# Bacterial Overgrowth & IBS: Too Soon To Tell



## eric (Jul 8, 1999)

FYIwith permission"Does Bacterial Overgrowth Play a Role in IBS?Bacterial Overgrowth & IBS: Too Soon To TellBy Philip Schoenfeld, MD, MSEd, MSc (Epi)Associate Professor of Medicine, University of Michigan School of Medicine Chief, Division of Gastroenterology, VA Ann Arbor Healthcare System Irritable bowel syndrome (IBS) has been described as a â€œfunctionalâ€ disorder, which is a â€œdiagnosis of exclusion.â€ Thus, many physicians still think IBS has no demonstrable pathophysiologic defects and that it can only be diagnosed after other â€œorganicâ€ disorders have been ruled out with multiple diagnostic tests.Recent data demonstrate the fallacy of this assumption. Irritable bowel syndrome IS characterized by multiple pathophysiologic defects:Altered gastrointestinal motility (1-2) Visceral hypersensitivity (1-2) Abnormal IL-10/IL-12 ratios consistent with pro-inflammatory Th-1 state (3) Infiltration of lymphocytes and neuronal degeneration in the myenteric plexus (4) Defects in serotonergic signaling mechanisms in the enteric nervous system of the GI tract (5) Unfortunately, these pathophysiologic defects cannot be identified by conventional laboratory testing. Therefore, we rely on the symptom-based IBS diagnostic criteria of the ROME committee (i.e., the presence of abdominal discomfort for at least 12 weeks in the past 12 months associated with a change in the consistency/frequency of stool or relief of discomfort with passage of stool) or the American College of Gastroenterology (i.e., IBS is defined as abdominal discomfort associated with altered bowel habits) (1-2). However, the reliance on symptom-based criteria to diagnose IBS should not de-emphasize the pathophysiologic defects expressed by IBS patients.Some suggest that small intestinal bacterial overgrowth and altered host-gut microbial relationship is a unifying mechanism for the pathophysiologic changes observed in IBS patients. The obvious corollary of this hypothesis: eradication of small intestinal bacterial overgrowth with antibiotics will produce relief of IBS symptoms. Is this the new â€œholy grailâ€ for IBS patients? Will this hypothesis follow the path of Helicobacter pylori where antibiotic treatment of H.pylori provided relief for peptic ulcer disease patients?Post-Infectious IBS: One Model for Altered Host-Gut Microbial Environment Amongst IBS researchers, it is commonly accepted that a sub-group of IBS patients develop their symptoms after an acute episode of bacterial gastroenteritis (6). Patients who have experienced an episode of bacterial gastroenteritis (on the basis of a positive stool sample) may have a 12-fold increased risk of developing new IBS symptoms in the same year (7). These patients also display exaggerated increases in mucosal T lymphocytes, which may predispose these patients to gut inflammation. Yet, the overwhelming majority of individuals with bacterial gastroenteritis never develop IBS. What defect predisposes certain individuals to develop post-infectious IBS?Altered GI Motility and Small Intestinal Bacterial Overgrowth: Is it the Chicken or the Egg? IBS may predispose patients to bacterial gastroenteritis (6). Patients who develop bacterial gastroenteritis are three times more likely to have a prior diagnosis of IBS, functional dyspepsia or functional diarrhea compared with a control population (8). Altered GI motility in IBS patients may predispose them to bacterial gastroenteritis. Given these data, which defect comes first: altered GI motility or abnormal host-gut bacteria microbial relationship?Although Dr. Lin suggests that disruption in host-gut bacterial interaction may be a unifying hypothesis for â€œfunctionalâ€ gastrointestinal disorders, defects in the enteric nervous system with concurrent abnormality in GI motility may be a better unifying hypothesis for â€œfunctionalâ€ gastrointestinal disorders. Certainly, epidemiologic studies (9) confirm a significant overlap between â€œfunctionalâ€ gastrointestinal disorders in different parts of the GI tract, including overlap between chronic constipation, IBS, functional dyspepsia and functional heartburn. Defects in the enteric nervous system may produce the observed alterations in GI motility and visceral hypersensitivity, which could produce a unifying hypothesis for â€œfunctional GI disorders in different parts of the GI tract.â€ However, it may be more difficult to ascribe the â€œfunctionalâ€ GI disorders of the stomach and esophagus to bacterial overgrowth since these parts of the GI tract are relatively sterile environments.Do Antibiotics Improve IBS Symptoms? Currently, there is very limited evidence that antibiotics improve IBS symptoms. Pimental and colleagues (10) published a double-blind, placebo-controlled randomized controlled trial (RCT) in IBS patients and demonstrated improvements in a â€œcomposite scoreâ€ of symptoms with neomycin. This study used a composite score calculated from abdominal discomfort, diarrhea and constipation, which were each graded on a scale of zero to five to generate a maximal score of 15 (most severe). Using this scale, neomycin-treated subjects were more likely to demonstrate a 50 percent or more improvement in their composite score compared with placebo-treated patients (43 percent versus 23 percent, p < 0.05). The effect was more pronounced among patients who successfully eradicated bacteria with neomycin and normalized their lactulose breath test. However, this appears to be the only U.S. double-blind RCT demonstrating improvement with antibiotic therapy. New data about rifaximin, a non-absorbable antibiotic, suggests that it produces moderate improvement in symptoms of bloating and flatulence in IBS (11).These RCTs demonstrate the importance of study design when evaluating IBS therapies. The rifaximin RCT (11) did not use ROME criteria to identify IBS patients and enrolled a heterogeneous population of IBS and non-IBS patients with flatulence. Patients had short follow-up after treatment (i.e., 10 days), and too few patients were enrolled to assess if rifaximin actually decreased colonic gas production. I admire the elegant study design of the RCT by Pimental and Lin (10). However, their study endpoint of composite score provides an imprecise estimate about global improvement in IBS symptoms. A simple binary endpoint provides a straightforward assessment of clinically important improvement in IBS symptoms (e.g., â€œHave you experienced satisfactory relief of your IBS symptoms in the past week: Yes/Noâ€). Appropriate study design criteria have been recommended by the ROME committee (Table 1), and future IBS therapy studies should follow these recommendations.It is also important to remember that changes in intermediate end points identify future research topics, but improvement in intermediate endpoints may not influence management. For example, uncontrolled studies (12) demonstrate that abnormal lactulose breath tests (LBTs) in IBS patients may be normalized after antibiotic therapy and produce symptom improvement. However, studies without a placebo control or appropriate blinding may lead to biased results and limit the application of study data to practice. Improvement in other intermediate endpoints may not correlate with improvement in IBS symptoms. Recent studies in IBS patients demonstrated an imbalance in IL-10/IL-12 ratios and also demonstrated that a probiotic, Bifidobacterium infantis, reverses this imbalance (3). These findings are exciting because they suggest an immune-mediated mechanism that produces inflammation in IBS patients. Unfortunately, reversal of IL-12/IL-10 imbalances was not associated with improvement in bowel symptoms and it is unclear if this reversal produced clinically important improvements in IBS symptoms.What We Know Our data about the pathophysiologic basis of IBS is growing rapidly. We know that:IBS is characterized by multiple pathophysiologic defects. It is not a â€œfunctionalâ€ disorder that is a â€œdiagnosis of exclusion.â€ A sub-group of IBS patients develop their symptoms after an episode of bacterial gastroenteritis. This finding suggests that an alteration in host-gut bacteria interactions may promote or contribute to the development of IBS symptoms. In order to demonstrate efficacy for an IBS therapy, multiple study design issues should be addressed. Currently, we have scant RCT data demonstrating clinically important IBS symptom improvement with probiotics or antibiotics. Intermediate end points (e.g., reversal of abnormal IL-10/IL-12 ratios) are promising avenues for future research, but changes in intermediate endpoints donâ€™t necessarily correlate with clinically important improvement in IBS symptoms. What We Donâ€™t Know With respect to the interaction between small intestinal bacterial overgrowth and IBS symptoms, we know relatively little. What we donâ€™t know is much more challenging than what we do know:We donâ€™t know the prevalence of small intestinal bacterial overgrowth among healthy controls without IBS symptoms and in IBS patients. These data should be obtained in the primary care setting or in a population-based study. We donâ€™t know if there is a unifying hypothesis for the development of IBS. If there is a unifying hypothesis, then we donâ€™t know if defects in the enteric nervous system, altered host-gut bacterial interactions or something else accounts for the development of the pathophysiologic changes observed in IBS patients. We donâ€™t know why a minority of patients who are diagnosed with bacterial gastroenteritis subsequently develop post-infectious IBS, while the majority of patients with bacterial gastroenteritis never develop IBS. We donâ€™t know if antibiotics will produce clinically important improvements in global IBS symptoms. We donâ€™t know if probiotics will produce clinically important improvements in global IBS symptoms. What Research is Needed in the Future? IBS is a heterogeneous disorder that probably develops based upon multiple factors. Small intestinal bacterial overgrowth may be one of these factors. However, I doubt that it represents the unifying hypothesis for the pathophysiologic changes observed in IBS patients. Nevertheless, this topic is an exciting area for several types of researchopulation-based studies of healthy controls and IBS patients to determine prevalence of small intestinal bacterial overgrowth in both groups. Studies about standardization of lactulose breath testing. Differences in breath testing techniques could account for differences in the observed prevalence of small bowel intestinal overgrowth seen at different centers. Standardization of this testing will produce more consistent results about the prevalence of small intestinal bacterial overgrowth in different populations. Large well-designed RCTâ€™s about the efficacy of antibiotics and probiotics for improvement in global IBS symptoms. These studies should prospectively plan sub-group analysis in patients with diarrhea-predominant IBS and constipation-predominant IBS patients since probiotics and antibiotics may demonstrate different efficacy in these sub-groups. Conclusion As I wrote this editorial, I thought about Barry Marshallâ€™s detractors. These researchers laughed when he proposed that a bacterium caused peptic ulcer disease. I do not wish to fall into that trap. I concede that small intestinal bacterial overgrowth may be a factor that contributes to the development of IBS, but it is possible (or likely?) that defects in the enteric nervous system with altered GI motility and visceral hypersensitivity are the key factors in the development of IBS. With this hypothesis, alterations in host-gut bacteria interactions and small intestinal bacterial overgrowth would merely reflect developments due to altered GI motility.I look forward to the publication of appropriately designed RCTs about the efficacy of antibiotics and probiotics in the management of IBS. We donâ€™t know if antibiotics or probiotics will consistently demonstrate efficacy in the treatment of IBS symptoms. This is the key question! But, given the lack of data, I canâ€™t support the routine use of antibiotics or probiotics in the treatment of IBS.Table 1: Quantitative Assessment of Study Methodology Scale* 1. ROME criteria to identify patients with IBS2. Randomization3. Parallel study design (i.e., no crossover studies)4. Double-blinding5. Complete follow-up of patients6. No placebo run-in7. Baseline observation of patients to assess symptoms8 Treatment duration of 8-12 weeks or longer9. Follow-up after treatment to assess symptoms10. Compliance with the treatment is measured11. Sample size calculation is provided and adequate sample size enrolled12. Primary outcome of the trial is improvement in global IBS symptoms13. Primary outcome is based on patient assessment14. A priori defined study endpoint15. Primary care setting for patient recruitment16. Validated scale used to measure improvement in IBS symptomsData from Veldhuyzen van Zanten SJO, Talley NJ, Bytzer P, et al for the Committee on Design of Treatment Trials for Functional Gastrointestinal Disorders. Gut 1999; 45 (suppl II): I169-77. Copyright Â© American Gastroenterological Association | Privacy Policy4930 Del Ray Avenue, Bethesda, MD 20814 301.654.2055 (p) 301.654.5920 (f)


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## eric (Jul 8, 1999)

The above article talks about Post Infectious IBS.Dr Spiller is a recognized leading expert on PI IBS and this is an up to date Paper on PI IBS.This is medscape and you have to register but its free. Its an excellent update"From Current Opinion in GastroenterologyPost-infectious Irritable Bowel SyndromePosted 12/08/2005Robin Spiller; Eugene Campbell Clinical FeaturesImportance of Psychiatric FeaturesRole of SerotoninRole of Inflammatory CytokinesRole of Mast CellsEvidence of Chronic Inflammation in Irritable Bowel SyndromeAnimal Models of Post-infective Irritable Bowel SyndromeAnti-inflammatory Effect of ProbioticsAnti-inflammatory Treatments in Irritable Bowel SyndromeConclusion--------------------------------------------------------------------------------Abstract and IntroductionAbstractPurpose of Review: Irritable bowel syndrome patients form a heterogeneous group with a variable contribution of central and peripheral components. The peripheral component is prominent in irritable bowel syndrome developing after infection (post-infectious irritable bowel syndrome) and this has proved a profitable area of research.Recent Findings: Recent studies have overthrown the dogma that irritable bowel syndrome is characterized by no abnormality of structure by demonstrating low-grade lymphocytic infiltration in the gut mucosa, increased permeability and increases in other inflammatory components including enterochromaffin and mast cells. Furthermore, increased inflammatory cytokines in both mucosa and blood have been demonstrated in irritable bowel syndrome. While steroid treatment has proved ineffective, preliminary studies with probiotics exerting an anti-inflammatory effect have shown benefit.Summary: The study of post-infectious irritable bowel syndrome has revealed the importance of low-grade inflammation in causing irritable bowel syndrome symptoms. It has suggested novel approaches to irritable bowel syndrome including studies of serotonin and histamine metabolism which may be relevant to other subtypes of of the disease."http://www.medscape.com/viewarticle/518355?src=mp


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## eric (Jul 8, 1999)

In regards to PI IBS it has recently beenReport from the 6th International Symposium on Functional Gastrointestinal DisordersBy: Douglas A. Drossman, MD and William F. Norton, IFFGD"Some of the major research advances that support the integrated or biopsychosocial approach include: Genetic and early environmental influences on the functional GI disorders The role of neurotransmitter and neurohormonal signaling in intestinal/enteric functionThe use of animal modelsNewer research relating to altered neuroimmune function, cytokine (cell molecules involved in the immune system response) activation, and brain-gut interactions*Demonstration of post-infectious IBS as a brain-gut disorder*The role of brain imaging in understanding the modulation of visceral pain http://www.iffgd.org/symposium2005report.html


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