1. Gut microbiota depletion exacerbates cholestatic liver injury via loss of FXR signalling
- Author
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Christian Trautwein, Maiju Myllys, Antje Mohs, Lena Susanna Candels, Till Strowig, Maximilian Hatting, Lijun Liao, Carolin V. Schneider, Tom H. Karlsen, A. Sloan Devlin, Sebastian Zühlke, Hanns-Ulrich Marschall, Konrad Kilic, Eric J. C. Gálvez, A Zaza, Annika Wahlström, Reham Hassan, Ahmed Ghallab, Johannes R. Hov, Jan G. Hengstler, Antonio Molinaro, Kai Markus Schneider, Marcus Henricsson, Dirk Drasdo, M. Frissen, C Elfers, Department of Medicine III, University hospital (UKA), University of Aachen (RWTH), Rheinisch-Westfälische Technische Hochschule Aachen (RWTH)-University hospital (UKA), Oslo University Hospital [Oslo], Leibniz Research Centre for Working Environment and Human Factors [Dortmund] (IFADO), Technische Universität Dortmund [Dortmund] (TU), Sahlgrenska Academy at University of Gothenburg [Göteborg], SImulations en Médecine, BIOtechnologie et ToXicologie de systèmes multicellulaires (SIMBIOTX ), Inria Saclay - Ile de France, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Department of Biological Chemistry and Molecular Pharmacology [Harvard Medical School], Harvard Medical School [Boston] (HMS), Helmholtz Centre for Infection Research, Braunschweig, Germany, Universitätsklinikum RWTH Aachen - University Hospital Aachen [Aachen, Germany] (UKA), Rheinisch-Westfälische Technische Hochschule Aachen University (RWTH), Modelling and Analysis for Medical and Biological Applications (MAMBA), Inria de Paris, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Laboratoire Jacques-Louis Lions (LJLL (UMR_7598)), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Helmholtz Centre for Infection Research (HZI), and This study was supported by the German Research Foundation (DFG) (grants CRC1382, TR285/10-2, GRK 2375 to C.T.), the Federal Ministry of Education and Research (ObiHep grant no. 01KU1214A to C.T.), the Liver-LiSyM grant (BMBF) to C.T. (031L0041), A.G. (FKZ 031L0052) and J.G.H. (031L0045), the HDHL-INTIMIC Di-Mi-Liv to C.T., K.M.S. and H.U.M., the BMBF Knowledge Platform on Food, Diet, Intestinal Microbiomics and Human Health to C.T. and K.M.S., the SFB 985 project C3 to C.T., the Interdisciplinary Centre for Clinical Research (START grant no. 691438) within the Faculty of Medicine at RWTH Aachen University, the Helmholtz Association (to T.S.), the Swedish Research Council to H.U.M., and the German National Academic Foundation (to C.E. and K.M.S.). C.V.S. is supported by a Walter-Benjamin Fellowship from the DFG (SCHN 1640/1-1). K.M.S. is supported by the DFG consortium (SCHN 1626/1-1).
- Subjects
ATP Binding Cassette Transporter, Subfamily B ,medicine.drug_class ,Endocrinology, Diabetes and Metabolism ,Cholangitis, Sclerosing ,Receptors, Cytoplasmic and Nuclear ,Gut flora ,Cholesterol 7 alpha-hydroxylase ,digestive system ,Primary sclerosing cholangitis ,Bile Acids and Salts ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Physiology (medical) ,Internal Medicine ,Medicine ,Animals ,Humans ,ComputingMilieux_MISCELLANEOUS ,030304 developmental biology ,Liver injury ,0303 health sciences ,Cholestasis ,biology ,Bile acid ,business.industry ,Bile duct ,digestive, oral, and skin physiology ,Cell Biology ,biology.organism_classification ,medicine.disease ,Prognosis ,[INFO.INFO-MO]Computer Science [cs]/Modeling and Simulation ,Pathophysiology ,3. Good health ,Anti-Bacterial Agents ,Gastrointestinal Microbiome ,medicine.anatomical_structure ,Liver ,Cancer research ,030211 gastroenterology & hepatology ,Farnesoid X receptor ,business ,Signal Transduction - Abstract
International audience; Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease of unknown aetiology for which there are no approved therapeutic options. Patients with PSC display changes in gut microbiota and in bile acid (BA) composition; however, the contribution of these alterations to disease pathogenesis remains controversial. Here we identify a role for microbiota-dependent changes in BA synthesis that modulates PSC pathophysiology. In a genetic mouse model of PSC, we show that loss of microbiota-mediated negative feedback control of BA synthesis results in increased hepatic BA concentrations, disruption of bile duct barrier function and, consequently, fatal liver injury. We further show that these changes are dependent on decreased BA signalling to the farnesoid X receptor, which modulates the activity of the rate-limiting enzyme in BA synthesis, CYP7A1. Moreover, patients with advanced stages of PSC show suppressed BA synthesis as measured by serum C4 levels, which is associated with poor disease prognosis. Our preclinical data highlight the microbiota-dependent dynamics of BA metabolism in cholestatic liver disease, which could be important for future therapies targeting BA and gut microbiome interactions, and identify C4 as a potential biomarker to functionally stratify patients with PSC and predict disease outcomes.
- Published
- 2021
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