Abstract
Background/Objectives: Alcoholic liver disease (ALD) is intricately linked to gut microbiota dysbiosis and metabolic disturbances along the gut-liver axis. Octenyl succinic anhydride (OSA) starch escapes digestion in the small intestine and ferments in the colon, modulating gut microbiota and metabolism. This study explored the protective effects of OSA starch against ALD and elucidated the underlying gut microbiota-metabolite interactions. Methods: A chronic ethanol-fed mouse model was conducted to evaluate the protective effects of OSA starch against ALD, and multi-omics analyses integrating 16S rRNA sequencing, PICRUSt2 functional predictions, and metabolomics were used to reveal potential mechanism. Results: OSA starch supplementation in ALD mice significantly reduced liver fat accumulation, lowered the liver index to 4.11%, and restored serum transaminase levels closer to normal. Multi-omics analyses revealed that OSA starch enriched beneficial gut bacteria such as Faecalibaculum rodentium and Bifidobacterium adolescentis. OSA starch also enhanced microbial metabolic functions, including pyruvate, butanoate, and propanoate metabolism. These shifts were accompanied by regulation of fecal and serum metabolites, including pyruvate, 2-hydroxybutanoic acid, and lactic acid. Structural equation modeling further confirmed that OSA starch ameliorates ALD via coordinated modulation of gut microbiota, microbial functions, metabolites, and serum markers. Conclusions: OSA starch protects against alcoholic liver injury by remodeling the gut-liver metabolic network, presenting a promising dietary strategy for ALD.