Theaflavin-3,3'-digallate prevents alcoholic liver injury by suppressing hepatic TLR4/NF-κB signaling and modulating the gut-liver axis in mice.

Dietary intervention is crucial for the clinical management of alcoholic liver injury. As the primary bioactive component in fermented tea, theaflavin-3,3'-digallate (TF3) possesses potent antioxidative and anti-inflammatory capacities, but its protective mechanisms against alcoholic liver injury via the gut-liver axis require systematic elucidation. This study evaluated the protective effects and underlying mechanisms of high-purity TF3 (2.5/5/10 mg/kg, 12-week oral gavage) against alcoholic liver injury in C57BL/6 J mice. TF3 administration significantly reduced serum lipids, attenuated hepatic steatosis, and suppressed oxidative stress and pro-inflammatory cytokine production in alcohol-fed mice. Mechanistically, TF3 enhanced intestinal barrier integrity by upregulating tight junction proteins in the colon and ileum, increased beneficial microbiota like Lactobacillus and Bifidobacterium, and modulated microbial metabolites including short-chain fatty acids (SCFAs) and tryptophan. These changes reduced circulating lipopolysaccharide (LPS), suppressed hepatic toll-like receptor 4 (TLR4)/nuclear factor kappa-B (NF-κB) pathway activation, and ultimately ameliorated hepatic inflammation while enhancing oxidative stress regulation. This work reveals novel mechanisms of TF3 in preventing alcoholic liver injury, providing a theoretical foundation for dietary applications.