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Intestinal dysbiosis augments liver disease progression via NLRP3 in a murine model of primary sclerosing cholangitis.

Journal article
Authors Lijun Liao
Kai Markus Schneider
Eric J C Galvez
Mick Frissen
Hanns-Ulrich Marschall
Huan Su
Maximilian Hatting
Annika Wahlström
Johannes Haybaeck
Philip Puchas
Antje Mohs
Jin Peng
Ina Bergheim
Anika Nier
Julia Hennings
Johanna Reißing
Henning W Zimmermann
Thomas Longerich
Till Strowig
Christian Liedtke
Francisco J Cubero
Christian Trautwein
Published in Gut
Volume 68
Issue 8
Pages 1477-92
ISSN 1468-3288
Publication year 2019
Published at Wallenberg Laboratory
Institute of Medicine, Department of Molecular and Clinical Medicine
Pages 1477-92
Language en
Subject categories Gastroenterology and Hepatology


There is a striking association between human cholestatic liver disease (CLD) and inflammatory bowel disease. However, the functional implications for intestinal microbiota and inflammasome-mediated innate immune response in CLD remain elusive. Here we investigated the functional role of gut-liver crosstalk for CLD in the murine Mdr2 knockout (Mdr2-/-) model resembling human primary sclerosing cholangitis (PSC).Male Mdr2-/-, Mdr2-/- crossed with hepatocyte-specific deletion of caspase-8 (Mdr2-/- /Casp8∆hepa) and wild-type (WT) control mice were housed for 8 or 52 weeks, respectively, to characterise the impact of Mdr2 deletion on liver and gut including bile acid and microbiota profiling. To block caspase activation, a pan-caspase inhibitor (IDN-7314) was administered. Finally, the functional role of Mdr2-/- -associated intestinal dysbiosis was studied by microbiota transfer experiments.Mdr2-/- mice displayed an unfavourable intestinal microbiota signature and pronounced NLRP3 inflammasome activation within the gut-liver axis. Intestinal dysbiosis in Mdr2-/- mice prompted intestinal barrier dysfunction and increased bacterial translocation amplifying the hepatic NLRP3-mediated innate immune response. Transfer of Mdr2-/- microbiota into healthy WT control mice induced significant liver injury in recipient mice, highlighting the causal role of intestinal dysbiosis for disease progression. Strikingly, IDN-7314 dampened inflammasome activation, ameliorated liver injury, reversed serum bile acid profile and cholestasis-associated microbiota signature.MDR2-associated cholestasis triggers intestinal dysbiosis. In turn, translocation of endotoxin into the portal vein and subsequent NLRP3 inflammasome activation contribute to higher liver injury. This process does not essentially depend on caspase-8 in hepatocytes, but can be blocked by IDN-7314.

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