Awoniyi, MuyiwaWang, JeremyNgo, BillyMeadows, VikTam, JasonViswanathan, AmbaLai, YunjiaMontgomery, StephanieFarmer, MorganKummen, MartinThingholm, LouiseSchramm, ChristophBang, CorinnaFranke, AndreLu, KunZhou, HuipingBajaj, Jasmohan S.Hylemon, Phillip B.Ting, JennyPopov, Yury V.Hov, Johannes RoksundFrancis, Heather L.Sartor, Ryan Balfour2023-12-202023-12-202023Awoniyi M, Wang J, Ngo B, et al. Protective and aggressive bacterial subsets and metabolites modify hepatobiliary inflammation and fibrosis in a murine model of PSC. Gut. 2023;72(4):671-685. doi:10.1136/gutjnl-2021-326500https://hdl.handle.net/1805/37440Objective: 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.en-USAttribution-NonCommercial 4.0 InternationalAntibioticsCholestatic liver diseasesIntestinal microbiologyPrimary sclerosing cholangitisShort chain fatty acidsArticle