Bile acid sequestrants (BASs) have often been used for bile acid diarrhea (BAD) but carry a high risk of adverse events. New generations of BASs show promising results; however, their efficacy remains unclear. This systematic review and meta-analysis was conducted using PubMed, Cochrane, and Embase to assess randomized controlled trials (RCTs) published up to November 2023 to retrieve studies that measured the parameters before and after the administration of BASs. The outcomes assessed were cessation or improvement in diarrhea, fecal consistency, abdominal cramping, frequency of diarrhea, and adverse events. Risk ratios (RRs) and mean differences with 95% confidence intervals (CIs) were pooled using a random-effects model. Statistical analyses were conducted using RStudio version 4.1.2. The protocol was prospectively registered with PROSPERO (CRD42023445444). Seven RCTs with a total of 311 patients were included, of which 168 (54%) were randomized to BASs. Among BAS-treated patients, 101 (60.1%) received colesevelam, 40 (23.8%) received chenodeoxycholate, 18 (10.7%) received cholestyramine, and 9 (5.3%) received colestid. BASs were associated with a significant improvement in the cessation of diarrhea (RR 3.27; 95% CI 2.08 to 5.15; P ≤  .05) and liquid stool to normal fecal consistency (RR 2.69; 95% CI 1.56 to 4.65; P ≤  .05), as well as an increase in abdominal cramps (RR 5.27; 95% CI 1.21 to 22.93; P ≤  .05). There were no differences in urgency, adverse events, or nausea between groups. These findings indicate that BASs are effective in the treatment of BAD, as indicated by the improvement or cessation of diarrhea episodes.

Disorders of Gut-Brain Interaction (DGBI) are widely prevalent and commonly encountered in gastroenterology practice. While several peripheral and central mechanisms have been implicated in the pathogenesis of DGBI, a recent body of work suggests an important role for the gut microbiome. In this review, we highlight how gut microbiota and their metabolites affect physiologic changes underlying symptoms in DGBI, with a particular focus on their mechanistic influence on GI transit, visceral sensitivity, intestinal barrier function and secretion, and CNS processing. This review emphasizes the complexity of local and distant effects of microbial metabolites on physiological function, influenced by factors such as metabolite concentration, duration of metabolite exposure, receptor location, host genetics, and underlying disease state. Large-scale in vitro work has elucidated interactions between host receptors and the microbial metabolome but there is a need for future research to integrate such preclinical findings with clinical studies. The development of novel, targeted therapeutic strategies for DGBI hinges on a deeper understanding of these metabolite-host interactions, offering exciting possibilities for the future of treatment of DGBI.

Inflammatory bowel disease (IBD), encompassing ulcerative colitis and Crohn's disease, is a group of chronic, immune-mediated disorders of the gastrointestinal tract that present substantial clinical challenges owing to their complex pathophysiology and tendency to relapse. A treat-to-target approach is recommended, involving iterative treatment adjustments to achieve clinical response, reduce inflammatory markers and achieve long-term goals such as mucosal healing. Lifelong medication is often necessary to manage the disease, maintain remission and prevent complications. The therapeutic landscape for IBD has evolved substantially; however, a ceiling on therapeutic efficacy remains and surgery is sometimes required (owing to uncontrolled disease activity or complications). Effective IBD management involves comprehensive care, including medication adherence and a collaborative clinician-patient relationship. This Review discusses current therapeutic options for IBD, detailing mechanisms of action, efficacy, safety profiles and guidelines for use of each drug class. We also explore emerging therapies and the role of surgery. Additionally, the importance of a multidisciplinary team and personalized care in managing IBD is emphasized, advocating for patient empowerment and involvement in treatment decisions. By synthesizing current knowledge and emerging trends, this Review aims to equip healthcare professionals with a thorough understanding of therapeutic options for IBD, enhancing informed, evidence-based decisions in clinical practice.

Chloroform is a prevalent toxic environmental pollutant in urban settings, posing risks to human health through exposure via various mediums such as air and tap water. The gut microbiota plays a pivotal role in maintaining host health. However, there is a paucity of research elucidating the impact of chloroform exposure on the gut microbiota. In this investigation, 18 SPF Kunming female mice were stratified into three groups (n = 6) and subjected to oral gavage with chloroform doses equivalent to 0, 50, and 150 mg/kg of body weight over 30 days. Our findings demonstrate that subchronic chloroform exposure significantly perturbs hematological parameters in mice and induces histopathological alterations in cecal tissues, consequently engendering marked disparities in the functional composition of cecal microbiota and metabolic equilibrium of cecal contents. Ultimately, our investigation revealed a statistically robust correlation, exhibiting a high degree of significance, between the intestinal microbiome composition and the metabolites that were differentially expressed consequent to chloroform exposure.

Bile acid malabsorption (BAM) is an important disorder of digestive pathophysiology as it generates chronic diarrhoea. This condition originates from intricate pathways involving bile acid synthesis and metabolism in the liver and gut, the composition of gut microbiota, enterohepatic circulation and key receptors as farnesoid X receptor (FXR), fibroblast growth factor receptor 4 (FGFR4), and the G-protein bile acid receptor-1 (GPBAR-1). Although symptoms can resemble those related to disorders of gut brain interaction, accurate diagnosis of BAM may greatly benefit the patient. The empiric diagnosis of BAM is primarily based on the clinical response to bile acid sequestrants. Specific tests including the 48-hour fecal bile acid test, serum levels of 7α-hydroxy-4-cholesten-3-one (C4) and fibroblast growth factor 19 (FGF19), and the 75Selenium HomotauroCholic Acid Test (SeHCAT) are not widely available. Nevertheless, lack of diagnostic standardization of BAM may account for poor recognition and delayed management. Beyond bile acid sequestrants, therapeutic approaches include the use of FXR agonists, FGF19 analogues, glucagon-like peptide-1 (GLP-1) receptor agonists, and microbiota modulation. These novel agents can best make their foray into the therapeutic armamentarium if BAM does not remain a diagnosis of exclusion. Ignoring BAM as a specific condition may continue to contribute to increased healthcare costs and reduced quality of life. Here, we aim to provide a comprehensive review of the pathophysiology, diagnosis, and management of BAM.

Irritable bowel syndrome (IBS) is a widespread gastrointestinal disorder known for its multifaceted pathogenesis and varied extraintestinal manifestations, yet its implications for bone and muscle health are underexplored. Recent studies suggest a link between IBS and musculoskeletal disorders, but a comprehensive understanding remains elusive, especially concerning the role of bile acids (BAs) in this context. This study aimed to elucidate the potential contribution of IBS to bone and muscle deterioration via alterations in gut microbiota and BA profiles, hypothesizing that cholestyramine could counteract these adverse effects. We employed a mouse model to characterize IBS and analysed its impact on bone and muscle health. Our results revealed that IBS promotes bone and muscle loss, accompanied by microbial dysbiosis and elevated BAs. Administering cholestyramine significantly mitigated these effects, highlighting its therapeutic potential. This research not only confirms the critical role of BAs and gut microbiota in IBS-associated bone and muscle loss but also demonstrates the efficacy of cholestyramine in ameliorating these conditions, thereby contributing significantly to the field's understanding and offering a promising avenue for treatment.

Bile acids regulate gastrointestinal motility by mechanisms that are poorly understood. Standard isolated tissue bath assays might not recapitulate in vivo physiology if contractile responses to certain bile acids require direct application to the intestinal mucosa. We sought to determine the feasibility of quantifying longitudinal smooth muscle contractile responses to bile acids from intact segments of everted mouse ileum. Ileum from adult female C57BL/6J mice was isolated, gently everted over a notched metal rod, and mounted in tissue baths. Individual bile acids and agonists of bile acid receptors were added to the baths, and longitudinal smooth muscle contractile responses were quantified by isometric force transduction. Ursodeoxycholic acid robustly increased contractile responses in a dose-dependent manner. Deoxycholic acid stimulated contractility at low doses but inhibited contractility at high doses. Chenodeoxycholic acid, glycocholic acid, and lithocholic acid did not alter contractility. The dose-dependent increase in contractility resulting from the application of ursodeoxycholic acid was recapitulated by INT-777, an agonist of the Takeda G protein-coupled receptor 5 (TGR5), and by cevimeline, a muscarinic acetylcholine receptor agonist. Agonists to the nuclear receptors farnesoid X receptor, glucocorticoid receptor, pregnane X receptor, vitamin D receptor, and to the plasma membrane epidermal growth factor receptor did not modify baseline contractile patterns. These results demonstrate that gentle eversion of intact mouse ileum facilitates the quantification of longitudinal smooth muscle contractile responses to individual bile acids. Prokinetic effects of ursodeoxycholic acid and low-dose deoxycholic acid are replicated by agonists to TGR5 and muscarinic acetylcholine receptors.

Imbalanced gut microbiota (GM) and abnormal fecal bile acid (BA) are thought to be the key factors for diarrhea-predominant irritable bowel syndrome (IBS-D), but the underlying mechanism remains unclear. Herein, we explore the influence of the GM-BA-Takeda G-protein-coupled receptor 5 (TGR5) axis on IBS-D. Twenty-five IBS-D patients and fifteen healthy controls were recruited to perform BA-related metabolic and metagenomic analyses. Further, the microbiota-humanized IBS-D rat model was established by fecal microbial transplantation (FMT) to investigate the GM-BA-TGR5 axis effects on the colonic barrier and visceral hypersensitivity (VH) in IBS-D. Finally, we used chenodeoxycholic acid (CDCA), an important BA screened out by metabolome, to evaluate whether it affected diarrhea and VH via the TGR5 pathway. Clinical research showed that GM associated with bile salt hydrolase (BSH) activity such as Bacteroides ovatus was markedly reduced in the GM of IBS-D, accompanied by elevated total and primary BA levels. Moreover, we found that CDCA not only was increased as the most important primary BA in IBS-D patients but also could induce VH through upregulating TGR5 in the colon and ileum of normal rats. TGR5 inhibitor could reverse the phenotype, depression-like behaviors, pathological change, and level of fecal BSH in a microbiota-humanized IBS-D rat model. Our findings proved that human-associated FMT could successfully induce the IBS-D rat model, and the imbalanced GM-BA-TGR5 axis may promote colonic mucosal barrier dysfunction and enhance VH in IBS-D.

Visceral hypersensitivity and intestinal mucosal barrier damage are important factors that cause abnormal brain-gut interaction in diarrhea-predominant irritable bowel syndrome (IBS-D). Recently, it was found that the imbalance of the gut microbiota-bile acid axis is closely related to them. Therefore, understanding the structure and function of the gut microbiota and bile acids and the underlying mechanisms by which they shape visceral hypersensitivity and mucosal barrier damage in IBS-D is critical. An examination of intestinal feces from IBS-D patients revealed that alterations in gut microbiota and bile acid metabolism underlie IBS-D and symptom onset. We also expanded beyond existing knowledge of well-studied gut microbiota and bile acid and found that Bacteroides ovatus and chenodeoxycholic acid may be potential bacteria and bile acid involved in the pathogenesis of IBS-D. Moreover, our data integration reveals the influence of the microbiota-bile acid-TGR5 axis on barrier function and visceral hypersensitivity.

Human fibroblast growth factor 19 (FGF19, or FGF15 in rodents) plays a central role in controlling bile acid (BA) synthesis through a negative feedback mechanism. This process involves a postprandial crosstalk between the BA-activated ileal farnesoid X receptor and the hepatic Klotho beta (KLB) coreceptor complexed with fibrobalst growth factor receptor 4 (FGFR4) kinase. Additionally, FGF19 regulates glucose, lipid, and energy metabolism by coordinating responses from functional KLB and FGFR1-3 receptor complexes on the periphery. Pharmacologically, native FGF19 or its analogs decrease elevated BA levels, fat content, and collateral tissue damage. This makes them effective in treating both cholestatic diseases such as primary biliary or sclerosing cholangitis (PBC or PSC) and metabolic abnormalities such as nonalcoholic steatohepatitis (NASH). However, chronic administration of FGF19 drives oncogenesis in mice by activating the FGFR4-dependent mitogenic or hepatic regenerative pathway, which could be a concern in humans. Agents that block FGF19 or FGFR4 signaling have shown great potency in preventing FGF19-responsive hepatocellular carcinoma (HCC) development in animal models. Recent phase 1/2 clinical trials have demonstrated promising results for several FGF19-based agents in selectively treating patients with PBC, PSC, NASH, or HCC. This review aims to provide an update on the clinical development of both analogs and antagonists targeting the FGF19-FGFR4 signaling pathway for patients with cholestatic, metabolic, and cancer diseases. We will also analyze potential safety and mechanistic concerns that should guide future research and advanced trials.

Constipation is a prevalent gastrointestinal symptom that can considerably affect a patients' quality of life. Although several drugs have been used to treat constipation, they are associated with high costs, side effects, and low universality. Therefore, alternative intervention strategies are urgently needed. Traditional lactic acid bacteria (LAB), such as Bifidobacterium and Lactobacillus, play a vital role in regulating intestinal microecology and have demonstrated favorable effects in constipation; however, a comprehensive review of their constipation relief mechanisms is limited. This review summarizes the pathogenesis of constipation and the relationship between intestinal motility and gut microbiota, elucidates the possible mechanism by which LAB alleviates of constipation through a systematic summary of animal and clinical research, and highlights the challenges and applications of LAB in the treatment of constipation. Our review can improve our understanding of constipation, and advance targeted microecological therapeutic agents, such as LAB.

Constipation and systemic inflammation are common in late pregnant and lactating sows, which cause health problems like uteritis, mastitis, dystocia, or even stillbirth, further influencing piglets' survival and growth. Probiotic supplementation can improve such issues, but the beneficial mechanism of relieving constipation and enhancing gut motility remains underexplored. This study aimed to investigate the effects and mechanism of probiotic supplementation in drinking water to late pregnant sows on constipation, inflammation, and piglets' growth performance. Seventy-four sows were randomly allocated to probiotic (n = 36) and control (n = 38) groups. Probiotic treatment significantly relieved sow constipation, enhanced serum IL-4 and IL-10 levels while reducing serum IL-1β, IL-12p40, and TNF-α levels, and increased piglet daily gain and weaning weight. Furthermore, probiotic administration reshaped the sow gut bacteriome and phageome structure/diversity, accompanied by increases in some potentially beneficial bacteria. At 113 days of gestation, the probiotic group was enriched in several gut microbial bioactive metabolites, multiple carbohydrate-active enzymes that degrade pectin and starch, fecal butyrate and acetate, and some serum metabolites involved in vitamin and amino acid metabolism. Our integrated correlation network analysis revealed that the alleviation of constipation and inflammation was associated with changes in the sow gut bacteriome, phageome, bioactive metabolic potential, and metabolism.

Bile acid diarrhoea (BAD) is debilitating yet treatable, but it remains underdiagnosed due to challenging diagnostics. We developed a blood test-based method to guide BAD diagnosis.

We included serum from 50 treatment-naive patients with BAD diagnosed by gold standard 75selenium homotaurocholic acid test, 56 feature-matched controls and 37 patients with non-alcoholic fatty liver disease (NAFLD). Metabolomes were generated using mass spectrometry covering 1295 metabolites and compared between groups. Machine learning was used to develop a BAD Diagnostic Score (BDS).

Metabolomes of patients with BAD significantly differed from controls and NAFLD. We detected 70 metabolites with a discriminatory performance in the discovery set with an area under receiver-operating curve metric above 0.80. Logistic regression modelling using concentrations of decanoylcarnitine, cholesterol ester (22:5), eicosatrienoic acid, L-alpha-lysophosphatidylinositol (18:0) and phosphatidylethanolamine (O-16:0/18:1) distinguished BAD from controls with a sensitivity of 0.78 (95% CI 0.64 to 0.89) and a specificity of 0.93 (95% CI 0.83 to 0.98). The model was independent of covariates (age, sex, body mass index) and distinguished BAD from NAFLD irrespective of fibrosis stage. BDS outperformed other blood test-based tests (7-alpha-hydroxy-4-cholesten-3-one and fibroblast growth factor 19) currently under development.

BDS derived from serum metabolites in a single-blood sample showed robust identification of patients with BAD with superior specificity and sensitivity compared with current blood test-based diagnostics.

Bile acid diarrhea (BAD) is characterized by increased frequency of bowel movements, looser stool consistency, urgency, and need for proximity to toilet facilities owing to the severity of the diarrhea, when compared with or relative to irritable bowel syndrome with diarrhea. Consequently, BAD leads to decreased quality of life. The condition is often misdiagnosed as irritable bowel syndrome with diarrhea or functional diarrhea. Patients with BAD have accelerated colonic transit, increased intestinal or colonic mucosal permeability, and altered stool microbiome composition associated with reduced dehydroxylation of primary to secondary bile acids. The established diagnostic test, selenium-75 homocholic acid taurine retention, is not available in the United States. Therefore, 48-hour fecal bile acid excretion has been the gold standard for diagnosis. With recent validation of combined measurement of primary bile acids in a single, random stool in addition to fasting serum 7α-hydroxy-4-cholesten-3-one, a practical point-of-care diagnostic test will soon be available. Randomized controlled trials have documented superiority of colesevelam to placebo and, in a separate study, superiority of the glucagon-like peptide 1 agonist liraglutide compared with colesevelam. Novel experimental approaches for BAD include farnesoid X receptor agonists and fibroblast growth factor 19 analogs. This article updates information on the pathophysiology, mechanisms, manifestations, diagnosis, and treatment of BAD.

Diet is an important determinant of health and consequently is often implicated in the development of disease, particularly gastrointestinal (GI) diseases, given the high prevalence of meal-related symptoms. The mechanisms underlying diet-driven pathophysiology are not well understood, but recent studies suggest that gut microbiota may mediate the effect of diet on GI physiology. In this review, we focus primarily on two distinct GI diseases where the role of diet has been best studied: irritable bowel syndrome and inflammatory bowel disease. We discuss how the concurrent and sequential utilization of dietary nutrients by the host and gut microbiota determines the eventual bioactive metabolite profiles in the gut and the biological effect of these metabolites on GI physiology. We highlight several concepts that can be gleaned from these findings, such as how distinct effects of an individual metabolite can influence diverse GI diseases, the effect of similar dietary interventions on multiple disease states, and the need for extensive phenotyping and data collection to help make personalized diet recommendations.

Bile acid diarrhea (BAD) is a common but under-recognized gastrointestinal condition that manifests with increased stool frequency and urgency, and a looser stool consistency. The aim of this review is to present recent advances in the pathophysiology, mechanisms, manifestations, diagnosis, and treatment of BAD.

Patients with BAD have evidence of accelerated colonic transit, increased gut mucosal permeability, altered stool microbiome composition, and decreased quality of life. Single, random stool measurements of bile acids, alone or in combination with fasting serum 7-alpha-hydroxy-4-cholesten-3-one, have shown good sensitivity and specificity for the diagnosis of BAD. Novel therapeutic approaches include farnesoid X receptor agonists and glucagon-like peptide 1 agonists.

Recent research has led to a better understanding of the pathophysiology and mechanisms of BAD, which might pave the way towards more targeted treatment strategies for BAD. Newer, more affordable, and easier diagnostic methods facilitate the diagnosis of BAD.

Functional constipation is a common problem in childhood worldwide and has a great impact on social, physical, and emotional functioning of affected children and their caregivers. It is a clinical diagnosis based on the Rome IV criteria. Non-pharmacological treatment involves education, demystification, lifestyle advice, and toilet training. Pharmacological treatment consists of disimpaction, maintenance treatment, and eventually weaning if possible. Polyethylene glycol is considered as the first choice of laxative for both disimpaction and maintenance treatment. Different osmotic laxatives, stimulant laxatives, lubricants, and enemas are available as alternative pharmacological treatment options. Novel drugs are emerging but evidence to support the widespread application of these drugs in the pediatric population is often lacking and more high-quality research is needed in this field. If children remain symptomatic despite optimal pharmacological treatment, botulinum toxin injections in the anal sphincter can be considered as an alternative, more invasive treatment option. This review provides an update on currently available literature concerning the pharmacologic treatment of functional constipation in children.

The irritable bowel syndrome (IBS) is a chronic disorder of gut-brain interaction. IBS is still associated with areas of uncertainties, especially regarding the optimal diagnostic work-up and the more appropriate management. Experts from 7 Italian Societies conducted a Delphi consensus with literature summary and voting process on 27 statements. Recommendations and quality of evidence were evaluated using the grading of recommendations, assessment, development, and evaluation (GRADE) criteria. Consensus was defined as >80% agreement and reached for all statements. In terms of diagnosis, the consensus supports a positive diagnostic strategy with a symptom-based approach, including the psychological comorbidities assessment and the exclusion of alarm symptoms, together with the digital rectal examination, full blood count, C-reactive protein, serology for coeliac disease, and fecal calprotectin assessment. Colonoscopy should be recommended in patients with alarm features. Regarding treatment, the consensus strongly supports a dietary approach for patients with IBS, the use of soluble fiber, secretagogues, tricyclic antidepressants, psychologically directed therapies and, only in specific IBS subtypes, rifaximin. A conditional recommendation was achieved for probiotics, polyethylene glycol, antispasmodics, selective serotonin reuptake inhibitors and, only in specific IBS subtypes, 5-HT3 antagonists, 5-HT4 agonists, bile acid sequestrants.

Constipation can seriously affect the quality of life and increase the risk of colorectal cancer. The present strategies for constipation therapy have adverse effects, such as causing irreversible intestinal damage and affecting the absorption of nutrients. Nanocrystalline cellulose (NCC), which is from natural plants, has good biocompatibility and high safety. Herein, we used NCC to treat constipation assessed by the black stool, intestinal tissue sections, and serum biomarkers. We studied the effect of NCC on gut microbiota and discussed the correlation of gut microbiota and metabolites. We evaluated the long-term biosafety of NCC. NCC could effectively treat constipation through gut microbiota metabolism, which required a small dosage and did not affect the organs and intestines. NCC could be used as an alternative to medications and dietary fiber for constipation therapy.

High dropping moisture (DM) in poultry production has deleterious effects on the environment, feeding cost, and public health of people and animals. To explore the contributing genetic components, we classified DM of 67-wk-old Rhode Island Red (RIR) hens at 4 different levels and evaluated the underlying genetic heritability. We found the heritability of DM to be 0.219, indicating a moderately heritable trait. We then selected chickens with the highest and lowest DM levels. Using transcriptome, we only detected 12 differentially expressed genes (DEGs) between these 2 groups from the spleen, and 1,507 DEGs from intestinal tissues (jejunum and cecum). The low number of DEGs observed in the spleen suggests that differing moisture levels are not attributed to pathogenic infection. Fourteen of the intestinal high expressed genes are associated with water-salt metabolism (WSM). We also investigated the gut microbial composition by 16S rRNA gene amplicon sequencing. Six different microbial operational taxonomic units (OTUs) (Cetobacterium, Sterolibacterium, Elusimicrobium, Roseburia, Faecalicoccus, and Megamonas) between the 2 groups from jejunum and cecum are potentially biomarkers related to DM levels. Our results identify a genetic component to chicken DM, and can guide breeding strategies.

Bile acid diarrhoea (BAD) can be severely debilitating and negatively affect patients' quality of life (QoL). We carried out a multi-centre prospective study exploring QoL outcomes in patients with BAD after treatment with colesevelam.

Patients with or without a positive 23-seleno-25-homotaurocholic acid (SeHCAT) scan were recruited and categorised into four groups: SeHCAT negative control group (CG), idiopathic BAD, post-cholecystectomy (PC) and post-terminal ileal resection for Crohn's disease (CD). Patients with a positive SeHCAT were treated with colesevelam and dosing was titrated to symptomatic response. Patients were reviewed at 4- and 8-weekly intervals and QoL was evaluated by EQ-5D-3L, SF-36, IBDQ-32 at each visit (where relevant). Patients with a negative SeHCAT (CG cohort) completed one set of questionnaires before being discharged from the study.

47 patients (BAD = 24, PC = 12, CD = 11) completed paired QoL questionnaires before and after treatment and 30 CG patients completed a baseline questionnaire. There was a significant improvement in IBDQ-32 mean scores before and after treatment in CD patients [134.6 (95%CI 112.5-156.6) and 158.4 (136.1-180.6), respectively (p = 0.007). Following treatment, BAD patients had significantly improved mean SF-36 scores in the "Role limitation due to physical health" dimension (p = 0.02) and in the overall mental component summary (p = 0.03). Prior to starting treatment, BAD patients had the lowest scores in the 'activity' dimension of the EQ-5D-3L (p = 0.04), which improved significantly after treatment (p = 0.002). Overall, the BAD and CD cohort showed improved mean scores with treatment in all components of the SF-36 and EQ-5D-3L, while the PC cohort showed a general decline in mean scores after treatment. 55% of patients clinically responded to treatment of which 41.7%, 58.3% and 81.8% responded from the BAD, PC and CD groups respectively. Correlations between those deemed as responders with improvements on the SF-36 and EQ-5D dimensions were not statistically significant.

Our results demonstrate improved QoL in the BAD and CD cohort with treatment. Further larger studies are recommended specifically investigating the PC cohort and whether patients may improve with newer treatments such as FXR agonists. Trial registration Ethical approval REC Ref: 16/LO/1325.

Patients with postoperative Crohn's disease are difficult to manage because of their risk of experiencing a more severe course, multiple symptom confounders, and poor sensitivity of symptomatic remission to rule out intestinal inflammation. In this group, data are lacking on biologic therapeutic efficacy, and recommendations are lacking for those with multiple medication failures. Novel noninvasive testing can simultaneously exclude alternate causes of symptoms (serum C4, fecal fat, small intestinal bowel overgrowth breath testing) and assess intestinal inflammation (fecal calprotectin, endoscopic healing index). In addition, endoscopy-based disease activity assessment and management are required. Endoscopy should be performed within 6 months of surgery, and aggressive disease activity monitoring can be considered with colonoscopy every 1-2 years subsequently to ensure late recurrence is detected. Patients with multiple resections should be screened for short bowel syndrome. Predictive biomarkers are needed to guide medication selection in this high-risk population. Postoperative prophylactic biologic therapy is prudent for patients with preoperative biologic failure. However, there are no high-quality data to guide which agent should be selected. Selecting biologics with an alternative mechanism of action in those who had failed a biologic with adequate drug concentrations and selection of different agents in those with previous intolerance are reasonable. Significantly more study is required to assess the efficacy of therapies in this setting.

Irritable bowel syndrome (IBS) is a common disorder of gut-brain interaction with an increasing prevalence, and its precise aetiology remains unclear. Gut microbiota dysbiosis has been found to be associated with IBS pathogenesis. In addition, a high incidence of bile acid diarrhoea and disturbed bile acid metabolism has been observed in IBS patients. The abundant microorganisms inhabited in human gut have essential functions in bile acid biotransformation, and can immensely affect the size and constitution of bile acid pool. Meanwhile, the alterations of bile acid profile can inversely interfere with the gut microbiota. This review discussed the role of intricate correlations between bile acids and gut microbiota in IBS pathogenesis and delineated the possible molecular mechanisms, mainly the signalling induced by farnesoid X receptor and transmembrane G protein-coupled receptor 5. Besides, some biomarkers for identifying bile acid diarrhoea in IBS population were listed, assisting the diagnosis and classification of IBS. Moreover, it also assessed some therapeutic strategies for IBS that regulate the bile acid-gut microbiota axis, such as dietary modulation, probiotics/prebiotics, faecal microbiota transplantation, and antibiotics. Collectively, this article illustrated the relationship between bile acids and gut microbiota in IBS pathophysiology and might offer some novel therapeutic options for IBS.

Bile acids are central to enterohepatic signaling pathways activated through natural receptors, farnesoid X receptor [FXR mediates synthesis of fibroblast growth factor-19 (FGF-19)], and G protein-coupled bile acid receptor 1 (GPBAR1, also known as TGR5). Although bile acid diarrhea (BAD) is more commonly encountered in ileal resection or disease, there is evidence documenting "idiopathic" BAD in about 20% of adolescents and 30% of adults presenting with chronic, non-bloody diarrhea often attributed to irritable bowel syndrome. Mechanism(s) leading to increased hepatic synthesis and colonic bile acid levels in "idiopathic" BAD include reduced synthesis of FGF-19 by the ileal mucosa, or genetic variation in hepatocyte proteins klotho β and FGF receptor 4 (FGFR4) that mediate negative feedback of bile acid synthesis.

The objective of this review is to summarize the diagnosis of BAD in adults and adolescents. In addition to ⁷⁵ SeHCAT retention for diagnosis of BAD, studies have validated fasting serum 7αC4 and FGF-19, respectively, by-product and inhibitor of hepatic bile acid synthesis, as well as fecal bile acid measurements. These assays are widely available through reference laboratories, and they are being simplified (eg, measurement of primary fecal bile acids in a random stool sample). BAD has also been identified as a co-factor contributing to persistent diarrhea in other diseases in remission including inflammatory bowel disease, microscopic colitis, celiac disease, and neuroendocrine tumors. In summary, advances in diagnosis of BAD provide opportunities for generalists and pediatric and adult gastroenterologists to provide targeted treatment for BAD presenting as chronic non-bloody diarrhea.

Bile acid malabsorption (BAM) is a debilitating disease characterized by loose stools and high stool frequency. The pathophysiology of BAM is not well-understood. We investigated postprandial enterohepatic and gluco-metabolic physiology, as well as gut microbiome composition and fecal bile acid content in patients with BAM.

Twelve participants with selenium-75 homocholic acid taurine test-verified BAM and 12 healthy controls, individually matched on sex, age, and body mass index, were included. Each participant underwent 2 mixed meal tests (with and without administration of the bile acid sequestrant colesevelam) with blood sampling and evaluation of gallbladder motility; bile acid content and microbiota composition were evaluated in fecal specimens.

Patients with BAM were characterized by increased bile acid synthesis as assessed by circulating 7-alpha-hydroxy-4-cholesten-3-one, fecal bile acid content, and postprandial concentrations of glucose, insulin, C-peptide, and glucagon. The McAuley index of insulin sensitivity was lower in patients with BAM than that in healthy controls. In patients with BAM, colesevelam co-administered with the meal reduced postprandial concentrations of bile acids and fibroblast growth factor 19 and increased 7-alpha-hydroxy-4-cholesten-3-one concentrations but did not affect postprandial glucagon-like peptide 1 responses or other gluco-metabolic parameters. Patients with BAM were characterized by a gut microbiome with low relative abundance of bifidobacteria and high relative abundance of Blautia, Streptococcus, Ruminococcus gnavus, and Akkermansia muciniphila.

Patients with BAM are characterized by an overproduction of bile acids, greater fecal bile acid content, and a gluco-metabolic profile indicative of a dysmetabolic prediabetic-like state, with changes in their gut microbiome composition potentially linking their enterohepatic pathophysiology and their dysmetabolic phenotype. ClinicalTrials.gov number NCT03009916.

Bile acids (BAs) are known to be important regulators of intestinal motility and epithelial fluid and electrolyte transport. Over the past two decades, significant advances in identifying and characterizing the receptors, transporters, and ion channels targeted by BAs have led to exciting new insights into the molecular mechanisms involved in these processes. Our appreciation of BAs, their receptors, and BA-modulated ion channels as potential targets for the development of new approaches to treat intestinal motility and transport disorders is increasing. In the current review, we aim to summarize recent advances in our knowledge of the different BA receptors and BA-modulated ion channels present in the gastrointestinal system. We discuss how they regulate motility and epithelial transport, their roles in pathogenesis, and their therapeutic potential in a range of gastrointestinal diseases.

Irritable bowel syndrome (IBS) is a common functional gastrointestinal disease that disturbs the physiology and psychology of patients and increases the burden on families, the healthcare system, society, and economic development, affecting more and more people around the world. Despite the multiple factors that account for IBS remaining incompletely studied, emerging evidence demonstrated the abnormal changes in gut microbiota and bile acids (BAs) metabolism closely associated with IBS. Moreover, microbiota drives significant modifications for BAs, consisting of deconjugation, 7α-dehydroxylation, oxidation, epimerization, desulfation, esterification, and so on, while BAs, in turn, affect the microbiota directly or indirectly. In light of the complex connection among gut microbiota, BAs, and IBS, it is urgent to review the latest research progress in this field. In this review, we described the disorders of intestinal microecology and BAs profiles in IBS-D and also highlighted the cross-talk between gut microbiota and BAs in the context of IBS-D. Integrating these, we suggest that new therapeutic strategies targeting the microbiota-BAs axis for IBS-D, even for other related diseases caused by bacteria-bile acid dysbiosis should be expected.

Functional gastrointestinal disorders (FGIDs) encompass a range of complex conditions with similar clinical characteristics and no overt pathology. Recent recognition of sub-clinical pathologies in FGIDs, in conjunction with physiological and biochemical abnormalities including increased intestinal permeability, microbial profile alterations, differences in metabolites and extra-intestinal manifestations of disease, call into question the designation of these conditions as 'functional'. This is despite significant heterogeneity in both symptom profile and specifics of reported physiological abnormalities hampering efforts to determine defined mechanisms that drive onset and chronicity of symptoms. Instead, the literature demonstrates these conditions are disorders of homeostatic imbalance, with disruptions in both host and microbial function and metabolism. This imbalance is also associated with extraintestinal abnormalities including psychological comorbidities and fatigue that may be a consequence of gastrointestinal disruption. Given the exploitation of such abnormalities will be crucial for improved therapeutic selection, an enhanced understanding of the relationship between alterations in function of the gastrointestinal tract and the response of the immune system is of interest in identifying mechanisms that drive FGID onset and chronicity. Considerations for future research should include the role of sex hormones in regulating physiological functions and treatment responses in patients, as well as the importance of high-level phenotyping of clinical, immune, microbial and physiological parameters in study cohorts. There is opportunity to examine the functional contribution of the microbiota and associated metabolites as a source of mechanistic insight and targets for therapeutic modulation.

An increased intestinal permeability has been described in various gastrointestinal and non-gastrointestinal disorders. Nevertheless, the concept and definition of intestinal permeability is relatively broad and includes not only an altered paracellular route, regulated by tight junction proteins, but also the transcellular route involving membrane transporters and channels, and endocytic mechanisms. Paracellular intestinal permeability can be assessed in vivo by using different molecules (e.g., sugars, polyethylene glycols, ⁵¹Cr-EDTA) and ex vivo in Ussing chambers combining electrophysiology and probes of different molecular sizes. The latter is still the gold standard technique for assessing the epithelial barrier function, whereas in vivo techniques, including putative blood biomarkers such as intestinal fatty acid-binding protein and zonulin, are broadly used despite limitations. In the second part of the review, the current evidence of the role of impaired barrier function in the pathophysiology of selected gastrointestinal and liver diseases is discussed. Celiac disease is one of the conditions with the best evidence for impaired barrier function playing a crucial role with zonulin as its proposed regulator. Increased permeability is clearly present in inflammatory bowel disease, but the question of whether this is a primary event or a consequence of inflammation remains unsolved. The gut-liver axis with a crucial role in impaired intestinal barrier function is increasingly recognized in chronic alcoholic and metabolic liver disease. Finally, the current evidence does not support an important role for increased permeability in bile acid diarrhea.

To compare both the faecal bile acids (BAs) and the levels of two bile acid receptors, Takeda G protein-coupled receptor 5 (TGR5) and vitamin D receptor (VDR), in the colonic mucosa between patients with irritable bowel syndrome with predominant diarrhea (IBS-D) and healthy controls, and explore the correlations among clinical characteristics, bile acid receptors expression, and BAs.

The severity of abdominal pain and diarrhoea was assessed in IBS-D patients using validated questionnaires, faecal BAs were measured by ultraperformance liquid chromatography coupled to tandem mass spectrometry, and rectosigmoid biopsies were taken for the analyses of TGR5 and VDR expression using immunohistochemistry.

The level of TGR5 immunoreactivity in rectosigmoid mucosal biopsies was significantly higher in IBS-D patients than in controls, while the VDR immunoreactivity displayed no significant difference between patients and controls. The patients with more severe or more frequent abdominal pain had significantly higher TGR5 level. Faecal primary BAs were significantly increased in IBS-D patients and were positively correlated with the severity of diarrhoea. The level of TGR5 was positively associated with primary BAs and negatively associated with secondary BAs among all participants providing both mucosal and stool samples.

Colonic mucosal TGR5 protein expression and faecal bile acids were correlated with the symptom severity of IBS-D patients.

Gut motility is regulated by the microbiome via mechanisms that include bile acid metabolism. To localize the effects of microbiome-generated bile acids, we colonized gnotobiotic mice with different synthetic gut bacterial communities that were metabolically phenotyped using a functional in vitro screen. Using two different marker-based assays of gut transit, we inferred that bile acids exert effects on colonic transit. We validated this using an intra-colonic bile acid infusion assay and determined that these effects were dependent upon signaling via the bile acid receptor, TGR5. The intra-colonic bile acid infusion experiments further revealed sex-biased bile acid-specific effects on colonic transit, with lithocholic acid having the largest pro-motility effect. Transcriptional responses of the enteric nervous system (ENS) were stereotypic, regional, and observed in response to different microbiota, their associated bile acid profiles, and even to a single diet ingredient, evidencing exquisite sensitivity of the ENS to environmental perturbations.

Excessive fecal bile acids in adults have been associated with diarrhea-predominant irritable bowel syndrome (IBS-D), but their role in pediatric IBS-D is unknown. Serum markers including 7α-hydroxy-4-cholesten-3-one (C4) and fibroblast growth factor-19 (FGF-19) were validated in adults to detect bile acid diarrhea (BAD) compared to 48-hour fecal bile acid collection (48FBA). Our aims were to assess fasting serum C4 and FGF-19 and 48FBA in a pediatric population, to compare measurements in IBS-D patients and healthy controls (HC), and to determine the prevalence of BAD among children with IBS-D.

Using a cross-sectional design, 26 patients with IBS-D and 56 HC were recruited in two pediatric tertiary care centers. Fasting serum C4 and FGF-19 and 48FBA were obtained. Participants completed a 7-day bowel diary coinciding with stool collection. Associations were analyzed using Spearman correlations.

Mean age was 14.7 ± 2.5 years (42.3% female) in IBS-D and 12.6 ± 2.4 years (39.3% female) in HC. There was a significant correlation of C4 with 48FBA (r = 0.48, P < 0.05) and an inverse association with FGF-19 (r = -0.43, P < 0.05). No significant differences were noted in C4 (P = 0.32), FGF-19 (P = 0.1), or 48FBA (P = 0.5) between IBS-D and HC groups; however, 20% of IBS-D patients had elevated C4 and 28% had low FGF-19 values.Fecal primary BA was significantly correlated with stool frequency (r = 0.45, P < 0.002).

Correlations of C4 with 48FBA and FGF-19 are confirmed in a pediatric population. Twenty percent of pediatric patients with IBS-D had abnormal fasting serum C4. This serum test could be applied to identify BAD in pediatric IBS-D.

Chronic constipation is one of the five most common symptoms seen by gastroenterologist. In the absence of alarm symptoms, a confident symptom-based diagnosis can often be made using the Rome criteria. Three different subtypes have been identified to date: normal transit constipation, defaecatory disorders and slow transit constipation. Differentiation between these subtypes can be made through functional testing using tests such as anorectal manometry with balloon expulsion and a radio-opaque marker test. In general, patients are initially advised to increase their fluid and fibre intake. When these general lifestyle recommendations do not improve patients' symptoms, a step-wise and add-on treatment approach should be applied. This review summarises the diagnostic criteria to differentiate functional constipation from other causes of chronic constipation. In addition, current drug treatment options, including discussion of new therapeutic targets are discussed. Further, practical treatment approaches (choice and dosing), include discussion of combination/augmentation, treatment failure (adherence/expectations), and relapse prevention are mentioned. Finally, treatment and management of pain and bloating aspects are included.

Bile acids (BAs) have attracted attention in the research of irritable bowel syndrome with predominant diarrhea (IBS-D) due to their ability to modulate bowel function and their tight connection with the gut microbiota. The composition of the fecal BA pool in IBS-D patients is reportedly different from that in healthy populations. We hypothesized that BAs may participate in the pathogenesis of IBS-D and the altered BA profile may be correlated with the gut microbiome.

To investigate the role of BAs in the pathogenesis of IBS-D and the correlation between fecal BAs and gut microbiota.

Fifty-five IBS-D patients diagnosed according to the Rome IV criteria and twenty-eight age-, sex-, and body mass index-matched healthy controls (HCs) were enrolled in this study at the gastroenterology department of China-Japan Friendship Hospital. First, clinical manifestations were assessed with standardized questionnaires, and visceral sensitivity was evaluated via the rectal distension test using a high-resolution manometry system. Fecal primary BAs including cholic acid (CA) and chenodeoxycholic acid (CDCA), secondary BAs including deoxycholic acid (DCA), lithocholic acid (LCA), and ursodeoxycholic acid (UDCA) as well as the corresponding tauro- and glyco-BAs were examined by ultraperformance liquid chromatography coupled to tandem mass spectrometry. The gut microbiota was analyzed using 16S rRNA gene sequencing. Correlations between fecal BAs with clinical features and gut microbiota were explored.

Fecal CA (IBS-D: 3037.66 [282.82, 6917.47] nmol/g, HC: 20.19 [5.03, 1304.28] nmol/g; P < 0.001) and CDCA (IBS-D: 1721.86 [352.80, 2613.83] nmol/g, HC: 57.16 [13.76, 1639.92] nmol/g; P < 0.001) were significantly increased, while LCA (IBS-D: 1621.65 [58.99, 2396.49] nmol/g, HC: 2339.24 [1737.09, 2782.40]; P = 0.002] and UDCA (IBS-D: 8.92 [2.33, 23.93] nmol/g, HC: 17.21 [8.76, 33.48] nmol/g; P = 0.025) were significantly decreased in IBS-D patients compared to HCs. Defecation frequency was positively associated with CA (r = 0.294, P = 0.030) and CDCA (r = 0.290, P = 0.032) and negatively associated with DCA (r = -0.332, P = 0.013) and LCA (r = -0.326, P = 0.015) in IBS-D patients. In total, 23 of 55 IBS-D patients and 15 of 28 HCs participated in the visceral sensitivity test. The first sensation threshold was negatively correlated with CDCA (r = -0.459, P = 0.028) in IBS-D patients. Furthermore, the relative abundance of the family Ruminococcaceae was significantly decreased in IBS-D patients (P < 0.001), and 12 genera were significantly lower in IBS-D patients than in HCs (P < 0.05), with 6 belonging to Ruminococcaceae. Eleven of these genera were negatively correlated with primary BAs and positively correlated with secondary BAs in all subjects.

The altered metabolism of BAs in the gut of IBS-D patients was associated with diarrhea and visceral hypersensitivity and might be ascribed to dysbiosis, especially the reduction of genera in Ruminococcaceae.

Approximately one-third of patients with IBS-diarrhea (IBS-D) have increased bile acid (BA) synthesis or excretion. An open-label study showed benefits of colesevelam on bowel functions, consistent with luminal BA sequestration by colesevelam. We compared the effects of colesevelam vs placebo on symptoms and gene expression patterns in the sigmoid colon mucosa in patients with BA diarrhea associated with IBS-D.

We performed a double-blind, parallel-group study of 30 adults with IBS-D and evidence of increased BA synthesis or fecal excretion, from December 2017 through December 2018 at a single center. Patients were randomly assigned (1:1) to groups given colesevelam (3 tablets, 625 mg each) or matching placebo, orally twice daily for 4 weeks. Stool diaries documented bowel functions for 8 days before and 28 days during colesevelam or placebo. Stool and fasting serum samples were collected for analyses of fecal BAs and serum levels of C4 and FGF19. We measured colonic transit by scintigraphy, mucosal permeability by in vivo excretion of saccharide probes, and mRNA levels in rectosigmoid biopsies. All measurements were made at baseline and on the last days of treatment. The primary endpoints were change in total fecal BA concentration and stool consistency.

Compared with placebo, colesevelam was associated with significant changes in sequestered fecal total BA excretion (P < .001) and serum levels of C4 and FGF19 (both P < .001), and with a mean increase in fecal level of deoxycholic acid (10%; P = .07) compared to placebo. Colesevelam decreased colon mucosal expression of NR1H4 and P2RY4 and increased expression of GPBAR1, compared with baseline. Stool frequency and consistency, colonic transit, and permeability did not differ significantly between groups. Colesevelam was well tolerated.

In a randomized trial, we found that colesevelam increases delivery of total and secondary BAs to stool, hepatic BA synthesis, and colonic mucosal expression of genes that regulate BA, farnesoid X, and GPBAR1 receptors. Larger studies are needed to determine the effects on clinical responses. ClinicalTrials.gov no: NCT03270085.