# Inflammation, Infection, and Irritable Bowel Syndrome: An Update



## Jeffrey Roberts (Apr 15, 1987)

http://www.medscape.com/viewarticle/434527 Inflammation, Infection, and Irritable Bowel Syndrome: An UpdateYehuda Ringel, MD Douglas A. Drossman, MDIntroduction Irritable bowel syndrome (IBS) is a chronic disorder of gastrointestinal function for which no specific pathophysiologic mechanism is known. However, it is generally accepted that IBS symptoms are multidetermined, and are generated from dysregulation at multiple levels of the brain-gut axis. They are manifest by abnormal motor reactivity to various stimuli, and low sensation and pain thresholds.[1] The growing interest of clinicians and researchers in the pathogenesis of functional gastrointestinal disorders led to several research presentations during this year's Digestive Disease Week meeting. Although these presentations addressed various factors implicated in the pathogenesis of these disorders (ie, behavioral/psychosocial, central and peripheral contributors), this article focuses on some new insights into the possible contribution of gut infection and inflammation in the development of symptoms and other potential clinical consequences.Copyright ï¿½ 1994-2002 by Medscape


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## Mike NoLomotil (Jun 6, 2000)

May 2002, Digestive Disease WeekIrritable Bowel Syndrome: Physiology and ManagementNicholas J. Talley, MD, PhD Introduction The field of irritable bowel syndrome (IBS) appears to be entering a new and exciting phase; evidence that at least some aspects of this disorder represent an organic or neurologic bowel disease has firmed, and novel management approaches are currently under investigation. At this year's Digestive Diseases Week meeting, data on current and emerging pharmacologic interventions and psychologic therapies were presented. This report reviews and discusses some of this novel and topical information. Postinfectious IBS One of the most exciting areas in terms of new research in IBS relates to the potential role of infection, inflammation, and its therapy within the setting of this syndrome. Composition of Colonic Inflammatory Infiltrate On routine histology, colonic biopsies appear normal in IBS. Studies by Gwee and colleagues,[1] and Spiller and coworkers,[2] among others, have shown that in at least a subset of IBS patients, there is a quantifiable, albeit modest, increase in colonic inflammatory cells. Hollerbach and associates[3] prospectively evaluated 20 patients with IBS (disease diagnosis based on Rome II criteria) and 15 healthy controls. Following careful histologic evaluation with quantitative morphometry, the study authors observed that patients with IBS had significantly greater numbers of (1) plasma cells in the rectum and sigmoid colon; (2) goblet cells in the transverse, descending, and sigmoid colon (as well as in the rectum); and (3) mast cells in the terminal ileum, cecum, and appendix. In contrast, the number of eosinophils was decreased in IBS patients compared with controls at all anatomic locations. Although these findings represented subtle differences, they appear to be real, and confirm that a residual inflammatory process is indeed present in some patients with classic IBS symptoms. Clinical Subtyping Dunlop 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) constipation-predominant IBS; and, (3) nonconstipated, non-postinfectious IBS. 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, (*1)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. (*2)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. (3) Therapeutic InterventionIn view of the increasing evidence of histologic abnormalities in IBS, and providing that this is indeed a true organic bowel disease, might intervention to reduce the inflammation have utility? (*3)If such intervention was able to prevent the development or progression of IBS, then this would be of major clinical importance.(*4) _____________________________________NOTES*1) This large subgroup of patients commonly diagnosed with 'IBS" has been studied with more scrutiny over the past few years using in vivo jejunal isolation techniques. The findings reported here as news, are at least (4) years old and have been repeatedly seen to be provocable by jejunal isolation and fod challenges by the group at Sahlgrens Medical University in Goteborg, Sweden. Persistent and repeatable provication of a loclaized inflammatory response in the small bowel by specific food challenges in the absence of clinical allergy quantifies the provoking mechanism of IBS symptoms in this pipulation, but not the etiology of the aberrant inflammatory response. T cell activtion, CD3, CD4 and even specific IgE have been recovered from the jejunum, suggesting a wholly unique set of abnormal immunocyte responses. These can be detetced with new technology and are the basis of an effective Disease Management Program for said patients:http://www.ibsgroup.org/cgi-local/ubbcgi/u...f=5&t=000126&p=[/UR L](*2) This is another in a series of confirmatory biopsy evidence of mast cell accumulation at a site of chronic provocation in IBS patients with diarrheic component dating back over a decade, increased mast cell density at the ileocecal junction has been repeatedly reported, as has therepautic response to immunomodulation with mast cell stablizers such as cromolyn sodium(*3)& (*4): This principle, avoidance of provocation of an aberrant inflammatory response as a method of symptomologic control is the entire basis of an effective patented-testing technology based physician and dietician-developed Disease Managment Program for d-type IBS victims. It is based upon accurately identifying any ingested substances which are not otherwise detectable by current methods which provoke this local inflammatory reaction, which then results in the releae of mediators from these immunocytes. It is this array of inflammatkry mediators which provides the source of the classic upregulation seen locally in the gut smooth muscle and enteric nervous system and along the brain-gut axis. This is their KNOWN cumulative effect, described in any immunology text as far as mediators are currently understood.To read about patients and doctors experiences clinically, which are "of significance" based upon these less than startling and not-new information, visit some of the following URL'sIET AND NUTRITION BULLETIN BOARDhttp://www.ibsgroup.org/cgi-local/ubbcgi/ultimatebb.cgi?ubb=forum&f=4&DaysPrune=30 http://www.ibsgroup.org/ubb/ultimatebb.php...ic;f=4;t=000285 http://www.ibsgroup.org/ubb/ultimatebb.php...ic;f=4;t=000287 http://www.ibsgroup.org/ubb/ultimatebb.php...ic;f=4;t=000286 http://www.ibsgroup.org/cgi-local/ubbcgi/u...f=5&t=000313&p=[/UR L]http://www.ibsgroup.org/ubb/ultimatebb.php?ubb=get_topic;f=4;t=000302http://www.ibsgroup.org/cgi-local/ubbcgi/u...pic;f=4;t=00029 3;p=2#000069[/URL] 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=[/UR L]http://www.ibsgroup.org/cgi-local/ubbcgi/ultimatebb.cgi?ubb=get_topic;f=4;t=000320#00 0016http://www.ibsgroup.org/cgi-local/ubbcgi/ultimatebb.cgi?ubb=get_topic&f=4&t=000298&p=[/UR L][URL=http://www.ibsgroup.org/cgi-local/ubbcgi/ultimatebb.cgi?ubb=get_topic&f=5&t=000126&p=]http://www.ibsgroup.org/cgi-local/ubbcgi/ultimatebb.cgi?ubb=get_topic&f=5&t=000126&p=[/UR L]______________________________The pursuit of clinical protocols for the effective avoidance of focal inflammatory responses, now clearly observable again, has been ongoing primarily in europe and among specific elements within the allergy/immunology community for over 25 years. These finidngs are not new, but merely being presented in this particualr forum for the first time and serve as further proof of the basis of therapeutics used successfully by doctors and dieticians who have understood these phenomena exist for over a decade.Ultimately it is going to become clearer, as has been suggested above in the presentation shown, that so called "IBS" is a syndrome not unlike COPD, with several distinct etiologies which may overlap to varying degrees, thus resulting in the varied clinical presentations and the varied range of aberrant findings of dysfunction in the CNS, ENS, Immune system, and Endocrine system all of which are inextricably interdependent. ____________________________A personal communication of one of the more noted investigators in this area, who was the innovator of the jejunal isolation methods of studying small bowel inflammatory repsonses in non-allergic patients with GI symptoms provoked by [URL=diet:SEPTEMBER]diet:SEPTEMBER 15, 2001Dear Mr Hoffman, Thank your for your kind letter. I think you have seen my papers from 1996 and 1997 when 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. Most of these adult patients had IBS symptoms with negative skin prick test and RAST but DBPCFC were positive. However, the method was time-consuming and expensive so we went on with immunohistocheminstry methods with biopsies from duodenum before and during challenges. In [the] near future we hope to publish our results. [note: the new "biopsy" results as opposed to collecting jejunal washings, which has been published]Even here [jejunal biopsy] we can show an allergy-like inflammation during challenges with parameters like Il-4, IFN-gamma, CD3, CD4, CD8 and IgE.Just now we have a lot of plans and I am afraid that other activities are too much for us. I hope we can keep contact and later on discuss how to develop better methods to investige patients with food problems. Looking for your comments.Sincerely YoursUlf BengtssonMD, PhD ______________________________Eat well. Think well. Be well.MNL


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## Mike NoLomotil (Jun 6, 2000)

Addenda to Ringel & Drossmans full presentation:If one clicks the link in the Post of Dr.'s Drossman and Ringels presentation and read the entire presenttion carefully, it is much more revealing than the first paragraph posted.Far many years a cadre of primarily Europen allergologists/immunologists have studied the presence of an aberrent "inflammatory process" which occurs in the small bowel (primary) and later, as it is chronic, shows up in the large bowel with more careful examination of biopsies.Chief among these investigations, dating all the way back to the early 1980's, was substantial published evidence that this occurs in patients diagnosed with IBS with a diarrheic component. This constutes, in the USA, roughyl 70% of the diagnosed IBS population.The aberrant inflammatory response (immunocyte activation) has been shown to occur regardless if the precurosr event might be infection (suggesting a persistent post infective inflammatory reaction), antibiotic therapy (suggestive of dysbiosis as a result), excessive use of NSAIDs, or where there is not obvious precursor event.Many studies also showed that, once established, the immunocyte responses seen result in the release of pro-inflammatory mediators within the bowel wall and microvasculatre which have known effects...among them upregulation of the enteric nervous system, smooth muscle, and systemic effects as well.It was also shown that episodic activation producing exacerbation occurs (manifesting as the classic "IBS attack", as well as a continuous low level presence of immunocyte activation was present.It was also shown many times, through the use of known susbtances which attenuate the reactivity of certain immunocytes, that the symptoms could be reduced or eliminated for a time (the classic is the plethora of cromolyn soidum studies from italy during the late 80's and early '90's). Several other immunomodulators were tried with inconsistent results due to the limited filed of action of those drugs.Finally, it was shown many times that these hidden inflammatory reactions, which throughout the 1990's were consistently pronounced non-existent by many respected investigators in spite of the finidngs elsewhere and which now are viewed as if they are a revelation, ONCE the aberrant reactivity of the gut immune system was activated by some event...exacerbations are provoked by dietary components, excessive stress, seprately or in combination.The dietary provocation goes beyond allergy to the food as this was shown to be a comorbidty in a higher percentage of IBS-d types than in the general population, rather up to (8) other mechanisms may be involved. The key cellular reactions, however, have been shown to be gut mas cells and lymphocytes...with other immunocytes involved in a secndary role up to and all the other leukocyte classes in some cases (mediators recovered).Further the advent of jejunal isolation technoques utilized in Sweden beginning in the 1990's allowed investigators to show in vivo these same reactions to be present which were described in these presentations as "new findings worthy of more investigation". Good.What is also worthwhile would be to go back and study all the other material already published, that which is well done and that which was flawed as investigators groped for ways of isolating these odd inflammtory reactions in the gut and what provokes them, so as to integrate that knowledge.There are decades of prior work in the area of isolating what PROVOKES this odd inflammatory repsonse menaifest by IBS-d type patients and how to either attenuate it or avoid it. It is this work which led to the development in the 1990's of a new in vitro method of anlayzing the responses of circulating immunocytes to chemical and food component exposure, already in existence and used as one imprtant tool in an effective Symptom Reduction program for diarrheic IBS victims with great succeess.It is based on the very phenomena which have been accepted as fact in these patients by others perhaps less well known in the USA for over 20 years...and applying that knowledge to how to isolate what provokes the episodic exacerbations of this response so it can be avoided. hence the confusion among many that food or chemical hypersensitivity is claimed to be the causal basis of IBS by physicians or technologists using that prophykactic approach.It is not causal, it is a MANIFESTION of an underlying group of aberrant immunocyet resposnes which appear to be potentially set in motion by several possible etiologies.It is a clincallly avoidable provocative set of events which then exacerbates the inflammatory reactions seen and results in cycles of increasing and descreasing symptom severity. The reactions canot be isolated by conventional means as circulaitn immunoglobulons were shown to be not present (except when food allergy was comorbid)and the reactivity is dose dependent and impossible to reproduce by food allergy chalenge methods (oral challenge). The only reliable way was to isolate the small bowel, challenge directyl, then recover the mediators and later the cells and cell-markers themselves. This was started back in 1994.Here is a very small sample of some prior publications wherein the authors produced evidence that these "inflammatory reactions" were indeed present. Indeed the discovery of increaed mast cell density, as sign of chronic local provocation at the outflow tract of the small bowel into the large bowel, is also old news. I provided one sample below of an early examination which discovered this long ago.The purpose of the comments and the few references posted is to amplify the findings set forth by the presenters, and make it clear that this is not new...only new to that forum...and that there is other information already known and in clincal use succesfully managing these patients base don an area that is now deemed "worthy of additional study"...the additional study began long ago and perhaps this Forum (Digestive Disease Week)will accelerate the prospects of getting more FUNDING for research into these phenomena...much of what has been done in that are ahs been privately funded, research and technology development. This has lead to some practical clinical tools for managing symptoms but NOT to the underlaying basis for WHY these patients lose oral tolerance to harmaless dietary components and aberrant immunocyte reactions occur which in vivo look allergic in the classic sense but which are not.When that is clarified then perhaps the science of managment of this population cn move eyond symptomatic prophylaxis or drug attanuation, to etiologic prophylaxis.This is just a small sampling og older work which first pointed to that information discussed by the presenters in may 2002. There are literally dozens and dozens and dozens of related works available if one looks "outside the box" for them and studies them.... ____________________________Ann Allergy 1983 Aug;51(2 Pt 2):249-50Prostaglandins in the pathogenesis of food intolerance.Lessof MH, Anderson JA, Youlten LJ.__________________________________Adv Prostaglandin Thromboxane Res 1980;8:1627-31An approach to evaluation of local intestinal PG production and clinical assessment of its inhibition by indomethacin in chronic diarrhea. Bukhave K, Rask-Madsen J __________________________________Clin Exp Allergy 1991 Sep;21(5):569-72	Double-blind cross-over trial of oral sodium cromoglycate in patients with irritable bowel syndrome due to food intolerance.Lunardi C, Bambara LM, Biasi D, Cortina P, Peroli P, Nicolis F, Favari F, Pacor MLIstituto Clinica Medica, Policlinico Borgo Roma, University of Verona, Italy.___________________________________Minerva Pediatr 1993 Jun;45(6):253-8	[Food intolerance and irritable bowel syndrome of childhood: clinical efficacy of oral sodium cromoglycate and elimination diet][Article in Italian]Grazioli I, Melzi G, Balsamo V, Castellucci G, Castro M, Catassi C, Ratsch JM, Scotta S.Schiapparelli Searle, Torino.__________________________________Scand J Gastroenterol 1995 Jun;30(6):535-41	Related Articles, Books, LinkOut Oral cromolyn sodium in comparison with elimination diet in the irritable bowel syndrome, diarrheic type. Multicenter study of 428 patients.Stefanini GF, Saggioro A, Alvisi V, Angelini G, Capurso L, di Lorenzo G, Dobrilla G, Dodero M, Galimberti M, Gasbarrini G, et alSant'Orsola Policlinic, University of Bologna, Italy.___________________________Dig Dis Sci 1993 Sep;38(9):1590-5	Related Articles, Books, LinkOut Terminal ileal mucosal mast cells in irritable bowel syndrome.Weston AP, Biddle WL, Bhatia PS, Miner PB Jr.Department of Medicine, University of Kansas Medical Center, Kansas City.___________________________At leaat now there may be some focus of the rest of the medical community strugglung with IBS care towards an understnding that there really are physiologic differences between the different symptom sets, and that there is a lot of merit to studying the schematics of those interractive influences upon gut function as set forth in this tutorial last year, and digrammed therein: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 Study this diagram:"Figure 1 . Pathogenesis of food hypersensitivity induced irritable bowel syndrome."You will no doubt find it interesting, and an easy way of visualizing some of the interactive elements of the psychoneuroimmunoendocexocrine mechnanisms in IBS.Eat well. Think well. Be well.MNL


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