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Reged: 12/09/02
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Loc: Seattle, WA
Enteric Bacteria and IBS
      11/26/06 02:51 PM

Advances in Functional Gastrointestinal Disorders -- Enteric Bacteria and IBS

Brooks D. Cash, MD, FACP, FACG
Las Vegas, Nevada; Monday, October 23, 2006 --

The functional gastrointestinal disorders (FGIDs), chief among them the irritable bowel syndrome (IBS), are extremely common reasons for seeking healthcare and can be extremely frustrating to patients and clinicians because of the lack of a reliably identifiable pathophysiologic etiology and an even less reliable response to therapy. Considered by many as heterogeneous disorders with a variety of organic and psychological causes, the FGIDs have been the topic of a great deal of groundbreaking research and clinical developments over the last several years. In IBS, organic abnormalities such as abnormal serotonin signaling and homeostasis, altered densities of inflammatory cells and humoral inflammatory mediators, and disturbed visceral proprioception and central processing of pain have all been demonstrated in select groups of patients. More recently, significant attention has been directed toward clarifying the role of intestinal bacteria in the evolution of IBS symptoms. The recognition of postinfectious IBS as a common sequel of acute infectious gastroenteritis,[1] in addition to data demonstrating prevalence values of small intestinal bacterial overgrowth (SIBO) between 30% and 70% in patients with IBS, is driving forward research into the fields of probiotic therapy as well as antibiotic therapy to ease IBS symptoms.[2,3] This report highlights the research in this area, as presented on Monday, October 23, 2006, at the annual scientific meeting of the American College of Gastroenterology (ACG).

Diagnosing SIBO in IBS

The typical methods involved in diagnosing SIBO are breath-test measurements of expired gases after a sugar load (most commonly glucose or lactulose) or small bowel fluid aspiration and culture. The prevalence of SIBO diagnosed via breath testing rages from 10% to as high as 84% in the literature.[4,5] Breath testing can be difficult to perform because of the strict requirements for patient compliance and, in the case of glucose breath testing, variability in the absorption of glucose. Similarly, the gold standard, jejunal aspirate and culture, is limited by the invasiveness of the procedure and the anatomic extent of aspirating tube advancement, usually to the proximal 40-60 cm of the small intestine. Several investigators reported their experience with each of these diagnostic techniques during this year's ACG meeting. Bratten and colleagues[6] from Northwestern University in Chicago, Illinois, performed lactulose breath testing (for hydrogen [H+] and methane [CH4+]) in 175 patients with IBS and 23 non-IBS controls. They found that 21% (37/175) of the IBS patients produced CH4+ compared with 9% (2/23) of controls (P = .16). They also found that patients who had CH4+-positive breath tests were more than twice as likely as CH4+-negative IBS patients to have constipation as their predominant stool pattern (odds ratio [OR] = 2.61; 95% confidence interval [CI]: 1.24-5.54; P = .01) and were significantly less likely to have diarrhea (OR = 0.28; 95% CI: 0.13-0.63; P = .001). The observation that CH4+-positive breath tests correlate with constipation has been made by other investigators, but the mechanisms underlying the association between CH4+ and constipation remain poorly understood.[7]

Ruff and colleagues[8] from the Mayo Clinic College of Medicine in Rochester, Minnesota, reported the results of a retrospective analysis of clinical parameters and results of duodenal aspirate culture in 690 patients. Using the criteria of > 100,000 colony-forming units (cfu)/mL of aspirate for the diagnosis of SIBO, these investigators failed to detect an increased prevalence of SIBO in patients with diagnosed IBS or the symptom of bloating. These results contrast with previous reports using less restrictive cfu/mL criteria for the diagnosis of SIBO, and should be viewed cautiously. Potential pitfalls in this analysis include that many of the patients were taking narcotics, a systematic program of aspiration in patients with IBS was not undertaken, and the duodenal aspirates may not be adequate to rule out distal SIBO.

Bacterial Overgrowth -- Is it Hype or Hope?

During a clinical symposium convened during this year's ACG meeting, leading experts in the field addressed issues surrounding the diagnosis of SIBO and the use of antibiotics and probiotics.[9-11] Dr. Jack DiPalma[9] opened the symposium with a discussion of bacterial overgrowth. He highlighted some of the clinical conditions that predispose patients to bacterial overgrowth, such as postsurgical states, age extremes, and motility abnormalities, as well as the symptoms of overgrowth such as chronic diarrhea, malabsorption, and nutrient deficiencies. He touched on the various diagnostic tests for bacterial overgrowth and identified the best predictive factors among these tests: fasting elevations in H+ or CH4+, a positive 14C D-xylose test, or jejunal culture with > 105 cfu/mL. Dr. DiPalma also discussed the well-known limits of the so-called "gold standard" of small bowel fluid aspiration and culture, which include the invasive nature of the test, oral floral contamination, culture transport difficulties, limited access to the distal small bowel, and the unclear relevance of colonization in the elderly. He concluded by reviewing the ideal testing measures that should be present when testing for bacterial overgrowth. These include measuring both H+ and CH4+, using a standard dose of breath-test substrate, confirming the fasting state of patients undergoing testing when fasting elevations are found during fructose or glucose testing, and the need to test before a colon cleansing (or waiting for at least 30 days after a colon cleansing to test).

Dr. Lawrence Schiller[10] followed with a discussion of prebiotics and probiotics. It is interesting to note that there are more than 1015 bacteria in the human gut, of which 500 different species have been identified and one third have been cultured. In comparison, the average human body contains approximately 1014 cells. The bacteria have been selected, through the innate immune system (that part of the immune system that responds to immunogenic patterns rather than specific antigens), to coexist in the gut and provide for enterocyte nutrients, vitamin production, defense against pathogenic bacteria, and to modulate mucosal inflammation and permeability. Prebiotics are substances that can be ingested and which foster bacterial growth, and include fructo-oligosaccharides, inulin, and lactulose. Very few data exist regarding the role of prebiotics as therapies for IBS. The probiotics are live organisms that can be ingested for health benefits, but there is little theoretical basis for the selection of particular strains of probiotics, and the exact contributions of probiotics to intestinal health are unknown. Examples of probiotics include Lactobacillus and Bifidobacterium species and Escherichia coli Nissle 1917. Yeasts such as Saccharomyces species can also be used as probiotic therapy. Potential mechanisms of action for probiotics include displacement of pathogens, enhancement of bacterial function, and modification of signaling. Although complications of probiotic therapy are rare and some mixtures have been reported to improve IBS symptoms, many unanswered questions remain. These include whether live organisms need to be ingested, whether enteric colonization occurs, the ideal duration of therapy, and what biochemical signatures are most predictive of treatment success.

Dr. Mark Pimentel[11] concluded the symposium with a discussion of the rationale for the use of antibiotics in IBS. He eloquently presented the evidence for the role of enteric bacteria in the etiology of IBS symptoms and how intrinsic or extrinsic factors can produce alterations in the normal motility pattern of the gut, leading to abnormal levels of enteric bacteria which then induce inflammation and/or further alterations in gut function through the elaboration of H+ and/or CH4+. Dr. Pimentel then reviewed the evidence supporting the use of antibiotics, often in combination with promotility agents such as tegaserod, for the effective treatment of IBS. The promotility agents are used to promote more effective peristalsis and intestinal stripping waves and may have a role in preventing recurrence, although this concept has not been studied rigorously. When used for this purpose, tegaserod is usually administered at a lower dose (2 mg) and in a fasting state (every night at bedtime) rather than the standard regimen used in the settings of IBS with constipation and chronic constipation (6 mg twice daily) in order to minimize potential motility-related side effects such as diarrhea. Although it is clear that there is much that we do not know regarding the role and effects of modulation of the enteric flora in patients with IBS, this is a very exciting corner of the IBS world and additional data are eagerly awaited.

One of the overarching concerns surrounding the use of probiotics is their safety. In another abstract presented during this meeting, Adler and colleagues[12] reported results of a safety study evaluating the effects of the probiotic E coli strain M-17 in 138 healthy individuals. Subjects ingested 120 mL/day of E coli strain M-17 every day for 8 weeks, a dose that represents a 10-fold increase over standard dosing regimens. The M-17 was generally well tolerated, with associated adverse events seen in 6.5% of patients, most of which were mild. Multiple laboratory parameters were followed, and although there were some changes from baseline, all laboratory values remained within normal limits. Additional clinical data reflecting effects on symptoms in patients with IBS are eagerly awaited.

Concluding Remarks
The field of FGIDs continues to generate meaningful and important research. Emerging data surrounding the role of enteric bacteria in the origin of IBS symptoms are among the hottest topics in this field. During this year's ACG meeting, excellent overviews and original research were presented regarding the yield of diagnostic maneuvers for the detection of SIBO and the various treatment approaches to IBS involving the manipulation of the intestinal flora; such data will no doubt add to this controversial growing body of literature.

Halvorson H, Schlett CD, Riddle MS. Postinfectious irritable bowel syndrome--a meta-analysis Am J Gastroenterol. 2006;101:1-6.
Whorwell PJ, Altringer L, Morel J, et al. Efficacy of an encapsulated probiotic Bifidobacterium infantis 35624 in women with irritable bowel syndrome. Am J Gastroenterol. 2006;101:1581-1590. Abstract
Pimentel M, Park S, Mirocha J, et al. The effect of a nonabsorbed oral antibiotic (rifaximin) on the symptoms of the irritable bowel syndrome: a randomized trial. Ann Intern Med. 2006;145:557-563. Abstract
Harris LA, Crowell MD, DiBaise JK, et al. Is small intestinal bacterial overgrowth (SIBO) really prevalent in irritable bowel syndrome (IBS)? Am J Gastroenterol. 2005;100:S336.
Pimentel M, Chow EJ, Lin HC. Normalization of lactulose breath testing correlates with symptom improvement in irritable bowel syndrome. a double-blind, randomized, placebo-controlled study. Am J Gastroenterol. 2003;98:412-419. Abstract
Bratten J, Spanier J, Jones MP Lactulose hydrogen breath testing (LHBT) in patients with IBS and controls: differences in methane (CH4) but not hydrogen (H2). Am J Gastroenterol. 2006;101;S479. [Abstract 1236]
Pimental M, Lin H, Enayati P, et al. Methane, a gas produced by enteric bacteria, slows intestinal transit and augments small intestinal contractile activity. Am J Physiol Gastrointest Liver Physiol. 2006;290:G1089-G1095. Abstract
Ruff KC, Saio-Loftus YA, Locke GR, et al. Failure to detect association with irritable bowel syndrome (IBS) and small intestinal bacterial overgrowth (SIBO). Am J Gastroenterol. 2006;101;S486. [Abstract 1261]
DiPalma JA. Diagnosis and treatment of bacterial overgrowth. In: ACG Clinical Symposium: Bacterial Overgrowth: Hype or Hope. Program and abstracts of the American College of Gastroenterology 2006 Annual Scientific Meeting and Postgraduate Course; October 20-25, 2006; Las Vegas, Nevada.
Schiller LR. Prebiotics and probiotics. In: ACG Clinical Symposium: Bacterial Overgrowth: Hype or Hope. Program and abstracts of the American College of Gastroenterology 2006 Annual Scientific Meeting and Postgraduate Course;