Exploring effectiveness of Metronidazole, Bismuth, and Rifaximin in treating small intestinal bacterial overgrowth and irritable bowel syndrome: A systematic review.

Lactulose breath testing, bacterial overgrowth, and IBS: just a lot of hot air?

Irritable bowel syndrome (IBS) and chronic idiopathic constipation ((CIC) also referred to as functional constipation) are two of the most common functional gastrointestinal disorders worldwide. IBS is a global problem, with anywhere from 5 to 15% of the general population experiencing symptoms that would satisfy a definition of IBS (1,2). In a systematic review on the global prevalence of IBS, Lovell and Ford (1) documented a pooled prevalence of 11% with all regions of the world suffering from this disorder at similar rates. Given its prevalence, the frequency of symptoms, and their associated debility for many patients and the fact that IBS typically occurs in younger adulthood, an important period for furthering education, embarking on careers, and/or raising families, the socioeconomic impact of IBS is considerable. These indirect medical costs are frequently compounded by the direct medical costs related to additional medical tests and the use of various medical and nonmedical remedies that may have limited impact. CIC is equally common; in another systematic review, Suares and Ford (3) reported a pooled prevalence of 14%, and also noted that constipation was more common in females, in older subjects, and those of lower socioeconomic status (3). Chronic constipation has also been linked to impaired quality of life (4), most notably among the elderly (5). Neither IBS nor CIC are associated with abnormal radiologic or endoscopic abnormalities, nor are they associated with a reliable biomarker; diagnosis currently rests entirely, therefore, on clinical grounds. Although a number of clinical definitions of both IBS and CIC have been proposed, the criteria developed through the Rome process, currently in its third iteration, have been those most widely employed in clinical trials and, therefore, most relevant to any review of the literature on the management of these disorders. According to Rome III, IBS is defined on the basis of the presence of: Recurrent abdominal pain or discomfort at least 3 days/month in the past 3 months associated with two or more of the following: Improvement with defecation Onset associated with a change in frequency of stool Onset associated with a change in form (appearance) of stool These criteria should be fulfilled for the past 3 months with symptom onset at least 6 months before diagnosis (6). Rome III defines functional constipation as: the presence of two or more of the following: Straining during at least 25% of defecations Lumpy or hard stools in at least 25% of defecations Sensation of incomplete evacuation for at least 25% of defecations Sensation of anorectal obstruction/blockage for at least 25% of defecations Manual maneuvers to facilitate at least 25% of defecations (e.g., digital evacuation, support of the pelvic floor) Fewer than three defecations per week Furthermore, loose stools are rarely present without the use of laxatives and there are insufficient criteria for IBS. Again, these criteria should be fulfilled for the past 3 months with symptom onset at least 6 months before diagnosis (6). In Rome III, IBS is subtyped according to predominant bowel habit as IBS with constipation (IBS-C), IBS with diarrhea (IBS-D), mixed type (IBS-M), and unclassified (IBS-U). The definition of bowel habit type is, in turn, based on the patient's description of stool form by referring to the Bristol Stool Scale (7). The recognition that IBS sufferers segregate into subtypes according to predominant bowel habit, together with research findings suggesting that IBS-C and IBS-D may be pathophysiologically distinct entities (8,9,10), led to the development of therapies specifically directed at each of these subtypes. Nonetheless, it is worth noting that symptoms may not be stable over a lifetime and individuals may exhibit one IBS subtype during a period, and then a different IBS subtype during another period in their lives. However, although there is general awareness of the Rome criteria, they are infrequently employed in the assessment of IBS and CIC in clinical practice (11). To provide more "clinician friendly" definitions, as well as to permit inclusion of studies that predated the Rome process, American College of Gastroenterology Task Forces suggested the following definitions in prior systematic reviews: IBS is defined by: abdominal discomfort associated with altered bowel habits (12). Constipation is defined as: a symptom-based disorder defined as unsatisfactory defecation and is characterized by infrequent stools, difficult stool passage, or both. Difficult stool passage includes straining, a sense of difficulty passing stool, incomplete evacuation, hard/lumpy stools, prolonged time to stool, or need for manual maneuvers to pass stool. CIC is defined as the presence of these symptoms for at least 3 months (13). It is important to note that the Rome III criteria state that individuals with chronic constipation do not fulfill criteria for IBS, with pain or discomfort being a major determinant in the latter. In practice, a clear separation between CIC and IBS with constipation may be challenging and studies have shown, not only considerable overlap between these entities (14,15,16), but also a significant tendency for patients to migrate between these diagnoses over time (15). It is appropriate therefore that in this update of prior American College of Gastroenterology monographs on IBS and CIC, these entities be addressed in the same exercise (12,13,17). The goal of this exercise, therefore, was to update the most recent systematic reviews commissioned by the American College of Gastroenterology on IBS from 2009 (17) and CIC from 2005 (13). METHODS We have conducted a series of systematic reviews on the efficacy of therapy in IBS and CIC. There have been several systematic reviews of therapy for IBS and CIC published in the past 5 years (18,19,20,21,22). There have been considerable data published in the intervening time, and hence we have, therefore, updated all these systematic reviews of IBS and CIC and synthesized the data, including the information from new trials, where appropriate. The primary objective of this exercise was to assess the efficacy of available therapies in treating IBS and CIC compared with placebo or no treatment. The secondary objectives included assessing the efficacy of available therapies in treating IBS according to predominant stool pattern reported (IBS with constipation, IBS with diarrhea, and mixed IBS), as well as assessing adverse events with therapies for both IBS and CIC. Systematic review methodology We evaluated manuscripts that studied adults (aged >16 years) using any definition of IBS or CIC. For IBS, this included a clinician-defined diagnosis, the Manning criteria (23), the Kruis score (24), or Rome I (25), II (26), or III (6) criteria. For CIC, this included symptoms diagnosed by any of the Rome criteria (6,25,26), as well as a clinician-defined diagnosis. We included only parallel-group randomized controlled trials (RCTs) comparing active intervention with either placebo or no therapy. Crossover trials were eligible for inclusion, provided extractable data were provided at the end of the first treatment period, before crossover. For IBS, the following treatments were considered: Diet and dietary manipulation Fiber Interventions that modify the microbiota: probiotics, prebiotics, antibiotics Antispasmodics Peppermint oil Loperamide Antidepressants Psychological therapies, including hypnotherapy Serotonergic agents Prosecretory agents Polyethylene glycol For CIC, the following were considered: Fiber Osmotic and stimulant laxatives 5-HT4 agonists Prosecretory agents Biofeedback Bile acid transporter inhibitors Probiotics Subjects needed to be followed up for at least 1 week. To be eligible, trials needed to include one or more of the following outcome measures: Global assessment of improvement in IBS or CIC symptoms Improvement in abdominal pain for IBS Global IBS symptom or abdominal pain scores for IBS Mean number of stools per week during therapy for CIC Search strategy for identification of studies MEDLINE (1946 to October 2013), EMBASE and EMBASE Classic (1947 to October 2013), and the Cochrane central register of controlled trials were searched. Studies on IBS were identified with the terms irritable bowel syndrome and functional diseases, colon (both as medical subject headings (MeSH) and free text terms), and IBS, spastic colon, irritable colon, and functional adj5 bowel (as free text terms). For RCTs of dietary manipulation, these were combined using the set operator AND with studies identified with the terms: diet, fat-restricted, diet, protein-restricted, diet, carbohydrate-restricted, diet, gluten-free, diet, macrobiotic, diet, vegetarian, diet, Mediterranean, diet fads, gluten, fructose, lactose intolerance, or lactose (both as MeSH and free text terms), or the following free text terms: FODMAP$, glutens, food adj5 intolerance, food allergy, or food hypersensitivity. For RCTs of fiber, antispasmodics, and peppermint oil, these were combined using the set operator AND with studies identified with the terms: dietary fiber, cereals, psyllium, methylcellulose, sterculia, karaya gum, parasympatholytics, hyoscyamine, scopolamine, trimebutine, muscarinic antagonists, or butylscopolammonium bromide (both as MeSH and free text terms), or the following free text terms: bulking agent, psyllium fiber, fiber, husk, bran, ispaghula, wheat bran, calcium polycarbophil, spasmolytics, spasmolytic agents, antispasmodics, mebeverine, alverine, pinaverium bromide, otilonium bromide, cimetropium bromide, hyoscine butyl bromide, butylscopolamine, peppermint oil, or colpermin. For RCTs of probiotics, these were combined using the set operator AND with studies identified with the terms: Saccharomyces, Lactobacillus, Bifidobacterium, Escherichia coli, or probiotics (both as MeSH and free text terms). For RCTs of prebiotics and synbiotics, these were combined using the set operator AND with studies identified with the term: prebiotic (both MeSH and free text terms) or synbiotic (both MeSH and free text terms). For RCTs of antibiotics, these were combined using the set operator AND with studies identified with the terms: anti-bacterial agents, penicillins, cephalosporins, rifamycins, quinolones, nitroimidazoles, tetracycline, doxycycline, amoxicillin, ciprofloxacin, metronidazole, or tinidazole (both as MeSH and free text terms), or the following free text terms: antibiotic or rifamixin. For RCTs of loperamide, these were combined using the set operator AND with studies identified with the terms: loperamide or antidiarrheals (both as MeSH and free text terms), or the following free text terms: imodium or lopex. For RCTs of antidepressants and psychological therapies, including hypnotherapy, these were combined using the set operator AND with studies identified with the terms: psychotropic drugs, antidepressive agents, antidepressive agents (tricyclic), desipramine, imipramine, trimipramine, doxepin, dothiepin, nortriptyline, amitriptyline, selective serotonin reuptake inhibitors, paroxetine, sertraline, fluoxetine, citalopram, venlafaxine, cognitive therapy, psychotherapy, behavior therapy, relaxation techniques, or hypnosis (both as MeSH and free text terms), or the following free text terms: behavioral therapy, relaxation therapy, or hypnotherapy. For RCTs of serotonergic agents, these were combined using the set operator AND with studies identified with the terms: serotonin antagonists, serotonin agonists, cisapride, receptors (serotonin, 5-HT3), or receptors (serotonin, 5-HT4) (both as MeSH and free text terms), or the following free text terms: 5-HT3, 5-HT4, alosetron, cilansetron, ramosetron, prucalopride, mosapride, or renzapride. For RCTs of pro-secretory agents, these were combined using the set operator AND with studies identified with the following free text terms: linaclotide or lubiprostone. For RCTs of polyethylene glycol (PEG), these were combined using the set operator AND with studies identified with the term polyethylene glycol (both as a MeSH and free text term). Studies on CIC were identified with the terms constipation or gastrointestinal transit (both as MeSH and free text terms), or functional constipation, idiopathic constipation, chronic constipation, or slow transit (as free text terms). For the search involving biofeedback, the free text terms dyssynergia, pelvic floor dysfunction, anismus, and outlet obstruction were also added. For RCTs of fiber, these were combined using the set operator AND with studies identified with the terms: dietary fiber, cellulose, plant extracts, psyllium, cereals, plantago, or methylcellulose (both as MeSH and free text terms), or the following free text terms: fiber, soluble fiber, insoluble fiber, bran, ispaghula, metamucil, fybogel, or ispaghula. For RCTs of osmotic and stimulant laxatives, these were combined using the set operator AND with studies identified with the terms: laxatives, cathartics, anthraquinones, phenolphthaleins, indoles, phenols, lactulose, polyethylene glycol, senna plant, senna extract, bisacodyl, phosphates, dioctyl sulfosuccinic acid, magnesium, magnesium hydroxide, sorbitol, poloxamer (both as MeSH and free text terms), or the following free text terms: sodium picosulphate, docusate, milk of magnesia, danthron, senna, and poloxalkol. For RCTs of 5-HT4 agonists, these were combined using the set operator AND with studies identified with the terms: serotonin agonists, receptors, or serotonin, 5-HT4 (both as MeSH and free text terms), or the following free text terms: prucalopride, velusetrag, or naronapride. For RCTs of pro-secretory agents, these were combined using the set operator AND with studies identified with the following free text terms: lubiprostone or linaclotide. For RCTs of biofeedback, these were combined using the set operator AND with studies identified with the MESH terms biofeedback and psychology and the following free text terms: biofeedback or neuromuscular training. For RCTs of bile acid transporter inhibitors, these were combined using the set operator AND with studies identified with the following free text terms: bile acid transporter, elobixibat, or A3309. For RCTs of probiotics, these were combined using the set operator AND with studies identified with the terms: Saccharomyces, Lactobacillus, Bifidobacterium, E. coli, or probiotics (both as MeSH and free text terms). For RCTs of prebiotics and synbiotics, these were combined using the set operator AND with studies identified with the term: prebiotic (both MESH and free text terms) or synbiotic (both MESH and free text terms). The search was limited to humans. No restrictions were applied with regard to language of publication. A recursive search of the bibliography of relevant articles was also conducted. DDW (Digestive Diseases Week) and UEGW (United European Gastroenterology Week) abstract books were hand searched between 2000 and 2013. Authors of trial reports that did not give enough detail for adequate data extraction were contacted and asked to contribute full data sets. Experts in the field were contacted for leads on unpublished studies. Trials were assessed for risk of bias according to the methods described in the Cochrane handbook [27] using the following characteristics: method used to generate the randomization schedule, method used to conceal treatment allocation, implementation of masking, completeness of follow-up, and conduct of an intention-to-treat analysis. Eligibility, quality, and outcome data were extracted by the lead reviewer (Alexander Ford) and by a masked second reviewer (Paul Moayyedi) on to specially developed forms. Any discrepancy was resolved by discussion between the two reviewers in order to reach a consensus. Data were extracted as intention-to-treat analyses, where all dropouts were assumed to be treatment failures, wherever trial reporting allowed this. Data synthesis For IBS, whenever possible, any improvement of global IBS symptoms as a binary outcome was taken as the primary outcome measure. If this was not available, improvement in abdominal pain was used. For CIC, any improvement of global CIC symptoms as a binary outcome was taken as the primary outcome measure. The impact of interventions was expressed as a relative risk (RR) of IBS or CIC symptoms not improving, together with 95% confidence intervals (CIs). If there were sufficient data, RRs were combined using the DerSimonian and Laird random effects model (28) to give a more conservative estimate of the efficacy of individual IBS therapies. For continuous data, such as global IBS symptom scores or individual IBS symptom scores, a standardized mean difference, with 95% CIs, was calculated. It should be noted that some treatments may be beneficial in IBS or CIC because of the effects on outcomes other than global symptoms or abdominal pain, but this was not evaluated and was outside of the scope of this review. Tests of heterogeneity were reported (29). When the test of heterogeneity was significant (P<0.10 and/or I2>25%), the reasons for this were explored by evaluating differences in study population, study design, or study end points in subgroup analyses. Publication bias or other causes of small study effects were evaluated using tests for funnel plot asymmetry (30), where sufficient studies were identified (31). The number needed to treat (NNT), which is the number of patients who would need to receive active therapy, over and above the control therapy, for one to experience an improvement in symptoms, and the number needed to harm (NNH), which is the number of patients who would need to receive active therapy, over and above the control therapy, for one to experience an adverse event were calculated as the inverse of the risk difference from the meta-analysis and checked using the formula: NNT = 100 / RRR × BR, where BR is baseline risk and RRR is relative risk reduction. Methodology for assessing levels of evidence and grading recommendations We used the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system for grading the quality of evidence and strength of recommendation for each medical intervention (32). The system has been widely used in evidence-based guidelines and is endorsed by all major gastrointestinal societies (http://www.gradeworkinggroup.org). The quality of the evidence is based on the study design, as well as the extent of risk of bias, inconsistency, indirectness, imprecision, and publication bias that exists for the evidence supporting the intervention (33). Quality of evidence is described as high to very low, depending on the extent to which further evidence would change the estimate of treatment effect (Box 1). The grading scheme also classifies recommendations as strong or weak, according to the quality of the evidence, applicability to all patient groups, balance of benefits and risks, patient preferences, and cost. With this graded recommendation, the clinician receives guidance about whether or not recommendations should be applied to most patients, and whether or not recommendations are likely to change in the future after production of new evidence. "Strong" recommendations represent a "recommendation that can apply to most patients in most circumstances and further evidence is unlikely to change our confidence in the estimate of treatment effect." The summary of the evidence for IBS is presented in Table 1, the reasons for the decision on the quality of that evidence in Table 2, and the reasons for the strength of recommendation in Table 3. Similarly, the summary of the evidence for CIC is presented in Table 4, the reasons for the decision on quality of the evidence in Table 5, and the reasons for the strength of recommendation in Table 6.Box 1.: Interpretation of the grading of the quality of evidenceTable 1: Summary of results of monograph on interventions for IBSTable 2: Reasons for quality of evidence of assessment for IBS data according to GRADE criteriaTable 2: Continued.Table 3: Reasons for strength of recommendation for IBS therapies according to GRADE criteriaTable 4: Summary of results of monograph on interventions for CICTable 5: Reasons for quality of evidence of assessment of data on CIC according to GRADE criteriaTable 6: Reasons for strength of recommendation for treatments of CIC according to GRADE criteriaRESULTS Irritable bowel syndrome 1. Diet and dietary manipulation in IBS (a) Role of diet in IBS: Although food intake is one of the most common precipitants of symptoms in IBS (34), responses to food and with of the diet have not typically in the of a on their IBS sufferers have their to this or guidance from dietary IBS patients that they have an to although food are in IBS although the prevalence of food in societies is between 1 and in of gastrointestinal patients that that their symptoms food or food IBS symptoms to represent food intolerance, although only of patients can the food in a on their with and a of objective evidence to a studies have that a of IBS patients dietary to an extent that may their Role of dietary manipulation in may symptoms in individual IBS Quality of very We identified RCTs that evaluated dietary intervention in IBS to data of relevant symptom data and an intervention week three RCTs involving patients The first of these addressed the impact of in IBS. In a patients with IBS were randomized to either on a diet or to receive of on of an In the reported that their symptoms were not controlled as compared with in the placebo symptom scores for abdominal pain, with stool and were in those who a The second of these studies the of food or as not by but by In a parallel-group IBS patients were randomized to either an diet based on the presence of to various or a were followed for and symptoms assessed using a global impact score and the IBS with in the diet in the diet intervention noted a significant improvement in The reported in those with high to their The third study the of and IBS patients were randomized to a diet or their diet for those randomized to the diet, reported adequate control of their symptoms compared with of the diet Stool did not between stool frequency was in the diet A significant of this study was the of the dietary the of dietary in the of symptoms, or in the of IBS, is being To two and have been addressed in clinical trials, although it is that other (e.g., of and with the may also be relevant to the effects of food or food the that any of the of an diet or of a food in IBS the data provide limited guidance on the of diet in the management of IBS. and but their in the management of IBS need to be Fiber in IBS Fiber symptom in IBS. Quality of but not bran, symptom in IBS. Quality of intake of dietary is frequently to bowel for IBS, for However, insoluble frequently and abdominal In our prior systematic review we identified two additional studies for a of RCTs involving but trials did not IBS by subtype and only two to IBS-C In the study to patients, of were IBS-C and were were randomized to one of three of the soluble psyllium, of the insoluble bran, or of a placebo for the first a of patients psyllium, but not bran, reported adequate symptom for at least compared with placebo psyllium 95% was more than placebo during the third of treatment only 3 months of symptom in the psyllium was by points compared with points in the placebo and points in the No differences were with to quality of was most common in the most because of in IBS. Data on adverse events were only provided by trials These trials evaluated patients, but as of adverse events were small in 5 of the trials, of data was not A of of patients reported adverse events compared with of in the placebo Although its use in the management of IBS is time the status of fiber, in in IBS, is from may symptoms and provide soluble and psyllium, in provide in IBS. These effects to benefits in terms of of 3. Interventions that modify the microbiota: probiotics, prebiotics, and antibiotics The that the be relevant to IBS first from the that a although of individuals who an of on to IBS IBS Although has been linked to and and in the have been described in IBS, the of the to or other symptoms in IBS, is although both small and and in the have also been linked to IBS the of to IBS and findings in to the in patient probiotics, and have been used for on an basis by IBS they have only been to in clinical The of studies in IBS challenging as studies have employed different and in various patient and in Although the suggested that more than of all IBS sufferers studies have, in to such a high prevalence of in IBS These results may to to the test that may provide an of the this provided a for assessing antibiotics in IBS. a has efficacy in clinical trials in and although significant were over placebo in global IBS symptoms as well as in it is important to note that tests for were not in these trials, the of of in IBS (a) and in IBS: There is insufficient evidence to prebiotics or in IBS. Quality of very Probiotics in as a probiotics global symptoms, and in IBS.

Background: Irritable bowel syndrome (IBS) is one of the most common functional gastrointestinal disorder with absence of organic damages to the intestine. The pathophysiology of IBS is still not completely understood, but in some cases psychological disorders may affect the onset and outcome of IBS. Some studies have found disparities between subtypes of irritable bowel syndrome (IBS) regarding socio-demographic characteristics and lifestyle factors.Methods: This cross-sectional study aimed to investigate whether there are differences in sociodemographic and lifestyle factors including smoking and physical activity between the subtypes of IBS. The study was performed on outpatients diagnosed as irritable bowel syndrome (from January 2015 to December 2015) in Dhaka Medical College Hospital and Shaheed Suhrawardy Medical College Hospital in Dhaka. A total of purposively selected 208 diagnosed IBS patients were interviewed by semi-structured questionnaire in which subtype of irritable bowel syndrome were measured by Rome-III criteria regarding stool consistency.Results: Mean age of the respondents was 32.3 (+ 10.32) years and majority of them were male (77%), married (66.8%), educated up to secondary level (35.6%), labour (skilled and unskilled) (30%), non- smoker (67.3%) and HEPA (health enhancing physical activity) active (65.9%). Diarrhea predominant irritable bowel syndrome (50%) was found the most common subtype among the irritable bowel syndrome respondents followed by mixed type irritable bowel syndrome (42%) and constipation predominant irritable bowel syndrome (8%) There were no statistical differences found between constipation predominant irritable bowel syndrome ( IBS-C), Diarrhea predominant irritable bowel syndrome (IBS-D), and mixed type irritable bowel syndrome (IBSM) patients regarding to socio-demographic characteristics and lifestyle factors (P&lt;0.05).Conclusion: Our study concluded that there are no different socio-demographic and lifestyle characteristics between IBS subtypes.J Shaheed Suhrawardy Med Coll, June 2017, Vol.9(1); 6-9

Objective To investigate the incidence of small intestinal bacterial overgrowth (SIBO) and systemic low-grade inflammation in patients with irritable bowel syndrome (IBS). Methods From June to October in 2017, 50 cases of IBS patients who met Rome Ⅳ criteria were consecutively collected at Outpatient Department of Gastroenterology of Shanghai Huashan Hospital. The incidence of SIBO was detected by hydrogen lactulose breath test (LBT) and methane LBT. The incidence of systemic low-grade inflammation in IBS patients was determined by fractional exhaled nitric oxide(FeNO) breath test. Chi-square test was used for statistical analysis. Results Among 50 IBS patients, the positive rate of FeNO was 70%(35/50), and the number of FeNO positive cases in diarrhea-predominant (n=28), constipation-predominant (n=14) and mix-type (n=8) IBS paitents was 18, 11 and six, respectively, and the difference was not statistically significant among three groups (χ2=1.020, P=0.600). The incidence rate of SIBO was 60% (30/50), with 20 cases (40%) being only positive for hydrogen LBT, seven cases (14%) being methane LBT, and three cases (6%) being both positive. The numbers of hydrogen LBT and methane LBT in diarrhea-predominant, constipation-predominant, and mix-type IBS patents were 17, three, three and two, six, two, respectively. There were statistically significant differences in positive rates of hydrogen LBT and methane LBT among three groups (χ2=6.076 and 6.392, both P<0.05). The positive rate of FeNO in IBS patients with SIBO was higher than that of IBS patients without SIBO (90%, 27/30 vs. 40%, 8/20), and the difference was statistically significant (χ2=14.286, P<0.01). Conclusions Combination of hydrogen LBT and methane LBT has a higher detection rate of SIBO than traditional single hydrogen LBT. There is a correlation between SIBO and systemic low-grade inflammation in IBS patients. Key words: Irritable bowel syndrome; Small intestinal bacterial overgrowth; Lactulose breath test; Systemic low-grade inflammation

Enteric microbiota is increasingly being recognized as an important factor in the pathogenesis of irritable bowel syndrome (IBS). The reported prevalence of small intestinal bacterial overgrowth (SIBO) in subjects with IBS is highly variable, and there is no consensus on the role of SIBO in different subtypes of IBS, and indications and methods of testing. A comprehensive literature search was performed for studies applying tests for SIBO in subjects with IBS. After applying prospectively decided exclusion criteria, the eligible papers were examined using a meta-analysis approach for the prevalence of SIBO in subjects with IBS using different tests. The odds ratios of SIBO among subjects with IBS as compared with healthy controls using different tests were calculated. Of the available studies (22, 17, 5, and 3 using lactulose and glucose hydrogen breath tests [LHBT and GHBT], jejunal aspirate culture, and more than one tests, respectively) meeting the inclusion criteria, 36.7% (95% confidence interval [CI] 24.2-44.6) had a positive test for SIBO. Patients with IBS were 2.6 (95% CI 1.3-6.9) and 8.3 (95% CI 3.0-5.9) times more likely to have a positive test for SIBO as compared with healthy controls using GHBT and jejunal aspirate culture, respectively. Patients with diarrhea-predominant IBS were more likely to have positive GHBT as compared with the other subtypes. Patients with IBS were more likely to have SIBO as compared with healthy subjects using GHBT and jejunal aspirate culture but not using LHBT. Patients with diarrhea-predominant IBS more often have SIBO.

Small intestinal bacterial overgrowth (SIBO) is a clinical condition caused by excessive number of bacteria in the small bowel. SIBO is characterized by symptoms of diarrhea, abdominal pain, or bloating which may be associated with excessive gas of small intestine due to increased production by bacterial fermentation in the gut. In the last decade, SIBO has been occupied as a hot topic of interests by a group of researchers because of its potential role in the development of irritable bowel syndrome (IBS).1 In the diagnosis of SIBO, a bacterial count greater than 105 colony-forming units/mL by small bowel culture is believed to be the gold standard.2 But small bowel culture through jejunal aspirate is time-consuming, invasive, and potential for contamination. Due to several flaws of small bowel culture, a number of non-invasive and indirect tests for diagnosing SIBO have been developed. Breath test, the most common indirect method for evaluating SIBO, utilizes the metabolism of carbohydrates by bacterial enzymes, in turn indirectly measures bacterial activity of small bowel. Different carbohydrates have different properties. As lactulose is a non-absorbable carbohydrate, it easily reaches the site of potential overgrowth in the small bowel, although non-absorbed carbohydrate has limitations by the intestinal transit time. In patients with rapid transit, lactulose may produce an early hydrogen peak which makes it difficult to discriminate the true SIBO from a phenomenon by rapid intestinal transit, therefore specificity of lactulose hydrogen breath test (LHBT) is relatively low.3 Pimentel and colleagues4 suggested a concept that SIBO is a major pathogenic mechanism underlying IBS in 2000. They have found 78% of 202 IBS subjects to be positive for LHBT which is suggestive of SIBO. They also demonstrated a significant improvement in symptoms including abdominal pain, bloating, and diarrhea by treating SIBO with antibiotics and converted many IBS patients from Rome criteria positive to negative. Since then, SIBO has been proposed as an etiologic factor in IBS, but also the potential role of SIBO in IBS has been strongly debated about the methods used in diagnosing SIBO. A prevalence of SIBO in subjects meeting diagnostic criteria for IBS varies from 4% to 64%, depending on the kind of test and criteria used to define a positive result.5 In addition, a recent well-designed study from the US6 using LHBT to diagnose SIBO could not discriminate patients with IBS from healthy subjects, which was a consistent finding the authors demonstrated previously.7 Therefore, the proposed etiologic role of SIBO diagnosed by LHBT in IBS patients is controversial and the correlation between the normalization of the LHBT following antibiotic treatment and symptom improvement has become less clear. Glucose, on the other hand, is rapidly absorbed in the proximal small bowel. Thereby detecting hydrogen in this test means SIBO in a proximal location. Glucose hydrogen breath test (GHBT) is the most commonly used test in the diagnosis of SIBO, although GHBT may be less sensitive for the diagnosis of SIBO since it is absorbed in the proximal small bowel. GHBT has been reported to have a overall sensitivity between 25% to 93% and a specificity from 34% to 96% in detecting SIBO.3,5 In this issue of the Journal of Neurogastroenterology and Motility, Ghoshal et al. reported the frequency of SIBO in patients with IBS and chronic non-specific diarrhea (CNSD) with comparison to healthy controls by using GHBT. The authors found that SIBO was more common in patients with CNSD (21.9%) than those with IBS (8.5%) and healthy controls (2%). Since CNSD including diarrhea predominant IBS (D-IBS) had higher frequency of SIBO, the authors suggested clinicians to consider testing for SIBO among them. However, since false positive GHBT could result from rapid intestinal transit in patients with diarrhea, the frequency of SIBO in patients with CNSD and D-IBS demonstrated in the author's study might have been overestimated in part.

Objective: Diarrhea-predominant irritable bowel syndrome (IBS-D) is the main subtype of IBS, a chronic functional gastrointestinal disorder. Small intestinal bacterial overgrowth (SIBO), which is characterized by dysbiosis of the bowel, causes gastrointestinal symptoms quite similar to IBS-D. However, whether SIBO correlates with IBS-D and its further mechanism remain unknown.Materials and Methods: The study included 60 IBS-D patients that fulfilled Rome IV criteria and 60 healthy controls. All subjects were undergoing a lactose breath test (LBT) to diagnose SIBO. IBS-D patients were further assigned to negative SIBO (SIBO-) subgroup and positive SIBO (SIBO+) subgroup to analyze the scores of symptoms and differences in the fecal microbiota.Results: The prevalence of SIBO in IBS-D patients was higher than that in healthy controls (51.7% vs. 16.7%, p ≤ .001). In addition, IBS-SSS in SIBO+ subgroup was significantly higher than SIBO- subgroup (p = .015). The 16S rRNA analyses showed that composition and abundance of fecal microbiota were obviously different between the two subgroups. There was a remarkable increase in Prevotella in IBS-D patients, especially in IBS-D SIBO+ sufferers. Meanwhile, there were a moderately positive correlation of the abundance of Prevotella (rho = 0.458, p ≤ .001) with IBS-SSS.Conclusion: SIBO is associated with IBS-D, which may be related to alteration in the intestinal microbiota. These findings suggest the potent role of Prevotella in gastrointestinal symptoms between SIBO and IBS-D, thus provide a novel insight into the connection between SIBO and IBS-D.

Functional Bowel Disorders

The pathogenesis of irritable bowel syndrome (IBS), once thought to be largely psychogenic in origin, is now understood to be multifactorial. One of the reasons for this paradigm shift is the realization that gut dysbiosis, including small intestinal bacterial overgrowth (SIBO), causes IBS symptoms. Between 4% and 78% of patients with IBS and 1% and 40% of controls have SIBO; such wide variations in prevalence might result from population differences, IBS diagnostic criteria, and, most importantly, methods to diagnose SIBO. Although quantitative jejunal aspirate culture is considered the gold standard for the diagnosis of SIBO, noninvasive hydrogen breath tests have been popular. Although the glucose hydrogen breath test is highly specific, its sensitivity is low; in contrast, the early-peak criteria in the lactulose hydrogen breath test are highly nonspecific. Female gender, older age, diarrhea-predominant IBS, bloating and flatulence, proton pump inhibitor and narcotic intake, and low hemoglobin are associated with SIBO among IBS patients. Several therapeutic trials targeting gut microbes using antibiotics and probiotics have further demonstrated that not all symptoms in patients with IBS originate in the brain but rather in the gut, providing support for the micro-organic basis of IBS. A recent proof-of-concept study showing the high frequency of symptom improvement in patients with IBS with SIBO further supports this hypothesis.

Small intestinal bacterial overgrowth (SIBO) is prevalent in irritable bowel syndrome (IBS), but its' association with other functional gastrointestinal disorders (FGIDs) is less certain. This study aimed to explore SIBO in a multi-racial Asian population with various FGIDs compared to non-FGID controls. Consecutive Asian adults with Rome III diagnosed common FGIDs (functional dyspepsia/FD, IBS and functional constipation/FC) and non-FGID controls were subjected to glucose breath testing, with hydrogen (H2) and methane (CH4) levels determined. A total of 244 participants (FGIDs n = 186, controls n = 58, median age 45years, males 36%, Malay ethnicity 76%) were recruited. FGIDs had a higher prevalence trend of SIBO compared to controls (16% FGIDs vs. 10% controls, p = 0.278) with 14% in FD, 18% in IBS and 17% in FC. Compared to controls, SIBO was associated with diarrhoea-predominant IBS (IBS-D) (24% vs. 10%, P = 0.050) but not with other types of FGIDs. IBS-D remained an independent predictor of SIBO (OR = 2.864, 95% CI 1.160-7.071, p = 0.023) but not PPI usage nor history of diabetes (both p > 0.050) at multivariate analysis. Compared to controls, SIBO in IBS-D was associated with an elevated H2 level (≥ 20ppm from baseline) (18% vs. 3%, p = 0.017), but not CH4 levels (≥ 10ppm) (9% vs. 7%, p = 0.493). In addition, no difference was found in the prevalence of methane-positive SIBO between chronic constipation (constipation-predominant IBS and FC) compared to controls (9% vs. 7%, P = 0.466). SIBO is prevalent amongst multi-ethnic Asian adults with and without FGIDs. Amongst various FGIDs, only IBS-D is significantly associated with SIBO.

Immune Activation in Patients With Irritable Bowel Syndrome

Актуальность. Статья посвящена проблеме возникновения синдрома избыточного бактериального роста (СИБР) при хронических воспалительных заболеваниях кишечника (ХВЗК) и синдроме раздраженного кишечника (СРК) и путям его коррекции. Цель: определить частоту возникновения СИБР при болезни Крона (БК), неспецифическом язвенном колите (НЯК) и СРК с диареей и оценить эффективность рифаксимина в коррекции микрофлоры тонкой кишки у больных с данными нозологиями. Материалы и методы. Проведено обследование 62 больных ХВЗК и СРК (27 — с НЯК, 13 — с БК и 22 — с СРК) на наличие СИБР путем выполнения дыхательного водородного теста (ВДТ) с нагрузкой глюкозой. Все больные группы исследования с наличием СИБР в составе комплексной терапии принимали рифаксимин (Альфа Нормикс) в дозе 1200 мг в сутки в течение 10 дней. Эффективность терапии определялась по динамике показателей ВДТ на 10 и 30 день наблюдения. Результаты. СИБР отмечался у 39 пациентов общей группы, из них 24 (61,5 %) человека страдали ХВЗК, СРК с диареей — 15 человек (38,5 %). В группе больных ХВЗК с СИБР преобладали пациенты с НЯК (15 человек; 62,5 %) по сравнению с БК (9 человек; 37,5 %). ВДТ, проведенный через 10 дней от начала лечения рифаксимином у 24 больных ХВЗК и 15 больных СРК с наличием СИБР, был отрицательным у 28 человек (70,9 %), положительным — у 11 (29,1 %). Подобный результат отмечен через 30 дней. СИБР был устранен у 70,9 % больных на фоне приема рифаксимина. Выводы. У большинства пациентов группы исследования (у 60 % — с ХВЗК и 68,1% — с СРК с диареей) был СИБР. Кишечный антисептик рифаксимин продемонстрировал высокую эффективность в коррекции СИБР при НЯК, БК и СРК.

Small intestinal bacterial overgrowth (SIBO) is one manifestation of gut microbiome dysbiosis and is highly prevalent in IBS (Irritable Bowel Syndrome). SIBO can be diagnosed either by a small bowel aspirate culture showing ≥103 colony-forming units (CFU) per mL of aspirate, or a positive hydrogen lactulose or glucose breath test. Numerous pathogenic organisms have been shown to be increased in subjects with SIBO and IBS, including but not limited to Enterococcus, Escherichia coli, and Klebsiella. In addition, Methanobrevibacter smithii, the causal organism in a positive methane breath test, has been linked to constipation predominant irritable bowel syndrome (IBS-C). As M. smithii is an archaeon and can overgrow in areas outside of the small intestine, it was recently proposed that the term intestinal methanogen overgrowth (IMO) is more appropriate for the overgrowth of these organisms. Due to gut microbiome dysbiosis, patients with IBS may have increased intestinal permeability, dysmotility, chronic inflammation, autoimmunity, decreased absorption of bile salts, and even altered enteral and central neuronal activity. As a consequence, SIBO and IBS share a myriad of symptoms including abdominal pain, distention, diarrhea, and bloating. Furthermore, gut microbiome dysbiosis may be associated with select neuropsychological symptoms, although more research is needed to confirm this connection. This review will focus on the role of the gut microbiome and SIBO in IBS, as well as novel innovations that may help better characterize intestinal overgrowth and microbial dysbiosis.

Objective: To explore the diet features of diarrhea predominant irritable bowel syndrome (IBS-D) with small intestinal bacterial overgrowth (SIBO). Methods: IBS-D patients were enrolled in outpatient department of Peking University Third Hospital from March 2015 to April 2016. Healthy volunteers were recruited as controls (HC). All the subjects completed screening examinations, clinical and food investigation, and lactulose methane and hydrogen breath test (LMHBT). The high fat diet is defined as the daily total calories supplying from fat is more than 50%. Results: Eighty-eight IBS-D patients and 32 HC were finally enrolled. The positive rate of LMHBT in IBS-D was significantly higher than that of HC[39.8% (35/88) vs 12.5%(4/28), P=0.005]. The 28 HC with negative LMHBT were enrolled in the follow-up analysis. (1) The BMI of IBS-P (IBS-D with positive LMHBT) was significantly lower than IBS-N (IBS-D with negative LMHBT) [(21.57±0.54) vs (23.30±0.53)kg/m(2,) P=0.032]. IBS-D patients with SIBO had higher scores of abdominal pain assess. (2) The proportion of dietary protein and carbohydrate in IBS-D was significantly higher than that of HC (14.39% vs 12.22%, P=0.001; 53.94% vs 46.25%, P=0.003, respectively). The proportion of diet fat was significantly higher in IBS-P than IBS-N[(47.19±2.62)% vs (40.74±1.66)%, P=0.038]. (3) The baseline of breath methane in IBS-P was significantly higher than that of in IBS-N[(8.69±0.39) ×10(-6) vs (6.39±0.47) ×10(-6,) P=0.002]. IBS-D patients with high fat diet had higher LMHBT positive rate than that of non-high fat diet patients[54.2% (13/24) vs 17.2% (11/64), P=0.001]. Breath methane peak value was positively correlated with the fat proportion of diet (r=0.413, P=0.022). Conclusions: About 39.8% IBS-D patients diagnosed by Rome Ⅲ are combined with SIBO. SIBO may affect IBS-D patients' nutritional status. High fat diet might be one of the risk factors for IBS-D with SIBO. Proper diet structure might reduce the prevalence of IBS-D, especially for IBS-D with SIBO.

Irritable bowel syndrome (IBS) is a common diagnosis in gastroenterology with patients usually subgrouped under the Rome clinical criteria according to their bowel pattern. Although an individual may be classified as diarrhea-predominant IBS or constipation-predominant IBS, patients often resist this subgrouping by saying that they have both constipation and diarrhea. Regardless of their predominant bowel complaint, 92% of IBS patients share the symptom of bloating. Bloating secondary to abnormal bacterial fermentation is a feature of small intestinal bacterial overgrowth (SIBO). The role for an antibiotic-sensitive mechanism in IBS such as SIBO is supported by 2 double-blind, randomized, placebo-controlled trial showing: (1) a 75% improvement in global bowel symptoms when bacterial overgrowth was successfully treated with a nonabsorbable antibiotic and (2) a sustained improvement of symptoms for a period of 10 weeks after the treatment with a small bowel-targeting antibiotic. Although diarrhea is a well-known symptom in SIBO, constipation may also be a consequence of altered host-gut microbial relationship through the action of the bacterial gas methane on intestinal motility. In addition to bloating and bowel symptoms, a number of extraintestinal complaints are common in patients with IBS, including psychologic changes such as anxiety. Animal data would suggest that anxiety may also be a consequence of altered host-gut microbial relationship. In this review, we will discuss the role of gut bacteria in the gastrointestinal and extraintestinal presentations of IBS.