RT Journal Article SR Electronic T1 Protective and aggressive bacterial subsets and metabolites modify hepatobiliary inflammation and fibrosis in a murine model of PSC JF Gut JO Gut FD BMJ Publishing Group Ltd and British Society of Gastroenterology SP gutjnl-2021-326500 DO 10.1136/gutjnl-2021-326500 A1 Muyiwa Awoniyi A1 Jeremy Wang A1 Billy Ngo A1 Vik Meadows A1 Jason Tam A1 Amba Viswanathan A1 Yunjia Lai A1 Stephanie Montgomery A1 Morgan Farmer A1 Martin Kummen A1 Louise Thingholm A1 Christoph Schramm A1 Corinna Bang A1 Andre Franke A1 Kun Lu A1 Huiping Zhou A1 Jasmohan S Bajaj A1 Phillip B Hylemon A1 Jenny Ting A1 Yury V Popov A1 Johannes Roksund Hov A1 Heather L Francis A1 Ryan Balfour Sartor YR 2022 UL http://gut.bmj.com/content/early/2022/06/14/gutjnl-2021-326500.abstract 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.