Multi-omics reveals gut microbiota-derived taurodeoxycholic acid mediates the protective effect of Lactobacillus rhamnosus GG against LPS-induced liver injury

Abstract

Gut microbiota-derived lipopolysaccharide (LPS) is a critical mediator in the pathogenesis of nonalcoholic fatty liver disease and metabolic syndrome. The liver plays a crucial role in mediating immune responses and detoxifying endotoxins through bile secretion. However, the precise role of bile acid metabolism in LPS-induced liver injury and the underlying regulatory mechanisms remain poorly understood. RNA sequencing of liver and ileum tissues, combined with targeted metabolomic profiling of liver and cecal chyme, and full-length 16S rRNA sequencing of cecal microbiota, revealed that LPS disrupted the enterohepatic circulation of bile acids. This disruption was characterized by reduced hepatic bile acid secretion and uptake, impaired ileal bile acid reabsorption, and increased fecal excretion of bile acids. Moreover, LPS altered the gut microbiota composition involved in secondary bile acid metabolism, particularly reducing Ligilactobacillus. Supplementation with Lactobacillus rhamnosus GG (LGG) alleviated LPS-induced inflammation and liver injury, while restoring hepatic conjugated secondary bile acids, particularly the taurodeoxycholic acid (TDCA). The regulatory effect of LGG on hepatic conjugated secondary bile acids was associated with enhanced ileal bile acid reabsorption and a balanced gut microbiota composition. Notably, the hepatoprotective effects were abolished by heat-killed LGG or by co-treatment with caffeic acid phenethyl ester, which diminished LGG's activity in the intestine. TDCA treatment alleviated LPS-induced hepatic inflammation in part through modulation of the oxidative phosphorylation pathway. Collectively, these findings identify disrupted bile acid metabolism as a key event in LPS-induced liver injury and highlight the modulation of TDCA metabolism by probiotics as a promising therapeutic target for endotoxin-related disorders.