Protective potential of the gallbladder in primary sclerosing cholangitis

Background & Aims: Gallbladder enlargement is common in patients with primary sclerosing cholangitis (PSC). The gallbladder may confer hepatoprotection against bile acid overload, through the sequestration and cholecystohepatic shunt of bile acids. The aim of this study was to assess the potential impact of the gallbladder on disease features and bile acid homeostasis in PSC.Methods: Patients with PSC from a single tertiary center who underwent liver MRI with three-dimensional cholangiography and concomitant analyses of serum bile acids were included. Gallbladder volume was measured by MRI and a cut-off of 50 ml was used to define gallbladder enlargement. Bile acid profiles and PSC severity, as assessed by blood tests and MRI features, were compared among patients according to gallbladder size (enlarged vs. normal-sized) or presence (removed vs. conserved). The impact of cholecystectomy was also assessed in the Abcb4 knockout mouse model of PSC.Results: Sixty-one patients with PSC, all treated with ursodeoxycholic acid (UDCA), were included. The gallbladder was enlarged in 30 patients, whereas 11 patients had been previously cholecystectomized. Patients with enlarged gallbladders had significantly lower alkaline phosphatase, a lower tauro-vs. glycoconjugate ratio and a higher UDCA vs. total bile acid ratio compared to those with normal-sized gallbladders. In addition, gallbladder volume negatively correlated with the hydrophobicity index of bile acids. Cholecystectomized patients displayed significantly higher aspartate aminotransferase and more severe bile duct strictures and dilatations compared to those with conserved gallbladder. In the Abcb4 knockout mice, cholecystectomy caused an increase in hepatic bile acid content and in circulating secondary bile acids, and an aggravation in cholangitis, inflammation and liver fibrosis.Conclusion: Altogether, our findings indicate that the gallbladder fulfills protective functions in PSC.Impact and implications: In patients with primary sclerosing cholangitis (PSC), gallbladder status impacts on bile acid homeostasis and disease features. We found evidence of lessened bile acid toxicity in patients with PSC and enlarged gall-bladders and of increased disease severity in those who were previously cholecystectomized. In the Abcb4 knockout mouse model of PSC, cholecystectomy causes an aggravation of cholangitis and liver fibrosis. Overall, our results suggest that the gallbladder plays a protective role in PSC.& COPY; 2022 The Authors. Published by Elsevier B.V. on behalf of European Association for the Study of the Liver (EASL). This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)

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

Le site antique et médiéval de Bessoncourt. Les Rives de l'Autruche

International audienc

Thervay, Entre Deux Vies : un établissement rural antique inédit dans la vallée de l'Ognon : rapport de fouille

Situé dans la vallée de l’Ognon, cet établissement rural antique inédit enrichit le corpus déjà dense des sites antiques de ce secteur géographique. La présence de nombreuses villae (Jallerange, Brans, Vitreux, ...) de différents gabarits est à mettre en relation avec une exploitation intensive du terroir, sur ces sols riches des terrasses alluviales de la rive gauche de cette vallée. L’établissement de Thervay appartient ainsi à l’arrière-pays rural de l’agglomération secondaire, située sous l’actuel village de Dammartin (Jura) où passe une voie qui relie le chef-lieu de la cité des Séquanes, aux agglomérations secondaires au sud du territoire lingon (Pontailler-sur-Saône, Mirebeau, Til-Châtel, Beneuvre, Dijon, Mâlain).Deux phases d’occupation ont été mises en évidence sur ce site : un état initial sur poteaux (Ier siècle de notre ère?) et une construction finale en maçonnerie assez bien conservée des IIe et IIIe siècles de notre ère. Le mobilier découvert (céramiques, monnaies…) et l’absence totale des monnaies antoniniennes tardives en billon de bas titre (notamment du monnayage de Victorinus et des Tetricus), rendent peu vraisemblable la pérennité de l’occupation au-delà du tournant des années 260-270, période à laquelle ces monnaies circulent en grande quantité.Le bâtiment en maçonnerie (25 × 20 m) possède un plan d’édifice rural déjà connu, en particulier dans le Nord de la Gaule : la villa à tour d’angles (Serville en Belgique, Konz et Leudersdof en Allemagne…). Il se compose d’un corps principal à pièce unique avec foyer (15 × 11 m), précédé en façade d’une galerie à portique (15 × 3 m) et flanqué de deux tours d’angle recevant chacune, deux pièces. Les sols sont essentiellement constitués de terre battue, si ce n’est les sols des pièces de la tour d’angle sud qui sont en terrazzo. Ce traitement particulier peut indiquer une fonction de stockage pour cet espace.Si une voie privative, en arrière de l’habitat, permettait d’atteindre la limite ouest du domaine signalée par un portail, la façade principale s’ouvre, quant à elle, à l’est, sur une cour close par un muret.Un dépôt de harnachement de cheval a été découvert à l’extérieur de la cour, dissimulé dans un caisson de tuiles, contre le parement extérieur du mur de clôture. La disposition des différents éléments de la bride (phalères, anneaux, rivets…) sur trois niveaux prouve que cette dernière a été déposée, soigneusement pliée. La présence d’équidé est confirmée par la découverte dans la cour de quatre hipposandales

Variations in gastrointestinal lipases, pH and bile acid levels with food intake, age and diseases: Possible impact on oral lipid-based drug delivery systems

International audienceThe lipids and some surfactants present in oral lipid-based drug delivery systems are potential substrates for the various lipases involved in gastrointestinal (GI) lipolysis. The levels of these enzymes, together with pH and biliairy secretion, are important parameters that condition the fate of lipid-based formulations (LBF) and the dispersion, solubilization and absorption of lipophilic drugs in the GI tract. Since in vitro methods of digestion are now combined with dissolution assays for a better assessment of LBF performance, it is essential to have a basic knowledge on lipase, pH and bile acid (BA) levels in vivo to develop relevant in vitro models. While these parameters and their variations in healthy subjects are today well documented, in vivo data on specific populations (age groups, patients with various diseases, patients with treatment affecting GI tract parameters, …) are scarce and obtaining them from clinical studies is sometimes difficult due to ethical limitations. Here we collected some in vivo data already available on the levels of digestive lipases, gastric and intestinal pH, and BAs at various ages and in patients with exocrine pancreatic insufficiency, a pathological situation that leads to drastic changes in GI tract parameters and impacts pharmacological treatments

Progressive and Preferential Cellular Accumulation of Hydrophobic Bile Acids Induced by Cholestatic Drugs Is Associated with Inhibition of Their Amidation and Sulfation

International audienceDrug-induced intrahepatic cholestasis is characterized by cellular accumulation of bile acids (BAs), whose mechanisms remain poorly understood. The present study aimed to analyze early and progressive alterations of BA profiles induced by cyclosporine A, chlorpromazine, troglitazone, tolcapone, trovafloxacin, and tacrolimus after 4-hour, 24-hour, and 6-day treatments of differentiated HepaRG cells. In BA-free medium, the potent cholestatic drugs cyclosporine A, chlorpromazine, and troglitazone reduced endogenous BA synthesis after 24 hours, whereas the rarely cholestatic drugs tolcapone, trovafloxacin, and tacrolimus reduced BA synthesis only after 6 days. In the presence of physiologic serum BA concentrations, cyclosporine A, chlorpromazine, and troglitazone induced early and preferential cellular accumulation of unconjugated lithocholic, deoxycholic, and chenodeoxycholic acids that increased 8- to 12-fold and 47- to 50-fold after 24 hours and 6 days, respectively. Accumulation of these hydrophobic BAs resulted from strong inhibition of amidation, and in addition, for lithocholic acid reduction of its sulfoconjugation, and was associated with variable alterations of uptake and efflux transporters. Trovafloxacin also caused BA accumulation, especially after 6 days, whereas tolcapone and tacrolimus were still without effect. However, when exogenous BAs were added to the medium at cholestatic serum concentrations, a 6-day treatment with all drugs resulted in cellular BA accumulation with higher folds of chenodeoxycholic and lithocholic acids. At the tested concentration, tolcapone had the lowest effect. These results bring the first demonstration that major cholestatic drugs can cause preferential and progressive in vitro cellular accumulation of unconjugated toxic hydrophobic BAs and bring new insights into mechanisms involved in drug-induced cellular accumulation of toxic BAs

Diurnal Interplay between Epithelium Physiology and Gut Microbiota as a Metronome for Orchestrating Immune and Metabolic Homeostasis

The behavior and physiology of most organisms are temporally coordinated and aligned with geophysical time by a complex interplay between the master and peripheral clocks. Disruption of such rhythmic physiological activities that are hierarchically organized has been linked to a greater risk of developing diseases ranging from cancer to metabolic syndrome. Herein, we summarize the molecular clockwork that is employed by intestinal epithelial cells to anticipate environmental changes such as rhythmic food intake and potentially dangerous environmental stress. We also discuss recent discoveries contributing to our understanding of how a proper rhythm of intestinal stem cells may achieve coherence for the maintenance of tissue integrity. Emerging evidence indicates that the circadian oscillations in the composition of the microbiota may operate as an important metronome for the proper preservation of intestinal physiology and more. Furthermore, in this review, we outline how epigenetic clocks that are based on DNA methylation levels may extensively rewire the clock-controlled functions of the intestinal epithelium that are believed to become arrhythmic during aging

Reverse changes in Duodenal and Plasma Bile Acid Concentrations in Severe Chronic Pancreatitis Patients and Healthy Volunteers during a Meal

International audienc