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

Abstract

Conflicting microbiota data exist for primary sclerosing cholangitis (PSC) and experimental models. 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 (<i>mdr2^-/-</i> ) mice and microbial profiles in PSC patient cohorts. 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 <i>mdr2^-/-</i> mice and targeted metagenomic analysis in PSC patients. GF <i>mdr2^-/-</i> 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 <i>Enterococcus faecalis</i> and <i>Escherichia coli</i> liver translocation. Colonisation of GF <i>mdr2^-/-</i> mice with translocated <i>E. faecalis</i> and <i>E. coli</i> strains accelerated hepatobiliary inflammation and mortality. Lachnospiraceae colonisation of antibiotic pretreated <i>mdr2^-/-</i> mice reduced liver fibrosis, inflammation and translocation of pathobionts, and SCFA-producing Lachnospiraceae and purified SCFA decreased fibrosis. Faecal Lachnospiraceae negatively associated, and <i>E. faecalis/ Enterobacteriaceae</i> positively associated, with PSC patients' clinical severity by Mayo risk scores. We identified novel functionally protective and detrimental resident bacterial species in <i>mdr2^-/-</i> mice and PSC patients with associated clinical risk score. These insights may guide personalised targeted therapeutic interventions in PSC patients.