Protective and aggressive bacterial subsets and metabolites modify hepatobiliary inflammation and fibrosis in PSC

Abstract

ObjectiveConflicting microbiota data exist for primary sclerosing cholangitis (PSC) and experimental models. Goal: Define complex interactions between resident microbes and their association in PSC patients by studying antibiotic-treated specific pathogen-free (SPF) and germ-free (GF) multi-drug-resistant 2 deficient (mdr2-/-) mice.DesignWe measured weights, liver enzymes, RNA expression, histological, immunohistochemical and fibrotic biochemical parameters, fecal 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 exaggerated hepatic inflammation and fibrosis with 100% mortality by 8 weeks; early SPF autologous stool transplantation rescued liver-related mortality. Broad-spectrum antibiotics and vancomycin alone accelerated disease in weanling SPF mdr2-/- mice, indicating that vancomycin-sensitive resident microbiota protect against hepatobiliary disease. Vancomycin treatment selectively decreased Lachnospiraceae and short-chain fatty acids (SCFAs) but expanded Enterococcus and Enterobacteriaceae. Antibiotics increased cytolysin-expressing E. faecalis and E. coli liver translocation; colonization of gnotobiotic mdr2-/- mice with translocated E. faecalis and E. coli strains accelerated liver inflammation and mortality. Lachnospiraceae colonization of antibiotic pre-treated mdr2-/- mice reduced liver fibrosis, inflammation and translocation of pathobionts, while Lachnospiraceae-produced SCFA decreased fibrosis. Fecal E. faecalis/ Enterobacteriaceae was positively and Lachnospiraceae was negatively associated with PSC patients’ clinical severity Mayo risk scores.ConclusionsWe identified specific functionally protective and detrimental resident bacterial species in mdr2-/- mice and PSC patients with associated clinical outcomes. These insights may guide personalized targeted therapeutic interventions in PSC patients.

Research reviews and prospects of gut microbiota in liver cirrhosis: a bibliometric analysis (2001–2023)

“…In addition this study Zhu et al 10.3389/fmicb.2024.1342356 Frontiers in Microbiology 16 frontiersin.org also revealed that the abundance of Oscillibacter (also a SCFAproducing bacterium) is markedly reduced accompanied by a notable decrease in the ratio of Firmicutes and Bacteroidetes along with the progression from compensated cirrhosis to decompensated cirrhosis. Further the SCFA-producing Lachnospiraceae family can reduce liver fibrosis and the SCFA-producing families (Ruminococcaceae and Lachnospiraceae) may have a potential association with the progression of HE in cirrhotic patients (Awoniyi et al, 2023). Supplementation with probiotics targeting to enhance the population of SCFA-producing bacteria emerges as a potential therapeutic strategy for cirrhotic patients.…”

Intestinal microbiota and biliary system diseases

“…An experiment on a PSC mouse model showed that the reduction of bacteria weakened the negative feedback regulation of BAs and then enhanced the accumulation of BAs in the liver. The decrease in bacteria also altered the composition of BAs (Schneider et al, 2021;Awoniyi et al, 2023). In addition, studies have shown that intestinal microbiota dysfunction plays an important role in the progression of PSC (Jin et al, 2022).…”