Dietary alpha-lipoic acid supplementation alleviates high-fat diet-induced hepatic steatosis and inflammation by remodeling the gut microbiota and restoring the primary bile acid pool.

BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent global health concern with limited therapeutic options. Alpha-lipoic acid (ALA), a naturally occurring organosulfur compound with potent antioxidant activity, shows hepatoprotective potential, but its mechanisms along the gut-liver axis remain poorly understood. This study investigated whether ALA ameliorates high-fat diet (HFD)-induced MASLD by repairing the intestinal barrier and restoring gut microbiota-mediated primary bile acid (BA) signaling. RESULTS: In C57BL/6 mice fed an HFD with or without ALA supplementation (60 mg/kg/d) for 12 weeks, ALA significantly attenuated HFD-induced obesity, dyslipidemia, insulin resistance, and hepatic injury (steatosis, apoptosis, oxidative stress), without altering caloric intake. ALA restored intestinal barrier function by up-regulating tight junction proteins (Occludin, ZO-1) and mucin (Muc2), reducing systemic inflammation and metabolic endotoxemia. Integrated 16S rRNA sequencing and targeted BA metabolomics revealed that ALA selectively enriched beneficial gut bacteria (e.g., Akkermansia, Lactobacillus) and reversed HFD-induced depletion of primary BAs including cholic acid (CA) and chenodeoxycholic acid (CDCA). These restored primary BAs were positively correlated with the enriched microbial taxa. CONCLUSION: These findings elucidate a novel 'gut microbiota-primary bile acid' axis underlying the hepatoprotective effects of dietary ALA, supporting its potential as a functional food component or dietary supplement for MASLD management. © 2026 Society of Chemical Industry.