American College of Gastroenterology Monograph on the Management of Irritable Bowel Syndrome and Chronic Idiopathic Constipation
2014; Lippincott Williams & Wilkins; Volume: 109; Linguagem: Inglês
10.1038/ajg.2014.187
ISSN1572-0241
AutoresAlexander C. Ford, Paul Moayyedi, Brian E. Lacy, Anthony Lembo, Yuri A. Saito, Lawrence R. Schiller, Edy Soffer, Brennan Spiegel, Eamonn M.M. Quigley,
Tópico(s)Infant Health and Development
ResumoIrritable 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 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 ingestion and interactions with components of the diet have not typically undergone rigorous evaluation in the context of a blinded trial. Based on their own experiences, IBS sufferers have generated their own theories to explain this phenomenon or seek guidance from other, usually unsupported, dietary remedies. Many IBS patients commonly believe that they have an allergy to certain foods, although true food allergies are uncommon in IBS (35). Thus, although the prevalence of true food allergies in Western societies is between 1 and 3% in adults, surveys of gastrointestinal clinic patients found that 30–50% believed that their symptoms represented food allergy or food intolerance (35,36,37). Most food-related IBS symptoms appear to represent food intolerance, although only 11–27% of patients can accurately identify the presumed offending food when re-challenged in a double-blind manner (38). Based on their own experiences with food, and despite a lack of objective evidence to incriminate a specific food, studies have shown that a majority of IBS patients institute dietary changes (39,40,41), sometimes to an extent that may compromise their nutrition (42). (b) Role of dietary manipulation in IBS:Specialized diets may improve symptoms in individual IBS patients. Recommendation: weak. Quality of evidence: very low. We identified 12 RCTs that evaluated dietary intervention in IBS (43,44,45,46,47,48,49,50,51,52,53,54). Following exclusions due to nonextractable data (46,48,50,52,53,54), lack of relevant symptom data (45,49,51), and an intervention lasting <1 week (46), three evaluable RCTs involving 230 patients remained (43,44,47). The first of these addressed the impact of gluten in IBS. In a double-blind, placebo-controlled trial, 34 patients with IBS were randomized to either remain on a gluten-free diet or to receive 16 g/day of gluten on completion of an open gluten-free run-in phase (44). In the gluten group, 68% (13/19) reported that their symptoms were not adequately controlled as compared with 6/15 (40%) in the placebo group. Continuous symptom scores for abdominal pain, bloating, satisfaction with stool consistency, and tiredness were statistically significantly better in those who maintained a gluten-free diet. The second of these studies examined the contribution of food allergy or hypersensitivity as assessed, not by immunoglobulin (Ig) E antibodies, but by IgG antibodies (43). In a double-blind, parallel-group trial, 150 IBS patients were randomized to either an exclusion diet based on the presence of IgG antibodies to various foods or a sham diet. Participants were followed for 12 weeks and symptoms assessed using a global impact score and the IBS severity score. Compared with 11/66 (17%) in the sham diet group (P=0.14), 28% (18/65) in the exclusion diet intervention arm noted a significant improvement in symptoms. The authors reported marginal statistical significance in those with high adherence to their diet. The third study examined the role of FODMAPs (fermentable oligosaccharides, disaccharides, monosaccharides, and polyols). Forty-one IBS patients were randomized to a low-FODMAP diet or their regular (habitual) diet for 4 weeks (47). Of those randomized to the low-FODMAP diet, 68% (13/19) reported adequate control of their symptoms compared with 5/22 (23%) of the habitual diet group (P=0.005). Stool consistency did not differ between groups; stool frequency was less in the low-FODMAP diet group. A significant limitation of this study was the lack of blinding regarding the dietary intervention. Summary: Belatedly perhaps, the role of dietary components in the precipitation of symptoms, or even in the basic pathogenesis of IBS, is now being addressed. To date, two mechanisms, intolerance and hypersensitivity, have been addressed in clinical trials, although it is highly plausible that other mechanisms (e.g., stimulation of gut hormones and interactions with the microbiota) may also be relevant to the effects of food or food components. While recognizing the challenges that any investigation of the role of an individual's diet or of a specific food component in IBS present, the current data provide limited guidance on the role of diet in the management of IBS. Gluten-free and low-FODMAP diets show promise but their precise role(s) in the management of IBS need to be defined. 2. Fiber in IBS Fiber provides overall symptom relief in IBS. Recommendation: weak. Quality of evidence: moderate. Psyllium, but not bran, provides overall symptom relief in IBS. Recommendation: weak. Quality of evidence: moderate. Increased intake of dietary fiber is frequently recommended to improve bowel function for IBS, particularly for constipation-related symptoms. However, insoluble fibers frequently cause bloating and abdominal discomfort. In updating our prior systematic review (18), we identified two additional studies for a total of 14 RCTs (55,56,57,58,59,60,61,62,63,64,65,66,67,68,69) involving 906 patients. All but five trials did not differentiate IBS by subtype and only two restricted recruitment to IBS-C (58,66). In the largest study to date, 275 patients, of whom 53–58% were IBS-C and 19–29% were IBS-D, were randomized to one of three arms: 10 g of the soluble fiber psyllium, 10 g of the insoluble fiber bran, or 10 g of a placebo once daily for 12 weeks (57). During the first month, a significantly greater proportion of patients receiving psyllium, but not bran, reported adequate symptom relief for at least 2 weeks compared with placebo (57% vs. 35% psyllium vs. placebo; RR 1.60, 95% CI 1.13–2.26). Bran was more effective than placebo during the third month of treatment only (57% vs. 32%; 1.70, 1.12–2.57). After 3 months of treatment, symptom severity in the psyllium group was reduced by 90 points compared with 49 points in the placebo group (P=0.03) and 58 points in the bran group (P=0.61 vs. placebo). No differences were found with respect to quality of life. Dropout was most common in the bran group; most commonly because of exacerbation in IBS. Data on overall adverse events were only provided by six trials (57,58,60,64,65,69). These trials evaluated 566 patients, but as numbers of adverse events were so small in 5 of the trials, pooling of data was not carried out. A total of 130 (38.8%) of 335 patients receiving fiber reported adverse events compared with 63 (27.3%) of 231 in the placebo arms. Summary: Although its use in the management of IBS is time honored, the status of fiber, in general, in IBS, is far from straightforward. Insoluble fibers may exacerbate symptoms and provide little relief; soluble fibers and psyllium, in particular, provide relief in IBS. These latter effects appear to transcend expected benefits in terms of relief of constipation. 3. Interventions that modify the microbiota: probiotics, prebiotics, and antibiotics The suggestion that the gut bacteria could be relevant to IBS first came from the observation that a small, although definite, proportion of individuals who suffer an episode of bacterial gastroenteritis will go on to develop IBS de novo; postinfectious IBS (70). Although bacterial fermentation has been linked to bloating and flatulence and changes in the microbiota have been described in IBS, the contribution of the microbiota to these, or other symptoms in IBS, is unclear. Thus, although both small intestinal bacterial overgrowth (SIBO) (71) and quantitative and qualitative changes in the fecal microbiota (72) have also been linked to IBS (73), the overall contribution of SIBO to IBS remains controversial (74), and findings in relation to the microbiota require confirmation in larger patient populations. Prebiotics, probiotics, and prebiotic–probiotic preparations have been used for decades on an empirical basis by IBS sufferers; they have only recently been subjected to scrutiny in clinical trials. The interpretation of probiotic studies in IBS remains challenging as studies have employed different species, strains, preparations, and doses in various patient populations and often in substandard trials. Although initial studies, employing the lactulose hydrogen breath test, suggested that more than "three quarters" of all IBS sufferers had SIBO (75), subsequent studies have, in general, failed to confirm such a high prevalence of SIBO in IBS (73,74). These divergent results may relate to problems inherent to the lactulose breath hydrogen test that may provide an overestimation of the true positive rate (73). Nevertheless, this finding provided a rationale for assessing antibiotics in IBS. Rifaximin, a nonabsorbable antibiotic, has demonstrated efficacy in clinical trials in IBS-D, and although statistically significant improvements were demonstrated over placebo in global IBS symptoms as well as in bloating, it is important to note that tests for SIBO were not performed in these pivotal trials, leaving the mechanism of action of rifaximin in IBS unclear (76). (a) Prebiotics and synbiotics in IBS: There is insufficient evidence to recommend prebiotics or synbiotics in IBS. Recommendation: weak. Quality of evidence: very low. (b) Probiotics in IBS:Taken as a whole, probiotics improve global symptoms, bloating, and flatulence in IBS. R
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