Journal Article

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

Thingholm, Louise, Sartor, Ryan Balfour, Montgomery, Stephanie, Ngo, Billy, Zhou, Huiping, Viswanathan, Amba, Schramm, Christoph, Bang, Corinna, Ting, Jenny, Francis, Heather L, Awoniyi, Muyiwa, Franke, Andre, Bajaj, Jasmohan S, Meadows, Vik, Kummen, Martin, Popov, Yury V, Farmer, Morgan, Lai, Yunjia, Tam, Jason, Hylemon, Phillip B, Wang, Jeremy, Lu, Kun, Hov, Johannes Roksund

2023

Overview

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 SPF mdr2−/− mice and targeted metagenomic analysis in PSC patients.ResultsGF 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.ConclusionsWe 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.

• Publisher: BMJ Publishing Group Ltd and British Society of Gastroenterology,BMJ Publishing Group LTD
• Subject: Animal models / Animals / Anti-Bacterial Agents - pharmacology / Anti-Bacterial Agents - therapeutic use / Antibiotics / Autografts / Bacteria / Bile / Cholangitis / Cholestasis / cholestatic liver diseases / Clostridiales / Colonization / Disease Models, Animal / E coli / Enterobacteriaceae / Escherichia coli / Fatty acids / Feces / Fibrosis / Gene expression / Germfree / Gnotobiotic / Gut microbiota / Homeostasis / Inflammation / intestinal microbiology / Lachnospiraceae / Liver Cirrhosis / Liver diseases / Liver transplantation / Metabolism / Metabolites / Metabolomics / Metagenomics / Mice / Microbiota / Mortality / Multidrug resistance / Pathogens / Pathophysiology / Patients / Phosphatase / primary sclerosing cholangitis / RNA, Ribosomal, 16S - genetics / Roles / rRNA 16S / short chain fatty acids / Specific pathogen free / Therapeutic applications / Vancomycin