PT - JOURNAL ARTICLE AU - Muyiwa Awoniyi AU - Jeremy Wang AU - Billy Ngo AU - Vik Meadows AU - Jason Tam AU - Amba Viswanathan AU - Yunjia Lai AU - Stephanie Montgomery AU - Morgan Farmer AU - Martin Kummen AU - Louise Thingholm AU - Christoph Schramm AU - Corinna Bang AU - Andre Franke AU - Kun Lu AU - Huiping Zhou AU - Jasmohan S Bajaj AU - Phillip B Hylemon AU - Jenny Ting AU - Yury V Popov AU - Johannes Roksund Hov AU - Heather L Francis AU - Ryan Balfour Sartor TI - Protective and aggressive bacterial subsets and metabolites modify hepatobiliary inflammation and fibrosis in a murine model of PSC AID - 10.1136/gutjnl-2021-326500 DP - 2022 Jun 14 TA - Gut PG - gutjnl-2021-326500 4099 - http://gut.bmj.com/content/early/2022/06/14/gutjnl-2021-326500.short 4100 - http://gut.bmj.com/content/early/2022/06/14/gutjnl-2021-326500.full AB - Objective Conflicting microbiota data exist for primary sclerosing cholangitis (PSC) and experimental models. Goal: define the function of complex resident microbes and their association relevant to PSC patients by studying germ-free (GF) and antibiotic-treated specific pathogen-free (SPF) multidrug-resistant 2 deficient (mdr2−/−) mice and microbial profiles in PSC patient cohorts.Design We measured weights, liver enzymes, RNA expression, histological, immunohistochemical and fibrotic biochemical parameters, faecal 16S rRNA gene profiling and metabolomic endpoints in gnotobiotic and antibiotic-treated SPF mdr2−/− mice and targeted metagenomic analysis in PSC patients.Results GF mdr2−/− mice had 100% mortality by 8 weeks with increasing hepatic bile acid (BA) accumulation and cholestasis. Early SPF autologous stool transplantation rescued liver-related mortality. Inhibition of ileal BA transport attenuated antibiotic-accelerated liver disease and decreased total serum and hepatic BAs. Depletion of vancomycin-sensitive microbiota exaggerated hepatobiliary disease. Vancomycin selectively decreased Lachnospiraceae and short-chain fatty acids (SCFAs) but expanded Enterococcus and Enterobacteriaceae. Antibiotics increased Enterococcus faecalis and Escherichia coli liver translocation. Colonisation of GF mdr2−/− mice with translocated E. faecalis and E. coli strains accelerated hepatobiliary inflammation and mortality. Lachnospiraceae colonisation of antibiotic pretreated mdr2−/− mice reduced liver fibrosis, inflammation and translocation of pathobionts, and SCFA-producing Lachnospiraceae and purified SCFA decreased fibrosis. Faecal Lachnospiraceae negatively associated, and E. faecalis/ Enterobacteriaceae positively associated, with PSC patients’ clinical severity by Mayo risk scores.Conclusions We identified novel functionally protective and detrimental resident bacterial species in mdr2−/− mice and PSC patients with associated clinical risk score. These insights may guide personalised targeted therapeutic interventions in PSC patients.Data are available on reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information.