RT Journal Article
SR Electronic
T1 Intestinal dysbiosis augments liver disease progression via NLRP3 in a murine model of primary sclerosing cholangitis
JF Gut
JO Gut
FD BMJ Publishing Group Ltd and British Society of Gastroenterology
SP 1477
OP 1492
DO 10.1136/gutjnl-2018-316670
VO 68
IS 8
A1 Lijun Liao
A1 Kai Markus Schneider
A1 Eric J C Galvez
A1 Mick Frissen
A1 Hanns-Ulrich Marschall
A1 Huan Su
A1 Maximilian Hatting
A1 Annika Wahlström
A1 Johannes Haybaeck
A1 Philip Puchas
A1 Antje Mohs
A1 Jin Peng
A1 Ina Bergheim
A1 Anika Nier
A1 Julia Hennings
A1 Johanna Reißing
A1 Henning W Zimmermann
A1 Thomas Longerich
A1 Till Strowig
A1 Christian Liedtke
A1 Francisco J Cubero
A1 Christian Trautwein
YR 2019
UL http://gut.bmj.com/content/68/8/1477.abstract
AB Objective 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).Design 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.Results 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.Conclusions 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.