Restoration of ethanol-induced Bifidobacterium pseudocatenulatum depletion ameliorates alcohol-associated liver disease.

Alcohol-associated liver disease (ALD), characterized by gut barrier disruption and microbial dysbiosis, is associated with significant depletion of the genus Bifidobacterium in patients, as evidenced by our cohort of 127 subjects. Functional screening revealed B. pseudocatenulatum as a protective strain. In a murine ALD model established with a Lieber-DeCarli ethanol diet, oral administration of B. pseudocatenulatum for 8 weeks ameliorated hepatomegaly, steatosis, and serum transaminase levels. Probiotic intervention restored intestinal barrier function, as indicated by reduced lipopolysaccharide-binding proteins and upregulated tight junction protein expression. Microbiome analysis revealed a mitigation of dysbiosis, with a reduction in pathogenic Escherichia-Shigella and Parabacteroides and an enrichment of beneficial Bifidobacterium and Blautia, concomitant with shifts in lipid metabolism. Mechanistically, B. pseudocatenulatum-derived short-chain fatty acids downregulated the expression of hepatic lipogenic genes (Cd36, Fasn, Accα) and pro-inflammatory cytokines (Il-1β, Ccl2, Tnf-α). These results suggest that B. pseudocatenulatum is a promising probiotic candidate for ALD management.