The bile acid TGR5 membrane receptor: From basic research to clinical application

AbstractThe TGR5 receptor (or GP-BAR1, or M-BAR) was characterized ten years ago as the first identified G-coupled protein receptor specific for bile acids. TGR5 gene expression is widely distributed, including endocrine glands, adipocytes, muscles, immune organs, spinal cord, and the enteric nervous system. The effect of TGR5 activation depends on the tissue where it is expressed and the signalling cascade that it induces. Animal studies suggest that TGR5 activation influences energy production and thereby may be involved in obesity and diabetes. TGR5 activation also influences intestinal motility. This review provides an overview of TGR5-bile acid interactions in health as well as the possible involvement of TGR5 in human disease

230: Heightened risk of coronary atheroma conferred by a decrease in the plasma concentrations of lithocholic acid

ContextThe bile acids receptors Farsenoid X and TGR5 protect against the formation of atheroma in mice, though no evidence have linked coronary atheroma and bile acid in human. Bile acids links these receptors with more or less efficient activation, depending on the species.ObjectiveTo test the hypothesis that changes in concentrations of circulating bile acid species influence the risk of developing coronary atheromas in humans.MethodsPilot, prospective, observational study conducted between June and September 2010. The serum concentrations of cholic, chenodeoxycholic, deoxycholic, and lithocholic acids were measured in a fasting blood sample. Consecutive hospitalized or ambulatory patients undergoing emergency or elective coronary angiograms were eligible for inclusion. Post-cardiac arrest and non-fasting states, hepatic disease, and treatment with antimicrobials, corticosteroids, statins or fibrates were exclusion criteria. Of 393 screened patients, 44 met the study entry criteria, and were divided between 27 patients with (Group A) and 17 without (Group B) angiographically visible coronary atheromas. The pool of circulating bile acids was analyzed to measure the plasmatic concentrations of 28 different bile acid species. The variables associated with the presence of angiographically visible coronary atheromas were examined by single and multiple variable logistic regression analysis.ResultsThe serum lithocholic acid concentration was significantly lower in group A than in group B. By multiple variable analysis, lithocholic acid was the only predictor of coronary atheroma independently of patient gender (odds ratio 2.41 per 0.05 decrease; 95% confidence interval 1.11 to 5.25, P=0.027ConclusionA low serum concentration of lithocholic acid was an independent predictor of coronary atheroma in human

Saccharomyces boulardii CNCM I-745 Modulates the Fecal Bile Acids Metabolism During Antimicrobial Therapy in Healthy Volunteers

Saccharomyces boulardii CNCM I-745 (SB) is a probiotic yeast used to lower the incidence of antibiotic-associated Clostridium difficile (C. difficile) infection, though its mechanism of action remains unclear. Cholic acid is a primary bile acid, which triggers the germination and promotes the growth of C. difficile. The intestinal microbiota transforms primary into secondary bile acids. This study examined (1) the antimicrobial-induced alteration of fecal bile acid content, and (2) whether the concomitant administration of SB influences this transformation. This is an ancillary work from a randomized study, which revealed that SB modulates fecal microbiota dysbiosis during antibiotic treatment. Healthy subjects were randomly assigned to (1) SB only, (2) amoxicillin-clavulanate (AC), (3) SB plus AC, or (4) no treatment. We analyzed fecal concentrations of BA by high performance liquid chromatography/tandem mass spectrometry. Compared to the untreated or the SB-treated groups, AC decreased the percentage of fecal secondary BA significantly (days 3 and 7). When SB and AC were administered concomitantly, this decrease in secondary BA was no longer significant. Following treatment with AC, a significant peak of fecal CA was measured on days 3 and 7, which was prevented by the concomitant administration of SB. AC administered to healthy volunteers altered the microbial transformation of primary BA, decreased secondary BA, and increased CA. The latter was prevented by the concomitant administration of SB and AC, suggesting a potent mechanism protection conferred by SB against post-antimicrobial C. difficile infection.Clinical Trial Registration:www.ClinicalTrials.gov, identifier NCT01473368

Inhibitory Effect of Ursodeoxycholic Acid on Clostridium difficile Germination Is Insufficient to Prevent Colitis: A Study in Hamsters and Humans

Introduction: Bile acids (BA) influence germination and growth of Clostridium difficile. Ursodeoxycholic acid (UDCA), a BA minor in human, used for cholestatic liver diseases, inhibits germination and growth of C. difficile in vitro, but was never tested in vivo with an infectious challenge versus control. We hypothesized that UDCA could prevent CDI. We evaluated the effects of UDCA on C. difficile in vitro and in hamsters, with pharmacokinetics study and with an infectious challenge. Then, we studied CDI incidence in UDCA–treated patients.Methods: We evaluated germination and growth of C. difficile, with 0.01, 0.05, and 0.1% UDCA. We analyzed fecal BA of hamsters receiving antibiotics and UDCA (50 mg/kg/day), antibiotics, or UDCA alone. Then, we challenged with spores of C. difficile at D6 hamsters treated with UDCA (50 mg/kg/day) from D1 to D13, versus control. In human, we analyzed the database of a cohort on CDI in acute flares of inflammatory bowel disease (IBD). As PSC-IBD patients were under UDCA treatment, we compared PSC-IBD patients to IBD patients without PSC.Results:In vitro, UDCA inhibited germination and growth of C. difficile at 0.05 and 0.1%, competing with 0.1% TCA (with 0.1%: 0.05% ± 0.05% colony forming unit versus 100% ± 0%, P < 0.0001). In hamsters, UDCA reached high levels only when administered with antibiotics (43.5% UDCA at D5). Without antibiotics, UDCA was in small amount in feces (max. 4.28%), probably because of UDCA transformation into LCA by gut microbiota. During infectious challenge, mortality was similar in animals treated or not with UDCA (62.5%, n = 5/8, P = 0.78). UDCA percentage was high, similar and with the same kinetics in dead and surviving hamsters. However, dead hamsters had a higher ratio of primary over secondary BA compared to surviving hamsters. 9% (n = 41/404) of IBD patients without PSC had a CDI, versus 25% (n = 4/12) of PSC-IBD patients treated with UDCA.Conclusion: We confirmed the inhibitory effect of UDCA on growth and germination of C. difficile in vitro, with 0.05 or 0.1% UDCA. However, in our hamster model, UDCA was inefficient to prevent CDI, despite high levels of UDCA in feces. Patients with PSC-IBD treated with UDCA did not have less CDI than IBD patients

Clinical Heterogeneity of Duchenne Muscular Dystrophy (DMD): Definition of Sub-Phenotypes and Predictive Criteria by Long-Term Follow-Up

International audienceBACKGROUND: To explore clinical heterogeneity of Duchenne muscular dystrophy (DMD), viewed as a major obstacle to the interpretation of therapeutic trials METHODOLOGY/PRINCIPAL FINDINGS: A retrospective single institution long-term follow-up study was carried out in DMD patients with both complete lack of muscle dystrophin and genotyping. An exploratory series (series 1) was used to assess phenotypic heterogeneity and to identify early criteria predicting future outcome; it included 75 consecutive steroid-free patients, longitudinally evaluated for motor, respiratory, cardiac and cognitive functions (median follow-up: 10.5 yrs). A validation series (series 2) was used to test robustness of the selected predictive criteria; it included 34 more routinely evaluated patients (age>12 yrs). Multivariate analysis of series 1 classified 70/75 patients into 4 clusters with distinctive intellectual and motor outcomes: A (early infantile DMD, 20%): severe intellectual and motor outcomes; B (classical DMD, 28%): intermediate intellectual and poor motor outcome; C (moderate pure motor DMD, 22%): normal intelligence and delayed motor impairment; and D (severe pure motor DMD, 30%): normal intelligence and poor motor outcome. Group A patients had the most severe respiratory and cardiac involvement. Frequency of mutations upstream to exon 30 increased from group A to D, but genotype/phenotype correlations were restricted to cognition (IQ>71: OR 7.7, 95%CI 1.6-20.4, p6 at 8 yrs" with "normal or borderline mental status" reliably assigned patients to group C (sensitivity: 1, specificity: 0.94). These criteria were also predictive of "early infantile DMD" and "moderate pure motor DMD" in series 2. CONCLUSIONS/SIGNIFICANCE: DMD can be divided into 4 sub-phenotypes differing by severity of muscle and brain dysfunction. Simple early criteria can be used to include patients with similar outcomes in future therapeutic trials

Dysbiose et métabolisme des acides biliaires (implications au cours du syndrome de l intestin irritable)

Le syndrome de l'intestin irritable associe douleurs abdominales chroniques et troubles du transit. C'est une pathologie digestive fréquente, qui dans sa physiopathologie inclue le concept de dysbiose, i.e les perturbations du microbiote intestinal (l'ensemble des micro organismes contenus dans un intestin). La dysbiose sous entend des perturbations du dialogue hôte-microbiote conduisant à la maladie, concept essentiellement descriptif à ce jour. Les acides biliaires sont synthétisés par le foie, métabolisés par les bactéries puis réabsorbés par l'intestin - donc potentiellement acteurs de ce dialogue. D'autres axes physiopathologiques incluent motricité, perméabilité, et sécrétion intestinale, des fonctions également régulées par les acides biliaires, via le récepteur membranaire TGR5. Ce travail présente et discute, à travers deux publications scientifiques les liens entre syndrome de l'intestin irritable, dysbiose, et récepteur TGR5The irritable bowel syndrome associates chronic abdominal pain and altered bowel transit. This is a common digestive disorder, which in its pathophysiology include the concept of dysbiosis, i.e disruption of the intestinal microbiota (overall micro organisms in a gut). Dysbiosis implies alterations of the host-microbiota dialogue leading to disease, a mainly descriptive concept to date. Bile acids are synthesized by the liver and metabolized by bacteria then reabsorbed from the intestine - so potentially involved in this dialogue. Other pathophysiological axes include motor, permeability, and intestinal secretion, and theses are functions also regulated by bile acids, through the membrane receptor TGR5. This work presents and discusses, through two scientific publications, the links between irritable bowel syndrome, dysbiosis, and TGR5 receptorPARIS-BIUSJ-Biologie recherche (751052107) / SudocSudocFranceF

Influence of Nutritional Factors on the Nature, Yield, and Composition of Exopolysaccharides Produced by Gluconacetobacter xylinus I-2281

The influence of substrate composition on the yield, nature, and composition of exopolysaccharides (EPS) produced by the food-grade strain Gluconacetobacter xylinus I-2281 was investigated during controlled cultivations on mixed substrates containing acetate and either glucose, sucrose, or fructose. Enzymatic activity analysis and acid hydrolysis revealed that two EPS, gluconacetan and levan, were produced by G. xylinus. In contrast to other acetic acid strains, no exocellulose formation has been measured. Considerable differences in metabolite yields have been observed with regard to the carbohydrate source. It was shown that glucose was inadequate for EPS production since most of this substrate (0.84 C-mol/C-mol) was oxidized into gluconic acid, 2-ketogluconic acid, and 5-ketogluconic acid. In contrast, sucrose and fructose supported a 0.35 C-mol/C-mol gluconacetan yield. In addition, growing G. xylinus on sucrose produced a 0.07 C-mol/C-mol levan yield. The composition of EPS remained unchanged during the course of the fermentations. Levan sucrase activity was found to be mainly membrane associated. In addition to levan production, an analysis of levan sucrase's activity also explained the formation of glucose oxides during fermentation on sucrose through the release of glucose. The biosynthetic pathway of gluconacetan synthesis has also been explored. Although the activity of key enzymes showed large differences to be a function of the carbon source, the ratio of their activities remained similar from one carbon source to another and corresponded to the ratio of precursor needs as deduced from the gluconacetan composition