Dual Mechanisms of Raffinose in Attenuating Alcoholic Liver Injury: Gut Microbiota Modulation and Microbiota-Independent Bile Acid Pool Reprogramming

Alcohol-related liver disease (ALD) poses a growing global health burden, yet current therapies remain limited. Here, we demonstrate that raffinose, a naturally occurring oligosaccharide, alleviates ALD through dual mechanisms involving gut microbiota modulation and microbiota-independent bile acid metabolism regulation. In ethanol-fed mice, oral raffinose (400 and 800 mg/kg/day) significantly alleviated hepatic inflammation, oxidative stress, and dysregulated lipid metabolism. Notably, 400 mg/kg/day optimally improved lipid profiles, increasing serum HDL-C by 1.15-fold and decreasing LDL-C by 1.33-fold versus the model group (<i>p</i> < 0.05). Mechanistically, in conventional mice, raffinose restored gut homeostasis by modulating microbiota (e.g., promoting <i>Akkermansia</i> and suppressing <i>Desulfovibrio</i>), thereby mitigating ALD via the gut-liver axis. Strikingly, in pseudogerm-free mice, it directly regulated bile acid metabolism (FXR/TGR5 signaling) and protected the gut-liver barrier. These results identify raffinose as a safe, food-derived agent that alleviates ALD through both microbiota-dependent and independent mechanisms, supporting its potential for preventing and treating gut-liver disorders.