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

Dorner H, Stolzer I, Mattner J, Kaminski S, Leistl S, Edrich LM, Schwendner R, Hobauer J, Sebald A, Leikam S, Gonzalez Acera M, Düll M, Lang R, Seidel G, Seitz T, Hellerbrand C, Fuhrmann G, Distler U, Tenzer S, Eichhorn P, Vieth M, Schramm C, Arnold P, Becker C, Weidinger C, Siegmund B, Atreya R, Leppkes M, Naschberger E, Sampaziotis F, Dietrich P, Rauh M, Wirtz S, Kremer A, Neurath M, Günther C (2024)

Publication Type: Journal article

Publication year: 2024

Journal

Gastroenterology Elsevier

DOI: 10.1053/j.gastro.2024.06.032

Abstract

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.

Authors with CRIS profile

Heidrun Dorner Medizinische Fakultät Iris Stolzer Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Jochen Mattner Institute of Microbiology – Clinical Microbiology, Immunology and Hygiene Sophie Kaminski Lehrstuhl für Innere Medizin I (Medizin 1) Lisa-Maria Edrich Lehrstuhl für Innere Medizin I (Medizin 1) Raphael Schwendner Lehrstuhl für Innere Medizin I (Medizin 1) Julia Hobauer Lehrstuhl für Innere Medizin I (Medizin 1) Adrian Sebald Lehrstuhl für Innere Medizin I (Medizin 1) Stefanie Leikam Lehrstuhl für Innere Medizin I (Medizin 1) Miguel Gonzalez Acera Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Miriam Düll Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Roland Lang Professur für Angeborene Immunität und Pathogenerkennung Tatjana Seitz Professur für Biochemie und Molekulare Pathobiologie Claus Hellerbrand Professur für Biochemie und Molekulare Pathobiologie Gregor Fuhrmann Lehrstuhl für Pharmazeutische Biologie Philip Eichhorn Institute of Pathology Philipp Arnold Lehrstuhl für Funktionelle und Klinische Anatomie Moritz Leppkes Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Elisabeth Naschberger Medizinische Fakultät Peter Dietrich Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Stefan Wirtz Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Andreas Kremer Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Markus Neurath Lehrstuhl für Innere Medizin I (Medizin 1) Claudia Günther Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology

Additional Organisation(s)

FAU Forschungszentrum Neue Wirkstoffe (FAU NeW)

Involved external institutions

Universitätsmedizin der Johannes Gutenberg-Universität Mainz DE Germany (DE) Charité - Universitätsmedizin Berlin DE Germany (DE) Universitätsklinikum Hamburg-Eppendorf (UKE) DE Germany (DE) Wellcome - MRC Cambridge Stem Cell Institute GB United Kingdom (GB)

How to cite

APA:

Dorner, H., Stolzer, I., Mattner, J., Kaminski, S., Leistl, S., Edrich, L.-M.,... Günther, C. (2024). Gut Pathobiont–Derived Outer Membrane Vesicles Drive Liver Inflammation and Fibrosis in Primary Sclerosing Cholangitis–Associated Inflammatory Bowel Disease. Gastroenterology. https://doi.org/10.1053/j.gastro.2024.06.032

MLA:

Dorner, Heidrun, et al. "Gut Pathobiont–Derived Outer Membrane Vesicles Drive Liver Inflammation and Fibrosis in Primary Sclerosing Cholangitis–Associated Inflammatory Bowel Disease." Gastroenterology (2024).

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