Cohabitation facilitates microbiome shifts that promote isoflavone transformation to ameliorate liver injury

Acetaminophen overuse is a leading cause of acute liver injury (ALI). Although ALI is linked to inter-individual differences in microbiome composition, the mechanisms remain unclear. We demonstrate that horizontal transmission of gut microbiota between male and female mice impacts ALI and identify Rikenella microfusus- mediated isoflavone transformation as determinants of ALI severity. R. microfusus increases upon cohabitation with bacterial β-galactosidase enhancing intestinal absorption of isoflavone biochanin-A (Bio-A). R. microfusus mono-colonization reduced ALI severity following acetaminophen overdose. Genetic or chemical-mediated inhibition of β-galactosidase blocked Bio-A release and negated the hepatoprotective effects of R. microfusus . Bio-A directly binds to pyruvate carboxylase (PC) and propionyl-CoA carboxylase subunit alpha (PCCA), augmenting the tricarboxylic acid cycle and promoting protective glutathione synthesis in hepatocytes. Additionally, immunohistochemical analysis revealed reduced hepatic PC and PCCA expression in liver failure (LF) patients. These findings highlight the impacts of microbiome composition on ALI and the ability of microbial isoflavone absorption to mitigate ALI severity.