Bacteroides uniformis -generated ornithine alleviates alcohol-associated liver disease via Sirt4-mediated mitochondrial regulation

Gut microbiota plays a pivotal role in alcohol-associated liver disease (ALD), yet the contributions of individual bacterial strains and their metabolites remain poorly defined. Here, we analyzed 16S rDNA sequencing data from an ALD patient cohort and validated the findings using the NIAAA mouse model combined with multi-omics approaches. Bacteroides uniformis was significantly depleted in ALD patients, and supplementation with live B. uniformis alleviated ALD in mice by reducing hepatic steatosis, inflammation, and oxidative stress. Metabolomic analysis identified ornithine as a key metabolite produced by B. uniformis, and direct ornithine administration largely recapitulated the protective effects. Mechanistically, ornithine upregulated hepatic Sirt4, thereby restoring mitochondrial homeostasis, whereas pharmacological inhibition of Sirt4 abolished these effects. Dietary flaxseed oil increased intestinal B. uniformis abundance and hepatic Sirt4 expression, ameliorating ALD outcomes. These findings reveal a B. uniformis–ornithine–Sirt4 axis that modulates ALD via mitochondrial regulation and highlight potential microbial and metabolic therapeutic targets.