Sodium butyrate combined with ethanol-metabolizing Lactobacillus strains attenuates alcoholic liver disease by restoring gut-liver homeostasis

Alcoholic liver disease (ALD) is characterized by hepatic lipid accumulation, inflammation, and intestinal barrier dysfunction, while limited effective pharmacological interventions remain currently available. This study investigated the protective effects of sodium butyrate (NaB), alone and in combination with newly isolated ethanol-metabolizing Lactobacillus strains on ALD, and examined the contribution of the gut microbiota. After 6 weeks of NaB intervention, associated indicators including liver injury, lipid metabolism, inflammatory mediators, alcohol-metabolizing enzyme activities, histopathology, intestinal barrier markers, and serum lipopolysaccharide (LPS) were assessed. 16S rRNA gene sequencing and antibiotic (ABX) pretreatment were used to evaluate microbiota involvement. In parallel, bacterial strains were isolated from long-term alcohol consumers without clinically apparent liver injury, and screened for ethanol-stress tolerance, ethanol-metabolizing capacity, and NaB-responsive growth, ultimately five strains (ML, MN, T2, T23, and TF) were firstly selected as the probiotic candidates for single or comined with NaB to evaluate in mice with ALD. As a result, NaB reduced indices of liver injury, dyslipidemia, inflammation, histopathological damage, and circulating LPS, while improving ADH/ALDH activity and ZO-1/Occludin expression. These effects were partially dependent on modulating gut microbiota. The five strains showed ethanol-metabolizing potential and NaB-responsive growth, and each strain improved several indices of alcohol-associated liver injury. Across multiple gut-liver axis endpoints, combination treatment generally provided enhanced protection than either intervention alone. Herein, a novel type of human-derived probiotic Lactobacillus strain, alone or combined with the postbiotic butyrate, effectively alleviated disease outcomes, highlighting its potential as a novel probiotic-postbiotic combination therapy..