Administration of a Microbiome Promotes Alcohol Degradation and Mitigates Alcoholic Liver Damage

Abstract

Alcohol-associated liver disease （ALD） is a progressive liver disorder with rising global mortality yet no approved pharmacological therapies. Disruption of the gut–liver axis, driven by intestinal barrier dysfunction and portal endotoxemia, is central to ALD pathogenesis. Yet most microbiome-based interventions have focused on restoring microbial composition rather than harnessing the strain-specific enzymatic capacity for direct luminal ethanol catabolism. Here, we systematically exploited the strain-specific enzymatic capacity of targeted microbiota for direct luminal ethanol catabolism as a strategy to intercept downstream hepatic injury. Through genomic profiling, we identified Lactococcus lactis, Streptococcus thermophilus, and Lactiplantibacillus plantarum as robust candidates harboring key ethanol-metabolizing genes. In vitro, these strains actively degraded ethanol, and their cell-free extracts mitigated ethanol-impaired hepatocyte function. In a murine ALD model, microbial administration accelerated systemic ethanol clearance and attenuated hepatomegaly and hepatic steatosis by suppressing lipogenesis （Scd1） while restoring fatty acid oxidation （Ppara, Cpt1a）. Microbial therapy further reinforced the gut–liver axis by preserving intestinal tight junction integrity, suppressing local and systemic pro- inflammatory cytokine expression, and restoring immune homeostasis through suppressing splenic Th17 polarization across all strains, with L. lactis additionally restoring the Treg/Th17 ratio. Collectively, these findings demonstrate that targeted, ethanol-degrading microbiota represents a gut–liver axis–directed intervention for ALD, exerting dual protection through direct luminal ethanol clearance and comprehensive host immune–metabolic rebalancing.