Protective and aggressive bacterial subsets and metabolites modify hepatobiliary inflammation and fibrosis in a murine model of PSC

Abstract

ObjectiveConflicting 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.DesignWe 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 SPFmdr2−/−mice and targeted metagenomic analysis in PSC patients.ResultsGFmdr2−/−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 increasedEnterococcus faecalisandEscherichia coliliver translocation. Colonisation of GFmdr2−/−mice with translocatedE. faecalisandE. colistrains accelerated hepatobiliary inflammation and mortality. Lachnospiraceae colonisation of antibiotic pretreatedmdr2−/−mice reduced liver fibrosis, inflammation and translocation of pathobionts, and SCFA-producing Lachnospiraceae and purified SCFA decreased fibrosis. Faecal Lachnospiraceae negatively associated, andE. faecalis/ Enterobacteriaceaepositively associated, with PSC patients’ clinical severity by Mayo risk scores.ConclusionsWe identified novel functionally protective and detrimental resident bacterial species inmdr2−/−mice and PSC patients with associated clinical risk score. These insights may guide personalised targeted therapeutic interventions in PSC patients.