Gut-to-Liver Escape of Viable Streptococcus salivarius Fuels Alcoholic Liver Disease via Fn14-Dependent NF-κB Signaling

Gut microbial dysbiosis contributes to alcoholic liver disease (ALD), but the pathogenic bacteria and mechanisms remain unclear. We investigated the role of Streptococcus salivarius (S. salivarius) in ALD mice using a modified 12-week NIAAA chronic-plus-binge ethanol regimen with oral gavage. S. salivarius aggravated hepatic steatosis, inflammation, fibrosis, and serum ALT elevation, while impairing colonic mucus and tight-junction integrity. Viable bacteria translocated from the gut to the liver. Integrated hepatic metabolomics and transcriptomics revealed disturbances in bile acid, glycerophospholipid, and choline metabolism and upregulation of Tnfrsf12a, encoding Fn14. S. salivarius activated NF-κB signaling without altering TLR2 or TLR4 abundance. Fn14 silencing or NF-κB inhibition attenuated the inflammatory response in vitro. Thus, our findings suggest that S. salivarius may contribute to ALD progression by impairing the intestinal barrier, translocating to the liver, and activating Fn14-dependent NF-κB signaling. The gut–liver translocation pathway and Fn14/NF-κB axis may represent therapeutic targets for ALD.