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

Medientyp: E-Artikel
Titel: Protective and aggressive bacterial subsets and metabolites modify hepatobiliary inflammation and fibrosis in a murine model of PSC
Beteiligte: Awoniyi, Muyiwa; Wang, Jeremy; Ngo, Billy; Meadows, Vik; Tam, Jason; Viswanathan, Amba; Lai, Yunjia; Montgomery, Stephanie; Farmer, Morgan; Kummen, Martin; Thingholm, Louise; Schramm, Christoph; Bang, Corinna; Franke, Andre; Lu, Kun; Zhou, Huiping; Bajaj, Jasmohan S; Hylemon, Phillip B; Ting, Jenny; Popov, Yury V; Hov, Johannes Roksund; Francis, Heather L; Sartor, Ryan Balfour
Erschienen: BMJ, 2023
Erschienen in: Gut
Sprache: Englisch
DOI: 10.1136/gutjnl-2021-326500
ISSN: 0017-5749; 1468-3288
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Beschreibung: <jats:sec><jats:title>Objective</jats:title><jats:p>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 (<jats:italic>mdr2<jats:sup>−/−</jats:sup></jats:italic>) mice and microbial profiles in PSC patient cohorts.</jats:p></jats:sec><jats:sec><jats:title>Design</jats:title><jats:p>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<jats:italic>mdr2<jats:sup>−/−</jats:sup></jats:italic>mice and targeted metagenomic analysis in PSC patients.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>GF<jats:italic>mdr2<jats:sup>−/−</jats:sup></jats:italic>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<jats:italic>Enterococcus faecalis</jats:italic>and<jats:italic>Escherichia coli</jats:italic>liver translocation. Colonisation of GF<jats:italic>mdr2<jats:sup>−/−</jats:sup></jats:italic>mice with translocated<jats:italic>E. faecalis</jats:italic>and<jats:italic>E. coli</jats:italic>strains accelerated hepatobiliary inflammation and mortality. Lachnospiraceae colonisation of antibiotic pretreated<jats:italic>mdr2<jats:sup>−/−</jats:sup></jats:italic>mice reduced liver fibrosis, inflammation and translocation of pathobionts, and SCFA-producing Lachnospiraceae and purified SCFA decreased fibrosis. Faecal Lachnospiraceae negatively associated, and<jats:italic>E. faecalis/ Enterobacteriaceae</jats:italic>positively associated, with PSC patients’ clinical severity by Mayo risk scores.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>We identified novel functionally protective and detrimental resident bacterial species in<jats:italic>mdr2<jats:sup>−/−</jats:sup></jats:italic>mice and PSC patients with associated clinical risk score. These insights may guide personalised targeted therapeutic interventions in PSC patients.</jats:p></jats:sec>

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