# altered serotonin signaling and ibs compilation



## eric

Just some compilations on serotonin and ibs.Basic science is starting to understand better the enteric nervous system and the bidirectional communication between the "gut brain (ENS) and the Brain and spinal cord or Central nervous sytem. CNSWhile doing so they learned the majority of serotonin 95% is stored in the gut and some of its actions in the bidirectional communication between the gut brain and the brain."Role of Serotonin in IBSDisruptions in integrated communications among the CNS, ANS, and ENS may contribute to the three key pathophysiological features of IBS: altered GI motility, visceral hypersensitivity, and altered intestinal secretion.[4] Numerous neurotransmitters and neuromodulators are involved in the communication between the IPANs and the effector systems (i.e., muscles and secretory and vascular cells) and in the mediation of bidirectional brain-gut communications. Serotonin appears to be the common link in GI motility, intestinal secretion, and pain perception and is involved at multiple levels in the bidirectional interactions between the ENS and the CNS; thus, it is considered to play an important role in the pathophysiological abnormalities observed in IBS.[4,38]"Very importantly it "Serotonin is directly involved in initiating the ENS-mediated peristaltic reflex""Serotonin and the Peristaltic ReflexSerotonin is directly involved in initiating the ENS-mediated peristaltic reflex (Figure 3).[3,45] Serotonin is released from EC cells in response to distention of the intestinal lumen (triggered by chemical or mechanical stimulation). Once released, serotonin interacts with 5-HT1p-receptors on the presynaptic nerve endings of the IPANs in the submucosal plexus. This initiates a cascade of events that facilitate the coordinated movement of the bowels. The signal from the 5-HT1p-receptors is communicated to 5-HT4-receptors located on the terminals of the submucosal IPANs. The 5-HT4-receptors then modulate peristaltic neurotransmission by facilitating the release of several neurotransmitters (e.g., acetylcholine and tachykinins) from these nerve cells, which results in muscle contractions proximal to the bolus and the release of other neurotransmitters (e.g., nitric oxide and vasoactive intestinal peptide), which in turn causes muscle relaxation distal to the bolus.[3,4,46-48] The net result is forward movement of the luminal contents through the GI tract."also"Serotonin and Visceral HypersensitivityPatients with IBS may have an increased sensitivity to painful stimuli or an exaggerated response to normal stimuli, specifically in the colon and rectum,[4,49,50] but they do not demonstrate generalized hypersensitivity to painful somatic stimulation.[38] Studies have demonstrated that patients with IBS may perceive painful stimuli in the colon and rectum with a lower threshold than do individuals without this disorder. For instance, patients with IBS are more sensitive to balloon distention in the rectum (i.e., feel discomfort at lower levels of balloon inflation) than patients without IBS.[49,50] This concept, referred to as visceral hypersensitivity, may help explain the presence of abdominal pain or discomfort in patients with IBS.Other studies have demonstrated altered processing of brain signals. Patients with IBS may differ from patients without IBS in how their CNS integrates and processes signals from the gut.[4,50] For example, positron emission tomography, which can identify areas of increased brain blood flow in healthy controls, showed that colorectal distention activated the anterior cingulate cortex, an area rich in opiate receptors that may be involved in inhibiting painful sensations. However, this area was not activated in patients with IBS. Patients with IBS may process CNS information differently, and this processing may fail to activate brain areas involved in pain inhibition or the processing of painful stimuli.[38,51] In another study, functional magnetic resonance imaging showed that the anterior cingulate cortex was activated upon painful visceral stimulation both in patients with IBS and in controls, but that IBS patients had enhanced pain sensitivity and perception of visceral afferent (sensory) signals in the brain-gut axis corresponding to increased subjective reports of pain.[52]Serotonin may play a major role in the visceral hypersensitivity seen in patients with IBS.[50] 5-HT3-receptors transmit sensory information from the gut to the spinal cord.[4] Although the exact mechanism by which 5-HT4-receptors are involved in visceral sensation remains unknown, stimulation of 5-HT4-receptors has been shown to decrease the activity of the visceral afferent nerve fibers.[4,50,53,54] Peripheral 5-HT4-receptor-mediated mechanisms are thought to be involved in colonic hypersensitivity. Agonism of 5-HT4-receptors was shown to normalize pain sensitivity in an in vitro splanchnic nerve colon preparation from rats"http://www.medscape.com/viewarticle/503569_5This puts it a little more simplyHarvard"The Trusted Source..Harold J. DeMonaco, M.S.Harold J. DeMonaco, M.S., is senior analyst, Innovative Diagnostics and Therapeutics, and the chair of the Human Research Committee at the Massachusetts General Hospital. He is author of over 20 publications in the pharmacy and medical literature and routinely reviews manuscript submissions for eight medical journals...June 19, 2001.A:Irritable bowel syndrome is now recognized as a disorder of serotonin activity. Serotonin is a neurotransmitter in the brain that regulates sleep, mood (depression, anxiety), aggression, appetite, temperature, sexual behavior and pain sensation. Serotonin also acts as a neurotransmitter in the gastrointestinal tract.Excessive serotonin activity in the gastrointestinal system (enteric nervous system) is thought to cause the diarrhea of irritable-bowel syndrome. The enteric nervous system detects bowel distension (expansion) on the basis of pressure-sensitive cells in the bowel lumen (opening). Once activated, these pressure-sensitive cells promote the release of serotonin, which in turn promotes both secretory function and peristaltic function (the contractions of the intestines that force the contents outward). At least four serotonergic receptors have been identified to be participants in the secretory and peristaltic response.Patients with diarrhea-predominant IBS may have higher levels of serotonin after eating than do people without the disorder. This recognition led to the development of the first drug used specifically to treat diarrheal symptoms of IBS, alosetron (also known as Lotronex). Alosetron blocked the specific serotonin receptors responsible for recognizing bowel distention. In doing so, it blocked the effects of serotonin and reduced both bowel secretions and peristalsis. Constipation was the most common side effect seen. (Note: Alosetron was removed from the market by the manufacturer after repeated reports of a dangerous condition known as ischemic colitis became known.) Tegaserod (Zelmac) is another drug under development and under review by the U.S. Food and Drug Administration for approval. Tegaserod is indicated for the treatment of constipation-predominant IBS and works to increase enteric nervous system serotonin activity.So, increasing serotonin activity in the enteric nervous system produces increased bowel secretions and peristalsis (and potentially diarrhea), whereas depressing serotonin activity produces reduced secretions and reduce peristalsis (and potentially constipation). Increasing serotonin activity in the brain would increase awareness and, in higher doses, produce anxiety, insomnia and restlessness."However, the mechanisms are not fully understood because its so complex and other factors are also very important in IBS.But this has in part explain why there is abnormal motility in IBS the D and c and d/c, that there is a problem in serotnin singaling in the gi tract. The cells that store the majority of it in the gi tract, EC cells or enterochromaffin cells. In post infectious IBS, that is one of the abnormalities they found, an increase in enterochromaffin cells for one. Distinctive Features of Postinfective Irritable Bowel Syndrome "July 25, 2003 â€" Patients with postinfective irritable bowel syndrome (PI-IBS) have more diarrheal symptoms, fewer psychiatric symptoms, and a greater increase in serotonin-containing enterochromaffin (EC) cells than those whose IBS did not start after an infectious disease, according to the results of a study published in the July issue of the American Journal of Gastroenterology. The investigators speculate that subclassifying patients may allow for better and more specific therapies for some patients with IBS. "IBS patients are heterogeneous, both in symptoms and in etiology, and progress in understanding pathogenesis has been limited for lack of objective measures to allow meaningful subdivision," write Simon P. Dunlop, MSc, from University Hospital in Nottingham, U.K., and colleagues. "Recently there has been progress in defining one subgroup of patients, i.e., those developing IBS symptoms after an episode of infective gastroenteritis."They have also given rats a kind of IBS by messing with the EC cells.Serotonin is also cruical for signaling sensations and pain to the brain. However"Visceral Sensations and Brain-Gut MechanismsBy: Emeran A. Mayer, M.D., Professor of Medicine, Physiology and Psychiatry; Director, Center for Neurovisceral Sciences & Women's Health, David Geffen School of Medicine at UCLA"Our brain-gut axis is not designed to generate conscious perceptions of every alteration in gut homeostasis and internal environment, in particular when these changes are chronic, and when there is no adaptive behavioral response an affected organism could generate. Evolution has not designed our brain-gut axis to experience abdominal pain every time the number of mast cells in our ileum goes up, or the number of our serotonin containing cells goes down. It would be counter productive for an animal with a chronic parasite infestation to experience constant visceral pain, and it wouldn't have any advantage for people living in third world countries with frequent enteric infections to suffer from chronic abdominal pain. It has even been suggested that visceral pain may be a secondary phenomenon of an elaborate system of signaling non-painful signals to the brain: hunger, fullness (satiety), well-being after a meal, urge to evacuate, etc. At the same time, powerful mechanisms have evolved that keep many other aversive signals out of conscious perception: contractions, luminal distension, gas volume, low-grade inflammation, etc. The most common symptoms of IBS patients are related to altered perception of sensations arising from the GI tract, and frequently from sites outside the GI tract, such as the genitourinary system or the musculoskeletal system. Sensations of bloating, fullness, gas, incomplete rectal evacuation and crampy abdominal pain are the most common symptoms patients experience. Numerous reports have demonstrated that a significant percentage of FBD patients (about 60%) rate experimental distensions of the colon as uncomfortable at lower distension volumes or pressures when compared to healthy control subjects. This finding of an increased perception of visceral signals ("visceral hypersensitivity") has been demonstrated during balloon distension tests of the respective part of the GI tract regardless of where their primary symptoms are â€" the esophagus, the stomach, or the lower abdomen. In contrast to the current emphasis on mechanisms that may result in sensitization of visceral afferent pathways in the gut, it may well be that alterations in the way the nervous system normally suppresses the perception of the great majority of sensory activity arising from our viscera are essential for the typical symptom constellation of IBS and other functional GI disorders to develop."http://www.aboutibs.org/Publications/VisceralSensations.htmlWhat's New in the Management of IBS and Chronic Constipation? CMEDisclosuresBrian E. Lacy, MD, PhD IntroductionOver 10,000 physicians, scientists, researchers, and allied health personnel from around the world attended this year's Digestive Disease Week (DDW) meeting. Judging from the large number of oral presentations and posters, research on the etiology, pathophysiology, and treatment of functional bowel disorders continues at a rapid pace. This report reviews information presented during DDW 2006 with a focus on the clinically important lower gastrointestinal functional disorders of chronic constipation and irritable bowel syndrome (IBS)."Factors in EtiologyAlthough the precise etiology of IBS remains unknown, proposed mechanisms include genetic predisposition, inflammation, infection, stress, and psychological distress.[20] In addition, evidence now suggests that a deficiency in serotonin is associated with IBS with constipation, whereas excess serotonin is associated with IBS with diarrhea.http://www.medscape.com/viewarticle/536306MedGenMed GastroenterologyIBS -- Review and What's NewIntroductionIBS -- a complex, multifaceted condition broadly characterized by abdominal pain/discomfort associated with altered bowel habits -- is among the most prevalent gastrointestinal (GI) motility disorders. Prevalence estimates for IBS range from 3% to 20%, with most estimates in North America ranging from 10% to 15%.[1-3] Women are affected by IBS more often than men (2:1 in the community setting and 3:1 to 4:1 in the tertiary care setting).[2] IBS-related symptoms are often chronic and bothersome, negatively affecting patient activities of daily living (eg, sleep, leisure time), social relationships, and productivity at work or school.[4-6] Patients with IBS typically score lower than population norms or those with other chronic GI and non-GI disorders on measures of quality of life.[7-10] IBS also puts a heavy economic burden on patients, employers, and the healthcare system, resulting in more than $10 billion in direct costs (eg, from office visits, medications) and $20 billion in indirect costs (eg, through work absenteeism and reduced productivity) each year.[11-14]Advances in research during the past several decades have provided insight into the underlying pathophysiology of IBS, particularly the role of serotonin in the GI tract; the development of stepwise, symptom-based diagnostic strategies; and the development of targeted treatment options. This review discusses recent advances in research and explores how these findings can be applied in the clinical practice setting."The Science of IBSGiven the lack of definitive organic markers for IBS, the absence of a unifying hypothesis regarding its underlying pathophysiology is not surprising. Nevertheless, important advances in research made during the past 50 years have brought us closer than ever to understanding the numerous putative etiologic factors involved in this multifaceted disorder, including environmental factors, genetic links, previous infection, food intolerance, and abnormal serotonergic signaling in the GI tract.Environmental InfluencesAlthough a patient's psychological state may influence the way in which he or she presents, copes with illness, and responds to treatment, no evidence supports the theory that psychological disturbances are the cause of IBS.[39,40] The biopsychosocial model proposed by Engel takes into account the interplay between biologic, psychological, and social factors.[41] This model proposes that there is an underlying biologic predisposition for IBS that may be acted on by environmental factors and psychological stressors, which contribute to disease development, the patient's perception of illness, and impact on treatment outcomes.[42,43]Studies evaluating the role of acute stress have shown that stress can result in release of stress-related hormones that affect colonic sensorimotor function (eg, corticotropin-releasing factor [CRF] and inflammatory mediators [eg, interleukin (IL)-1]), leading to inflammation and altering GI motility and sensation.[44] For example, CRF-1 receptors located in the central nervous system (CNS) and gut can affect colonic motility, epithelial water transport, and gut permeability.[45] Sagami and colleagues[46] determined that the peripheral administration of a nonselective corticotropin-releasing hormone (CRH) receptor antagonist improved GI motility, visceral perception, and negative mood in response to gut stimulation in patients with IBS. These findings suggest that CRH may play an important role in the pathophysiology of IBS.GeneticsStudies with twins have shown that IBS is twice as prevalent in monozygotic twins as in dizygotic twins.[47-49] Limited research on familial aggregation has found that individuals who have a family member (other than a spouse) with a history of abdominal pain or bowel disorder have more than 2-fold increased odds of having IBS. It is likely that environmental influences may help explain this finding (eg, awareness of the symptom status of family members may make sufferers more open to discussing their symptoms and seeking help for the condition).[50] Preliminary findings also suggest that IBS may be associated with select gene polymorphisms, including those in IL-10, G-protein GNb3, alpha adrenoceptor, and serotonin reuptake transporter (SERT).[47, 51-54] Despite these potential links, however, conclusive evidence for a genetic basis for IBS has not been established.Postinfectious IBSThe presence of postinfectious (PI)-IBS, referring to the development of IBS symptoms -- particularly abdominal pain and diarrhea -- shortly after an enteric infection, is based on research from prospective studies in which IBS symptoms developed in 7% to 32% of patients after they recovered from bacterial gastroenteritis.[52,55,56] Specific risk factors for the development of PI-IBS have been identified, including younger age, female sex, presence of severe infectious gastroenteritis for a prolonged period, use of antibiotics to treat this infection, and presence of concomitant psychological disorders (eg, anxiety).[39,52,55,57] Difficulty in downregulating intestinal inflammation in the colonic mucosa has been suggested as a potential underlying mechanism in this condition.[52] Also suggested as a potential underlying mechanism is the presence of colonic changes shown in patients with PI-IBS compared with controls, including increased gut permeability, increased mucosal enterochromaffin cell production, and increased concentration of mast cells and T lymphocytes in the gut mucosa.[39,52,55,57] Despite considerable evidence linking IBS with an inflammatory etiology (perhaps triggered by enteric infection), in a controlled trial of patients with PI-IBS, anti-inflammatory treatment with prednisolone was not more effective than placebo in improving patient symptoms.[58] The true role of prior infection as a key factor in PI-IBS remains to be established.[59]The use of probiotics (products containing live or attenuated bacteria that have a positive effect on the host) in alleviating symptoms in patients with PI-IBS is an area of recent focus.[60,61] The potential utility of probiotics in this setting stems from their antibacterial, antiviral, and immune-modulating properties; their ability to modify intestinal flora; and their potential to enhance intestinal mucus secretion or influence stool consistency or volume and gas handling.[60] The number of studies evaluating the efficacy of probiotic preparations in patients with IBS is limited but growing.[60-68] Because trials vary in study design, dose, and strain (Lactobacillus and Bifidobacteria alone or in combination; mixture of Lactobacillus, Bifidobacteria, and Streptococcus), direct comparison of results is challenging. Overall, some degree of IBS symptom improvement has been demonstrated in symptoms such as abdominal pain,[65,66] bloating,[63,66] gas,[66] and daily symptom scores.[62,65] O'Mahoney and colleagues[60] have recently demonstrated that results with the Bifidobacterium infantis strain are particularly promising. In a separate analysis, these investigators showed that the baseline characteristics of urgency and hard stool increased the odds ratio of response to this strain, whereas straining and alcohol consumption reduced the likelihood of response.[69,70] The ultimate place in therapy of probiotics in IBS remains to be elucidated.Small Intestinal Bacterial OvergrowthThe presence of a higher than usual population of bacteria in the small intestine (leading to bacterial fermentation of poorly digestible starches and subsequent gas production) has been proposed as a potential etiologic factor in IBS.[71] Pimentel and colleagues have shown that, when measured by the lactose hydrogen breath test (LHBT), small intestinal bacterial overgrowth (SIBO) has been detected in 78% to 84% of patients with IBS.[71,72] However, the accuracy of the LHBT in testing for the presence of SIBO has been questioned.[73] Sensitivity of the LHBT for SIBO has been shown to be as low as 16.7%, and specificity approximately 70%.[74] Additionally, this test may suboptimally assess treatment response.[75] The glucose breath test has been shown to be a more reliable tool,[76] with a 75% sensitivity for SIBO[77] vs 39% with LHBT for the "double-peak" method of SIBO detection.[74] In a recently conducted retrospective study involving review of patient charts for the presence of gastrointestinal-related symptoms (including IBS) in patients who were referred for glucose hydrogen breath tests for SIBO, of 113 patients who met Rome II criteria for IBS, 11% tested positive for SIBO.[78] Thus, results demonstrated that IBS symptoms are often unrelated to the presence of SIBO. Despite the controversy regarding the contribution of SIBO to the underlying pathophysiology of IBS and its symptoms, short-term placebo-controlled clinical studies with select antibiotics, including neomycin and rifaximin, have demonstrated symptom improvement in IBS patients.[61,72,79] Antibiotics may therefore have potential utility in select subgroups of IBS patients in whom SIBO contributes to symptoms. However, the chronic nature of IBS symptoms often leads to the need for long-term treatment. Given the fact that long-term use of antibiotics is generally undesirable, the place of antibiotics in IBS therapy remains to be established.[73]Food IntoleranceFood intolerance has been proposed as a potential cause of GI symptoms in some patients with IBS; however, this link is not well established. Although some patients associate onset of IBS symptoms with ingestion of particular foods, identification of a true food intolerance is challenging, and elimination diets are typically time-consuming and difficult to implement. Recent research involving exclusion of foods to which patients had immunoglobulin (Ig) G antibodies, which are associated with a more delayed response after antigen exposure than IgE antibodies, resulted in significantly better symptom improvement than in patients in the nonexclusion group.[80] Further research into the role of food intolerance in IBS is warranted.Serotonin Signaling The effect of serotonergic mechanisms in the manifestation of IBS symptoms has led to development of a new drug class for the treatment of IBS patients: the GI serotonergic agents.Normal GI function relies on a properly functioning brain-gut axis, which involves the coordinated interplay of the GI musculature, the CNS, the autonomic nervous system, and the enteric nervous system (ENS). The ENS contains millions of neurons embedded in the wall of the digestive tract and functions, at least in part, independently of the CNS. The size, complexity, and independent function of the ENS has resulted in application of the terms "the second brain" and "the mini-brain."[81] Impaired function or coordination of any of these systems, or the communication between these systems and the GI musculature, can lead to symptoms of dysmotility and altered sensory perception, which are characteristic of IBS and select other GI motility disorders.[82]The neurotransmitter serotonin (5-hydroxytryptamine [5-HT]) is a predominant signaling molecule in the ENS. Most (90% to 95%) of the body's serotonin is found in the gut, and smaller amounts are found in the brain (about 3%) and in platelets (about 2%).[83] In the GI tract, serotonin facilitates communication between the ENS and its effector systems (muscles, secretory endothelium, endocrine cells, and vasculature of the GI tract), thus playing a key role in normal GI tract functioning.[84] In addition, serotonin plays a role in the communication between the ENS and the CNS.In the gut, serotonin is synthesized by and stored in the enterochromaffin cells, which are located within the mucosa of the intestinal wall. When material passes through the lumen and the mucosa is stimulated, enterochromaffin cells release serotonin, which then binds to its receptors (primarily 5-HT1P receptors) on intrinsic primary afferent neurons, initiating peristalsis and secretion. Serotonin also binds to 5-HT4 receptors on interneurons, which augments the transmission of signals to motor neurons, resulting in enhanced peristaltic activity. In transgenic mice lacking 5-HT4 receptors, colonic motility is abnormally slow, confirming the role of these receptors in facilitating normal colonic motility.[85] By binding to 5-HT3 receptors on efferent sensory innervations coming from the vagus and the spinal nerves, serotonin mediates signaling between the ENS and the CNS and, thus, modulates pain perception.To regulate the signaling process, excess serotonin must be removed; this is accomplished by the SERT molecule expressed by intestinal epithelial cells.[86] Human studies have shown that defects in serotonin signaling contribute to the pathophysiology of IBS and, potentially, other GI motility disorders. In a recent study by Coates and colleagues,[87] biopsy specimens from patients with IBS showed significantly lower mucosal serotonin concentrations than those from healthy controls, potentially the result of lower mRNA levels for tryptophan hydroxylase (the rate-limiting enzyme in serotonin synthesis), which were also significantly lower in patients with inflammatory bowel disease.[87] There was no significant difference in the number of enterochromaffin cells or in the capacity of these cells to release serotonin under stimulated conditions. In another study, higher serotonin levels were observed in mucosal biopsy samples from patients with IBS with constipation (IBS-C) than in patients with IBS-D or in healthy volunteers.[88]Serotonin levels may also be affected by altering the amount or function of SERT. The study by Coates and colleagues[87] showed a significant decrease in the level of SERT mRNA and SERT protein expressed in the intestinal epithelial cells of IBS patients compared with that of healthy volunteers. In another study,[89] SERT expression and binding capacity in platelets were decreased in women with IBS-D compared with expression and binding capacity in healthy controls. Furthermore, Chen and colleagues[90] showed that mice with a SERT gene deletion had altered colonic motility. It is interesting to note that the mice thrived in laboratory housing conditions, indicating that other transporters could compensate for the lack of SERT. Additional studies have focused on SERT polymorphisms. Yeo and colleagues[91] showed an association between patients with IBS-D and the homozygous short polymorphism of the SERT gene promoter. This mutation results in lower levels of SERT gene transcription and reduced amounts of SERT protein available for reuptake of serotonin. In addition, Camilleri and colleagues[92] showed a possible link between the long promoter polymorphism and patient response to therapy.Thus, a substantially large body of work shows that normal gut physiology is predicated on the interplay between the GI musculature and the ENS, autonomic nervous system, and CNS. One of the central mediators of this complex interplay is the neurotransmitter serotonin. Impairment or imbalance in serotonergic signaling, which can affect GI motility, secretion, and visceral sensitivity, may be affected by defects or deficiencies in serotonin production, specific serotonin receptors, or proteins such as SERT. These changes can manifest in symptoms associated with IBS, including abdominal pain, altered bowel habits (constipation, diarrhea, or alternation between these 2 states), and bloating."http://www.medscape.com/viewarticle/532089_printGastroenterology. 2007 Jan;132(1):397-414.The Serotonin Signaling System: From Basic Understanding To Drug Development for Functional GI Disorders.Gershon MD, Tack J. Department of Pathology & Cell Biology, Columbia University, College of Physicians and Surgeons, New York, New York. Serotonin is an important gastrointestinal signaling molecule. It is a paracrine messenger utilized by enterochromaffin (EC) cells, which function as sensory transducers. Serotonin activates intrinsic and extrinsic primary afferent neurons to, respectively, initiate peristaltic and secretory reflexes and to transmit information to the central nervous system. Serotonin is also a neurotransmitter utilized by a system of long descending myenteric interneurons. Serotonin is synthesized through the actions of 2 different tryptophan hydroxylases, TpH1 and TpH2, which are found, respectively, in EC cells and neurons. Serotonin is inactivated by the serotonin reuptake transporter (SERT)-mediated uptake into enterocytes or neurons. The presence of many serotonin receptor subtypes enables selective drugs to be designed to therapeutically modulate gastrointestinal motility, secretion, and sensation. Current examples include tegaserod, a 5-HT(4) partial agonist, which has been approved for treatment of irritable bowel syndrome (IBS) with constipation in women and for chronic constipation in men and women. The 5-HT(3) antagonists, granisetron and ondansetron, are useful in combating the nausea associated with cancer chemotherapy, and alosetron is employed in the treatment of IBS with diarrhea. Serotonergic signaling abnormalities have also been putatively implicated in the pathogenesis of functional bowel diseases. Other compounds, for which efficacy has not been rigorously established, but which may have value, include tricyclic antidepressants and serotonin selective reuptake inhibitors to combat IBS, and 5-HT(1) agonists, which enhance gastric accommodation, to treat functional dyspepsia. The initial success encountered with serotonergic agents holds promise for newer and more potent insights and therapies of brain-gut disorders. PMID: 17241888http://www.usnews.com/usnews/health/articl.../6healthweb.htm


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## eric

Expert Opin Investig Drugs. 2007 Jun;16(6):761-5.5-HT and the brain-gut axis: opportunities for pharmacologic intervention.Crowell MD, Wessinger SB. Interactions between the enteric nervous system of the gut and the brain occur bidirectionally over sympathetic and parasympathetic pathways. Coordinated actions of the central, autonomic and enteric nervous systems modulate intestinal motor, sensory and secretory activities by neuromodulators, including 5-HT, noradrenaline and dopamine. 5-HT is an important signaling molecule in the brain-gut axis and the 5-HT released from enterochromaffin cells modulates peristaltic, secretory, vasodilatory, vagal and nociceptive reflexes. Irritable bowel syndrome is associated with altered motility, secretion and sensation; enteric 5-HT signaling may be defective in this disorder. In this editorial, recent data are reviewed and the potential for the development of pharmacologic intervention is assessed.PMID: 17501688


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## Rowe2

Hi Eric..this was SO interesting! Thanks for sharing!


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## sronan

Hiya Eric!!! very interesting post..I know the mind, body and spirit connection is important to understanding all disease/suffering. i have a question... is there a test that determines the serotonin level?


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## eric

Rowe sronan, I asked the same question in the past. There is a test for serotonin, but in IBS its not the amount really but the regulation from specific gut cells. It doesn't travel to the brain but triggers nerve fibers that in turn signal to the brain.As far as I know there is not a test for serotonin specifically for IBS.


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## eric

Neurogastroenterol Motil. 2007 May 21; [Epub ahead of print]Sigmoid-colonic motility in health and irritable bowel syndrome: a role for 5-hydroxytryptamine.Houghton LA, Atkinson W, Lockhart S, Fell C, Whorwell PJ, Keevil B.Neurogastroenterology Unit, Academic Division of Medicine and Surgery, Wythenshawe Hospital, Manchester, UK.Evidence suggests that sigmoid-colonic motility is increased in patients with irritable bowel syndrome (IBS). 5-Hydroxytryptamine (5-HT) plays a role in the control of motility, but its involvement in the dysmotility seen in IBS remains unclear. To investigate the relationship between platelet depleted plasma 5-HT (PDP 5-HT) concentration and sigmoid-colonic motility in patients with IBS and healthy volunteers. Pre- and postprandial PDP 5-HT concentrations were assessed while recording sigmoid-colonic motility in 35 IBS patients (aged 19-53 years, eight male) and 16 healthy volunteers (aged 18-39 years, six male). Motility was recorded using a five-channel solid-state catheter introduced to a depth of 35 cm into an unprepared bowel. 5-Hydroxytryptamine concentration was measured by reverse-phase HPLC with fluorimetric detection. Irritable bowel syndrome patients had elevated concentrations of PDP 5-HT under fasting (P < 0.004) and fed (P = 0.079) conditions compared with controls. Likewise, they exhibited increased sigmoid-colonic motility under fasting (activity index: P < 0.02) and fed (P < 0.05) conditions compared with controls. Platelet depleted plasma 5-HT concentration positively correlated with colonic activity index under both fasting (r = 0.402; P = 0.003) and fed (r = 0.439; P = 0.001) conditions. These data show a possible relationship between endogenous concentrations of 5-HT and sigmoid-colonic motility recorded in both IBS and healthy subjects.PMID: 17539895


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## eric

Neurogastroenterol Motil. 2007 Aug;19 Suppl 2:13-8. Importance of 5-hydroxytryptamine receptors on intestinal afferents in the regulation of visceral sensitivity.Greenwood-van Meerveld B.Veteran's Affairs Medical Center and Oklahoma Center for Neuroscience, University of Oklahoma Health Science Center, Oklahoma City, OK 73104, USA. [email protected] (5-HT) plays an important role as a signalling molecule in the gastrointestinal (GI) tract. The regulation of GI sensitivity via 5-HT is mediated by specific 5-HT receptor subytypes on intrinsic and extrinsic afferents. This review discusses visceral afferent hypersensitivity in irritable bowel syndrome (IBS) and the importance of 5HT(3), 5HT(4), and 5HT(2B) receptor-mediated mechanisms in the regulation of visceral sensitivity.PMID: 17620083 Neurogastroenterol Motil. 2007 Aug;19 Suppl 2:19-24. Serotonin and neuroprotection in functional bowel disorders.Gershon MD, Liu MT.Department of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA. [email protected] 5-HT(4) partial agonist tegaserod is effective in the treatment of chronic constipation and constipation predominant irritable bowel syndrome. 5-HT(4) receptors are located on presynaptic terminals in the enteric nervous system. Stimulation of 5-HT(4) receptors enhances the release of acetylcholine and calcitonin gene related peptide from stimulated nerve terminals. This action strengthens neurotransmission in prokinetic pathways, enhancing gastrointestinal motility. The knockout of 5-HT(4) receptors in mice not only slows gastrointestinal activity but also, after 1 month of age, increases the age-related loss of enteric neurons and decreases the size of neurons that survive. 5-HT(4) receptor agonists, tegaserod and RS67506, increase numbers of enteric neurons developing from precursor cells and/or surviving in culture; they also increase neurite outgrowth and decrease apoptosis. The 5-HT(4) receptor antagonist, GR113808, blocks all of these effects, which are thus specific and 5-HT(4)-mediated. 5-HT(4) receptor agonists, therefore, are neuroprotective and neurotrophic for enteric neurons. Because the age-related decline in numbers of enteric neurons may contribute to the dysmotilities of the elderly, the possibility that the neuroprotective actions of 5-HT agonists can be utilized to prevent the occurrence or worsening of these conditions should be investigated.PMID: 17620084Neurogastroenterol Motil. 2007 Aug;19 Suppl 2:25-31. Recent advances in understanding the role of serotonin in gastrointestinal motility in functional bowel disorders: alterations in 5-HT signalling and metabolism in human disease.Spiller R.Professor of Gastroenterology, Wolfson Digestive Diseases Centre, Nottingham, UK. [email protected] (5-hydroxytryptamine, 5-HT) is present in abundance within the gut, most stored in enterochromaffin cell granules. It is released by a range of stimuli, most potently by mucosal stroking. Released 5-HT stimulates local enteric nervous reflexes to initiate secretion and propulsive motility. It also acts on vagal afferents altering motility and in large amounts induces nausea. Rapid reuptake by a specific transporter (serotonin transporter, SERT) limits its diffusion and actions. Abnormally increased 5-HT is found in a range of gastrointestinal disorders including chemotherapy-induced nausea and vomiting, carcinoid syndrome, coeliac disease, inflammatory bowel disease and irritable bowel syndrome (IBS) with diarrhoea (IBS-D), especially that developing following enteric infection. Impaired SERT has been described in IBS-D and might account for some of the increase in mucosal 5-HT availability. 5-HT(3) receptor antagonists inhibit chemotherapy-induced nausea and diarrhoea associated with both carcinoid syndrome and IBS. While IBS-D is associated with increased 5-HT postprandially, IBS with constipation (IBS-C) is associated with impaired 5-HT response and responds to 5-HT(4) agonists such as Prucalopride and 5-HT(4) partial agonists such as Tegaserod.PMID: 17620085 Neurogastroenterol Motil. 2007 Aug;19 Suppl 2:40-5. Pharmacogenomics and serotonergic agents: research observations and potential clinical practice implications.Camilleri M.CENTER Program, Mayo Clinic College of Medicine, Rochester, MN 55905, USA. [email protected] of serotonin are potentially relevant in research and clinical practice. There are few proven examples of the importance of pharmacogenetics of serotonin-modifying agents used in functional gastrointestinal or motility disorders. Drug metabolism is dependent on function of the cytochrome P450 enzymes, such as 2D6 and 3A4. Genetic variations in transporters and translation mechanisms have been associated with responses to treatment in irritable bowel syndrome and in obesity. Research on the impact of polymorphisms of key proteins on the pharmacokinetics and pharmacodynamics of drugs that alter serotonin-mediated signalling will assist in explaining diverse responses to those drugs and ultimately improve clinical practice, individualizing medicine.PMID: 17620087


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Chin Med J (Engl). 2007 Dec 5;120(23):2069-74.Expression and role of 5-HT7 receptor in brain and intestine in rats with irritable bowel syndrome.Zou BC, Dong L, Wang Y, Wang SH, Cao MB.Department of Gastroenterology, Second Hospital of Xi'an Jiaotong University, Xi'an 710004, China.BACKGROUND: The 5-hydroxytryptamine7 receptor (5-HT(7) receptor, 5-HT(7)R) plays an important role in the regulation of smooth muscle relaxation and visceral sensation and might be involved in the pathogenesis of the gastrointestinal dyskinesia, abdominal pain and visceral paresthesia in irritable bowel syndrome (IBS). The aim of this study was to investigate the role of the 5-HT(7) receptor in the pathogenesis of IBS. METHODS: A rat model of irritable bowel syndrome with diarrhea (IBS-D) was established by colonic instillation of acetic acid and restraint stress. A rat model with irritable bowel syndrome with constipation (IBS-C) was established by stomach irrigated with 0 - 4 degrees C cool water daily for 14 days. The content and distribution of 5-HT in the brain and gut were examined by immunohistochemistry and the mRNA expression of the 5-HT(7) receptor was determined by fluorescent quantitative reverse transcription polymerase chain reaction. The accumulation of cyclic adenosine monophosphate (cAMP) in all the same tissues was measured by radioimmunity. RESULTS: The models of IBS were reliable by identification. The immunohistochemistry results showed that there were significantly more 5-HT positive cells in the IBS-D group than in the control group in the hippocampus, hypothalamus, jejunum, ileum, proximate colon and distal colon (P < 0.05), as well as more than were found in the IBS-C group in jejunum and ileum (P < 0.05). There were more 5-HT positive cells in the IBS-C group than in the control hippocampus, hypothalamus, ileum, proximate colon, and distal colon (P < 0.05). Real time-PCR results showed that the expression level of the 5-HT(7) receptor in both the IBS-C and IBS-D groups were enhanced compared with the control group in the hippocampus and hypothalamus (P < 0.05). The expression level of 5-HT(7) receptors in the IBS-C group was notably greater when compared with the controls in the ileum and colon (P < 0.05). The cAMP accumulation in the hippocampus and hypothalamus in both the IBS-C and IBS-D groups was higher than that in the control group (P < 0.01 and P < 0.05). The cAMP accumulation in the IBS-C group was higher than that in the control group in the proximal and distal colon (P < 0.05). CONCLUSIONS: The increased 5-HT content in the brain and intestine is related to the IBS pathogenesis. The up-regulated expression of the 5-HT(7) receptor in the brain and colon might play an important role in the pathogenesis of IBS-C.PMID: 18167178 World J Gastroenterol. 2007 Dec 7;13(45):6041-7. LinksDecreased expression of serotonin in the jejunum and increased numbers of mast cells in the terminal ileum in patients with irritable bowel syndrome.Wang SH, Dong L, Luo JY, Gong J, Li L, Lu XL, Han SP.Department of Gastroenterology, Second Hospital of Xi'an Jiaotong University, 157, Xi 5 Road, Xi'an 710004, Shaanxi Province, China. [email protected]: To investigate if there are changes in serotonin (5-HT) levels, enterochromaffin (EC) cells and mast cells in small intestinal mucosa of patients with irritable bowel syndrome (IBS). METHODS: Diarrhea-predominant (IBS-D, n = 20), or constipation-predominant (IBS-C, n = 18) IBS patients and healthy controls (n = 20) underwent colonoscopy and peroral small intestinal endoscopy, and mucosal samples were obtained at the descending part of the duodenum, proximal end of jejunum and terminal ileum. High-performance liquid chromatography-electrochemistry and immunohistochemical methods were used to detect 5-HT content, EC cells and mast cells. RESULTS: (1) There were no differences in the number and distribution of EC cells between IBS patients and the normal group. (2) The mucosal 5-HT contents at the duodenum, jejunum and ileum in IBS-C patients were 182 +/- 90, 122 +/- 54, 61 +/- 35 ng/mg protein, respectively, which were all lower than those in the normal group (256 +/- 84, 188 +/- 91, and 93 +/- 45 ng/mg protein, respectively), with a significant difference at the jejunum (P < 0.05). There were no differences in the small intestinal mucosal 5-HT contents between IBS-D patients and the normal group. The mucosal 5-HT contents at the duodenum were significantly higher than those at the ileum in the three groups (P < 0.001). (3) The numbers of mast cells in patients with IBS-C and IBS-D at the ileum were 38.7 +/- 9.4 and 35.8 +/- 5.5/high power field (hpf), respectively, which were significantly more than that in the normal group (29.8 +/- 4.4/hpf) (P < 0.001). There was no significant difference in the numbers of mast cells at the other two parts between IBS patients and the normal group. The numbers of mast cells in IBS-C, IBS-D, and normal groups were all significantly higher at the ileum (38.7 +/- 9.4, 35.8 +/- 5.5, 29.8 +/- 4.4/hpf, respectively) than at the duodenum (19.6 +/- 4.7, 18.5 +/- 6.3, 19.2 +/- 3.3/hpf, respectively, P < 0.001). CONCLUSION: The changes in the 5-HT signaling pathway at the jejunum of IBS-C patients and the increase in mast cells in patients with IBS at the terminal ileum may offer evidence to explain the pathogenesis of IBS.PMID: 18023097 [PubMed - in process]Cell Mol Life Sci. 2007 Dec 15 [Epub ahead of print] LinksRole of serotonin in the hepato-gastroIntestinal tract: an old molecule for new perspectives.Lesurtel M, Soll C, Graf R, Clavien PA.Swiss HPB Center, Department of Visceral and Transplant Surgery, University Hospital of Zurich, Rämistrasse 100, CH-8091, Zürich, Switzerland, [email protected] its role as a neurotransmitter in the central nervous system, serotonin appears to be a central physiologic mediator of many gastrointestinal (GI) functions and a mediator of the brain-gut connection. By acting directly and via modulation of the enteric nervous system, serotonin has numerous effects on the GI tract. The main gut disturbances in which serotonin is involved are acute chemotherapy-induced nausea and vomiting, carcinoid syndrome and irritable bowel syndrome. Serotonin also has mitogenic properties. Platelet-derived serotonin is involved in liver regeneration after partial hepatectomy. In diseased liver, serotonin may play a crucial role in the progression of hepatic fibrosis and the pathogenesis of steatohepatitis. Better understanding of the role of the serotonin receptor subtypes and serotonin mechanisms of action in the liver and gut may open new therapeutic strategies in hepato-gastrointestinal diseases.PMID: 18080089Gastroenterology. 2007 Jan;132(1):397-414. LinksThe serotonin signaling system: from basic understanding to drug development for functional GI disorders.Gershon MD, Tack J.Department of Pathology & Cell Biology, Columbia University, College of Physicians and Surgeons, 630 West 168th Street, New York, NY 10032, USA. [email protected] is an important gastrointestinal signaling molecule. It is a paracrine messenger utilized by enterochromaffin (EC) cells, which function as sensory transducers. Serotonin activates intrinsic and extrinsic primary afferent neurons to, respectively, initiate peristaltic and secretory reflexes and to transmit information to the central nervous system. Serotonin is also a neurotransmitter utilized by a system of long descending myenteric interneurons. Serotonin is synthesized through the actions of 2 different tryptophan hydroxylases, TpH1 and TpH2, which are found, respectively, in EC cells and neurons. Serotonin is inactivated by the serotonin reuptake transporter (SERT)-mediated uptake into enterocytes or neurons. The presence of many serotonin receptor subtypes enables selective drugs to be designed to therapeutically modulate gastrointestinal motility, secretion, and sensation. Current examples include tegaserod, a 5-HT(4) partial agonist, which has been approved for treatment of irritable bowel syndrome (IBS) with constipation in women and for chronic constipation in men and women. The 5-HT(3) antagonists, granisetron and ondansetron, are useful in combating the nausea associated with cancer chemotherapy, and alosetron is employed in the treatment of IBS with diarrhea. Serotonergic signaling abnormalities have also been putatively implicated in the pathogenesis of functional bowel diseases. Other compounds, for which efficacy has not been rigorously established, but which may have value, include tricyclic antidepressants and serotonin selective reuptake inhibitors to combat IBS, and 5-HT(1) agonists, which enhance gastric accommodation, to treat functional dyspepsia. The initial success encountered with serotonergic agents holds promise for newer and more potent insights and therapies of brain-gut disorders.PMID: 17241888 Biol Res Nurs. 2007 Oct;9(2):161-9. LinksRelationship of SERT polymorphisms to depressive and anxiety symptoms in irritable bowel syndrome.Jarrett ME, Kohen R, Cain KC, Burr RL, Poppe A, Navaja GP, Heitkemper MM.Department of Biobehavioral Nursing & Health Systems, University of Washington, Seattle, Washington 98195-7266, USA. [email protected] study investigates the association of psychological symptoms with the distribution of two serotonin transporter gene (SERT) polymorphisms, located in the promoter region (5-HTTLPR) and in intron 2 (STin2 VNTR), in patients with irritable bowel syndrome (IBS). Participants, 21 men and 117 women, were assessed for mental health history and current psychological distress. A blood sample was used for genotyping. Participants who were homozygous for the short allele of 5-HTTLPR or carried a STin2.9 VNTR allele were significantly more likely to have a history of depression. Participants did not differ by genotype in their history of anxiety or suicidal ideation nor in their current levels of depression, anxiety, or general psychological distress. The results support a biopsychosocial model of IBS in which SERT genotype modifies the risk for depressive episodes. Long term, practitioners may individualize treatment of patients with IBS using genotype as one of the factors.PMID: 17909168


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The Experts SpeakAt IFFGD's 7th International Symposium on Functional Gastrointestinal Disorders in April 2007, we had the opportunity to talk to some of the international experts in functional GI disorders. Our discussions covered some of the most recent developments in this field. Click the topic titles below to go to the video interviews!Video Corner: Serotonin Increasingly our understanding of IBS is that it is a heterogeneous disorder - that is, multiple factors contribute to the well defined symptoms of the disorder. One of these suspected underlying dysfunctions involves serotonin, which is a neurotransmitter or messenger to nerves. Most serotonin in the body is in cells that line the gut where it senses what is going on and through receptors signals nerves that stimulate a response. The serotonin must then be reabsorbed (a process called re-uptake) into cells. This process appears to be disrupted in people with IBS.SerotoninHow does serotonin affect gut function? An interview with Gary M. Mawe, PhD, Professor of Anatomy and Neurobiology, University of Vermont, Burlington, VT. Dr. Mawe is a basic scientist.http://www.aboutibs.org/site/learning-cent...orner/serotoninhttp://www.aboutibs.org/site/learning-center/video-corner/


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FYI J Pharmacol Exp Ther. 2008 Jan 11 [Epub ahead of print] LinksDiscovery and Characterization of Novel Tryptophan Hydroxylase Inhibitors That Selectively Inhibit Serotonin Synthesis in the Gastrointestinal Tract.Liu Q, Yang Q, Sun W, Vogel P, Heydorn W, Yu XQ, Hu Z, Yu A, Jonas B, Pineda R, Calderon-Gay V, Germann M, O'Neill E, Brommage R, Cullinan E, Platt KA, Wilson A, Powell DR, Sands AT, Zambrowicz BP, Shi ZC.Lexicon Pharmaceuticals, Inc.Serotonin (5-HT) is a neurotransmitter with both central and peripheral functions, including the modulation of mood, appetite, hemodynamics; and gastrointestinal (GI) sensation, secretion, and motility. Its synthesis is initiated by the enzyme tryptophan hydroxylase (TPH). Two isoforms of TPH have been discovered: TPH1, primarily expressed in the enterochromaffin cells of the gastrointestinal tract, and TPH2, expressed exclusively in neuronal cells. Mice lacking Tph1 contain little to no 5-HT in the blood and GI tract while maintaining normal levels in the brain. Since GI 5-HT is known to play important roles in normal and patho physiology, we set out to discover and characterize novel compounds that selectively inhibit biosynthesis of GI 5-HT. We describe here two of a series of these inhibitors that are potent for TPH activity both in biochemical and cell-based assays. This class of compounds has unique properties with respect to their pharmacokinetic and pharmacodynamic effects on GI serotonin production. Similar to the Tph1 knockout results, these TPH inhibitors have the ability to selectively reduce 5-HT levels in the murine GI tract without affecting brain 5-HT levels. In addition, administration of these compounds in a ferret model of chemotherapy-induced emesis caused modest reductions of intestinal serotonin levels as well as a decreased emetic response. These findings suggest that GI-specific TPH inhibitors may provide novel treatments for various gastrointestinal disorders associated with dysregulation of the GI serotonergic system, such as chemotherapy-induced emesis and irritable bowel syndrome (IBS).PMID: 18192499


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Neurogastroenterol Motil. 2008 Jan 13 [Epub ahead of print]Evidence of an enhanced central 5HT response in irritable bowel syndrome and in the rat maternal separation model.o'mahony S, Chua AS, Quigley EM, Clarke G, Shanahan F, Keeling PW, Dinan TG.Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland.Efforts to define either a biomarker for irritable bowel syndrome (IBS) or a valid animal model have proven disappointing. The aims of this study were to determine if buspirone stimulates prolactin release through the 5-hydroxytryptamine (5HT)1a receptor and whether this response is altered in patients with IBS and in the rat maternal separation model. Buspirone (30 mg) was used to stimulate prolactin release in 40 patients with IBS and in 40 healthy controls. In study 1, 10 IBS patients and 10 controls underwent pretreatment with pindolol (5HT1a antagonist) or placebo followed by buspirone. In study 2, 30 patients with IBS and 30 healthy controls had prolactin release stimulated by buspirone. Maternally separated and nonseparated rats were also treated with buspirone and prolactin monitored. Serotonin metabolites were measured together with the expression of the 5HT1a and serotonin transporter (SERT) gene. Pindolol produced a dose-dependent decrease in the buspirone prolactin response. Patients with IBS and maternally separated rats showed an exaggerated release of prolactin in response to buspirone. In the animal model, an increased turnover of 5HT was found in the brainstem together with a trend toward increased activity of the SERT gene. In conclusion altered central serotonin responses are found in both IBS and in an animal model.PMID: 18194152


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Clin Gastroenterol Hepatol. 2008 Jan 30 [Epub ahead of print]Effects of 5-Hydroxytryptamine (Serotonin) Type 3 Antagonists on Symptom Relief and Constipation in Nonconstipated Irritable Bowel Syndrome: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.Andresen V, Montori VM, Keller J, West CP, Layer P, Camilleri M.Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER) Program; Department of Internal Medicine, Israelitic Hospital, University of Hamburg, Germany.BACKGROUND & AIMS: We performed a systematic review and meta-analyses to estimate treatment efficacy and constipation rate of 5-hydroxytryptamine (serotonin) (5-HT(3)) antagonists in patients with nonconstipated (NC) or diarrhea-predominant (D)-irritable bowel syndrome (IBS). METHODS: Two reviewers independently searched MEDLINE, EMBASE, and Web of Science (January 1, 1966 to December 15, 2006) for randomized controlled trials of 5-HT(3) antagonists in IBS reporting clinical end points of the IBS symptom complex and safety parameters. Study characteristics, markers of methodologic quality, and outcomes for the intention-to-treat population for each randomized controlled trial were extracted independently. RESULTS: We found 14 eligible randomized controlled trials of alosetron (n = 3024) or cilansetron (n = 1116) versus placebo (n = 3043) or mebeverine (n = 304). Random-effects meta-analyses found 5-HT(3) antagonists more effective than the comparators in achieving global improvement in IBS symptoms (pooled relative risk, 1.60; 95% confidence interval [CI], 1.49-1.72; I(2) = 0%) and relief of abdominal pain and discomfort (pooled relative risk, 1.30; 95% CI, 1.22-1.39; I(2) = 22%). Benefit was apparent for both agents, in patients of either sex. These agents were more likely to cause constipation (pooled relative risk, 4.28; 95% CI, 3.28-5.60, I(2) = 65%); there was less constipation with 5-HT(3) antagonists in D-IBS patients than in mixed populations (NC-IBS and D-IBS; relative risk ratio, 0.65; 95% CI, 0.41-0.99). Nine patients (0.2%) using 5-HT(3) antagonists had possible ischemic colitis versus none in control groups. CONCLUSIONS: 5-HT(3) antagonists significantly improve symptoms of NC-IBS or D-IBS in men and women. There is an increased risk of constipation with 5-HT(3) antagonists, although the risk is lower in those with D-IBS.PMID: 18242143


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J Gastroenterol Hepatol. 2007 Dec;22(12):2330-7. LinksPlasma and gastric mucosal 5-hydroxytryptamine concentrations following cold water intake in patients with diarrhea-predominant irritable bowel syndrome.Zuo XL, Li YQ, Yang XZ, Guo M, Guo YT, Lu XF, Li JM, Desmond PV.Department of Gastroenterology, Qilu Hospital, Shandong University, Jinan, China.BACKGROUND AND AIM: The purpose of the present paper was to investigate the effects of cold water intake on 5-hydroxytryptamine (5-HT) and its metabolite 5-hydroxyindole acetic acid (5-HIAA) in diarrhea-predominant irritable bowel syndrome (d-IBS) patients, and to observe the relationship between 5-HT and symptomatology. METHODS: The plasma 5-HT/5-HIAA concentrations at 0, 30 min, 60 min, 90 min, 120 min, 150 min and 180 min following cold or warm water intake were investigated in 32 female subjects with d-IBS and 21 healthy female subjects. Gastric mucosal 5-HT under fasting conditions and following water intake were further investigated in 15 d-IBS patients and nine healthy subjects. Symptomatology was assessed throughout the study. RESULTS: The plasma 5-HT concentrations in IBS patients were significantly higher than those of controls at 30 min (P = 0.022), 60 min (P < 0.001), 90 min (P < 0.001), 120 min (P < 0.001) and 150 min (P = 0.001) after cold water intake. The peak plasma 5-HT/5-HIAA and area under the curve for 5-HT/5-HIAA were also higher in d-IBS patients (P < 0.001). Gastric mucosal 5-HT in d-IBS patients and controls did not show any significant differences both under fasting condition (P = 0.596) and after cold water intake (P = 0.426). Last, the d-IBS patients with symptoms had higher 5-HT concentration (P < 0.001) and there was a positive correlation (r = 0.714, P = 0.001)between the symptomatology and plasma 5-HT level. CONCLUSIONS: These data suggest that symptomatology following cold water intake may be associated with increased plasma 5-HT concentrations in female subjects with d-IBS.PMID: 18265445 J Gastroenterol. 2006 Apr;41(4):311-7. LinksVisceral hypersensitivity following cold water intake in subjects with irritable bowel syndrome.Zuo XL, Li YQ, Shi L, Lv GP, Kuang RG, Lu XF, Li JM, Desmond PV.Department of Gastroenterology, Qilu Hospital, Shandong University, Jinan 250012, China.BACKGROUND: Visceral hypersensitivity has been shown to be present in irritable bowel syndrome (IBS). This study sought to investigate rectal sensitivity and abdominal symptoms in IBS patients before and after 220 ml cold water intake. METHODS: A total of 60 IBS patients and 18 healthy controls participated in this study. Both the perception thresholds and defecation thresholds to rectal balloon distension were measured. Then, all subjects were asked to drink 220 ml 37 degrees C warm water or 4 degrees C cold water, and these steps were repeated 20 min later. Symptoms including abdominal pain/discomfort, bloating, and diarrhea were recorded during the study. RESULTS: Compared with the controls, the thresholds of initial sensation to rectal balloon distention in IBS patients were significantly lower while the defecation thresholds were higher in constipation-predominant IBS patients. After drinking cold water, the perception thresholds in IBS patients and the defecation thresholds in diarrhea-predominant IBS patients were further decreased. However, warm water intake did not change the perception thresholds significantly in either IBS patients or controls. A negative linear correlation was found between the symptoms and the visceral perception thresholds in diarrhea-predominant IBS patients who showed significant symptoms after cold water intake. CONCLUSION: The results indicated that cold water intake leads to lowered visceral perception thresholds in IBS patients that were inversely relevant to the abdominal symptoms in symptomatic diarrhea-predominant IBS patients. The alteration of rectal sensitivity and abdominal symptoms following cold water stimulation provided further objective evidence for visceral hypersensitivity in IBS patients.PMID: 16741609 [PubMed - indexed for MEDLINE]


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## physicsstudent13

so what kinds of treatments can you suggest based on these studies to stop exhaustion and brain fog from IBS?


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