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Chenodeoxycholate in Females With Irritable Bowel Syndrome-Constipation: A Pharmacodynamic and Pharmacogenetic Analysis
Abstract
Sodium chenodeoxycholate (CDC) accelerates colonic transit in health. Our aim was to examine pharmacodynamics (colonic transit, bowel function) and pharmacogenetics of CDC in constipation-predominant irritable bowel syndrome (IBS-C).
In a double-blind placebo-controlled study, 36 female patients with IBS-C were randomized to treatment with delayed-release oral formulations of placebo, 500 mg CDC, or 1000 mg CDC for 4 days. We assessed gastrointestinal and colonic transit, stool characteristics, and associations of transit with fasting serum 7αC4 (surrogate of bile acid synthesis) and FGF19 (negative regulator of bile acid synthesis) levels. Candidate genetic polymorphisms involved in regulation of bile acid synthesis were analyzed in the 36 patients with IBS-C and 57 healthy volunteers to assess genetic influence on effects of CDC on transit.
Overall colonic transit and ascending colon emptying (AC t(½)) were significantly accelerated in the CDC group compared with placebo (P = .005 and P = .028, respectively). Looser stool consistency (P = .003), increased stool frequency (P = .018), and greater ease of passage (P = .024) were noted with CDC compared with placebo. The most common side effect was lower abdominal cramping/pain (P = .01). Fasting serum 7αC4 (but not FGF19) was positively associated with colonic transit (r(s) = 0.749, P = .003, placebo group). Genetic variation in FGFR4 was associated with AC t(½) in response to CDC (uncorrected P = .015); αKlothoβ variant showed a gene-by-treatment interaction based on patient subgroup (uncorrected P = .0088).
CDC accelerates colonic transit and improves bowel function in female patients with IBS-C. The rate of bile acid synthesis influences colonic transit. Genetic variation in negative feedback inhibition of bile acid synthesis may affect CDC-mediated acceleration of colonic transit.
... Interventional studies delivering secretory BAs such as CDCA, used for the resolution of bile stones, have shown to increase GI motility and loosen stool consistency (8). In female patients suffering from IBS-C, 500-1,000 mg sodium chenodeoxycholate (CDC), delivered as a Eudragit S100-coated capsule formulation, was effective in treating symptoms of IBS-C (9). Among other end points, CDC accelerated colonic transit, increased stool frequency, and loosened stool consistency compared with the control group receiving no treatment. ...
... BA, bile acid. In vitro release pattern of (a) 1 g CDC capsules (used in a clinical front-runner study (9) linked to a high frequency of abdominal pain), (d) bilayered delivery systems, and (g) single-layered delivery systems (serving as control for a conventional extended release delivery system exposed to SGF [ ). An in silico pharmacokinetic model was used to understand the CDC levels over time in the colon for (b) 1 g CDC capsule, (e) the bilayered delivery system (32), and the (h) single-layered delivery system (32). ...
... A clinical challenge of colonic CDC delivery is noticeable abdominal cramping and pain in patients (9). We had hypothesized that this symptom was because of massive contractions triggered by local superphysiological CDC levels within the proximal colon. ...
Introduction:
Bile acids, such as chenodeoxycholic acid, play an important role in digestion but are also involved in intestinal motility, fluid homeostasis, and humoral activity. Colonic delivery of sodium chenodeoxycholate (CDC) has demonstrated clinical efficacy in treating irritable bowel syndrome with constipation but was associated with a high frequency of abdominal pain. We hypothesized that these adverse effects were triggered by local super-physiological CDC levels caused by an unfavorable pharmacokinetic profile of the delayed release formulation.
Methods:
We developed novel release matrix systems based on hydroxypropyl methylcellulose (HPMC) for sustained release of CDC. These included standard HPMC formulations as well as bi-layered formulations to account for potential delivery failures due to low colonic fluid in constipated patients. We evaluated CDC release profiles in silico (pharmacokinetic modeling), in vitro and in vivo in swine (pharmacokinetics, rectal manometry).
Results:
For the delayed release formulation in vitro release studies demonstrated pH triggered dose dumping which was associated with giant colonic contractions in vivo. Release from the bi-layered HPMC systems provided controlled release of CDC while minimizing the frequency of giant contractions and providing enhanced exposure as compared to standard HPMC formulations in vivo.
Discussion:
Bi-phasic CDC release could help treat constipation while mitigating abdominal pain observed in previous clinical trials. Further studies are necessary to demonstrate the therapeutic potential of these systems in humans.
... Sodium chenodeoxycholate (NaCDC) is a hydrophobic di-alpha hydroxy bile salt [67][68][69]. Its beneficial effect in IBS-C associates with the overall influence of bile acids on GI motility [67,68]. ...
... Sodium chenodeoxycholate (NaCDC) is a hydrophobic di-alpha hydroxy bile salt [67][68][69]. Its beneficial effect in IBS-C associates with the overall influence of bile acids on GI motility [67,68]. ...
... What is more, patients reported looser stool consistency, increased stool frequency and greater ease of passage. The most common side effect was decrease in abdominal pain (P = 0.01) [67,68]. ...
Introduction: Irritable bowel syndrome (IBS) is a complex functional gut disorder that typically manifests in early adult years. More than a third of IBS patients are diagnosed with predominant constipation subtype (IBS-C). This syndrome has a distressing impact on the quality of life and is challenging both for patients and physicians.
Areas covered: This review focuses on the pathophysiology of constipation in IBS and presents current management options. It also covers the latest findings that may lead to novel pharmacological options in IBS-C management. The authors intend to highlight the results of published research including abstracts, records from the clinicaltrials.gov database (second and third phases of the study) and information from original FDA documents.
Expert opinion: Current therapeutic options for IBS-C treatment are based on linaclotide, lubiprostone, plecanatide, and the reintroduced tegaserod. Drugs present on the market as well as those in pre-clinical development should increase the lower esophageal sphincter pressure, promote gastric motility, accelerate gastric emptying and improve gastro-duodenal coordination. Most significantly, they shall not induce severe side effects.
... In an RCT in female IBS-C patients, CDCA administration dose-dependently accelerated colonic transit and improved stool frequency and form compared with placebo [156]. Elobixibat interrupts the enterohepatic circulation of BAs, thereby upregulating hepatic BA synthesis. ...
... Intestinal secretagogues (gastrointestinal epithelium modifiers) [149][150][151][152][153]234] are indicated for cases with IBS-C or constipation as the main feature. Laxatives [162][163][164][165][166][167][168] except for long-term use of anthraquinones [169,170], bile acids [156], and ileal bile acid transporter inhibitors [157,158] are the next in line for IBS-C. In IBS-M, IBS-U, or abdominal pain-dominant cases, anticholinergic agents can be used [103,[108][109][110][111]. In some cases, kampo [191][192][193][194][195][196], anti-allergic agents [200,201], antibiotics [202][203][204][205], or peppermint oil [207][208][209][210] may be administered. ...
Managing irritable bowel syndrome (IBS) has attracted international attention because single-agent therapy rarely relieves bothersome symptoms for all patients. The Japanese Society of Gastroenterology (JSGE) published the first edition of evidence-based clinical practice guidelines for IBS in 2015.
Much more evidence has accumulated since then, and new pharmacological agents and non-pharmacological methods have been developed. Here, we report the second edition of the JSGE-IBS guidelines comprising 41 questions including 12 background questions on epidemiology, pathophysiology, and diagnostic criteria, 26 clinical questions on diagnosis and treatment, and 3 questions on future research. For each question, statements with or without recommendations and/or evidence level are given and updated diagnostic and therapeutic algorithms are provided based on new evidence.
Algorithms for diagnosis are requisite for patients with chronic abdominal pain or associated symptoms and/or abnormal bowel movement. Colonoscopy is indicated for patients with one or more alarm symptoms/signs, risk factors, and/or abnormal routine examination results. The diagnosis is based on the Rome IV criteria. Step 1 therapy consists of diet therapy, behavioral modification, and gut-targeted pharmacotherapy for 4 weeks. For non-responders, management proceeds to step 2 therapy, which includes a combination of different mechanistic gut-targeted agents and/or psychopharmacological agents and basic psychotherapy for 4 weeks. Step 3 therapy is for non-responders to step 2 and comprises a combination of gut-targeted pharmacotherapy, psychopharmacological treatments, and/or specific psychotherapy. These updated JSGE-IBS guidelines present best practice strategies for IBS patients in Japan and we believe these core strategies can be useful for IBS diagnosis and treatment globally.
... In the CDCA experiment, conventional male Wistar rats aged 7 weeks (200 ± 20 g) were randomly divided into two groups (n = 5 per group), the CDCA group (CDCA) was administered gavage CDCA for 4 weeks at a dose of 160 mg/kg (15), and the NC group (NC) was given an equal dose of physiological saline. Other feeding conditions are consistent with the above. ...
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.
IMPORTANCE
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.
... Several engineered FGF19 analogs have been evaluated in clinical trials in patients with primary sclerosing cholangitis or non-alcoholic steatohepatitis (NASH) Hirschfield et al., 2019;Sanyal et al., 2021). Strategies targeting modulating FGF19/FXR signaling, such as FXR agonists, assessed FGF19 levels as endpoints in clinical studies in patients with NASH, primary BA diarrhea or bowel syndrome (Rao et al., 2010;Sanyal et al., 2023;Walters et al., 2015). Inhibition of FGF19/FGFR4 signaling including genetic deletion and application of FGFR4 neutralizing antibody has been identified to prevent hepatocellular carcinoma development in preclinical animal models (Desnoyers et al., 2008;French et al., 2012). ...
The circadian clock is an endogenous biochemical timing system that coordinates the physiology and behavior of organisms to earth's ∼24-hour circadian day/night cycle. The central circadian clock synchronized by environmental cues hierarchically entrains peripheral clocks throughout the body. The circadian system modulates a wide variety of metabolic signaling pathways to maintain whole-body metabolic homeostasis in mammals under changing environmental conditions. Endocrine fibroblast growth factors (FGFs), namely FGF15/19, FGF21, and FGF23, play an important role in regulating systemic metabolism of bile acids, lipids, glucose, proteins, and minerals. Recent evidence indicates that endocrine FGFs function as nutrient sensors that mediate multifactorial interactions between peripheral clocks and energy homeostasis by regulating the expression of metabolic enzymes and hormones. Circadian disruption induced by environmental stressors or genetic ablation is associated with metabolic dysfunction and diurnal disturbances in FGF signaling pathways that contribute to the pathogenesis of metabolic diseases. Time-restricted feeding strengthens the circadian pattern of metabolic signals to improve metabolic health and prevent against metabolic diseases. Chronotherapy, the strategic timing of medication administration to maximize beneficial effects and minimize toxic effects, can provide novel insights into linking biologic rhythms to drug metabolism and toxicity within the therapeutical regimens of diseases. Here we review the circadian regulation of endocrine FGF signaling in whole-body metabolism and the potential effect of circadian dysfunction on the pathogenesis and development of metabolic diseases. We also discuss the potential of chrononutrition and chronotherapy for informing the development of timing interventions with endocrine FGFs to optimize whole-body metabolism in humans. SIGNIFICANCE STATEMENT: The circadian timing system governs physiological, metabolic, and behavioral functions in living organisms. The endocrine fibroblast growth factor (FGF) family (FGF15/19, FGF21, and FGF23) plays an important role in regulating energy and mineral metabolism. Endocrine FGFs function as nutrient sensors that mediate multifactorial interactions between circadian clocks and metabolic homeostasis. Chronic disruption of circadian rhythms increases the risk of metabolic diseases. Chronological interventions such as chrononutrition and chronotherapy provide insights into linking biological rhythms to disease prevention and treatment.
... BAs can stimulate defecation by increasing the permeability of the intestinal mucosa and promoting the secretion of water in the intestinal lumen [53]. An inhibitor of the ileal bile acid transporter could alleviate constipation by inhibiting the reabsorption of bile acids and increasing the concentrations of BAs in the colon lumen [54,55]. In this study, we detected serum metabolites using untargeted metabolomic analysis through LC-MS/MS and found that 21 of the 28 BAs detected using untargeted metabolomics were increased in the LOP group compared to the CTR group. ...
Structural changes in the gut microbiota are closely related to the development of functional constipation, and regulating the gut microbiota can improve constipation. Rifaximin is a poorly absorbed antibiotic beneficial for regulating gut microbiota, but few studies have reported its effects on constipation. The purpose of this study was to investigate the effect of rifaximin on loperamide-induced constipation in SD rats. The results showed that rifaximin improved constipation by increasing serum 5-HT, SP, and the mRNA expression of AQP3, AQP8, and reducing the mRNA expression of TLR2 and TLR4. In addition, rifaximin could regulate the gut microbiota of constipated rats, such as increasing the potentially beneficial bacteria Akkermansia muciniphila and Lactobacillus murinus, reducing the Bifidobacterium pseudolongum. According to metabolomics analysis, many serum metabolites, including bile acids and steroids, were changed in constipated rats and were recovered via rifaximin intervention. In conclusion, rifaximin might improve loperamide-induced constipation in rats by increasing serum excitatory neurotransmitters and neuropeptides, modulating water metabolism, and facilitating intestinal inflammation. Muti-Omics analysis results showed that rifaximin has beneficial regulatory effects on the gut microbiota and serum metabolites in constipated rats, which might play critical roles in alleviating constipation. This study suggests that rifaximin might be a potential strategy for treating constipation.
... 2,9,10 Impairments within the EHC of BA have been linked to cholestatic drug-induced liver injury, chronic liver disease, cholesterol gallstone disease, malabsorption, dyslipidemia, and atherosclerosis. [11][12][13][14][15][16] In this context, the model was applied to predict the effect of BA malabsorption (BAM) as cause for idiopathic BA diarrhea (BAD) 43 and impairment of the intestinal barrier function-as 14,53,54 and overflow of reabsorption resulted in a strong accumulation of BAs in the LI lumen, whereas malabsorption in the terminal ileum without ileal or other obvious gastrointestinal (GI) disease did not suffice to induce BAD. 55 As a first assessment of a "leaky gut," the paracellular intestinal permeability was altered in all gut segments equally. ...
Bile acid (BA) metabolism is a complex system that includes a wide variety of primary and secondary, as well as conjugated and unconjugated BAs that undergo continuous enterohepatic circulation (EHC). Alterations in both composition and dynamics of BAs have been associated with various diseases. However, a mechanistic understanding of the relationship between altered BA metabolism and related diseases is lacking. Computational modeling may support functional analyses of the physiological processes involved in the EHC of BAs along the gut-liver axis. In this study, we developed a physiologically based model of murine BA metabolism describing synthesis, hepatic and microbial transformations, systemic distribution, excretion, and EHC of BAs at the whole-body level. For model development, BA metabolism of specific pathogen-free (SPF) mice was characterized in vivo by measuring BA levels and composition in various organs, expression of transporters along the gut, and cecal microbiota composition. We found significantly different BA levels between male and female mice that could only be explained by adjusted expression of the hepatic enzymes and transporters in the model. Of note, this finding was in agreement with experimental observations. The model for SPF mice could also describe equivalent experimental data in germ-free mice by specifically switching off microbial activity in the intestine. The here presented model can therefore facilitate and guide functional analyses of BA metabolism in mice, e.g., the effect of pathophysiological alterations on BA metabolism and translation of results from mouse studies to a clinically relevant context through cross-species extrapolation.
... Bile salts comprise free bile acids. Chenodeoxycholic acid is a primary bile acid that improves colonic transit times and increases the number of bowel movement in adults [97,98]. Fecal bile acid composition was determined in 165 children with and without FC in an observational study [99]. ...
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.
... 130 Furthermore, oral administration of CDCA improved bowel function in patients with either IBS-C or chronic constipation. 131,132 BAs can also affect gut sensitivity. Rectal infusion of DCA and CDCA at physiological concentrations reduces rectal sensory thresholds. ...
Gut microbiota and their metabolites like bile acid (BA) have been investigated as causes of irritable bowel syndrome (IBS) symptoms. Primary BAs are synthesized and conjugated in the liver and released into the duodenum. BA biotransformation by gut microbiota begins in the intestine and results in production of a broad range of secondary BAs. Deconjugation is considered the gateway reaction for further modification and is mediated by bile salt hydrolase, which is widely expressed by the gut microbiota. However, gut bacteria that convert primary BAs to secondary BAs belong to a limited number of species, mainly Clostridiales. Like gut microbiota modify BA profile, BAs can shape gut microbiota via direct and indirect actions. BAs have prosecretory effects and regulates gut motility. BAs can also affect gut sensitivity. Because of the vital role of the gut microbiota and BAs in gut function, their bidirectional relationship may contribute to the pathophysiology of IBS. Individuals with IBS have been reported to have altered microbial profiles and modified BA profiles. A significant increase in fecal primary BA and a corresponding decrease in secondary BA have been observed in IBS with predominant diarrhea. In addition, primary BA was positively correlated with IBS symptoms. In IBS with predominant diarrhea, bacteria with reduced abundance mainly belonged to the genera in Ruminococcaceae and exhibited a negative correlation with primary BAs. Integrating the analysis of the gut microbiota and BAs could better understanding of IBS pathophysiology. The gap in this field needs to be further filled in the future.
... Elobixibat resolved constipation in the short term (10 mg/day for 2 weeks) and was well tolerated with short-term and long-term (5 mg/day or 15 mg/ day, or maintain the 10 mg/day dose for 1 year) treatments resulting from a randomized, double-blind, placebo-controlled, phase 3 trial and an open-label, single-arm, phase 3 trial (Nakajima et al., 2018). In a double-blind placebo randomized controlled study of oral sodium CDCA (500 mg/day or 1,000 mg/day for 4 days) in the treatment of 36 female patients with constipation-predominant irritable bowel syndrome, it was found that compared with the control group, treatment with sodium CDCA could improve the clinical symptoms including accelerating the transit of the entire colon, increasing the defecation of the patients, and softening the feces to make it easier to excrete from the body (Rao et al., 2010). Evidence supported the use of increasing the concentration of endogenous BAs to treat chronic constipation. ...
Destructions in the intestinal ecosystem are implicated with changes in slow transit constipation (STC), which is a kind of intractable constipation characterized by colonic motility disorder. In order to deepen the understanding of the structure of the STC gut microbiota and the relationship between the gut microbiota and fecal metabolites, we first used 16S rRNA amplicon sequencing to evaluate the gut microbiota in 30 STC patients and 30 healthy subjects. The α-diversity of the STC group was changed to a certain degree, and the β-diversity was significantly different, which indicated that the composition of the gut microbiota of STC patients was inconsistent with healthy subjects. Among them, Bacteroides, Parabacteroides, Desulfovibrionaceae, and Ruminiclostridium were significantly upregulated, while Subdoligranulum was significantly downregulated. The metabolomics showed that different metabolites between the STC and the control group were involved in the process of bile acids and lipid metabolism, including taurocholate, taurochenodeoxycholate, taurine, deoxycholic acid, cyclohexylsulfamate, cholic acid, chenodeoxycholate, arachidonic acid, and 4-pyridoxic acid. We found that the colon histomorphology of STC patients was significantly disrupted, and TGR5 and FXR were significantly downregulated. The differences in metabolites were related to changes in the abundance of specific bacteria and patients’ intestinal dysfunction. Analysis of the fecal genomics and metabolomics enabled separation of the STC from controls based on random forest model prediction [STC vs. control (14 gut microbiota and metabolite biomarkers)—Sensitivity: 1, Specificity: 0.877]. This study provided a perspective for the diagnosis and intervention of STC related with abnormal bile acid metabolism.
... Function prediction of the gut Fig. 5 Metabolic pathways of potential biomarkers. 1. Taurine and hypotaurine metabolism; 2. primary bile acid biosynthesis; 3. arachidonic acid metabolism; 4. biosynthesis of unsaturated fatty acids; 5. steroid hormone biosynthesis; 6. sphingolipid metabolism; 7. α-Linolenic acid metabolism; 8. steroid biosynthesis microbiota also indicated that primary bile acid biosynthesis was increased by rhubarb in constipated rats, consistent with the results of pathway analysis in the fecal metabolome. Bile acids are natural laxatives that affect the colon secretion and promote the intestinal motility as prokinetic agents (Rao et al. 2010). Bile acids are synthesized in the liver and form conjugates with some amino acids. ...
Rhubarb, a traditional herb, has been used in clinical practice for hundreds of years to cure constipation, but its mechanism is still not clear enough. Currently, growing evidence suggests that intestinal flora might be a potential target for the treatment of constipation. Thus, the aim of this study was to clarify the laxative effect of rhubarb via systematically analyzing the metagenome and metabolome of the gut microbiota. In this study, the laxative effects of rhubarb were investigated by loperamide-induced constipation in rats. The gut microbiota was determined by high-throughput sequencing of 16S rRNA gene. Ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry was used for fecal metabolomics analysis. The data showed that rhubarb could significantly shorten gastrointestinal transit time, increase fecal water content and defecation frequency, improve gastrointestinal hormone disruption, and protect the colon mucus layer. Analysis of 16S rRNA gene sequencing indicated that rhubarb could improve the disorder of intestinal microbiota in constipated rats. For example, beneficial bacteria such as Ligilactobacillus, Limosilalactobacillus, and Prevotellaceae UCG-001 were remarkably increased, and pathogens such as Escherichia-Shigella were significantly decreased after rhubarb treatment. Additionally, the fecal metabolic profiles of constipated rats were improved by rhubarb. After rhubarb treatment, metabolites such as chenodeoxycholic acid, cholic acid, prostaglandin F2α, and α-linolenic acid were markedly increased in constipation rats; in contrast, the metabolites such as lithocholic acid, calcidiol, and 10-hydroxystearic acid were notably reduced in constipation rats. Moreover, correlation analysis indicated a close relationship between intestinal flora, fecal metabolites, and biochemical indices associated with constipation. In conclusion, the amelioration of rhubarb in constipation might modulate the intestinal microflora and its metabolism. Moreover, the application of fecal metabolomics could provide a new strategy to uncover the mechanism of herbal medicines.
Key points
• Rhubarb could significantly improve gut microbiota disorder in constipation rats.
• Rhubarb could markedly modulate the fecal metabolite profile of constipated rats.
... In addition, B. lactis HN019 TM may also influence gut motility via gut commensals, which are known to be involved in serotonin biosynthesis and bile acid metabolism (92,93). Bile salts are known to stimulate colonic contractility and transit in humans (94)(95)(96), where probiotic strains may deconjugate bile salts, leading to the formation of secondary bile salts with laxative effects (6). However, to date, no data is available on the ability of B. lactis HN019 TM to deconjugate bile salts. ...
Optimal gut motility is central to bowel function and gut health. The link between the gut dysmotility related disorders and dysfunctional-intestinal barriers has led to a hypothesis that certain probiotics could help in normalizing gut motility and maintain gut health. This review investigates the roles of Bifidobacterium animalis subsp. lactis HN019 (B. lactis HN019™) on gut health, and its mechanisms of action in various pre-clinical and clinical studies. Research supports the hypothesis that B. lactis HN019™ has a beneficial role in maintaining intestinal barrier function during gastrointestinal infections by competing and excluding potential pathogens via different mechanisms; maintaining normal tight junction function in vitro; and regulating host immune defense toward pathogens in both in vitro and human studies. This has been observed to lead to reduced incidence of diarrhea. Interestingly, B. lactis HN019™ also supports normal physiological function in immunosenescent elderly and competes and excludes potential pathogens. Furthermore, B. lactis HN019™ reduced intestinal transit time and increased bowel movement frequency in functional constipation, potentially by modulating gut–brain–microbiota axis, mainly via serotonin signaling pathway, through short chain fatty acids derived from microbial fermentation. B. lactis HN019™ is thus a probiotic that can contribute to relieving gut dysmotility related disorders.
... Fecal bile acids promote laxation [13,16]. The fecal concentration of CDCA and CA was higher in the combined diarrhea group (IBS-D + FD) compared to the combined constipation (IBS-C + FC) and healthy control groups, consistent with the findings of others [11,13]. ...
Bile acids are metabolites involved in nutrient absorption and signaling with levels influenced by dietary intake, metabolic processes, and the gut microbiome. We aimed to quantify 23 bile acids in fecal samples to ascertain if concentrations differed between healthy participants and those with functional gut disorders. Fecal bile acids were measured using liquid chromatography-mass spectrometry (LC-MS) in the COMFORT (The Christchurch IBS cohort to investigate mechanisms for gut relief and improved transit) cohort of 250 participants with Rome IV IBS (IBS-constipation (C), IBS-diarrhea (D), IBS-mixed (M)), functional gut disorders (functional constipation (FC), functional diarrhea (FD)) and healthy controls (FC n = 35, FD n = 13, IBS-C n = 24, IBS-D n = 52, IBS-M n = 29, and control n = 97). Dietary information was recorded to ascertain three-day dietary intake before fecal samples were collected. Fecal bile acid concentrations, predominantly primary bile acids, were significantly different between all functional gut disorder participants and healthy controls (CDCA p = 0.011, CA p = 0.003) and between constipation (FC + IBS-C) and diarrhea (FD + IBS-D) groups (CDCA p = 0.001, CA p = 0.0002). Comparison of bile acids between all functional groups showed four metabolites were significantly different, although analysis of combined groups (FC + IBS-C vs. FD + IBS-D) showed that 10 metabolites were significantly different. The bile acid profiles of FD individuals were similar to those with IBS-D, and likewise, those with FC were similar to IBS-C. Individuals with a diarrhea phenotype (FD + IBS-D) had higher concentrations of bile acids compared to those with constipation (FC + IBS-C). Bile acid metabolites distinguish between individuals with functional gut disorders and healthy controls but are similar in constipation (or diarrhea) whether classified as IBS or not.
... 26 Sodium chenodeoxycholate is a bile salt that can accelerate colonic transit times and improve stool consistency and frequency in patients with chronic constipation, including IBS-C. 106,107 Elobixibat (approved in Japan) is a minimally absorbed, highly selective ileal bile acid transporter inhibitor. By inhibiting the active reabsorption of bile acids in the ileum, elobixibat increases bile acid concentrations in the colon, promoting fluid secretion and motility. ...
Background:
Chronic constipation is a common, heterogeneous disorder with multiple symptoms and pathophysiological mechanisms. Patients are often referred to a gastroenterology provider after laxatives fail. However, there is limited knowledge of the spectrum and management of constipation disorders.
Aim:
To discuss the latest understanding of the spectrum of constipation disorders, tools for identifying a pathophysiologic-based diagnosis in the specialist setting, treatment options and the patient's perspective of constipation.
Methods:
Literature searches were conducted using PubMed for constipation diagnostic criteria, diagnostic tools and approved treatments. The authors provided insight from their own practices.
Results:
Clinical assessment, stool diaries and Rome IV diagnostic criteria can facilitate diagnosis, evaluate severity and distinguish between IBS with constipation, chronic idiopathic constipation and dyssynergic defecation. Novel smartphone applications can help track constipation symptoms. Rectal examinations, anorectal manometry and balloon expulsion, assessments of neuromuscular function with colonic transit time and colonic manometry can provide mechanistic understanding of underlying pathophysiology. Treatments include lifestyle and diet changes, biofeedback therapy and pharmacological agents. Several classes of laxatives, as well as prokinetic and prosecretory agents, are available; here we describe their mechanisms of action, efficacy and side effects.
Conclusions:
Constipation includes multiple overlapping subtypes identifiable using detailed history, current diagnostic tools and smartphone applications. Recognition of individual subtype(s) could pave the way for optimal, evidence-based treatments by a gastroenterology provider.
... Previous randomised, double-blind, placebo-controlled studies have shown that, when chenodeoxycholic acid was given to healthy volunteers and females with IBS-C, there was a significant acceleration of colonic transit, increased stool frequency and decreased stool consistency. 12,13 Alternatively, in patients with IBS-D, treatment with bile acid sequestrants was associated with delayed colonic transit and firmer stools. 12 These pharmacological studies illustrate the potential of bile acids to accelerate colonic transit and relieve constipation. ...
Background:
A subset of patients with chronic constipation has associated slow colonic transit and reduced faecal bile acid excretion. In addition to traditional approaches to treat chronic constipation, a novel therapeutic option is to increase the colonic concentration of intraluminal bile acids. This can be achieved through inhibition of the ileal bile acid transporter.
Aim:
To evaluate the evidence for efficacy and safety of an ileal bile acid transport inhibitor in the treatment of chronic constipation METHODS: We reviewed published literature on elobixibat, based on a PubMed search.
Results:
Elobixibat is a novel ileal bile acid transport inhibitor that has demonstrated efficacy in proof of concept studies in experimental animals as well as phase 1, 2 and 3 trials in humans. Phase 4 studies have now documented that the beneficial effects are related to increase in the secretory bile acids in the colon as measured by stool bile acid content. The studies documented efficacy in patients with severe constipation, which is often associated with slow colonic transit. These changes in bile acid composition were associated with minor differences in the faecal microbiota in patients treated with elobixibat compared to placebo. Elobixibat appears to be safe. The only adverse effects of note are associated with its pharmacological actions in patients with chronic constipation,namely the induction of diarrhoea and abdominal pain.
Conclusion:
This new class of compound appears to be safe and efficacious in the treatment of chronic constipation.
... In animal experiments, people found that DCA could induce colon net water secretion and have an excitatory effect on motility in the rat proximal colon [67,68]; that is one of the reasons of IBS-D [69,70]. Oral administration of CDCA could increase defecation fre-quency and accelerate colonic transit in a dose-dependent manner [69,71,72]. ...
The occurrence of diarrhea-predominant irritable bowel syndrome (IBS-D) is the result of multiple factors, and its pathogenesis has not yet been clarified. Emerging evidence indicates abnormal changes in gut microbiota and bile acid (BA) metabolism have a close relationship with IBS-D. Gut microbiota is involved in the secondary BA production via deconjugation, 7α-dehydroxylation, oxidation, epimerization, desulfation, and esterification reactions respectively. Changes in the composition and quantity of gut microbiota have an important impact on the metabolism of BAs, which can lead to the occurrence of gastrointestinal diseases. BAs, synthesized in the hepatocytes, play an important role in maintaining the homeostasis of gut microbiota and the balance of glucose and lipid metabolism. In consideration of the complex biological functional connections among gut microbiota, BAs, and IBS-D, it is urgent to review the latest research progress in this field. In this review, we summarized the alterations of gut microbiota in IBS-D and discussed the mechanistic connections between gut microbiota and BA metabolism in IBS-D, which may be involved in activating two important bile acid receptors, G-protein coupled bile acid receptor 1 (TGR5) and farnesoid X receptor (FXR). We also highlight the strategies of prevention and treatment of IBS-D via regulating gut microbiota-bile acid axis, including probiotics, fecal microbiota transplantation (FMT), cholestyramine, and the cutting-edge technology about bacteria genetic engineering.
... • Agonistas opioides (loperamida) (8). ...
El síndrome de intestino irritable se caracteriza por la existencia de dolor abdominal relacionado con cambios en el ritmo evacuatorio. A pesar de los avances en el conocimiento de su fisiopatología y de la aparición de nuevas formas terapéuticas, los antiespasmódicos se han mantenido en el tiempo como una forma efectiva para el manejo de los síntomas de este síndrome, en especial para el dolor. Así pues, el propósito de esta revisión es la búsqueda de evidencia científica que soporte el uso de antiespasmódicos en el manejo de los síntomas del síndrome de intestino irritable.
... Administration of a colonic release formulation of chenodeoxycholic acid was associated with acceleration of colonic transit, looser stool consistency, increased stool frequency and greater ease of passage in female patients with IBS-C. 52 Increasing colonic bile acids to relieve constipation was achieved with the ileal bile acid transport inhibitor, elobixibat, which accelerated colonic transit 53 and relieved constipation in a 2-week, randomised, placebo-controlled trial and during 52-week, open-label treatment. 54 Treatment with elobixibat in 19 patients with chronic constipation was associated with increased fasting serum C4, increased total and primary faecal bile acids, as well as improvement in the number of spontaneous and complete spontaneous bowel movements, stool consistency scores and other constipation-related symptoms to levels almost comparable to those of a control healthy subject cohort studied simultaneously. ...
... Primary bile acids, cholic acid and chenodeoxycholic acid, are derived from cholesterol by an enzymatic reaction occurring mainly in the liver [37] . Chenodeoxycholate has shown to increase colonic transit and improves bowel function [38] . Dietary cholic acid supplementation in rats caused a significant increase in colon tumors [39] . ...
Background:
Obesity is a risk factor for colorectal cancer, yet metabolic distinctions between healthy right and left colon tissue, before cancer is diagnosed, remains largely unknown. This study compared right-ascending and left-descending colon tissue metabolomes to identify differences from the stool metabolome in normal weight, overweight, and obese adults.
Aim:
To examine right and left colon tissue metabolites according to body mass index that may serve as mechanistic targets for interventions and biomarkers for colon cancer risk.
Methods:
Global, non-targeted metabolomics was applied to assess right-ascending and left-descending colon tissue collected from healthy adults undergoing screening colonoscopies to test the hypothesis that BMI differentially impacts colon tissue metabolite profiles. The colon tissue and stool metabolome of healthy adults (n = 24) was analyzed for metabolite signatures and metabolic pathway networks implicated in progression of colorectal cancer.
Results:
Ascending and descending colon contained 504 host, food, and microbiota-derived metabolites from normal weight, overweight and obese adults grouped according to body mass index. Amino acids, lipids, and nucleotides were among the chemical types that further differentiated from the stool metabolite profiles. Normal weight adults had 46 significantly different metabolites between ascending and descending colon tissue locations, whereas there were 37 metabolite differences in overweight and 28 metabolite differences for obese adults (P < 0.05). Obese adults had trimethylamine N-oxide, endocannabinoids and monoacylglycerols with different relative abundances identified between ascending and descending colon. Primary and secondary bile acids, vitamins, and fatty acids also showed marked relative abundance differences in colon tissue from overweight/obese adults.
Conclusion:
There were metabolite profile differences between right-ascending and left-descending colon tissue in healthy adults. Colon lipids and other metabolites in obese and overweight adults were distinguished from normal weight participants and associated with gut inflammation, nutrient absorption, and products of microbiota metabolism.
... This drug is currently approved only in Japan for the treatment of chronic constipation. A small randomized controlled trial of 29 women with IBS-C found that chenodeoxycholate (a delayed release oral form of bile acid which increases the colonic bile acid pool), was superior to placebo with regards to accelerating colonic transit time and improving bowel function [39]. Further trials are needed for both elobixibat and chenodeoxycholate. ...
Introduction: Chronic constipation is highly prevalent, affecting between 10% and 15% of the population. The Rome IV criteria categorizes disorders of chronic constipation into four subtypes: (a) functional constipation, (b) irritable bowel syndrome with constipation, (c) opioid-induced constipation, and (d) functional defecation disorders, including inadequate defecatory propulsion and dyssynergic defecation. The initial management approach for these disorders is similar, focusing on diet, lifestyle and the use of standard over-the-counter laxatives. If unsuccessful, further therapy is tailored according to subtype.
Areas covered: This review covers the definition, epidemiology, diagnostic criteria, investigations and management of the Rome IV disorders of chronic constipation.
Expert opinion: By adopting a logical step-wise approach toward the diagnosis of chronic constipation and its individual subtypes, clinicians have the opportunity to tailor therapy accordingly and improve symptoms, quality of life, and patient satisfaction.
... Normally, bile salts are reabsorbed into the small intestine via the apical ileal bile acid transporter and ~5% pass into the colon where they are deconjugated and dehydroxylated. Chenodeoxycholic acid, a primary bile acid, was shown to be effective in improving stool consistency in adults with IBS 179 . In children with functional constipation, Hofmann et al. 180 showed an altered faecal chenodeoxycholic acid profile, suggesting a possible role of bile acids in the pathophysiology of functional constipation but, to date, no studies on the use of bile acids have been performed in children with functional constipation. ...
Functional constipation is common in children and adults worldwide. Functional constipation shows similarities in children and adults, but important differences also exist regarding epidemiology, symptomatology, pathophysiology, diagnostic workup and therapeutic management. In children, the approach focuses on the behavioural nature of the disorder and the initial therapeutic steps involve toilet training and laxatives. In adults, management focuses on excluding an underlying cause and differentiating between different subtypes of functional constipation — normal transit, slow transit or an evacuation disorder — which has important therapeutic consequences. Treatment of adult functional constipation involves lifestyle interventions, pelvic floor interventions (in the presence of a rectal evacuation disorder) and pharmacological therapy. When conventional treatments fail, children and adults are considered to have intractable functional constipation, a troublesome and distressing condition. Intractable constipation is managed with a stepwise approach and in rare cases requires surgical interventions such as antegrade continence enemas in children or colectomy procedures for adults. New drugs, including prokinetic and prosecretory agents, and surgical strategies, such as sacral nerve stimulation, have the potential to improve the management of children and adults with intractable functional constipation.
Bile acids, once considered mere dietary surfactants, now emerge as critical modulators of macronutrient (lipid, carbohydrate, protein) metabolism and the systemic pro-inflammatory/anti-inflammatory balance. Bile acid metabolism and signaling pathways play a crucial role in protecting against, or if aberrant, inducing cardiometabolic, inflammatory, and neoplastic conditions, strongly influencing health and disease. No curative treatment exists for any bile acid influenced disease, while the most promising and well-developed bile acid therapeutic was recently rejected by the FDA. Here, we provide a bottom-up approach on bile acids, mechanistically explaining their biochemistry, physiology, and pharmacology at canonical and non-canonical receptors. Using this mechanistic model of bile acids, we explain how abnormal bile acid physiology drives disease pathogenesis, emphasizing how ceramide synthesis may serve as a unifying pathogenic feature for cardiometabolic diseases. We provide an in-depth summary on pre-existing bile acid receptor modulators, explain their shortcomings, and propose solutions for how they may be remedied. Lastly, we rationalize novel targets for further translational drug discovery and provide future perspectives. Rather than dismissing bile acid therapeutics due to recent setbacks, we believe that there is immense clinical potential and a high likelihood for the future success of bile acid therapeutics.
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.
Impaired gastrointestinal motility is associated with gut dysbiosis. Probiotics, such as Bifidobacteria, can improve this bowel disorder; however, efficacy is strain-dependent. We determine that a genetic factor, the abfA cluster governing arabinan utilization, in Bifidobacterium longum impacts treatment efficacy against functional constipation (FC). In mice with FC, B. longum, but not an abfA mutant, improved gastrointestinal transit time, an affect that was dependent upon dietary arabinan. abfA genes were identified in other commensal bacteria, whose effects in ameliorating murine FC were similarly abfA-dependent. In a double-blind, randomized, placebo-controlled clinical trial, supplementation with abfA-cluster-carrying B. longum, but not an abfA-deficient strain, enriched arabinan-utilization residents, increased beneficial metabolites, and improved FC symptoms. Across human cohorts, abfA-cluster abundance can predict FC, and transplantation of abfA cluster-enriched human microbiota to FC-induced germ-free mice improved gut motility.
Collectively, these findings demonstrate a role for microbial abfA cluster in ameliorating FC, establishing principles for genomics-directed probiotic therapies.
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.
Irritable bowel syndrome (IBS) is a relatively common functional gastrointestinal disease with a disturbance of intestinal bacteria. Bile acids, gut microbiota, and the host have close and complex interactions, which play a central role in modulating host immune and metabolic homeostasis. Recent studies suggested that the bile acid‐gut microbiota axis played a key role in the development of IBS patients. In order to investigate the role of bile acids in the pathogenesis of IBS and present potentially relevant clinical implications. We conducted a literature search on intestinal interactions between bile acid and gut microbiota. The intestinal crosstalk between bile acids and gut microbiota shapes the compositional and functional alterations in IBS, manifesting as gut microbial dysbiosis, disturbed bile acid pathway, and alteration of the microbial metabolites. Collaboratively, bile acid conducts the pathogenesis of IBS through the alterations of the farnesoid‐X receptor and G protein‐coupled receptor. Diagnostic markers and treatments targeting the bile acids and its receptor showed promising potential in the management of IBS. Bile acids and gut microbiota play a key role in the development of IBS and make attractive biomarkers for treatments. Individualized therapy aiming at bile acids and its receptor may provide significant diagnostic and requires further investigation.
Childhood constipation is a common and worldwide pediatric healthcare problem. The diagnosis is based on history and physical examination, in accordance with the pediatric diagnostic Rome IV criteria. Diagnostic tests are only indicated if the diagnosis is not clear or in order to rule out an underlying organic disease. Non-pharmacological management involves education, demystification, a toilet program with reward system, and daily bowel diary, and in some cases additional cognitive behavior therapy is helpful. Pharmacological treatment with laxatives consists of disimpaction, maintenance treatment, and weaning from medication. Polyethylene glycol (PEG) is the treatment of first choice for both disimpaction and maintenance treatment. If PEG is not available or poorly tolerated, other laxatives are available as second-line or additional treatment if treatment with PEG is insufficient. In children with more severe symptoms not improving with the previously listed interventions, pelvic floor physiotherapy, sacral nerve stimulation, and surgery can be considered.
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.
Bile acids are strongly associated with the pathogenesis of functional gastrointestinal diseases. In recent years, blue laser imaging (BLI) endoscopy has emerged as a novel image-enhanced endoscopic method, which illustrates bile as a reddish hue. The present study investigated the factors that affect the area of bile in duodenal bulbs using BLI. For this purpose, patients (356 cases) who underwent upper endoscopy with BLI between April, 2017 and December, 2019, and completed patient background and symptom questionnaires [Constipation Scoring System (CSS), Bristol Stool Form Scale (BSFS) and Frequency Scale for Symptoms of gastroesophageal reflux disease (FSSG)], were retrospectively investigated. Each BLI bile score was calculated as a percentage of bile area in a field of view in the duodenal bulb using a KS400 image analysis system, and the association with abdominal symptoms was examined using multiple regression analysis. The patient characteristics included the following: Age (in years), 69.9±11.3; male/female ratio, 146/210; body mass index, 23.0±3.8; reflux esophagitis (M/A/B/C), 143/19/3/3; atrophic gastritis (C-0/C1-3/O1-3), 132/100/124; proton pump inhibitor potassium competitive acid blocker/aspirin/ursodeoxycholic acid/gall bladder stones/cholecystectomy, 105/27/18/43/18; BLI bile score, 7.10 (±14.34); CSS score, 3.55 (±3.80); BSFS score, 3.91 (±1.02); and FSSG score, 4.80 (±5.76). Correlation coefficients (P<0.05) for the BLI bile score were found for cholecystectomy (Rho=0.137) and aspirin use (Rho=0.118). In multiple regression analysis, independent predictors of the BLI bile score were cholecystectomy [standardized partial regression coefficient (β)=0.169, P=0.001] and the BSFS score (β=0.107, P=0.042). On the whole, the present study demonstrates that the duodenal bile area in BLI upper endoscopy is associated with cholecystectomy and fecal characteristics.
Aside from facilitating solubilisation and absorption of dietary lipids and lipid‐soluble vitamins, amphipathic bile acids (BAs) also act as bioactive signalling molecules. A plethora of conjugated or unconjugated primary and bacterially modified secondary BA moieties have been identified, with significant divergence between species. These molecules are excreted into the external environment of the intestinal lumen, yet nuclear and membrane receptors that are sensitive to BAs are expressed internally in the liver, intestinal and neural tissues, amongst others. The diversity of BAs and receptors underpins the multitude of distinct bioactive functions attributed to BAs, but also hampers elucidation of the physiological mechanisms underpinning these actions. In this Topical Review, we have considered the potential of BAs as cross‐barrier signalling molecules that contribute to interoceptive pathways informing the central nervous system of environmental changes in the gut lumen. Activation of BAs on FGF19‐secreting enterocytes, enteroendocrine cells coupled to sensory nerves or intestinal immune cells would facilitate indirect signalling, whereas direct activation of BA receptors in the brain is likely to occur primarily under pathophysiological conditions when concentrations of BAs are elevated. image
The concept of small intestinal bacterial overgrowth (SIBO) arose in the context of maldigestion and malabsorption among patients with obvious risk factors that permitted the small bowel to be colonized by potentially injurious colonic microbiota. Such colonization resulted in clinical signs, symptoms and laboratory abnormalities that were explicable within a coherent pathophysiological framework. Coincident with advances in medical science, diagnostic testing evolved from small bowel culture to breath tests and on to next generation, culture-independent microbial analytics. The advent and ready availability of breath tests generated a dramatic expansion in both the rate of diagnosis of SIBO and the range of associated gastrointestinal and non-gastrointestinal clinical scenarios. However, issues with the specificity of these same breath tests have clouded their interpretation and aroused some skepticism regarding the role of SIBO in this expanded clinical repertoire. Furthermore, the pathophysiological plausibility that underpins SIBO as a cause of maldigestion/malabsorption is lacking in regard to its purported role in irritable bowel syndrome, for example. One hopes that the application of an ever-expanding armamentarium of modern molecular microbiology to the human small intestinal microbiome in both health and disease will ultimately resolve this impasse and provide an objective basis for the diagnosis of SIBO.
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 bowel disorders such as irritable bowel syndrome (IBS) are common, multifactorial and have a major impact on the quality of life of individuals diagnosed with the condition. Heterogeneity in symptom manifestation, which includes changes in bowel habit and visceral pain sensitivity, are an indication of the complexity of the underlying pathophysiology. It is accepted that dysfunctional gut-brain communication, which incorporates efferent and afferent branches of the peripheral nervous system, circulating endocrine hormones and local paracrine and neurocrine factors, such as host and microbially-derived signaling molecules, underpins symptom manifestation. This review will focus on the potential role of hepatic bile acids in modulating gut-to-brain signaling in IBS patients. Bile acids are amphipathic molecules synthesized in the liver, which facilitate digestion and absorption of dietary lipids. They are also important bioactive signaling molecules however, binding to bile acid receptors which are expressed on many different cell types. Bile acids have potent anti-microbial actions and thereby shape intestinal bacterial profiles. In turn, bacteria with bile salt hydrolase activity initiate the critical first step in transforming primary bile acids into secondary bile acids. Individuals with IBS are reported to have altered microbial profiles and modified bile acid pools. We have assessed the evidence to support a role for bile acids in the pathophysiology underlying the manifestation of IBS symptoms.
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 bile acids (BAs) has 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.
Introduction. I BS is a functional bowel disorder that has a significant impact on patients and society, especially in terms of quality of life and medical costs.
Pathogenesis . It is believed that the pathogenesis of IBS consists of several mechanisms: the syndrome of intersection of functional disorders (gut-brain), stress, visceral hypersensitivity and changes in motor skills.
Visceral hypersensitivity. Changes in visceral sensitivity in IBS are characterized by central abnormalities in areas of the cerebral cortex. Motility impairment in IBS manifests itself as abnormal myoelectric activity in the colon, resulting in repetitive contractions of the small intestine and colon, which appear to cause pain.
Intestinal microflora . FODMAPs are found in high amounts in some fruits, artificial sweeteners, legumes, and green vegetables and are poorly absorbed by all people. FODMAPs have enzymatic and osmotic effects that may contribute to the onset of symptoms in some patients.
The principles of IBS therapy . Treatment for IBS should be based on the type and severity of symptoms. For the treatment of IBS, drugs of various pharmacological groups are used, depending on the prevailing symptoms. These include opioid receptor agonists, bile acid sequestrants, guanylate cyclase agonists, chlorine channel activators, as well as antibiotics, probiotics, antidepressants, 5-HT3 receptor antagonists, and antispasmodics.
Myotropic antispasmodics . Drugs with antispasmodic activity are used to treat functional and organic diseases of the gastrointestinal tract as a basic therapy or «on demand». Mebeverine quickly and effectively relieves spasm, pain and the entire complex of intestinal symptoms, in addition, the drug reduces visceral hypersensitivity due to a local anesthetic effect. The drug has a high safety profile and has a number of advantages over drugs of the same pharmacological group.
Conclusion . Myotropic antispasmodics have been shown to be highly effective in the treatment of IBS. Mebeverine occupies a special place among myotropic antispasmodics. Its combined action provides a pronounced antispasmodic activity along with a high safety profile.
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.
This article addresses the management of chronic constipation and opioid-induced constipation. Apart from increasing dietary fiber, there are several classes of medications that can be used for treatment of constipation, and these include osmotic and secretory laxatives, agents that impede the re-absorption of endogenous bile acids resulting in stimulation of motor and secretory functions in the colon, and agents that stimulate the motor function of the colon thereby propelling stool towards the rectum. Several drug classes are also available for the treatment of opioid-induced constipation including peripherally active mu-opioid receptor antagonists, and some of the same secretory agents and prokinetics that are used for chronic constipation. For both of these indications, there have recently been studies that compared efficacy and safety of the available drugs through network meta-analyses, which are also summarized in this article.
Goals:
There is an unmet need in investigating corticosteroid-sparing treatments for induction and maintenance of remission in microscopic colitis (MC). The authors' aim was to evaluate the outcomes of patients with MC treated with bile acid sequestrants (BAS).
Background:
MC is a common chronic diarrheal illness. Budesonide is effective induction therapy, but relapses are high after cessation of treatment.
Study:
Our cohort consisted of patients enrolled in our institutional MC registry, a biorepository of histology-confirmed diagnoses of MC. Patients receiving BAS for the treatment of MC were reviewed at each clinical visit for efficacy or ability to decrease budesonide maintenance dosing.
Results:
The authors included 79 patients (29 collagenous colitis and 50 lymphocytic colitis) with a median follow-up period of 35 months (range, 1 to 120). Most patients were female individuals (78%) and the median age was 69 years (range, 29 to 87). BAS therapy was used in 21 patients who were budesonide-naive, with a response rate of 76% (16/21). In patients treated previously with budesonide, 46 patients were budesonide-dependent and given BAS as maintenance therapy. Of these patients, 23 (50%) were able to decrease their budesonide dosing and 9 (20%) were able to stop budesonide completely. Seven of 46 patients (15%) stopped BAS because of intolerance, perceived lack of benefit, or treatment of concomitant diarrhea illness.
Conclusions:
BAS may be an effective corticosteroid-sparing option in the treatment of MC and should be considered after budesonide induction. Larger controlled studies are needed to confirm the efficacy for long-term maintenance and tolerability of BAS in patients with MC.
Background:
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.
Aim:
To investigate the role of BAs in the pathogenesis of IBS-D and the correlation between fecal BAs and gut microbiota.
Methods:
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.
Results:
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.
Conclusion:
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.
The report provides a critical analysis of the provisions of the Rome Consensus IV, related to irritable bowel syndrome. The comparative characteristic differences between the Roman criteria I, II, III and IV, relating to basic requirements for the diagnosis and treatment of this disease and try to bring them into the process of evolution to the basic requirements of evidence-based medicine.
Abstract Background Pigmented bile salts darken the small-bowel lumen and are present with bile acid, which is involved in the development of bowel habits. The small-bowel water content (SBWC) in the ileum could represent the colonic environment, but no studies have focused on this feature. However, measurement of crude SBWC can be challenging because of the technical difficulty of the endoscopic approach without preparation. Our aim was to evaluate optically active bile pigments in the SBWC of patients with abnormal bowel habits using capsule endoscopy (CE) to investigate the impact of bile acid on bowel habits. Methods The study population included 37 constipated patients, 20 patients with diarrhea, and 77 patients with normal bowel habits who underwent CE between January 2015 and May 2018. Patients with secondary abnormal bowel habits were excluded. In addition to conventional imaging, we used flexible spectral imaging color enhancement (FICE) setting 1 imaging, in which the effects of bile pigments on color are suppressed. Intergroup color differences of SBWC in the ileum (ΔE) were evaluated from conventional and FICE setting 1 images. Color values were assessed using the CIE L*a*b* color space. Differences in SBWC lightness (black to white, range 0–100) were also evaluated. Results The ΔE values from the comparison of conventional images between patients with constipation and with normal bowel habits and between patients with diarrhea and with normal bowel habits were 12.4 and 11.2, respectively. These values decreased to 4.4 and 3.3, respectively, when FICE setting 1 images were evaluated. Patients with constipation and diarrhea had significantly brighter (34.4 versus 27.6, P
Bile acids (BAs) are the central signals in enterohepatic communication, and they also integrate microbiota-derived signals into enterohepatic signaling. The tissue distribution and signaling pathways activated by BAs through natural receptors, farsenoid X receptor and G protein-coupled BA receptor 1 (GPBAR1, also known as Takeda G-coupled receptor 5), have led to a greater understanding of the mechanisms and potential therapeutic agents. BA diarrhea is most commonly encountered in ileal resection or disease, in idiopathic disorders (with presentation similar to functional diarrhea or irritable bowel syndrome with diarrhea), and in association with malabsorption such as chronic pancreatitis or celiac disease. Diagnosis of BA diarrhea is based on Se-homocholic acid taurine retention, 48-hour fecal BA excretion, or serum 7αC4; the latter being a marker of hepatic BA synthesis. BA diarrhea tends to be associated with higher body mass index, increased stool weight and stool fat, and acceleration of colonic transit. Biochemical markers of increased BA synthesis or excretion are available through reference laboratories. Current treatment of BA diarrhea is based on BA sequestrants, and, in the future, it is anticipated that farsenoid X receptor agonists may also be effective. The optimal conditions for an empiric trial with BA sequestrants as a diagnostic test are still unclear. However, such therapeutic trials are widely used in clinical practice. Some national guidelines recommend definitive diagnosis of BA diarrhea over empirical trial.
For the first time thin films of chenodeoxycholic acid (CDCH) were electrodeposited from sodium chenodeoxycholate (CDCNa) solutions potentiodynamically and by constant voltage deposition. The proposed deposition method was based on pH-dependent gel-forming properties of CDCH. CDCNa was found to be an efficient anionic surfactant for electrophoretic deposition (EPD) of carbon materials, such as submicrometre diamond, nanodiamond, carbon nanotubes, as well as memory type Zr-doped hydrotalcite (MHT) and poly(tetrafluoroethylene) (PTFE). In this approach, bifacial amphipathic CDCNa acted as a compatibilizing agent between the hydrophobic material surface and water. This study enabled the fabrication of composite coatings using CDCNa as a co-dispersing surfactant. An important practical outcome of this work was the development of advanced coatings for corrosion protection. We present a conceptually new strategy which enhances the protective properties of polymer coatings. It is based on the memory properties of MHT, which are linked to its ability to restore the original structure and composition after thermal dehydration. The protection mechanism involves in-situ MHT reconstruction, which limits water diffusion in pores of coatings. Another new finding was that CDCNa facilitated solubilization and EPD of ibuprofen in water. This finding paves the way for the development of drug delivery technologies and deposition of various water insoluble organic functional materials. Particularly important for future applications is the possibility of EPD of various hydrophobic polymers and composites using a biomimetic approach based on the CDCNa mediated deposition.
Introduction: Irritable bowel syndrome (IBS), globally affecting 11.2% of the population and imposing a direct annual cost of $1.7bn-$10bn in the US, is one of the today’s major therapeutic challenges. Therefore, there is urgent need to address this issue through reviewing tolerability and efficacy of available medications.
Areas covered: Over the past decade, related experiments were cited through Clinicaltrials.gov, PubMed, WHO ICTRP, and Cochrane library. Pharmacological parameters of approved medications available in the USFDA, EMA, TGA and PMDA were also stated.
Expert opinion: Anti-spasmodics are used as the first-line treatment in pain-predominant IBS and IBS-D, among which calcium channel blockers and neurokinin-type 2 receptor antagonists seem to replace anti-cholinergic drugs. As second-line treatments, rifaximin is considered to be the best for IBS-D though it has lower efficacy than alosetron and eluxadoline.
For IBS-C, linaclotide is the most effective and the safest second-line therapy, following laxatives/fibers, which may be replaced by tenapanor, in the future. When moderate to severe IBS is associated with severe pain or comorbid psychological disorders, gut-brain neuromodulators could also be prescribed.
Regarding all this, there is still a paramount need to conduct careful clinical studies on efficacy, safety and cost-effectiveness of current approved and non-approved treatments.
Background Pigmented bile salts darken the small-bowel lumen and are present with bile acid, which is involved in the development of bowel habits. The small-bowel water content (SBWC) in the ileum could represent the colonic environment, although no studies have focused on this feature. However, measurement of the crude SBWC can be challenging because of the technical difficulty of the endoscopic approach without preparation. Our aim was to evaluate optically active bile pigments in the SBWC of patients with abnormal bowel habits using capsule endoscopy (CE), to investigate the impact of bile acid on bowel habits. In addition to conventional imaging, we used flexible spectral imaging color enhancement (FICE) setting 1 imaging, in which the effects of bile pigments on color are suppressed.
Methods The study population included 37 constipated patients, 20 patients with diarrhea, and 77 patients with normal bowel habits who underwent CE between January 2015 and May 2018. Patients with secondary abnormal bowel habits were excluded. Intergroup color differences of SBWC in the ileum (ΔE) were evaluated from conventional and FICE setting 1 images. Color values were assessed using the CIE L*a*b* color space. Differences in lightness (black to white, range 0 to 100) of SBWC were also evaluated.
Results Values of ΔE calculated from comparisons of conventional images of constipated and normal-bowel-habit patients, and patients with diarrhea and normal-bowel-habit patients were 11.3 and 10.7, respectively. These values decreased to 3.9 and 3.2, respectively, when FICE setting 1 images were evaluated. The SBWC lightness of patients with constipation and diarrhea was significantly brighter (34.0 versus 27.2, P < .0001) and darker (18.8 versus 27.2, P < .0001), respectively, compared with the normal-bowel-habit patients. Examination of the FICE setting 1 images did not reveal significant differences in SBWC lightness between the constipated and normal-bowel-habit groups (44.7 versus 46.7, P = .33) or between the diarrhea and normal-bowel-habit groups (44.7 versus 42.3, P = .39).
Conclusions Differences in color and darkness of the SBWC in the ileum appear to be attributable to bile pigments. Therefore, bile pigments in SBWC could reflect bowel habits.
Secondary bile acids (SBAs) are derived from primary bile acids (PBAs) in a process reliant on biosynthetic capabilities possessed by few microbes. To evaluate the role of BAs in intestinal inflammation, we performed metabolomic, microbiome, metagenomic, and transcriptomic profiling of stool from ileal pouches (surgically created resevoirs) in colectomy-treated patients with ulcerative colitis (UC) versus controls (familial adenomatous polyposis [FAP]). We show that relative to FAP, UC pouches have reduced levels of lithocholic acid and deoxycholic acid (normally the most abundant gut SBAs), genes required to convert PBAs to SBAs, and Ruminococcaceae (one of few taxa known to include SBA-producing bacteria). In three murine colitis models, SBA supplementation reduces intestinal inflammation. This anti-inflammatory effect is in part dependent on the TGR5 bile acid receptor. These data suggest that dysbiosis induces SBA deficiency in inflammatory-prone UC patients, which promotes a pro-inflammatory state within the intestine that may be treated by SBA restoration.
Background
Tegaserod (Zelnorm®) is a 5-hydroxytryptamine (serotonin) type 4 receptor agonist for the treatment of hypomotility disorders of the lower gastrointestinal tract associated with the irritable bowel syndrome with constipation (IBS-C).
Objective
The authors provide the reader with a better understanding on tegaserod mechanism of action, on its pharmacodynamics and pharmacokinetic properties, on safety and tolerability, with a summary of the key published clinical trials conducted in patients with IBS. Its effects on colon inflammation have also been described.
Results
Tegaserod was withdrawn in 2007 due to increased risks of cardiovascular adverse effects. The manufacturer denied this, because pre-existing cardiovascular disease or risk factors were attributed to all affected patients. Thus, no causal relationship between tegaserod use and cardiovascular events was clearly shown. A matched case-control study of tegaserod-treated with untreated patients found no association between tegaserod and adverse cardiovascular outcomes. Despite its adverse effects, tegaserod resulted to be effective in treating chronic constipation in adult women aged < 65 years with IBS-C, while the safety and effectiveness of tegaserod in men with IBS-C have not been established. Tegaserod was resubmitted to the Food and Drug Administration in 2018 for use in a low-risk population. Moreover, tegaserod has also been shown to improve symptoms, enhance gastric accommodation and significantly attenuate visceral pain arising from the colon in functional dyspepsia patients. Treatment with tegaserod seems also to exert a protective effect in inflamed colons, reducing the severity of colitis in animal models.
Constipation, a condition characterized by heterogeneous symptoms, is common in Western society. It is associated with reduced physical health, mental health, and social functioning. Because constipation is rarely due to a life-threatening disease (for example, colon cancer), current guidelines recommend empiric therapy. Limited surveys suggest that fewer than half of treated individuals are satisfied with treatment, perhaps because the efficacy of drugs is limited, they are associated with undesirable side effects, or they may not target the underlying pathophysiology. For example, although a substantial proportion of constipated patients have a defecatory disorder that is more appropriately treated with pelvic floor biofeedback therapy than with laxatives, virtually no pharmacological trials formally assessed for anorectal dysfunction. Recent advances in investigational tools have improved our understanding of the physiology and pathophysiology of colonic and defecatory functions. In particular, colonic and anorectal high-resolution manometry are now available. High-resolution anorectal manometry, which is increasingly used in clinical practice, at least in the United States, provides a refined assessment of anorectal pressures and may uncover structural abnormalities. Advances in our understanding of colonic molecular physiology have led to the development of new therapeutic agents (such as secretagogues, pro-kinetics, inhibitors of bile acid transporters and ion exchangers). However, because clinical trials compare these newer agents with placebo, their efficacy relative to traditional laxatives is unknown. This article reviews these physiologic, diagnostic, and therapeutic advances and focuses particularly on newer therapeutic agents.
Epithelial cells line the entire surface of the gastrointestinal tract and its accessory organs where they primarily function in transporting digestive enzymes, nutrients, electrolytes, and fluid to and from the luminal contents. At the same time, epithelial cells are responsible for forming a physical and biochemical barrier that prevents the entry into the body of harmful agents, such as bacteria and their toxins. Dysregulation of epithelial transport and barrier function is associated with the pathogenesis of a number of conditions throughout the intestine, such as inflammatory bowel disease, chronic diarrhea, pancreatitis, reflux esophagitis, and cancer. Driven by discovery of specific receptors on intestinal epithelial cells, new insights into mechanisms that control their synthesis and enterohepatic circulation, and a growing appreciation of their roles as bioactive bacterial metabolites, bile acids are currently receiving a great deal of interest as critical regulators of epithelial function in health and disease. This review aims to summarize recent advances in this field and to highlight how bile acids are now emerging as exciting new targets for disease intervention.
Primary (idiopathic) bile acid malabsorption (BAM) is a common, yet underrecognized, chronic diarrheal syndrome. Diagnosis is difficult without selenium homocholic acid taurine (SeHCAT) testing. The diarrhea results from excess colonic bile acids, but the pathogenesis is unclear. Fibroblast growth factor 19 (FGF19), produced in the ileum in response to bile acid absorption, regulates hepatic bile acid synthesis. We proposed that FGF19 is involved in bile acid diarrhea and measured its levels in patients with BAM.
Blood was collected from fasting patients with chronic diarrhea; BAM was diagnosed by SeHCAT. Serum FGF19 was measured by enzyme-linked immunosorbent assay. Serum 7alpha-hydroxy-4-cholesten-3-one (C4) was determined using high-performance liquid chromatography, to quantify bile acid synthesis. Data were compared between patients and subjects without diarrhea (controls). Samples were taken repeatedly after meals from several subjects.
The median C4 level was significantly higher in patients with primary BAM than in controls (51 vs 18 ng/mL; P < .0001). The median FGF19 level was significantly lower in patients with BAM (120 vs 231 pg/mL; P < .0005). There was a significant inverse relationship between FGF19 and C4 levels (P < .0004). Low levels of FGF19 were also found in patients with postcholecystectomy and secondary bile acid diarrhea. Abnormal patterns of FGF19 levels were observed throughout the day in some patients with primary BAM.
Patients with BAM have reduced serum FGF19 which may be useful in diagnosis. We propose a mechanism whereby impaired FGF19 feedback inhibition causes excessive bile acid synthesis that exceeds the normal capacity for ileal reabsorption, producing bile acid diarrhea.
Colonic motor activity was initiated by infusions of bile salts into the caecum or rectum of the anaesthetized rabbit. Primary bile acids were examined proximally and distally in the colon and elicited marked motor responses. Sinc dihydroxy bile acids are known to be potent inhibitors of electrolyte and water absorption in the colon, the secondary bile acid deoxycholic acid, the dihydroxyl compound most related to cholic acid which is the main bile acid in the rabbit, was examined distally and was also active, but to a lesser extent than cholic acid conjugates in this species. In man, a relationship was found between the faecal bile acid excretion and colonic motility: the introduction of bile acids directly into the human sigmoid colon and rectum also stimulated colonic motility. In man, the dihydroxy compound chenodeoxycholic acid was slightly more active than conjugates of cholic acid.
Twenty individual diarrhoeal stools from three patients with ileal resection were centrifuged at 14 000 g for one hour at 10 degrees C to separate the stool into pellet and supernatant. Bile acids and electrolytes were measured in each phase. Relationships were examined between chenodeoxycholic acid and cholic acid in each phase and in toto to electrolyte and water loss. Chenodeoxycholic acid was associated with electrolyte and water loss whether present in solid or liquid phase. The association varied between individuals. The cholic acid content of the stool showed no association with electrolyte and water loss. It would appear that it is the total amount of chenodeoxycholic acid entering the colon, irrespective of its physical state, that is important in the diarrhoea of ileal dysfunction.
Each of the three major bile acids of man was tested for its influence on electrolyte and water absorption in the human colon. Transport from isotonic solutions, with or without added bile acids, was compared in 35 studies on 20 healthy volunteers by colonic perfusions under steady-state conditions. Electrolytes and water were always absorbed from control solutions, but dihydroxy bile acid solutions induced continuous secretion or inhibition of sodium, potassium, and water absorption, which was reversible. Deoxycholic acid caused consistent secretion at 3 mm concentrations, whereas chenodeoxycholic acid did not induce secretion until the concentration was 5 mm. The trihydroxy bile acid (cholic acid) produced no significant change in absorption at 10 mm. Inhibition of absorption was also induced by mixtures of the glycine or taurine conjugated bile acids. Secretion of sodium and chloride, induced by bile acid perfusion, was linearly correlated with secretion of water; potassium secretion was relatively constant regardless of the volume of secretion. These results establish a striking influence of bile acids on colonic absorptive activity, provide an explanation in part for the diarrhea that frequently accompanies ileal disease or resection, and imply that diarrhea should occur in other disease states that produce elevated concentrations of dihydroxy bile acids in the colonic lumen.
The aim of this study was to investigate whether the cathartic effect of chenodeoxycholic acid (CDCA) could be helpful in the management of chronic constipation. Twenty cholesterol gall-stone patients with chronic constipation were randomly treated with either CDCA (750 mg/day in three divided doses at meals) or placebo for a period of 4 weeks.
The administration of CDCA produced a significant increase of stool frequency and a decrease of stool consistency, while placebo was not effective in improving the bowel habit of the patients. As some patients complained of diarrhoea, and some had no modification of bowel frequency, further studies are needed to determine the most appropriate dose for each patient.
To evaluate the usefulness of 7a-hydroxy-4-cholesten-3-one (HCO) serum concentrations as a diagnostic marker of bile acid malabsorption, we determined the reference range of HCO in 106 normal subjects (age 40.2+/-16.8 years; 55 women, 51 men) and conducted a utility study in 23 patients with chronic diarrhea of unknown origin (age 49.4+/-15.3 years, 13 women, 10 men). The diagnosis of bile acid malabsorption was made on the basis of a decreased retention of [75Se]homocholyltaurine after oral application (75SeHCAT test). HCO (reference range: 6-48 ng/ml) and the 75SeHCAT test yielded the same results in 19/23 (83%) patients. Bile acid malabsorption was identified by an increase of HCO in serum with a sensitivity of 90% and a specificity of 79%. Analysis of HCO in serum may serve as a novel, simple, and sensitive method for the detection of bile acid malabsorption in patients with chronic diarrhea of unknown origin.
We aimed to determine whether rectal distension and/or infusion of bile acids stimulates propagating or nonpropagating activity in the unprepared proximal colon in 10 healthy volunteers using a nasocolonic manometric catheter (16 recording sites at 7.5-cm spacing). Sensory thresholds and proximal colonic motor responses were assessed following rectal distension by balloon inflation and rectal instillation of chenodeoxycholic acid. Maximum tolerated balloon volume and the volume that stimulated a desire to defecate were both significantly (P < 0.01) reduced after rectal chenodeoxycholic acid. The frequency of colonic propagating pressure wave sequences decreased significantly in response to initial balloon inflations (P < 0.05), but the frequency doubled after subsequent chenodeoxycholic acid infusion (P < 0.002). Nonpropagating activity decreased after balloon inflation, was not influenced by acid infusion, and demonstrated a further decrease in response to repeat balloon inflation. We concluded that rectal chenodeoxycholic acid in physiological concentrations is a potent stimulus for propagating pressure waves arising in the proximal colon and reduces rectal sensory thresholds. Rectal distension inhibits all colonic motor activity.
Intestinal and systemic illnesses have been linked to increased gut permeability. Bile acids, whose luminal profile can be altered in human disease, modulate intestinal paracellular permeability. We investigated the mechanism by which selected bile acids increase gut permeability using a validated in vitro model. Human intestinal Caco-2 cells were grown in monolayers and challenged with a panel of bile acids. Transepithelial electrical resistance and luminal-to-basolateral fluxes of 10-kDa Cascade blue-conjugated dextran were used to monitor paracellular permeability. Immunoprecipitation and immunoblot analyses were employed to investigate the intracellular pathway. Redistribution of tight junction proteins was studied by confocal laser microscopy. Micromolar concentrations of cholic acid, deoxycholic acid (DCA), and chenodeoxycholic acid (CDCA) but not ursodeoxycholic acid decreased transepithelial electrical resistance and increased dextran flux in a reversible fashion. Coincubation of 50 muM CDCA or DCA with EGF, anti-EGF monoclonal antibody, or specific src inhibitor 4-Amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP-2) abolished the effect. A concentration of 50 muM of either CDCA or DCA also induced EGF receptor phosphorylation, occludin dephosphorylation, and occludin redistribution at the tight junction level in the same time frame and in a reversible fashion. We conclude that selected bile acids modulate intestinal permeability via EGF receptor autophosphorylation, occludin dephosphorylation, and rearrangement at the tight junction level. The effect is mediated by the src family kinases and is abolished by EGF treatment. These data also support the role of bile acids in the genesis of necrotizing enterocolitis and the protective effect of EGF treatment.
Synopsis Chenodeoxycholic acid1 (chenic acid; CDCA) is 1 of the 3 major biliary bile acids in man. When administered in pharmacological doses it causes a decrease in cholesterol saturation of bile, which in turn may lead to gradual dissolution of cholesterol gallstones. The stone dissolution rate during CDCA therapy has varied considerably from about one- third of patients overall to 80 to 90 % in a highly selected group of patients. Radiolucent gallstones in a functioning gallbladder are absolute requirements. CDCA is well tolerated; diarrhoea (sometimes requiring dosage reduction) is the only frequent side effect. Although hepatotoxicity has occurred in certain animal species, and slight hypertransaminasaemia has occurred in some patients, definite liver damage has not been observed in man. CDCA is considered contraindicated in pregnancy, and in those patients with the complications from gallstones which require immediate surgery. Care should be taken in patients with liver disease. The only other proven agent for dissolving gallstones is the 7β-epimer of CDCA, ursodeoxycholic acid (UDCA). Preliminary results show that UDCA is as effective as CDCA, but at one- half to two- thirds the dose, without causing diarrhoea. Further studies need to be done with both CDCA and UDCA to improve criteria for selection of patients most likely to respond, and to establish optimum schedules for dosage and duration of treatment. Pharmacodynamic Studies Chenodeoxycholic acid is 1 of the 2 primary bile acids synthesised in human liver. Conjugated with either taurine or glycine, it normally makes up approximately one-third of total biliary bile acids. Normal synthesis of CDCA is autoregulated by the relative composition of bile and the bile acid flux through the hepatocyte. When given orally in pharmacological doses of 10 to 15mg/kg/day, CDCA represents 70 to 95% of the biliary bile acids. At these levels cholesterol secretion into bile is reduced, both in absolute terms and relative to bile acids and phospholipids, the 2 agents that hold cholesterol in micellar solution in bile. Reduced cholesterol saturation allows for the gradual solubilisation of cholesterol from gallstones, leading to their eventual dissolution. In healthy subjects, and in gallstone patients, the saturation of bile with cholesterol varies throughout the day, often being supersaturated when fasting. CDCA therapy renders bile unsaturated in the fasting state, in which case it is likely to be unsaturated for at least 75% of the day. The mechanism of action of pharmacological doses of CDCA is still unclear. While uncoupling the normal relationship between cholesterol, phospholipid and bile acid secretion, CDCA also probably acts partly by inhibiting hepatic cholesterol synthesis and perhaps by reducing intestinal cholesterol absorption. Reduction in dietary cholesterol is thought to possibly enhance its effect. The changes in hepatic cholesterol metabolism do not result in altered serum cholesterol levels or changes in cholesterol pool sizes, but many studies have shown an approximate 20 % fall in serum triglyceride levels. However, this reduction has tended to diminish with continued treatment. Exogenous CDCA is hepatotoxic in some animal species, including the rhesus monkey, rabbit, rat and baboon, but appears safe in the squirrel monkey and chimpanzee. Although occasional elevations in serum liver enzyme levels occur, no hepatotoxicity has been observed in man, probably because of a superior ability to excrete the toxic metabolite, lithocholic acid. Pharmacokinetic Studies From limited studies in man it appears that unconjugated CDCA is completely absorbed from the small intestine after single doses of up to 400mg. Peak serum concentrations occur 50 to 120 minutes after ingestion. When taken with meals, absorption is usually delayed, but bioavailability is unaltered. Once absorbed, it is bound to plasma proteins and cleared efficiently by the liver. Subsequent clearance from the plasma is also efficient, so that fasting serum levels of CDCA are barely detectable. In the liver exogenous CDCA is conjugated with glycine more than taurine, and secreted into bile along with the pool of endogenous bile acids in the enterohepatic circulation. Conjugated CDCA is either reabsorbed in the terminal ileum, or deconjugated before either excretion or conversion to lithocholic acid (LCA). Absorbed LCA is conjugated and sulphated in the liver to reduce reabsorption on recycling. Thus, continued hepatic sulphation and intestinal excretion of LCA prevent accumulation in bile. Therapeutic Trials Controlled trials with CDCA against placebo or other agents were soon curtailed when it became clear that only CDCA was effective in dissolving gallstones. More recently the 7β-epimer of CDCA, ursodeoxycholic acid, has also been used successfully. Based mainly on retrospective analysis, the optimal dose of CDCA has been 13 to 15mg/kg of bodyweight per day. Single trials in each case have suggested improved efficacy with a low cholesterol diet, concomitant treatment with β-sitosterol, night-time dosage, and a combination of night-time dosage and low cholesterol diet. Overall, radiolucent (presumed cholesterol-rich) gallstones have dissolved in from 30 to 70% of patients. However, results obviously depend on the duration of treatment, which in many reports has not been stated precisely. Because of relatively small numbers of patients, changing study designs, and the presence of multiple variables such as duration of treatment, there has been disagreement on the influence of various factors on response. Nevertheless, most studies have shown that small stones usually dissolve in 6 to 12 months, and occasionally as early as 3 months. Stones from 10 to 20mm in diameter take from 12 to 36 months to dissolve, while no definite response has been seen in larger stones. Changes in bile lipid composition after 1 month of treatment with CDCA have been of predictive value, but again discordant results have been reported by several groups. Obese patients require a higher dose on a bodyweight basis, but studies in such patients are limited. When results were calculated for patients exhibiting apparently favourable prognostic factors, 78% of patients were reported to show complete and 93 % partial and complete gallstone dissolution after 12 months of treatment. Comparative studies with UDCA have shown that UDCA is as effective as CDCA at one-half to two-thirds the dose of CDCA, and that it does not seem to have any side effects. Thus, at this stage, UDCA would appear to have an advantage over CDCA, but further well designed studies are needed to confirm these early findings. In approximately 50% of the small number of such patients studied, CDCA has resulted in disappearance of common bile duct stones, but other methods of treatment would seem preferable. CDCA may be of use in hypertriglyceridaemia as a supplemental approach, particularly in conjunction with clofibrate both to enhance the triglyceride-lowering effect and to reverse the tendency to cholesterol saturation and gallstone formation induced by clofibrate. Again, more studies are required. Side Effects The only side effect frequently reported is diarrhoea, which may occur in 50% of patients or more. Although it is usually mild and transient, settling within a few weeks of commencing treatment, in some patients it may be more persistent. It may be minimised by gradual introduction of therapy and weighting towards a night-time dose. When troublesome, it can be treated with simple antidiarrhoeal medication or temporary or permanent reduction in dosage. During treatment patients are still likely to develop symptoms and complications from gallstones, but uncontrolled observations have suggested that indigestion, bloating and biliary colic are diminished during therapy. The Place of Chenodeoxycholic Acid in Therapy At present, the use of CDCA is restricted in certain countries. It should only be used for radiolucent gallstones in a currently functioning gallbladder. Treatment of large stones should be undertaken only with the understanding that successful treatment may take years. Pregnancy, and complications from gallstones requiring more immediate management, are the only definite contraindications. Dosage and Administration For gallbladder gallstones, CDCA is usually started at a dose of 13 to 15mg/kg of bodyweight per day in divided doses after meals, with a weighting towards the night-time dosage. At this dose, monitoring of bile lipids is probably unnecessary in most patients. However, obese patients are often less responsive, and may require up to 20mg/kg/day. Cholecystograms are usually performed at 6-monthly intervals. When complete stone dissolution has apparently occurred this should be confirmed by either x-ray or ultrasonography.
To evaluate the usefulness of7a-hydroxy-4-cholesten-3-one (HCO) serumconcentrations as a diagnostic marker of bile acidmalabsorption, we determined the reference range of HCOin 106 normal subjects (age 40.2 ± 16.8 years; 55 women, 51men) and conducted a utility study in 23 patients withchronic diarrhea of unknown origin (age 49.4 ±15.3 years, 13 women, 10 men). The diagnosis of bileacid malabsorption was made on the basis of a decreased retentionof [75Se]homocholyltaurine after oralapplication (75SeHCAT test). HCO (referencerange: 6-48 ng/ml) and the 75SeHCAT testyielded the same results in 19/23 (83%) patients. Bile acid malabsorption wasidentified by an increase of HCO in serum with asensitivity of 90% and a specificity of 79%. Analysis ofHCO in serum may serve as a novel, simple, and sensitive method for the detection of bile acidmalabsorption in patients with chronic diarrhea ofunknown origin.
ABSTRACT– A self-assessment scale has been developed and found to be a reliable instrument for detecting states of depression and anxiety in the setting of an hospital medical outpatient clinic. The anxiety and depressive subscales are also valid measures of severity of the emotional disorder. It is suggested that the introduction of the scales into general hospital practice would facilitate the large task of detection and management of emotional disorder in patients under investigation and treatment in medical and surgical departments.
In vitro studies have suggested that the cyclic AMP system may be the mediator of bile acid-induced colonic secretion. The aims of our experiments were to quantify thein vivo effect of various doses of deoxycholic acid (DCA) on adenylate cyclase activity (AC) and net secretion in the rabbit colon. AC increased significantly (P<0.01) with each increasing concentration of DCA; at 8 mM the activity was 126±6 pmoles cAMP/mg protein/min, or 4 times the control. Phosphodiesterase activity (PDE) was affected and significantly decreased (P<0.01) only by 8 mM DCA. The volume of luminal fluid increased significantly (P<0.01) as a bicarbonate-rich solution with 4, 6, and 8 mM DCA in graded fashion. In conclusion, stimulation of a colonic mucosal cAMP system is strongly implicated as mediating DCA-induced colonic secretion.
BACKGROUND Abnormalities of colonic motility were reported in relatively small studies of patients with lower functional gastrointestinal disorders (FGID) including irritable bowel syndrome (IBS). The influence of gender and body mass on the observed motor pathophysiology is unclear. We sought to compare colonic transit in patients within different lower FGID subgroups and healthy controls, controlling for gender and BMI, and to determine whether BMI independently influences colonic motility. METHODS We evaluated a scintigraphic gastrointestinal and colonic transit database of 287 lower FGID patients associated with constipation (IBS-C, or functional constipation, n = 118), diarrhoea (IBS-D or functional diarrhoea, n = 139) or mixed bowel function (IBS-M, n = 30) and 170 healthy controls. We measured colon filling at 6 h (CF 6 h), and overall colonic transit at 8, 24 and 48 h. KEY RESULTS Colon filling at 6 h did not differentiate health from FGID. Colonic transit was abnormal at 24 h (GC24 of <1.50 or >3.86) in 29.7% of all lower FGID patients. There was a significant overall association between colonic transit and subject group (healthy controls and FGID subgroups) at 8 (P = 0.01), 24 (P < 0.001) and 48 h (P < 0.001) in particular for those with diarrhoea or constipation at 24 and 48 h (P < 0.05), even after adjusting for age, gender and BMI. In addition, BMI was associated with colonic transit after adjusting for age, gender and subject group. CONCLUSIONS & INFERENCES Abnormal transit is documented non-invasively with scintigraphy in 30% of lower FGID patients; transit measurement may help document pathophysiology and inform selection of therapy in lower FGID.
The inter- and intra-subject variations of scintigraphy, which are used to identify colonic transit disturbances in irritable bowel syndrome (IBS), are unclear. The relationship between colonic transit and bowel functions is incompletely understood. To assess inter- and intra-subject variations of scintigraphic colonic transit measurements in 86 IBS patients and 17 healthy subjects and to quantify the relationship between colonic transit and bowel symptoms in 147 IBS patients and 46 healthy subjects.
Data from participants with multiple colonic transit measurements were analysed. Primary end points were colonic filling at 6 h (CF6h) and geometric center (GC) at 24 and 48 h for colonic transit. Bowel functions were assessed by daily stool diaries.
Inter- and intra-subject variations were greater for small intestinal than colonic transit. Overall, inter- and intra-subject variations were relatively narrow for colonic transit (both GC24h and GC48h, with lower COV at 48 h); there was little intra-subject variation in health and IBS-constipation over a period of <or=3 weeks and over 2.0 years (median, range 0.1, 11.0 years). Significant intra-individual differences in GC24h were observed only in IBS-D patients. Colonic transit was significantly associated with stool form (accounting for 19-27% of the variance), frequency (19%), and ease of stool passage (12%).
Despite inter-subject variation in scintigraphic colonic transit results, the intra-subject measurements are reproducible over time in healthy volunteers and patients with IBS; significant changes in colonic transit at 24 h were observed only in IBS-D. Colonic transit is associated with stool form, frequency and ease of passage.
Bile acid malabsorption (BAM) is a syndrome of chronic watery diarrhoea with excess faecal bile acids. Disruption of the enterohepatic circulation of bile acids following surgical resection is a common cause of BAM. The condition is easily diagnosed by the selenium homocholic acid taurine (SeHCAT) test and responds to bile acid sequestrants. Idiopathic BAM (IBAM, primary bile acid diarrhoea) is the condition where no definitive cause for low SeHCAT retention can be identified.
Review of PubMed and major journals.
Evidence is accumulating that BAM is more prevalent than first thought. Management of chronic diarrhoea involves excluding secondary causes. Treatment of the condition is with bile acid binders.
SeHCAT testing is not widely performed, limiting awareness of how common this condition can be. The underlying mechanism for IBAM has been unclear.
Increasing awareness of the condition is important. Alternative mechanisms of IBAM have been suggested which involve an increased bile acid pool size and reduced negative feedback regulation of bile acid synthesis by FGF19. New sequestrants are available.
Further research into the precise mechanism of IBAM is needed. Improvements in the recognition of the condition and optimization of treatment are required.
Di-alpha hydroxy bile salt, sodium chenodeoxycholate (CDC), and bile acid binding have unclear effects on colonic transit in health and disease.
We performed 2 randomized, double-blind, placebo-controlled studies. In healthy volunteers (20 per group), we evaluated the effects of oral placebo, 500 mg, or 1000 mg of CDC (delayed-release, each given for 4 days) on gastrointestinal and colonic transit. A second trial compared the effects of colesevelam (1.875 g, twice daily) versus placebo in 24 patients (12 per group) with diarrhea-predominant irritable bowel syndrome (IBS-D) on transit, daily bowel frequency and consistency, and colonic mucosal permeability. Serum fasting 7alpha-hydroxy-4-cholesten-3-one (7alphaC4) was measured to screen for bile acid malabsorption. Effects of treatments on transit were compared using analysis of covariance with body mass index and 7alphaC4 as covariates.
In healthy volunteers, CDC significantly accelerated colonic transit (at 24 and 48 hours, P = .01 and P < .0001, respectively), increased stool frequency and ease of passage (both P < .001), and evacuation (P = .02), and decreased stool consistency (P < .001). Four of the 24 IBS-D patients had increased serum 7alphaC4 levels. In IBS-D, colesevelam modestly affected overall colonic transit (24 h; P = .22). Emptying of the ascending colon took an average of 4 hours longer in patients given colesevelam compared with placebo; treatment effect was associated with baseline serum 7alphaC4 levels (P = .0025). Colesevelam was associated with greater ease of stool passage (P = .048) and somewhat firmer stool consistency (P = .12). No effects on mucosal permeability or safety were identified.
Sodium chenodeoxycholate in health and colesevelam in IBS-D patients have opposite effects on colonic transit and fecal parameters.
Bile acid malabsorption (BAM) is reported in up to 50% of patients with functional diarrhoea and irritable bowel syndrome with diarrhoea (IBS-D). Serum 7alpha-hydroxy-4-cholesten-3-one (7alphaHCO or 7alphaC4), an indirect measurement of hepatic bile acid synthesis, has been validated as a measurement of BAM relative to the (75)SeHCAT retention test. Our aim was to develop a serum 7alphaC4 assay, normal values, and compare results from healthy controls, patients with ileal Crohn's disease or resection, and patients with IBS-D or IBS with constipation (IBS-C). Stored serum samples were used from adult men and women in the following groups: 111 normal healthy controls, 15 IBS-D, 15 IBS-C, 24 with distal ileal Crohn's disease and 20 with distal ileal resection for Crohn's disease. We adapted a published high pressure liquid chromatography, tandem mass spectrometry (HPLC-MS/MS) assay. The HPLC-MS/MS assay showed good linearity in concentration range 0-200 ng mL(-1), sensitivity (lowest limit of detection 0.04 ng mL(-1)), and high analytical recovery (average 99%, range 93-107%). The 5th to 95th percentile for 111 normal healthy controls was 6-60.7 ng mL(-1). There were significant overall group differences (anovaon ranks, P < 0.001), with significantly higher values for terminal ileal disease or resection. There were significant differences between health and IBS (anova, P = 0.043) with higher mean values in IBS-D relative to controls (rank sum test, P = 0.027). We have established a sensitive non-isotopic assay based on HPLC-MS/MS, determined normal 7alphaC4 values, and identified increased 7alphaC4 in IBS-D and in distal ileal resection and disease. This assay has potential as a non-invasive test for BAM in IBS.
An elevated concentration in the colon of the primary bile acid chenodeoxycholic acid (CDCA) or the secondary bile acid deoxycholic acid (DCA) is known to induce water secretion, causing diarrhea. We hypothesized that of the many fecal bile acids, only CDCA and DCA function as endogenous laxatives; therefore, a decrease in their proportion may be a cause of childhood functional constipation. To test this possibility, fecal bile acid composition was determined in children with functional constipation and in nonconstipated control children.
Fecal samples were obtained from 207 children, 103 with functional constipation and 104 with normal bowel habits. Bile acid classes were determined by use of electrospray ionization-single ion monitoring-mass spectrometry (ESI-SIM-MS), and individual bile acids were measured by gas chromatography (GC)-MS (GC-MS). The structure of individual sulfated bile acids was obtained by use of liquid chromatography (LC)-MS (LC-MS).
By ESI-SIM-MS, the proportions of DCA did not differ in constipated children (n = 73) from that in control children (n = 92), but monosulfated dihydroxy bile acids were greater (P < 0.05). The difference was attributable to 6 patients in the constipated group whose major fecal bile acid by LC-MS was the 3-sulfate of CDCA. Sulfation of CDCA is known to abolish its secretory activity. By GC-MS, the bile acid profile was identical in the 2 groups.
In most children with functional constipation, the fecal bile acid profile seems to be normal. There is a small subset of children, however, whose dominant fecal bile acid is the 3-sulfate of CDCA, indicating a novel disturbance in bile acid metabolism. Such sulfation abolishes the secretory activity of CDCA and may contribute to constipation.
Bile acids are derived from cholesterol and are potent physiological laxatives. The aim of this study was to investigate whether bile acid synthesis is altered in constipation.
Female patients with constipation (23 IBS-C, 4 functional constipation (FC)) were studied and compared with non-constipated subjects (16 IBS-D, 20 healthy women). Body mass index (BMI), blood lipids, lanosterol, sitosterol, colonic transit (oro-anal transit time (OATT), reference < or =4.3 days) and stool frequency were measured. C4 (7-alpha-hydroxy-4-cholesten-3-one) levels reflecting bile acid synthesis were measured at 0800 h and 1300 h.
When all the groups of constipated and non-constipated subjects were compared, it was found that only stool frequency and OATT differed between groups (p <0.001). When constipated patients were categorized according to OATT, absence of the usual C4 increase at lunchtime was noted in 82% of patients with delayed OATT compared with 17% in subjects with normal OATT (p <0.001). Symptom severity did not differ between groups. A subset of the patients with severely delayed OATT had markedly elevated C4 levels.
Patients with IBS-C and FC have marked changes in bile acid synthesis in relation to colonic transit. The diurnal rhythm is altered in the slow transit colon when there is no C4 peak at lunchtime. Alterations in bile acid metabolism may be implicated in the pathophysiology of constipation.
An in vivo intestinal perfusion system was used to study the effects of different bile acids on fluid secretion, mucosal permeability, and mucosal morphology in the rabbit colon. To define the structure-activity relationships of the bile acids, nine unconjugated bile acids were used, varying only in the number (two or three) or position (3, 7, or 12 or various combinations) of hydroxy or keto nuclear substituents. Results showed that bile acids with two hydroxy groups in the alpha configuration at the 3,7 position, 3,12 position, or 7,12 position induced fluid secretion, increased mucosal permeability, and produced mucosal damage as assessed by light and scanning electron microscopy and quantitated by DNA loss during perfusion. Replacement of hydroxy groups by keto groups or a change from alpha to beta configuration for the hydroxylic substituent in the 7 position abolished all three activities. Trisubstituted derivatives, whether hydroxy or keto, did not affect fluid secretion permeability or cause mucosal damage. These studies indicate that of the major primary and secondary bile acids in man, only deoxycholic and chenodeoxycholic acids alter colonic structure and function in the rabbit. They show further that the cathartic effects of bile acids have specific structural requirements; and they show that bile acid-induced secretion was invariably associated with increased mucosal permeability and epitheliolysis.
The effect of various doses of cheno-deoxycholic acid (C.D.C.A.) (250, 500, 750, and 1000 mg. per day) on bile-lipid composition and the frequency of side-effects were studied in 38 patients with gallstones. At a dose of 250 mg. per day, C.D.C.A. therapy did not reduce cholesterol saturation of bile in 3 of 7 patients, but treatment with 500 mg. C.D.C.A. per day or more led to a progressive desaturation of bile with cholesterol, the saturation index (unity representing a saturated, greater than unity a supersaturated, and less than unity an undersaturated solution) falling to 0·91 (±S.E.M. 0·11) with 500 mg., to 0·88±0·08 with 750 mg., and to 0·85±0·06 with 1000 mg. C.D.C.A. per day. While the response of bile-lipid composition to C.D.C.A. in individual patients was variable, the overall pattern of results suggested that the higher the dose, the greater the reduction in the saturation of bile with cholesterol. Diarrhœa was present in 40% of patients taking between 750-1000 mg. C.D.C.A. per day, and at these doses serum-glutamic-oxalo-acetic-transaminase was found to be slightly raised on at least one occasion during monthly checks in 7 out of 27 patients: a similar pattern was seen for serum isocitric dehydrogenase. However, other studies of liver function and structure were normal, irrespective of dose. On withdrawal of C.D.C.A. therapy, bile-lipid composition reverted to its supersaturated state, suggesting that once gallstones have been dissolved, long-term maintenance or intermittent C.D.C.A. therapy may be necessary.
In a double-blind controlled study of ursodeoxycholic acid (400 and 800 mg/day) and chenodeoxycholic acid (375 and 750 mg/day), in comparison with placebo, ursodeoxycholic acid was significantly more effective than chenodeoxycholic acid in dissolving gallstones after 12 mo of treatment. Although there continued to be better dissolution during ursodeoxycholic acid treatment (dissolution complete in 30% and partial in another 30% of the patients) than during chenodeoxycholic acid treatment (dissolution complete in 7% and partial in 40%) at 24 mo, this difference between the treatment groups was no longer statistically significant. The incidence of floating stones was significantly higher in the patients who dissolved their stones than in those who did not (p less than 0.001). The three failures of dissolution of floating stones during bile acid treatment were associated with chenodeoxycholic acid therapy--two of them with the 750-mg and the third with the 375-mg doses. Gallstone dissolution with ursodeoxycholic acid occurred in spite of a rise in biliary cholesterol saturation, which was consistent with a nonmicellar mechanism of cholelitholysis. Furthermore, more than threefold serum elevations of L-alanine aminotransferase were observed only during chenodeoxycholic acid therapy. They occurred in 2 patients treated with 375 and 750 mg/day, respectively. The enzyme levels normalized after discontinuation of chenodeoxycholic acid and have remained normal for 13 and 8 mo, respectively, after the institution of treatment with 800 mg/day of ursodeoxycholic acid. There was no correlation between the liver tests and biliary levels of lithocholic acid. Of all the symptoms studied, only constipation showed changes that approached statistical significance (p = 0.0681). There was a significant improvement of constipation in the combined chenodeoxycholic acid groups when they were compared with the combined ursodeoxycholic acid groups. The total bile acid pool expanded significantly in both the chenodeoxycholic acid and in the 800-mg ursodeoxycholic acid treatment groups. The marked increases of biliary ursodeoxycholic acid and chenodeoxycholic acid, respectively, indicated compliance with the treatment in all but 1 bile acid-treated patient. Neither serum triglycerides nor serum cholesterol showed significant changes in any of the treatment groups. The study shows that ursodeoxycholic acid dissolves gallstones faster and with fewer side effects than chenodeoxycholic acid. The results of the study are also consistent with the view that ursodeoxycholic acid is cholelitholytic at a lower dose than is chenodeoxycholic acid.
A self-assessment scale has been developed and found to be a reliable instrument for detecting states of depression and anxiety in the setting of an hospital medical outpatient clinic. The anxiety and depressive subscales are also valid measures of severity of the emotional disorder. It is suggested that the introduction of the scales into general hospital practice would facilitate the large task of detection and management of emotional disorder in patients under investigation and treatment in medical and surgical departments.
Chenodeoxycholic acid (chenic acid; CDCA) is 1 of the 3 major biliary bile acids in man. When administered in pharmacological doses it causes a decrease in cholesterol saturation of bile, which in turn may lead to gradual dissolution of cholesterol gallstones. The stone dissolution rate during CDCA therapy has varied considerably from about one-third of patients overall to 80 to 90% in a highly selected group of patients. Radiolucent gallstones in a functioning gallbladder are absolute requirements. CDCA is well tolerated; diarrhoea (sometimes requiring dosage reduction) is the only frequent side effect. Although hepatotoxicity has occurred in certain animal species, and slight hypertransaminasaemia has occurred in some patients, definite liver damage has not been observed in man. CDCA is considered contraindicated in pregnancy, and in those patients with the complications from gallstones which require immediate surgery. Care should be taken in patients with liver disease. The only other proven agent for dissolving gallstones is the 7 beta-epimer of CDCA, ursodeoxycholic acid (UDCA). Preliminary results show that UDCA is as effective as CDCA, but at one-half to two-thirds the dose, without causing diarrhoea. Further studies need to be done with both CDCA and UDCA to improve criteria for selection of patients most likely to respond, and to establish optimum schedules for dosage and duration of treatment.
The effects of bile acid (BA) concentration on fluid secretion, mucus secretion, and mucosal damage were investigated during dose-response studies in the rabbit colon with 1, 2.5, and 5 mM sodium chenodeoxycholate (NaCDC). 1 mM NaCDC resulted in mucus secretion followed by mucosal damage but no change in fluid transport was observed. At 2.5 mM concentration, mucus secretion and mucosal damage were evident within 1 hr of perfusion whereas fluid secretion developed in the second hour only. At 5 mM concentrations, all changes occurred simultaneously. The magnitude of changes increased with the concentration of BA perfused. These results are consistent with the hypothesis that mucus secretion with loss of its cytoprotective effect precedes, and thus may permit, the detergent effects of the di-alpha-hydroxy bile acid on the mucosa, resulting in mucosal damage. Both these effects precede changes in fluid and electrolyte transport.
The effect of equimolar concentrations of chenodeoxycholic (CDCA) and ursodeoxycholic acid (UDCA) on the colonic absorption of water, sodium and oxalate, and on the transmural potential difference was examined in the rat colon by an open perfusion technique. In addition, the ileal absorption of D-glucose, oxalate, water and sodium was measured in the presence and absence of CDCA and UDCA. CDCA reversed the absorption of water and sodium into secretion more effectively than UDCA Oxalate absorption and permeability of the colon measured by the disappearance of D-mannitol were enhanced by CDCA, but to a lesser extent by UDCA. The ileal absorption of water and sodium was nearly abolished by CDCA and inhibited to a lesser extent by UDCA in the presence of D-glucose in the perfusate. At equimolar concentrations, CDCA induced a more marked inhibitory effect on colonic function than UDCA. This quantitative difference may account for the less frequent side-effects of diarrhoea in cholelitholytic treatment with UDCA compared to CDCA.
Stool form scales are a simple method of assessing intestinal transit rate but are not widely used in clinical practice or research, possibly because of the lack of evidence that they are responsive to changes in transit time. We set out to assess the responsiveness of the Bristol stool form scale to change in transit time.
Sixty-six volunteers had their whole-gut transit time (WGTT) measured with radiopaque marker pellets and their stools weighed, and they kept a diary of their stool form on a 7-point scale and of their defecatory frequency. WGTT was then altered with senna and loperamide, and the measurements were repeated.
The base-line WGTT measurements correlated with defecatory frequency (r = 0.35, P = 0.005) and with stool output (r = -0.41, P = 0.001) but best with stool form (r = -0.54, P < 0.001). When the volunteers took senna (n = 44), the WGTT decreased, whereas defecatory frequency, stool form score, and stool output increased (all, P < 0.001). With loperamide (n = 43) all measurements changed in the opposite direction. Change in WGTT from base line correlated with change in defecatory frequency (r = 0.41, P < 0.001) and with change in stool output (n = -0.54, P < 0.001) but best with change in stool form (r = -0.65, P < 0.001).
This study has shown that a stool form scale can be used to monitor change in intestinal function. Such scales have utility in both clinical practice and research.
In 1990, when the Program on the Surgical Control of the Hyperlipidemias (POSCH) reported its in-trial results strongly supporting the conclusion that effective lipid modification reduces progression of atherosclerosis, the differences for the end points of overall mortality and mortality from atherosclerotic coronary heart disease (ACHD) did not reach statistical significance.
The Program on the Surgical Control of the Hyperlipidemias recruited men and women with a single documented myocardial infarction between the ages of 30 and 64 years who had a plasma cholesterol level higher than 5.69 mmol/L (220 mg/dL) or higher than 5.17 mmol/L (200 mg/dL) if the low-density lipoprotein cholesterol level was in excess of 3.62 mmol/L (140 mg/dL). Between 1975 and 1983, 838 patients were randomized: 417 to the diet control group and 421 to the diet plus partial ileal bypass intervention group. Mean patient follow-up for this 5-year posttrial report was 14.7 years (range, 12.2-20 years).
At 5 years after the trial, statistical significance was obtained for differences in overall mortality (P = .049) and mortality from ACHD (P = .03). Other POSCH end points included overall mortality (left ventricular ejection fraction > or =50%) (P = .01), mortality from ACHD (left ventricular ejection fraction > or =50%) (P = .05), mortality from ACHD and confirmed nonfatal myocardial infarction (P<.001), confirmed nonfatal myocardial infarction (P<.001), mortality from ACHD, confirmed and suspected myocardial infarction and unstable angina (P<.001), incidence of coronary artery bypass grafting or percutaneous transluminal coronary angioplasty (P<.001), and onset of clinical peripheral vascular disease (P = .02). There were no statistically significant differences between groups for cerebrovascular events, mortality from non-ACHD, and cancer. All POSCH patients have been available for follow-up.
At 5 years after the trial, all POSCH mortality and atherosclerosis end points, including overall mortality and mortality from ACHD, demonstrated statistically significant differences between the study groups.
The intra- and inter-individual reproducibility of gastrointestinal and colonic transit tests require full characterization.
(i) To characterize the normal values and reproducibility effects of age and gender on the scintigraphic transit of solids in health. (ii) To compare scintigraphic and radio-opaque marker measurements of colonic transit. (iii) To estimate demonstrable effect sizes for different transit end-points based on observed variations.
A scintigraphic gastrointestinal and colonic transit study and the mean colonic transit time were measured using radio-opaque markers in 37 healthy volunteers; 21 subjects had a repeat scintigraphic test 3 weeks later.
Gastric emptying at 4 h was highly reproducible (coefficient of variation, 4%) on repeat testing. The colonic measurement varied by more than 1 geometric centre unit in 37% of subjects at 24 h and in 26% of subjects at 48 h. There were no age- or gender-related differences in transit. Effect sizes demonstrable with 14 subjects per group were in the range previously shown to be clinically relevant: 25% change in gastric emptying at 4 h; 1.5 geometric centre unit change in colonic transit at 48 h.
These data demonstrate the reproducibility and performance to be expected of transit measurements and are essential for designing studies in experimental therapeutics.
Sensorimotor disorders of the stomach, small intestine and colon have a limited repertoire of clinical manifestations, and there is the potential for more than one mechanism to lead to symptoms. In many recent clinical trial programs of novel agents in neurogastroenterology, the emphasis has been primarily on symptom assessment of broad groups of patients identified by the Rome criteria. Drugs of potential value have fallen by the wayside with this approach. We propose the current paradigm is partly to blame; physiological testing should provide the basis for identifying more homogeneous populations and therapeutic targets within functional bowel disease, and this applies to the upper and lower gut. Here we summarize the evidence that certain biomarkers can, in a limited fashion, be used to predict the success of an experimental medicine in common disorders of gastrointestinal function, including the irritable bowel syndrome and functional dyspepsia. Although the current evidence is limited and is most convincingly demonstrated with examples of transit measurements (for loperamide, alosetron, tegaserod and piboserod), we perceive this paradigm that studies using validated and responsive biomarkers have an important role to play in drug development.
Bile acids play essential roles in the absorption of dietary lipids and in the regulation of bile acid biosynthesis. Recently, a G protein-coupled receptor, TGR5, was identified as a cell-surface bile acid receptor. In this study, we show that bile acids promote glucagon-like peptide-1 (GLP-1) secretion through TGR5 in a murine enteroendocrine cell line STC-1. In STC-1 cells, bile acids promoted GLP-1 secretion in a dose-dependent manner. As STC-1 cells express TGR5 mRNA, we examined whether bile acids induce GLP-1 secretion through TGR5. RNA interference experiments showed that reduced expression of TGR5 resulted in reduced secretion of GLP-1. Furthermore, transient transfection of STC-1 cells with an expression plasmid containing TGR5 significantly enhanced GLP-1 secretion, indicating that bile acids promote GLP-1 secretion through TGR5 in STC-1 cells. Bile acids induced rapid and dose-dependent elevation of intracellular cAMP levels in STC-1 cells. An adenylate cyclase inhibitor, MDL12330A, significantly suppressed bile acid-promoted GLP-1 secretion, suggesting that bile acids induce GLP-1 secretion via intracellular cAMP production in STC-1 cells.
Bile acid malabsorption has been shown to be associated with diarrhea in cases such as ileal resection Crohn's disease of the ileum, and radiation enteritis. The mechanisms of bile acid-induced diarrhea are not fully understood. Although the induction of colonic chloride secretion in response to bile acids has been extensively investigated, to date the direct effect of bile acids on intestinal chloride absorption has not been well defined. Therefore, the current studies were undertaken to investigate the effect of bile acids on the apical Cl(-)/OH(-) exchange process utilizing Caco2 monolayers as an in vitro cellular model. Cl(-)/OH(-) exchange activity was measured as DIDS-sensitive pH gradient-driven (36)Cl uptake. The results are summarized as follows: (i) short-term exposure (20 min) of Caco2 cells to taurodeoxycholate (TDC; 200 microM) and glycochenodeoxycholate (GCDC; 200 microM) acids significantly inhibited apical Cl(-)/OH(-) exchange (by approximately 60-70%); (ii) the Ca(2+) chelator BAPTA-AM blocked the inhibition by TDC; (iii) the reduction in Cl(-)/OH(-) exchange by TDC was reversed by the PKC inhibitor, chelerythrine chloride; (iv) functional and inhibitor studies indicated that TDC induced inhibition of Cl(-)/OH(-) exchange was mediated via the activation of the PKC beta I isoform; (v) the effect of TDC on apical Cl(-)/OH(-) exchange was completely blocked by the PI3 kinase inhibitor LY294002 (5 microM); and (vi) the PKA inhibitor, RpcAMP, had no effect on TDC induced inhibition of Cl(-)/OH(-) exchange. In conclusion, our studies provide direct evidence for inhibition of human intestinal apical Cl(-)/OH(-) exchange activity by bile acids via Ca(2+)-, PI3 kinase-, and PKC beta I-dependent pathways in Caco2 cells.
Oral linaclotide, a novel agonist of guanylate cylase-C, stimulates intestinal fluid secretion and transit, and decreases visceral hypersensitivity in animal studies. In healthy volunteers, linaclotide was safe, well tolerated, increased stool frequency, and decreased stool consistency and time to first bowel movement. This randomized, double-blind, placebo-controlled study evaluated the effects of oral linaclotide, 100 and 1000 microg once daily, in 36 women with constipation-predominant irritable bowel syndrome; colonic transit was normal in >50% patients.
Participants underwent 5-day baseline and 5-day treatment periods; gastrointestinal transit (by validated scintigraphy) and bowel function (by daily diaries) were assessed. Treatment effects were compared using analysis of covariance (baseline colonic transit as covariate) with pairwise comparisons of each dose vs placebo.
There was a significant overall treatment effect on ascending colon emptying half-time (P = .015) and overall colonic transit at 48 hours (P = .02) but not overall transit at 24 hours (P = ns), with a significant acceleration by linaclotide 1000 microg vs placebo (P = .004 and P = .01, respectively) but no significant effect of linaclotide 100-microg dose. There were significant overall treatment effects on stool frequency, stool consistency, ease of passage, and time to first bowel movement with a strong dose response for stool consistency (overall, P < .001). No safety issues were identified.
In women with constipation-predominant irritable bowel syndrome, linaclotide 1000 microg once daily significantly accelerated ascending colonic transit and altered bowel function. Further randomized controlled trials of clinical efficacy of linaclotide are warranted.
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