Theaflavins, theaflavin-3,3′-digallate, and its nanoparticles attenuate chronic alcohol-induced gastric injury and hepatic fibrosis by activating the AMPK/mTOR/Beclin1/LC3 autophagy pathway and modulating intestinal microbiota in ICR mice

This study investigated the protective effects of theaflavins (TFs), theaflavin-3,3′-digallate (TFDG), and TFDG nanoparticles (TFDGN) against chronic alcohol-induced gastric and hepatic injuries in mice. Using an eight-week alcohol administration model, this study demonstrated that TFs, TFDG, and TFDGN significantly reduced mortality, liver index, and serum biomarkers of hepatic injury, while increasing glutathione levels. Histopathology confirmed the attenuation of hepatic inflammation, fibrosis, and gastric mucosal damage. Mechanistically, these compounds activated gastric cell autophagy via the downregulation of p-mTOR and the upregulation of p-AMPK, Beclin1, and LC3-II. Additionally, they modulated gut microbiota by enriching probiotics ( Lactobacillus , Akkermansia and Oscillibacter ) while reducing pathogens ( Allobaculum , Faecalibaculum and Enterococcus ). Among the tested compounds, TFDGN exhibited superior efficacy. These findings demonstrate that TFs, TFDG, and TFDGN provide protection against alcohol-induced damage by regulating autophagy, reducing fibrosis, and restoring gut microbiota balance, highlighting their potential as natural therapeutics for alcohol-related gastric and hepatic disorders. • TFs, TFDG and TFDGN alleviate chronic alcohol-induced gastric mucosa injury in mice. • TFs, TFDG and TFDGN attenuate alcohol-induced hepatic fibrosis and liver injury. • TFs, TFDG and TFDGN protect the gastric mucosa by AMPK/mTOR/Beclin1/LC3 pathway. • TFs, TFDG and TFDGN restore intestinal microbiota homeostasis in alcohol-exposed mice.