Multi-omics analysis reveals leucine deprivation promotes bile acid synthesis by upregulating hepatic CYP7A1 and intestinal Turicibacter sanguinis in mice.

BACKGROUND: Leucine, a branched-chain amino acid (BCAA), participates in the regulation of lipid metabolism and the composition of the intestinal microbiota. However, the related mechanism remains unclear.

OBJECTIVES: Here, we aimed to reveal the potential mechanisms by which the hepatic CYP7A1 (a rate-limiting enzyme for bile acid [BA] synthesis) and gut microbiota co-regulated BA synthesis under leucine deprivation.

METHODS: To this aim, 8-week-old C57BL/6J mice were fed with either regular diets or leucine-free diets for 1 week. Then, we investigated whether secondary BAs were synthesized by Turicibacter sanguinis in 7-week-old C57BL/6J germ-free mice gavaged with T.sanguinis for 2 weeks by determining BA concentrations in the plasma, liver, and cecum contents using liquid chromatography-tandem mass spectrometry.

RESULTS: The results showed that leucine deprivation resulted in a significant increase in total BA concentration in the plasma and an increase in the liver, but no difference in total BA was observed in the cecum contents before and after leucine deprivation. Furthermore, leucine deprivation significantly altered BA profiles such as taurocholic acid and omega-muricholic acid in the plasma, liver, and cecum contents. The expression of CYP7A1 was significantly upregulated in the liver under leucine deprivation. Leucine deprivation also regulated the composition of the gut microbiota, especially it significantly up-regulated the relative abundance of T.sanguinis, thus enhancing the conversion of primary BAs into secondary BAs by intestinal T.sanguinis in mice.

CONCLUSIONS: Overall, leucine deprivation regulated BA profiles in enterohepatic circulation by upregulating hepatic CYP7A1 expression and increasing intestinal T.sanguinis abundance. Our findings reveal the contribution of gut microbiota to BA metabolism under dietary leucine deprivation.