Gut Pathobiont-Derived Outer Membrane Vesicles Drive Liver Inflammation and Fibrosis in Primary Sclerosing Cholangitis-Associated Inflammatory Bowel Disease.

Autor:	Dorner H; Department of Medicine 1, Universitätsklinikum Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany., Stolzer I; Department of Medicine 1, Universitätsklinikum Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany., Mattner J; Institute of Clinical Microbiology, Immunology and Hygiene, Universitätsklinikum Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany; Friedrich-Alexander-Universität Erlangen-Nürnberg Profile Center Immunomedicine, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany., Kaminski S; Department of Medicine 1, Universitätsklinikum Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany., Leistl S; Department of Medicine 1, Universitätsklinikum Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany., Edrich LM; Department of Medicine 1, Universitätsklinikum Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany., Schwendner R; Department of Medicine 1, Universitätsklinikum Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany., Hobauer J; Department of Medicine 1, Universitätsklinikum Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany., Sebald A; Department of Medicine 1, Universitätsklinikum Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany., Leikam S; Department of Medicine 1, Universitätsklinikum Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany., Gonzalez Acera M; Department of Medicine 1, Universitätsklinikum Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany., Düll M; Department of Medicine 1, Universitätsklinikum Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany., Lang R; Institute of Clinical Microbiology, Immunology and Hygiene, Universitätsklinikum Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany; Friedrich-Alexander-Universität Erlangen-Nürnberg Profile Center Immunomedicine, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany., Seidel G; Microbiology, Department of Biology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany., Seitz T; Institute of Biochemistry, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany., Hellerbrand C; Institute of Biochemistry, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany., Fuhrmann G; Department of Biology, Pharmaceutical Biology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany., Distler U; Institute of Immunology, University Medical Center of the Johannes-Gutenberg University, Mainz, Germany., Tenzer S; Institute of Immunology, University Medical Center of the Johannes-Gutenberg University, Mainz, Germany., Eichhorn P; Institute of Pathology, Universitätsklinikum Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany., Vieth M; Institute of Pathology, Klinikum Bayreuth, Friedrich-Alexander-Universität Erlangen-Nürnberg, Bayreuth, Germany., Schramm C; Department of Medicine, Martin Zeitz Center for Rare Diseases, University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Arnold P; Institute of Functional and Clinical Anatomy, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany., Becker C; Department of Medicine 1, Universitätsklinikum Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany; Friedrich-Alexander-Universität Erlangen-Nürnberg Profile Center Immunomedicine, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany; Deutsches Zentrum Immuntherapie, Universitätsklinikum Erlangen, Erlangen, Germany., Weidinger C; Division of Gastroenterology, Infectiology and Rheumatology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany., Siegmund B; Division of Gastroenterology, Infectiology and Rheumatology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany., Atreya R; Department of Medicine 1, Universitätsklinikum Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany; Friedrich-Alexander-Universität Erlangen-Nürnberg Profile Center Immunomedicine, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany; Deutsches Zentrum Immuntherapie, Universitätsklinikum Erlangen, Erlangen, Germany., Leppkes M; Department of Medicine 1, Universitätsklinikum Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany; Deutsches Zentrum Immuntherapie, Universitätsklinikum Erlangen, Erlangen, Germany., Naschberger E; Division of Molecular and Experimental Surgery, Department of Surgery, Universitätsklinikum Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany., Sampaziotis F; Wellcome-Medical Research Council Cambridge Stem Cell Institute, Cambridge, United Kingdom; Cambridge Liver Unit, Cambridge University Hospitals National Health Service Foundation Trust, Cambridge, United Kingdom; Department of Medicine, University of Cambridge, Cambridge, United Kingdom., Dietrich P; Department of Medicine 1, Universitätsklinikum Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany; Institute of Biochemistry, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany., Rauh M; Research Laboratory, Division of Pediatrics, Universitätsklinikum Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany., Wirtz S; Department of Medicine 1, Universitätsklinikum Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany; Friedrich-Alexander-Universität Erlangen-Nürnberg Profile Center Immunomedicine, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany; Deutsches Zentrum Immuntherapie, Universitätsklinikum Erlangen, Erlangen, Germany., Kremer AE; Department of Medicine 1, Universitätsklinikum Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany; Deutsches Zentrum Immuntherapie, Universitätsklinikum Erlangen, Erlangen, Germany; Department of Gastroenterology and Hepatology, University Hospital Zürich, University of Zürich, Zürich, Switzerland., Neurath MF; Department of Medicine 1, Universitätsklinikum Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany; Friedrich-Alexander-Universität Erlangen-Nürnberg Profile Center Immunomedicine, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany; Deutsches Zentrum Immuntherapie, Universitätsklinikum Erlangen, Erlangen, Germany., Günther C; Department of Medicine 1, Universitätsklinikum Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany; Friedrich-Alexander-Universität Erlangen-Nürnberg Profile Center Immunomedicine, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany; Deutsches Zentrum Immuntherapie, Universitätsklinikum Erlangen, Erlangen, Germany. Electronic address: c.guenther@uk-erlangen.de.
Jazyk:	angličtina
Zdroj:	Gastroenterology [Gastroenterology] 2024 Nov; Vol. 167 (6), pp. 1183-1197.e16. Date of Electronic Publication: 2024 Jul 09.
DOI:	10.1053/j.gastro.2024.06.032
Abstrakt:	Background & Aims: Primary sclerosing cholangitis (PSC), often associated with inflammatory bowel disease (IBD), presents a multifactorial etiology involving genetic, immunologic, and environmental factors. Gut dysbiosis and bacterial translocation have been implicated in PSC-IBD, yet the precise mechanisms underlying their pathogenesis remain elusive. Here, we describe the role of gut pathobionts in promoting liver inflammation and fibrosis due to the release of bacterial outer membrane vesicles (OMVs). Methods: Preclinical mouse models in addition to ductal organoids were used to acquire mechanistic data. A proof-of-concept study including serum and liver biopsies of a patient cohort of PSC (n = 22), PSC-IBD (n = 45), and control individuals (n = 27) was performed to detect OMVs in the systemic circulation and liver. Results: In both preclinical model systems and in patients with PSC-IBD, the translocation of OMVs to the liver correlated with enhanced bacterial sensing and accumulation of the NLRP3 inflammasome. Using ductal organoids, we were able to precisely attribute the pro-inflammatory and pro-fibrogenic properties of OMVs to signaling pathways dependent on Toll-like receptor 4 and NLRP3-gasdermin-D. The immunostimulatory potential of OMVs could be confirmed in macrophages and hepatic stellate cells. Furthermore, when we administered gut pathobiont-derived OMVs to Mdr2 -/- mice, we observed a significant enhancement in liver inflammation and fibrosis. In a translational approach, we substantiated the presence of OMVs in the systemic circulation and hepatic regions of severe fibrosis using a PSC-IBD patient cohort. Conclusions: This study demonstrates the contribution of gut pathobionts in releasing OMVs that traverse the mucosal barrier and, thus, promote liver inflammation and fibrosis in PSC-IBD. OMVs might represent a critical new environmental factor that interacts with other disease factors to cause inflammation and thus define potential new targets for fibrosis therapy. (Copyright © 2024 AGA Institute. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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