, each of which deals with different aspects of pain symptomatology."ï¿½ï¿½ ______________________________________________The same response applies hereï¿½.no one disputes what is seen, what has to be studied is what the causal basis is which results in altered blood flow to these areasï¿½and one can see that the possibilities are indeed very very wide ranging. Integrtaive effort which would include immunohistochemistry and challenge-response investigation at the same time in the same patients, and mediator assay within all compartments would surely make it easier to glean a causal basis ï¿½at this time all one can do is postulate. _____________________________________________ï¿½ï¿½ Up to 95% of patients with IBS will have altered pain perceptionï¿½etc and inclusiveï¿½ï¿½ ________________________________________________Ditto. No wonder. Look at the chemical mediatrs recovered from the lamina propria and plasmaï¿½what is needed too is what is in the Cerebrospinal fluid? That would be intriguing. ________________________________________ï¿½Different Sensations, Different Destinationsï¿½ï¿½all that follows up to and including:ï¿½ï¿½ A lot of this is mediated through autonomic responses, and the important aspect here is that perception of pain in itself elicits responses that will then, in turn, alter the response and the reactivity of the gut. Eliciting painful visceral sensation will involve activation of sympathetic spinal afferents that, in turn, will lead to homeostatic visceral responses that will be associated with vagal afferent responses leading to symptoms such as satiety, nausea, and even bloating. These afferent pathways will then lead to efferent responses that are associated with visceral perception. And this is important because these pathways can in turn modulate the intensity of the afferent input."ï¿½ ______________________________________________Indeedï¿½as can these pathways if we invert the primary event.. Hopefully it can be seen from a broader view of the literature that a primary locus of provocation which is immunologic, as has been elicited via jejunal isoation, also creates a model utilizing the exact same pathways but mediated or activated by primary release of proinflammatory mediators in response to mucosal and GALT (gut associated lymphoidal tissue) challenge. There is a bottom-up mechanism and a top-down mechanism.The discussions of these mechanisms that go on in some length are correctly qualified by the author via the inclusion of this statement in the tutorial: ______________________________________________ï¿½ï¿½The understanding of these mechanisms is still evolving and begins to explain the 2 dimensions that we see with IBS patients, pain and altered bowel function."ï¿½ï¿½ ________________________________________________Vital to always note what ï¿½still evolvingï¿½ and ï¿½beginsï¿½ mean when we are discussing these mechanisms to kepp them in their proper perspective.I found this interesting as I remember this study being around here somewhere: __________________________________________________ï¿½ï¿½One of the best studies looking at this is a study that looked at auditory stress and showed that an unpleasant external stressor, a noise in this case, altered both the perceptual and emotional rating that you experience in response to a visceral stimulusï¿½.ï¿½ ____________________________________________________here ï¿½tisig Dis Sci 2000 Jun;45(6):1160-5Intestinal reactivity to words with emotional content and brain information processing in irritable bowel syndrome.Blomhoff S, Spetalen S, Jacobsen MB, Vatn M, Malt UF.Department of Psychosomatic and Behavioural Medicine, National Hospital, Oslo, Norway.The intestinal reactivity to emotional experiences is poorly understood. We therefore compared healthy controls with nonpsychiatric irritable bowel syndrome (IBS) patients and IBS patients with comorbid phobic anxiety disorders with respect to rectal wall reactivity during exposure to everyday words with emotional content. We found that 70.3% of the subjects responded either with increased or decreased rectal tone during exposure to anger words, 75.0% when exposed to sadness words, and 76.6% when exposed to anxiety words. We also investigated event-related potentials in the brain to the same stimuli. We observed significant group differences in the frontal brain to sadness (P less than 0.001) and anxiety P = 0.013 distracter words, and threshold significant group difference to anger (P = 0.053) distracter words. Rectal wall reactivity during the word series significantly predicted frontal amplitude to the same word series, indicating a close interaction among mind, brain, and gut. ___________________________________________________________What of course is missing is the ability to draw any new conclusions from that which are not already known about ï¿½mind-body physiologyï¿½. What would be interesting to do would be to perform blood chemistry assays on known selected mediators of various types to find if there is a smoking gun in thereï¿½I suspect based on the wide range of findings from elsewhere that there is a whole battalion.Oh now we go to the place that is mist thinï¿½ ______________________________________________ï¿½ï¿½When we look at the other dimension, enteric factors, many patients tell us that certain foods will produce symptoms. It is difficult to determine whether this is a pharmacological, a chemical, or even an immune mechanismï¿½.ï¿½ _________________________________________________It may be difficult but it has been done many times and continues to be done via jejunal isolation and challenge. The trouble is it is not done much over here I think as it is not an area of abiding interest. As I pointed out earlier, when it has been done on patients who present with symptoms of IBS provoked by foods (other than the obvious pseudoallergy) and in whom no food allergy is present it has been a simple matter to quantify abnormal humoral and cell-mediated responses to everything from milk antigens to meats to fruits to vegetables including a waide array with no endogenous chemical basis for these reactions. Hence the Merck manual authors stating themselves, with clarity, that there are confirmed mechanisms and a population of the following: ____________________________________________________ï¿½Page 1051 of the hard copy of the 17th edition of the Merck Manual, and online Merck Manual at http://www.merck.com/pubs/mmanual/section1...ter148/148b.htm "Recently Food Intolerance was found to be responsible for symptoms of some patients with the IRRITABLE BOWEL SYNDROME, confirmed by double-blind food challenge.An increase in rectal prostaglandin levels was noted when a reaction occurred.Preliminary information suggests the same phenomenon may take place in patients with chronic ulcerative colitis.ï¿½Further on, the section on post-infectious IBS symptoms speaks for itdelf as this is one potential predictor with the caveat that recently it was confirmed that there are plenty of patients who had IBS prior to the enteric infection so investigators need to be careful to exclude those from any population before study. __________________________________________ï¿½There is increasing awareness that in the substantial group of patients, although the proportion remains to be determined, infectious events seem to lead to the subsequent development of IBSï¿½.etc.ï¿½ ___________________________________________Am J Gastroenterol 2003 Feb;98(2):327-31Is irritable bowel syndrome more common in patients presenting with bacterial gastroenteritis? A community-based, case-control study.Parry SD, Stansfield R, Jelley D, Gregory W, Phillips E, Barton JR, Welfare MR.Northumbria Division, University of Newcastle Faculty of Medicine, North Tyneside Hospital, Rake Lane, North Shields, United KingdomIrritable bowel syndrome (IBS) has been reported to follow infectious diarrhea. Food-borne infections affect 76 million people in the United States and 9.4 million in England per year; of these, only a small percentage of patients see their doctor, and even fewer will have stool culture confirmation. We hypothesized that patients who present to their doctor with gastroenteritis and have positive stool samples may be different from the normal population with regard to their pre-existing bowel symptoms. Our aim was to determine if patients with bacterial gastroenteritis were more likely to have prior IBS, functional dyspepsia, or functional diarrhea, compared with a control population.Between January, 2000 and January, 2001, subjects with stool positive bacterial gastroenteritis and control subjects from the same primary care practice were invited to participate. The main outcome measure was the presence of IBS, functional dyspepsia, or functional diarrhea diagnosed using self-report Rome II modular questionnaires.A total of 217 people with recent bacterial gastroenteritis and 265 community controls consented to participate in the study. Of these, 89/217 cases and 46/265 controls had one of the functional GI disorders OR = 3.3; 95% CI = 2.17-5.00. IBS was present in 67 cases (31%) and 26 controls 10% OR = 4.1; 95% CI = 2.49-6.72. There was no statistically significant difference in the presence of prior functional dyspepsia or functional diarrhea. IBS is more frequent before diagnosis in people with bacterial gastroenteritis presenting to their primary care physician than in community controls. Studies that examine the rate of IBS after bacterial gastroenteritis need to carefully exclude people with prior IBS in a systematic way. ____________________________________________________Makes one wonder if enteric infection is a predictor of IBS, or is IBS predispose people to enteric infection?You know thatï¿½s the thing about dataï¿½its like an Al-Queda member: if you torture it enough it will say anything.Sort of like some of this stuffï¿½ ____________________________________ï¿½ï¿½In postinfectious IBS patients, there is accelerated gut transit in many patients, increased visceral sensitivity, and evidence for alteration of intestinal permeability, something very relevant to chronic diarrhea in these patients. _________________________________________Well there damn well should be if you look at what locally released proinflammatory mediators do to smooth muscles and to the various nerves of the myenteric plexus, and to gut wall permability and the possible transient loss of ral tolerance which can result from macromoleculr migration from the lumen. __________________________________________ï¿½There's clear evidence in many patients of increased presence of enterochromaffin EC cells in the colon. Therefore, there is the possibility of increased release of serotonin 5-HT in these patients."ï¿½ï¿½ ___________________________________________Of course there is. And for 10 years so far there has also been repeat evidence of increased mast cell density as well, mast cell activation , and in the last 5 years lymphocytic aggregates at the root ganglia within the myenteric plexus and the ability to recover their various rpeformed and synthesized mediators from the jejunal washings after jejunal challenge.So it is necessary to not only examine 5HT but the other 100 mediators as well when considering the symptomology and altered gut motility and visceral perception. Otherwise we are looking at it through the wrong end of the telescope. ____________________________________________ï¿½ï¿½Serotonin is involved at just about every level of the communication between gut and brain, both going from gut to brain and then from brain to gut. One appealing therapeutic avenue is to focus on the site where most of the 5-HT is being released and try to affect outcome and symptoms by modulating symptoms at the level of the gut trying to avoid the possible side effects that may come with more central modulation of serotoninergic pathways." _______________________________________This elucidates the basis for the focus on 5HT and 5HT[x] receptors, at times to the exclusion of all other mediators which are know to affect the brain-gut and HPA axis and all points in between: it is one of the ï¿½universal mediatorsï¿½ï¿½so you have a greater chance of developing new drug therapies with wide-ranging impact by focusing in on this one mechanism . That does not denote automatically that the phenomenon of IBS is based upon some root causal pathology of primary dysfunction of serotoninï¿½this may be one primary mechanism some of the time and other times it may be a consequential event with its own impact. For example, it is sometimes too easy to make a leap of faith based on looking at a sinlge parameter in a relative vacuum, without checking other concommittant parameters _________________________________________ï¿½ï¿½"Slide 19. Plasma 5-HT Levels in IBS vs Controlsï¿½We know that 5-HT release is actually increased in IBS patients with the diarrhea-dominant component, suggesting that, again, 5-HT may play a role in subsets of patients with IBS."..ï¿½ _________________________________________I recall that sometimes much is made of this finding, as if it implicates a fundamental 5HT dysfunctional basis for diarrheic IBS. To do so you must disregard a whole host of other findings and biochemical mediators implicated in various diarrheic IBS patients.One also has to consider the compartments wherein 5HT is stored or transported and either released or synthesized from in response to what stimuli as part of what various mechanisms.For example, increased plasma serotonin concentrations are also seen and reproducible in asthmatics after antigen challenge and the onset of symptoms, whereas it does not occur in non-asthmatic controls and levels are normal when the asthmatic is asymptomatic.(Annals of Allergy, Asthma and Immunology, Vol. 77, Sept. 1996 ï¿½Increased Levels of Free Serotonin in Plasma of Symptomatic Asthma Patientsï¿½)Platelets transport about 90% of the 5HT that is carried in the blood at any time, and increased plasma concentrations are often associated with platelet reaction (platelet aggregation). Considering the many parallels between the pulmonary immune response and structure, GI immune response and structure, and asthma comorbidity with IBS one needs to not be too hasty to form a conclusion about the mechanisms involved as a platelet reaction as a consequence of antigen presentation in the small bowel (depending upon which type of reaction occurs, mediators which will elicit platelet response my be liberated) is one of the possible mechanisms which needs to be ruled out by further more careful study of the finding.Sometimes we can behave a bit like an alien seeing a Kentucky Fried Chicken store for the first time. What is that? The door is locked and he cannot get inside. So he sees people throwing things in the dumpster out back. Quickly examining the dumpster he findsï¿½garbage. Conclusion? This is a place which manufactures garbage!!! _________________________________________________This is very important as it makes a pijt very clearly between assuming pathogenesis versus pursuit of therapeutic targets: ______________________________________________ï¿½ï¿½"Slide 20. Serotonin and EC Cells in Altered GI Motilityï¿½This may be further demonstrated in the sense that there is increased circulating 5-HT in patients with diarrhea-dominant IBS and increased EC cell population in the gut, ï¿½ï¿½ ________________________________________________Along with a whole bunch of other biochemical things going on which may account for symptoms, 5HT levels observed, or both, found in different patients by different people at different times by different means but apparently the same clinical prsentationï¿½it goes onï¿½ ________________________________________________ï¿½ï¿½whereas in some subgroup of patients with chronic constipation, there appears to be a decreased number of EC cells suggesting that, if we stimulate serotoninergic pathways, we might be able to improve symptoms in these patients."ï¿½ï¿½ _________


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## eric (Jul 8, 1999)

"G.W. Thompson forecast in 1985: ï¿½the IBS is organic; that is all sufferers will eventually be found to have measurable, unique pathologic defects."G W Thompson CMAJ 1999" Neither psychological nor specific dietary factors cause IBS, but both can trigger symptoms."Recommendations for the management of irritable bowel syndrome in family practice. IBS Consensus Conference Participants.Paterson WG, Thompson WG, Vanner SJ, Faloon TR, Rosser WW, Birtwhistle RW, Morse JL, Touzel TA.Department of Medicine, Queen's University, Kingston, Ont.To help family physicians manage patients with irritable bowel syndrome IBS, a consensus conference was convened in June 1997 at which 5 internationally recognized experts in IBS presented position papers on selected topics previously circulated to the conference participants. Five working groups comprising family physicians, gastroenterologists and allied health care professionals from across Canada were then charged with developing recommendations for the diagnosis, patient education, psychosocial management, dietary advice and pharmacotherapy, respectively. An evidence-based approach was used where possible; otherwise, recommendations were made by consensus. The participants concluded that family physicians can make a positive diagnosis of IBS using symptom criteria. The pathophysiology is poorly understood, but motility and sensory disturbances appear to play a role. Neither psychological nor specific dietary factors cause IBS, but both can trigger symptoms. Drug therapy is not recommended for the routine treatment of IBS, but short-term trials of drug therapy may be targeted to predominant symptoms in selected patients. A step-wise, patient-centred approach to management is outlined.Publication Types: * Review * Review, TutorialMeSH Terms: * Colonic Diseases, Functional/therapy* * Colonic Diseases, Functional/psychology * Colonic Diseases, Functional/drug therapy * Colonic Diseases, Functional/diagnosis* * Consensus Development Conferences * Decision Trees * Diagnosis, Differential * Family Practice * Human * Primary Health Care * Support, Non-U.S. Gov'tPMID: 10439825


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## Mike NoLomotil (Jun 6, 2000)

Curious post # 6,000,001: ___________________________________________"" Neither psychological nor specific dietary factors cause IBS, but both can trigger symptoms." _____________________________________It makes it so easy when someone repeats the very point I make over and over for me. Saves a lot of time. Yes this is indeed the point...cause is pathogenesis, which must be differentiated from the mechanisms of symptom generation which are a consequence of the pathogenesis of a disease. food intolerance and stress response mechanisms are the practical mechanisms of the clinical presentation of the IBS patient: symptom generating mechanisms upon which to base effective prophylactic treatment.In the case of the mixed IBS population, various and multitudinous mechanisms of food or chemcial intolerance and sensisitiviy are mechanisms by which symptoms can be generated. Since we can quantifiy and isolate what those mechanisms are, and what provokes them, we can treat the patient and provide relief with patient-specific dietary therapy.Likewise with pscyhological factors...there are both behavioral and clear biochemical pathways to the end result of symptome generation in IBS, and there are treatments which can blunt symptoms generated by those mecahnisms which are behavioral in nature.The combination of these two approaches dimisnishes or eliminates the need for pharmacotherapy in the affecte population.When research has indeed reached the point that each specific pathologic process which can lead to the development of the dysfunctions clinically presenting as the heterogeneous "IBS" have each be discovered, then each disease will have been isolated and slowly but surely the present multipopulational IBS population will diminish.Nothing discovered by anyone in the last 15 years so far has yet altered the validity of that proposition.Hey, very good, you are cathcing on ton what integrated disease managment means since you posted an article about an integrative patient-specific disease managment apraoch to IBS...that which the physicians Iw ork with and myself are vocal proactive advocates of!! _____________________________________" step-wise, patient-centred approach to management is outlined." ____________________________________Yes indeed, and that appproach as acknowledged by that group as well as every group of note includespatient specific dietary therapybehavioral adjunctive therapypharmacotherapy PRN.Again, no debate when you get down to how tot reat the matient to be as effective as possible. And the MORE patient specific you can make it the better the outcome!end of story







MNL


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## eric (Jul 8, 1999)

GastroenterologyThe ï¿½organificationï¿½ of functional GI disorders: Implications for researchI recently attended an international meeting that focused on potential new mechanisms to help understand the functional gastrointestinal GI disorders. It was exciting to hear experts address new concepts on how: 1 mucosal inflammation could alter neurotransmitter, ion channel, or nerve growth factor activity and early gene expression, all of which might influence motility and visceral sensation; 2 distention of in series tension-sensitive mechanoreceptors in the proximal gastric fundus may lead to dyspeptic symptoms; 3 animal models now exist to show that chemical stimulation of gut mucosa alters visceral sensitivity, and can even be modified via descending input from higher brain centers; and 4 early genetic studies suggest that 5HT or G-protein receptor polymorphisms may help explain the variability in the clinical expression of irritable bowel syndrome IBS or in the response to pharmacological agents. The organizers are to be congratulated for their foresight, almost 4 years ago, to plan the topics for this meeting. There is little question that some important scientific advances have recently occurred that may lead to greater understanding of the basic mechanisms underlying these disorders, and this is likely to improve treatment.But is this enough? At this meeting, I also heard comments such as: ï¿½At last we have ï¿½organifiedï¿½ IBS,ï¿½ ï¿½Now that we have an animal model, we can find a cure,ï¿½ and ï¿½Surely it will now be easier to get research funding.ï¿½ Implicit in these statements is an assumption that knowledge of the basic mechanisms underlying neuroenteric reactivity or symptom generation is all that is needed to understand our patients with functional GI disorders. At a deeper level, I believe that there is a shared and perhaps desperate concern that unless we ï¿½legitimizeï¿½ research in the functional GI disorders by further prioritizing basic and translational research, we will not be able to ï¿½cureï¿½ the patients, nor will investigators not involved in basic research be acknowledged for their scientific accomplishments or be funded. While all of this may be true, I believe the logic is misdirected.The beliefs leading to these statements are intrinsic to the mores of modern Western science, although they are not necessarily held in other cultures, or even in Western society prior to a few hundred years ago. These beliefs were most influenced through the writings of Descartes and relate to the concept of biomedical reductionism.1 This concept holds that disease i.e., structural or functional abnormalities of tissues and organs and illness i.e., the patients perception of ill health are understood in terms of linear causality. In other words, the existence of an etiological factor e.g., an altered gene, or an infection is both necessary and sufficient to explain disease, and the disease is necessary and sufficient to explain illness.Although the reader may tacitly accept this concept as valid, it is in fact only a theory that has so permeated our scientific establishment that it seems unthinkable to be challenged. However, while biomedical investigation is of great value in explaining the basic mechanisms of disease, it is not a practical means to understand human illness. Most clinical symptoms that patients bring to physicians are not explained by specific diseases.2 Furthermore, medical disease, when present, exhibits immense variability in its clinical expression across individuals so afflicted. Persons with inflammatory bowel or acid peptic disease may vary from having none to severe symptoms, given the same degree of disease localization and activity, and successful treatment of the disease may still be associated with retention of symptoms. This can often be explained by alterations in peripheral or central regulatory mechanisms that influence perception of visceral afferent signals. Interestingly, one important concept that emerged from this meeting is that the functional GI disorders now designated by the ROME committees as disorders of GI function are not diseases per se, but rather are clusters of symptoms i.e., illnesses that result from a complex interplay of peripheral, central, and environmental factors interacting on the brain-gut axis, and they do so to different degrees across individuals and even for the same individual over time.Thus, as perhaps most clinicians know, it is not likely that an altered gene or set of specific biological etiologies will explain these complex human disorders, let alone their treatments. Furthermore, if there were major breakthroughs in basic or translational research, their clinical application may take years, if not decades, to bear relevancy. There are major health care needs that need to be addressed now. For the moment, the clinician must appraise, within a clinical context, the degree to which any of several physiological determinants e.g., visceral hypersensitivity, dysmotility, postinfectious inflammation, psychosocial factors, or any combination explain the clinical presentation, and this will determine the proper set of treatments.So if knowledge of the basic mechanisms of GI motor and neuroenteric function is not sufficient to explain the complexity of these human illnesses and does not currently meet the needs of clinicians or their patients, what else can be done? What is also needed is good clinical research that seeks to understand the biopsychosocial interactions affecting the illness experience and health behaviors of our patients, and applies this information in treatment. This would include:1 research on the biological and physiological gut and brain influences on symptom experience and behavior and the factors that modulate these outcomes; 2 the study of coping and adaptation to chronic illness, outcome, and health services research to help physicians identify more efficient and economic treatment methods for patients; 3 clinical trials of pharmaceutical and behavioral treatments to reduce symptoms and improve quality of life; 4 research on educational methods to help health care providers become more efficient, compassionate, and knowledgeable about their patients; and 5 helping patients find the ways to help themselves.Finally, we must demonstrate that human investigational research is equal in its relevancy and legitimacy to basic science research, and needs to be treated as such. The key is through the application of sound and rigorous scientific methodology. One way to accomplish this is to increase the exposure of well-designed clinical studies, which can serve as templates for young investigators looking toward careers in clinical investigation. With Dr. David Brenner's leadership as editor of GASTROENTEROLOGY since 2001, the journal has been proactive in encouraging the publication of scientifically rigorous clinical studies. Furthermore, the launching of the new AGA journal Clinical Gastroenterology and Hepatology edited by Dr. Michael Camillieri will provide an additional access point for such publications. We are hopeful that in the future, a partnership will exist between basic and clinical investigation such that both will be meeting the needs of our patients and will be receiving equal recognition and support. References TOP 1. Drossman DA. Presidential address: gastrointestinal illness and biopsychosocial model. Psychosom Med 1998;60:258ï¿½267. 2. Kroenke K, Mangelsdorff AD. Common symptoms in ambulatory care: incidence, evaluation, therapy, and outcome. Am J Med 1989;86:262ï¿½266.MEDLINESo you know they have recently reclassified these conditions."disorders of GI function" instead of functional GI disorders."Interestingly, one important concept that emerged from this meeting is that the functional GI disorders now designated by the ROME committees as disorders of GI function are not diseases per se, but rather are clusters of symptoms (i.e., illnesses that result from a complex interplay of peripheral, central, and environmental factors interacting on the brain-gut axis, and they do so to different degrees across individuals and even for the same individual over time. " http://www2.us.elsevierhealth.com/scripts/...16508503500105&


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## kel1059 (Feb 28, 2003)

Eric,I am convinced that you do not understand nor do you have the intelligence to understand the material that you are posting.Concerning Heather's cookbook -- you must be joking. If i ate the things that she is recommending, I be on the floor in pain instead of healthy like I was as a teenager.Heather's information works for some people but not all, and her ideas on sugar being healthy are from a different solar system.


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## Mike NoLomotil (Jun 6, 2000)

Intriguing spin-doctoring of the normal transitory processes involved in discovery of pathogenesis of disease states: ________________________""disorders of GI function" instead of functional GI disorders." ______________________So far so good, as this draws the distinction that clinicians and researchers studying the symptom-sets (note the continued use of this phraseology over a period of years...symptom-sets) have been trying to set forth: the symptoms have an organic basis...the only reason symptom-sets are ever classified as "functional" is because the causal basis is a yet undiscovered. The assignation of this term is always transitory throughout the history of evolution of understanding of the human organism.There exists at this very moment, before the very eyes of the world patient population, the exquisitely perfect example of a SYMPTOM SET which has emerged without an OBVIOUS CAUSAL BASIS for which the entire world medical community is frantically seeking the causal basis SARS!!! [Sever Acute respiratory Syndrome]. The main difference, which accelerates the process, is thata. it is at times fatal, and IBS is not, so there is some added motivation andb. it is clearly infectious...which makes it easier to isolate an investigatory line, wheras so called IBS symptom sets are clearly multi-symptom dysfunctions with multiple possible precursor eventsSo now, as some early and diverse signs of organic basis for the symptom-sets begin to become so obvious as to no longer be ignored, we have the following transitory position statement, which is also not revolutionary, rather characteristic of the evolutionary nature of advancement of understanding: __________________________"Interestingly, one important concept that emerged from this meeting is that the functional GI disorders now designated by the ROME committees as disorders of GI function are not diseases per se, but rather are clusters of symptoms (i.e., illnesses that result from a complex interplay of peripheral, central, and environmental factors interacting on the brain-gut axis, and they do so to different degrees across individuals and even for the same individual over time. " _____________________________Again, a reflection of this particular transitory stage of the evolutionary process. So far it is still not clear what the underlying disease processes are which are associated with the different symptom sets...so they are characterized exactly as they appear at this stage: "illnesses that result from a complex interplay of peripheral, central, and environmental factors interacting on the brain-gut axis, and they do so to different degrees across individuals and even for the same individual over time"An accurate clinical description of what the manifestations are as they are so far understood.The plus-side is that enough of the mechanisms of symptom generation are understood such that physicians can develop programs which integrate therapies which are proven effective at symptom reduction, or even remission, in a large portion of the populationdietary, behavioral, and pharmacotherapies.MNLPSKels observations regarding standardized diets for IBS are apt, as one must always remember the fact of the matter is that there is no such thing as THE IBS diet....dietary approaches range widely, from the oligoantigenic diets evolved from elimination-challenge protocols, through diets in books which are based upon an understanding of probabilities of ood tolerance.Each has its place and each is effective to some degree, which varies widely from patient to patient. But the longer one ignores the reality that "one mans' meat is anothers poison" in the large population in particular of IBS victims with diarrheic symptoms, the less serviece one does for ones patients.Most authors of dietary therapy protocols understand this, and qualify their recommendations accordingly. Some people do not understand dietary therapy for IBS nor how to create patient specificity. Such is the world...no one person can be expert in all things. So it is advisable to stick to that which we each know.


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## eric (Jul 8, 1999)

kel, thanks for the nice comments. You don't know me or do you have a clue of who I am or what I know."I am convinced that you do not understand nor do you have the intelligence to understand the material that you are posting."The Brain Gut Axis"Symptoms in IBS occur either because of abnormalities of intestinal motility or because of abnormalities of sensation - or through a combination of the two.It is easy therefore to imagine how violent contractions or spasm of muscle surrounding the intestines can give rise to pain.In normal people, distension of the gut will trigger nerve fibres lining the gut to transmit signals to higher centres in the brain that register pain. In IBS sufferers, it has been proved that pain is perceived at much lower levels of distension. This is known as the 'hypersensitive gut' or in scientific terms visceral hyperalgesia. It follows that abnormal motility or contractility of the intestines will lead to areas of distension that will react because of the hypersensitive gut and register the sensation of pain in the higher centres of the brainA variety of features that affect function of the central nervous system or brain have now been shown to affect, by virtue of the connections of the brain gut axis, the events described above at the 'end organ' level. I.e. in the intestines." http://www.ibs-research-update.org.uk/IBS/brain1ie4.html


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## Mike NoLomotil (Jun 6, 2000)

"kel, thanks for the nice comments. You don't know me or do you have a clue of who I am or what I know." __________________________







that happens alot around here.MNL


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## Guest (Apr 4, 2003)

Hi all,I felt the need to post what I know.About a year ago when I first came to this board, I was in a lot of deep distress.... much of it due to denial. I was sick, frustrated, angry and I took it out on Eric.Since then, I've learned that what he was telling me all along ..... was the absolute truth. And the proof has been in the significant healing that I have experienced in the last few months... mostly due to the introduction of clinical IBS-specific hypnotherapy. This therapy has had such a monumentally favorable effect on my IBS and my behavioral health that it has exceeded my wildest dreams!!My one remaining problem of Gas... is easily remedied with some simple dietary alternations such as reducing simple sugar intake and high fat foods or excessive animal protein.I owe Eric a great deal for sticking with me even after I went for his throat. He has helped me, supported me, and guided me into a type of wellbeing that I never thought existed for me. I still struggle with multiple health challenges, but I have learned that the single most important factor in healing virtually all health challenges... lies in our thoughts... which in turn invoke emotions...... and thereby exert control over our bodily functions and our good health.I owe Eric my present sense of wellbeing. And if more of us were to learn to be kinder to each other... more of us might also begin to experience healing of the systemic kind.Trust me.... I, of all persons, understand the impact that our behavioral health can have on our bodies.... and further... that our attention to our *spiritual health will, in the end, either make or break us.So in the *Spirit of good faith..... let's please start to look more WITHIN for the answers... instead of pointing fingers.Regards, Evie


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## eric (Jul 8, 1999)

Thanks Evie, glad I could help.







FYIClinical ResearchActivation of the mucosal immune system in irritable bowel syndrome Abstract Background & Aims: A role for the mucosal immune system in the pathogenesis of irritable bowel syndrome is suggested by its association with intestinal infections.Methods: To investigate this, we performed histologic and immunohistologic studies on colonoscopic biopsy specimens from 77 patients with symptoms satisfying the Rome criteria and 28 asymptomatic control patients.Results: Histologic assessment of biopsy specimens from symptomatic patients indicated 3 different groups. The first 38 of 77 had normal conventional histology; however, immunohistology showed increased intraepithelial lymphocytes median, 1.8-fold; range, 1.74ï¿½1.86, lamina propria CD3+ cells 2-fold; range, 1.55ï¿½2.91, and CD25+ cells 6.5-fold; range, 4.98ï¿½8.13 compared with asymptomatic controls. The second group 31 of 77 had nonspecific microscopic inflammation and on immunohistology showed similar increases in lymphocyte populations not significant vs. the uninflamed group as well as increased numbers of neutrophil leukocytes and mast cells P < 0.0001 vs. controls and the uninflamed group. The third group 8 of 77 fulfilled histologic and immunohistologic criteria for classic lymphocytic colitis.Conclusions: Examination of colonoscopic biopsy specimens from patients meeting the Rome criteria for a clinical diagnosis of irritable bowel syndrome showed subgroups with normal and abnormal conventional histology. All groups showed increased numbers of activated immunocompetent cells in the intestinal mucosa on quantitative immunohistology, implicating the mucosal immune system in pathogenesis. * *Wakefield Gastroenterology Centre and Research Institute, Wakefield Hospital; and ï¿½Medical Laboratory Wellington, Wellington, New Zealand * Received July 12, 2001. * Accepted February 14, 2002. * GASTROENTEROLOGY 2002;122:1778-1783 * Address requests for reprints to: Vinton S. Chadwick, M.D., Wakefield Gastroenterology Centre and Research Institute, Wakefield Hospital, Private Bag 7909, Rintoul Street, Wellington 6002, New Zealand. e-mail: vchadwick###clear.net.nz ; fax: 64 4-381-8111. * Supported by the Health Research Council of New Zealand. * Articles with References to this Article TOP This article is referenced by these articles:Immune activation in irritable bowel syndrome: Wrong title or wrong disease? Part 2GastroenterologyApril 2003 ï¿½ Volume 124 ï¿½ Number 4ReplyGastroenterologyApril 2003 ï¿½ Volume 124 ï¿½ Number 4FULL TEXTNeuropathology of IBS?GastroenterologyDecember 2002 ï¿½ Volume 123 ï¿½ Number 6Robin C. SpillerFULL TEXTA case for an immunological basis for irritable bowel syndromeGastroenterologyJune 2002 ï¿½ Volume 122 ï¿½ Number 7Stephen M. CollinsImmune activation in irritable bowel syndrome: Wrong title or wrong disease? Part 2 ï¿½ Related articles in PubMedDear Sir:Chadwick et al.,1 in a very interesting paper entitled ï¿½Activation of the mucosal immune system in irritable bowel syndromeï¿½ published in the June 2002 issue of GASTROENTEROLOGY, described increased number of activated immunocompetent cells in the colonic mucosa of patients meeting the Rome criteria for clinical diagnosis of IBS.As reported by the authors, ï¿½microscopic inflammation sufficient to describe as microscopic colitis was reported by our pathologists in 50% of samples.ï¿½ We recognize that microscopic colitis may still be a confounding issue of uncertain significance,2 but we believe that these patients with histological abnormalities diagnostic of microscopic colitis should not be classified as IBS. According to the authors, the message from the paper would be maintained; we are very happy of this, although it is difficult to separate both populations in the report. As discussed, in the editorial by Collins,3 this paper is important to support the immunological basis for IBS, but I believe that for research purposes where clear identification of patient subgroups is a key target, as well as for clinical purposes are steroids used for treatment of lBS patients? patients with microscopic colitis should not be called IBS.We had similar comments4 regarding another paper published recently in GASTROENTEROLOGY5 where celiac disease markers were found in patients with diarrhea of unknown origin. Diagnostic criteria for IBS are applicable ï¿½in the absence of structural or metabolic abnormalities to explain the symptoms.ï¿½6 Patients suspected of IBS where the investigation identifies lesions diagnostic of microscopic colitis, celiac diseases, as well as other conditions such as IBD for example, are not IBS patients anymore. Although they could indeed suffer concomitantly from functional, as well as lesional disorders.doi:10.1053/gast.2003.50195Pierre PoitrasHï¿½pital Saint-Luc du CHUM, Montrï¿½al, CanadaReferences 1. Chadwick VS, Chen W, Chu D, Paulus B, Bethwaite P, Tie A, Wilson I. Activation of the mucosal immune system in irritable bowel syndrome. Gastroenterology 2002;122:1778-1783. 2. Blumberg D, Wald A. Other diseases of the colon and rectum. In: Feldman M, Friedman LS, Sleisenger MH, eds. Sleisenger and Fordtran's Gastrointestinal and liver diseases. Philadelphia, PA: Saunders, 2002:2294-2318. 3. Collins SM. A case for immunological basis for irritable bowel syndrome. Gastroenterology 2002;122:2078-2079. MEDLINE FULL TEXT 4. Poitras P. Celiac disease-like abnormalities in IBS: wrong title or wrong disease? letter Gastroenterology 2002;123:954. 5. Wahnschaffe U, Ullrich R, Riecken EO, Schulzke JD. Celiac disease-like abnormalities in a subgroup of patients with irritable bowel syndrome. Gastroenterology 2001;121:1329-1338. MEDLINE ABSTRACT FULL TEXT 6. Thompson WG, Longstreth G, Drossman DA, Heaton K, Irvine EJ, Muller-Lissner S. Functional bowel disorders and functional abdominal pain. In: Drossman DA, et al., eds. Rome II. The functional gastrointestinal disorders, 2nd ed. McLean, Virginia: Degnon Associates, 2000:351-432.In his response to our paper entitled ï¿½Activation of the mucosal immune system in irritable bowel syndromeï¿½ in the June 2002 issue of GASTROENTEROLOGY,1 Dr. Poitras argues that patients with symptoms meeting the Rome Criteria for IBS, who are subsequently shown to have microscopic histologic abnormalities in colonoscopic biopsies should not be classified as IBS. He wishes us to draw a clear line between what he calls ï¿½functionalï¿½ and ï¿½lesionalï¿½ disorders.For patients with normal endoscopic appearances, but biopsies that show granulomatous, eosinophilic, collagenous, or lymphocytic microscopic colitis, reclassification is obviously appropriate. Patients with nonspecific microscopic colitis could also be reclassified, although they are indistinguishable in terms of demographics, symptoms, and disease duration from patients whose biopsies show no obvious inflammatory changes. Poitras is happy to accept that this last group those with normal conventional histology have IBS, but in doing so he ignores or fails to address the immunohistologic abnormalities in this group, which include increased IELs, lamina propria CD3+ and CD25+ cells as detailed in the paper. Does Poitras regard histologic abnormalities as ï¿½lesionalï¿½ and immunohistologic abnormalities as ï¿½nonlesionalï¿½ or ï¿½functionalï¿½?If immunohistologic abnormalities are ï¿½lesionalï¿½ and IBS patients cannot have lesions, then few if any of the patients in our study group meet the Poitras' criteria for IBS. IBS then becomes a very rare, rather than a very common disorder. Furthermore, we are left without a suitable diagnostic category for the majority of patients with symptoms meeting the Rome criteria.While we are sympathetic to Poitras' call for accurate patient subgroup classification for research purposes, his ï¿½wrong title or wrong diseaseï¿½ descriptor for our paper does not really advance this issue.doi:10.1053/gast.2003.50196Vinton S. ChadwickWangxue ChenDairu ShuBarbara PaulusIan WilsonWakefield Gastroenterology Centre and Research Institute, Gastroenterology/Research, Wellington, New ZealandPeter BethwaiteAndy TieMedical Laboratory Wellington, Wellington, New ZealandReferences1. Chadwick VS, Chen W, Chu D, Paulus B, Bethwaoite P, Tie A, Wilson I. Activation of the mucosal immune system in irritable bowel syndrome. Gastroenterology 2002;122:1778-1783.EditorialsNeuropathology of IBS?Robin C. Spiller Sections See article on page 1972.The irritable bowel syndrome IBS is currently diagnosed on the basis of a characteristic cluster of symptoms in the absence of objective abnormalities of structure. This lack of objective measures has considerably hampered further understanding of IBS because it forces us to lump together patients whose widely differing symptoms suggest differing underlying pathologies. Several investigators have attempted to develop more objective tests by which to categorize patients, including measurement of intestinal transit,1,2 colonic,3,4 and small bowl motility,5,6 as well as threshold for discomfort during rectal balloon distention.7 Although differences have been shown between IBS patients and healthy controls, these tests have not been adopted into routine practice because they are either poorly reproducible or impractical.By contrast, psychological measures of anxiety, hypochondriasis, and concern about the meaning of symptoms are easy to use and have shown much greater consistency since, with a nonfatal condition like IBS, they are the main determinants of whether an individual with symptoms ever sees a doctor. This has led to the perception that psychological factors predominate, when in reality it simply reflects the crudeness of the tools we have available to detect other factors such as disorders of the enteric nervous system.The study in the current issue of GASTROENTEROLOGY by Tornblom et al.8 is a valiant attempt to redress this imbalance. The study is somewhat audacious in obtaining full-thickness small bowel biopsy specimens in 10 cases of disabling IBS. Patients had already undergone a full work up including small intestinal manometry with inconclusive results. The biopsy specimen provided the unique opportunity to examine changes in the myenteric plexus, an area inaccessible to mucosal biopsy, yet critical to controlling small bowel motility. Three of these IBS patients were diarrhea-predominant, 2 of which had a clear postinfectious onset of their symptoms; the remainder were described as having alternating 5 or constipated 2 bowel habit.The main findings were that all patients had some neural degeneration in the ganglia of the myenteric plexus, associated in 9 of 10 with an infiltrate of CD3-positive T lymphocytes, which were not seen in the control autopsy specimens. The authors also reported longitude muscle hypertrophy in all, although the numerical data were not provided. Four cases were reported to have increased numbers of interstitial cells of Cajal and 2 had decreased numbers focally around the myenteric plexus, but again, the numerical values are not given. Intraepithelial lymphocyte IEL counts were above their upper limit of normal 26/100 epithelial cells in 4 of 10 cases. They argue that inflammatory damage to the neural structures leads to dysmotility and secondary longitude muscle hypertrophy. The raised IELs suggested to the authors that in some subjects the inflammation was driven by luminal factors, but this was not found in 6, suggesting that even within this extreme group there remain important differences in underlying mechanisms. Plainly, it is impossible to relate the observed pathology to other factors like symptoms, concomitant drugs, or diseases because the numbers are so small. This must therefore be regarded as a pilot study that needs repeating with much larger numbers.Although undoubtedly important, we should be cautious before accepting these findings at face value. The use of autopsy controls, as a comparison for a laparoscopically obtained small bowel, raises several concerns. Although the patients studied had a mean age of 40 years range, 23ï¿½57, autopsy material might be expected to come from a much older age group, but this is not specified in the report. Older people have fewer mucosal-associated lymphocytes and a decreased response to infection, which might account for some of the differences. Furthermore, autolysis of autopsy material may well have reduced the ability to detect the subtle changes reported. A further important difference between the patients and autopsy controls is the manipulation of the small bowel through the tiny incision used in laparoscopy. Whether this could induce inflammation within the myenteric plexus is unknown, but in animals, merely handling the bowel activates macrophages within a matter of hours.9 A final issue is the wisdom of scoring the ganglia with the most lymphocytes. This introduces an unknown effect because most other studies use random sampling to ensure a fair representation of the whole tissue. Since the pathologist who scored the biopsies was blinded as to the clinical details, this would not account for the finding of a difference between IBS and controls, but it might have the effect of exaggerating any difference.If we accept the validity of the findings, then what are the implications? If some cases of severe IBS are caused by inflammatory damage to the enteric nervous system, this could arise by several mechanisms. The most common precipitant is likely to be a bacterial infection damaging the mucosa, activating the immune response, and indirectly damaging the myenteric plexus. Alternatives include direct damage by neurotropic viruses10 such as Herpes zoster, Epstein-Barr virus, cytomegalovirus, or an autoimmune attack initiated by exposure to cross-reacting antigens. Of course, inflammatory bowel disease is associated with neural damage including nerve trunk hypertrophy,11 alteration in neuropeptide profile,12,13 and receptor expression14; however, these cases are unlikely to be confused with IBS.IBS can certainly begin acutely after bacterial enteritis15,16-18 and symptoms can persist for at least 6 years.19 The changes in mucosal histology have been described in some detail20 following Campylobacter infection, which has the highest incidence of postinfectious IBS.17 An acute increase in lamina propria CD3-positive lymphocytes, IELs, and serotonin-containing enteroendocrine cells were described together with an influx of activated macrophages. Simultaneously, a decrease in neural staining with PGP9.5 was observed,21 suggesting an acute damage to mucosal nerves. These human studies used mucosal biopsy specimens and so were unable to examine changes in the myenteric plexus. However, in experimental animals, a chemically induced colitis induces infiltration of the myenteric plexus with eosinophils within 6 hours,22 whereas the mild trauma induced by rubbing the colon with a cotton wool wad activates macrophages within 3 hours.9 It also induces the production of the intracellular adhesion molecule ICAM-1, recruits circulating blood monocytes, and induces epithelial cells to produce cytokines, particularly interleukin IL-8. Inflammatory cells and altered permeability allows access of colonic bacterial products, especially endotoxin, which induces secondary responses including IL-1 production by glial cells surrounding afferent nerve terminals.23 These experimental data make it quite plausible that an acute bacterial enteritis might initiate an inflammatory response in the myenteric plexus. Why this might continue for months and years is unclear but may relate to either continued exposure to antigen or genetic differences in immunoregulation. Thus, high producers of IL-10, an anti-inflammatory cytokine, are less likely to develop IBS, suggesting that down-regulation of inflammatory response might be protective.24 This would also fit with the reduced risk of developing postinfective IBS in those aged >65 years17 in whom immune responsiveness is reduced.Autoimmune damage to peripheral and autonomic nerves25 can develop after bacterial infection if the organism has a cross-reacting antigen such as Campylobacter, whose lipopolysaccharide26 mimics the GM1 ganglioside found on peripheral nerves. Whether a lesser form of this response might explain the postinfectious IBS following Campylobacter or other infections is unknown.Viral-induced injury is of a different nature because viral gastroenteritis usually heals with little residual inflammatory injury to the gut mucosa. However, neurotropic viruses can easily enter enteric nerves without significant mucosal damage. One such virus, Herpes zoster, has been associated with damage to the myenteric plexus and the development of pseudo-obstruction in immunocompromised patients.27 Other investigators have found evidence of residual viral DNA in the myenteric plexus and lamina propria in patients with chronic idiopathic pseudo-obstruction.10 The viruses included cytomegalovirus and the Epstein-Barr virus. The latter has also been associated with an acute cholinergic dysautonomia and marked gastrointestinal dysfunction, although in this case the colonic myenteric plexus was normal.28 Cytomegalovirus infection after liver transplantation has been shown to be associated with chronic gastrointestinal symptoms, including delayed gastric emptying,29 and the same infection in an immunocompromised host has also been associated with delayed gastric emptying and disordered small bowel manometry.30Ganglionitis, or inflammation limited to the myenteric plexus as reported in the present paper,8 has been associated with pseudo-obstruction that can be paraneoplastic, autoimmune, or idiopathic in origin. The mechanism in some cases of paraneoplastic syndrome associated with small cell lung cancer appears to be a neoantigen, the Hu protein expressed in the cancer, which induces an immunological reaction antibodies and cytotoxic T cells that cross-reacts with and damages the myenteric plexus. Antineuronal antibodies cross-reacting with the Hu antigen have also been reported in autoimmune diseases such as Sjï¿½rgren's syndrome and are associated with intestinal dysmotility.31 These immunoglobulin G antibodies have been shown to passively transfer motility disturbances when injected into immunosuppressed rats.32 Similarly, antibodies cross-reacting with myenteric nerves have been observed in achalsia.33Of special relevance to the present study, chronic ganglionitis has been reported in a number of patients without cancer or autoimmune disease34-36 with severe intestinal dysmotility, 2 of whom had autoantibodies cross-reacting with the same Hu antigen.34 Three of these patients with severe pseudo-obstruction34,36 and 1 with intractable vomiting35 were responsive to immunosuppressive therapy. This chance of reversing what would otherwise be a lifelong disability makes identifying such cases potentially very important.Cases of pseudo-obstruction are unlikely to be confused with IBS, but they could represent a tip of the iceberg, and it is possible that there are many less severe cases of ganglionitis who never undergo small bowel biopsy and who are currently diagnosed as IBS.It is important to note that the histological picture may depend on when the biopsy specimen is taken. Both Smith et al.34 and Di Giorgio et al.36 found that obvious ganglionitis was replaced by a picture of aganglionosis without any evidence of the previous inflammation when the biopsy was repeated some years later. Because the IBS patients reported by Tornblom et al.8 had put up with symptoms for many years before having biopsies performed, evidence of the initiating inflammation may well have subsided, possibly accounting for the low-grade inflammation observed. This is analogous to insulin-dependent diabetes mellitus, in which the clearest evidence of inflammation, both histological and serological anti-islet antibodies, is seen early on but fades with time. Increased apoptosis is another mechanism that might account for ganglion cell loss without inflammation, and decreased expression of the antiapoptotic proto-oncogene bcl-2 has been found in some such cases,37 although the significance of this finding is unclear.The authors' idea that neurological dysfunction leads to functional obstruction and subsequent muscular hypertrophy is interesting, but equally, cytokines and growth factors induced by tissue damage may well be responsible because these changes are seen in many different models of experimental inflammation.38,39 The increase in IELs has parallels with other studies recently published.20,40 While clearly it can be a residue of previous infection,20 it could also be part of an allergic response to luminal antigen as is seen in celiac disease. Determining exactly what these cells are reacting to would be most informative.It is clear that this study is preliminary and needs repeating. Furthermore, it only considers very severe examples of IBS and may only be relevant for a tiny minority. However, it is important because it suggests that there may be a small subgroup of IBS patients who might respond to anti-inflammatory treatment. Furthermore, it adds increasing weight to the argument that in IBS, both central and peripheral components need careful consideration. Previous disappointment in attempts to show disordered gut function has led to the current emphasis on central components, particularly the emotional reaction to visceral stimuli, which are undoubtedly important. However, the pendulum may have swung too far in that direction, something the current study should help to correct. References TOP 1. Cann PA, Read NW, Brown C. Irritable bowel syndrome: relationship of disorders in the transit of a single solid meal to symptom patterns. Gut 1983;24:405ï¿½411. MEDLINE 2. Aggarwal A, Cutts TF, Abell TL, Cardoso S, Familoni B, Bremer J, Karas J. Predominant symptoms in irritable bowel syndrome correlate with specific autonomic nervous system abnormalities. Gastroenterology 1994;106:945ï¿½950. MEDLINE ABSTRACT 3. Sullivan MA, Cohen S, Snape WJJ. Colonic myoelectrical activity in irritable-bowel syndrome. Effect of eating and anticholinergics. N Engl J Med 1978;298:878ï¿½883. MEDLINE 4. Chey WY, Jin HO, Lee MH, Sun SW, Lee KY. Colonic motility abnormality in patients with irritable bowel syndrome exhibiting abdominal pain and diarrhea. Am J Gastroenterol 2001;96:1499ï¿½1506. MEDLINE 5. Kellow JE, Phillips SF, Miller LJ, Zinsmeister AR. Dysmotility of the small intestine in irritable bowel syndrome. Gut 1988;29:1236ï¿½1243. MEDLINE 6. Schmidt T, Hackelsberger N, Widmer R, Meisel C, Pfeiffer A, Kaess H. Ambulatory 24-hour jejunal motility in diarrhea-predominant irritable bowel syndrome. Scand J Gastroenterol 1996;31:581ï¿½589. MEDLINE 7. Mertz H, Naliboff B, Munakata J, Niazi N, Mayer EA. Altered rectal perception is a biological marker of patients with irritable bowel syndrome. Gastroenterology 1995;109:40ï¿½52. MEDLINE ABSTRACT 8. Tornblom H, Lindberg G, Nyberg B, Veress B. Full-thickness biopsy of the jejunum reveals inflammation and enteric neuropathy in the irritable bowel syndrome. Gastroenterology 2002;123:1972ï¿½1979. ABSTRACT FULL TEXT 9. Turler A, Moore BA, Pezzone MA, Overhaus M, Kalff JC, Bauer AJ. Colonic postoperative inflammatory ileus in the rat. Ann Surg 2002;236:56ï¿½66. MEDLINE CROSSREF 10. Debinski HS, Kamm MA, Talbot IC, Khan G, Kangro HO, Jeffries DJ. DNA viruses in the pathogenesis of sporadic chronic idiopathic intestinal pseudo-obstruction. Gut 1997;41:100ï¿½106. MEDLINE 11. Dvorak AM, Osage JE, Monahan RA, Dickersin GR. Crohn's disease: transmission electron microscopic studies. III. Target tissues. Proliferation of and injury to smooth muscle and the autonomic nervous system. Hum Pathol 1980;11:620ï¿½634. MEDLINE 12. Belai A, Boulos PB, Robson T, Burnstock G. Neurochemical coding in the small intestine of patients with Crohn's disease. Gut 1997;40:767ï¿½774. MEDLINE 13. Watanabe T, Kubota Y, Muto T. Substance P containing nerve fibers in rectal mucosa of ulcerative colitis. Dis Colon Rectum 1997;40:718ï¿½725. MEDLINE 14. Yiangou Y, Facer P, Dyer NH, Chan CL, Knowles C, Williams NS, Anand P. Vanilloid receptor 1 immunoreactivity in inflamed human bowel. Lancet 2001;357:1338ï¿½1339. MEDLINE CROSSREF 15. Caplan MS, Hedlund E, Hill N, MacKendrick W. The role of endogenous nitric oxide and platelet-activating factor in hypoxia-induced intestinal injury in rats. Gastroenterology 1994;106:346ï¿½352. MEDLINE ABSTRACT 16. Gwee KA, Graham JC, McKendrick MW, Collins SM, Marshall JS, Walters SJ, Underwood E, Read NW. Psychometric scores and persistence of irritable bowel after infectious diarrhoea. Lancet 1996;347:150ï¿½153. MEDLINE 17. Neal KR, Hebden J, Spiller R. Prevalence of gastrointestinal symptoms six months after bacterial gastroenteritis and risk factors for development of the irritable bowel syndrome: postal survey of patients. BMJ 1997;314:779ï¿½782. MEDLINE 18. Gwee KA, Leong YL, Graham C, McKendrick MW, Collins SM, Walters SJ, et al. The role of psychological and biological factors in postinfective gut dysfunction. Gut 1999;44:400ï¿½406. MEDLINE 19. Neal K, Barker L, Spiller RC. Prognosis in post infective irritable bowel syndrome: a 6 year follow up study. Gut 2002;51:410ï¿½413. MEDLINE CROSSREF 20. Spiller RC, Jenkins D, Thornley JP, Hebden JM, Wright T, Skinner M, Neal KR. Increased rectal mucosal enteroendocrine cells, T lymphocytes and increased gut permeability following acute Campylobacter enteritis and in post-dysenteric irritable bowel syndrome. Gut 2000;47:804ï¿½811. MEDLINE CROSSREF 21. Jenkins D, Thornley JP, Wright T, Skinner M, Knox KR, Neal K, Spiller RC. Enterchromaffin & mast cell hyperplasia parallels mucosal nerve damage following Campylobacter enteritis abstr. Neurogastroenterol Motil 1998;10:464. 22. Sanovic S, Lamb DP, Blennerhassett MG. Damage to the enteric nervous system in experimental colitis. Am J Pathol 1999;155:1051ï¿½1057. MEDLINE 23. Goehler LE, Gaykema RP, Nguyen KT, Lee JE, Tilders FJ, Maier SF, Watkins LR. Interleukin-1 beta in immune cells of the abdominal vagus nerve: a link between the immune and nervous systems? J Neurosci 1999;19:2799ï¿½2806. MEDLINE 24. Chan J, Gonsalkorale WM, Perrey C, Previca V, Hajeer AH, Whorwell PJ. IL-10 and TGF-B genotypes in irritable bowel syndrome: evidence to support an inflammatory component? abstr. Gastroenterology 2000;118:A184. 25. Oomes PG, Jacobs BC, Hazenberg MPH, Banffer JRJ, Van der Meche FGA. Anti-GM1 IgG antibodies and Campylobacter bacteria Guillain-Barre syndrome: evidence of molecular mimicry. Ann Neurol 1995;38:170ï¿½175. MEDLINE 26. Moran AP, Prendergast MM, Appelmelk BJ. Molecular mimicry of host structures by bacterial lipopolysaccharides and its contribution to disease. FEMS Immunol Med Microbiol 1996;16:105ï¿½115. MEDLINE 27. Welgan P, Meshkinpour H, Beeler M. Effect of anger on colon motor and myoelectric activity in irritable bowel syndrome. Gastroenterology 1988;94:1150ï¿½1156. MEDLINE ABSTRACT 28. Vassallo M, Camilleri M, Caron BL, Low PA. Gastrointestinal motor dysfunction in acquired selective cholinergic dysautonomia associated with infectious mononucleosis. Gastroenterology 1991;100:252ï¿½258. MEDLINE ABSTRACT 29. Van Thiel DH, Gavaler JS, Schade RR, Chien MC, Starzl TE. Cytomegalovirus infection and gastric emptying. Transplantation 1992;54:70ï¿½73. MEDLINE 30. Nowak TV, Goddard M, Batteiger B, Cummings OW. Evolution of acute cytomegalovirus gastritis to chronic gastrointestinal dysmotility in a nonimmunocompromised adult. Gastroenterology 1999;116:953ï¿½958. MEDLINE ABSTRACT FULL TEXT 31. Moll JW, Markusse HM, Henzen-Logmans SC, Vecht CJ. Anti-neuronal antibodies in Sjogren's syndrome and in paraneoplastic neurological disease (letter). Lancet 1994;343:1299. MEDLINE 32. Eaker EY, Kuldau JG, Verne GN, Ross SO, Sallustio JE. Myenteric neuronal antibodies in scleroderma: passive transfer evokes alterations in intestinal myoelectric activity in a rat model. J Lab Clin Med 1999;133:551ï¿½556. MEDLINE ABSTRACT FULL TEXT 33. Verne GN, Sallustio JE, Eaker EY. Anti-myenteric neuronal antibodies in patients with achalasia. A prospective study. Dig Dis Sci 1997;42:307ï¿½313. MEDLINE 34. Smith VV, Gregson N, Foggensteiner L, Neale G, Milla PJ. Acquired intestinal aganglionosis and circulating autoantibodies without neoplasia or other neural involvement. Gastroenterology 1997;112:1366ï¿½1371. MEDLINE ABSTRACT 35. De Giorgio R, Barbara G, Stanghellini V, Cogliandro RF, Arrigoni A, Santini D, Ceccarelli C, Salvioli B, Rossini FP, Corinaldesi R. Idiopathic myenteric ganglionitis underlying intractable vomiting in a young adult. Eur J Gastroenterol Hepatol 2000;12:613ï¿½616. MEDLINE 36. De Giorgio R, Barbara G, Stanghellini V, De Ponti F, Salvioli B, Tonini M, Velio P, Bassotti G, Corinaldesi R. Clinical and morphofunctional features of idiopathic myenteric ganglionitis underlying severe intestinal motor dysfunction: a study of three cases. Am J Gastroenterol 2002;97:2454ï¿½2459. MEDLINE 37. De Giorgio R, Barbara G, Stanghellini V, De Ponti F, Guerrini S, Cogliandro L, Ceccarelli A, Salvioli B, Adamo C, Cogliandro R, Tonini M, Corinaldesi R. Reduced bcl-2 expression in the enteric nervous system ENS as a marker for neural degeneration in atients with gastrointestinal motor disorders GIMD abstr. Gastroenterology 2002;118:A867. 38. Blennerhassett MG, Vignjevic P, Vermillion DL, Collins SM. Inflammation causes hyperplasia and hypertrophy in smooth muscle of rat small intestine. Am J Physiol 1992;262:G1041ï¿½G1046. MEDLINE 39. Hosseini JM, Goldhill JM, Bossone C, Pineiro-Carrero V, Shea-Donohue T. Progressive alterations in circular smooth muscle contractility in TNBS- induced colitis in rats. Neurogastroenterol Motil 1999;11:347ï¿½356. MEDLINE CROSSREF 40. Chadwick VS, Chen W, Shu D, Paulus B, Bethwaite P, Tie A, Wilson I. Activation of the mucosal immune system in irritable bowel syndrome. Gastroenterology 2002;122:1778ï¿½1783. MEDLINEEditorialsA case for an immunological basis for irritable bowel syndromeStephen M. Collins See article on page 1778.Irritable bowel syndrome IBS is a clinical descriptor rather than a diagnosis with an established underlying etiology. Definitions of IBS focus on the presence of pain and the multiplicity and chronicity of abdominal symptoms. The clinical heterogeneity of this condition has prompted its classification into symptomatically homogeneous subgroups.1,2 Congruency between these clinical subgroups and the underlying pathogeneses seems unlikely. Several pathogenetic processes have been postulated for IBS and among these is a growing body of evidence that inflammation and immune activation contribute to a least a subset of IBS patients. The article by Chadwick et al.3 is a significant contribution to this thesis.In this study, Chadwick et al.3 examine mucosa biopsies from 77 IBS patients who met Rome criteria. Of these patients, 55% were diarrhea-predominant, 31% alternated between diarrhea and constipation, and 14% were constipation-predominant. A sudden onset suggestive of an acute infective trigger was described in 36%, but the majority had an insidious onset. The mean duration of symptoms was 2.5 years with actual durations ranging from as low as 3 months to 29 years.The striking finding of this study was that almost 90% of the patients with IBS showed evidence of immune activation, regardless of the type of onset, the duration of illness, dominant symptom profile, or the presence or absence of increased cellularity of the mucosa on routine histological examination. More than half these patients had a normal mucosa biopsy appearance on routine examination and the remainder had increased cellularity of the mucosa and submucosa consistent with a diagnosis of microscopic colitis.The authors' interpretation of their findings as evidence of immune activation arises from finding higher numbers of CD25+ve cells in the IBS patient group. CD25 is a component of the IL-2 receptor and an expression of cell activation. CD25+ve cells are regulatory T cells that are considered important in the prevention of autoimmunity, as well in controlling inflammatory responses in the gut4,5; their absence in mice leads to spontaneous colitis.4 The increased presence of CD25+ve cells in IBS raises the possibility that there is auto- or exogenous antigen challenge in these patients, and that the CD25+ cells are preventing the progression to a more florid inflammatory response. One may speculate that in a subset of patients with IBS, inflammation is in check, and may, under certain conditions, progress to a clinically more relevant state of inflammation.6The finding of increased intraepithelial lymphocytes IELs, CD3+ve cells, natural killer NK, and mast cells contributes to a growing body of literature demonstrating an increased inflammatory cell presence in the colonic mucosa of certain IBS patients. This is well documented in patients with postinfective IBS in which T cell subgroups remain increased for more than a year after infection, and may reflect activation by luminal antigen because intestinal permeability is increased in these patients.7 Other studies, cited by the authors, describe an increase in the number of mast cells and macrophages in IBS patients.Although each patient experienced abdominal pain and met an earlier version of the Rome criteria, several observations prompt reconsideration of the extent to which the findings can be extrapolated to the general IBS population. First, the sample of IBS patients in a tertiary care setting is clearly subject to a referral bias. Second, the distribution of symptoms among these patients is unusual in that the majority of cases are diarrhea predominant; this subgroup is often in the minority in other IBS populations. Third, the finding of lymphocytic colitis, a rare diagnosis by most standards, in 10% of the study group raises questions about the nature of population under study. Thus, caution is urged in extrapolating these results to the general IBS population.Two recent studies have shown that latent celiac disease may present with IBS-like symptoms.8,9 From a study of 300 consecutive Rome II positive IBS patients referred to a teaching hospital, 66 patients had positive celiac serology. Of these, 14 had celiac disease compared with 2 controls.9 The authors concluded that IBS is significantly associated with celiac disease P = 0.004, odds ratio = 7.0 95% CI, 1.7ï¿½28.0. In another study, 70% of patients with diarrhea-predominant IBS-like symptoms had at least one marker of celiac disease, and 26 patients with these markers were fed a gluten-free diet for 6 months. Those patients stratified for the HLA-DQ2 genotype, or positive anti-gliadin or tissue transglutaminase antibodies in duodenal aspirate responded to the diet with a significant reduction in stool frequency. In contrast, those patients lacking these markers failed to respond.8 Although celiac disease is an unlikely explanation for the findings of Chadwick et al.,3 as a practical point, it should be remembered that increased lymphocytes are also present in colonic biopsies of patients with untreated celiac disease.10,11There is evidence that patients with postinfective IBS have increased cellularity of the lamina propria,12 increased IELs, as well as T lymphocytes.7 In the study by Chadwick et al.,3 prominence of these cells might be expected in the patients with acute onset and short duration IBS. This was not the case. Indeed, evidence of immune activation, as reflected by CD25+ve staining, and the number of IELs were more prominent in patients with insidious onset and chronic IBS compared to those with abrupt onset and a shorter history. This finding is counterintuitive and suggests that inflammation or immune activation may extend beyond the postinfective subset of IBS patients. This is supported by the results of a preliminary report of increased lymphocytes in the mucosa and myenteric plexus of a group of patients who submitted themselves to a laparoscopic-assisted full-thickness intestinal biopsy.13 Similarly, reports of increased numbers of other inflammatory cell types in IBS have not been restricted http://www2.gastrojournal.org/scripts/om.d...202078&nav=full http://www2.us.elsevierhealth.com/scripts/...16508503001902&


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## eric (Jul 8, 1999)

Can J Gastroenterol 2003 Mar;17 3:191-6 Related Articles, Links Sex differences of brain serotonin synthesis in patients with irritable bowel syndrome using a-11Cmethyl-l-tryptophan, positron emission tomography and statistical parametric mapping. Nakai A, Kumakura Y, Boivin M, Rosa P, Diksic M, D'Souza D, Kersey K. Fukui Medical University School of Medicine, Fukui, Japan. BACKGROUND: Irritable bowel syndrome IBS is the most common functional bowel disorder and has a strong predominance in women. Recent data suggest that the brain may play an important role in the pathophysiology of IBS in the brain-gut axis. It is strongly suspected that serotonin 5-HT, a neurotransmitter found in the brain and gut, may be related to the pathophysiology of IBS. It is reported that a 5-HT3 antagonist is effective only in female patients with diarrhea-predominant IBS. OBJECTIVE: In the present study, 5-HT synthesis was measured using positron emission tomography, with a-11Cmethyl-l-tryptophan as the tracer, in patients with IBS. The aim of the present study was to compare 5-HT synthesis in the IBS patients with that in the controls, and to compare 5-HT synthesis between male and female IBS patients. METHODS: Six male and six female nonconstipated IBS patients were scanned. Age-matched healthy volunteers were scanned as controls. Eighty minute dynamic scans were performed. Functional 5-HT synthesis images were analyzed using statistical parametric mapping. RESULTS: 5-HT synthesis was greater only in the female IBS patients in the right medial temporal gyrus multimodal sensory association cortex compared with the female controls P<0.001. CONCLUSIONS: The greater brain 5-HT synthesis in the female IBS patients than in the controls may be related to the pathological visceral pain processing of the IBS patients, a larger female predominance of the disorder, and the sex difference of the efficacy of the 5-HT3 antagonist in treatment.PMID: 12677270 PubMed - in process


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## eric (Jul 8, 1999)

bump


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## eric (Jul 8, 1999)

FYI"There is evidence that IBS is a heterogeneous disorder in which different physiologic subgroups contribute to the clinical expression of the syndrome. For example, there is a subgroup of patients, called ï¿½post-infectious IBSï¿½ who appear to respond to an enteric infection such as campylobactor jejuni with an increased inflammatory cell response.22 This is associated with activating enterochromaffin cells to produce 5HT, and CD3 cells to produce cytokines, which in turn leads to enhanced motility and lowered visceral sensation thresholds.22,23 But microscopic inflammation cannot be a diagnostic marker for IBS because it does not typically produce pain in those who have it. All patients with active celiac disease have microscopic inflammation, but a large proportion do not have abdominal pain, and patients with ulcerative colitis who also have microscopic inflammation when compared with patients with IBS seem to have higher pain thresholds.24 In individuals with these disorders, there may be central nervous system counter-regulatory measures responding to the peripheral pain/inflammatory processes that increase pain thresholds.With regard to IBS, the gut-related effects of microscopic inflammation may be only one component of a dysfunctional brain-gut system. In addition, and often in response to stress, there may be a failure to activate descending pain inhibitory systems that enable the clinical experience of pain and other symptoms that typify this disorder.25 In one prospective study of postinfectious IBS, it was found that those who retained their symptoms 3 months after an enteric infection had not only increased mucosal cellularity, but also had increased psychosocial distress at the time of the infection. Furthermore, lowered visceral sensation thresholds and increased motility were present after the infection regardless of whether or not the patients retained their symptoms.26 Therefore, the microscopic inflammation and its physiologic effects on motility and sensation contribute to, but are not always sufficient for, the clinical expression of IBS pain. At least for postinfectious IBS, this provides some evidence that psychologic distress alters brain pain regulatory pathways to amplify incoming visceral signals leading to the full clinical expression of this syndrome.27,28 Recent studies using brain imaging29,30 may help us to understand the physiologic mechanisms that modulate these central nervous system responses to pain, and in the process, identify the subgroup with IBS that are more amenable to psychologic and psychopharmacological treatments." http://www2.us.elsevierhealth.com/scripts/...16508501174998&


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## eric (Jul 8, 1999)

Gut 2003 May;52 5:663-70 Related Articles, Links Increased platelet depleted plasma 5-hydroxytryptamine concentration following meal ingestion in symptomatic female subjects with diarrhoea predominant irritable bowel syndrome. Houghton LA, Atkinson W, Whitaker RP, Whorwell PJ, Rimmer MJ. Academic Department of Medicine, University Hospital of South Manchester, Manchester, UK Department of Chemical Pathology, Leicester Royal Infirmary, Leicester, UK Biomedical Data Sciences, GlaxoSmithKline, Stockley Park, UK. BACKGROUND: Meal ingestion is often associated with exacerbation of gastrointestinal symptoms in subjects with irritable bowel syndrome IBS. Furthermore, recent preliminary data suggest that 5-hydroxytryptamine 5-HT concentration in platelet poor plasma is elevated following meal ingestion in some subjects with diarrhoea predominant IBS d-IBS compared with healthy subjects, although it is not known whether this is related to postprandial symptomatology. Aim: To expand on previous data by evaluating a larger number of subjects but also to assess plasma 5-hydroxyindole acetic acid 5-HIAA concentrations, 5-HT turnover, platelet 5-HT stores, and any relationship to symptomatology. METHODS: We assessed platelet depleted plasma 5-HT and 5-HIAA concentrations for two hours 60 minute intervals under fasting conditions, and then for a further four hours 30 minute intervals after a standard carbohydrate meal 457 kcal, together with fasting platelet 5-HT concentrations in 39 female subjects with d-IBS aged 19-52 years; mean age 33 and 20 healthy female volunteers aged 20-46 years, mean age 28. IBS symptomatology, in particular abdominal pain and bloating, and urgency to defecate were assessed throughout the study RESULTS: When related to fasting levels, there was no statistically significant difference in postprandial plasma 5-HT concentrations between d-IBS and healthy subjects. However, when fasting levels were not taken into consideration, d-IBS subjects exhibited higher postprandial plasma 5-HT concentrations compared with healthy subjects p=0.040. Furthermore, d-IBS subjects who exhibited postprandial symptomatology had higher levels of postprandial plasma 5-HT, whether assessed with respect to fasting baseline levels p=0.069 or not p=0.047, compared with d-IBS subjects who did not report postprandial symptomatology. This appeared to be associated with a concomitant increase in plasma 5-HIAA p=0.161 but reduction in turnover p=0.058. Lastly, d-IBS subjects had higher platelet concentrations of 5-HT than healthy subjects p=0.009. CONCLUSIONS: These data suggest that postprandial symptomatology may be associated with increased platelet depleted plasma 5-HT concentrations in female subjects with d-IBS. In addition, the presence of increased platelet stores of 5-HT may act as a useful marker for the diagnosis and management of d-IBS.PMID: 12692050


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## eric (Jul 8, 1999)

"Pathophysiology of irritable bowel syndrome: Irritable bowel syndrome has been investigated extensively. Over the past several years a great deal of information regarding brain-gut interaction has evolved. A model, which includes scientific and psychological components, has been developed to evaluate patients with IBS. Neurologic innervation of the gastrointestinal tract, associated with altered interpretation of neurologic messages from the GI tract by the central nervous system may result in the symptoms experienced by IBS patients. Input to the CNS, from the gastrointestinal tract arrives at the hypothalamus, periaqueductal gray PAG area and amygdala. These centers are associated with interpretation and modulation of pain perception. Neurologic output from these areas of the central nervous system CNS are then returned to the gastrointestinal tract via the spinal cord. This circuit from gut to brain and brain to gut appears to be abnormal in patients with irritable bowel syndrome. The exact abnormalities are unclear. Emotional stressors commonly exacerbate symptoms in IBS. How these emotional factors are processed by the central nervous system and their subsequent effects on the gastrointestinal tract is unclear. In some cases it appears that the amount of serotonin involved in transmission of neurologic impulses to the GI tract is abnormal. Thus, medications such as alosetran Lotronex appear to be extremely useful in these patients by modulating the amount of serotonin available. The alosetran Lotronex has been shown to be effective in patients with diarrhea predominant IBS. Patients report a significant reduction in the amount of diarrhea and the severity, and frequency, of their abdominal pain." http://www.gastromd.com/education/irritabl...elsyndrome.html


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## Mike NoLomotil (Jun 6, 2000)

Of particular note in the discussion of inflammatory response of the intestinal mucosa in diarrheic IBS patients is that most of these mechanisms were first documented, and have been examined thoroughly, since about 1980.From all the diverse information regarding abnormal immune activation in the IBS subpopulations it is quite simple to conclude that the phenomenon exists, and is largely responsible for the symptoms of a large segment of the so-called 'IBS population'.The possible pathogenesis, as have all been discussed, linked to anything from a primary loss of oral tolerance to persistent post-inflammatory responses, are of intriguing scientific interest for utlimatle isolating which subpopulation has suffered which insult and thus which pathwsy to the end result of aberrant immune response.Once it has occurred, be it primary immune dysfunction or primary neurologic influence over immune response, the cardinal mechanisms demand the need for effective disease managemtn programs to include1. patient specifoc diatry therapy, beyond the marhinally useful broad-spectrum dietary instructions typically given by most therapists and which produce equivocal results at best...and2. psychotherapeutics specific to the patients predisposition to acceptance of the modality.be it hypnothaerapy or cognitive behavioral therapy, the net effcet is that the modality which will be most effective at attenuating stress response and influence will be the modality that the patient accepts, thus actually follows.An example of a discussion of a properly integrated Disease Managment program for the symptomatic releif of IBS in patients with a diarrheic componenet, which reflects the effects of loss of oral tolerance to dietary components and exagerrated stress response (external and internal stimuli) follows...excerpted from other disscussions, where the opportunity to explain, in simple terms to an interested patient, the symptom generating mechanisms which result from aberrant mucosal and sstemic imune dysfunction in IBS, and the various provoking mechanisms and how to treat them: __________________________WINTERY MAD...The problem you are experiencing is that, contrary to what is often said about abnormal reactions to foods or chemicals in food intolerant people, the assay of specific immunoglobulins like IgE or IgG[x] does not correlate well with the actual sum of food intolerances experienced by IBS victims.This is because research has clearly shown, sometimes by direct jeunal isolation and challenge(!) that the provoking foods are not accompanied by the presecne of circulating antibodies to the foods responsible.Rats.So, we have (2) problems that some immunlogists observed long ago. One is what I just told you and the other is that even in those cases where a specific antibody against a food is found in the blood, there are many times when this does not indicate actual allergic reaction to that food when challenge test is done.Ohm thirdly, when it IS positive (confirmatory oral challenge) we are still only looking at one or two of the many known pathways to abnormal reactions to foods to which we should not react.there are half a dozen other mechanisms by which a patient can suffer food-induced including immunocyte-driven mechanisms which have no need of specific antibody in blood for a reaction to occur.This is the first difference between a RAST or ELISA food test...the test upon which LEAP Disease Managment Programs are based (MRT) checks for the common end point of all possible cellular reactions. No matter what the pathway the end game is the same...one or more types of white blood cells go through one or more types of reactions al of which result in the release from those cells of the chemicals (mediators) which lead to symptoms.healthy people tolerate foods and have immune mechanisms which accurate;y tell the difference between safe (food) and not safe (pathogens). Many IBS patients, for one reason or another, have a gut-immune interface which cannot do this reliably. There are multiple ways by which this fucntion can be compromised, but they all end up in the same place...chemicala re relased that should not be.So the test doen with the LEAP program checks for that. Then there is a dietary protocol which was also carefully developed to isolate OTHER FORMS of food intolerance which NO SINGLE BLOOD TEST ON EARTH at this time can detect...these include false food allergy (pseudoallergy)mechanisms and deficincies in enzyme processing of certain foods, an other more "esoteric" causes of abnormal processing of food in the gut which can lead to symptoms.This is why this is a PROGRAM not a test. The PROGRAM for IBS people who can benefit (there is a specific population which can benefit, and which can be identified by symptoms and history before any cost is incurred) not only inlcudes this testing and then structured phased dietary plan for isolating other intolerancews, but a proven stress and anxiety reduction program on CD for the patient to use in conjunctio with the dietary planning.Hope that makes sense...LEAP is a DM Program for managing IBS symptoms, based on several tools one of which is the MRT assay. remember no "blood test" ever solved anything. BUT if you understand the information they yield, and the info is applicable, you can do a better job of devising a plan for each specific patient which will provide significant help.for example:____________________________From Bob http://www.ibsgroup.org/cgi-local/ubbcgi/u...t=000427#000015 "I'm a relative newbie to the LEAP program having had my blood drawn on April 15th (tax day) of this year. That makes it about 3 months on the program so far. Let me say that I didn't expect a great improvement ... some improvement but nothing major. I had expected to feel a bit better and hoped to reduce the medications I was taking. I had figured that if my symptoms were reduced about 20% to 30% I would be satisfied. However, I had no idea how much of a change the program would provide.The results have been nothing short of amazing! It is the best [money] I've ever spent. After suffering about 30 years with IBS-D I've finally found major relief. My drug intake is reduced about 97% (Imodium and Bentyl). I rarely get 'digestive disturbances' any more and when they happen I can easily pinpoint the foods that caused it. I don't get the squirts for a week at a time anymore. Now that I know exactly what foods to avoid life is much more pleasant. I don't live from toilet-to-toilet like I used to. I'm still not like a 'normal' non-IBS-D person, but I'm doing so much better than I had been doing for many years. My recommendation: If you've got IBS-D go to the LEAP website and fill out the qualification form to see if they feel you will benefit from their program. If so, do it! It doesn't matter if insurance will pay for it or not, just find a way to get the test done. Your health and quality-of-life are worth much more than the cost of this test. " ____________________________Bobs son also went into the program and benefitted greatly.and____________________________Posted 4.9.03 by Bob: http://www.ibsgroup.org/ubb/ultimatebb.php...=4;t=000285;p=7 ï¿½Well, it's coming up on a year since I started the LEAP program and things are still going fine. This is absolutely the BEST thing I've done for my health and quality of life. To be honest, I have not followed the diet exactly. Sometimes I just can't resist and eat foods I really shouldn't and then I pay for it, but not nearly as bad as I used to 'pre-LEAP'. I know what I can and can't eat and, best of all, which 'offending' foods I can tolerate in small amounts. If I overdo it I suffer a bit for a day or so, but at least I can predict when and how severe the reaction will be. That's the beauty of the LEAP program -- with it I've been able to classify essentially everything I would eat into "yes", "no", or "just a little". My drug intake is almost nil. A box of Imodium lasts a year. I've had maybe 10 Rolaids tablets in the past year. This is significant because I used to buy these drugs at Costco in large quantities. Maybe that's why drug stocks are dropping this year, because I'm not buying pills in mass quantities anymore!Mike, my son Bobby is also doing fine. Sometimes he does the same stupid things I do and eats something he shouldn't and then he pays for it. Since being tested last year he has not had any vomiting attacks and only gets the squirts when he doesn't eat properly. He's 18 and on his own and is a taxpaying citizen. He couldn't have done it if he was still having his guts exploding at random. Thanks to LEAP he won't have to spend years going to doctors and taking all kinds of pills like I did. It's amazing what happens when you eat foods your body tolerates and eliminate those that it hates. I never would have been able to find all my reactive foods without the LEAP test (god knows I tried for many years). I hope all my fellow 'LEAPers' are doing as well as my son and I have. ï¿½ From: Winter Springs, FL USA____________________________January 20, 2003To Whom It May Concern,I have been asked to comment regarding my experience with the L.E.A.P. (Lifestyle, Eating and Performance) Program. We have been performing these tests for well over a year now and have had phenomenal results.Our most impressive results have come with Irritable Bowel Syndrome and Fibromyalgia, though we have had very impressive results as well with other conditions such as migraine, depression, and gastroesophageal reflux disease.Our experience has been a 95% or better success rate, in that this percentage of persons have either become completely symptom free or have improved in their symptomology. Reimbursement is excellent and easily obtained from private insurance companies. Signet Laboratories has been very easy to work with and are very aggressive about keeping us well stocked on supplies for these tests. Overall, our experience has been a tremendous success and I would highly recommend it to any physician who deals with any of these problems.Sincerely,W. Brad Wilson, M.D.(Texas) http://www.ibsgroup.org/ubb/ultimatebb.php...ic;f=5;t=000407 ___________________________ http://www.ibsgroup.org/cgi-local/ubbcgi/u...t=000407#000002 http://www.ibsgroup.org/ubb/ultimatebb.php...=4;t=000286;p=4 http://www.ibsgroup.org/cgi-local/ubbcgi/u...0286;p=3#000106 http://www.ibsgroup.org/ubb/ultimatebb.php...ic;f=4;t=000364 http://www.ibsgroup.org/cgi-local/ubbcgi/u...=4&DaysPrune=30 http://www.ibsgroup.org/ubb/ultimatebb.php...ic;f=4;t=000286 http://www.ibsgroup.org/ubb/ultimatebb.php...ic;f=4;t=000285 http://www.ibsgroup.org/cgi-local/ubbcgi/u...t=000331#000001 http://www.ibsgroup.org/ubb/ultimatebb.php...ic;f=4;t=000302 http://www.ibsgroup.org/ubb/ultimatebb.php...ic;f=4;t=000287 http://www.ibsgroup.org/ubb/ultimatebb.php...ic;f=4;t=000364 http://www.ibsgroup.org/cgi-local/ubbcgi/u...f=5&t=000313&p= http://www.ibsgroup.org/cgi-local/ubbcgi/u...0293;p=2#000069 http://www.ibsgroup.org/ubb/ultimatebb.php...ic;f=4;t=000276 http://www.ibsgroup.org/ubb/ultimatebb.php...ic;f=5;t=000073 http://www.ibsgroup.org/cgi-local/ubbcgi/u...f=5&t=000356&p= http://www.ibsgroup.org/cgi-local/ubbcgi/u...t=000320#000016 http://www.ibsgroup.org/cgi-local/ubbcgi/u...t=000383#000010 http://www.ibsgroup.org/cgi-local/ubbcgi/u...f=5&t=000126&p= http://www.ibsgroup.org/ubb/ultimatebb.php...c;f=17;t=000033 http://www.ibsgroup.org/cgi-local/ubbcgi/u...t=000363#000002 http://www.ibsgroup.org/cgi-local/ubbcgi/u...t=028290#000001 http://www.ibsgroup.org/cgi-local/ubbcgi/u...t=000335#000009 http://www.ibsgroup.org/cgi-local/ubbcgi/u...f=1&t=028290&p= http://www.ibsgroup.org/ubb/ultimatebb.php...ic;f=4;t=000353 http://www.ibsgroup.org/ubb/ultimatebb.php...ic;f=4;t=000389 http://www.ibsgroup.org/cgi-local/ubbcgi/u...t=000427#000006 http://www.ibsgroup.org/ubb/ultimatebb.php...ic;f=4;t=000421 http://www.ibsgroup.org/cgi-local/ubbcgi/u...t=000427#000015 http://www.ibsgroup.org/cgi-local/ubbcgi/u...t=030178#000003 http://www.ibsgroup.org/ubb/ultimatebb.php...ic;f=4;t=000476 http://www.ibsgroup.org/cgi-local/ubbcgi/u...t=029840#000027 http://www.ibsgroup.org/ubb/ultimatebb.php...ic;f=4;t=000478 http://www.ibsgroup.org/ubb/ultimatebb.php...ic;f=4;t=000488 (OHNOMETOO One year anniversary) http://www.ibsgroup.org/ubb/ultimatebb.php...ic;f=4;t=000478 http://www.ibsgroup.org/cgi-local/ubbcgi/u...=4;t=000285;p=7 ______________________________These books may also be helpfulIBS: A DOCTORS PLAN FOR CHRONIC DIGESTIVE TROUBLESBy Gerard Guillory, M.D.; Vanessa Ameen, M.D.; Paul Donovan, M.D.; Jack Martin, Ph.D. http://www.amazon.com/exec/obidos/ASIN/088...3369143-6824157 ï¿½FOOD ALLERGIES AND FOOD INTOLERANCE: THE COMPLETE GUIDE TO THEIR IDENTIFICTION AND TREATMENTï¿½, Professor Jonathan Brostoff , M.D.. Allergy, Immunology and Environmental Medicine, Kingsï¿½ College, London http://www.amazon.com/exec/obidos/ASIN/089...6487508-3420903 Gotta run...MNL--------------------Eat Well. Think Well. Be Well. http://www.ibsgroup.org/cgi-local/ubbcgi/u...=1;DaysPrune=30


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## eric (Jul 8, 1999)

"PRESENT PATHOPHYSIOLOGICAL OBSERVATIONSDespite differences among the functional gastrointestinal disorders, in location and symptom features, common characteristics are shared with regard to: o motor and sensory physiology, o central nervous system relationships, o approach to patient care.What follows are the general observations and guidelines.MotilityIn healthy subjects, stress can increase motility in the esophagus, stomach, small and large intestine and colon. Abnormal motility can generate a variety of GI symptoms including vomiting, diarrhea, constipation, acute abdominal pain, and fecal incontinence. Functional GI patients have even greater increased motility in response to stressors in comparison to normal subjects. While abnormal motility plays a vital role in understanding many of the functional GI disorders and their symptoms, it is not sufficient to explain reports of chronic or recurrent abdominal pain.Visceral HypersensitivityVisceral hypersensitivity helps to account for disorders associated with chronic or recurrent pain, which are not well correlated with changes in gastrointestinal motility, and in some cases, where motility disturbances do not exist. Patients suffering from visceral hypersensitivity have a lower pain threshold with balloon distension of the bowel or have increased sensitivity to even normal intestinal function. Additionally, there may be an increased or unusual area of somatic referral of visceral pain. Recently it has been concluded that visceral hypersensitivity may be induced in response to rectal or colonic distension in normal subjects, and to a greater degree, in persons with IBS. Therefore, it is possible that the pain of functional GI disorders may relate to sensitization resulting from chronic abnormal motor hyperactivity, GI infection, or trauma/injury to the viscera.Brain-Gut AxisThe concept of brain-gut interactions brings together observations relating to motility and visceral hypersensitivity and their modulation by psychosocial factors. By integrating intestinal and CNS central nervous system activity, the brain-gut axis explains the symptoms relating to functional GI disorders. In other words, senses such as vision and smell, as well as enteroceptive information (i.e. emotion and thought) have the capability to affect gastrointestinal sensation, motility, secretion, and inflammation. Conversely, viscerotopic effects reciprocally affect central pain perception, mood, and behavior. For example, spontaneously induced contractions of the colon in rats leads to activation of the locus coeruleus in the pons, an area closely connected to pain and emotional centers in the brain. Jointly, the increased arousal or anxiety is associated with a decrease in the frequency of MMC activity of the small bowel possibly mediated by stress hormones in the brain. Based on these observations, it is no longer rational to try to discriminate whether physiological or psychological factors produce pain or other bowel symptoms. Instead, the Functional GI disorders are understood in terms of dysregulation of brain-gut function, and the task is to determine to what degree each is remediable. Therefore, a treatment approach consistent with the concept of brain-gut dysfunction may focus on the neuropeptides and receptors that are present in both enteric and central nervous systems." http://www.med.unc.edu/medicine/fgidc/hist...aldisorders.htm


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## eric (Jul 8, 1999)

FYILevels of 5-Hydroxytryptamine Increase After Meals in Women With Irritable Bowel SyndromeNEW YORK Reuters Health May 05 - Platelet-depleted plasma 5-hydroxytryptamine 5-HT levels increase after meals in women with diarrhea-predominant irritable bowel syndrome d-IBS whose symptoms increase following food ingestion, according to a report in the May issue of Gut.In small studies, 5-HT concentrations in platelet-poor plasma appear higher in women with d-IBS than in healthy women, the authors explain, suggesting a possible link between 5-HT and postprandial symptom exacerbations or IBS itself.Dr. L. A. Houghton from University Hospital of South Manchester, UK and colleagues assessed 5-HT and 5-HIAA its metabolite concentrations, 5-HT turnover, and platelet 5-HT stores in 39 women with d-IBS and 20 healthy female volunteers before and after a standard carbohydrate meal.Although there was no difference in the ratio of postprandial to fasting 5-HT levels between d-IBS patients and healthy controls, the authors report, d-IBS subjects did have higher postprandial concentrations of 5-HT with earlier peak 5-HT levels than did healthy women.Women with d-IBS who reported symptoms following the meal also tended to have higher 5-HT concentrations and higher peak concentrations than did other women, the report indicates, though there was no difference in the time to peak levels compared with asymptomatic women with d-IBS.Fasting 5-HIAA levels were higher in d-IBS women than in healthy controls, the researchers note, but postprandial concentrations did not differ.Fasting and postprandial 5-HT turnover the ratio of 5-HIAA to 5-HT levels did not differ between healthy controls and women with d-IBS, the results indicate, but d-IBS subjects with postprandial symptoms tended to have a lower 5-HT turnover than did d-IBS women without symptoms.Women with d-IBS had significantly higher platelet 5-HT stores than did healthy women, the investigators find, though levels did not differ between d-IBS patients with and without postprandial symptoms."Our results have shown for the first time that symptom exacerbation following meal ingestion in female subjects with d-IBS is associated with increased levels of plasma 5-HT, together with a reduction in 5-HT turnover," the authors conclude. "In addition, baseline platelet stores of 5-HT are elevated in female subjects with d-IBS compared with healthy subjects, supporting increased exposure of platelets to 5-HT in the systemic circulation.""Platelet 5-HT concentrations may have a potential role to play as a marker in the diagnosis and management of d-IBS," the researchers suggest. "This would be similar to the way glycosylated hemoglobin is used to reflect mean blood glucose concentration over a prolonged time period in patients with diabetes mellitus."The investigators add, "Further studies addressing both mucosal 5-HT concentrations and enteroendocrine cell numbers in subjects with d-IBS, as well as similar studies to the present one conducted in subjects with constipation predominant IBS and assessing the transient relationship between symptoms and the 5-HT system need to be performed."Gut 2003;52:663-670. http://www.medscape.com/viewarticle/453489


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## Mike NoLomotil (Jun 6, 2000)

"Based on these observations, it is no longer rational to try to discriminate whether physiological or psychological factors produce pain or other bowel symptoms. Instead, the Functional GI disorders are understood in terms of dysregulation of brain-gut function, and the task is to determine to what degree each is remediable." _____________________________Comment:Not everyone (not all physicians, investigative and clinical) would agree with this opinion.Especially those who have quantified unique and heretorfore unseen "antigenic activity" (fopr lack of a better word as yet) on blinded food challenge within the isolated proximal small bowel of patients presenting with symptoms which are diagnosed as IBS based on symptom based criteria, and have no circulating antibodies to food antigens. Many also show systemic immune activation accounting for comorbid systenmic symptoms. Stress and anxiety changes present as consequences, not causal factors, in these patients (and others as well).Removal of the antigenic challenge relieves the symptoms. Ergo this population should not be restricted to this single-minded approach to clinical evaluation and treatment as the outcomes would be suboptimal for these patients.The key is to be able to clinically discriminate the patient with a primary "antigen precipitated" set of symptoms, from the patient where the primary activation lies elsewhere within the brain-gut "hierarchy".This can be done, and is now done, successfully as the means exists for these patients in some places.The fundamental problem may be that simpe symptom based diagnosis may not be adequate to discriminate the subpopulations, or the criteri are not adequately applied when disgnosis is made and a large population of patients with an organic basis for this symptoms are simply misdiagnosed as having a functional condition. So patient selection must be examined as well.It is interesting to note that in general the large population of patients which presents with IBS symptoms which can be relieved with a properly developed oligoantigenic diet are not only unique by their prevalence of diarrheic symptoms and comorbid systemic symptomology, but in general suffer abdominal pain which is not immediately releived by defecation. In fact "multiple evacuations" over periods of hours amy be required in some cases to result in relief of abdominal pain. Yet these patients alsmost without fail, as they present in all other ways consistent with the criteria, are diagnosed with "IBS" by their physician.An intriguing direct observation over 8 years of an association with physcians and dieticians treating (via dietary therapeutics in a disease management format) large numbers of patients presenting with an IBS diagnosis.MNL


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## eric (Jul 8, 1999)

Mike, I just find it odd you never talk about the serotonin connection in IBS, as the very important chemical problem it is, it always seems like you want to avoid it and I am interested in why you argue every piece of information on it, even though they know its a major problem in IBS.The act of eating can trigger an attack, why is it you want to argue that fact!!!. The trigger can start from the act of eating, not a loss of oral tolerence. Why don't you seperate the issueses like they should be seperated, there are many, many other problems in IBS that cannot be explained by foods and loss of oral tolernce or even inflammatiom. There is definetly a serotonin connection in IBS. The immune system is activated from the serotonin problem in the gut that signals the brain to activate the HPA axis for one.Levels of 5-Hydroxytryptamine Increase After Meals in Women With Irritable Bowel SyndromeNEW YORK Reuters Health May 05 - Platelet-depleted plasma 5-hydroxytryptamine 5-HT levels increase after meals in women with diarrhea-predominant irritable bowel syndrome d-IBS whose symptoms increase following food ingestion, according to a report in the May issue of Gut.In small studies, 5-HT concentrations in platelet-poor plasma appear higher in women with d-IBS than in healthy women, the authors explain, suggesting a possible link between 5-HT and postprandial symptom exacerbations or IBS itself.Dr. L. A. Houghton from University Hospital of South Manchester, UK and colleagues assessed 5-HT and 5-HIAA its metabolite concentrations, 5-HT turnover, and platelet 5-HT stores in 39 women with d-IBS and 20 healthy female volunteers before and after a standard carbohydrate meal.Although there was no difference in the ratio of postprandial to fasting 5-HT levels between d-IBS patients and healthy controls, the authors report, d-IBS subjects did have higher postprandial concentrations of 5-HT with earlier peak 5-HT levels than did healthy women.Women with d-IBS who reported symptoms following the meal also tended to have higher 5-HT concentrations and higher peak concentrations than did other women, the report indicates, though there was no difference in the time to peak levels compared with asymptomatic women with d-IBS.Fasting 5-HIAA levels were higher in d-IBS women than in healthy controls, the researchers note, but postprandial concentrations did not differ.Fasting and postprandial 5-HT turnover the ratio of 5-HIAA to 5-HT levels did not differ between healthy controls and women with d-IBS, the results indicate, but d-IBS subjects with postprandial symptoms tended to have a lower 5-HT turnover than did d-IBS women without symptoms.Women with d-IBS had significantly higher platelet 5-HT stores than did healthy women, the investigators find, though levels did not differ between d-IBS patients with and without postprandial symptoms."Our results have shown for the first time that symptom exacerbation following meal ingestion in female subjects with d-IBS is associated with increased levels of plasma 5-HT, together with a reduction in 5-HT turnover," the authors conclude. "In addition, baseline platelet stores of 5-HT are elevated in female subjects with d-IBS compared with healthy subjects, supporting increased exposure of platelets to 5-HT in the systemic circulation.""Platelet 5-HT concentrations may have a potential role to play as a marker in the diagnosis and management of d-IBS," the researchers suggest. "This would be similar to the way glycosylated hemoglobin is used to reflect mean blood glucose concentration over a prolonged time period in patients with diabetes mellitus."The investigators add, "Further studies addressing both mucosal 5-HT concentrations and enteroendocrine cell numbers in subjects with d-IBS, as well as similar studies to the present one conducted in subjects with constipation predominant IBS and assessing the transient relationship between symptoms and the 5-HT system need to be performed."Gut 2003;52:663-670. http://www.medscape.com/viewarticle/453489


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## eric (Jul 8, 1999)

FYIIBS how far do you go in the workup? http://www.romecriteria.org/reading1.html


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## kel1059 (Feb 28, 2003)

Eric,Go back to cooking.


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## eric (Jul 8, 1999)

Kel, maybe you should read this http://www.med.miami.edu/patients/glossary...?ArticleKey=396 DietIt is unclear if diet has much effect on the symptoms of IBS. Nevertheless, patients often associate their symptoms with specific foods such as salads, fats, etc.. Although specific foods might worsen IBS, it is clear that they are not the cause of IBS. The common placebo response in IBS also may explain the improvement of symptoms in some people with the elimination of specific foods.Dietary fiber often is recommended for patients with IBS. Fiber probably is of benefit to IBS patients with constipation, but it does not reduce abdominal pain. Lactose milk sugar intolerance often is blamed for diarrhea-predominant IBS, but it does not cause IBS. Because they are both common, lactose intolerance and IBS may coexist. In this situation, restricting lactose will improve, but not eliminate the symptoms. Lactose intolerance is easily determined by testing the effect of lactose hydrogen breath testing or trying a strict lactose elimination diet.


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## Mike NoLomotil (Jun 6, 2000)

"Mike, I just find it odd you never talk about the serotonin connection in IBS, as the very important chemical problem it is, it always seems like you want to avoid it and I am interested in why you argue every piece of information on it, even though they know its a major problem in IBS." ___________________________Better to remain silent and appear ignorant than to speak and remove all doubt.







Duh. I find it odd you never have seemed to pick up any of the books on the subject of Food Allergy and Intolerance and read them. Try this one on a least:FOOD ALLERGY AND INTOLERANCE, Professor Jonathan Brostoff, MD, Stephen Challacombe, MD (NEW 2002) http://www.amazon.com/exec/obidos/ASIN/070...product-details ï¿½	Hardcover: 1120 pages ï¿½	Publisher: W B Saunders Co; ISBN: 0702020389; 2nd edition (August 9, 2002) ï¿½Book Description:In the 15 years since the first edition of Food Allergy and Intolerance was published, the subject has become the focus of intense public interest. Not only are more people aware of the phenomena involved, but new evidence and practices are constantly being introduced, and there has been an unprecedented growth of the field. The second edition encompasses the rigor and depth of the first, whilst incorporating all the changes required to produce the definitive guide to the subject for all those involved. The symptoms of a food allergy or intolerance impacts not only on all allergists, immunologists, nutritionists, gastroenterologists, and pathologists, but doctors of respiratory medicine, dermatologists, general practitioners, pharmcologists and all those in environmental medicine. Book InfoKing's College, London, UK. Provides information on food allergy and intolerance. Topics include immune response, animal models, mediators in food allergy, enzyme deficiency, abnormal nutrition, foods as allergens, migraines, and epilepsy. For primary care physicians, clinicians, pathologists, and pharmacologists. Includes detailed halftone images. Previous edition: c1987.ï¿½ _____________________________Also try studying a wide range of articles from other peer reviewed journals both here and abroad over the last 30 yeatrs to gain some perspective on where the single mediator 5HT and its physiology fits into the bigger picture.Link this deep study on proinflammatory mediators their effects origins and the systems they interract with including the brain-gut axis, so that you see that serotonin is one of many mediators which have been quantified as "involved" in symptom generation in IBS subjects. This constant need to create an adverserail relationship in forume where your sole purpose is allegedly to assit the sick at finding as many wasy as possible to improve their conditrion is clearly due to selective thinking. This problem, which is very common both within and without the "medical community" is unfortunate for the IBS patient...or any sick person for that matter. But it is human nature to exercise bias.So is the use of fallacious reasoning as applied to findings in various investigations...which are then fallaciously interpreted from postulate, theorum or putataive mechanism into "proven fact".Hence my present disdain for wasting valuable time in the pursit of never-ending rhetoric rather than proper logical analysis.This might be a good place for you to improve your abilities in this area...or perhaps actually enter the healthcare field so you are awrae of what your responsibilities are to sick people before you try acting like one and violate those responsibilities on a regular basis: http://www.goodart.org/fallazoo.htm and here as well http://www.cygnus-group.com/CIDM/reason.html As regards your foolish assertions as to my beleif systems or activities, Almighty Serotonin 5is not excluded by myself or anyone as involved in symptom genration in IBS. It is however often overemphasized by many to the exlcusion of a wide range of other information and biochemical processes. Mainly this is because manipulation of 5HT[x] recepetors biochemcially (old drugs with a new life, or new drugs in development) holds promise. for tx and sales....so much work done is from that perspective...put into that context or looked at through that viewfinder. Or the strictly psychosicial viewfinder from hence we can enahnce the appllcation of psychotherapy and psychopharamceuticals. All valid and helpful but not the only viewpoints. One must also approach from other angles or one misses imoprtant elements which can help sick people achive rapid relief with simple therapeutics.For example, the post prandial presence of eleveted 5HT levels in plasma in one study is of great interest...but so is the finding of at least 20 (so far) OTHER proinflammatory mediators within the jejunal washings and myenteric plexus of food-challenge positive IBS subjects in a number of other studies. This information must be considered together, along with studies of altered CNS response and other oblique findings such as comorbidities from asthma to FMS to CFS.Since this does not, however, fit neatkly and well with the pure "psychosocial phsyiologic model" of so called IBS as if it applies to the entire disparate population, it is oft overlooked or disregarded as not relevant. But not by me as you allege.I really wish I had as much time to banter with you over such silliness as this...but so many people are getting well using the LEAP protocols and so many more doctors are beginning to try it and have success with it each day, it is getting damn busy around here. Actually helping people feel better in real time is a much more rewarding and worthwile inbvestment of my time...Imagine! Hundreds and hundreds of people whose symptoms are entering remission merely as a result of altering their diet based on the identification of hypersensitivity reactions, some of which indeed may involve the mediator 5HT, many of which involve more than 5HT...a whole host of proinflammatory mediators released by a multitude of different cells procvoked by multple mechansims, al of which avoidable!Ah, but it may please you to know though that certain work is being done to be able to assess the degree and frequency of altered serotonin levels "in vitro" after food challenge, and correlate that to in vivo actvity so as to seek to to quantify the actual source and mechanisms of this intriguing finding and place it in the context of the non-IgE and IgE mediated markers that have been quantified by direct recovery from the gut as well.One needs to consider deeply what the cell mediated immune mechansism are that are seen in food intolerant IBS subjects, and how this may relate to the platelet characteristics and 5HT characteristics observed in the investigation noted. It is actaully quite fascinating to consider you may find that this provides another immunologic link to the cell mediated hypsersensitivity to food antigens experienced by doarrheic IBS victims. Wouldn't that be a hoot for you!Our immunologists and technologists are working on the protocol and the added lab equipment we will need to delve into this interesting aspect...this one mediator of 100 possible mediators which can be and are involved in the highly complex and integrated problem of the so called IBS population.It would surprise some people to note that if they broadened their perspective there already are mediator markers for IBS...but because they are all over the board this is why a commone end point assay was developed!Even so....a "marker" does not produce the end game which is prophylaxis. Lukcily that is already available.Busy hands.....







MNL


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## Mike NoLomotil (Jun 6, 2000)

PS TO KEL who is directed to "read this" followed by link and qoute....Maybe after you read it you should disregard it as inaccurate and out of date...regardless of where it came from. The tutorial from UM also includes this declarative, which so many investigators and clinicians involved in IBS have FORGOTTEN that it is astounding: ________________________________"Occasionally, diseases that are thought to be functional are ultimately found to be associated with abnormalities that can be seen. Then, the disease moves out of the functional category."and"The distinction between functional disease and non-functional disease may, in fact, be blurry. Thus, even functional diseases probably have associated biochemical or molecular abnormalities that ultimately will be able to be measured."And so forth. ________________________________Bingo.Truth is truth and fact is fact as they are matters of things not opinions, which are matters of speech. There is alot of opinion bandied about which conflicts with the facts in this subject area as facts tend to be what a given person wants them to be as they may suit them. This is a prize example of selctive thinking in action. You are given this referecnce and only the parts which suit the person derogating you are set forth before you to indict you. The other stuff we don't want to think about, and consider, well, thats just not important.KEL, you cannot have a meaningful objective exchange of information with folks who fall victim to this kind of thinking and faulty reasoning. So don't expect it.Remember, in case no one told you before, ASTHMA used to be a "functional disease", a "psychological condition"...since they could observe stress and symptoms got worse with stress ans symptoms produced stress behaviors and if you sedayed the patient the symptoms seemed a bit better, the faulty logic of A casues B was employed for many years. Why? Nobody had discovered friggin IgE yet!!! OOOPS!! Maybe asthma is NOT a psychosocial condition...gee its an ALLERGIC condition. Fancy that!







_____________________"It is unclear if diet has much effect on the symptoms of IBS." ____________________The only way it is possibly unclear is if adequate attention has not been paid to all the literature and/or to correct protocols for patient specific oligoantigenic dietary therapy. The well established proof of all the various mechansism by which symptoms can be generated this way have been set forth already. If we did not see it does it not exist? ____________________________ "Nevertheless, patients often associate their symptoms with specific foods such as salads, fats, etc.. Although specific foods might worsen IBS, it is clear that they are not the cause of IBS." ______________________________Indeed no one knows the "cause of IBS" as there will be seen to be multiple causes as the symptom sets re[present more than one condition. No one says IBS is caused by food. Food intiolerance provoked the symptoms of IBS. Isolate the provoking foods and the symptom will go into remission. ___________________________"The common placebo response in IBS also may explain the improvement of symptoms in some people with the elimination of specific foods." ____________________________The "common placebo response" presumed to exist based upon drug placebo repsonse may or may not manifest itself the same with dietary therapy. But one thing is for sure.If you remove the foods and the symptoms go away and stay away...permanently....then this is not placebo.If the food challenge provokes the rlease of proinflammatory mediators when diorectl;y instilled into the jejunum this is not placebo.When foods produce system cell mediated immune activation in the absence of circulating antibodies this is not placebo response. ______________________________"Dietary fiber often is recommended for patients with IBS. Fiber probably is of benefit to IBS patients with constipation, but it does not reduce abdominal pain." _________________________________Indeed, it may worsen it...though it is ofetn good at producing gas and bloating. Fiber therapy is beneficial. to some patients for reasosn that are clear when one considers the mechanical effects of solubke and insolubkle fiber of various types when instilled into the chyme. _______________________________"Lactose milk sugar intolerance often is blamed for diarrhea-predominant IBS, but it does not cause IBS. Because they are both common, lactose intolerance and IBS may coexist. In this situation, restricting lactose will improve, but not eliminate the symptoms. Lactose intolerance is easily determined by testing the effect of lactose hydrogen breath testing or trying a strict lactose elimination diet." ________________________________Best part of the whole quote posted. Lactose intolerance causes lactose intolerance symptoms, which are agreed as at times comorbid with IBS symptoms, but not as ofetn as some patients think. However sensitivity to the other milk fractions is more copmmon than people think which is why lactase does not help but milk withdrawal may.KEL this book may be of interest to you...both in fact if you would like to study information from authorities on the subject of food allergy and intolernace and sensitivity and whatever term du jour we may like to include...IBS: A DOCTORS PLAN FOR CHRONIC DIGESTIVE TROUBLESBy Gerard Guillory, M.D.; Vanessa Ameen, M.D.; Paul Donovan, M.D.; Jack Martin, Ph.D. http://www.amazon.com/exec/obidos/ASIN/088...3369143-6824157 ï¿½FOOD ALLERGIES AND FOOD INTOLERANCE: THE COMPLETE GUIDE TO THEIR IDENTIFICTION AND TREATMENTï¿½, Professor Jonathan Brostoff , M.D.. Allergy, Immunology and Environmental Medicine, Kingsï¿½ College, London http://www.amazon.com/exec/obidos/ASIN/089...6487508-3420903







MNL


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## Mike NoLomotil (Jun 6, 2000)

Oh Yeah KEL, PS...more from the reference you are supposed to read and learn from,







with the key wordsseparatedfor emphasis: ____________________________________"As already mentioned, abnormal function of the nerves of the gastrointestinal organs, at least theoretically, might occur in the organ, spinal cord, or brain. Moreover, the abnormalities might occur in the sensory nerves, the motor nerves, or at processing centers in the intestine, spinal cord, or brain. Some researchers argue that the cause of functional diseases is abnormalities in the function of the sensory nerves." ________________________As some famous Roman once said:"Res ipsa loquitur, sed quid infernos dicet?"







MNL


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## kel1059 (Feb 28, 2003)

Eric,What it comes down to is..."has your information helped me?" Answer.....No, it has not.Has Mike NL's information helped me? Answer.....Yes, it has.Your endless ramblings about a "faulty, fluctuating 5-HT transporter mechanism that explains alternating D & C" is more than I can possibly take. Give it a rest. What is your hangup anyway with serotonin? It is only one of a dozen neurotransmitters involved. You make it sound like this is the "smoking gun". It is not.What has helped me tremendously is strict attention to food intolerances and reversing intestinal dysbiosis.


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## Mike NoLomotil (Jun 6, 2000)

Other things which must be considered and taken into account when investigating so called IBS are the extraintestinal symptomology, not all of which can be linked to a single mediator imbalance. There are simply too many sources of evidenxce to the contrary....like a baseball game there are many players on the field. Now we may be able to find that serotonin is, say, the pitcher, or first baseman or merely someone who got on base and is the only guy on seen on base if the TV camera only LOOKS at first base. But to conclude and then promulgate the theorum of the "single base runner" without looking at second or third is fallacious reasoning.In simple terms, one example.... _______________________"As many as one-third of Irritable Bowel Syndrome (IBS) patients have described extra intestinal symptoms such as rashes, tension headaches, and muscle aches and pains. Research has shown that as many as 60% of IBS patients also suffer from fibromyalgia syndrome (FMS). Conversely, as many as 70% of FMS patients have reported experiencing symptoms of IBS.(1) Could there be a common cause for the two conditions?" ___________________________________From a discussion at: http://ibscrohns.about.com/library/weekly/aa050503a.htm A few references were posted there by the author.Have a DFD if possible!MNL


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## kel1059 (Feb 28, 2003)

Eric,Just because your girlfriend has IBS and probably reads all of your posts does not mean you must stubbornly hang on to your incorrect thinking.i think she would admire you more if you just admitted you are wrong. Otherwise you are just making things worse.


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## Mike NoLomotil (Jun 6, 2000)

Something I posted here on 6.27.03 so called Food Triggers might help http://www.ibsgroup.org/ubb/ultimatebb.php...ic;f=4;t=000616 MNL


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