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The efficacy of probiotics in the treatment of irritable bowel syndrome: a systematic review. Moayyedi P,Ford A C,Talley N J,Cremonini F,Foxx-Orenstein A E,Brandt L J,Quigley E M M Gut INTRODUCTION:Probiotics may benefit irritable bowel syndrome (IBS) symptoms, but randomised controlled trials (RCTs) have been conflicting; therefore a systematic review was conducted. METHODS:MEDLINE (1966 to May 2008), EMBASE (1988 to May 2008) and the Cochrane Controlled Trials Register (2008) electronic databases were searched, as were abstracts from DDW (Digestive Diseases Week) and UEGW (United European Gastroenterology Week), and authors were contacted for extra information. Only parallel group RCTs with at least 1 week of treatment comparing probiotics with placebo or no treatment in adults with IBS according to any acceptable definition were included. Studies had to provide improvement in abdominal pain or global IBS symptoms as an outcome. Eligibility assessment and data extraction were performed by two independent researchers. Data were synthesised using relative risk (RR) of symptoms not improving for dichotomous data and standardised mean difference (SMD) for continuous data using random effects models. RESULTS:19 RCTs (18 papers) in 1650 patients with IBS were identified. Trial quality was generally good, with nine reporting adequate methods of randomisation and six a method of concealment of allocation. There were 10 RCTs involving 918 patients providing outcomes as a dichotomous variable. Probiotics were statistically significantly better than placebo (RR of IBS not improving=0.71; 95% CI 0.57 to 0.88) with a number needed to treat (NNT)=4 (95% CI 3 to 12.5). There was significant heterogeneity (chi(2)=28.3, p=0.001, I(2)=68%) and possible funnel plot asymmetry. Fifteen trials assessing 1351 patients reported on improvement in IBS score as a continuous outcome (SMD=-0.34; 95% CI -0.60 to -0.07). There was statistically significant heterogeneity (chi(2)=67.04, p<0.001, I(2)=79%), but this was explained by one outlying trial. CONCLUSION:Probiotics appear to be efficacious in IBS, but the magnitude of benefit and the most effective species and strain are uncertain. 10.1136/gut.2008.167270
Gender differences in irritable bowel syndrome. Chang Lin,Heitkemper Margaret M Gastroenterology In the United States and other Western cultures, a greater number of women seek health care services for symptoms of functional pain disorders, including irritable bowel syndrome, than men. Recent clinical trials indicate that gender differences in responsiveness to drug therapy also occur. Several lines of inquiry have focused on explaining this gender-related difference due to the higher prevalence of these disorders in women. Evidence of a physiologic component is based on gender differences in gastrointestinal transit time, visceral sensitivity, central nervous system pain processing, and specific effects of estrogen and progesterone on gut function. Additional factors may play a role, including gender-related differences in neuroendocrine, autonomic nervous system, and stress reactivity, which are related to bowel function and pain. However, the link between these measures and gut motility or sensitivity remains to be clarified. Psychological characteristics, including somatization, depression, and anxiety as well as a history of sexual abuse, may also contribute to gender-related differences in the prevalence of irritable bowel syndrome. Although gender differences in the therapeutic benefit of serotonergic agents have been observed, less is known about potential differences in responsiveness to nondrug therapies for irritable bowel syndrome. 10.1053/gast.2002.36603
Genetic approaches to functional gastrointestinal disorders. Gastroenterology Functional gastrointestinal disorders are complex symptom-based disorders without agreed upon biomarkers or pathophysiology. A better understanding of the genetic architecture of these disorders would help to better identify their complex biology and explain the common comorbidity with other disorders of persistent pain, mood, and affect, as well as possibly make it possible to identify subgroups of patients who respond to customized therapies. In contrast to monogenic diseases, polygenic diseases and traits are characterized by the contribution of common variants in a large number of genes, as well as environmental factors, to the vulnerability of an individual. Family and twin studies have clearly established a genetic component in irritable bowel syndrome. Although candidate gene studies have identified a few gene polymorphisms that may be correlated with the syndrome, small sample size, lack of reproducibility in large data sets, and the unreliability of the clinical phenotype require caution when extrapolating to a major role of any of the reported polymorphisms in the pathophysiology of irritable bowel syndrome. Future progress in this area will require better characterization of intermediate phenotypes with large effect size for the clinical phenotype, as well as consideration of gene-gene, environment-gene (epigenetics), and sex-gene interactions, genome-wide association, and whole genome sequencing approaches in large data sets. 10.1053/j.gastro.2010.02.037
Irritable bowel syndrome: a little understood organic bowel disease? Talley Nicholas J,Spiller Robin Lancet (London, England) Irritable bowel syndrome affects 10% of adults with an unexplained female predominance. Although only a few people see their family doctor, the disease causes reduced quality of life and represents a multi-billion pound health-care problem. The disorder clusters in families, which is possibly because of intra-familial learning and a genetic predisposition. Visceral hypersensitivity is a key feature in most patients. Results of imaging studies of regional cerebral blood flow during rectal distension suggest underlying disturbances of central processing of afferent signals, though this is not unique to the disorder, since it is seen in other chronic pain syndromes. Environmental factors that are strongly implicated in at least some patients include gastrointestinal infection and inflammation and chronic stress. Diagnosis is based on positive symptoms and absence of any alarm indicators. Treatment remains unsatisfactory and hinges on an excellent doctor-patient relationship, with drugs for symptom exacerbations. Cognitive behavioural treatment, psychotherapy, and hypnosis could provide long-lasting benefit in some patients. Tricyclic antidepressants in low doses seem to be the most effective class of drugs for the disorder on the basis of limited data. 10.1016/S0140-6736(02)09712-X
Targeting serotonin synthesis to treat irritable bowel syndrome. Tack Jan,Janssen Pieter,Wouters Mira,Boeckxstaens Guy Gastroenterology 10.1053/j.gastro.2011.06.024
Challenges to the therapeutic pipeline for irritable bowel syndrome: end points and regulatory hurdles. Camilleri Michael,Chang Lin Gastroenterology Recent advances in our understanding of basic neuroenteric mechanisms and the role of effectors and transmitters in the brain-gut axis have provided opportunities to develop new therapeutic agents for irritable bowel syndrome (IBS). Furthermore, human pharmacodynamic studies utilizing transit, colonic, or rectal sensitivity and brain imaging have been useful in determining therapeutic efficacy (particularly for drugs that act on motor function). This review provides an overview of medications that have not yet been approved for treatment of patients with IBS yet have shown promise in phase IIB trials. These include drugs that act on the serotonin receptor and transporter system: antidepressants, norepinephrine reuptake inhibitors, opioids, cholecystokinin antagonists, neurokinin-antagonists, chloride channel activators, guanylate cyclase C agonists, atypical benzodiazepines, probiotics, and antibiotics. The changing landscape in the regulatory approval process has impacted the development of IBS drugs. Guidance documents from regulatory agencies in Europe and the United States have focused on patients' reported outcomes and associated quality of life. After a decade of experience with different end points that have generated some data on psychometric validation and unprecedented information about responsiveness of the binary or global end points to drug therapy, it is necessary to pursue further validation studies before or during pivotal phase IIB or III trials. The hope of providing relief to patients should galvanize all parties to achieve these goals. 10.1053/j.gastro.2008.09.005
The irritable bowel syndrome. Horwitz B J,Fisher R S The New England journal of medicine 10.1056/NEJM200106143442407
Functional bowel disorders and functional abdominal pain. Thompson W G,Longstreth G F,Drossman D A,Heaton K W,Irvine E J,Müller-Lissner S A Gut The Rome diagnostic criteria for the functional bowel disorders and functional abdominal pain are used widely in research and practice. A committee consensus approach, including criticism from multinational expert reviewers, was used to revise the diagnostic criteria and update diagnosis and treatment recommendations, based on research results. The terminology was clarified and the diagnostic criteria and management recommendations were revised. A functional bowel disorder (FBD) is diagnosed by characteristic symptoms for at least 12 weeks during the preceding 12 months in the absence of a structural or biochemical explanation. The irritable bowel syndrome, functional abdominal bloating, functional constipation, and functional diarrhea are distinguished by symptom-based diagnostic criteria. Unspecified FBD lacks criteria for the other FBDs. Diagnostic testing is individualized, depending on patient age, primary symptom characteristics, and other clinical and laboratory features. Functional abdominal pain (FAP) is defined as either the FAP syndrome, which requires at least six months of pain with poor relation to gut function and loss of daily activities, or unspecified FAP, which lacks criteria for the FAP syndrome. An organic cause for the pain must be excluded, but aspects of the patient's pain behavior are of primary importance. Treatment of the FBDs relies upon confident diagnosis, explanation, and reassurance. Diet alteration, drug treatment, and psychotherapy may be beneficial, depending on the symptoms and psychological features. 10.1136/gut.45.2008.ii43
Efficacy of antidepressants and psychological therapies in irritable bowel syndrome: systematic review and meta-analysis. Ford A C,Talley N J,Schoenfeld P S,Quigley E M M,Moayyedi P Gut OBJECTIVE:Irritable bowel syndrome (IBS) is a chronic functional gastrointestinal disorder. Evidence for treatment of the condition with antidepressants and psychological therapies is conflicting. DESIGN:Systematic review and meta-analysis of randomised controlled trials (RCTs). MEDLINE, EMBASE and the Cochrane Controlled Trials Register were searched (up to May 2008). SETTING:RCTs based in primary, secondary and tertiary care. PATIENTS:Adults with IBS. INTERVENTIONS:Antidepressants versus placebo, and psychological therapies versus control therapy or "usual management". MAIN OUTCOME MEASURES:Dichotomous symptom data were pooled to obtain a relative risk (RR) of remaining symptomatic after therapy, with a 95% confidence interval (CI). The number needed to treat (NNT) was calculated from the reciprocal of the risk difference. RESULTS:The search strategy identified 571 citations. Thirty-two RCTs were eligible for inclusion: 19 compared psychological therapies with control therapy or "usual management", 12 compared antidepressants with placebo, and one compared both psychological therapy and antidepressants with placebo. Study quality was generally good for antidepressant but poor for psychological therapy trials. The RR of IBS symptoms persisting with antidepressants versus placebo was 0.66 (95% CI, 0.57 to 0.78), with similar treatment effects for both tricyclic antidepressants and selective serotonin reuptake inhibitors. The RR of symptoms persisting with psychological therapies was 0.67 (95% CI, 0.57 to 0.79). The NNT was 4 for both interventions. CONCLUSIONS:Antidepressants are effective in the treatment of IBS. There is less high-quality evidence for routine use of psychological therapies in IBS, but available data suggest these may be of comparable efficacy. 10.1136/gut.2008.163162
Prevalence, Risk Factors, and Outcomes of Irritable Bowel Syndrome After Infectious Enteritis: A Systematic Review and Meta-analysis. Klem Fabiane,Wadhwa Akhilesh,Prokop Larry J,Sundt Wendy J,Farrugia Gianrico,Camilleri Michael,Singh Siddharth,Grover Madhusudan Gastroenterology BACKGROUND & AIMS:Foodborne illness affects 15% of the US population each year, and is a risk factor for irritable bowel syndrome (IBS). We evaluated risk of, risk factors for, and outcomes of IBS after infectious enteritis. METHODS:We performed a systematic review of electronic databases from 1994 through August 31, 2015 to identify cohort studies of the prevalence of IBS 3 months or more after infectious enteritis. We used random-effects meta-analysis to calculate the summary point prevalence of IBS after infectious enteritis, as well as relative risk (compared with individuals without infectious enteritis) and host- and enteritis-related risk factors. RESULTS:We identified 45 studies, comprising 21,421 individuals with enteritis, followed for 3 months to 10 years for development of IBS. The pooled prevalence of IBS at 12 months after infectious enteritis was 10.1% (95% confidence interval [CI], 7.2-14.1) and at more than 12 months after infectious enteritis was 14.5% (95% CI, 7.7-25.5). Risk of IBS was 4.2-fold higher in patients who had infectious enteritis in the past 12 months than in those who had not (95% CI, 3.1-5.7); risk of IBS was 2.3-fold higher in individuals who had infectious enteritis more than 12 months ago than in individuals who had not (95% CI, 1.8-3.0). Of patients with enteritis caused by protozoa or parasites, 41.9% developed IBS, and of patients with enteritis caused by bacterial infection, 13.8% developed IBS. Risk of IBS was significantly increased in women (odds ratio [OR], 2.2; 95% CI, 1.6-3.1) and individuals with antibiotic exposure (OR, 1.7; 95% CI, 1.2-2.4), anxiety (OR, 2; 95% CI, 1.3-2.9), depression (OR, 1.5; 95% CI, 1.2-1.9), somatization (OR, 4.1; 95% CI, 2.7-6.0), neuroticism (OR, 3.3; 95% CI, 1.6-6.5), and clinical indicators of enteritis severity. There was a considerable level of heterogeneity among studies. CONCLUSIONS:In a systematic review and meta-analysis, we found >10% of patients with infectious enteritis develop IBS later; risk of IBS was 4-fold higher than in individuals who did not have infectious enteritis, although there was heterogeneity among studies analyzed. Women-particularly those with severe enteritis-are at increased risk for developing IBS, as are individuals with psychological distress and users of antibiotics during the enteritis. 10.1053/j.gastro.2016.12.039
Ondansetron and irritable bowel syndrome. Luthra Pavit,Ford Alexander C Gut 10.1136/gutjnl-2014-307551
A Rome Working Team Report on Brain-Gut Behavior Therapies for Disorders of Gut-Brain Interaction. Keefer Laurie,Ballou Sarah K,Drossman Douglas A,Ringstrom Gisela,Elsenbruch Sigrid,Ljótsson Brjánn Gastroenterology BACKGROUND AND AIMS:This Rome Foundation Working Team Report reflects the consensus of an international interdisciplinary team of experts regarding the use of behavioral interventions, specifically brain-gut behavior therapies (BGBTs), in patients with disorders of gut-brain interaction (DGBIs). METHODS:The committee members reviewed the extant scientific literature and, when possible, addressed gaps in this literature through the lens of their clinical and scientific expertise. The Delphi method was used to create consensus on the goals, structure, and framework before writing the report. The report is broken into 5 parts: 1) definition and evidence for BGBT, 2) the gut-brain axis as the mechanistic basis for BGBT, 3) targets of BGBTs, 4) common and unique therapeutic techniques seen in BGBT, and 5) who and how to refer for BGBT. RESULTS:We chose to not only review for the reader the 5 existing classes of BGBT and their evidence, but to connect DGBI-specific behavioral targets and techniques as they relate directly, or in some cases indirectly, to the gut-brain axis. In doing so, we expect to increase gastrointestinal providers' confidence in identifying and referring appropriate candidates for BGBT and to support clinical decision making for mental health professionals providing BGBT. CONCLUSIONS:Both gastrointestinal medical providers and behavioral health providers have an opportunity to optimize care for DGBIs through a collaborative integrated approach that begins with an effective patient-provider relationship, thoughtful communication about the brain-gut axis and, when appropriate, a well communicated referral to BGBT. 10.1053/j.gastro.2021.09.015
IBS and IBD - separate entities or on a spectrum? Spiller Robin,Major Giles Nature reviews. Gastroenterology & hepatology The acute phase of IBD with inflamed gut and often ulcerated mucosa is clearly different from the apparently normal mucosa characteristic of IBS. However, more detailed assessment has detected immune activation, increased gut permeability, increased mucosal serotonin availability, abnormalities of enteric nerve structure and function, and dysbiosis in gut microbiota in IBS - all features seen in IBD. Furthermore, as treatments for inflammation in IBD have become more effective it is now apparent that ∼1 in 3 patients with IBD in remission from inflammation still have persistent abnormalities of sensation, motility and gut microbiota, which might cause IBS-like symptoms. This Perspective explores the overlap between IBS and IBD and their treatments, proposing future directions for research in this stimulating area. 10.1038/nrgastro.2016.141
Irritable bowel syndrome: pathogenesis and management. Thompson W G Lancet (London, England) An international working team defined the irritable bowel syndrome as distinct from other functional bowel disorders. Symptom criteria for the irritable bowel syndrome are known as the Rome criteria. Since there is no pathophysiological marker for any of these syndromes we must rely on symptoms for their definition and classification. The Rome nosology is a step towards better understanding of functional gastrointestinal disorders because the disparate syndromes are likely to have different causes and treatments. 10.1016/0140-6736(93)90705-l
An update on the use and investigation of probiotics in health and disease. Sanders Mary Ellen,Guarner Francisco,Guerrant Richard,Holt Peter R,Quigley Eamonn M M,Sartor R Balfour,Sherman Philip M,Mayer Emeran A Gut Probiotics are derived from traditional fermented foods, from beneficial commensals or from the environment. They act through diverse mechanisms affecting the composition or function of the commensal microbiota and by altering host epithelial and immunological responses. Certain probiotic interventions have shown promise in selected clinical conditions where aberrant microbiota have been reported, such as atopic dermatitis, necrotising enterocolitis, pouchitis and possibly irritable bowel syndrome. However, no studies have been conducted that can causally link clinical improvements to probiotic-induced microbiota changes. Whether a disease-prone microbiota pattern can be remodelled to a more robust, resilient and disease-free state by probiotic administration remains a key unanswered question. Progress in this area will be facilitated by: optimising strain, dose and product formulations, including protective commensal species; matching these formulations with selectively responsive subpopulations; and identifying ways to manipulate diet to modify bacterial profiles and metabolism. 10.1136/gutjnl-2012-302504
Brain-gut microbiome interactions and functional bowel disorders. Gastroenterology Alterations in the bidirectional interactions between the intestine and the nervous system have important roles in the pathogenesis of irritable bowel syndrome (IBS). A body of largely preclinical evidence suggests that the gut microbiota can modulate these interactions. A small and poorly defined role for dysbiosis in the development of IBS symptoms has been established through characterization of altered intestinal microbiota in IBS patients and reported improvement of subjective symptoms after its manipulation with prebiotics, probiotics, or antibiotics. It remains to be determined whether IBS symptoms are caused by alterations in brain signaling from the intestine to the microbiota or primary disruption of the microbiota, and whether they are involved in altered interactions between the brain and intestine during development. We review the potential mechanisms involved in the pathogenesis of IBS in different groups of patients. Studies are needed to better characterize alterations to the intestinal microbiome in large cohorts of well-phenotyped patients, and to correlate intestinal metabolites with specific abnormalities in gut-brain interactions. 10.1053/j.gastro.2014.02.037
Diet low in FODMAPs reduces symptoms of irritable bowel syndrome as well as traditional dietary advice: a randomized controlled trial. Böhn Lena,Störsrud Stine,Liljebo Therese,Collin Lena,Lindfors Perjohan,Törnblom Hans,Simrén Magnus Gastroenterology BACKGROUND & AIMS:A diet with reduced content of fermentable short-chain carbohydrates (fermentable oligo-, di-, monosaccharides, and polyols [FODMAPs]) has been reported to be effective in the treatment of patients with irritable bowel syndrome (IBS). However, there is no evidence of its superiority to traditional dietary advice for these patients. We compared the effects of a diet low in FODMAPs with traditional dietary advice in a randomized controlled trial of patients with IBS. METHODS:We performed a multi-center, parallel, single-blind study of 75 patients who met Rome III criteria for IBS and were enrolled at gastroenterology outpatient clinics in Sweden. Subjects were randomly assigned to groups that ate specific diets for 4 weeks-a diet low in FODMAPs (n = 38) or a diet frequently recommended for patients with IBS (ie, a regular meal pattern; avoidance of large meals; and reduced intake of fat, insoluble fibers, caffeine, and gas-producing foods, such as beans, cabbage, and onions), with greater emphasis on how and when to eat rather than on what foods to ingest (n = 37). Symptom severity was assessed using the IBS Symptom Severity Scale, and patients completed a 4-day food diary before and at the end of the intervention. RESULTS:A total of 67 patients completed the dietary intervention (33 completed the diet low in FODMAPs, 34 completed the traditional IBS diet). The severity of IBS symptoms was reduced in both groups during the intervention (P < .0001 in both groups before vs at the end of the 4-week diet), without a significant difference between the groups (P = .62). At the end of the 4-week diet period, 19 patients (50%) in the low-FODMAP group had reductions in IBS severity scores ≥50 compared with baseline vs 17 patients (46%) in the traditional IBS diet group (P = .72). Food diaries demonstrated good adherence to the dietary advice. CONCLUSIONS:A diet low in FODMAPs reduces IBS symptoms as well as traditional IBS dietary advice. Combining elements from these 2 strategies might further reduce symptoms of IBS. ClinicalTrials.gov ID NCT02107625. 10.1053/j.gastro.2015.07.054
Best Practice Update: Incorporating Psychogastroenterology Into Management of Digestive Disorders. Keefer Laurie,Palsson Olafur S,Pandolfino John E Gastroenterology Chronic digestive diseases, including irritable bowel syndrome, gastroesophageal reflux disease, and inflammatory bowel diseases, cannot be disentangled from their psychological context-the substantial burden of these diseases is co-determined by symptom and disease severity and the ability of patients to cope with their symptoms without significant interruption to daily life. The growing field of psychogastroenterology focuses on the application of scientifically based psychological principles and techniques to the alleviation of digestive symptoms. In this Clinical Practice Update, we describe the structure and efficacy of 2 major classes of psychotherapy-cognitive behavior therapy and gut-directed hypnotherapy. We focus on the impact of these brain-gut psychotherapies on gastrointestinal symptoms, as well as their ability to facilitate improved coping, resilience, and self-regulation. The importance of the gastroenterologist in the promotion of integrated psychological care cannot be overstated, and recommendations are provided on how to address psychological issues and make an effective referral for brain-gut psychotherapy in routine practice. 10.1053/j.gastro.2018.01.045
Guidelines on the irritable bowel syndrome: mechanisms and practical management. Gut BACKGROUND:IBS affects 5-11% of the population of most countries. Prevalence peaks in the third and fourth decades, with a female predominance. AIM:To provide a guide for the assessment and management of adult patients with irritable bowel syndrome. METHODS:Members of the Clinical Services Committee of The British Society of Gastroenterology were allocated particular areas to produce review documents. Literature searching included systematic searches using electronic databases such as Pubmed, EMBASE, MEDLINE, Web of Science, and Cochrane databases and extensive personal reference databases. RESULTS:Patients can usefully be classified by predominant bowel habit. Few investigations are needed except when diarrhoea is a prominent feature. Alarm features may warrant further investigation. Adverse psychological features and somatisation are often present. Ascertaining the patients' concerns and explaining symptoms in simple terms improves outcome. IBS is a heterogeneous condition with a range of treatments, each of which benefits a small proportion of patients. Treatment of associated anxiety and depression often improves bowel and other symptoms. Randomised placebo controlled trials show benefit as follows: cognitive behavioural therapy and psychodynamic interpersonal therapy improve coping; hypnotherapy benefits global symptoms in otherwise refractory patients; antispasmodics and tricyclic antidepressants improve pain; ispaghula improves pain and bowel habit; 5-HT(3) antagonists improve global symptoms, diarrhoea, and pain but may rarely cause unexplained colitis; 5-HT(4) agonists improve global symptoms, constipation, and bloating; selective serotonin reuptake inhibitors improve global symptoms. CONCLUSIONS:Better ways of identifying which patients will respond to specific treatments are urgently needed. 10.1136/gut.2007.119446
Manipulation of the microbiota for treatment of IBS and IBD-challenges and controversies. Shanahan Fergus,Quigley Eamonn M M Gastroenterology There is compelling rationale for manipulating the microbiota to treat inflammatory bowel diseases (IBDs). Although studies of animal models of intestinal inflammation produced promising results, trials in humans have been disappointing. In contrast to IBD, the role of the microbiota in the development of irritable bowel syndrome (IBS) only recently has been considered, but early stage results have been encouraging. As pharmaceutical companies develop fewer truly novel agents for treatment of these disorders, consumers seek safer, long-term strategies to deal with chronic symptoms. We assess the rationale for modulating the microbiota for treatment of IBD and IBS, and discuss whether current concepts are simplistic and overstated or simply under-researched. Are claims exaggerated and expectations unrealistic? Difficulties with microbiota terminology and technologies, as well as differences among patients and the heterogeneity of these diseases, pose additional challenges in developing microbiota-based therapies for IBD and IBS. 10.1053/j.gastro.2014.01.050
Postinfectious irritable bowel syndrome. Spiller Robin C Gastroenterology A small but significant subgroup of patients with irritable bowel syndrome (IBS) report a sudden onset of their IBS symptoms after a bout of gastroenteritis. Population-based surveys show that although a history of neurotic and psychologic disorders, pain-related diseases, and gastroenteritis are all risk factors for developing IBS, gastroenteritis is the most potent. More toxigenic organisms increase the risk 11-fold, as does an initial illness lasting more than 3 weeks. Hypochondriasis and adverse life events double the risk for postinfective (PI)-IBS and may account for the increased proportion of women who develop this syndrome. PI-IBS is associated with modest increases in mucosal T lymphocytes and serotonin-containing enteroendocrine cells. Animal models and some preliminary human data suggest this leads to excessive serotonin release from the mucosa. Both the histologic changes and symptoms in humans may last for many years with only 40% recovering over a 6-year follow-up. Celiac disease, microscopic colitis, lactose intolerance, early stage Crohn's disease, and bile salt malabsorption should be excluded, as should colon cancer in those over the age of 45 years or in those with a positive family history. Treatment with Loperamide, low-fiber diets, and bile salt- binding therapy may help some patients. Serotonin antagonists are logical treatments but have yet to be evaluated. 10.1016/s0016-5085(03)00324-x
Irritable bowel syndrome. Mertz Howard R The New England journal of medicine 10.1056/NEJMra035579
Antibiotic therapy for the irritable bowel syndrome. Tack Jan The New England journal of medicine 10.1056/NEJMe1011211
Serotoninergic neuroenteric modulators. Talley N J Lancet (London, England) Irritable bowel syndrome (IBS) is common and can be disabling. Several drugs that modulate serotonin (5HT) and other neurotransmitters in the gut (neuroenteric modulators) have either become available or are in development, but progress has been slowed by toxicity. Blockade of 5HT(3) receptors slows colonic transit, increases fluid absorption and increases left colon compliance. Alosetron, a potent 5HT(3) receptor antagonist, has, in women but not in men, a clinically significant but modest therapeutic gain over placebo in the relief of abdominal pain and discomfort and bowel-habit disturbance (but not bloating) in diarrhoea-predominant IBS. However, the drug unexpectedly was associated with ischaemic colitis and, very rarely, severe constipation-induced complications, and alosetron has been withdrawn. Cilansetron may have similar efficacy in men and women. 5HT(4) receptor stimulation results in accelerated colonic transit, and tegaserod, a partial 5HT(4) receptor agonist, has modest but clinically significant advantage over placebo in constipation-predominant IBS; the benefit seems to be confined to females. Long-term published data are lacking and safety concerns have been raised. Prucalopride, a full 5HT(4) agonist that has been promising in idiopathic chronic constipation, may also be limited by toxicity. Other 5HT receptor antagonists and agonists are under development for IBS. However, for modulators of single receptors to achieve a substantial therapeutic gain, and to do so safely, drug targets based on the pathophysiology of IBS need to be better defined. 10.1016/S0140-6736(01)07103-3
Pharmacotherapy: non-serotonergic mechanisms. Spiller R Gut Antidepressants rapidly relieve pain in irritable bowel syndrome (IBS) and are effective at low doses. Noradrenaline reuptake inhibitors appear to be more effective than selective serotonergic reuptake inhibitors, suggesting that pathways other than those modulated by serotonin may be involved in visceral sensation. Visceral sensitivity is reduced by both centrally and peripherally acting opioids, suggesting the possible existence of an endogenous opioid deficiency in patients with IBS. The alpha(2) adrenoceptor antagonist clonidine, as well as somatostatin, oxytocin, and possibly amitriptyline have also been shown to act as visceral analgesics. As knowledge increases, there are undoubtedly many other possible targets, and new drugs currently undergoing development may provide future benefit in patients with IBS. 10.1136/gut.51.suppl_1.i87
Rifaximin therapy for patients with irritable bowel syndrome without constipation. Pimentel Mark,Lembo Anthony,Chey William D,Zakko Salam,Ringel Yehuda,Yu Jing,Mareya Shadreck M,Shaw Audrey L,Bortey Enoch,Forbes William P, The New England journal of medicine 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.). 10.1056/NEJMoa1004409
The serotonin signaling system: from basic understanding to drug development for functional GI disorders. Gershon Michael D,Tack Jan Gastroenterology Serotonin is an important gastrointestinal signaling molecule. It is a paracrine messenger utilized by enterochromaffin (EC) cells, which function as sensory transducers. Serotonin activates intrinsic and extrinsic primary afferent neurons to, respectively, initiate peristaltic and secretory reflexes and to transmit information to the central nervous system. Serotonin is also a neurotransmitter utilized by a system of long descending myenteric interneurons. Serotonin is synthesized through the actions of 2 different tryptophan hydroxylases, TpH1 and TpH2, which are found, respectively, in EC cells and neurons. Serotonin is inactivated by the serotonin reuptake transporter (SERT)-mediated uptake into enterocytes or neurons. The presence of many serotonin receptor subtypes enables selective drugs to be designed to therapeutically modulate gastrointestinal motility, secretion, and sensation. Current examples include tegaserod, a 5-HT(4) partial agonist, which has been approved for treatment of irritable bowel syndrome (IBS) with constipation in women and for chronic constipation in men and women. The 5-HT(3) antagonists, granisetron and ondansetron, are useful in combating the nausea associated with cancer chemotherapy, and alosetron is employed in the treatment of IBS with diarrhea. Serotonergic signaling abnormalities have also been putatively implicated in the pathogenesis of functional bowel diseases. Other compounds, for which efficacy has not been rigorously established, but which may have value, include tricyclic antidepressants and serotonin selective reuptake inhibitors to combat IBS, and 5-HT(1) agonists, which enhance gastric accommodation, to treat functional dyspepsia. The initial success encountered with serotonergic agents holds promise for newer and more potent insights and therapies of brain-gut disorders. 10.1053/j.gastro.2006.11.002
Gut microbiota composition and functional changes in inflammatory bowel disease and irritable bowel syndrome. Vich Vila Arnau,Imhann Floris,Collij Valerie,Jankipersadsing Soesma A,Gurry Thomas,Mujagic Zlatan,Kurilshikov Alexander,Bonder Marc Jan,Jiang Xiaofang,Tigchelaar Ettje F,Dekens Jackie,Peters Vera,Voskuil Michiel D,Visschedijk Marijn C,van Dullemen Hendrik M,Keszthelyi Daniel,Swertz Morris A,Franke Lude,Alberts Rudi,Festen Eleonora A M,Dijkstra Gerard,Masclee Ad A M,Hofker Marten H,Xavier Ramnik J,Alm Eric J,Fu Jingyuan,Wijmenga Cisca,Jonkers Daisy M A E,Zhernakova Alexandra,Weersma Rinse K Science translational medicine Changes in the gut microbiota have been associated with two of the most common gastrointestinal diseases, inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS). Here, we performed a case-control analysis using shotgun metagenomic sequencing of stool samples from 1792 individuals with IBD and IBS compared with control individuals in the general population. Despite substantial overlap between the gut microbiome of patients with IBD and IBS compared with control individuals, we were able to use gut microbiota composition differences to distinguish patients with IBD from those with IBS. By combining species-level profiles and strain-level profiles with bacterial growth rates, metabolic functions, antibiotic resistance, and virulence factor analyses, we identified key bacterial species that may be involved in two common gastrointestinal diseases. 10.1126/scitranslmed.aap8914
Dietary and pharmacological treatment of abdominal pain in IBS. Camilleri Michael,Boeckxstaens Guy Gut This review introduces the principles of visceral sensation and appraises the current approaches to management of visceral pain in functional GI diseases, principally IBS. These approaches include dietary measures including fibre supplementation, low fermentable oligosaccharides, disaccharides, monosaccharides and polyols diet, and pharmacological approaches such as antispasmodics, peppermint oil, antidepressants (tricyclic agents, selective serotonin reuptake inhibitors), 5-HT receptor antagonists (alosetron, ondansetron, ramosetron), non-absorbed antibiotic (rifaximin), secretagogues (lubiprostone, linaclotide), μ-opioid receptor (OR) and κ-OR agonist, δ-OR antagonist (eluxadoline), histamine H1 receptor antagonist (ebastine), neurokinin-2 receptor antagonist (ibodutant) and GABAergic agents (gabapentin and pregabalin). Efficacy and safety are discussed based on pivotal trials or published systematic reviews and meta-analysis, expressing ORs or relative risks and their 95% CIs. Potential new approaches may be based on recent insights on mucosal expression of genes, and microRNA and epigenetic markers in human biopsies and in animal models of visceral hypersensitivity.The objectives of this review are to appraise the physiology and anatomy of gut sensation and the efficacy in the relief of visceral pain (typically in IBS) of several classes of therapies. These include fermentable oligosaccharides, disaccharides, monosaccharides and polyols (FODMAPs) and different classes of medications (box 1). Box 1Classes of pharmacological agents for visceral painAntidepressants (tricyclic agents, selective serotonin reuptake inhibitors)Peppermint oil5-HT receptor antagonists (alosetron, ondansetron, ramosetron)Non-absorbed antibiotic (rifaximin)Secretagogues (lubiprostone, linaclotide)μ-Opioid receptor (OR) and κ-OR agonist and δ-OR antagonist (eluxadoline)Histamine H1 receptor antagonist (ebastine)Neurokinin-2 receptor antagonist (ibodutant)GABAergic agents (gabapentin and pregabalin). 10.1136/gutjnl-2016-313425
Serum Amyloid A Proteins Induce Pathogenic Th17 Cells and Promote Inflammatory Disease. Lee June-Yong,Hall Jason A,Kroehling Lina,Wu Lin,Najar Tariq,Nguyen Henry H,Lin Woan-Yu,Yeung Stephen T,Silva Hernandez Moura,Li Dayi,Hine Ashley,Loke P'ng,Hudesman David,Martin Jerome C,Kenigsberg Ephraim,Merad Miriam,Khanna Kamal M,Littman Dan R Cell Lymphoid cells that produce interleukin (IL)-17 cytokines protect barrier tissues from pathogenic microbes but are also prominent effectors of inflammation and autoimmune disease. T helper 17 (Th17) cells, defined by RORγt-dependent production of IL-17A and IL-17F, exert homeostatic functions in the gut upon microbiota-directed differentiation from naive CD4 T cells. In the non-pathogenic setting, their cytokine production is regulated by serum amyloid A proteins (SAA1 and SAA2) secreted by adjacent intestinal epithelial cells. However, Th17 cell behaviors vary markedly according to their environment. Here, we show that SAAs additionally direct a pathogenic pro-inflammatory Th17 cell differentiation program, acting directly on T cells in collaboration with STAT3-activating cytokines. Using loss- and gain-of-function mouse models, we show that SAA1, SAA2, and SAA3 have distinct systemic and local functions in promoting Th17-mediated inflammatory diseases. These studies suggest that T cell signaling pathways modulated by the SAAs may be attractive targets for anti-inflammatory therapies. 10.1016/j.cell.2019.11.026
Efficacy of a low FODMAP diet in irritable bowel syndrome: systematic review and network meta-analysis. Gut OBJECTIVE:A diet low in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAP) is recommended for irritable bowel syndrome (IBS), if general lifestyle and dietary advice fails. However, although the impact of a low FODMAP diet on individual IBS symptoms has been examined in some randomised controlled trials (RCTs), there has been no recent systematic assessment, and individual trials have studied numerous alternative or control interventions, meaning the best comparator is unclear. We performed a network meta-analysis addressing these uncertainties. DESIGN:We searched the medical literature through to 2 April 2021 to identify RCTs of a low FODMAP diet in IBS. Efficacy was judged using dichotomous assessment of improvement in global IBS symptoms or improvement in individual IBS symptoms, including abdominal pain, abdominal bloating or distension, and bowel habit. Data were pooled using a random effects model, with efficacy reported as pooled relative risks (RRs) with 95% CIs, and interventions ranked according to their P-score. RESULTS:We identified 13 eligible RCTs (944 patients). Based on failure to achieve an improvement in global IBS symptoms, a low FODMAP diet ranked first vs habitual diet (RR of symptoms not improving=0.67; 95% CI 0.48 to 0.91, P-score=0.99), and was superior to all other interventions. Low FODMAP diet ranked first for abdominal pain severity, abdominal bloating or distension severity and bowel habit, although for the latter it was not superior to any other intervention. A low FODMAP diet was superior to British Dietetic Association (BDA)/National Institute for Health and Care Excellence (NICE) dietary advice for abdominal bloating or distension (RR=0.72; 95% CI 0.55 to 0.94). BDA/NICE dietary advice was not superior to any other intervention in any analysis. CONCLUSION:In a network analysis, low FODMAP diet ranked first for all endpoints studied. However, most trials were based in secondary or tertiary care and did not study effects of FODMAP reintroduction and personalisation on symptoms. 10.1136/gutjnl-2021-325214
Impaired cell surface expression and digestive function of sucrase-isomaltase gene variants are associated with reduced efficacy of low FODMAPs diet in patients with IBS-D. Husein Diab M,Naim Hassan Y Gut 10.1136/gutjnl-2019-319411
Durability and Effectiveness of Cognitive-Behavioral Therapy for Irritable Bowel Syndrome. Shapiro Jordan,El-Serag Hashem B,Chan Johanna Gastroenterology 10.1053/j.gastro.2019.10.010
Use of Treatments for Irritable Bowel Syndrome and Patient Satisfaction Based on the IBS in America Survey. Rangan Vikram,Ballou Sarah,Shin Andrea,Camilleri Michael, ,Lembo Anthony Gastroenterology 10.1053/j.gastro.2019.10.036
Efficacy of faecal microbiota transplantation for patients with irritable bowel syndrome in a randomised, double-blind, placebo-controlled study. El-Salhy Magdy,Hatlebakk Jan Gunnar,Gilja Odd Helge,Bråthen Kristoffersen Anja,Hausken Trygve Gut OBJECTIVE:Faecal microbiota transplantation (FMT) from healthy donors to patients with irritable bowel syndrome (IBS) has been attempted in two previous double-blind, placebo-controlled studies. While one of those studies found improvement of the IBS symptoms, the other found no effect. The present study was conducted to clarify these contradictory findings. DESIGN:This randomised, double-blind, placebo-controlled study randomised 165 patients with IBS to placebo (own faeces), 30 g FMT or 60 g FMT at a ratio of 1:1:1. The material for FMT was obtained from one healthy, well-characterised donor, frozen and administered via gastroscope. The primary outcome was a reduction in the IBS symptoms at 3 months after FMT (response). A response was defined as a decrease of 50 or more points in the total IBS symptom score. The secondary outcome was a reduction in the dysbiosis index (DI) and a change in the intestinal bacterial profile, analysed by 16S rRNA gene sequencing, at 1 month following FMT. RESULTS:Responses occurred in 23.6%, 76.9% (p<0.0001) and 89.1% (p<00.0001) of the patients who received placebo, 30 g FMT and 60 g FMT, respectively. These were accompanied by significant improvements in fatigue and the quality of life in patients who received FMT. The intestinal bacterial profiles changed also significantly in the groups received FMT. The FMT adverse events were mild self-limiting gastrointestinal symptoms. CONCLUSIONS:FMT is an effective treatment for patients with IBS. Utilising a well-defined donor with a normal DI and favourable specific microbial signature is essential for successful FMT. The response to FMT increases with the dose. www.clinicaltrials.gov (NCT03822299) and www.cristin.no (ID657402). 10.1136/gutjnl-2019-319630
The Low-FODMAP Diet Helps IBS Symptoms, but Questions Remain. Slomski Anita JAMA 10.1001/jama.2020.0691
Faecal microbial transplantation in IBS: ready for prime time? Barbara Giovanni,Ianiro Gianluca Gut 10.1136/gutjnl-2019-320411
Faecal microbiota transplantation in IBS - new evidence for success? König Julia,Brummer Robert Jan Nature reviews. Gastroenterology & hepatology 10.1038/s41575-020-0282-z
Evidence-based and mechanistic insights into exclusion diets for IBS. Moayyedi Paul,Simrén Magnus,Bercik Premysl Nature reviews. Gastroenterology & hepatology Exclusion diets are becoming increasingly popular in the management of irritable bowel syndrome (IBS). Several mechanisms exist by which food items might cause gastrointestinal symptoms, such as direct osmotic effects of food in the gut lumen, changes to the gut microbiota and immune activation. These effects have been demonstrated in animal models and in human studies, particularly in the case of gluten-free diets and diets low in fermentable oligosaccharides, disaccharides, monosaccharides and polyols (FODMAPs). Indeed, randomized controlled trials (RCTs) suggest that gluten-free diets and low-FODMAP diets improve IBS symptoms, and guidelines recommend the latter approach for treating symptoms in some patients with IBS. Designing such RCTs is challenging as participants need to eat so an 'inert' placebo is not an option. Blinding is also an issue with these studies; in the future, new exclusion diets should not advertise what the diet consists of until it is proved to reduce symptoms. In this Review, we outline the advantages and disadvantages of each choice of control group and emphasize the importance of collecting mechanistic data (regarding direct effects of food on the gut lumen, changes in gut microbiota and intestinal inflammation) as well as symptom data in RCTs of exclusion diets in IBS. 10.1038/s41575-020-0270-3
Why a Low FODMAP Diet Was Ineffective for IBS Symptoms in Quiescent Crohn's Disease. Uno Yoshiharu Gastroenterology 10.1053/j.gastro.2020.03.042
Efficacy of psychological therapies for irritable bowel syndrome: systematic review and network meta-analysis. Black Christopher J,Thakur Elyse R,Houghton Lesley A,Quigley Eamonn M M,Moayyedi Paul,Ford Alexander C Gut OBJECTIVES:National guidelines for the management of irritable bowel syndrome (IBS) recommend that psychological therapies should be considered, but their relative efficacy is unknown, because there have been few head-to-head trials. We performed a systematic review and network meta-analysis to try to resolve this uncertainty. DESIGN:We searched the medical literature through January 2020 for randomised controlled trials (RCTs) assessing efficacy of psychological therapies for adults with IBS, compared with each other, or a control intervention. Trials reported a dichotomous assessment of symptom status after completion of therapy. We pooled data using a random effects model. Efficacy was reported as a pooled relative risk (RR) of remaining symptomatic, with a 95% CI to summarise efficacy of each comparison tested, and ranked by therapy according to P score. RESULTS:We identified 41 eligible RCTs, containing 4072 participants. After completion of therapy, the psychological interventions with the largest numbers of trials, and patients recruited, demonstrating efficacy included self-administered or minimal contact cognitive behavioural therapy (CBT) (RR 0.61; 95% CI 0.45 to 0.83, P score 0.66), face-to-face CBT (RR 0.62; 95% CI 0.48 to 0.80, P score 0.65) and gut-directed hypnotherapy (RR 0.67; 95% CI 0.49 to 0.91, P score 0.57). After completion of therapy, among trials recruiting only patients with refractory symptoms, group CBT and gut-directed hypnotherapy were more efficacious than either education and/or support or routine care, and CBT via the telephone, contingency management, CBT via the internet and dynamic psychotherapy were all superior to routine care. Risk of bias of trials was high, with evidence of funnel plot asymmetry; the efficacy of psychological therapies is therefore likely to have been overestimated. CONCLUSIONS:Several psychological therapies are efficacious for IBS, although none were superior to another. CBT-based interventions and gut-directed hypnotherapy had the largest evidence base and were the most efficacious long term. TRIAL REGISTRATION NUMBER:The study protocol was published on the PROSPERO international prospective register of systematic reviews (registration number CRD 42020163246). 10.1136/gutjnl-2020-321191
Peppermint Oil in Irritable Bowel Syndrome. Black Christopher J,Moayyedi Paul,Quigley Eamonn M M,Ford Alexander C Gastroenterology 10.1053/j.gastro.2019.09.055
FMT in IBS: a call for caution. Camilleri Michael Gut 10.1136/gutjnl-2020-321529
Is CBT the dominant non-drug IBS treatment? The rise of dietary therapies. Rej Anupam,Buckle Rachel Louise,Shaw Christian Charles,Trott Nick,Aziz Imran,Sanders David S Gut 10.1136/gutjnl-2020-321658
Fecal microbiota transplantation in gastrointestinal disorders: time for precision medicine. Benech Nicolas,Sokol Harry Genome medicine Fecal microbiota transplantation (FMT) has demonstrated efficacy in treating inflammatory bowel diseases and irritable bowel syndrome in an increasing number of randomized controlled trials. Recently published data gives striking insights into the factors associated with FMT success paving the road for the use of precision medicine in gastrointestinal disorders. 10.1186/s13073-020-00757-y
FMT in IBS: how cautious should we be? El-Salhy Magdy Gut 10.1136/gutjnl-2020-322038
Epidemiologic Burden and Treatment of Chronic Symptomatic Functional Bowel Disorders in the United States: A Nationwide Analysis. Gastroenterology BACKGROUND & AIMS:Functional bowel disorders (FBDs) are the most common gastrointestinal problems managed by physicians. We aimed to assess the burden of chronic symptomatic FBDs on ambulatory care delivery in the United States and evaluate patterns of treatment. METHODS:Data from the National Ambulatory Medical Care Survey were used to estimate annual rates and associated costs of ambulatory visits for symptomatic irritable bowel syndrome, chronic functional abdominal pain, constipation, or diarrhea. The weighted proportion of visits associated with pharmacologic and nonpharmacologic (stress/mental health, exercise, diet counseling) interventions were calculated, and predictors of treatment strategy were evaluated in multivariable multinomial logistic regression. RESULTS:From 2007-2015, approximately 36.9 million (95% CI, 31.4-42.4) weighted visits in patients of non-federally employed physicians for chronic symptomatic FBDs were sampled. There was an annual weighted average of 2.7 million (95% CI, 2.3-3.2) visits for symptomatic irritable bowel syndrome/chronic abdominal pain, 1.0 million (95% CI, 0.8-1.2) visits for chronic constipation, and 0.7 million (95% CI, 0.5-0.8) visits for chronic diarrhea. Pharmacologic therapies were prescribed in 49.7% (95% CI, 44.7-54.8) of visits compared to nonpharmacologic interventions in 19.8% (95% CI, 16.0-24.2) of visits (P < .001). Combination treatment strategies were more likely to be implemented by primary care physicians and in patients with depression or obesity. The direct annual cost of ambulatory clinic visits alone for chronic symptomatic FBDs is approximately US$358 million (95% CI, 233-482 million). CONCLUSIONS:The management of chronic symptomatic FBDs is associated with considerable health care resource use and cost. There may be an opportunity to improve comprehensive FBD management because fewer than 1 in 5 ambulatory visits include nonpharmacologic treatment strategies. 10.1053/j.gastro.2020.09.041
Effect of resolvins on sensitisation of TRPV1 and visceral hypersensitivity in IBS. Perna Eluisa,Aguilera-Lizarraga Javier,Florens Morgane V,Jain Piyush,Theofanous Stavroula A,Hanning Nikita,De Man Joris G,Berg Maya,De Winter Benedicte,Alpizar Yeranddy A,Talavera Karel,Vanden Berghe Pieter,Wouters Mira,Boeckxstaens Guy Gut OBJECTIVE:Resolvins (RvD1, RvD2 and RvE1) are endogenous anti-inflammatory lipid mediators that display potent analgesic properties in somatic pain by modulating transient receptor potential vanilloid 1 (TRPV1) activation. To what extent these molecules could also have a beneficial effect on TRPV1 sensitisation and visceral hypersensitivity (VHS), mechanisms involved in IBS, remains unknown. DESIGN:The effect of RvD1, RvD2 and RvE1 on TRPV1 activation and sensitisation by histamine or IBS supernatants was assessed on murine dorsal root ganglion (DRG) neurons using live Ca imaging. Based on the results obtained in vitro, we further studied the effect of RvD2 in vivo using a murine model of post-infectious IBS and a rat model of post-inflammatory VHS. Finally, we also tested the effect of RvD2 on submucosal neurons in rectal biopsies of patients with IBS. RESULTS:RvD1, RvD2 and RvE1 prevented histamine-induced TRPV1 sensitisation in DRG neurons at doses devoid of an analgesic effect. Of note, RvD2 also reversed TRPV1 sensitisation by histamine and IBS supernatant. This effect was blocked by the G protein receptor 18 (GPR18) antagonist O-1918 (3-30 µM) and by pertussis toxin. In addition, RvD2 reduced the capsaicin-induced Ca response of rectal submucosal neurons of patients with IBS. Finally, treatment with RvD2 normalised pain responses to colorectal distention in both preclinical models of VHS. CONCLUSIONS:Our data suggest that RvD2 and GPR18 agonists may represent interesting novel compounds to be further evaluated as treatment for IBS. 10.1136/gutjnl-2020-321530
Transplanting Microbes for Irritable Bowels or Irritated Microbes or Both? O'Toole Paul W,Shanahan Fergus Gastroenterology 10.1053/j.gastro.2020.10.023
Behavioral and Diet Therapies in Integrated Care for Patients With Irritable Bowel Syndrome. Chey William D,Keefer Laurie,Whelan Kevin,Gibson Peter R Gastroenterology Irritable bowel syndrome (IBS) is a common, symptom-based condition that has negative effects on quality of life and costs health care systems billions of dollars each year. Until recently, management of IBS has focused on over-the-counter and prescription medications that reduce symptoms in fewer than one-half of patients. Patients have increasingly sought natural solutions for their IBS symptoms. However, behavioral techniques and dietary modifications can be effective in treatment of IBS. Behavioral interventions include gastrointestinal-focused cognitive behavioral therapy and gut-directed hypnotherapy to modify interactions between the gut and the brain. In this pathway, benign sensations from the gut induce maladaptive cognitive or affective processes that amplify symptom perception. Symptoms occur in response to cognitive and affective factors that trigger fear of symptoms or lack of acceptance of disease, or from stressors in the external environment. Among the many dietary interventions used to treat patients with IBS, a diet low in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols is the most commonly recommended by health care providers and has the most evidence for efficacy. Patient with IBS who choose to follow a diet low in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols should be aware of its 3 phases: restriction, reintroduction, and personalization. Management of IBS should include an integrated care model in which behavioral interventions, dietary modification, and medications are considered as equal partners. This approach offers the greatest likelihood for success in management of patients with IBS. 10.1053/j.gastro.2020.06.099
Functional Gastrointestinal Disorders and the Microbiome-What Is the Best Strategy for Moving Microbiome-based Therapies for Functional Gastrointestinal Disorders into the Clinic? Gastroenterology There have been numerous human studies reporting associations between the intestinal microbiome and functional gastrointestinal disorders (FGIDs), and independently animal studies have explored microbiome-driven mechanisms underlying FGIDs. However, there is often a disconnect between human and animal studies, which hampers translation of microbiome findings to the clinic. Changes in the microbiota composition of patients with FGIDs are generally subtle, whereas changes in microbial function, reflected in the fecal metabolome, appear to be more precise indicators of disease subtype-specific mechanisms. Although we have made significant progress in characterizing the microbiome, to effectively translate microbiome science in a timely manner, we need concurrent and iterative longitudinal studies in humans and animals to determine the precise microbial functions that can be targeted to address specific pathophysiological processes in FGIDs. A systems approach integrating multiple data layers rather than evaluating individual data layers of symptoms, physiological changes, or -omics data in isolation will allow for validation of mechanistic insights from animal studies while also allowing new discovery. Patient stratification for clinical trials based on functional microbiome alterations and/or pathophysiological measurements may allow for more accurate determination of efficacy of individual microbiome-targeted interventions designed to correct an underlying abnormality. In this review, we outline current approaches and knowledge, and identify gaps, to provide a potential roadmap for accelerating translation of microbiome science toward microbiome-targeted personalized treatments for FGIDs. 10.1053/j.gastro.2020.10.058
The Microbiota-Gut-Brain Axis: From Motility to Mood. Margolis Kara G,Cryan John F,Mayer Emeran A Gastroenterology The gut-brain axis plays an important role in maintaining homeostasis. Many intrinsic and extrinsic factors influence signaling along this axis, modulating the function of both the enteric and central nervous systems. More recently the role of the microbiome as an important factor in modulating gut-brain signaling has emerged and the concept of a microbiota-gut-brain axis has been established. In this review, we highlight the role of this axis in modulating enteric and central nervous system function and how this may impact disorders such as irritable bowel syndrome and disorders of mood and affect. We examine the overlapping biological constructs that underpin these disorders with a special emphasis on the neurotransmitter serotonin, which plays a key role in both the gastrointestinal tract and in the brain. Overall, it is clear that although animal studies have shown much promise, more progress is necessary before these findings can be translated for diagnostic and therapeutic benefit in patient populations. 10.1053/j.gastro.2020.10.066
Minority Patients With Irritable Bowel Syndrome Receive More Gastroenterology-Related Procedures Than White Counterparts: Nuances in Disparities Research. Gastroenterology 10.1053/j.gastro.2021.10.023
The FODMAP diet: more than just a symptomatic therapy? Gut 10.1136/gutjnl-2021-326284
Two microbiota subtypes identified in irritable bowel syndrome with distinct responses to the low FODMAP diet. Gut OBJECTIVE:Reducing FODMAPs (fermentable oligosaccharides, disaccharides, monosaccharides and polyols) can be clinically beneficial in IBS but the mechanism is incompletely understood. We aimed to detect microbial signatures that might predict response to the low FODMAP diet and assess whether microbiota compositional and functional shifts could provide insights into its mode of action. DESIGN:We used metagenomics to determine high-resolution taxonomic and functional profiles of the stool microbiota from IBS cases and household controls (n=56 pairs) on their usual diet. Clinical response and microbiota changes were studied in 41 pairs after 4 weeks on a low FODMAP diet. RESULTS:Unsupervised analysis of baseline IBS cases pre-diet identified two distinct microbiota profiles, which we refer to as IBS (pathogenic-like) and IBS (health-like) subtypes. IBS microbiomes were enriched in Firmicutes and genes for amino acid and carbohydrate metabolism, but depleted in Bacteroidetes species. IBS microbiomes were similar to controls. On the low FODMAP diet, IBS and control microbiota were unaffected, but the IBS signature shifted towards a health-associated microbiome with an increase in Bacteroidetes (p=0.009), a decrease in Firmicutes species (p=0.004) and normalisation of primary metabolic genes. The clinical response to the low FODMAP diet was greater in IBS subjects compared with IBS (p=0.02). CONCLUSION:50% of IBS cases manifested a 'pathogenic' gut microbial signature. This shifted towards the healthy profile on the low FODMAP diet; and IBS cases showed an enhanced clinical responsiveness to the dietary therapy. The effectiveness of FODMAP reduction in IBS may result from the alterations in gut microbiota and metabolites produced. Microbiota signatures could be useful as biomarkers to guide IBS treatment; and investigating IBS species and metabolic pathways might yield insights regarding IBS pathogenic mechanisms. 10.1136/gutjnl-2021-325177
Immune activation in irritable bowel syndrome: what is the evidence? Nature reviews. Immunology Irritable bowel syndrome (IBS) is a chronic functional gastrointestinal disorder that is characterized by abdominal pain and an altered defecation pattern. It affects between 5 and 20% of the general population and can seriously impact quality of life. The pathophysiology of IBS is rather complex and multifactorial including, for example, altered signalling by the gut-brain axis, dysbiosis, abnormal visceral pain signalling and intestinal immune activation. The latter has gained particular interest in recent years, with growing insight into the bidirectional communication between the nervous system and the immune system. In this Review, we detail the current evidence suggesting that immune activation contributes to the pathology seen in patients with IBS and discuss the potential mechanisms involved. Moreover, we describe how immune mediators, particularly those released by mast cells, can directly activate or sensitize pain-transmitting nerves, leading to increased pain signalling and abdominal pain. Finally, we discuss the potential of interventions targeting immune activation as a new therapeutic strategy for patients suffering from IBS. 10.1038/s41577-022-00700-9
Diet or medication in primary care patients with IBS: the DOMINO study - a randomised trial supported by the Belgian Health Care Knowledge Centre (KCE Trials Programme) and the Rome Foundation Research Institute. Gut BACKGROUND:In Europe, IBS is commonly treated with musculotropic spasmolytics (eg, otilonium bromide, OB). In tertiary care, a low fermentable oligosaccharides, disaccharides, monosaccharides and polyols (FODMAP) diet provides significant improvement. Yet, dietary treatment remains to be explored in primary care. We evaluated the effect of a smartphone FODMAP-lowering diet application versus OB on symptoms in primary care IBS. METHODS:IBS patients, recruited by primary care physicians, were randomised to 8 weeks of OB (40 mg three times a day) or diet and followed for 24 weeks. We compared IBS Symptom Severity Score and the proportion of responders (improvement ≥50 points) in all patients and the subgroup fulfilling Rome IV criteria (Rome+). We also evaluated treatment efficacy, quality of life, anxiety, depression, somatic symptom severity (Patient Health Questionnaire (PHQ15, PHQ9)) and treatment adherence and analysed predictors of response. RESULTS:459 primary care IBS patients (41±15 years, 76% female, 70% Rome+) were randomised. The responder rate after 8 weeks was significantly higher with diet compared with OB (71% (155/218) vs 61% (133/217), p=0.03) and more pronounced in Rome+ (77% (118/153) vs 62% (98/158), p=0.004). Patients allocated to diet (199/212) were 94% adherent compared with 73% with OB (148/202) (p<0.001). The significantly higher response rate with diet was already observed after 4 weeks (62% (132/213) vs 51% (110/215), p=0.02) and a high symptom response persisted during follow-up. Predictors of response were female gender (OR=2.08, p=0.04) for diet and PHQ15 (OR=1.10, p=0.02) for OB. CONCLUSION:In primary care IBS patients, a FODMAP-lowering diet application was superior to a spasmolytic agent in improving IBS symptoms. A FODMAP-lowering diet should be considered the first-line treatment for IBS in primary care. TRIAL REGISTRATION NUMBER:NCT04270487. 10.1136/gutjnl-2021-325821
Identification of shared and disease-specific host gene-microbiome associations across human diseases using multi-omic integration. Nature microbiology While gut microbiome and host gene regulation independently contribute to gastrointestinal disorders, it is unclear how the two may interact to influence host pathophysiology. Here we developed a machine learning-based framework to jointly analyse paired host transcriptomic (n = 208) and gut microbiome (n = 208) profiles from colonic mucosal samples of patients with colorectal cancer, inflammatory bowel disease and irritable bowel syndrome. We identified associations between gut microbes and host genes that depict shared as well as disease-specific patterns. We found that a common set of host genes and pathways implicated in gastrointestinal inflammation, gut barrier protection and energy metabolism are associated with disease-specific gut microbes. Additionally, we also found that mucosal gut microbes that have been implicated in all three diseases, such as Streptococcus, are associated with different host pathways in each disease, suggesting that similar microbes can affect host pathophysiology in a disease-specific manner through regulation of different host genes. Our framework can be applied to other diseases for the identification of host gene-microbiome associations that may influence disease outcomes. 10.1038/s41564-022-01121-z
Further research needed to determine first-line therapy for IBS in primary care. Gut 10.1136/gutjnl-2022-328047
Double-blinded randomised placebo controlled trial of enterosgel (polymethylsiloxane polyhydrate) for the treatment of IBS with diarrhoea (IBS-D). Gut OBJECTIVE:Irritable bowel syndrome with diarrhoea (IBS-D) is a common and challenging condition that significantly reduces quality of life. Enterosgel (polymethylsiloxane polyhydrate) is an intestinal adsorbent which sequesters harmful molecules and is safe and effective in acute infective diarrhoea. This randomised controlled multicentre trial aimed to investigate its safety and efficacy in patients with IBS-D. DESIGN:After a 2-week screening phase, participants were randomised into an 8-week double-blind phase, followed by an 8-week open-label and follow-up phase. Participants recorded stool consistency, pain and global symptoms in e-diaries and questionnaires. The primary outcome was the percentage of responders on a composite abdominal pain (≥30% decrease in the weekly score) and stool consistency (50% reduction in days per week with at least one stool of BSFS type 6 or 7) score during at least 4 weeks of the treatment period. RESULTS:440 patients with IBS-D were randomised to the double-blind phase with 393 continuing to the open-label phase. The Primary outcome responder rate by intention-to-treat for enterosgel versus placebo was 37.4% vs 24.3% (OR 1.95, NNT 8, p=0.002). Enterosgel also improved stool consistency (48.5% vs 32.5%, p<0.0001) abdominal pain (53.3% vs 40.2%, p=0.003), stool frequency (treatment effect -0.32 (-0.62 to -0.02)) and urgency (treatment effect -0.59 (-0.85 to -0.33)). 60% of patients reported adequate relief of symptoms after open-label treatment. Adverse event frequency was similar in both groups, with no serious events attributable to enterosgel. CONCLUSION:Enterosgel is safe and effective in IBS-D, providing an alternative to the limited current treatment options. TRIAL REGISTRATION NUMBER:ISRCTN17149988. 10.1136/gutjnl-2022-327293
Durable IBS Response From Fecal Microbiota Transplant. JAMA 10.1001/jama.2022.12179
Targeting the endocannabinoid system for the treatment of abdominal pain in irritable bowel syndrome. Nature reviews. Gastroenterology & hepatology The management of visceral pain in patients with disorders of gut-brain interaction, notably irritable bowel syndrome, presents a considerable clinical challenge, with few available treatment options. Patients are increasingly using cannabis and cannabinoids to control abdominal pain. Cannabis acts on receptors of the endocannabinoid system, an endogenous system of lipid mediators that regulates gastrointestinal function and pain processing pathways in health and disease. The endocannabinoid system represents a logical molecular therapeutic target for the treatment of pain in irritable bowel syndrome. Here, we review the physiological and pathophysiological functions of the endocannabinoid system with a focus on the peripheral and central regulation of gastrointestinal function and visceral nociception. We address the use of cannabinoids in pain management, comparing them to other treatment modalities, including opioids and neuromodulators. Finally, we discuss emerging therapeutic candidates targeting the endocannabinoid system for the treatment of pain in irritable bowel syndrome. 10.1038/s41575-022-00682-y
Role of the DOMINO diet application for managing IBS in primary care and beyond. Gut 10.1136/gutjnl-2022-328315
Irritable bowel syndrome: treatment based on pathophysiology and biomarkers. Gut OBJECTIVE:To appraise the evidence that pathophysiological mechanisms and individualised treatment directed at those mechanisms provide an alternative approach to the treatment of patients with irritable bowel syndrome (IBS). DESIGN:A PubMED-based literature review of mechanisms and treatment of IBS was conducted independently by the two authors, and any differences of perspective or interpretation of the literature were resolved following discussion. RESULTS:The availability of several noninvasive clinical tests can appraise the mechanisms responsible for symptom generation in IBS, including rectal evacuation disorders, abnormal transit, visceral hypersensitivity or hypervigilance, bile acid diarrhoea, sugar intolerances, barrier dysfunction, the microbiome, immune activation and chemicals released by the latter mechanism. The basic molecular mechanisms contributing to these pathophysiologies are increasingly recognised, offering opportunities to intervene with medications directed specifically to food components, receptors and potentially the microbiome. Although the evidence supporting interventions for each mechanism is not at the same level of proof, the current state-of-the-art provides the opportunity to advance the practice from treatment based on symptoms to individualisation of treatment guided by pathophysiology and clinically identified biomarkers. CONCLUSION:These advances augur well for the implementation of evidence-based individualised treatment for patients with IBS based on actionable biomarkers or psychological disturbances. 10.1136/gutjnl-2022-328515
Diet-induced modifications to human microbiome reshape colonic homeostasis in irritable bowel syndrome. Cell reports Changes in microbiome composition are associated with a wide array of human diseases, turning the human microbiota into an attractive target for therapeutic intervention. Yet, clinical translation of these findings requires the establishment of causative connections between specific microbial taxa and their functional impact on host tissues. Here, we infuse gut organ cultures with longitudinal microbiota samples collected from therapy-naive patients with irritable bowel syndrome (IBS) under a low-fermentable oligo-, di-, mono-saccharides and polyols (FODMAP) diet. We show that post-diet microbiota regulates intestinal expression of inflammatory and neuro-muscular gene sets. Specifically, we identify Bifidobacterium adolescentis as a diet-sensitive pathobiont that alters tight junction integrity and disrupts gut barrier functions. Collectively, we present a pathway discovery platform for mechanistic dissection and identification of functional diet-host-microbiota modules. Our data support the hypothesis that the gut microbiota mediates the beneficial effects of a low-FODMAP diet and reinforce the potential feasibility of microbiome-based therapies in IBS. 10.1016/j.celrep.2022.111657
Changes in signalling from faecal neuroactive metabolites following dietary modulation of IBS pain. Gut OBJECTIVE:Dietary therapies for irritable bowel syndrome (IBS) have received increasing interest but predicting which patients will benefit remains a challenge due to a lack of mechanistic insight. We recently found evidence of a role for the microbiota in dietary modulation of pain signalling in a humanised mouse model of IBS. This randomised cross-over study aimed to test the hypothesis that pain relief following reduced consumption of fermentable carbohydrates is the result of changes in luminal neuroactive metabolites. DESIGN:IBS (Rome IV) participants underwent four trial periods: two non-intervention periods, followed by a diet low (LFD) and high in fermentable carbohydrates for 3 weeks each. At the end of each period, participants completed questionnaires and provided stool. The effects of faecal supernatants (FS) collected before (IBS FS) and after a LFD (LFD FS) on nociceptive afferent neurons were assessed in mice using patch-clamp and ex vivo colonic afferent nerve recording techniques. RESULTS:Total IBS symptom severity score and abdominal pain were reduced by the LFD (N=25; p<0.01). Excitability of neurons was increased in response to IBS FS, but this effect was reduced (p<0.01) with LFD FS from pain-responders. IBS FS from pain-responders increased mechanosensitivity of nociceptive afferent nerve axons (p<0.001), an effect lost following LFD FS administration (p=NS) or when IBS FS was administered in the presence of antagonists of histamine receptors or protease inhibitors. CONCLUSIONS:In a subset of IBS patients with improvement in abdominal pain following a LFD, there is a decrease in pronociceptive signalling from FS, suggesting that changes in luminal mediators may contribute to symptom response. 10.1136/gutjnl-2022-327260
Haemorrhoidal disease reduces the risk of diverticular disease and irritable bowel syndrome: a Mendelian randomisation study. Gut 10.1136/gutjnl-2022-329307
The neurobiology of irritable bowel syndrome. Molecular psychiatry Irritable bowel syndrome (IBS) is the most prevalent disorder of brain-gut interactions that affects between 5 and 10% of the general population worldwide. The current symptom criteria restrict the diagnosis to recurrent abdominal pain associated with altered bowel habits, but the majority of patients also report non-painful abdominal discomfort, associated psychiatric conditions (anxiety and depression), as well as other visceral and somatic pain-related symptoms. For decades, IBS was considered an intestinal motility disorder, and more recently a gut disorder. However, based on an extensive body of reported information about central, peripheral mechanisms and genetic factors involved in the pathophysiology of IBS symptoms, a comprehensive disease model of brain-gut-microbiome interactions has emerged, which can explain altered bowel habits, chronic abdominal pain, and psychiatric comorbidities. In this review, we will first describe novel insights into several key components of brain-gut microbiome interactions, starting with reported alterations in the gut connectome and enteric nervous system, and a list of distinct functional and structural brain signatures, and comparing them to the proposed brain alterations in anxiety disorders. We will then point out the emerging correlations between the brain networks with the genomic, gastrointestinal, immune, and gut microbiome-related parameters. We will incorporate this new information into a systems-based disease model of IBS. Finally, we will discuss the implications of such a model for the improved understanding of the disorder and the development of more effective treatment approaches in the future. 10.1038/s41380-023-01972-w
Gelatin-Based Ingestible Impedance Sensor to Evaluate Gastrointestinal Epithelial Barriers. Advanced materials (Deerfield Beach, Fla.) Low-profile and transient ingestible electronic capsules for diagnostics and therapeutics can replace widely used yet invasive procedures such as endoscopies. Several gastrointestinal diseases such as reflux disease, Crohn's disease, irritable bowel syndrome, and eosinophilic esophagitis result in increased intercellular dilation in epithelial barriers. Currently, the primary method of diagnosing and monitoring epithelial barrier integrity is via endoscopic tissue biopsies followed by histological imaging. Here, a gelatin-based ingestible electronic capsule that can monitor epithelial barriers via electrochemical impedance measurements is proposed. Toward this end, material-specific transfer printing methodologies to manufacture soft-gelatin-based electronics, an in vitro synthetic disease model to validate impedance-based sensing, and tests of capsules using ex vivo using porcine esophageal tissue are described. The technologies described herein can advance next generation of oral diagnostic devices that reduce invasiveness and improve convenience for patients. 10.1002/adma.202211581
The Gut Microbial Bile Acid Modulation and Its Relevance to Digestive Health and Diseases. Gastroenterology The human gut microbiome has been linked to numerous digestive disorders, but its metabolic products have been much less well characterized, in part due to the expense of untargeted metabolomics and lack of ability to process the data. In this review, we focused on the rapidly expanding information about the bile acid repertoire produced by the gut microbiome, including the impacts of bile acids on a wide range of host physiological processes and diseases, and discussed the role of short-chain fatty acids and other important gut microbiome-derived metabolites. Of particular note is the action of gut microbiome-derived metabolites throughout the body, which impact processes ranging from obesity to aging to disorders traditionally thought of as diseases of the nervous system, but that are now recognized as being strongly influenced by the gut microbiome and the metabolites it produces. We also highlighted the emerging role for modifying the gut microbiome to improve health or to treat disease, including the "engineered native bacteria'' approach that takes bacterial strains from a patient, modifies them to alter metabolism, and reintroduces them. Taken together, study of the metabolites derived from the gut microbiome provided insights into a wide range of physiological and pathophysiological processes, and has substantial potential for new approaches to diagnostics and therapeutics of disease of, or involving, the gastrointestinal tract. 10.1053/j.gastro.2023.02.022
Gut enterochromaffin cells drive visceral pain and anxiety. Nature Gastrointestinal (GI) discomfort is a hallmark of most gut disorders and represents an important component of chronic visceral pain. For the growing population afflicted by irritable bowel syndrome, GI hypersensitivity and pain persist long after tissue injury has resolved. Irritable bowel syndrome also exhibits a strong sex bias, afflicting women three times more than men. Here, we focus on enterochromaffin (EC) cells, which are rare excitable, serotonergic neuroendocrine cells in the gut epithelium. EC cells detect and transduce noxious stimuli to nearby mucosal nerve endings but involvement of this signalling pathway in visceral pain and attendant sex differences has not been assessed. By enhancing or suppressing EC cell function in vivo, we show that these cells are sufficient to elicit hypersensitivity to gut distension and necessary for the sensitizing actions of isovalerate, a bacterial short-chain fatty acid associated with GI inflammation. Remarkably, prolonged EC cell activation produced persistent visceral hypersensitivity, even in the absence of an instigating inflammatory episode. Furthermore, perturbing EC cell activity promoted anxiety-like behaviours which normalized after blockade of serotonergic signalling. Sex differences were noted across a range of paradigms, indicating that the EC cell-mucosal afferent circuit is tonically engaged in females. Our findings validate a critical role for EC cell-mucosal afferent signalling in acute and persistent GI pain, in addition to highlighting genetic models for studying visceral hypersensitivity and the sex bias of gut pain. 10.1038/s41586-023-05829-8
Irritable bowel syndrome and mental health comorbidity - approach to multidisciplinary management. Nature reviews. Gastroenterology & hepatology Irritable bowel syndrome (IBS) affects 5-10% of the global population. Up to one-third of people with IBS also experience anxiety or depression. Gastrointestinal and psychological symptoms both drive health-care use in people with IBS, but psychological comorbidity seems to be more important for long-term quality of life. An integrated care approach that addresses gastrointestinal symptoms with nutrition and brain-gut behaviour therapies is considered the gold standard. However, best practice for the treatment of individuals with IBS who have a comorbid psychological condition is unclear. Given the rising prevalence of mental health disorders, discussion of the challenges of implementing therapy for people with IBS and anxiety and depression is critical. In this Review, we draw upon our expertise in gastroenterology, nutrition science and psychology to highlight common challenges that arise when managing patients with IBS and co-occurring anxiety and depression, and provide recommendations for tailoring clinical assessment and treatment. We provide best practice recommendations, including dietary and behavioural interventions that could be applied by non-specialists and clinicians working outside an integrated care model. 10.1038/s41575-023-00794-z
Diagnosis of irritable bowel syndrome. Olden Kevin W Gastroenterology Irritable bowel syndrome (IBS) is the most common disorder seen in gastroenterology practice. It is also a large component of primary care practices. Although the classic IBS symptoms of lower abdominal pain, bloating, and alteration of bowel habits is easily recognizable to most physicians, diagnosing IBS remains a challenge. This is in part caused by the absence of anatomic or physiologic markers. For this reason, the diagnosis of IBS currently needs to be made on clinical grounds. A number of symptom-based diagnostic criteria have been proposed over the last 15 years. The most recent of these, the Rome II criteria, seem to show reasonable sensitivity and specificity in diagnosing IBS. However, the role of the Rome II criteria in clinical practice remains ill defined. A review of the literature shows that, in patients with no alarm symptoms, the Rome criteria have a positive predictive value of approximately 98%, and that additional diagnostic tests have a yield of 2% or less. Diagnostic evaluation should also include a psychosocial assessment specifically addressing any history of sexual or physical abuse because these issues significantly influence management strategies and treatment success. 10.1053/gast.2002.33741
Guanylate cyclase-C as a therapeutic target in gastrointestinal disorders. Gut Functional gastrointestinal disorders (FGIDs) and IBDs are two of the most prevalent disorders of the GI tract and consume a significant proportion of healthcare resources. Recent studies have shown that membrane-bound guanylate cyclase-C (GC-C) receptors lining the GI tract may serve as novel therapeutic targets in the treatment of FGIDs and IBDs. GC-C receptor activation by its endogenous paracrine hormones uroguanylin and guanylin, and the resulting intracellular production of its downstream effector cyclic GMP, occurs in a pH-dependent manner and modulates key physiological functions. These include fluid and electrolyte homeostasis, maintenance of the intestinal barrier, anti-inflammatory activity and regulation of epithelial regeneration. Studies of the GC-C paracrine signalling axis have revealed the therapeutic potential of these receptors in treating GI disorders, including chronic idiopathic constipation and irritable bowel syndrome-constipation. This review focuses on the evolving understanding of GC-C function in health and disease, and strategies for translating these principles into new treatments for FGIDs and IBDs. 10.1136/gutjnl-2018-316029
Diagnosis and management of IBS. Khan Sarah,Chang Lin Nature reviews. Gastroenterology & hepatology IBS is a common gastrointestinal condition characterized by chronic or recurrent abdominal pain associated with altered bowel habits. IBS is considered a functional bowel disorder (that is, not defined by structural or biochemical abnormalities) and is diagnosed using symptom-based criteria. Limited and judicious use of diagnostic testing is recommended, particularly in patients with typical symptoms of IBS without alarm signs and symptoms. Management of IBS is based on a multifactorial approach and includes establishment of an effective patient-provider relationship, education, reassurance, dietary alterations, pharmacotherapy, behavioral and psychological treatment. Patient-centered care is recommended, in which management is focused on the patient's most bothersome and impactful symptoms, their preferences and previous experiences with treatment, and addressing factors associated with the onset and exacerbation of symptoms. Pharmacotherapy is typically targeted against the predominant symptom. This Review discusses the current evidence-based recommendations for the diagnosis and management of IBS. An improved understanding of the recommended diagnostic and therapeutic approaches for IBS will lead to greater patient satisfaction, as well as reduced health-care costs. 10.1038/nrgastro.2010.137
Irritable bowel syndrome. Lynn R B,Friedman L S The New England journal of medicine 10.1056/NEJM199312233292608
Postinfectious irritable bowel syndrome. Spiller Robin,Garsed Klara Gastroenterology Approximately 1 in ten patients with irritable bowel syndrome (IBS) believe their IBS began with an infectious illness. Prospective studies have shown that 3% to 36% of enteric infections lead to persistent new IBS symptoms; the precise incidence depends on the infecting organism. Whereas viral gastroenteritis seems to have only short-term effects, bacterial enteritis and protozoan and helminth infections are followed by prolonged postinfective IBS (PI-IBS). Risk factors for developing PI-IBS include, in order of importance, prolonged duration of initial illness, toxicity of infecting bacterial strain, smoking, mucosal markers of inflammation, female gender, depression, hypochondriasis, and adverse life events in the preceding 3 months. Age older than 60 years might protect against PI-IBS, whereas treatment with antibiotics has been associated with increased risk. The mechanisms that cause PI-IBS are unknown but could include residual inflammation or persistent changes in mucosal immunocytes, enterochromaffin and mast cells, enteric nerves, and the gastrointestinal microbiota. Adverse psychological factors contribute to persistent low-grade inflammation. The prognosis for patients with PI-IBS is somewhat better than for those with unselected IBS, but PI-IBS can still take years to resolve. There are no specific treatments for PI-IBS; these should be tailored to the predominant bowel disturbance, which is most frequently diarrhea. 10.1053/j.gastro.2009.02.074
Food elimination based on IgG antibodies in irritable bowel syndrome: a randomised controlled trial. Atkinson W,Sheldon T A,Shaath N,Whorwell P J Gut BACKGROUND:Patients with irritable bowel syndrome (IBS) often feel they have some form of dietary intolerance and frequently try exclusion diets. Tests attempting to predict food sensitivity in IBS have been disappointing but none has utilised IgG antibodies. AIMS:To assess the therapeutic potential of dietary elimination based on the presence of IgG antibodies to food. PATIENTS:A total of 150 outpatients with IBS were randomised to receive, for three months, either a diet excluding all foods to which they had raised IgG antibodies (enzyme linked immunosorbant assay test) or a sham diet excluding the same number of foods but not those to which they had antibodies. METHODS:Primary outcome measures were change in IBS symptom severity and global rating scores. Non-colonic symptomatology, quality of life, and anxiety/depression were secondary outcomes. Intention to treat analysis was undertaken using a generalised linear model. RESULTS:After 12 weeks, the true diet resulted in a 10% greater reduction in symptom score than the sham diet (mean difference 39 (95% confidence intervals (CI) 5-72); p = 0.024) with this value increasing to 26% in fully compliant patients (difference 98 (95% CI 52-144); p<0.001). Global rating also significantly improved in the true diet group as a whole (p = 0.048, NNT = 9) and even more in compliant patients (p = 0.006, NNT = 2.5). All other outcomes showed trends favouring the true diet. Relaxing the diet led to a 24% greater deterioration in symptoms in those on the true diet (difference 52 (95% CI 18-88); p = 0.003). CONCLUSION:Food elimination based on IgG antibodies may be effective in reducing IBS symptoms and is worthy of further biomedical research. 10.1136/gut.2003.037697
Food components and irritable bowel syndrome. Gibson Peter R,Varney Jane,Malakar Sreepurna,Muir Jane G Gastroenterology Ingestion of food has long been linked with gut symptoms, and there is increasing interest in using diet in the management of patients with irritable bowel syndrome (IBS). The West has developed an intense interest in specialized, restrictive diets, such as those that target multiple food groups, avoid gluten, or reduce fermentable oligo-, di-, and mono-saccharides and polyols. However, most gastroenterologists are not well educated about diets or their effects on the gut. It is important to understand the various dietary approaches, their putative mechanisms, the evidence that supports their use, and the benefits or harm they might produce. The concepts behind, and delivery of, specialized diets differ from those of pharmacologic agents. High-quality research is needed to determine the efficacy of different dietary approaches and the place of specific strategies. 10.1053/j.gastro.2015.02.005
Psyllium reduces inulin-induced colonic gas production in IBS: MRI and fermentation studies. Gut OBJECTIVE:Health-promoting dietary fibre including inulin often triggers gastrointestinal symptoms in patients with IBS, limiting their intake. Our aim was to test if coadministering psyllium with inulin would reduce gas production. DESIGN:A randomised, four-period, four-treatment, placebo-controlled, crossover trial in 19 patients with IBS. Subjects ingested a 500 mL test drink containing either inulin 20 g, psyllium 20 g, inulin 20 g+ psyllium 20 g or dextrose 20 g (placebo). Breath hydrogen was measured every 30 min with MRI scans hourly for 6 hours. Faecal samples from a subset of the patients with IBS were tested using an fermentation model. Primary endpoint was colonic gas assessed by MRI. RESULTS:Colonic gas rose steadily from 0 to 6 hours, with inulin causing the greatest rise, median (IQR) AUC 3145 (848-6502) mL·min. This was significantly reduced with inulin and psyllium coadministration to 618 (62-2345) mL·min (p=0.02), not significantly different from placebo. Colonic volumes AUC were significantly larger than placebo for both inulin (p=0.002) and inulin and psyllium coadministration (p=0.005). Breath hydrogen rose significantly from 120 min after inulin but not psyllium; coadministration of psyllium with inulin delayed and reduced the maximum increase, AUC from 7230 (3255-17910) ppm·hour to 1035 (360-4320) ppm·hour, p=0.007.Fermentation produced more gas with inulin than psyllium. Combining psyllium with inulin did not reduce gas production. CONCLUSIONS:Psyllium reduced inulin-related gas production in patients with IBS but does not directly inhibit fermentation. Whether coadministration with psyllium increases the tolerability of prebiotics in IBS warrants further study. TRIAL REGISTRATION NUMBER:NCT03265002. 10.1136/gutjnl-2021-324784
Histamine Receptor H1-Mediated Sensitization of TRPV1 Mediates Visceral Hypersensitivity and Symptoms in Patients With Irritable Bowel Syndrome. Wouters Mira M,Balemans Dafne,Van Wanrooy Sander,Dooley James,Cibert-Goton Vincent,Alpizar Yeranddy A,Valdez-Morales Eduardo E,Nasser Yasmin,Van Veldhoven Paul P,Vanbrabant Winde,Van der Merwe Schalk,Mols Raf,Ghesquière Bart,Cirillo Carla,Kortekaas Inge,Carmeliet Peter,Peetermans Willy E,Vermeire Séverine,Rutgeerts Paul,Augustijns Patrick,Hellings Peter W,Belmans Ann,Vanner Stephen,Bulmer David C,Talavera Karel,Vanden Berghe Pieter,Liston Adrian,Boeckxstaens Guy E Gastroenterology BACKGROUND & AIMS:Histamine sensitizes the nociceptor transient reporter potential channel V1 (TRPV1) and has been shown to contribute to visceral hypersensitivity in animals. We investigated the role of TRPV1 in irritable bowel syndrome (IBS) and evaluated if an antagonist of histamine receptor H1 (HRH1) could reduce symptoms of patients in a randomized placebo-controlled trial. METHODS:By using live calcium imaging, we compared activation of submucosal neurons by the TRPV1 agonist capsaicin in rectal biopsy specimens collected from 9 patients with IBS (ROME 3 criteria) and 15 healthy subjects. The sensitization of TRPV1 by histamine, its metabolite imidazole acetaldehyde, and supernatants from biopsy specimens was assessed by calcium imaging of mouse dorsal root ganglion neurons. We then performed a double-blind trial of patients with IBS (mean age, 31 y; range, 18-65 y; 34 female). After a 2-week run-in period, subjects were assigned randomly to groups given either the HRH1 antagonist ebastine (20 mg/day; n = 28) or placebo (n = 27) for 12 weeks. Rectal biopsy specimens were collected, barostat studies were performed, and symptoms were assessed (using the validated gastrointestinal symptom rating scale) before and after the 12-week period. Patients were followed up for an additional 2 weeks. Abdominal pain, symptom relief, and health-related quality of life were assessed on a weekly basis. The primary end point of the study was the effect of ebastine on the symptom score evoked by rectal distension. RESULTS:TRPV1 responses of submucosal neurons from patients with IBS were potentiated compared with those of healthy volunteers. Moreover, TRPV1 responses of submucosal neurons from healthy volunteers could be potentiated by their pre-incubation with histamine; this effect was blocked by the HRH1 antagonist pyrilamine. Supernatants from rectal biopsy specimens from patients with IBS, but not from the healthy volunteers, sensitized TRPV1 in mouse nociceptive dorsal root ganglion neurons via HRH1; this effect could be reproduced by histamine and imidazole acetaldehyde. Compared with subjects given placebo, those given ebastine had reduced visceral hypersensitivity, increased symptom relief (ebastine 46% vs placebo 13%; P = .024), and reduced abdominal pain scores (ebastine 39 ± 23 vs placebo 62 ± 22; P = .0004). CONCLUSIONS:In studies of rectal biopsy specimens from patients, we found that HRH1-mediated sensitization of TRPV1 is involved in IBS. Ebastine, an antagonist of HRH1, reduced visceral hypersensitivity, symptoms, and abdominal pain in patients with IBS. Inhibitors of this pathway might be developed as a new treatment approach for IBS. ClinicalTrials.gov no: NCT01144832. 10.1053/j.gastro.2015.12.034
Fructan, Rather Than Gluten, Induces Symptoms in Patients With Self-Reported Non-Celiac Gluten Sensitivity. Skodje Gry I,Sarna Vikas K,Minelle Ingunn H,Rolfsen Kjersti L,Muir Jane G,Gibson Peter R,Veierød Marit B,Henriksen Christine,Lundin Knut E A Gastroenterology BACKGROUND & AIMS:Non-celiac gluten sensitivity is characterized by symptom improvement after gluten withdrawal in absence of celiac disease. The mechanisms of non-celiac gluten sensitivity are unclear, and there are no biomarkers for this disorder. Foods with gluten often contain fructans, a type of fermentable oligo-, di-, monosaccharides and polyols. We aimed to investigate the effect of gluten and fructans separately in individuals with self-reported gluten sensitivity. METHODS:We performed a double-blind crossover challenge of 59 individuals on a self-instituted gluten-free diet, for whom celiac disease had been excluded. The study was performed at Oslo University Hospital in Norway from October 2014 through May 2016. Participants were randomly assigned to groups placed on diets containing gluten (5.7 g), fructans (2.1 g), or placebo, concealed in muesli bars, for 7 days. Following a minimum 7-day washout period (until the symptoms induced by the previous challenge were resolved), participants crossed over into a different group, until they completed all 3 challenges (gluten, fructan, and placebo). Symptoms were measured by Gastrointestinal Symptom Rating Scale Irritable Bowel Syndrome (GSRS-IBS) version. A linear mixed model for analysis was used. RESULTS:Overall GSRS-IBS scores differed significantly during gluten, fructan, and placebo challenges; mean values were 33.1 ± 13.3, 38.6 ± 12.3, and 34.3 ± 13.9, respectively (P = .04). Mean scores for GSRS-IBS bloating were 9.3 ± 3.5, 11.6 ± 3.5, and 10.1 ± 3.7, respectively, during the gluten, fructan, and placebo challenges (P = .004). The overall GSRS-IBS score for participants consuming fructans was significantly higher than for participants consuming gluten (P = .049), as was the GSRS bloating score (P = .003). Thirteen participants had the highest overall GSRS-IBS score after consuming gluten, 24 had the highest score after consuming fructan, and 22 had the highest score after consuming placebo. There was no difference in GSRS-IBS scores between gluten and placebo groups. CONCLUSIONS:In a randomized, double-blind, placebo-controlled crossover study of individuals with self-reported non-celiac gluten sensitivity, we found fructans to induce symptoms, measured by the GSRS-IBS. Clinicaltrials.gov no: NCT02464150. 10.1053/j.gastro.2017.10.040
A Diet Low in FODMAPs Reduces Symptoms in Patients With Irritable Bowel Syndrome and A Probiotic Restores Bifidobacterium Species: A Randomized Controlled Trial. Staudacher Heidi Maria,Lomer Miranda C E,Farquharson Freda M,Louis Petra,Fava Francesca,Franciosi Elena,Scholz Matthias,Tuohy Kieran M,Lindsay James O,Irving Peter M,Whelan Kevin Gastroenterology BACKGROUND & AIMS:Dietary restriction of fermentable carbohydrates (a low FODMAP diet) has been reported to reduce symptoms in some patients with irritable bowel syndrome (IBS). We performed a randomized, placebo-controlled study to determine its effects on symptoms and the fecal microbiota in patients with IBS. METHODS:We performed a 2×2 factorial trial of 104 patients with IBS (18-65 years old), based on the Rome III criteria, at 2 hospitals in the United Kingdom. Patients were randomly assigned (blinded) to groups given counselling to follow a sham diet or diet low in FODMAPs for 4 weeks, along with a placebo or multistrain probiotic formulation, resulting in 4 groups (27 receiving sham diet/placebo, 26 receiving sham diet/probiotic, 24 receiving low FODMAP diet /placebo, and 27 receiving low FODMAP diet/probiotic). The sham diet restricted a similar number of staple and non-staple foods as the low FODMAP diet; the diets had similar degrees of difficulty to follow. Dietary counselling was given to patients in all groups and data on foods eaten and compliance were collected. The incidence and severity of 15 gastrointestinal symptoms and overall symptoms were measured daily for 7 days before the study period; along with stool frequency and consistency. At baseline, global and individual symptoms were measured, along with generic and disease-specific health-related quality of life, using standard scoring systems. All data were collected again at 4 weeks, and patients answered questions about adequate symptom relief. Fecal samples were collected at baseline and after 4 weeks and analyzed by quantitative PCR and 16S rRNA sequencing. The co-primary endpoints were adequate relief of symptoms and stool Bifidobacterium species abundance at 4 weeks. RESULTS:There was no significant interaction between the interventions in adequate relief of symptoms (P = .52) or Bifidobacterium species (P = .68). In the intention-to-treat analysis, a higher proportion of patients in the low FODMAP diet had adequate symptom relief (57%) than in the sham diet group (38%), although the difference was not statistically significant (P = .051). In the per-protocol analysis, a significantly higher proportion of patients on the low FODMAP diet had adequate symptom relief (61%) than in the sham diet group (39%) (P = .042). Total mean IBS-Severity Scoring System score was significantly lower for patients on the low FODMAP diet (173 ± 95) than the sham diet (224 ± 89) (P = .001), but not different between those given probiotic (207 ± 98) or placebo (192 ± 93) (P = .721) Abundance of Bifidobacterium species was lower in fecal samples from patients on the low FODMAP diet (8.8 rRNA genes/g) than patients on the sham diet (9.2 rRNA genes/g) (P = .008), but higher in patients given probiotic (9.1 rRNA genes/g) than patients given placebo (8.8 rRNA genes/g) (P = .019). There was no effect of the low FODMAP diet on microbiota diversity in fecal samples. CONCLUSIONS:In a placebo-controlled study of patients with IBS, a low FODMAP diet associates with adequate symptom relief and significantly reduced symptom scores compared with placebo. It is not clear whether changes resulted from collective FODMAP restriction or removal of a single component, such as lactose. Co-administration of the multistrain probiotic increased numbers of Bifidobacterium species, compared with placebo, and might be given to restore these bacteria to patients on a low FODMAP diet. Trial registration no: ISRCTN02275221. 10.1053/j.gastro.2017.06.010
FODMAPs alter symptoms and the metabolome of patients with IBS: a randomised controlled trial. Gut OBJECTIVE:To gain mechanistic insights, we compared effects of low fermentable oligosaccharides, disaccharides and monosaccharides and polyols (FODMAP) and high FODMAP diets on symptoms, the metabolome and the microbiome of patients with IBS. DESIGN:We performed a controlled, single blind study of patients with IBS (Rome III criteria) randomised to a low (n=20) or high (n=20) FODMAP diet for 3 weeks. Symptoms were assessed using the IBS symptom severity scoring (IBS-SSS). The metabolome was evaluated using the lactulose breath test (LBT) and metabolic profiling in urine using mass spectrometry. Stool microbiota composition was analysed by 16S rRNA gene profiling. RESULTS:Thirty-seven patients (19 low FODMAP; 18 high FODMAP) completed the 3-week diet. The IBS-SSS was reduced in the low FODMAP diet group (p<0.001) but not the high FODMAP group. LBTs showed a minor decrease in H production in the low FODMAP compared with the high FODMAP group. Metabolic profiling of urine showed groups of patients with IBS differed significantly after the diet (p<0.01), with three metabolites (histamine, p-hydroxybenzoic acid, azelaic acid) being primarily responsible for discrimination between the two groups. Histamine, a measure of immune activation, was reduced eightfold in the low FODMAP group (p<0.05). Low FODMAP diet increased Actinobacteria richness and diversity, and high FODMAP diet decreased the relative abundance of bacteria involved in gas consumption. CONCLUSIONS:IBS symptoms are linked to FODMAP content and associated with alterations in the metabolome. In subsets of patients, FODMAPs modulate histamine levels and the microbiota, both of which could alter symptoms. TRIAL REGISTRATION NUMBER:NCT01829932. 10.1136/gutjnl-2015-311339
Transplantation of fecal microbiota from patients with irritable bowel syndrome alters gut function and behavior in recipient mice. De Palma Giada,Lynch Michael D J,Lu Jun,Dang Vi T,Deng Yikang,Jury Jennifer,Umeh Genevieve,Miranda Pedro M,Pigrau Pastor Marc,Sidani Sacha,Pinto-Sanchez Maria Ines,Philip Vivek,McLean Peter G,Hagelsieb Moreno-Gabriel,Surette Michael G,Bergonzelli Gabriela E,Verdu Elena F,Britz-McKibbin Philip,Neufeld Josh D,Collins Stephen M,Bercik Premysl Science translational medicine Irritable bowel syndrome (IBS) is a common disorder characterized by altered gut function and often is accompanied by comorbid anxiety. Although changes in the gut microbiota have been documented, their relevance to the clinical expression of IBS is unknown. To evaluate a functional role for commensal gut bacteria in IBS, we colonized germ-free mice with the fecal microbiota from healthy control individuals or IBS patients with diarrhea (IBS-D), with or without anxiety, and monitored gut function and behavior in the transplanted mice. Microbiota profiles in recipient mice clustered according to the microbiota profiles of the human donors. Mice receiving the IBS-D fecal microbiota showed a taxonomically similar microbial composition to that of mice receiving the healthy control fecal microbiota. However, IBS-D mice showed different serum metabolomic profiles. Mice receiving the IBS-D fecal microbiota, but not the healthy control fecal microbiota, exhibited faster gastrointestinal transit, intestinal barrier dysfunction, innate immune activation, and anxiety-like behavior. These results indicate the potential of the gut microbiota to contribute to both intestinal and behavioral manifestations of IBS-D and suggest the potential value of microbiota-directed therapies in IBS patients. 10.1126/scitranslmed.aaf6397
Improvement in Gastrointestinal Symptoms After Cognitive Behavior Therapy for Refractory Irritable Bowel Syndrome. Lackner Jeffrey M,Jaccard James,Keefer Laurie,Brenner Darren M,Firth Rebecca S,Gudleski Gregory D,Hamilton Frank A,Katz Leonard A,Krasner Susan S,Ma Chang-Xing,Radziwon Christopher D,Sitrin Michael D Gastroenterology BACKGROUND & AIMS:There is an urgent need for safe treatments for irritable bowel syndrome (IBS) that relieve treatment-refractory symptoms and their societal and economic burden. Cognitive behavior therapy (CBT) is an effective treatment that has not been broadly adopted into routine clinical practice. We performed a randomized controlled trial to assess clinical responses to home-based CBT compared with clinic-based CBT and patient education. METHODS:We performed a prospective study of 436 patients with IBS, based on Rome III criteria, at 2 tertiary centers from August 23, 2010, through October 21, 2016. Subjects (41.4 ± 14.8 years old; 80% women) were randomly assigned to groups that received the following: standard-CBT (S-CBT, n = 146, comprising 10 weekly, 60-minute sessions that emphasized the provision of information about brain-gut interactions; self-monitoring of symptoms, their triggers, and consequences; muscle relaxation; worry control; flexible problem solving; and relapse prevention training), or 4 sessions of primarily home-based CBT requiring minimal therapist contact (MC-CBT, n = 145), in which patients received home-study materials covering the same procedures as S-CBT), or 4 sessions of IBS education (EDU, n = 145) that provided support and information about IBS and the role of lifestyle factors such as stress, diet, and exercise. The primary outcome was global improvement of IBS symptoms, based on the IBS-version of the Clinical Global Impressions-Improvement Scale. Ratings were performed by patients and board-certified gastroenterologists blinded to treatment allocation. Efficacy data were collected 2 weeks, 3 months, and 6 months after treatment completion. RESULTS:A higher proportion of patients receiving MC-CBT reported moderate to substantial improvement in gastrointestinal symptoms 2 weeks after treatment (61.0% based on ratings by patients and 55.7% based on ratings by gastroenterologists) than those receiving EDU (43.5% based on ratings patients and 40.4% based on ratings by gastroenterologists) (P < .05). Gastrointestinal symptom improvement, rated by gastroenterologists, 6 months after the end of treatment also differed significantly between the MC-CBT (58.4%) and EDU groups (44.8%) (P = .05). Formal equivalence testing applied across multiple contrasts indicated that MC-CBT is at least as effective as S-CBT in improving IBS symptoms. Patients tended to be more satisfied with CBT vs EDU (P < .05) based on immediate posttreatment responses to the Client Satisfaction Questionnaire. Symptom improvement was not significantly related to concomitant use of medications. CONCLUSIONS:In a randomized controlled trial, we found that a primarily home-based version of CBT produced significant and sustained gastrointestinal symptom improvement for patients with IBS compared with education. Clinicaltrials.gov no.: NCT00738920. 10.1053/j.gastro.2018.03.063
A diet low in FODMAPs reduces symptoms of irritable bowel syndrome. Halmos Emma P,Power Victoria A,Shepherd Susan J,Gibson Peter R,Muir Jane G Gastroenterology BACKGROUND & AIMS:A diet low in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs) often is used to manage functional gastrointestinal symptoms in patients with irritable bowel syndrome (IBS), yet there is limited evidence of its efficacy, compared with a normal Western diet. We investigated the effects of a diet low in FODMAPs compared with an Australian diet, in a randomized, controlled, single-blind, cross-over trial of patients with IBS. METHODS:In a study of 30 patients with IBS and 8 healthy individuals (controls, matched for demographics and diet), we collected dietary data from subjects for 1 habitual week. Participants then randomly were assigned to groups that received 21 days of either a diet low in FODMAPs or a typical Australian diet, followed by a washout period of at least 21 days, before crossing over to the alternate diet. Daily symptoms were rated using a 0- to 100-mm visual analogue scale. Almost all food was provided during the interventional diet periods, with a goal of less than 0.5 g intake of FODMAPs per meal for the low-FODMAP diet. All stools were collected from days 17-21 and assessed for frequency, weight, water content, and King's Stool Chart rating. RESULTS:Subjects with IBS had lower overall gastrointestinal symptom scores (22.8; 95% confidence interval, 16.7-28.8 mm) while on a diet low in FODMAPs, compared with the Australian diet (44.9; 95% confidence interval, 36.6-53.1 mm; P < .001) and the subjects' habitual diet. Bloating, pain, and passage of wind also were reduced while IBS patients were on the low-FODMAP diet. Symptoms were minimal and unaltered by either diet among controls. Patients of all IBS subtypes had greater satisfaction with stool consistency while on the low-FODMAP diet, but diarrhea-predominant IBS was the only subtype with altered fecal frequency and King's Stool Chart scores. CONCLUSIONS:In a controlled, cross-over study of patients with IBS, a diet low in FODMAPs effectively reduced functional gastrointestinal symptoms. This high-quality evidence supports its use as a first-line therapy. CLINICAL TRIAL NUMBER:ACTRN12612001185853. 10.1053/j.gastro.2013.09.046
Functional bowel disorders. Longstreth George F,Thompson W Grant,Chey William D,Houghton Lesley A,Mearin Fermin,Spiller Robin C Gastroenterology Employing a consensus approach, our working team critically considered the available evidence and multinational expert criticism, revised the Rome II diagnostic criteria for the functional bowel disorders, and updated diagnosis and treatment recommendations. Diagnosis of a functional bowel disorder (FBD) requires characteristic symptoms during the last 3 months and onset > or =6 months ago. Alarm symptoms suggest the possibility of structural disease, but do not necessarily negate a diagnosis of an FBD. Irritable bowel syndrome (IBS), functional bloating, functional constipation, and functional diarrhea are best identified by symptom-based approaches. Subtyping of IBS is controversial, and we suggest it be based on stool form, which can be aided by use of the Bristol Stool Form Scale. Diagnostic testing should be guided by the patient's age, primary symptom characteristics, and other clinical and laboratory features. Treatment of FBDs is based on an individualized evaluation, explanation, and reassurance. Alterations in diet, drug treatment aimed at predominant symptoms, and psychotherapy may be beneficial. 10.1053/j.gastro.2005.11.061
Probiotic Bifidobacterium longum NCC3001 Reduces Depression Scores and Alters Brain Activity: A Pilot Study in Patients With Irritable Bowel Syndrome. Pinto-Sanchez Maria Ines,Hall Geoffrey B,Ghajar Kathy,Nardelli Andrea,Bolino Carolina,Lau Jennifer T,Martin Francois-Pierre,Cominetti Ornella,Welsh Christopher,Rieder Amber,Traynor Jenna,Gregory Caitlin,De Palma Giada,Pigrau Marc,Ford Alexander C,Macri Joseph,Berger Bernard,Bergonzelli Gabriela,Surette Michael G,Collins Stephen M,Moayyedi Paul,Bercik Premysl Gastroenterology BACKGROUND & AIMS:Probiotics can reduce symptoms of irritable bowel syndrome (IBS), but little is known about their effects on psychiatric comorbidities. We performed a prospective study to evaluate the effects of Bifidobacterium longum NCC3001 (BL) on anxiety and depression in patients with IBS. METHODS:We performed a randomized, double-blind, placebo-controlled study of 44 adults with IBS and diarrhea or a mixed-stool pattern (based on Rome III criteria) and mild to moderate anxiety and/or depression (based on the Hospital Anxiety and Depression scale) at McMaster University in Canada, from March 2011 to May 2014. At the screening visit, clinical history and symptoms were assessed and blood samples were collected. Patients were then randomly assigned to groups and given daily BL (n = 22) or placebo (n = 22) for 6 weeks. At weeks 0, 6, and 10, we determined patients' levels of anxiety and depression, IBS symptoms, quality of life, and somatization using validated questionnaires. At weeks 0 and 6, stool, urine and blood samples were collected, and functional magnetic resonance imaging (fMRI) test was performed. We assessed brain activation patterns, fecal microbiota, urine metabolome profiles, serum markers of inflammation, neurotransmitters, and neurotrophin levels. RESULTS:At week 6, 14 of 22 patients in the BL group had reduction in depression scores of 2 points or more on the Hospital Anxiety and Depression scale, vs 7 of 22 patients in the placebo group (P = .04). BL had no significant effect on anxiety or IBS symptoms. Patients in the BL group had a mean increase in quality of life score compared with the placebo group. The fMRI analysis showed that BL reduced responses to negative emotional stimuli in multiple brain areas, including amygdala and fronto-limbic regions, compared with placebo. The groups had similar fecal microbiota profiles, serum markers of inflammation, and levels of neurotrophins and neurotransmitters, but the BL group had reduced urine levels of methylamines and aromatic amino acids metabolites. At week 10, depression scores were reduced in patients given BL vs placebo. CONCLUSION:In a placebo-controlled trial, we found that the probiotic BL reduces depression but not anxiety scores and increases quality of life in patients with IBS. These improvements were associated with changes in brain activation patterns that indicate that this probiotic reduces limbic reactivity. ClinicalTrials.gov no. NCT01276626. 10.1053/j.gastro.2017.05.003
Therapeutic potential of fecal microbiota transplantation. Smits Loek P,Bouter Kristien E C,de Vos Willem M,Borody Thomas J,Nieuwdorp Max Gastroenterology There has been growing interest in the use of fecal microbiota for the treatment of patients with chronic gastrointestinal infections and inflammatory bowel diseases. Lately, there has also been interest in its therapeutic potential for cardiometabolic, autoimmune, and other extraintestinal conditions that were not previously considered to be associated with the intestinal microbiota. Although it is not clear if changes in the microbiota cause these conditions, we review the most current and best methods for performing fecal microbiota transplantation and summarize clinical observations that have implicated the intestinal microbiota in various diseases. We also discuss case reports of fecal microbiota transplantations for different disorders, including Clostridium difficile infection, irritable bowel syndrome, inflammatory bowel diseases, insulin resistance, multiple sclerosis, and idiopathic thrombocytopenic purpura. There has been increasing focus on the interaction between the intestinal microbiome, obesity, and cardiometabolic diseases, and we explore these relationships and the potential roles of different microbial strains. We might someday be able to mine for intestinal bacterial strains that can be used in the diagnosis or treatment of these diseases. 10.1053/j.gastro.2013.08.058
Functional dyspepsia. Enck Paul,Azpiroz Fernando,Boeckxstaens Guy,Elsenbruch Sigrid,Feinle-Bisset Christine,Holtmann Gerald,Lackner Jeffrey M,Ronkainen Jukka,Schemann Michael,Stengel Andreas,Tack Jan,Zipfel Stephan,Talley Nicholas J Nature reviews. Disease primers Functional dyspepsia is one of the most prevalent functional gastrointestinal disorders. Functional dyspepsia comprises three subtypes with presumed different pathophysiology and aetiology: postprandial distress syndrome (PDS), epigastric pain syndrome (EPS) and a subtype with overlapping PDS and EPS features. Functional dyspepsia symptoms can be caused by disturbed gastric motility (for example, inadequate fundic accommodation or delayed gastric emptying), gastric sensation (for example, sensations associated with hypersensitivity to gas and bloating) or gastric and duodenal inflammation. A genetic predisposition is probable but less evident than in other functional gastrointestinal disorders, such as irritable bowel syndrome (IBS). Psychiatric comorbidity and psychopathological state and trait characteristics could also play a part, although they are not specific to functional dyspepsia and are less pronounced than in IBS. Possible differential diagnoses include Helicobacter pylori infection and peptic ulceration. Pharmacological therapy is mostly based on the subtype of functional dyspepsia, such as prokinetic and fundus-relaxing drugs for PDS and acid-suppressive drugs for EPS, whereas centrally active neuromodulators and herbal drugs play a minor part. Psychotherapy is effective only in a small subset of patients, whereas quality of life can be severely affected in nearly all patients. Future therapies might include novel compounds that attempt to treat the underlying gastric and duodenal inflammation. 10.1038/nrdp.2017.81
Irritable bowel syndrome. Grayson Michelle Nature 10.1038/533S101a
Irritable Bowel Syndrome. Ford Alexander C,Lacy Brian E,Talley Nicholas J The New England journal of medicine 10.1056/NEJMra1607547
Irritable bowel syndrome: a clinical review. Chey William D,Kurlander Jacob,Eswaran Shanti JAMA IMPORTANCE:Irritable bowel syndrome (IBS) affects 7% to 21% of the general population. It is a chronic condition that can substantially reduce quality of life and work productivity. OBJECTIVES:To summarize the existing evidence on epidemiology, pathophysiology, and diagnosis of IBS and to provide practical treatment recommendations for generalists and specialists according to the best available evidence. EVIDENCE REVIEW:A search of Ovid (MEDLINE) and Cochrane Database of Systematic Reviews was performed for literature from 2000 to December 2014 for the terms pathophysiology, etiology, pathogenesis, diagnosis, irritable bowel syndrome, and IBS. The range was expanded from 1946 to December 2014 for IBS, irritable bowel syndrome, diet, treatment, and therapy. FINDINGS:The database search yielded 1303 articles, of which 139 were selected for inclusion. IBS is not a single disease but rather a symptom cluster resulting from diverse pathologies. Factors important to the development of IBS include alterations in the gut microbiome, intestinal permeability, gut immune function, motility, visceral sensation, brain-gut interactions, and psychosocial status. The diagnosis of IBS relies on symptom-based criteria, exclusion of concerning features (symptom onset after age 50 years, unexplained weight loss, family history of selected organic gastrointestinal diseases, evidence of gastrointestinal blood loss, and unexplained iron-deficiency anemia), and the performance of selected tests (complete blood cell count, C-reactive protein or fecal calprotectin, serologic testing for celiac disease, and age-appropriate colorectal cancer screening) to exclude organic diseases that can mimic IBS. Determining the predominant symptom (IBS with diarrhea, IBS with constipation, or mixed IBS) plays an important role in selection of diagnostic tests and treatments. Various dietary, lifestyle, medical, and behavioral interventions have proven effective in randomized clinical trials. CONCLUSIONS AND RELEVANCE:The diagnosis of IBS relies on the identification of characteristic symptoms and the exclusion of other organic diseases. Management of patients with IBS is optimized by an individualized, holistic approach that embraces dietary, lifestyle, medical, and behavioral interventions. 10.1001/jama.2015.0954
Diagnosis and Treatment of Irritable Bowel Syndrome: A Review. Camilleri Michael JAMA Importance:The prevalence of irritable bowel syndrome (IBS) in the United States is between 7% and 16%, most common in women and young people, with annual direct costs estimated at more than $1 billion dollars in the United States. Traditionally, the diagnosis of IBS has been based on the positive identification of symptoms that correlate with several different syndromes associated with disorders such as IBS diarrhea, IBS constipation, functional diarrhea, functional constipation, chronic functional abdominal pain, or bloating. Several peripheral and central mechanisms initiate gastrointestinal motor and sensory dysfunctions leading to IBS symptoms. Those dysfunctions may require evaluation in patients whose symptoms do not respond to first-line treatments. Observations:Validation studies of consensus symptom-based criteria have identified deficiencies that favor a simpler identification of the predominant symptoms of abdominal pain, bowel dysfunction, and bloating and exclusion of alarm symptoms such as unintentional weight loss, rectal bleeding, or recent change in bowel function. Symptom-based diagnosis of IBS is enhanced with additional history for symptoms of somatoform and psychological disorders and alarm symptoms, physical examination including digital rectal examination, and screening tests to exclude organic disease (by measuring hemoglobin and C-reactive protein concentrations). The initial treatment plan should include patient education, reassurance, and first-line treatments such as fiber and osmotic laxatives for constipation, opioids for diarrhea, antispasmodics for pain and for management of associated psychological disorders. For patients who do not respond to those IBS treatments, testing for specific functional disorders may be required in a minority of patients with IBS. These disorders include rectal evacuation disorder, abnormal colonic transit, and bile acid diarrhea. Their identification is followed by individualized treatment, such as pelvic floor retraining for rectal evacuation disorders, sequestrants for bile acid diarrhea, and secretory agents for constipation, although there is only limited evidence that this individualized management approach is effective. Conclusions and Relevance:Advances in the identification of specific dysfunctions as causes of individual symptoms in the "IBS spectrum" leads to the potential to enhance the diagnosis and management of symptoms for the majority of patients for whom first-line therapies of IBS and management of comorbid psychological disorders are insufficient. 10.1001/jama.2020.22532
Irritable bowel syndrome. Nature reviews. Disease primers Irritable bowel syndrome (IBS) is a functional gastrointestinal disease with a high population prevalence. The disorder can be debilitating in some patients, whereas others may have mild or moderate symptoms. The most important single risk factors are female sex, younger age and preceding gastrointestinal infections. Clinical symptoms of IBS include abdominal pain or discomfort, stool irregularities and bloating, as well as other somatic, visceral and psychiatric comorbidities. Currently, the diagnosis of IBS is based on symptoms and the exclusion of other organic diseases, and therapy includes drug treatment of the predominant symptoms, nutrition and psychotherapy. Although the underlying pathogenesis is far from understood, aetiological factors include increased epithelial hyperpermeability, dysbiosis, inflammation, visceral hypersensitivity, epigenetics and genetics, and altered brain-gut interactions. IBS considerably affects quality of life and imposes a profound burden on patients, physicians and the health-care system. The past decade has seen remarkable progress in our understanding of functional bowel disorders such as IBS that will be summarized in this Primer. 10.1038/nrdp.2016.14
Chronic diarrhoea: the indications for lower GI endoscopy when functional bowel disease is suspected. Ong John,Swift Carla,Allwood Ian,Norman Roger,Al-Naeeb Yasseen,Shankar Arun Gut 10.1136/gutjnl-2018-317574
The 2019 James W. Freston Conference: Food at the Intersection of Gut Health and Disease. Mullin Gerard E,Chey William D,Crowe Sheila E, Gastroenterology 10.1053/j.gastro.2020.03.036
Zonulin in serum as a biomarker fails to identify the IBS, functional dyspepsia and non-coeliac wheat sensitivity. Talley Nicholas J,Holtmann Gerald J,Jones Michael,Koloski Natasha A,Walker Marjorie M,Burns Grace,Potter Michael D E,Shah Ayesha,Keely Simon Gut 10.1136/gutjnl-2019-318664
White small bowel in a patient with chronic diarrhoea. Gut 10.1136/gutjnl-2021-326421
Reduced efficacy of low FODMAPs diet in patients with IBS-D carrying sucrase-isomaltase () hypomorphic variants. Zheng Tenghao,Eswaran Shanti,Photenhauer Amanda L,Merchant Juanita L,Chey William D,D'Amato Mauro Gut 10.1136/gutjnl-2018-318036
AGA Clinical Practice Guidelines on the Laboratory Evaluation of Functional Diarrhea and Diarrhea-Predominant Irritable Bowel Syndrome in Adults (IBS-D): Patient Summary. Gastroenterology 10.1053/j.gastro.2019.07.038
AGA Clinical Practice Guidelines on the Laboratory Evaluation of Functional Diarrhea and Diarrhea-Predominant Irritable Bowel Syndrome in Adults (IBS-D). Smalley Walter,Falck-Ytter Corinna,Carrasco-Labra Alonso,Wani Sachin,Lytvyn Lyubov,Falck-Ytter Yngve Gastroenterology 10.1053/j.gastro.2019.07.004
Letter to the editor: prospective, double-blind diagnostic multicentre study of confocal laser endomicroscopy for wheat sensitivity in patients with irritable bowel syndrome. Gut 10.1136/gutjnl-2021-326252
Serine proteases as luminal mediators of intestinal barrier dysfunction and symptom severity in IBS. Edogawa Shoko,Edwinson Adam L,Peters Stephanie A,Chikkamenahalli Lakshmikanth L,Sundt Wendy,Graves Sara,Gurunathan Sakteesh V,Breen-Lyles Margaret,Johnson Stephen,Dyer Roy,Graham Rondell,Chen Jun,Kashyap Purna,Farrugia Gianrico,Grover Madhusudan Gut OBJECTIVE:The intestinal lumen contains several proteases. Our aim was to determine the role of faecal proteases in mediating barrier dysfunction and symptoms in IBS. DESIGN:39 patients with IBS and 25 healthy volunteers completed questionnaires, assessments of in vivo permeability, ex vivo colonic barrier function in Ussing chambers, tight junction (TJ) proteins, ultrastructural morphology and 16 s sequencing of faecal microbiota rRNA. A casein-based assay was used to measure proteolytic activity (PA) in faecal supernatants (FSNs). Colonic barrier function was determined in mice (ex-germ free) humanised with microbial communities associated with different human PA states. RESULTS:Patients with IBS had higher faecal PA than healthy volunteers. 8/20 postinfection IBS (PI-IBS) and 3/19 constipation- predominant IBS had high PA (>95th percentile). High-PA patients had more and looser bowel movements, greater symptom severity and higher in vivo and ex vivo colonic permeability. High-PA FSNs increased paracellular permeability, decreased occludin and increased phosphorylated myosin light chain (pMLC) expression. Serine but not cysteine protease inhibitor significantly blocked high-PA FSN effects on barrier. The effects on barrier were diminished by pharmacological or siRNA inhibition of protease activated receptor-2 (PAR-2). Patients with high-PA IBS had lower occludin expression, wider TJs on biopsies and reduced microbial diversity than patients with low PA. Mice humanised with high-PA IBS microbiota had greater in vivo permeability than those with low-PA microbiota. CONCLUSION:A subset of patients with IBS, especially in PI-IBS, has substantially high faecal PA, greater symptoms, impaired barrier and reduced microbial diversity. Commensal microbiota affects luminal PA that can influence host barrier function. 10.1136/gutjnl-2018-317416
Six vs 12 Sessions of Gut-focused Hypnotherapy for Irritable Bowel Syndrome: A Randomized Trial. Gastroenterology 10.1053/j.gastro.2021.02.058
Assessing the Impact of Changes to the Rome IV Criteria for Clinical Practice in Irritable Bowel Syndrome. Gastroenterology 10.1053/j.gastro.2022.01.021
Predicting Response to Rifaximin in Irritable Bowel Syndrome with Diarrhea: Is the Answer Blowing in the Wind? Black Christopher J,Ford Alexander C Gastroenterology 10.1053/j.gastro.2020.02.018
Factor Analysis of the Rome IV Criteria for Major Disorders of Gut-Brain Interaction (DGBI) Globally and Across Geographical, Sex, and Age Groups. Gastroenterology BACKGROUND & AIMS:The Rome criteria are widely accepted for diagnosing disorders of gut-brain interaction, but their global applicability has been debated. This study aimed to evaluate the validity of the Rome IV criteria by factor analysis globally, across geographical regions, by sex, and by age groups. METHODS:Data were collected in 26 countries using the Rome IV questionnaire. Forty-nine ordinal variables were used in exploratory factor analysis (EFA) to identify clusters of inter-correlated variables (factors) within the data set. Confirmatory factor analysis with predefined factors of the disorders of gut-brain interaction was compared with the factors in the EFA. Analyses were performed globally, for each geographical region (North and Latin America, Western and Eastern Europe, Middle East, Asia), sex, and age groups (18-34, 35-49, 50-64, ≥65). RESULTS:A total of 54,127 people were included. The EFA identified 10 factors accounting for 57% of the variance: irritable bowel syndrome, constipation, diarrhea, upper gastrointestinal symptoms, globus, regurgitation/retching, chest pain, nausea/vomiting, and 2 right upper quadrant pain factors. Most factors had close correspondence to a Rome IV criteria diagnosis, but notably, functional dysphagia and heartburn symptoms were often included in the same factor and/or in upper gastrointestinal symptoms. Most factors were consistent across geographical regions, sex, and age groups, and compatible to the global results. All prespecified factors in the confirmatory analysis had a loading ≥0.4, indicating validity of the Rome IV criteria. CONCLUSIONS:The results indicate that the Rome IV criteria for irritable bowel syndrome, functional dyspepsia, functional constipation, globus, and biliary pain are globally valid and represent universal diagnostic entities that are similar across sex and age groups. 10.1053/j.gastro.2023.02.033
How to Approach a Patient with Difficult-to-Treat IBS. Chang Lin Gastroenterology 10.1053/j.gastro.2021.07.034
Spotlight: Laboratory Evaluation of Functional Diarrhea and Diarrhea-Predominant Irritable Bowel Syndrome in Adults (IBS-D). Smalley Walter,Falck-Ytter Corinna,Carrasco-Labra Alonso,Wani Sachin,Lytvyn Lyubov,Falck-Ytter Yngve Gastroenterology 10.1053/j.gastro.2019.07.053
Bile Acid Diarrhea Is Associated With Increased Intestinal Permeability Compared With Irritable Bowel Syndrome-Diarrhea. Gastroenterology 10.1053/j.gastro.2021.12.243
Assessing telephone-delivered cognitive-behavioural therapy (CBT) and web-delivered CBT versus treatment as usual in irritable bowel syndrome (ACTIB): a multicentre randomised trial. Everitt Hazel Anne,Landau Sabine,O'Reilly Gilly,Sibelli Alice,Hughes Stephanie,Windgassen Sula,Holland Rachel,Little Paul,McCrone Paul,Bishop Felicity,Goldsmith Kimberley,Coleman Nicholas,Logan Robert,Chalder Trudie,Moss-Morris Rona, Gut OBJECTIVE:To evaluate the clinical effectiveness of two modes of cognitive-behavioural therapy (CBT) for IBS compared with treatment as usual (TAU) in refractory IBS. DESIGN:A three-arm randomised controlled trial assessing telephone-delivered CBT (TCBT), web-based CBT (WCBT) with minimal therapist support, and TAU. Blinding participants and therapists was not possible. Chief investigator, assessors and statisticians were blinded. Participants were adults with refractory IBS (clinically significant symptoms for ≥12 months despite first-line therapies), recruited by letter and opportunistically from 74 general practices and three gastroenterology centres in London and South of England between May 2014 to March 2016. Co-primary outcomes were IBS Symptom Severity Score (IBS-SSS) and Work and Social Adjustment Scale (WSAS) at 12 months. RESULTS:558/1452 (38.4%) patients screened for eligibility were randomised: 76% female: 91% white: mean age 43 years. (391/558) 70.1% completed 12 months of follow-up. Primary outcomes: Compared with TAU (IBS-SSS 205.6 at 12 months), IBS-SSS was 61.6 (95% CI 33.8 to 89.5) points lower (p<0.001) in TCBT and 35.2 (95% CI 12.6 to 57.8) points lower (p=0.002) in WCBT at 12 months. Compared with TAU (WSAS score 10.8 at 12 months) WSAS was 3.5 (95% CI 1.9 to 5.1) points lower (p<0.001) in TCBT and 3.0 (95% CI 1.3 to 4.6) points lower (p=0.001) in WCBT. All secondary outcomes showed significantly greater improvement (p≤0.002) in CBT arms compared with TAU. There were no serious adverse reactions to treatment. CONCLUSION:Both CBT interventions were superior to TAU up to 12 months of follow-up. TRIAL REGISTRATION NUMBER:ISRCTN44427879. 10.1136/gutjnl-2018-317805
No distinct microbiome signature of irritable bowel syndrome found in a Swedish random population. Hugerth Luisa W,Andreasson Anna,Talley Nicholas J,Forsberg Anna M,Kjellström Lars,Schmidt Peter Thelin,Agreus Lars,Engstrand Lars Gut OBJECTIVE:The ethiopathogenesis of irritable bowel syndrome (IBS) is unknown. While a link to the gut microbiome is postulated, the heterogeneity of the healthy gut makes it difficult to draw definitive conclusions. We aimed to describe the faecal and mucosa-associated microbiome (MAM) and health correlates on a community cohort of healthy and IBS individuals with no colonoscopic findings. DESIGN:The PopCol study recruited a random sample of 3556 adults; 745 underwent colonoscopy. IBS was defined by Rome IV criteria and organic disease excluded. 16S rRNA gene sequencing was conducted on sigmoid biopsy samples from 376 representative individuals (63 IBS cases) and faecal samples from 185 individuals (32 IBS cases). RESULTS:While sigmoid MAM was dominated by Lachnospiraceae, faeces presented a higher relative abundance of Ruminococcaceae. Microbial richness in MAM was linearly correlated to that in faeces from the same individual (R²=0.255, p<3E-11) as was diversity (R²=0.06, p=0.0022). MAM diversity decreased with increasing body mass index (BMI; Pearson's r=-0.1, p=0.08) and poorer self-rated health (r=-0.15, p=0.007), but no other health correlates. Faecal microbiome diversity was correlated to stool consistency (r=-0.16, p=0.043). Several taxonomic groups were correlated to age, BMI, depression and self-reported health, including associated with lower levels of depression (r=-0.003, p=0.00017). The degree of heterogeneity observed between IBS patients is higher than that observed between healthy individuals. CONCLUSIONS:No distinct microbial signature was observed in IBS. Individuals presenting with low self-rated health or high BMI have lower gut microbiome richness. 10.1136/gutjnl-2019-318717
PEG and Mucosal Biofilms in Irritable Bowel Syndrome and Ulcerative Colitis. Reinisch Walter Gastroenterology 10.1053/j.gastro.2021.06.053
A neuropsychosocial signature predicts longitudinal symptom changes in women with irritable bowel syndrome. Molecular psychiatry Irritable bowel syndrome (IBS) is a common disorder of brain-gut interactions characterized by chronic abdominal pain, altered bowel movements, often accompanied by somatic and psychiatric comorbidities. We aimed to test the hypothesis that a baseline phenotype composed of multi-modal neuroimaging and clinical features predicts clinical improvement on the IBS Symptom Severity Scale (IBS-SSS) at 3 and 12 months without any targeted intervention. Female participants (N = 60) were identified as "improvers" (50-point decrease on IBS-SSS from baseline) or "non-improvers." Data integration analysis using latent components (DIABLO) was applied to a training and test dataset to determine whether a limited number of sets of multiple correlated baseline'omics data types, including brain morphometry, anatomical connectivity, resting-state functional connectivity, and clinical features could accurately predict improver status. The derived predictive models predicted improvement status at 3-months and 12-months with 91% and 83% accuracy, respectively. Across both time points, non-improvers were classified as having greater correlated morphometry, anatomical connectivity and resting-state functional connectivity characteristics within salience and sensorimotor networks associated with greater pain unpleasantness, but lower default mode network integrity and connectivity. This suggests that non-improvers have a greater engagement of attentional systems to perseverate on painful visceral stimuli, predicting IBS exacerbation. The ability of baseline multimodal brain-clinical signatures to predict symptom trajectories may have implications in guiding integrative treatment in the age of precision medicine, such as treatments targeted at changing attentional systems such as mindfulness or cognitive behavioral therapy. 10.1038/s41380-021-01375-9
Rome Foundation Working Team Report on Post-Infection Irritable Bowel Syndrome. Gastroenterology BACKGROUND & AIMS:The existence of postinfection irritable bowel syndrome (PI-IBS) has been substantiated by epidemiology studies conducted in diverse geographic and clinical settings. However, the available evidence has not been well summarized, and there is little guidance for diagnosis and treatment of PI-IBS. The ROME Foundation has produced a working team report to summarize the available evidence on the pathophysiology of PI-IBS and provide guidance for diagnosis and treatment, based on findings reported in the literature and clinical experience. METHODS:The working team conducted an evidence-based review of publication databases for articles describing the clinical features (diagnosis), pathophysiology (intestinal sensorimotor function, microbiota, immune dysregulation, barrier dysfunction, enteroendocrine pathways, and genetics), and animal models of PI-IBS. We used a Delphi-based consensus system to create guidelines for management of PI-IBS and a developed treatment algorithm based on published findings and experiences of team members. RESULTS:PI-IBS develops in about 10% of patients with infectious enteritis. Risk factors include female sex, younger age, psychological distress during or before acute gastroenteritis, and severity of the acute episode. The pathogenesis of PI-PBS appears to involve changes in the intestinal microbiome as well as epithelial, serotonergic, and immune system factors. However, these mechanisms are incompletely understood. There are no evidence-based, effective pharmacologic strategies for treatment of PI-IBS. We provide a consensus-based treatment algorithm, based on clinical presentation and potential disease mechanisms. CONCLUSIONS:Based on a systematic review of the literature and team experience, we summarize the clinical features, pathophysiology (from animal models and human studies), and progression of PI-IBS. Based on these findings, we present an algorithm for diagnosis and treatment of PI-IBS based on team consensus. We also propose areas for future investigation. 10.1053/j.gastro.2018.07.011
Chronic diarrhea, bile acids, and Clostridia. Walters Julian Rf,Marchesi Julian R The Journal of clinical investigation Excessive fecal bile acid (BA) loss causes symptoms in a large proportion of people diagnosed with irritable bowel syndrome with diarrhea, a common functional bowel disorder. This BA diarrhea (BAD) results from increased hepatic synthesis of BAs, with impaired negative feedback regulation by the ileal hormone fibroblast growth factor 19 (FGF19). In this issue of the JCI, Zhao et al. investigated BA metabolism, including fecal BAs, serum BAs, and FGF19, in patients and controls. They identified associations between fecal bacterial BA metabolism and specific microbiota, especially Clostridium scindens. These findings have been tested in a mouse model using microbiota transplants and antibiotic treatment. This group of organisms has potential as a biomarker for BAD and to be a target for therapy. 10.1172/JCI133117
Role of brain imaging in disorders of brain-gut interaction: a Rome Working Team Report. Mayer Emeran A,Labus Jennifer,Aziz Qasim,Tracey Irene,Kilpatrick Lisa,Elsenbruch Sigrid,Schweinhardt Petra,Van Oudenhove Lukas,Borsook David Gut Imaging of the living human brain is a powerful tool to probe the interactions between brain, gut and microbiome in health and in disorders of brain-gut interactions, in particular IBS. While altered signals from the viscera contribute to clinical symptoms, the brain integrates these interoceptive signals with emotional, cognitive and memory related inputs in a non-linear fashion to produce symptoms. Tremendous progress has occurred in the development of new imaging techniques that look at structural, functional and metabolic properties of brain regions and networks. Standardisation in image acquisition and advances in computational approaches has made it possible to study large data sets of imaging studies, identify network properties and integrate them with non-imaging data. These approaches are beginning to generate brain signatures in IBS that share some features with those obtained in other often overlapping chronic pain disorders such as urological pelvic pain syndromes and vulvodynia, suggesting shared mechanisms. Despite this progress, the identification of preclinical vulnerability factors and outcome predictors has been slow. To overcome current obstacles, the creation of consortia and the generation of standardised multisite repositories for brain imaging and metadata from multisite studies are required. 10.1136/gutjnl-2019-318308
A Minty Breath of Fresh Air for Irritable Bowel Syndrome. Cash Brooks D Gastroenterology 10.1053/j.gastro.2019.11.010
Abdominal pain in irritable bowel syndrome. Nature reviews. Gastroenterology & hepatology 10.1038/s41575-022-00599-6
Efficacy of pharmacological therapies in patients with IBS with diarrhoea or mixed stool pattern: systematic review and network meta-analysis. Black Christopher J,Burr Nicholas E,Camilleri Michael,Earnest David L,Quigley Eamonn Mm,Moayyedi Paul,Houghton Lesley A,Ford Alexander C Gut OBJECTIVE:Over half of patients with IBS have either diarrhoea (IBS-D) or a mixed stool pattern (IBS-M). The relative efficacy of licenced pharmacological therapies is unclear in the absence of head-to-head trials. We conducted a network meta-analysis to resolve this uncertainty. DESIGN:We searched MEDLINE, Embase, Embase Classic, the Cochrane central register of controlled trials, and Clinicaltrials.gov through January 2019 to identify randomised controlled trials (RCTs) assessing the efficacy of licenced pharmacological therapies (alosetron, eluxadoline, ramosetron and rifaximin) in adults with IBS-D or IBS-M. Trials included in the analysis reported a dichotomous assessment of overall response to therapy, and data were pooled using a random effects model. Efficacy and safety of all pharmacological therapies were reported as a pooled relative risk with 95% CIs to summarise the effect of each comparison tested. Treatments were ranked according to their p score. RESULTS:We identified 18 eligible RCTs (seven alosetron, five ramosetron, two rifaximin and four eluxadoline), containing 9844 patients. All were superior to placebo for the treatment of IBS-D or IBS-M at 12 weeks, according to the Food and Drug Administration (FDA)-recommended endpoint for trials in IBS. Alosetron 1 mg twice daily was ranked first for efficacy, based on the FDA-recommended composite endpoint of improvement in both abdominal pain and stool consistency, effect on global symptoms of IBS and effect on stool consistency. Ramosetron 2.5µg once daily was ranked first for effect on abdominal pain. Total numbers of adverse events were significantly greater with alosetron 1 mg twice daily and ramosetron 2.5µg once daily, compared with placebo. Rifaximin 550 mg three times daily ranked first for safety. Constipation was significantly more common with all drugs, except rifaximin 550 mg three times daily. CONCLUSION:In a network meta-analysis of RCTs of pharmacological therapies for IBS-D and IBS-M, we found all drugs to be superior to placebo, but alosetron and ramosetron appeared to be the most effective. 10.1136/gutjnl-2018-318160
Fecal Microbiota Transplantation Is Highly Effective in Real-World Practice: Initial Results From the FMT National Registry. Kelly Colleen R,Yen Eugene F,Grinspan Ari M,Kahn Stacy A,Atreja Ashish,Lewis James D,Moore Thomas A,Rubin David T,Kim Alison M,Serra Sonya,Nersesova Yanina,Fredell Lydia,Hunsicker Dea,McDonald Daniel,Knight Rob,Allegretti Jessica R,Pekow Joel,Absah Imad,Hsu Ronald,Vincent Jennifer,Khanna Sahil,Tangen Lyn,Crawford Carl V,Mattar Mark C,Chen Lea Ann,Fischer Monika,Arsenescu Razvan I,Feuerstadt Paul,Goldstein Jonathan,Kerman David,Ehrlich Adam C,Wu Gary D,Laine Loren Gastroenterology BACKGROUND & AIMS:Fecal microbiota transplantation (FMT) is used commonly for treatment of Clostridioides difficile infections (CDIs), although prospective safety data are limited and real-world FMT practice and outcomes are not well described. The FMT National Registry was designed to assess FMT methods and both safety and effectiveness outcomes from North American FMT providers. METHODS:Patients undergoing FMT in clinical practices across North America were eligible. Participating investigators enter de-identified data into an online platform, including FMT protocol, baseline patient characteristics, CDI cure and recurrence, and short and long-term safety outcomes. RESULTS:Of the first 259 participants enrolled at 20 sites, 222 had completed short-term follow-up at 1 month and 123 had follow-up to 6 months; 171 (66%) were female. All FMTs were done for CDI and 249 (96%) used an unknown donor (eg, stool bank). One-month cure occurred in 200 patients (90%); of these, 197 (98%) received only 1 FMT. Among 112 patients with initial cure who were followed to 6 months, 4 (4%) had CDI recurrence. Severe symptoms reported within 1-month of FMT included diarrhea (n = 5 [2%]) and abdominal pain (n = 4 [2%]); 3 patients (1%) had hospitalizations possibly related to FMT. At 6 months, new diagnoses of irritable bowel syndrome were made in 2 patients (1%) and inflammatory bowel disease in 2 patients (1%). CONCLUSIONS:This prospective real-world study demonstrated high effectiveness of FMT for CDI with a good safety profile. Assessment of new conditions at long-term follow-up is planned as this registry grows and will be important for determining the full safety profile of FMT. 10.1053/j.gastro.2020.09.038
Development and Validation of Test for "Leaky Gut" Small Intestinal and Colonic Permeability Using Sugars in Healthy Adults. Gastroenterology BACKGROUND:Oral monosaccharides and disaccharides are used to measure in vivo human gut permeability through urinary excretion. AIMS:The aims were as follows: (1) to obtain normative data on small intestinal and colonic permeability; (2) to assess variance on standard 16 g fiber diet performed twice; (3) to determine whether dietary fiber influences gut permeability measurements; and (4) to present pilot data using 2 selected probes in patients with diarrhea-predominant irritable bowel syndrome (IBS-D). METHODS:Sixty healthy female and male adults, age 18-70 years, participated in 3 randomized studies (2 studies on 16.25 g and 1 study on 32.5 g fiber) in otherwise standardized diets. At each test, the following sugars were ingested: C-mannitol, C-mannitol, rhamnose (monosaccharides), sucralose, and lactulose (disaccharides). Standardized meals were administered from 24 hours before and during 24 hours post-sugars with 3 urine collections: 0-2, 2-8, and 8-24 hours. Sugars were measured using high-performance liquid chromatography-tandem mass spectrometry. Eighteen patients with IBS-D underwent 24-hour excretion studies after oral C-mannitol and lactulose. RESULTS:Baseline sugars (>3-fold above lower limits of quantitation) were identified in the 3 studies: C-mannitol in all participants; sucralose in 4-8, and rhamnose in 1-3. Median excretions/24 h (percentage of administered dose) for C-mannitol, rhamnose, lactulose, and sucralose were ∼30%, ∼15%, 0.32%, and 2.3%, respectively. C-mannitol and rhamnose reflected mainly small intestinal permeability. Intraindividual saccharide excretions were consistent, with minor differences with 16.25 g vs 32.5 g fiber diets. Median interindividual coefficient of variation was 76.5% (10-90 percentile: 34.6-111.0). There were no significant effects of sex, age, or body mass index on permeability measurements in health. C-mannitol measurements are feasible in IBS-D. CONCLUSIONS:Baseline C-mannitol excretion precludes its use; C-mannitol is the preferred probe for small intestinal permeability. 10.1053/j.gastro.2021.04.020
Fecal Microbiota Transplantation Reduces Symptoms in Some Patients With Irritable Bowel Syndrome With Predominant Abdominal Bloating: Short- and Long-term Results From a Placebo-Controlled Randomized Trial. Holvoet Tom,Joossens Marie,Vázquez-Castellanos Jorge F,Christiaens Evelien,Heyerick Lander,Boelens Jerina,Verhasselt Bruno,van Vlierberghe Hans,De Vos Martine,Raes Jeroen,De Looze Danny Gastroenterology BACKGROUND & AIMS:Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder associated with intestinal dysbiosis. Given the reported promising results of open-label fecal microbiota transplantation (FMT) therapy in patients with predominant abdominal bloating, we studied efficacy of this treatment in a randomized, placebo-controlled trial. METHODS:Patients with refractory IBS, defined as failure of ≥3 conventional therapies, were randomly assigned to single-dose nasojejunal administration of donor stools (n = 43) or autologous stools (n = 19) in a double-blind study, performed from December 2015 through October 2017, and were followed up for 1 year. IBS-related symptoms were assessed by using a daily symptom diary to determine general abdominal discomfort, abdominal bloating, abdominal pain, and flatulence on a scale of 1-6. Number of daily bowel movements, consistency of the stools, and abdominal circumference were also recorded. Patients completed the IBS-specific quality of life questionnaire. Primary endpoints were improvement of IBS symptoms and bloating at 12 weeks (response). Secondary endpoints were changes in IBS symptom scores and quality of life. Stool samples were collected for microbiota amplicon sequencing. Open-label retransplantation was offered after the trial. RESULTS:At week 12, 56% of patients given donor stool reported improvement in both primary endpoints compared with 26% of patients given placebo (P = .03). Patients given donor stool had significant improvements in level of discomfort (mean reduction, 19%; median score before FMT, 3.98; range, 2.13-6.00; median score after FMT, 3.1; range, 951.29-5.90), stool frequency (mean reduction, 13%; median score before FMT, 2.10; range, 0.57-14.29; median score after FMT 1.7; range, 0.71-4.29), urgency (mean reduction, 38%; median score before FMT, 0.61; range, 0.00-1.00; median score after FMT, 0.37; range, 0.00-1.00), abdominal pain (mean reduction, 26%; median score before FMT, 3.88; range, 1.57-5.17; median score after FMT, 2.80; range, 1.14-4.94), flatulence (mean reduction, 10%; median score before FMT, 3.42; range, 0.71-6.00; median score after FMT, 3.07; range, 0.79-4.23), and quality of life (mean increase, 16%; median score before FMT 32.6; range, 11-119; median score after FMT, 43.1; range, 32.25-99). A significantly higher proportion of women given donor stool (69%) had a response than men (29%) (P = .01). Fecal samples from responders had higher diversity of microbiomes before administration of donor material than fecal samples from nonresponders (P = .04) and distinct baseline composition (P = .04), but no specific marker taxa were associated with response. After single FMT, 21% of patients given donor stool reported effects that lasted for longer than 1 year compared with 5% of patients given placebo stool. A second FMT reduced symptoms in 67% of patients with an initial response to donor stool but not in patients with a prior nonresponse. CONCLUSIONS:In a randomized trial of patients with treatment-refractory IBS with predominant bloating, FMT relieved symptoms compared with placebo (autologous transplant), although the effects decreased over 1 year. A second FMT restored the response patients with a prior response. Response was associated with composition of the fecal microbiomes before FMT; this might be used to as a biomarker to select patients for this treatment. ClinicalTrials.gov, Number: NCT02299973. 10.1053/j.gastro.2020.07.013
Differences in Fecal Microbiomes and Metabolomes of People With vs Without Irritable Bowel Syndrome and Bile Acid Malabsorption. Jeffery Ian B,Das Anubhav,O'Herlihy Eileen,Coughlan Simone,Cisek Katryna,Moore Michael,Bradley Fintan,Carty Tom,Pradhan Meenakshi,Dwibedi Chinmay,Shanahan Fergus,O'Toole Paul W Gastroenterology BACKGROUND & AIMS:Irritable bowel syndrome (IBS) is a heterogeneous disorder, but diagnoses and determination of subtypes are made based on symptoms. We profiled the fecal microbiomes of patients with and without IBS to identify biomarkers of this disorder. METHODS:We collected fecal and urine samples from 80 patients with IBS (Rome IV criteria; 16-70 years old) and 65 matched individuals without IBS (control individuals), along with anthropometric, medical, and dietary information. Shotgun and 16S ribosomal RNA amplicon sequencing were performed on feces, whereas urine and fecal metabolites were analyzed by gas chromatography and liquid chromatography-mass spectrometry. Co-occurrence networks were generated based on significant Spearman correlations between data. Bile acid malabsorption (BAM) was identified in patients with diarrhea by retention of radiolabeled selenium-75 homocholic acid taurine. RESULTS:Patients with IBS had significant differences in network connections between diet and fecal microbiomes compared with control individuals; these were accompanied by differences in fecal metabolomes. We did not find significant differences in fecal microbiota composition among patients with different IBS symptom subtypes. Fecal metabolome profiles could discriminate patients with IBS from control individuals. Urine metabolomes also differed significantly between patients with IBS and control individuals, but most discriminatory metabolites were related to diet or medications. Fecal metabolomes, but not microbiomes, could distinguish patients with IBS with vs those without BAM. CONCLUSIONS:Despite the heterogeneity of IBS, patients have significant differences in urine and fecal metabolomes and fecal microbiome vs control individuals, independent of symptom-based subtypes of IBS. Fecal metabolome analysis can be used to distinguish patients with IBS with vs those without BAM. These findings might be used for developing microbe-based treatments for these disorders. 10.1053/j.gastro.2019.11.301
Comparison of biochemical, microbial and mucosal mRNA expression in bile acid diarrhoea and irritable bowel syndrome with diarrhoea. Gut OBJECTIVE:There are altered mucosal functions in irritable bowel syndrome with diarrhoea (IBS-D); ~30% of patients with IBS-D have abnormal bile acid (BA) metabolism (ABAM) and diarrhoea (summarised as BAD). AIM:To compare biochemical parameters, gastrointestinal and colonic transit, rectal sensation and pathobiological mechanisms in IBS-D without ABAM and in BAD (serum 7C4>52 ng/mL). DESIGN:In patients with Rome III criteria of IBS-D, we compared biochemical features, colonic transit, rectal sensation, deep genotype of five BA-related genes, ileal and colonic mucosal mRNA (differential expression (DE) analysis) and stool dysbiosis (including functional analysis of microbiome). Results in BAD were compared with IBS-D without ABAM. RESULTS:Compared with 161 patients with IBS-D without ABAM, 44 patients with BAD had significantly faster colonic transit, lower microbial alpha diversity, different compositional profile (beta diversity) and higher Firmicutes to Bacteroidetes ratio with evidence of decreased expression of bile acid thiol ligase (involved in transformation of primary to secondary BAs) and decreased sulfatases. In BAD (compared with IBS-D without ABAM), terminal ileal biopsies showed downregulation of (a BA transporter), and ascending colon biopsies showed upregulation in barrier-weakening genes (), serine protease inhibitors, immune activation, cellular differentiation and a cellular transporter (; BA binding). No DE of genes was documented in descending colon biopsies. The two groups had similar rectal sensation. CONCLUSION:Though sharing clinical symptoms with IBS-D, BAD is associated with biological differences and mechanisms that have potential to enhance diagnosis and treatment targeting barrier dysfunction, inflammatory and microbial changes. 10.1136/gutjnl-2022-327471
Risk Factors for Abdominal Pain-Related Disorders of Gut-Brain Interaction in Adults and Children: A Systematic Review. Gastroenterology BACKGROUND & AIMS:Many studies have assessed risk factors of irritable bowel syndrome (IBS) and other abdominal pain-related disorders of gut-brain interaction (AP-DGBI); however, the role of these factors is unclear due to heterogeneous study designs. The aim of this systematic review was to extensively evaluate the literature and determine clinical risk and protective factors for the presence and persistence of AP-DGBI in children and adults. METHODS:A PubMed search identified studies investigating potential risk and protective factors for AP-DGBI in adults and children. Inclusion criteria included fully published studies with a control group; exclusion criteria included poor-quality studies (using a validated scale). For each factor, the proportion of studies that found the factor to be a risk factor, protective factor, or neither was summarized. The number of studies, diagnostic criteria, number of subjects, and average study quality rating provided further context. Whenever possible, a meta-analysis generated pooled odds ratios or mean difference. RESULTS:The systematic review included 348 studies. Female sex, gastroenteritis, abuse, stress, psychological disorders, somatic symptoms, and poor sleep were consistent risk factors for developing AP-DGBI in adults and children. In adults, additional risk factors included obesity, smoking, and increased use of medical resources. Protective AP-DGBI factors in adults included social support and optimism; no studies for protective factors were found for children. CONCLUSIONS:There are multiple risk factors for AP-DGBI in adults and children. These include female sex, gastroenteritis, abuse, stress, poor sleep, obesity, psychological disorders, and somatic symptoms. Additional studies are needed in children, on protective factors, and on factors associated with persistence of AP-DGBI. 10.1053/j.gastro.2022.06.028
AGA Technical Review on the Evaluation of Functional Diarrhea and Diarrhea-Predominant Irritable Bowel Syndrome in Adults (IBS-D). Carrasco-Labra Alonso,Lytvyn Lyubov,Falck-Ytter Yngve,Surawicz Christina M,Chey William D Gastroenterology BACKGROUND & AIMS:The evaluation of patients with chronic watery diarrhea represents a diagnostic challenge for clinicians because organic causes, including inflammatory bowel disease, microscopic colitis, and chronic infection, must be differentiated from functional diarrhea and diarrhea-predominant irritable bowel syndrome. The purpose of this review is to summarize the available evidence on the usefulness of diagnostic tests in such patients. METHODS:We searched MEDLINE and EMBASE via OVID, from 1978 until April 2017. We included diagnostic test accuracy studies reporting on the use of fecal and blood tests for the evaluation of adult patients with functional diarrhea, including irritable bowel syndrome. We assessed the risk of bias of included studies using a modified version of the Quality Assessment of Diagnostic Accuracy Studies II, and the certainty in the evidence using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) approach. We calculated pooled sensitivity and specificity, and the proportion of patients with true and false positive and negative results. We evaluated the following tests: erythrocyte sedimentation rate, C-reactive protein, fecal lactoferrin, fecal calprotectin, serologic tests for celiac disease, tests for bile acid diarrhea, the commercially available version of anti-cytolethal distending toxin B and anti-vinculin antibodies, and tests for Giardia infection. We did not evaluate breath tests for small intestinal bacterial overgrowth, as they are not part of a standard diarrhea workup. RESULTS:Thirty-eight studies proved eligible to evaluate 1 or more of these tests. Erythrocyte sedimentation rate and C-reactive protein were similar at discriminating organic from functional disease, with sensitivity and specificity, respectively, of 0.54-0.78 and 0.46-0.95 for erythrocyte sedimentation rate and 0.73 and 0.78 for C-reactive protein. Among fecal tests, fecal calprotectin in a range of 50-60 μg/g (pooled sensitivity 0.81; 95% confidence interval [CI], 0.75-0.86; pooled specificity 0.87; 95% CI, 0.78-0.92) and fecal lactoferrin in a range of 4.0-7.25 μg/g (pooled sensitivity 0.79; 95% CI, 0.73-0.84; pooled specificity 0.93; 95%CI 0.63-0.99) presented the lowest proportion of false-negative results (low certainty in the evidence). Among tests for celiac disease, IgA tissue transglutaminase presented the best diagnostic test accuracy (sensitivity range, 0.79-0.99; specificity range, 0.90-0.99) with moderate certainty in the evidence. Among tests for bile acid diarrhea, the selenium homotaurocholic acid test performed better than serum fibroblast growth factor 19 and 7α-hydroxy-4-cholesten-3-one, but is not available in the United States. There was insufficient evidence to recommend serologic tests for irritable bowel syndrome at this time. There are several good diagnostic tests for Giardia infection. CONCLUSIONS:Moderate to low certainty in the evidence indicates that available fecal and blood tests may play a role in the diagnostic workup of adult patients with functional diarrhea. At the moment, no tests are available to reliably rule in irritable bowel syndrome. 10.1053/j.gastro.2019.06.014
Multi-Omics Analyses Show Disease, Diet, and Transcriptome Interactions With the Virome. Gastroenterology BACKGROUND & AIMS:The gut virome includes eukaryotic viruses and bacteriophages that can shape the gut bacterial community and elicit host responses. The virome can be implicated in diseases, such as irritable bowel syndrome (IBS), where gut bacteria play an important role in pathogenesis. We provide a comprehensive and longitudinal characterization of the virome, including DNA and RNA viruses and paired multi-omics data in a cohort of healthy subjects and patients with IBS. METHODS:We selected 2 consecutive stool samples per subject from a longitudinal study cohort and performed metagenomic sequencing on DNA and RNA viruses after enriching for viral-like particles. Viral sequence abundance was evaluated over time, as well as in the context of diet, bacterial composition and function, metabolite levels, colonic gene expression, host genetics, and IBS subsets. RESULTS:We found that the gut virome was temporally stable and correlated with the colonic transcriptome. We identified IBS-subset-specific changes in phage populations; Microviridae, Myoviridae, and Podoviridae species were elevated in diarrhea-predominant IBS, and other Microviridae and Myoviridae species were elevated in constipation-predominant IBS compared to healthy controls. We identified correlations between subsets of the virome and bacterial composition (unclassifiable "dark matter" and phages) and diet (eukaryotic viruses). CONCLUSIONS:We found that the gut virome is stable over time but varies among subsets of patients with IBS. It can be affected by diet and potentially influences host function via interactions with gut bacteria and/or altering host gene expression. 10.1053/j.gastro.2021.06.077
Efficacy of Fecal Microbiota Transplantation for Patients With Irritable Bowel Syndrome at 3 Years After Transplantation. Gastroenterology BACKGROUND & AIMS:The long-term efficacy and possible adverse events of fecal microbiota transplantation (FMT) for irritable bowel syndrome (IBS) are unknown. This study performed a 3-year follow-up of the patients in our previous clinical trial to clarify these aspects. METHODS:This study included 125 patients (104 females, and 21 males): 38 in a placebo group, 42 who received 30 g of donor feces, and 45 who received 60 g of donor feces. Feces was administered to the duodenum. The patients provided a fecal sample and completed 5 questionnaires at baseline and at 2 and 3 years after FMT. Fecal bacteria and dysbiosis index were analyzed using 16S ribosomal RNA gene polymerase chain reaction DNA amplification/probe hybridization covering the V3 to V9 regions. RESULTS:Response rates were 26.3%, 69.1%, and 77.8% in the placebo, 30-g, and 60-g groups, respectively, at 2 years after FMT, and 27.0%, 64.9%, and 71.8%, respectively, at 3 years after FMT. The response rates were significantly higher in the 30-g and 60-g groups than in the placebo group. Patients in the 30-g and 60-g groups had significantly fewer IBS symptoms and fatigue, and a greater quality of life both at 2 and 3 years after FMT. The dysbiosis index decreased only in the active treatment groups at 2 and 3 years after FMT. Fluorescent signals of 10 bacteria had significant correlations with IBS symptoms and fatigue after FMT in the 30-g and 60-g groups. No long-term adverse events were recorded. CONCLUSIONS:FMT performed according to our protocol resulted in high response rates and long-standing effects with only few mild self-limited adverse events. This study was registered at www. CLINICALTRIALS:gov (NCT03822299). 10.1053/j.gastro.2022.06.020
AGA Clinical Practice Update on the Role of Diet in Irritable Bowel Syndrome: Expert Review. Gastroenterology DESCRIPTION:Irritable bowel syndrome (IBS) is a commonly diagnosed gastrointestinal disorder that can have a substantial impact on quality of life. Most patients with IBS associate their gastrointestinal symptoms with eating food. Mounting evidence supports dietary modifications, such as the low-fermentable oligo-, di-, and monosaccharides and polyols (FODMAP) diet, as a primary treatment for IBS symptoms. The aim of this American Gastroenterological Association (AGA) Clinical Practice Update (CPU) is to provide best practice advice statements, primarily to clinical gastroenterologists, covering the role of diet in IBS treatment. METHODS:This expert review was commissioned and approved by the AGA CPU Committee and the AGA Governing Board to provide timely guidance on a topic of high clinical importance to the AGA membership, and underwent internal peer review by the CPU Committee and external peer review through standard procedures of Gastroenterology. The best practice advice statements were drawn from reviewing existing literature combined with expert opinion to provide practical advice on the role of diet in treating patients with IBS. Because this was not a systematic review, formal rating of the quality of evidence or strength of the presented considerations was not performed. Best Practice Advice Statements BEST PRACTICE ADVICE 1: Dietary advice is ideally prescribed to patients with IBS who have insight into their meal-related gastrointestinal symptoms and are motivated to make the necessary changes. To optimize the quality of teaching and clinical response, referral to a registered dietitian nutritionist (RDN) should be made to patients who are willing to collaborate with a RDN and patients who are not able to implement beneficial dietary changes on their own. If a gastrointestinal RDN is not available, other resources can assist with implementation of diet interventions. BEST PRACTICE ADVICE 2: Patients with IBS who are poor candidates for restrictive diet interventions include those consuming few culprit foods, those at risk for malnutrition, those who are food insecure, and those with an eating disorder or uncontrolled psychiatric disorder. Routine screening for disordered eating or eating disorders by careful dietary history is critical because they are common and often overlooked in gastrointestinal conditions. BEST PRACTICE ADVICE 3: Specific diet interventions should be attempted for a predetermined length of time. If there is no clinical response, the diet intervention should be abandoned for another treatment alternative, for example, a different diet, medication, or other form of therapy. BEST PRACTICE ADVICE 4: In preparation for a visit with a RDN, patients should provide dietary information that will assist in developing an individualized nutrition care plan. BEST PRACTICE ADVICE 5: Soluble fiber is efficacious in treating global symptoms of IBS. BEST PRACTICE ADVICE 6: The low-FODMAP diet is currently the most evidence-based diet intervention for IBS. Healthy eating advice as described by the National Institute of Health and Care Excellence Guidelines, among others, also offers benefit to a subset of patients with IBS. BEST PRACTICE ADVICE 7: The low-FODMAP diet consists of the following 3 phases: 1) restriction (lasting no more than 4-6 weeks), 2) reintroduction of FODMAP foods, and 3) personalization based on results from reintroduction. BEST PRACTICE ADVICE 8: Although observational studies found that most patients with IBS improve with a gluten-free diet, randomized controlled trials have yielded mixed results. BEST PRACTICE ADVICE 9: There are limited data showing that selected biomarkers can predict response to diet interventions in patients with IBS, but there is insufficient evidence to support their routine use in clinical practice. 10.1053/j.gastro.2021.12.248
Association between and irritable bowel syndrome with diarrhoea. Jabbar Karolina S,Dolan Brendan,Eklund Lisbeth,Wising Catharina,Ermund Anna,Johansson Åsa,Törnblom Hans,Simren Magnus,Hansson Gunnar C Gut OBJECTIVE:The incidence of IBS increases following enteric infections, suggesting a causative role for microbial imbalance. However, analyses of faecal microbiota have not demonstrated consistent alterations. Here, we used metaproteomics to investigate potential associations between mucus-resident microbiota and IBS symptoms. DESIGN:Mucus samples were prospectively collected from sigmoid colon biopsies from patients with IBS and healthy volunteers, and their microbial protein composition analysed by mass spectrometry. Observations were verified by immunofluorescence, electron microscopy and real-time PCR, further confirmed in a second cohort, and correlated with comprehensive profiling of clinical characteristics and mucosal immune responses. RESULTS:Metaproteomic analysis of colon mucus samples identified peptides from potentially pathogenic species in a subset of patients with IBS. Using multiple diagnostic methods, mucosal colonisation was detected in a total of 19/62 (31%) patients with IBS from two prospective cohorts, versus 0/31 healthy volunteers (p<0.001). The prevalence of colonisation in IBS with diarrhoea (IBS-D) was 40% in both cohorts (p=0.02 and p=0.006 vs controls). attachment to the colonocyte apical membrane was observed in 20% of patients with IBS and associated with accelerated oro-anal transit, mild mucosal inflammation, mast cell activation and alterations of molecular pathways linked to bacterial uptake and ion-fluid homeostasis. Metronidazole treatment paradoxically promoted relocation into goblet cell secretory granules-possibly representing a novel bacterial strategy to evade antibiotics. CONCLUSION:Mucosal colonisation was significantly more common in IBS and associated with distinctive clinical, histological and molecular characteristics. Our observations suggest a role for in the pathogenesis of IBS, particularly IBS-D. 10.1136/gutjnl-2020-321466
Efficacy and Safety of Peppermint Oil in a Randomized, Double-Blind Trial of Patients With Irritable Bowel Syndrome. Weerts Zsa Zsa R M,Masclee Ad A M,Witteman Ben J M,Clemens Cees H M,Winkens Bjorn,Brouwers Jacobus R B J,Frijlink Henderik W,Muris Jean W M,De Wit Niek J,Essers Brigitte A B,Tack Jan,Snijkers Johanna T W,Bours Andrea M H,de Ruiter-van der Ploeg Annieke S,Jonkers Daisy M A E,Keszthelyi Daniel Gastroenterology BACKGROUND & AIMS:Peppermint oil is frequently used to treat irritable bowel syndrome (IBS), despite a lack of evidence for efficacy from high-quality controlled trials. We studied the efficacy and safety of small-intestinal-release peppermint oil in patients with IBS and explored the effects of targeted ileocolonic-release peppermint oil. METHODS:We performed a double-blind trial of 190 patients with IBS (according to Rome IV criteria) at 4 hospitals in The Netherlands from August 2016 through March 2018; 189 patients were included in the intent-to-treat analysis (mean age, 34.0 years; 77.8% female; 57.7% in primary care), and 178 completed the study. Patients were randomly assigned to groups given 182 mg small-intestinal-release peppermint oil, 182 mg ileocolonic-release peppermint oil, or placebo for 8 weeks. The primary endpoint was abdominal pain response, as defined by the US Food and Drug Administration: at least a 30% decrease in the weekly average of worst daily abdominal pain compared with baseline in at least 4 weeks. The co-primary endpoint was overall relief of IBS symptoms, as defined by the European Medicines Agency. Secondary endpoints included abdominal pain, discomfort, symptom severity, and adverse events. RESULTS:Abdominal pain response did not differ significantly between the peppermint oil and placebo groups: 29 of 62 patients in the small-intestinal-release peppermint oil group had a response (46.8%, P = .170 vs placebo), 26 of 63 patients in the ileocolonic-release peppermint oil group had a response (41.3%, P = .385 vs placebo), and 22 of 64 patients in the placebo group had a response (34.4%). We did not find differences among the groups in overall relief (9.7%, P = .317 and 1.6%, P = .351 vs 4.7% for placebo). The small intestinal peppermint oil did, however, produce greater improvements than placebo in secondary outcomes of abdominal pain (P = .016), discomfort (P = .020), and IBS severity (P = .020). Adverse events, although mild, were more common in both peppermint oil groups (P < .005). CONCLUSIONS:In a randomized trial of patients with IBS, we found that neither small-intestinal-release nor ileocolonic-release peppermint oil (8 weeks) produced statistically significant reductions in abdominal pain response or overall symptom relief, when using US Food and Drug Administration/European Medicines Agency recommended endpoints. The small-intestinal-release peppermint oil did, however, significantly reduce abdominal pain, discomfort, and IBS severity. These findings do not support further development of ileocolonic-release peppermint oil for treatment of IBS. Clinicaltrials.gov, Number: NCT02716285. 10.1053/j.gastro.2019.08.026
Recipient factors in faecal microbiota transplantation: one stool does not fit all. Nature reviews. Gastroenterology & hepatology Faecal microbiota transplantation (FMT) is a promising therapy for chronic diseases associated with gut microbiota alterations. FMT cures 90% of recurrent Clostridioides difficile infections. However, in complex diseases, such as inflammatory bowel disease, irritable bowel syndrome and metabolic syndrome, its efficacy remains variable. It is accepted that donor selection and sample administration are key determinants of FMT success, yet little is known about the recipient factors that affect it. In this Perspective, we discuss the effects of recipient parameters, such as genetics, immunity, microbiota and lifestyle, on donor microbiota engraftment and clinical efficacy. Emerging evidence supports the possibility that controlling inflammation in the recipient intestine might facilitate engraftment by reducing host immune system pressure on the newly transferred microbiota. Deciphering FMT engraftment rules and developing novel therapeutic strategies are priorities to alleviate the burden of chronic diseases associated with an altered gut microbiota such as inflammatory bowel disease. 10.1038/s41575-021-00441-5
Effects of Low FODMAP Diet on Symptoms, Fecal Microbiome, and Markers of Inflammation in Patients With Quiescent Inflammatory Bowel Disease in a Randomized Trial. Cox Selina R,Lindsay James O,Fromentin Sébastien,Stagg Andrew J,McCarthy Neil E,Galleron Nathalie,Ibraim Samar B,Roume Hugo,Levenez Florence,Pons Nicolas,Maziers Nicolas,Lomer Miranda C,Ehrlich S Dusko,Irving Peter M,Whelan Kevin Gastroenterology BACKGROUND & AIMS:There is limited evidence that a diet low in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs) reduces gut symptoms in quiescent inflammatory bowel disease (IBD). We performed a randomized, controlled trial to investigate the effects of a low FODMAP diet on persistent gut symptoms, the intestinal microbiome, and circulating markers of inflammation in patients with quiescent IBD. METHODS:We performed a single-blind trial of 52 patients with quiescent Crohn's disease or ulcerative colitis and persistent gut symptoms at 2 large gastroenterology clinics in the United Kingdom. Patients were randomly assigned to groups that followed a diet low in FODMAPs (n = 27) or a control diet (n = 25), with dietary advice, for 4 weeks. Gut symptoms and health-related quality of life were measured using validated questionnaires. Stool and blood samples were collected at baseline and end of trial. We assessed fecal microbiome composition and function using shotgun metagenomic sequencing and phenotypes of T cells in blood using flow cytometry. RESULTS:A higher proportion of patients reported adequate relief of gut symptoms following the low FODMAP diet (14/27, 52%) than the control diet (4/25, 16%, P=.007). Patients had a greater reduction in irritable bowel syndrome severity scores following the low FODMAP diet (mean reduction of 67; standard error, 78) than the control diet (mean reduction of 34; standard error, 50), although this difference was not statistically significant (P = .075). Following the low FODMAP diet, patients had higher health-related quality of life scores (81.9 ± 1.2) than patients on the control diet (78.3 ± 1.2, P = .042). A targeted analysis revealed that in stool samples collected at the end of the study period, patients on the low FODMAP diet had significantly lower abundance of Bifidobacterium adolescentis, Bifidobacterium longum, and Faecalibacterium prausnitzii than patients on control diet. However, microbiome diversity and markers of inflammation did not differ significantly between groups. CONCLUSIONS:In a trial of the low FODMAP diet vs a control diet in patients with quiescent IBD, we found no significant difference after 4 weeks in change in irritable bowel syndrome severity scores, but significant improvements in specific symptom scores and numbers reporting adequate symptom relief. The low FODMAP diet reduced fecal abundance of microbes believed to regulate the immune response, compared with the control diet, but had no significant effect on markers of inflammation. We conclude that a 4-week diet low in FODMAPs is safe and effective for managing persistent gut symptoms in patients with quiescent IBD. www.isrctn.com no.: ISRCTN17061468. 10.1053/j.gastro.2019.09.024
Mucosal Biofilms Are an Endoscopic Feature of Irritable Bowel Syndrome and Ulcerative Colitis. Gastroenterology BACKGROUND & AIMS:Irritable bowel syndrome (IBS) and inflammatory bowel diseases result in a substantial reduction in quality of life and a considerable socioeconomic impact. In IBS, diagnosis and treatment options are limited, but evidence for involvement of the gut microbiome in disease pathophysiology is emerging. Here we analyzed the prevalence of endoscopically visible mucosal biofilms in gastrointestinal disease and associated changes in microbiome composition and metabolism. METHODS:The presence of mucosal biofilms was assessed in 1426 patients at 2 European university-based endoscopy centers. One-hundred and seventeen patients were selected for in-depth molecular and microscopic analysis using 16S ribosomal RNA gene amplicon-sequencing of colonic biopsies and fecal samples, confocal microscopy with deep learning-based image analysis, scanning electron microscopy, metabolomics, and in vitro biofilm formation assays. RESULTS:Biofilms were present in 57% of patients with IBS and 34% of patients with ulcerative colitis compared with 6% of controls (P < .001). These yellow-green adherent layers of the ileum and right-sided colon were microscopically confirmed to be dense bacterial biofilms. 16S-sequencing links the presence of biofilms to a dysbiotic gut microbiome, including overgrowth of Escherichia coli and Ruminococcus gnavus. R. gnavus isolates cultivated from patient biofilms also formed biofilms in vitro. Metabolomic analysis found an accumulation of bile acids within biofilms that correlated with fecal bile acid excretion, linking this phenotype with a mechanism of diarrhea. CONCLUSIONS:The presence of mucosal biofilms is an endoscopic feature in a subgroup of IBS and ulcerative colitis with disrupted bile acid metabolism and bacterial dysbiosis. They provide novel insight into the pathophysiology of IBS and ulcerative colitis, illustrating that biofilm can be seen as a tipping point in the development of dysbiosis and disease. 10.1053/j.gastro.2021.06.024
Understanding the physiology of human defaecation and disorders of continence and evacuation. Nature reviews. Gastroenterology & hepatology The act of defaecation, although a ubiquitous human experience, requires the coordinated actions of the anorectum and colon, pelvic floor musculature, and the enteric, peripheral and central nervous systems. Defaecation is best appreciated through the description of four phases, which are, temporally and physiologically, reasonably discrete. However, given the complexity of this process, it is unsurprising that disorders of defaecation are both common and problematic; almost everyone will experience constipation at some time in their life and many will develop faecal incontinence. A detailed understanding of the normal physiology of defaecation and continence is critical to inform management of disorders of defaecation. During the past decade, there have been major advances in the investigative tools used to assess colonic and anorectal function. This Review details the current understanding of defaecation and continence. This includes an overview of the relevant anatomy and physiology, a description of the four phases of defaecation, and factors influencing defaecation (demographics, stool frequency/consistency, psychobehavioural factors, posture, circadian rhythm, dietary intake and medications). A summary of the known pathophysiology of defaecation disorders including constipation, faecal incontinence and irritable bowel syndrome is also included, as well as considerations for further research in this field. 10.1038/s41575-021-00487-5
Randomised placebo-controlled trial of dietary glutamine supplements for postinfectious irritable bowel syndrome. Gut BACKGROUND:More effective treatments are needed for patients with postinfectious, diarrhoea-predominant, irritable bowel syndrome (IBS-D). Accordingly, we conducted a randomised, double-blind, placebo-controlled, 8-week-long trial to assess the efficacy and safety of oral glutamine therapy in patients who developed IBS-D with increased intestinal permeability following an enteric infection. METHODS:Eligible adults were randomised to glutamine (5 g/t.i.d.) or placebo for 8 weeks. The primary end point was a reduction of ≥50 points on the Irritable Bowel Syndrome Severity Scoring System (IBS-SS). Secondary endpoints included: raw IBS-SS scores, changes in daily bowel movement frequency, stool form (Bristol Stool Scale) and intestinal permeability. RESULTS:Fifty-four glutamine and 52 placebo subjects completed the 8-week study. The primary endpoint occurred in 43 (79.6%) in the glutamine group and 3 (5.8%) in the placebo group (a 14-fold difference). Glutamine also reduced all secondary endpoint means: IBS-SS score at 8 weeks (301 vs 181, p<0.0001), daily bowel movement frequency (5.4 vs 2.9±1.0, p<0.0001), Bristol Stool Scale (6.5 vs 3.9, p<0.0001) and intestinal permeability (0.11 vs 0.05; p<0.0001). 'Intestinal hyperpermeability' (elevated urinary lactulose/mannitol ratios) was normalised in the glutamine but not the control group. Adverse events and rates of study-drug discontinuation were low and similar in the two groups. No serious adverse events were observed. CONCLUSIONS:In patients with IBS-D with intestinal hyperpermeability following an enteric infection, oral dietary glutamine supplements dramatically and safely reduced all major IBS-related endpoints. Large randomised clinical trials (RCTs) should now be done to validate these findings, assess quality of life benefits and explore pharmacological mechanisms. TRIAL REGISTRATION NUMBER:NCT01414244; Results. 10.1136/gutjnl-2017-315136
AGA Clinical Practice Update on Small Intestinal Bacterial Overgrowth: Expert Review. Quigley Eamonn M M,Murray Joseph A,Pimentel Mark Gastroenterology DESCRIPTION:Thanks to ready access to hydrogen breath testing, small intestinal bacterial overgrowth (SIBO) is now commonly diagnosed among individuals presenting with a variety of gastrointestinal and even nongastrointestinal symptoms and is increasingly implicated in lay press and media in the causation of a diverse array of disorders. Its definition, however, remains controversial and true prevalence, accordingly, undefined. The purpose of this review, therefore, was to provide a historical background to the concept of SIBO, critically review current concepts of SIBO (including symptomatology, pathophysiology, clinical consequences, diagnosis and treatment), define unanswered questions and provide a road map toward their resolution. METHODS:Best Practice Advice statements were developed following discussion by the 3 authors. Two authors each developed text around certain Best Practice Advice based on a review of available literature. All 3 authors reviewed the complete draft and after discussion, redrafting, and further review and revision, all of the authors agreed on a final draft. BEST PRACTICE ADVICE 1: The definition of SIBO as a clinical entity lacks precision and consistency; it is a term generally applied to a clinical disorder where symptoms, clinical signs, and/or laboratory abnormalities are attributed to changes in the numbers of bacteria or in the composition of the bacterial population in the small intestine. BEST PRACTICE ADVICE 2: Symptoms traditionally linked to SIBO include bloating, diarrhea, and abdominal pain/discomfort. Steatorrhea may be seen in more severe cases. BEST PRACTICE ADVICE 3: There is insufficient evidence to support the use of inflammatory markers, such as fecal calprotectin to detect SIBO. BEST PRACTICE ADVICE 4: Laboratory findings can include elevated folate and, less commonly, vitamin B-12 deficiency, or other nutritional deficiencies. BEST PRACTICE ADVICE 5: A major impediment to our ability to accurately define SIBO is our limited understanding of normal small intestinal microbial populations-progress in sampling technology and techniques to enumerate bacterial populations and their metabolic products should provide much needed clarity. BEST PRACTICE ADVICE 6: Controversy remains concerning the role of SIBO in the pathogenesis of common functional symptoms, such as those regarded as components of irritable bowel syndrome. BEST PRACTICE ADVICE 7: Management should focus on the identification and correction (where possible) of underlying causes, correction of nutritional deficiencies, and the administration of antibiotics. This is especially important for patients with significant maldigestion and malabsorption. BEST PRACTICE ADVICE 8: Although irritable bowel syndrome has been shown to respond to therapy with a poorly absorbed antibiotic, the role of SIBO or its eradication in the genesis of this response warrants further confirmation in randomized controlled trials. BEST PRACTICE ADVICE 9: There is a limited database to guide the clinician in developing antibiotic strategies for SIBO, in any context. Therapy remains, for the most part, empiric but must be ever mindful of the potential risks of long-term broad-spectrum antibiotic therapy. 10.1053/j.gastro.2020.06.090
Small Intestinal Bacterial Overgrowth-Pathophysiology and Its Implications for Definition and Management. Gastroenterology The concept of small intestinal bacterial overgrowth (SIBO) arose in the context of maldigestion and malabsorption among patients with obvious risk factors that permitted the small bowel to be colonized by potentially injurious colonic microbiota. Such colonization resulted in clinical signs, symptoms, and laboratory abnormalities that were explicable within a coherent pathophysiological framework. Coincident with advances in medical science, diagnostic testing evolved from small bowel culture to breath tests and on to next-generation, culture-independent microbial analytics. The advent and ready availability of breath tests generated a dramatic expansion in both the rate of diagnosis of SIBO and the range of associated gastrointestinal and nongastrointestinal clinical scenarios. However, issues with the specificity of these same breath tests have clouded their interpretation and aroused some skepticism regarding the role of SIBO in this expanded clinical repertoire. Furthermore, the pathophysiological plausibility that underpins SIBO as a cause of maldigestion/malabsorption is lacking in regard to its purported role in irritable bowel syndrome, for example. One hopes that the application of an ever-expanding armamentarium of modern molecular microbiology to the human small intestinal microbiome in both health and disease will ultimately resolve this impasse and provide an objective basis for the diagnosis of SIBO. 10.1053/j.gastro.2022.04.002
Worldwide Prevalence and Burden of Functional Gastrointestinal Disorders, Results of Rome Foundation Global Study. Sperber Ami D,Bangdiwala Shrikant I,Drossman Douglas A,Ghoshal Uday C,Simren Magnus,Tack Jan,Whitehead William E,Dumitrascu Dan L,Fang Xuicai,Fukudo Shin,Kellow John,Okeke Edith,Quigley Eamonn M M,Schmulson Max,Whorwell Peter,Archampong Timothy,Adibi Payman,Andresen Viola,Benninga Marc A,Bonaz Bruno,Bor Serhat,Fernandez Luis Bustos,Choi Suck Chei,Corazziari Enrico S,Francisconi Carlos,Hani Albis,Lazebnik Leonid,Lee Yeong Yeh,Mulak Agata,Rahman M Masudur,Santos Javier,Setshedi Mashiko,Syam Ari Fahrial,Vanner Stephen,Wong Reuben K,Lopez-Colombo Aurelio,Costa Valeria,Dickman Ram,Kanazawa Motoyori,Keshteli Ammar Hassanzadeh,Khatun Rutaba,Maleki Iradj,Poitras Pierre,Pratap Nitesh,Stefanyuk Oksana,Thomson Sandie,Zeevenhooven Judith,Palsson Olafur S Gastroenterology BACKGROUND & AIMS:Although functional gastrointestinal disorders (FGIDs), now called disorders of gut-brain interaction, have major economic effects on health care systems and adversely affect quality of life, little is known about their global prevalence and distribution. We investigated the prevalence of and factors associated with 22 FGIDs, in 33 countries on 6 continents. METHODS:Data were collected via the Internet in 24 countries, personal interviews in 7 countries, and both in 2 countries, using the Rome IV diagnostic questionnaire, Rome III irritable bowel syndrome questions, and 80 items to identify variables associated with FGIDs. Data collection methods differed for Internet and household groups, so data analyses were conducted and reported separately. RESULTS:Among the 73,076 adult respondents (49.5% women), diagnostic criteria were met for at least 1 FGID by 40.3% persons who completed the Internet surveys (95% confidence interval [CI], 39.9-40.7) and 20.7% of persons who completed the household surveys (95% CI, 20.2-21.3). FGIDs were more prevalent among women than men, based on responses to the Internet survey (odds ratio, 1.7; 95% CI, 1.6-1.7) and household survey (odds ratio, 1.3; 95% CI, 1.3-1.4). FGIDs were associated with lower quality of life and more frequent doctor visits. Proportions of subjects with irritable bowel syndrome were lower when the Rome IV criteria were used, compared with the Rome III criteria, in the Internet survey (4.1% vs 10.1%) and household survey (1.5% vs 3.5%). CONCLUSIONS:In a large-scale multinational study, we found that more than 40% of persons worldwide have FGIDs, which affect quality of life and health care use. Although the absolute prevalence was higher among Internet respondents, similar trends and relative distributions were found in people who completed Internet vs personal interviews. 10.1053/j.gastro.2020.04.014
Post COVID-19 irritable bowel syndrome. Gut OBJECTIVES:The long-term consequences of COVID-19 infection on the gastrointestinal tract remain unclear. Here, we aimed to evaluate the prevalence of gastrointestinal symptoms and post-COVID-19 disorders of gut-brain interaction after hospitalisation for SARS-CoV-2 infection. DESIGN:GI-COVID-19 is a prospective, multicentre, controlled study. Patients with and without COVID-19 diagnosis were evaluated on hospital admission and after 1, 6 and 12 months post hospitalisation. Gastrointestinal symptoms, anxiety and depression were assessed using validated questionnaires. RESULTS:The study included 2183 hospitalised patients. The primary analysis included a total of 883 patients (614 patients with COVID-19 and 269 controls) due to the exclusion of patients with pre-existing gastrointestinal symptoms and/or surgery. At enrolment, gastrointestinal symptoms were more frequent among patients with COVID-19 than in the control group (59.3% vs 39.7%, p<0.001). At the 12-month follow-up, constipation and hard stools were significantly more prevalent in controls than in patients with COVID-19 (16% vs 9.6%, p=0.019 and 17.7% vs 10.9%, p=0.011, respectively). Compared with controls, patients with COVID-19 reported higher rates of irritable bowel syndrome (IBS) according to Rome IV criteria: 0.5% versus 3.2%, p=0.045. Factors significantly associated with IBS diagnosis included history of allergies, chronic intake of proton pump inhibitors and presence of dyspnoea. At the 6-month follow-up, the rate of patients with COVID-19 fulfilling the criteria for depression was higher than among controls. CONCLUSION:Compared with controls, hospitalised patients with COVID-19 had fewer problems of constipation and hard stools at 12 months after acute infection. Patients with COVID-19 had significantly higher rates of IBS than controls. TRIAL REGISTRATION NUMBER:NCT04691895. 10.1136/gutjnl-2022-328483
AGA Clinical Practice Guideline on the Pharmacological Management of Irritable Bowel Syndrome With Constipation. Gastroenterology BACKGROUND & AIMS:Irritable bowel syndrome (IBS) is a common disorder of gut-brain interaction associated with significant disease burden. This American Gastroenterological Association guideline is intended to support practitioners in decisions about the use of medications for the pharmacological management of IBS-C and is an update of a prior technical review and guideline. METHODS:The Grading of Recommendations Assessment, Development and Evaluation framework was used to assess evidence and make recommendations. The technical review panel prioritized clinical questions and outcomes according to their importance for clinicians and patients and conducted an evidence review of the following agents: tenapanor, plecanatide, linaclotide, tegaserod, lubiprostone, polyethylene glycol laxatives, tricyclic antidepressants, selective serotonin reuptake inhibitors, and antispasmodics. The Guideline Panel reviewed the evidence and used the Evidence-to-Decision Framework to develop recommendations. CONCLUSIONS:The panel agreed on 9 recommendations for the management of patients with IBS-C. The panel made a strong recommendation for linaclotide (high certainty) and conditional recommendations for tenapanor, plecanatide, tegaserod, and lubiprostone (moderate certainty), polyethylene glycol laxatives, tricyclic antidepressants, and antispasmodics (low certainty). The panel made a conditional recommendation against the use of selective serotonin reuptake inhibitors (low certainty). 10.1053/j.gastro.2022.04.016
British Society of Gastroenterology guidelines on the management of irritable bowel syndrome. Vasant Dipesh H,Paine Peter A,Black Christopher J,Houghton Lesley A,Everitt Hazel A,Corsetti Maura,Agrawal Anurag,Aziz Imran,Farmer Adam D,Eugenicos Maria P,Moss-Morris Rona,Yiannakou Yan,Ford Alexander C Gut Irritable bowel syndrome (IBS) remains one of the most common gastrointestinal disorders seen by clinicians in both primary and secondary care. Since publication of the last British Society of Gastroenterology (BSG) guideline in 2007, substantial advances have been made in understanding its complex pathophysiology, resulting in its re-classification as a disorder of gut-brain interaction, rather than a functional gastrointestinal disorder. Moreover, there has been a considerable amount of new evidence published concerning the diagnosis, investigation and management of IBS. The primary aim of this guideline, commissioned by the BSG, is to review and summarise the current evidence to inform and guide clinical practice, by providing a practical framework for evidence-based management of patients. One of the strengths of this guideline is that the recommendations for treatment are based on evidence derived from a comprehensive search of the medical literature, which was used to inform an update of a series of trial-based and network meta-analyses assessing the efficacy of dietary, pharmacological and psychological therapies in treating IBS. Specific recommendations have been made according to the Grading of Recommendations Assessment, Development and Evaluation system, summarising both the strength of the recommendations and the overall quality of evidence. Finally, this guideline identifies novel treatments that are in development, as well as highlighting areas of unmet need for future research. 10.1136/gutjnl-2021-324598
AGA Clinical Practice Guideline on the Pharmacological Management of Irritable Bowel Syndrome With Diarrhea. Gastroenterology BACKGROUND & AIMS:Irritable bowel syndrome (IBS) is a common functional gastrointestinal disorder associated with significant disease burden. This American Gastroenterological Association Guideline is intended to support practitioners in decisions about the use of medications for the pharmacological management of IBS with predominant diarrhea (IBS-D) and is an update of a prior technical review and guideline. METHODS:The Grading of Recommendations Assessment, Development and Evaluation framework was used to assess evidence and make recommendations. The technical review panel prioritized clinical questions and outcomes according to their importance for clinicians and patients and conducted an evidence review of the following agents: eluxadoline, rifaximin, alosetron, loperamide, tricyclic antidepressants, selective serotonin reuptake inhibitors, and antispasmodics. The guideline panel reviewed the evidence and used the Evidence-to-Decision Framework to develop recommendations. CONCLUSIONS:The panel agreed on 8 recommendations for the management of patients with IBS-D. The panel made conditional recommendations for eluxadoline, rifaximin, alosetron, (moderate certainty), loperamide (very low certainty), tricyclic antidepressants, and anstispasmodics (low certainty). The panel made a conditional recommendation against the use of selective serotonin reuptake inhibitors (low certainty). 10.1053/j.gastro.2022.04.017
Longitudinal Multi-omics Reveals Subset-Specific Mechanisms Underlying Irritable Bowel Syndrome. Cell The gut microbiome has been implicated in multiple human chronic gastrointestinal (GI) disorders. Determining its mechanistic role in disease has been difficult due to apparent disconnects between animal and human studies and lack of an integrated multi-omics view of disease-specific physiological changes. We integrated longitudinal multi-omics data from the gut microbiome, metabolome, host epigenome, and transcriptome in the context of irritable bowel syndrome (IBS) host physiology. We identified IBS subtype-specific and symptom-related variation in microbial composition and function. A subset of identified changes in microbial metabolites correspond to host physiological mechanisms that are relevant to IBS. By integrating multiple data layers, we identified purine metabolism as a novel host-microbial metabolic pathway in IBS with translational potential. Our study highlights the importance of longitudinal sampling and integrating complementary multi-omics data to identify functional mechanisms that can serve as therapeutic targets in a comprehensive treatment strategy for chronic GI diseases. VIDEO ABSTRACT. 10.1016/j.cell.2020.08.007
Functional gastrointestinal disorders: advances in understanding and management. Black Christopher J,Drossman Douglas A,Talley Nicholas J,Ruddy Johannah,Ford Alexander C Lancet (London, England) Gastrointestinal symptoms are highly prevalent, but many people who have them will have no organic explanation for their symptoms. Most of these people will be labelled as having a functional gastrointestinal disorder, such as irritable bowel syndrome, functional dyspepsia, or functional constipation. These conditions affect up to 40% of people at any one point in time, and two-thirds of these people will have chronic, fluctuating symptoms. The pathophysiology of functional gastrointestinal disorders is complex, but involves bidirectional dysregulation of gut-brain interaction (via the gut-brain axis), as well as microbial dysbiosis within the gut, altered mucosal immune function, visceral hypersensitivity, and abnormal gastrointestinal motility. Hence, nomenclature refers to the conditions as disorders of gut-brain interaction. Psychological comorbidity is common; however, whether or not this predates, or is driven by, symptoms is not clear. Patients with functional gastrointestinal disorders can feel stigmatised, and often this diagnosis is not communicated effectively by physicians, nor is education provided. Prompt identification and treatment of these conditions is crucial as they have a considerable impact on health-care systems and society as a whole because of repeated consultations, unnecessary investigations and surgeries, prescriptions and over-the-counter medicine use, and impaired health-related quality of life and ability to work. Symptom-based criteria are used to make a diagnosis, with judicious use of limited investigations in some patients. The general principles of treatment are based on a biopsychosocial understanding and involve management of physical symptoms and, if present, psychological comorbidity. In the future, treatment approaches to functional gastrointestinal disorders are likely to become more personalised, based not only on symptoms but also underlying pathophysiology and psychology. 10.1016/S0140-6736(20)32115-2
Dietary fibre in gastrointestinal health and disease. Gill Samantha K,Rossi Megan,Bajka Balazs,Whelan Kevin Nature reviews. Gastroenterology & hepatology Epidemiological studies have consistently demonstrated the benefits of dietary fibre on gastrointestinal health through consumption of unrefined whole foods, such as wholegrains, legumes, vegetables and fruits. Mechanistic studies and clinical trials on isolated and extracted fibres have demonstrated promising regulatory effects on the gut (for example, digestion and absorption, transit time, stool formation) and microbial effects (changes in gut microbiota composition and fermentation metabolites) that have important implications for gastrointestinal disorders. In this Review, we detail the major physicochemical properties and functional characteristics of dietary fibres, the importance of dietary fibres and current evidence for their use in the management of gastrointestinal disorders. It is now well-established that the physicochemical properties of different dietary fibres (such as solubility, viscosity and fermentability) vary greatly depending on their origin and processing and are important determinants of their functional characteristics and clinical utility. Although progress in understanding these relationships has uncovered potential therapeutic opportunities for dietary fibres, many clinical questions remain unanswered such as clarity on the optimal dose, type and source of fibre required in both the management of clinical symptoms and the prevention of gastrointestinal disorders. The use of novel fibres and/or the co-administration of fibres is an additional therapeutic approach yet to be extensively investigated. 10.1038/s41575-020-00375-4
Global burden of irritable bowel syndrome: trends, predictions and risk factors. Black Christopher J,Ford Alexander C Nature reviews. Gastroenterology & hepatology Irritable bowel syndrome (IBS) is one of the most common disorders of gut-brain interaction worldwide, defined according to patterns of gastrointestinal symptoms as described by the Rome diagnostic criteria. However, these criteria, developed with reference to research conducted largely in Western populations, might be limited in their applicability to other countries and cultures. Epidemiological data show a wide variation in the prevalence of IBS globally and more rigorous studies are needed to accurately determine any differences that might exist between countries as well as the potential explanations. The effects of IBS on the individual, in terms of their quality of life, and on health-care delivery and society, in terms of economic costs, are considerable. Although the magnitude of these effects seems to be comparable between nations, their precise nature can vary based on the existence of societal and cultural differences. The pathophysiology of IBS is complex and incompletely understood; genetics, diet and the gut microbiome are all recognized risk factors, but the part they play might be influenced by geography and culture, and hence their relative importance might vary between countries. This Review aims to provide an overview of the burden of IBS in a global context, to discuss future implications for the care of people with IBS worldwide, and to identify key areas for further research. 10.1038/s41575-020-0286-8
Update on lactose malabsorption and intolerance: pathogenesis, diagnosis and clinical management. Misselwitz Benjamin,Butter Matthias,Verbeke Kristin,Fox Mark R Gut Lactose is the main source of calories in milk, an essential nutriedigestion, patients with visceral hypersensitivity nt in infancy and a key part of the diet in populations that maintain the ability to digest this disaccharide in adulthood. Lactase deficiency (LD) is the failure to express the enzyme that hydrolyses lactose into galactose and glucose in the small intestine. The genetic mechanism of lactase persistence in adult Caucasians is mediated by a single C→T nucleotide polymorphism at the LCTbo -13'910 locus on chromosome-2. Lactose malabsorption (LM) refers to any cause of failure to digest and/or absorb lactose in the small intestine. This includes primary genetic and also secondary LD due to infection or other conditions that affect the mucosal integrity of the small bowel. Lactose intolerance (LI) is defined as the onset of abdominal symptoms such as abdominal pain, bloating and diarrhoea after lactose ingestion by an individual with LM. The likelihood of LI depends on the lactose dose, lactase expression and the intestinal microbiome. Independent of lactose digestion, patients with visceral hypersensitivity associated with anxiety or the Irritable Bowel Syndrome (IBS) are at increased risk of the condition. Diagnostic investigations available to diagnose LM and LI include genetic, endoscopic and physiological tests. The association between self-reported LI, objective findings and clinical outcome of dietary intervention is variable. Treatment of LI can include low-lactose diet, lactase supplementation and, potentially, colonic adaptation by prebiotics. The clinical outcome of these treatments is modest, because lactose is just one of a number of poorly absorbed carbohydrates which can cause symptoms by similar mechanisms. 10.1136/gutjnl-2019-318404
The pros, cons, and many unknowns of probiotics. Suez Jotham,Zmora Niv,Segal Eran,Elinav Eran Nature medicine Consumption of over-the-counter probiotics for promotion of health and well-being has increased worldwide in recent years. However, although probiotic use has been greatly popularized among the general public, there are conflicting clinical results for many probiotic strains and formulations. Emerging insights from microbiome research enable an assessment of gut colonization by probiotics, strain-level activity, interactions with the indigenous microbiome, safety and impacts on the host, and allow the association of probiotics with physiological effects and potentially useful medical indications. In this Perspective, we highlight key advances, challenges and limitations in striving toward an unbiased interpretation of the large amount of data regarding over-the-counter probiotics, and propose avenues to improve the quality of evidence, transparency, public awareness and regulation of their use. 10.1038/s41591-019-0439-x
Irritable bowel syndrome. Ford Alexander C,Sperber Ami D,Corsetti Maura,Camilleri Michael Lancet (London, England) Irritable bowel syndrome is a functional gastrointestinal disorder with symptoms including abdominal pain associated with a change in stool form or frequency. The condition affects between 5% and 10% of otherwise healthy individuals at any one point in time and, in most people, runs a relapsing and remitting course. The best described risk factor is acute enteric infection, but irritable bowel syndrome is also more common in people with psychological comorbidity and in young adult women than in the rest of the general population. The pathophysiology of irritable bowel syndrome is incompletely understood, but it is well established that there is disordered communication between the gut and the brain, leading to motility disturbances, visceral hypersensitivity, and altered CNS processing. Other less reproducible mechanisms might include genetic associations, alterations in gastrointestinal microbiota, and disturbances in mucosal and immune function. In most people, diagnosis can be made on the basis of clinical history with limited and judicious use of investigations, unless alarm symptoms such as weight loss or rectal bleeding are present, or there is a family history of inflammatory bowel disease or coeliac disease. Once the diagnosis is made, an empathetic approach is key and can improve quality of life and symptoms, and reduce health-care expenditure. The mainstays of treatment include patient education about the condition, dietary changes, soluble fibre, and antispasmodic drugs. Other treatments tend to be reserved for people with severe symptoms and include central neuromodulators, intestinal secretagogues, drugs acting on opioid or 5-HT receptors, or minimally absorbed antibiotics (all of which are selected according to predominant bowel habit), as well as psychological therapies. Increased understanding of the pathophysiology of irritable bowel syndrome in the past 10 years has led to a healthy pipeline of novel drugs in development. 10.1016/S0140-6736(20)31548-8