Mark Pimentel

Eradication of small intestinal bacterial overgrowth reduces symptoms of irritable bowel syndrome

OBJECTIVES:Irritable bowel syndrome is the most common gastrointestinal diagnosis. The symptoms of irritable bowel syndrome are similar to those of small intestinal bacterial overgrowth. The purpose of this study was to test whether overgrowth is associated with irritable bowel syndrome and whether treatment of overgrowth reduces their intestinal complaints.METHODS:Two hundred two subjects in a prospective database of subjects referred from the community undergoing a lactulose hydrogen breath test for assessment of overgrowth were Rome I criteria positive for irritable bowel syndrome. They were treated with open label antibiotics after positive breath test. Subjects returning for follow-up breath test to confirm eradication of overgrowth were also assessed. Subjects with inflammatory bowel disease, abdominal surgery, or subjects demonstrating rapid transit were excluded. Baseline and after treatment symptoms were rated on visual analog scales for bloating, diarrhea, abdominal pain, defecation relief, mucous, sensation of incomplete evacuation, straining, and urgency. Subjects were blinded to their breath test results until completion of the questionnaire.RESULTS:Of 202 irritable bowel syndrome patients, 157 (78%) had overgrowth. Of these, 47 had follow-up testing. Twenty-five of 47 follow-up subjects had eradication of small intestinal bacterial overgrowth. Comparison of those that eradicated to those that failed to eradicate revealed an improvement in irritable bowel syndrome symptoms with diarrhea and abdominal pain being statistically significant after Bonferroni correction (p < 0.05). Furthermore, 48% of eradicated subjects no longer met Rome criteria (χ2= 12.0, p < 0.001). No difference was seen if eradication was not successful.CONCLUSIONS:Small intestinal bacterial overgrowth is associated with irritable bowel syndrome. Eradication of the overgrowth eliminates irritable bowel syndrome by study criteria in 48% of subjects.

Rifaximin Therapy for Patients with Irritable Bowel Syndrome without Constipation

BACKGROUND Evidence suggests that gut flora may play an important role in the pathophysiology of the irritable bowel syndrome (IBS). We evaluated rifaximin, a minimally absorbed antibiotic, as treatment for IBS. METHODS In two identically designed, phase 3, double-blind, placebo-controlled trials (TARGET 1 and TARGET 2), patients who had IBS without constipation were randomly assigned to either rifaximin at a dose of 550 mg or placebo, three times daily for 2 weeks, and were followed for an additional 10 weeks. The primary end point, the proportion of patients who had adequate relief of global IBS symptoms, and the key secondary end point, the proportion of patients who had adequate relief of IBS-related bloating, were assessed weekly. Adequate relief was defined as self-reported relief of symptoms for at least 2 of the first 4 weeks after treatment. Other secondary end points included the percentage of patients who had a response to treatment as assessed by daily self-ratings of global IBS symptoms and individual symptoms of bloating, abdominal pain, and stool consistency during the 4 weeks after treatment and during the entire 3 months of the study. RESULTS Significantly more patients in the rifaximin group than in the placebo group had adequate relief of global IBS symptoms during the first 4 weeks after treatment (40.8% vs. 31.2%, P=0.01, in TARGET 1; 40.6% vs. 32.2%, P=0.03, in TARGET 2; 40.7% vs. 31.7%, P<0.001, in the two studies combined). Similarly, more patients in the rifaximin group than in the placebo group had adequate relief of bloating (39.5% vs. 28.7%, P=0.005, in TARGET 1; 41.0% vs. 31.9%, P=0.02, in TARGET 2; 40.2% vs. 30.3%, P<0.001, in the two studies combined). In addition, significantly more patients in the rifaximin group had a response to treatment as assessed by daily ratings of IBS symptoms, bloating, abdominal pain, and stool consistency. The incidence of adverse events was similar in the two groups. CONCLUSIONS Among patients who had IBS without constipation, treatment with rifaximin for 2 weeks provided significant relief of IBS symptoms, bloating, abdominal pain, and loose or watery stools. (Funded by Salix Pharmaceuticals; ClinicalTrials.gov numbers, NCT00731679 and NCT00724126.).

Normalization of Lactulose Breath Testing Correlates With Symptom Improvement in Irritable Bowel Syndrome: A Double-Blind, Randomized, Placebo-Controlled Study

OBJECTIVE:We have recently found an association between abnormal lactulose breath test (LBT) findings and irritable bowel syndrome (IBS). The current study was designed to test the effect of antibiotic treatment for IBS in a double-blind fashion.METHODS:Consecutive IBS subjects underwent an LBT with the results blinded. All subjects were subsequently randomized into two treatment groups (neomycin or placebo). The prevalence of abnormal LBT was compared with a gender-matched control group. Seven days after completion of treatment, subjects returned for repeat LBT. A symptom questionnaire was administered on both days.RESULTS:After exclusion criteria were met, 111 IBS subjects (55 neomycin, 56 placebo) entered the study, with 84% having an abnormal LBT, compared with 20% in healthy controls (p < 0.01). In an intention-to-treat analysis of all 111 subjects, neomycin resulted in a 35.0% improvement in a composite score, compared with 11.4% for placebo (p < 0.05). Additionally, patients reported a percent bowel normalization of 35.3% after neomycin, compared with 13.9% for placebo (p < 0.001). There was a graded response to treatment, such that the best outcome was observed if neomycin was successful in normalizing the LBT (75% improvement) (one-way ANOVA, p < 0.0001). LBT gas production was associated with IBS subgroup, such that methane excretion was 100% associated with constipation-predominant IBS. Methane excretors had a mean constipation severity of 4.1, compared with 2.3 in all other subjects (p < 0.001).CONCLUSIONS:An abnormal LBT is common in subjects with IBS. Normalization of LBT with neomycin leads to a significant reduction in IBS symptoms. The type of gas seen on LBT is also associated with IBS subgroup.

The effect of a nonabsorbed oral antibiotic (rifaximin) on the symptoms of the irritable bowel syndrome: a randomized trial.

Context Few trials have evaluated the effects of antibiotics on symptoms of the irritable bowel syndrome (IBS). Contribution In this double-blind trial, 87 patients with IBS were randomly assigned to either rifaximin (400 mg 3 times daily) or placebo for 10 days. Over a 10-week follow-up period, the rifaximin recipients reported global improvements in overall symptoms and less bloating more frequently than the placebo recipients. No major differences in abdominal pain, diarrhea, or constipation were observed between the groups. Cautions The duration of therapy and follow-up was short. Implications Rifaximin may improve some symptoms in some patients with IBS. The Editors The irritable bowel syndrome (IBS) is one of the most common chronic medical conditions (16), yet its cause is unknown. Among other contributors, alterations in gut flora have been identified as potentially important. Results of recent studies indicate that up to 84% of patients with IBS have an abnormal lactulose breath test result, suggesting small-intestinal bacterial overgrowth (7, 8). On the basis of this concept, the antibiotic neomycin can statistically significantly improve the symptoms of IBS (7, 8). In addition, the effect of neomycin correlates with the elimination of bacterial overgrowth, as indicated by the normalization of the lactulose breath test result (7, 8). Although neomycin seems to improve symptoms, it effectively eliminates bacterial overgrowth in only about 25% of patients with IBS (8). Furthermore, side effects limit the use of neomycin. Low efficacy also applies to other antibiotics (for example, doxycycline and amoxicillinclavulanate) that have been previously investigated for treating bacterial overgrowth (9). An ideal antibiotic for IBS is, arguably, one with negligible systemic absorption, minimal side effects, and high efficacy for bacterial overgrowth. Rifaximin is a gut-selective antibiotic with negligible systemic absorption (0.4%) and broad-spectrum activity in vitro against gram-positive and gram-negative aerobes and anaerobes (10). On the basis of this broad spectrum, eradication rates with rifaximin in bacterial overgrowth are as high as 70% (11). Furthermore, rifaximin has a similar tolerability profile to that of placebo and has known activity against Clostridium difficile (12). These properties make it a good candidate for treating a condition that is as common as IBS. Our study aimed to determine whether the nonabsorbed antibiotic rifaximin is more effective than placebo in reducing symptoms in adults with IBS. Methods Setting and Participants Our study was conducted at the Cedars-Sinai Medical Center, Los Angeles, California, and the University of Chicago, Chicago, Illinois. We recruited patients with IBS through advertising in local media (radio and news publications). We did not recruit patients from the IBS clinics of the Cedars-Sinai Gastrointestinal Motility Program to avoid enrollment of tertiary care patients. The institutional review board of both centers approved the study, and all patients provided written informed consent. Patients between 18 and 65 years of age who met Rome I criteria (13) were eligible. Exclusion criteria were the presence of underlying conditions that are known to predispose to bacterial overgrowth, including diabetes; narcotic use; previous bowel resection; inflammatory bowel disease; cirrhosis; known bowel adhesions; or any known chronic gastroenterological disease, such as celiac disease. We excluded patients who were taking tegaserod and antidepressants unless these treatments were discontinued before study entry. We also excluded participants who reported taking an oral antibiotic within the previous 3 months. After participant inclusion and exclusion, we recruited 84 participants from the Cedars-Sinai Medical Center and 3 participants from the University of Chicago. We followed participants in special research clinics at both centers. Randomization and Interventions Eligible patients completed a 7-day stool diary that was based on the Bristol stool form scale (14). Patients returned to the clinic after a 12-hour fast and completed a symptom questionnaire about the preceding 7 days of symptoms. We then randomly assigned patients to double-blind treatment with 400 mg of rifaximin 3 times daily for 10 days or a matching placebo. We chose this dosage on the basis of a previous study that demonstrated the efficacy of rifaximin in bacterial overgrowth (11). The randomization of rifaximin versus placebo was conducted outside of Cedars-Sinai Medical Center in a 1:1 ratio into blocks of 4 patients. The allocation sequence was determined and coded at Salix Pharmaceuticals, Morrisville, North Carolina. Since this was an investigator-initiated study, the rifaximin and placebo were distributed to the Cedars-Sinai Medical Center, and nonstratified medicine and placebo were sent to the University of Chicago in groups of 4 as enrollment progressed. The medicine and placebo were prepackaged to conceal content at all times. Research personnel who were involved in product distribution were also blinded to package content. Assessments and Follow-up After completing the 10-day course of study medication, patients immediately began another stool diary for 7 days then returned to complete a follow-up questionnaire and to return their pill container for a pill count to determine adherence. Patients then entered the follow-up phase, during which they completed a weekly self-administered symptom questionnaire at home that documented their symptoms for an additional 9 weeks (for a total of 10 weeks of post-treatment follow-up). During this time, we asked participants to fax their responses to the research office. When a fax was not received on the appropriate day, research assistants called patients to ensure adherence. During this phase of study, no physician interaction occurred. During the last week of follow-up, patients completed a daily stool diary. At the end of the follow-up period, patients returned to the clinic for a final visit, which included another symptom questionnaire. For the initial symptom questionnaire, patients were asked to indicate the severity of each of 9 symptoms (abdominal pain, diarrhea, constipation, bloating, urgency, incomplete evacuation, mucus, sense of incomplete evacuation, and gas) on a visual analogue scale (VAS) ranging from 0 mm to 100 mm, with 100 mm being extreme. We used all 9 symptoms to verify IBS criteria in patients, but we assigned only diarrhea, constipation, abdominal pain, and bloating a priori as treatment end points. We asked patients to rate the severity of their symptoms on the VAS again 7 days after the completion of rifaximin treatment or placebo. Furthermore, we asked patients to provide a percentage of global improvement in their overall IBS symptoms from 0% to 100%. We chose global improvement since the Rome Consensus Group considers it to be the preferred end point measure in IBS treatment studies (15). Patients then rated the severity of their symptoms on the VAS and rated global improvement again each week for 8 weeks of follow-up and at the final visit to provide a total of 10 weeks of follow-up data. Table 1 depicts the number of patients with outcomes at various time points during the study. Table 1. Study Recruitment and Enrollment Summary At the first follow-up visit, physicians evaluated adverse events by asking patients, in an open-ended manner, whether they had experienced adverse events while receiving therapy and to elaborate on any that occurred. Although breath testing and breath methane level determinations were performed, we do not report them in our paper. Statistical Analysis We determined the number of patients for the study on the basis of the neomycin effect in a recent double-blind study for IBS on global improvement (8). To detect a difference of 35% (SD, 50%) with a power of 90%, we needed to assign 44 participants per group. Assuming a dropout rate of 10%, we calculated that approximately 96 patients would need to be recruited. The primary end point was global improvement in IBS symptoms during follow-up. As seen in Figure 1 , data were not available for all 10 weeks of follow-up. Figure 1. Study flow chart. We assessed the primary end point (percentage of global improvement) across the 10 weeks of follow-up by using an approach analogous to a repeated measures analysis of variance. Specifically, we used a mixed model with visit week (at 10 levels), treatment group (rifaximin or placebo), and group-by-week interaction as the fixed factors and patient as the random factor. The interaction and group factors were the main factors of interest in the analyses. We estimated mixed models by using the restricted maximum likelihood method. Because the global improvement percentage varied widely across week for most individuals, we considered week to be a categorical variable in the mixed model. Within-patient correlation across time was addressed by an autoregressive (first-order) model for the covariance structure. Missing data were mostly intermittent, and we assumed them to be missing at random. The normality assumption was rarely satisfied in either group at any week. However, at least 34 observations were recorded per group per week and the sample sizes were well-balanced, so we used the mixed-model analysis. We analyzed models with a single covariate (baseline diarrhea, constipation, abdominal pain, or bloating severity score). The covariate models did not improve the fit nor did they change the substantive results. Hence, we presented the simpler (no covariate) model results. We used a similar mixed-model approach to assess the secondary end points of abdominal pain, bloating, diarrhea, and constipation. Within-patient correlation was modeled by an autoregressive covariance structure. The normality assumption was rarely satisfied for the diarrhea outcome, with a similar floor effect for the primary outcome.

Methane Production During Lactulose Breath Test Is Associated with Gastrointestinal Disease Presentation

It has recently been determined that there is an increased prevalence of bacterial overgrowth in IBS. Since there are two gases (hydrogen and methane) measured on lactulose breath testing, we evaluated whether the different gas patterns on lactulose breath testing coincide with diarrhea and constipation symptoms in IBS and IBD. Consecutive patients referred to the gastrointestinal motility program at Cedars-Sinai Medical Center for lactulose breath testing were given a questionnaire to evaluate their gastrointestinal symptoms. Symptoms were graded on a scale of 0–5. Upon completion of the breath test, the results were divided into normal, hydrogen only, hydrogen and methane, and methane only positive breath tests. A comparison of all subjects and IBS subjects was undertaken to evaluate diarrhea and constipation with regards to the presence or absence of methane. This was further contrasted to Crohns and ulcerative colitis (UC) patients in the database. After exclusion criteria, 551 subjects from the database were available for comparison. Of the 551 subjects (P < 0.05, one-way ANOVA) and in a subgroup of 296 IBS subjects (P < 0.05, one-way ANOVA), there was a significant association between the severity of reported constipation and the presence of methane. The opposite was true for diarrhea (P < 0.001). If a breath test was methane positive, this was 100% associated with constipation predominant IBS. Furthermore, IBS had a greater prevalence of methane production than Crohns or UC. In fact, methane was almost nonexistent in the predominantly diarrheal conditions of Crohns and UC. In conclusion, a methane positive breath test is associated with constipation as a symptom.

Neomycin Improves Constipation-Predominant Irritable Bowel Syndrome in a Fashion That Is Dependent on the Presence of Methane Gas: Subanalysis of a Double-Blind Randomized Controlled Study

Recent studies have shown that normalization of the lactulose breath test (LBT) with neomycin leads to a significant reduction in irritable bowel syndrome (IBS) symptoms. This subanalysis was done on the constipation-predominant IBS subgroup of patients (C-IBS) to test the ability of neomycin to improve constipation and its correlation with the elimination of methane on breath test. IBS subjects underwent LBT in a blinded fashion. They were then randomly allocated to neomycin or placebo groups. For the purpose of this analysis, only the C-IBS subjects were identified. They were then evaluated for global improvement, abdominal pain, and constipation severity. The ability of neomycin to eliminate methane and its associated improvement in constipation was also determined. One hundred eleven subjects meeting Rome I criteria for IBS were included in the study. Thirty-nine of these had C-IBS. Of these, 20 received placebo and 19 received neomycin. With neomycin, a global improvement of 36.7±7.9% was seen, compared to 5.0±3.2% for placebo (P < .001) in the intention-to-treat analysis. Constipation was improved by 32.6±9.9% with neomycin compared to 18.7±7.2% for placebo (P=.26). Of the original 111 subjects, 12 demonstrated methane on breath test. All 12 of these patients were constipation predominant. In the methane producers receiving neomycin or placebo, improvement in constipation was significantly greater in those receiving neomycin (44.0±12.3%) compared to placebo (5.0±5.1%) (P < .05). Treatment with neomycin improves constipation in C-IBS. This improvement depends on the presence and elimination of methane on breath test.

Lower frequency of MMC is found in IBS subjects with abnormal lactulose breath test, suggesting bacterial overgrowth.

We have recently described an association between irritable bowel syndrome (IBS) and abnormal lactulose breath test, suggesting small intestinal bacterial overgrowth (SIBO). However, the mechanism by which SIBO develops in IBS is unknown. In this case–control study we evaluate the role of small intestinal motility in subjects with IBS and SIBO. Small intestinal motility was studied in consecutive IBS subjects with SIBO on lactulose breath test. After fluoroscopic placement of an eight-channel water-perfused manometry catheter, 4-hr fasting recordings were obtained. Based on this, the number and duration of phase III was compared to 30 control subjects. To test whether there was a relationship between the motility abnormalities seen and the SIBO status of the patient at the time of the motility, subjects with a breath test within 5 days of the antroduodenal manometry were also compared. Sixty-eight subjects with IBS and SIBO were compared to controls. The number of phase III events was 0.7 ± 0.8 in IBS subjects and 2.2 ± 1.0 in controls (P < 0.000001). The duration of phase III was 305 ± 123 sec in IBS subjects and 428 ± 173 in controls (P < 0.001). Subjects whose SIBO was still present at the time of manometry had less frequent phase III events than subjects with eradicated overgrowth (P < 0.05). In conclusion, phase III is reduced in subjects with IBS and SIBO. Eradication of bacterial overgrowth seems to result in some normalization of motility.

The Degree of Breath Methane Production in IBS Correlates With the Severity of Constipation

BACKGROUND:Recent work has demonstrated that among irritable bowel syndrome (IBS) subjects, methane on lactulose breath test (LBT) is nearly universally associated with constipation predominance. This work has been based on subjective constipation outcomes. In this study, methane is compared to constipation in another population of IBS subjects with constipation being determined both subjectively and objectively.METHODS:A nested study was conducted in subjects enrolled in a double-blind randomized placebo-controlled study. After consent, subjects were asked to complete a stool diary for 7 days. This included logging of all bowel movements that week as well as documenting the stool consistency for each during the same period using the Bristol Stool Score. After 7 days, subjects were asked to rate their symptoms on a visual analogue scale (VAS) score (0–100 mm) for diarrhea and constipation. They then had an LBT to evaluate both methane and hydrogen profiles over 180 min. Subjects with methane were compared to those without methane for Bristol Stool Score, stool frequency, as well as VAS scores for diarrhea and constipation. The degree of constipation was then compared to the quantity of methane production on LBT based on area under the curve.RESULTS:Among 87 subjects, 20 (23.8%) produced methane. IBS subjects with methane had a mean constipation severity of 66.1 ± 36.7 compared to 36.2 ± 30.8 for nonmethane producers (P < 0.001). The opposite was noted for diarrhea (P < 0.01). On LBT, the quantity of methane seen on breath test was directly proportional to the degree of constipation reported (r = 0.60, P < 0.01). In addition, greater methane production correlated with a lower stool frequency (r = −0.70, P < 0.001) and Bristol Stool Score (r = −0.58, P < 0.01).CONCLUSION:Methane on LBT is associated with constipation both subjectively and objectively. The degree of methane production on breath test appears related to the degree of constipation.

Methane and the Gastrointestinal Tract

AbstractIntroductionSeveral gases are produced through enteric fermentation in the intestinal tract. Carbon dioxide, hydrogen, hydrogen sulfide, and methane are thought to be the most common of these. Recent evidence suggests that methane may not be inert. In this review article, we summarize the findings with methane.MethodsThis is a review article discussing the various component gases in the gastrointestinal tract and their relevance to health and disease. Specific attention was paid to understanding methane.ResultsThe majority of these gases are eliminated via flatus or absorbed into systemic circulation and expelled from the lungs. Excessive gas evacuation or retention causes gastrointestinal functional symptoms such as belching, flatulence, bloating, and pain. Between 30 and 62% of healthy subjects produce methane. Methane is produced exclusively through anaerobic fermentation of both endogenous and exogenous carbohydrates by enteric microflora in humans. Methane is not utilized by humans, and analysis of respiratory methane can serve as an indirect measure of methane production. Recent literature suggests that gases such as hydrogen sulfide and methane may have active effects on gut function. In the case of hydrogen sulfide, evidence demonstrates that this gaseous product may be produced by human eukaryotic cells. However, in the case of methane, there is increasing evidence that this gas has both physical and biological effects on gut function. It is now often associated with functional constipation and may have an active role here.ConclusionThis review of the literature discusses the significance of enteric flora, the biogenesis of methane, and its clinical associations. Furthermore, we examine the evidence for an active role of methane in gastrointestinal motility and the potential applications to future therapeutics.

Measurement of Gastrointestinal Transit

An abnormality in transit is commonly considered to account for unexplained gastrointestinal (GI) symptoms. Since the symptoms of delayed transit overlap with those of accelerated transit, direct measurement of GI transit is needed to establish an accurate diagnosis. Similarly, since symptoms originating from one part of the gut may overlap with symptoms from another, localizing transit abnormality to one organ vs. another using direct measurement is an important part of diagnostic evaluations. Consequently, noninvasive tests of GI transit should be done early in the evaluation to guide therapy. We now have tools to measure transit accurately; results of transit tests often depend on the conditions selected for the test, so test results will match clinical expectations most closely when test conditions are selected to reproduce the circumstances for symptom production. This review describes the most commonly used methods for the measurement of GI transit including the gastric emptying test for some dyspeptic symptoms, small bowel transit test for dyspeptic symptoms and diarrhea, colonic transit test for constipation, and factors that influence the result of these studies. As we make progress in our understanding of the pathophysiology of transit disorders, the clinical usefulness of these diagnostic tests will be further enhanced.