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BACKGROUND AND AIMS: Conditions such as irritable bowel syndrome (IBS), functional dyspepsia, and functional constipation are among the prevalent gastrointestinal (GI) disorders classified as disorders of gut-brain interaction (DGBI), which can adversely affect the lives of sufferers. This study aimed to assess the degree and consequences of overlapping DGBI in a large population-based global scale. METHODS: Internet survey data from 54,127 adults (49.1% women) in 26 countries were analyzed by 4 GI anatomic regions (esophageal, gastroduodenal, bowel, and anorectal). The number of DGBI-affected GI regions was assessed, including associations with sex, age, disease severity, quality of life, psychosocial variables, and health care utilization. RESULTS: A total of 40.3% of surveyed individuals met Rome IV criteria for a DGBI. The percentages with 1-4 DGBI-affected GI regions were 68.3%, 22.3%, 7.1%, and 2.3%, respectively. The IBS symptom severity score increased significantly from 1 (207.6) to 4 (291.6) regions, as did non-GI symptom reporting (somatization), anxiety and depression, concerns and embarrassment about bowel function, doctor visits, medications, and abdominal surgeries (all P < .0001). Quality of life decreased with increasing number of DGBI regions (P < .0001). In a logistic mixed model, non-GI symptoms (odds ratio [OR], 1.09; 95% confidence interval [CI], 1.08-1.10), being very vs not concerned (OR, 2.55; 95% CI, 2.27-2.90), being very vs not embarrassed about bowel function (OR, 1.20; 95% CI, 1.08-1.33), and mean number of doctor visits (OR, 1.23; 95% CI, 1.115-1.32) were most strongly associated with number of DGBI regions. CONCLUSIONS: DGBI in multiple anatomic GI regions is associated with increased psychological comorbidity, health care utilization, and IBS severity. Physician awareness of overlap could improve quality of care, prevent unnecessary interventions, and yield more positive health outcomes. ispartof: CLINICAL GASTROENTEROLOGY AND HEPATOLOGY vol:20 issue:5 pages:E945-E956 ispartof: location:United States status: published

Chronic inflammatory diseases including human immunodeficiency virus infection, psoriasis, rheumatoid arthritis, and systemic lupus erythematosus predispose to atherosclerotic cardiovascular disease (ASCVD). Inflammatory bowel disease (IBD) is a common chronic inflammatory condition, and the United States has the highest prevalence worldwide. IBD has so far been overlooked as a contributor to the burden of ASCVD among young and middle-age adults, but meta-analyses of cohort studies suggest that IBD is an independent risk factor for ASCVD. This review discusses the epidemiological links between IBD and ASCVD and potential mechanisms underlying these associations. ASCVD risk management of patients with IBD is challenging because of their young age and the inability of current risk scores to fully capture their increased risk. The role of IBD in current primary prevention guidelines is evaluated, and strategies for enhanced ASCVD risk reduction in patients with IBD are outlined. Finally, the authors discuss knowledge gaps and future research directions in this innovative field.

Purpose of review Irritable bowel syndrome (IBS) is a very common disorder whose clinical presentation varies considerably between patients as well as within the same individual over time. Many of its symptoms, such as pain, diarrhea, constipation and bloating, may be manifestations of a host of other gastrointestinal diseases; some accompanied by increased mortality. This presents the clinician with a real dilemma: how to sensibly investigate the patient in which one suspects IBS but there is a nagging doubt that 'it could be something else'? Could one miss 'something serious'? This short review attempts to provide both an evidence-based response to these vexing questions and a practical guide to detecting alternative diagnoses in the subject with IBS-type symptoms. Recent findings Clinical features, patient demographics and the clinical context can help to significantly narrow the differential diagnosis of the individual with IBS-type symptoms and may permit a positive diagnosis of IBS. The advent of noninvasive serological and stool tests has greatly facilitated differentiation from celiac disease and inflammatory bowel disease, respectively. In the older, female diarrhea sufferer microscopic colitis should be considered. The role of bile acid diarrhea in the individual with diarrhea-predominant IBS is emphasized; the status of small intestinal bacterial overgrowth in IBS remain uncertain. Summary Attention to detail in the clinical evaluation of the individual with IBS-like symptoms will facilitate a selective and targeted approach to investigation. Wherever indicated, widely available serological and fecal tests will serve to bolster the diagnosis by excluding other options. Proceeding to more invasive testing should be dictated by clinical presentation and scenario with the threshold for intervention being generally lower among those with prominent diarrhea.

Frequent observation of abnormal manometric patterns consistent with dyssynergia in healthy volunteers has warranted the need for reassessment of the current methods to enhance the diagnostic value of anorectal manometry in functional defecatory disorders. Whether rectal distention at simulated evacuation will affect anorectal pressure profile and increase rectoanal gradient is not known. One hundred and eight consecutive patients with chronic constipation, 93 females, median age 53 years (interquartile range: 40–65), were studied. Simulated evacuation was performed firstly with empty balloon and subsequently after balloon distention to 50 and 100 ml. Anorectal pressures were compared. We also performed subgroup analysis in relation to outcome of balloon expulsion test (BET). In addition, we studied the effect of rectal distension on the rectoanal pressure gradient with respect to rectal sensory function. Rectal balloon distension at simulated evacuation improved rectoanal gradient and decreased the rate of dyssynergia during high-resolution anorectal manometry. In subgroup analysis, the increase in rectoanal gradient and correction of dyssynergia with rectal distension was limited to the patients who had normal BET and normal rectal sensory function. Rate of anal relaxation, residual anal pressures, and rectoanal gradient were significantly different between patients with and without normal BET at 50 ml of rectal distension. Rectoanal gradient recorded only after rectal distension, along with BMI and maximum tolerable volumes, could predict BET results independently in patients with chronic constipation. Rectal distension during simulated evacuation will affect the anorectal pressure profile. Increase in rectoanal gradient and correction of dyssynergia was only significant in patients with normal rectal sensory function and normal BET.

PURPOSE OF REVIEW Cancer cachexia is a complex condition that occurs in approximately 50% of cancer patients and in 80% of those with advanced cancer. It is characterized by lean body mass loss, adipose tissue loss, altered metabolism, increased inflammation, and a decrease in quality of life. Cancer cachexia is a frustrating condition to manage and treatment requires an innovative approach. The purpose of this article is to review the current treatments for cancer cachexia and how they could be used in a multimodal approach. RECENT FINDINGS Cancer cachexia has many causes, but is primarily a result of reduced energy-protein intake and altered metabolism augmented by a proinflammatory state. There is not a formal consensus on diagnosing cancer cachexia, but proactive screening and assessments for malnutrition are an effective first step toward identifying high-risk patients. Treatment of cancer cachexia includes optimizing nutrition care, using appropriate pharmacological agents, preserving lean body mass, and the cooperation of the healthcare team. SUMMARY Cancer cachexia is a complex multifactorial condition that can only be successfully managed and treated with a multimodal approach that involves a multidisciplinary team that includes an oncology registered dietitian nutritionist and exercise physiologist that target early detection and management of cancer cachexia.

Evidence accumulates to implicate a role for the gut microbiota in non-alcoholic fatty liver disease (NAFLD)-a disorder that has reached almost epidemic proportions around the globe. For some time a disturbance in the gut microbiome, small intestinal bacterial overgrowth (SIBO), has been described among patients with liver disease, in general, and in the development and progression of NAFLD to nonalcoholic steatohepatitis (NASH), decompensated liver disease and hepatocellular cancer (HCC), in particular. More recently and permitted by the advent of high-throughput sequencing and allied molecular techniques, a much more detailed analysis of gut microbiota in NAFLD and NASH has become possible. In animal models, several mechanisms have been delineated which reveal how gut bacteria and their products could promote steatosis, hepatic inflammation, fibrosis, cirrhosis, and carcinogenesis. For understandable reasons evidence from human studies is less complete, but here again a plausible case is beginning to emerge to incriminate microbiota in NAFLD and NASH pathogenesis. Therapeutic interventions based on the modulation of the microbiome have been explored to some extent, but their application to everyday medical practice is still in the future.

Inflammatory bowel disease (IBD) is a chronic immune-mediated disease affecting the gastrointestinal tract. IBD consists of 2 subtypes: ulcerative colitis and Crohn disease. IBD is thought to develop as a result of interactions between environmental, microbial, and immune-mediated factors in a genetically susceptible host. Of late, the potential role of the microbiome in the development, progression, and treatment of IBD has been a subject of considerable interest and enquiry. Indeed, studies in human subjects have shown that the gut microbiome is different in patients with IBD compared with that in healthy control subjects. Other evidence in support of a fundamental role for the microbiome in patients with IBD includes identification of mutations in genes involved in microbiome-immune interactions among patients with IBD and epidemiologic observations implicating such microbiota-modulating risk factors as antibiotic use, cigarette smoking, levels of sanitation, and diet in the pathogenesis of IBD. Consequently, there has been much interest in the possible benefits of microbiome-modulating interventions, such as probiotics, prebiotics, antibiotics, fecal microbiota transplantation, and gene manipulation in the treatment of IBD. In this review we will discuss the role of the gut microbiome in patients with IBD; our focus will be on human studies.

[No Abstract Available]

Background and AimsThe over-prescription of antibiotics is thought to represent a major threat to public health worldwide and is more frequently observed in some low- and middle-income countries. In the Asia-Pacific region, economic development, health care organization and population demographics are very heterogenous. The objective of this survey was to investigate antibiotic use and probiotic co-prescription among adult patients in this area.MethodsAn online survey of physicians from seven countries of the Asia-Pacific region (Australia, Japan, Indonesia, India, China, Singapore and South Korea) was performed in 2018. The questionnaire explored current practices of physicians concerning antibiotics and probiotics and factors related to prescribing decisions.ResultsA total of 387 general practitioners and 350 gastroenterologists completed the questionnaire. Physicians in Australia, Japan and South-Korea were low prescribers of antibiotics (11% to 19% of visits resulted in an antibiotic prescription), while physicians in Indonesia, India, China and Singapore were high prescribers (41% to 61%). A large majority (85%) of physicians agreed that antibiotics disrupted intestinal microbiota. The rates of co-prescription of probiotics varied from 16% in Japan to 39% in Singapore (overall, 27%). Conditions considered by physicians to be prevented by probiotics were mostly antibiotic-associated diarrhea (62%) and Clostridium difficile colitis (43%).ConclusionsRates of probiotic co-prescription remain low in many countries although the negative effects of antibiotics on the gut microbiota and the benefits of co-prescribing probiotics are generally known.

Irritable bowel syndrome and inflammatory bowel disease differ in their natural evolution, etiopathogenesis, diagnostic criteria, and therapeutic approach. However, recent evidence has suggested some similarities in mechanisms underlying symptom development and progression. There is a relevant role for alterations in the microbiome-brain-gut axis in both diseases. The presence of irritable bowel syndrome symptoms in patients with quiescent inflammatory bowel disease is common in clinical practice. To determine the cause of irritable bowel syndrome symptoms in patients with quiescent inflammatory bowel disease is a clinical challenge. This review aims to illustrate possible causes and solutions for these patients.

BACKGROUND Chronic constipation is a prevalent disorder that affects quality of life of patients and consumes resources in healthcare systems worldwide. In clinical practice, it is still considered a challenge as clinicians frequently are unsure as to which treatments to use and when. Over a decade ago, a Neurogastroenterology and Motility journal supplement devoted to the investigation and management of constipation was published (Neurogastroenterol Motil 2009;21(Suppl 2):1). In October 2018, the 3rd London Masterclass, entitled "Contemporary management of constipation" was held. The faculty members of this symposium were invited to write two reviews to present a collective synthesis of talks presented and discussions held during this meeting. The first review addresses epidemiology, diagnosis, clinical associations, pathophysiology, and investigation. PURPOSE The present is the second of these reviews, providing contemporary perspectives and clinical challenges regarding behavioral, conservative, medical, and surgical treatments for patients presenting with constipation. It includes a management algorithm to guide clinical practice.

In the original version of this Consensus Statement article published online, a bar in Figure 1 was incorrectly labelled as “parabiotics” when it should have been labelled as “paraprobiotics”. This error has now been corrected in the HTML and PDF version of the article. Figure 1 | Total number of mentions in the literature of different terms referring to inanimate microorganisms and/or their metabolites.

Summary Background There are several drugs available for the treatment of chronic idiopathic constipation, but their relative efficacy is unclear because there have been no head-to-head randomised controlled trials. We did a network meta-analysis to compare the efficacy of these therapies in patients with chronic idiopathic constipation. Methods We searched Medline, Embase, Embase Classic, and the Cochrane Central Register of Controlled Trials for randomised controlled trials published from inception to week 3 June, 2019, to identify randomised controlled trials assessing the efficacy of drugs (osmotic or stimulant laxatives, elobixibat, linaclotide, lubiprostone, mizagliflozin, naronapride, plecanatide, prucalopride, tegaserod, tenapanor, or velusetrag) in adults with chronic idiopathic constipation. Participants had to be treated for a minimum of 4 weeks, and we extracted data for all endpoints preferentially at 4 weeks, 12 weeks, or both. Trials included in the analysis reported a dichotomous assessment of overall response to therapy (response or no response to therapy). We pooled the data using a random effects model, and reported efficacy and safety of all treatments as a pooled relative risk (RR) with 95% CIs to summarise the effect of each comparison tested. To rank treatments, we used P-scores, which measure the extent of certainty that a treatment is better than another treatment, averaged over all competing treatments. Findings We identified 33 eligible randomised controlled trials of drugs, comprising 17 214 patients. Based on an endpoint of failure to achieve three or more complete spontaneous bowel movements (CSBMs) per week, the stimulant diphenyl methane laxatives bisacodyl and sodium picosulfate, at a dose of 10 mg once daily, were ranked first at 4 weeks (RR 0·55, 95% CI 0·48–0·63, P-score 0·99), and prucalopride 2 mg once daily ranked first at 12 weeks (0·82, 0·78–0·86, P-score 0·96). When response to therapy was defined as falilure to achieve an increase of one or more CSBM per week from baseline, diphenyl methane laxatives at a dose of 10 mg once daily ranked first at 4 weeks (0·44, 0·37–0·54, P-score 0·99), with prucalopride 4 mg once daily ranked first at 12 weeks (0·74, 0·66–0·83, P-score 0·79), although linaclotide 290 μg once daily and prucalopride 2 mg once daily had similar efficacy (P-scores of 0·76 and 0·71, respectively). Bisacodyl ranked last in terms of safety for total number of adverse events and abdominal pain (P-score 0·08). Interpretation Almost all drugs studied were superior to placebo, according to either failure to achieve three or more CSBMs per week or or failure to achieve an increase of one or more CSBM per week over baseline. Although diphenyl methane laxatives ranked first at 4 weeks, patients with milder symptoms might have been included in these trials. Prucalopride ranked first at 12 weeks, and many of the included trials recruited patients who previously did not respond to laxatives, suggesting that this drug is likely to be the most efficacious for patients with chronic idiopathic constipation. However, because treatment duration in most trials was 4–12 weeks, the long-term relative efficacy of these drugs is unknown. Funding None.

Colorectal cancer is the most preventable form of cancer worldwide. The pathogenesis of colorectal cancer includes gut inflammation, genetic and microbial composition factors. İmpairment of the gut microbiota has been associated with development of colorectal cancer. The genus Bifidobacterium is an important component of the commensal gut microbiota. Bifidobacteria are considered to have important roles in multiple homeostatic functions: immunologic, hormonal and metabolic. Mucosal-associated invariant T cells (MAIT) are components of the immune system involved in protection against infectious pathogens and regulate the pathogenesis of various inflammatory diseases and, potentially, colorectal cancer. Engagement between Bifidobacterium and MAIT cells could exert a beneficial effect on colorectal cancer prevention and treatment.

ObjectiveOver 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.DesignWe 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.ResultsWe 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.ConclusionIn 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.

Antibiotics and probiotics are often used as adjunctive therapy in inflammatory bowel disease. However, data are limited and randomised controlled trials are too inconsistent to provide generalised recommendations for their use in all patients with ulcerative colitis or Crohn’s disease. Antibiotics are best used in the management of infectious complications and fistulas in Crohn’s disease and, perhaps, in reducing the intensity of inflammation in luminal disease. Ciprofloxacin, metronidazole and rifaximin have been most widely used and studied. On the other hand, there appears to be a limited role for antibiotics in ulcerative colitis (UC). Probiotics are most effective in pouchitis, and may have a role in the initial therapy and maintenance of remission in mild UC; the probiotic cocktail VSL#3 has been the most widely studied. There is scant evidence of efficacy for probiotics in Crohn’s disease.

Background Gallbladder dyskinesia (gallbladder spasm, biliary dyskinesia or chronic acalculous cholecystitis) is a poorly defined entity which presents as biliary-type pain without any identifiable organic pathology. Abnormal gallbladder ejection fraction (GBEF) is used by some to select those likely to benefit from cholecystectomy. The validity of this approach has been questioned. Aim To systematically review the literature and summarise the evidence surrounding the practice of cholecystectomy based on GBEF for gallbladder dyskinesia. Methods We conducted a systematic search of PubMed/MEDLINE and SCOPUS from 1980 to 2016 to identify the relevant literature. Results Twenty-nine studies including 2891 patients were included in the final analysis. In comparing cholecystectomy with medical management, patients with a normal GBEF did not benefit from cholecystectomy; whereas those with low GBEF had a higher chance (RR, relative risk = 2.37) of symptomatic improvement following surgery. When those classified as "low" and "normal" GBEF were compared in terms of outcome following cholecystectomy, the rate of improvement following surgery was similar in the two groups (RR 1.09) which suggests a placebo effect of surgery. Conclusions While a low GBEF may provide some guidance in identifying those with gallbladder dyskinesia who may benefit from cholecystectomy, the available data are inconsistent and based on studies of poor quality which are often subject to bias and the impact of confounding factors. For these reasons, we conclude that the role of scintigraphy and cholecystectomy in the definition and management of this disorder remain unclear pending definitive study.

As the importance of the gut microbiota in health and disease is increasingly recognized interest in interventions that can modulate the microbiota and its interactions with its host has soared. Apart from diet, prebiotics and probiotics represent the most commonly used substances taken in an effort to sustain a healthy microbiome or restore balance when it is believed bacterial homeostasis has been disturbed in disease. While a considerable volume of basic science attests to the ability of various prebiotic molecules and probiotic strains to beneficially influence host immune responses, metabolic processes and neuro-endocrine pathways, the evidence base from human studies leaves much to be desired. This translational gap owes much to the manner in which this sector is regulated but also speaks to the challenges that confront the investigator who seeks to explore microbiota modulation in either healthy populations or those who suffer from common digestive ailments. For many products marketed as probiotics, some of the most fundamental issues relating to quality control, such as characterization, formulation, viability safety are scarcely addressed.

The term "small intestinal bacterial overgrowth" (SIBO) has been used to refer to a disorder resulting from the colonization of the small bowel by an increased number of microorganisms or by the presence of bacteria that are not usual constituents of this part of the gastrointestinal tract. Clinical presentations, often in patients with certain risk factors, can range from a full-blown malabsorption syndrome to such "functional" complaints as bloating and flatulence. SIBO is diagnosed by either culture of a small bowel aspirate or one of several breath tests. Treatment of SIBO entails risk factor modification, correction of nutritional deficiencies, and oral antibiotics.

Gastroparesis, whether idiopathic or related to an underlying disease, is thought to be common but data on the actual community prevalence of the disorder are scanty. Hospital admission data, which, of course are highly selective, suggest that gastroparesis imposes a significant burden on health care systems and is a cause of significant morbidity for the affected individual. One of the major barriers to the generation of accurate epidemiological data is the very definition of gastroparesis – its symptoms are non-specific and the most widely available objective test to document gastric emptying delay involves radiation exposure. The availability of non-invasive and non-radiation emitting alternatives should open the way to providing accurate epidemiological data on this challenging condition and, thereby, close an enormous gap in our understanding.

Introduction: Chronic inflammatory disease states are associated with higher incidence of premature atherosclerotic cardiovascular disease (ASCVD) in the young. However, data on whether younger patients with inflammatory bowel disease (IBD) are particularly at higher risk for subclinical atherosclerotic disease is scarce. Methods: Using data obtained from the CLARIFY registry (Clinicaltrials.gov NCT04075162), a prospective study of no-charge coronary artery calcium (CAC) testing at University Hospitals, we identified all patients with ulcerative colitis or Crohn’s disease and compared the presence (>0) and high (≥100) CAC with all patients in CLARIFY without IBD stratified by age group (non-elderly: ≤65 years; elderly >65 years), and adjusting for traditional ASCVD risk factors. Results: A total of 475 patients with IBD (252 UC, 196 CD, 27 both) and 43,437 controls without IBD were included. Compared with control, patients with IBD were more likely to be female (59% vs 50%, P100 compared to 28% without IBD (p=0.10). The respective prevalence was 25% vs. 21% (p=0.08) among non-elderly participants, and 45% vs. 47% (p=0.49) among elderly. In the total population, no association between IBD and CAC>0 or CAC>100 was noted. However, there was evidence of effect modification by pre-specified age strata (p-value for interaction 0.012, figure), where the odds of CAC≥100 was 1.38-fold higher (95% CI: 1.02-1.89) for IBD among participants ≤65 years vs among elderly participants [OR 0.84, 95% CI: 0.57-1.22]. Conclusions: Non-elderly IBD patients are at increased risk for significant coronary calcified atherosclerotic disease. Further studies are needed to understand underlying biological processes and implications of increased atherosclerotic disease risk among young adults with IBD.

Introduction: Inflammatory Bowel Disease (IBD), comprised of Ulcerative Colitis (UC) and Crohn’s Disease (CD) is a chronic inflammatory disease with systemic involvement. Inflammation predisposes to atherosclerosis and studies suggest that IBD is associated with premature atherosclerotic cardiovascular disease (ASCVD). There is, however, limited population-based data on cardiovascular risk factor (CRF) burden in IBD among those who have not yet developed clinical ASCVD. We sought to study the association between IBD and CRFs among a nationally representative population with IBD and without established ASCVD. Methods: The study population was derived from the 2015-2016 National Health Interview Survey database. ASCVD was defined as myocardial infarction, angina or stroke; those with ASCVD were excluded. IBD was defined as either CD or UC. We computed weighted prevalence estimates of various traditional CRFs for the US population by IBD status. Univariate and multivariate logistic regression models were used to evaluate associations between CRFs and IBD. Average and poor cardiovascular risk profiles were defined as 2-3 and ≥4 CRFs, respectively. Results: Overall 786 (1.2%) representing 2.6 million ASCVD-free adults reported IBD. Individuals with IBD had higher prevalence of multiple CRFs (Figure, top). In adjusted models those with IBD had significantly higher odds of having prevalent hypertension, diabetes mellitus and hypercholesterolemia (Figure, bottom). These associations were similar among elderly and young participants. Those with IBD were almost 2-fold more likely to have a poor cardiovascular risk profile. Conclusion: Our findings from a nationally representative US population suggest an increased burden and clustering of CRFs among IBD patients without clinical ASCVD. Future efforts are needed to understand the underlying mechanisms, and enhance the detection and treatment of these CRFs to reduce ASCVD risk in IBD patients.

Background and Aims: Functional defecatory dysfunction is attributed to the pathophysiology of fecal incontinence (FI) in some patients. We hypothesized that patients with FI and abnormal balloon expulsion test (BET) have distinct manometric characteristics as compared to the patients with FI and normal BET. We aimed to compare the anorectal pressure profile in patients with FI, with or without abnormal BET and to identify risk factors associated with abnormal BET in FI. Methods: We performed a retrospective review of 77 consecutive patients with ROME IV FI. Wilcoxon rank sum test, t-test, and Fisher exact tests were performed for comparison. Multivariable logistic regression was performed to identify factors associated with abnormal BET. Results: Thirty-two percent of patients had abnormal BET. Demographics and surgical history and clinical symptoms, except for sensation of incomplete evacuation (p=0.02) and abdominal pain (p=0.03), were comparable in both groups. Anorectal pressure profile except for the median rectal propulsive pressures were similar between groups. Rectal propulsive pressures at simulated defecation were significantly lower in patients with abnormal BET (p=0.02). Mean sensory threshold for first sensation was also significantly higher in patients who had abnormal BET (p=0.03). Rectal propulsive pressures (OR: 1.03, 95% CI: 1.00-1.06, p=0.032) and rectal sensory threshold for first sensation (OR:0.94, 95% CI: 0.90-0.99, p=0.02) were able to predict abnormal BET independently. Conclusions: In patients with FI and similar clinical and anal pressure profile, rectal sensory threshold and rectal propulsive pressures at simulated defecation can determine normal BET.

For some time, the concept of the gut-brain axis has served as a useful paradigm to explain the many interactions between the “big brain” (the central nervous system [CNS]) and the “little brain” (the enteric nervous system). Recently, the gut microbiome has been added to the equation and the proposition that gut microbes could influence brain structure and function and vice versa has emerged. Research in this field has been facilitated by dramatic progress in technologies that permit the delineation of the microbial constituents of the gut and their function in health and disease. Studies in a variety of animal models have amply supported the concept of a microbiota-gut-brain-axis and demonstrated that interventions that modulate the microbiome can influence animal behavior and CNS physiology. Understandably, studies of the impact of the microbiome on human brain structure and function are less numerous, but sufficient evidence does exist to indicate that this axis is operating in humans. In terms of neurodegenerative disorders, here again animal data dominate, but a sufficient body of evidence has accumulated to justify further explorations of the role of gut microbiota in Parkinson’s disease and Alzheimer’s disease, as well as in the aging process per se—“inflammaging.” Many confounding factors complicate the interpretation of human studies of the microbiome, and large, longitudinal studies that attempt to account for such confounders are needed. A number of interventions can be entertained—most notably, diet, probiotics, and prebiotics. To date, studies of any such interventions in neurodegenerative disease in humans are scanty.

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.

Background Constipated patients remain dissatisfied with current treatments suggesting a need for alternative therapies. Aim Evaluate the mechanistic effects of oral vibrating capsule in chronic idiopathic constipation (CIC) by examining the temporal relationships between the onset of vibrations, complete spontaneous bowel movements (CSBM), and circadian rhythm. Methods In post hoc analyses of two double-blind studies, CIC patients (Rome III) were randomized to receive 5 active or sham capsules/week for 8 weeks. The capsules were programmed for single vibration (study 1) or two vibration sessions with two modes, 8 hours apart (study 2). Daily electronic diaries assessed stool habit and percentage of CSBMs associated with vibrations. Responders were patients with ≥ 1 CSBM per week over baseline. Results 250 patients were enrolled (active = 133, sham = 117). During and within 3 hours of vibration, there were significantly more % CSBMs in the active vs. sham group (50% vs. 42%; P = .0018). In study 2, there were two CSBM peaks associated with vibration sessions. Significantly more % CSBMs occurred in active mode 1 (21.5%) vs. sham (11.5%); (P = .0357). Responder rates did not differ in study 1 (active vs. sham: 26.9% vs. 35.9%, P = .19) or study 2 (mode 1 vs. sham: 50% vs. 31.8%, P = .24; mode 2 vs. sham: 38.1% vs. 31.8%, P = .75). Device was well-tolerated barring mild vibration sensation. Conclusions Vibrating capsule may increase CSBMs possibly by enhancing the physiologic effects of waking and meals, and augmenting circadian rhythm, although responder rate was not different from sham. Two vibration sessions were associated with more CSBMs.

ObjectivesNational 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.DesignWe 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.ResultsWe 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.ConclusionsSeveral 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 numberThe study protocol was published on the PROSPERO international prospective register of systematic reviews (registration number CRD 42020163246).

As our knowledge of the various roles of the gut microbiota in the maintenance of homeostasis grows and as we learn how a disrupted microbiota may contribute to disease, therapeutic strategies that target our microbial fellow-travellers become ever more attractive. Most appealing are those interventions that seek to modify or supplement our diet through the addition of nutraceuticals. We now know that our diet, whether in the short or long term, is a major modifier of microbiota composition and function. Of the various nutraceuticals, two categories, prebiotics and probiotics, have received the greatest attention in basic research and product development. While our understanding of the impacts of prebiotics and probiotics on the indigenous microbiota and host biology have been described in great detail in vitro and in animal models, the clinical literature leaves much to be desired. While many claims have been made, few are supported by high quality clinical trials. LINKED ARTICLES: This article is part of a themed section on The Pharmacology of Nutraceuticals. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.6/issuetoc.

We are in the midst of “the microbiome revolution”—not a day goes by without some new revelation on the potential role of the gut microbiome in some disease or disorder. From an ever-increasing recognition of the many roles of the gut microbiome in health and disease comes the expectation that its modulation could treat or prevent these very same diseases. A variety of interventions could, at least in theory, be employed to alter the composition or functional capacity of the microbiome, ranging from diet to fecal microbiota transplantation (FMT). For some, such as antibiotics, prebiotics, and probiotics, an extensive, albeit far from consistent, literature already exists; for others, such as other dietary supplements and FMT, high-quality clinical studies are still relatively few in number. Not surprisingly, researchers have turned to the microbiome itself as a source for new entities that could be used therapeutically to manipulate the microbiome; for example, some probiotic strains currently in use were sourced from the gastrointestinal tract of healthy humans. From all of the extant studies of interventions targeted at the gut microbiome, a number of important themes have emerged. First, with relatively few exceptions, we are still a long way from a precise definition of the role of the gut microbiome in many of the diseases where a disturbed microbiome has been described—association does not prove causation. Second, while animal models can provide fascinating insights into microbiota–host interactions, they rarely recapitulate the complete human phenotype. Third, studies of several interventions have been difficult to interpret because of variations in study population, test product, and outcome measures, not to mention limitations in study design. The goal of microbiome modulation is a laudable one, but we need to define our targets, refine our interventions, and agree on outcomes.

Interactions between the gut and the liver in relation to immunological responses and metabolic functions have been recognized as central to homeostasis for decades. The roles of gut bacteria in the pathogenesis of certain complications of cirrhosis such as hepatic encephalopathy, spontaneous bacterial peritonitis, and systemic sepsis were also delineated decades ago – what is new is the idea that interactions between luminal bacteria in the gut (microbiota), the gut itself, and the liver may play a more fundamental role in the pathogenesis of a number of metabolic and immunological diseases. From basic animal research, as well as observations in human disease, a general hypothesis has emerged to explain how interplay between these factors might initiate or perpetuate alcoholic liver disease, nonalcoholic fatty liver disease, and even immunologically mediated liver diseases. In this framework, disrupted microbiota and their products gain access to the gut-associated immune system via a permeable gut barrier and generate inflammatory responses. Disruption of the gut vascular barrier then permits access for bacterial components as well as pro-inflammatory cytokines to the portal circulation and onto the liver where inflammatory and metabolic responses drive the genesis of various liver diseases. Cross-reactivity between bacterial antigens and biliary epitopes has also been invoked in relation to primary sclerosing cholangitis and primary biliary cholangitis. As we learn more of the details of these interactions and of the primacy, or otherwise, of the microbiota in this microbiota-gut-liver axis, new preventive strategies and therapeutic avenues may open up.

Background Irritable bowel syndrome (IBS) is a chronic functional bowel disorder. Disturbances in the gastrointestinal microbiome may be involved in its aetiology. Aim To perform a systematic review and meta‐analysis to examine the efficacy of prebiotics, probiotics, synbiotics and antibiotics in IBS. Methods MEDLINE, EMBASE, and the Cochrane Controlled Trials Register were searched (up to July 2017). Randomised controlled trials (RCTs) recruiting adults with IBS, comparing prebiotics, probiotics, synbiotics or antibiotics with placebo or no therapy were eligible. Dichotomous symptom data were pooled to obtain a relative risk (RR) of remaining symptomatic after therapy, with a 95% confidence interval (CI). Continuous data were pooled using a standardised mean difference with a 95% CI. Results The search identified 4017 citations. Data for prebiotics and synbiotics were sparse. Fifty‐three RCTs of probiotics, involving 5545 patients, were eligible. Particular combinations of probiotics, or specific species and strains, appeared to have beneficial effects on global IBS symptoms and abdominal pain, but it was not possible to draw definitive conclusions about their efficacy. There were five trials of similar design that used rifaximin in non‐constipated IBS patients, which was more effective than placebo (RR of symptoms persisting = 0.84; 95% CI 0.79‐0.90). Adverse events were no more common with probiotics or antibiotics. Conclusions Which particular combination, species or strains of probiotics are effective for IBS remains, for the most part, unclear. Rifaximin has modest efficacy in improving symptoms in non‐constipated IBS.

The BURDEN IBS-C study was conducted to better understand the experiences, attitudes, and unmet needs of sufferers of irritable bowel syndrome with constipation (IBS-C) in comparison to the perceptions and challenges of healthcare providers (HCPs) who treat IBS-C patients. This was an author-developed, online questionnaire using KnowledgePanel® to survey individuals with IBS-C (N = 1311). HCPs participated in a complementary online questionnaire and were recruited separately (N = 331). The study was fielded from June 29, 2016, to January 30, 2017. Most patients had used (86%) and/or were using (76%) over-the-counter treatments for their IBS-C, with 12% currently on prescription therapy. At the time this study was conducted, 66% and 63% were not satisfied/completely satisfied with over-the-counter or prescription treatment, respectively, citing inadequate efficacy (55%) and side effects (39%), most commonly diarrhea, as common reasons for dissatisfaction. IBS-C respondents most commonly reported feeling frustrated (43%) and stressed (28%) regarding IBS-C, though 39% were accepting of IBS-C as part of daily life. HCPs were aligned with patients in thinking that patients were frustrated (76%) and stressed (65%) but HCPs were less likely to recognize that patients had become accepting of their IBS-C (13%). Most HCPs (79%) were not satisfied/completely satisfied with the prescription treatments available at the time this study was conducted. Inadequate response rates to current therapies (55%) and treatment adherence/compliance issues (58%) were the most frequent challenges encountered by HCPs. IBS-C respondents reported that their symptoms impacted productivity and personal activity, on average, 4 and 3 days/month, respectively. These results suggest that current management pathways may not be adequately addressing the symptoms and needs of individuals with IBS-C, most notably side effects and lack of efficacy. Patients and HCPs expressed dissatisfaction with over-the-counter and prescription treatments available at the time this study was conducted. Additional treatment options and improved dialogue would be beneficial to HCPs and patients. Synergy Pharmaceuticals Inc.

Dyspepsia is an umbrella term used to encompass a number of symptoms thought to originate from the upper gastrointestinal tract. These symptoms are relatively nonspecific; not surprisingly, therefore, a myriad of conditions may present with any one or a combination of these symptoms. Therein lays the clinician's first challenge: detecting the minority who may have a potentially life-threatening disorder, such as gastric cancer, from a population whose symptoms are, for the most part, considered functional in origin. The second challenge lies in the definition and management of those individuals with functional dyspepsia (FD); the major focus of this review. The Rome process has addressed the issue of FD definition and a look back at the evolution of Rome criteria for this disorder illustrates the complexities that have so frustrated us. There has been no shortage of hypotheses to explain symptom pathogenesis in FD; initially focused on gastric sensorimotor dysfunction, these have now strayed well into the duodenum and have come to entertain such factors as immune responses and the microbiome. FD has proven to be an equally challenging area for therapeutics; while the staple approaches of acid suppression and eradication of Helicobacter pylori have some limited efficacy in select populations, strategies to ameliorate symptoms in the majority of sufferers based on presumed pathophysiology have largely foundered. Lacking a validated biomarker(s) FD continues to be an elusive target and is likely to remain so until we can better define the various phenotypes that it must surely contain.

The Asia-Pacific region is diverse, with regard to ethnicity, culture, and economic development incorporating some of the world's least and most developed nations. Gastrointestinal diseases are common in the Asia-Pacific region, and their prevalence, presentation, and management vary considerably within the region. There is growing evidence for an important role for the human gut microbiota in gastrointestinal health. As a consequence, geographic variations in the composition of the gut microbiota may contribute to variations in both the prevalence and response to therapy of specific diseases. Probiotics have been proposed as a valuable option in the prevention and treatment of a number of gastrointestinal illnesses, but the quality of available evidence to support their efficacy is variable. A meeting of international experts in adult and pediatric gastroenterology was held at the Sorbonne University, Paris, France, on April 11 and 12, 2016, to discuss current evidence supporting the use of probiotics in gastrointestinal disorders in the Asia-Pacific region. This article provides an overview of the discussions held at this meeting and recommends the formation of an Asia-Pacific Consortium on Gut Microbiota similar to those established in Europe and North America.

Introduction There is limited literature comparing the experiences and attitudes of patients with chronic idiopathic constipation (CIC) to those of healthcare professionals (HCPs) treating CIC patients. The BURDEN-CIC study was conducted to better understand the experiences and ongoing needs of CIC patients and to assess their alignment versus disconnection with the perceptions and needs of HCPs who treat CIC patients. Methods The BURDEN-CIC study was an author-developed, online questionnaire that used KnowledgePanel® to survey individuals with CIC (n = 1223). HCPs who treat CIC patients were recruited separately and participated in a complementary online questionnaire (n = 331). Results Most patients had used (58%) or were using (51%) over-the-counter treatments for their CIC, with only 16% currently on prescription therapy. More than half (59%) of current CIC prescription users were not satisfied/completely satisfied with their current chronic treatment. Many patients (42%) felt frustrated regarding their CIC, and a similar percentage (40%) expressed acceptance that CIC was part of their daily life. The majority of HCPs agreed that CIC patients were frustrated (72%), stressed (50%), or fed up (43%) with current treatment options but were relatively unaware (21%) that patients were accepting of their CIC. HCPs reported the greatest challenges in treating CIC patients as response rates to current therapies (55%), treatment adherence (55%), management of treatment-related diarrhea (34%), and lack of treatment options (34%). Conclusion BURDEN-CIC identified that many patients and HCPs are frustrated and not satisfied with current CIC treatments due to lack of efficacy and side effects, such as diarrhea. The survey identified that many patients are “accepting” of their disease, potentially compromising treatment outcomes. More dialogue is needed between HCPs and CIC patients, especially regarding management of treatment expectations and side effects. Further, additional treatment options would be useful for both patients and HCPs. Funding Synergy Pharmaceuticals Inc.

Chronic constipation (CC) is a highly prevalent and often under-appreciated gastrointestinal disorder associated with significant impairment in quality of life. Symptoms of constipation are typically present for a number of years prior to a patient seeking help. Lifestyle modifications followed by, or coupled with, over-the-counter laxatives represent the initial treatment option; however, relief for many is limited and dissatisfaction rates for these approaches remain high. Over recent years, therefore, considerable effort has been exerted on the development of novel pharmacological approaches. Two major targets have emerged, motility and secretion. Research on the former led to the development of a number of prokinetic agents capable of stimulating colonic motility and, thus, accelerating colonic transit. Of these, earlier prototypes such as cisapride and tegaserod, though effective, were ultimately withdrawn due to cardiovascular adverse events due in part to receptor non-selectivity. Highly selective serotonergic receptor agonists have since emerged which appear to be equally effective in stimulating gut motility but are devoid of cardiac side effects. One such agent is prucalopride, which has now been approved for the management of chronic idiopathic constipation in several countries, but not in the United States. Multiple multicenter, randomized placebo-controlled clinical trials have demonstrated superiority for prucalopride compared to placebo in the short to medium term in relieving the major symptoms of constipation in both men and women across a broad spectrum of ages, ethnicities and geographic locations. To date, prucalopride has enjoyed a favorable safety profile and there have been no signals to suggest arrythmogenicity. Efficacy over longer periods of treatment remains to be confirmed. Evidence for efficacy in other forms of constipation, such as opioid-induced constipation and that related to Parkinson’s disease is beginning to emerge; its status in the management of constipation-predominant irritable bowel syndrome or foregut motility disorders, such as gastroparesis, remains to be established.