Lactobacillus helveticus ZJUIDS12 Rescues Alcohol-Associated Liver Disease via a Clostridium butyricum-Regulated Intestinal Reg3γ Pathway

Alcohol-associated liver disease (ALD) has become a serious public health issue worldwide. This study was conducted to investigate the protective role of Lactobacillus helveticus ZJUIDS12 (Z12) on ALD. Z12 (10 9 CFU/day) significantly reversed alcohol-induced liver injury, hepatic steatosis, oxidative stress, and inflammation by restoring lipid metabolism and gut barrier integrity. Z12's effects, abolished in antibiotic-treated mice, involve gut microbiota, notably Clostridium sensu stricto 1, linked to Reg3γ upregulation. Clostridium butyricum (a representative strain of Clostridium sensu stricto 1) or butyric acid replicated Z12's benefits, which were absent in Reg3γ −/− mice. Further studies revealed that the heat-inactivated postbiotics of Z12 and its secreted exopolysaccharides still significantly alleviated ALD, similar to the effects of the live Z12. Our present study suggests that Z12 probiotics and their postbiotics ameliorate alcohol-induced hepatic steatosis and liver injury in mice by enhancing butyrate production via C. butyricum , mediated through the Reg3γ pathway. These findings support the therapeutic potential of probiotic and postbiotic interventions for ALD.