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

被引：5

作者：

Dorner, Heidrun ^{[1
,2
]}

Stolzer, Iris ^{[1
,2
]}

Mattner, Jochen ^{[3
,4
]}

Kaminski, Sophie ^{[1
,2
]}

Leistl, Sofia ^{[1
,2
]}

Edrich, Lisa-Maria ^{[1
,2
]}

Schwendner, Raphael ^{[1
,2
]}

Hobauer, Julia ^{[1
,2
]}

Sebald, Adrian ^{[1
,2
]}

Leikam, Stefanie ^{[1
,2
]}

Acera, Miguel Gonzalez ^{[1
,2
]}

Duell, Miriam ^{[1
,2
]}

Lang, Roland ^{[2
,3
,4
]}

Seidel, Gerald ^{[5
]}

Seitz, Tatjana ^{[6
]}

Hellerbrand, Claus ^{[6
]}

Fuhrmann, Gregor ^{[7
]}

Distler, Ute ^{[8
]}

Tenzer, Stefan ^{[8
]}

Eichhorn, Phillip ^{[2
,9
]}

Vieth, Michael ^{[10
]}

Schramm, Christoph ^{[11
]}

Arnold, Philipp ^{[12
]}

Becker, Christoph ^{[1
,2
,4
,13
]}

Weidinger, Carl ^{[14
,15
,16
]}

Siegmund, Britta ^{[14
,15
,16
]}

Atreya, Raja ^{[4
,13
]}

Leppkes, Moritz ^{[13
]}

Naschberger, Elisabeth ^{[2
,17
]}

Sampaziotis, Fotios ^{[18
,19
,20
]}

Dietrich, Peter ^{[2
,6
]}

Rauh, Manfred ^{[2
,21
]}

Wirtz, Stefan ^{[1
,2
,4
,13
]}

Kremer, Andreas E. ^{[1
,2
,13
,22
]}

Neurath, Markus F. ^{[1
,2
,4
,13
]}

Guenther, Claudia ^{[1
,2
,4
,13
]}

机构：

[1] Dept Med 1, Universitatsklinikum Erlangen, Dept Med Gastroenterol Pneumol & Endocrinol 1, Kussmaulallee 4, D-91054 Erlangen, Germany

[2] Friedrich Alexander Univ Erlangen Nurnberg, Erlangen, Germany

[3] Univ Kinikum Erlangen, Inst Clin Microbiol, Erlangen, Germany

[4] Friedrich Alexander Univ Erlangen Nurnberg, Profile Ctr Immunomedicine, Erlangen, Germany

[5] Friedrich Alexander Univ Erlangen Nurnberg, Dept Biol, Microbiol, Erlangen, Germany

[6] Friedrich Alexander Univ Erlangen Nurnberg, Inst Biochem, Erlangen, Germany

[7] Friedrich Alexander Univ Erlangen Nurnberg, Dept Biol, Erlangen, Germany

[8] Johannes Gutenberg Univ Mainz, Univ Med Ctr, Inst Immunol, Mainz, Germany

[9] Univ Klinikum Erlangen, Inst Pathol, Erlangen, Germany

[10] Friedrich Alexander Univ Erlangen Nurnberg, Inst Pathol, Klinikum Bayreuth, Bayreuth, Germany

[11] Univ Med Ctr Hamburg Eppendorf, Martin Zeitz Ctr Rare Dis, Hamburg, Germany

[12] Friedrich Alexander Univ Erlangen Nurnberg, Inst Funct & Clin Anat, Erlangen, Germany

[13] Univ Klinikum Erlangen, Deutsch Zent Immuntherapie, Erlangen, Germany

[14] Charite Univ Med Berlin, Div Gastroenterol Infectiol & Rheumatol, Berlin, Germany

[15] Free Univ Berlin, Berlin, Germany

[16] Humboldt Univ, Berlin, Germany

[17] Univ Klinikum Erlangen, Dept Surg, Div Mol & Expt Surg, Erlangen, Germany

[18] Wellcome Med Res Council Cambridge Stem Cell Inst, Cambridge, England

[19] Cambridge Univ Hosp Natl Hlth Serv Fdn Trust, Cambridge Liver Unit, Cambridge, England

[20] Univ Cambridge, Dept Med, Cambridge, England

[21] Univ Klinikum Erlangen, Div Pediat, Res Lab, Henkestr 91, D-91054 Erlangen, Germany

[22] Univ Zurich, Univ Hosp Zurich, Dept Gastroenterol & Hepatol, Zurich, Switzerland

来源：

GASTROENTEROLOGY | 2024年 / 167卷 / 06期

关键词：

Bacterial Extracellular Vesicle; Hepatic Inflammation; PSC-IBD; Inflammasome; CELLS;

D O I：

10.1053/j.gastro.2024.06.032

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

摘要：

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 fi brosis 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 inflamma- some. 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 fi brosis. In a translational approach, we substantiated the presence of OMVs in the systemic circulation and hepatic regions of severe fi brosis 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 fi brosis 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 fi brosis therapy.

引用

页码：1183 / 1197.e16

页数：31