Gentamicin alleviates cholestatic liver injury by decreasing gut microbiota-associated bile salt hydrolase activity in rats

Intrahepatic cholestasis lacks effective therapeutic drugs. The gut microbiota-associated bile salt hydrolases (BSH) may be a potential therapeutic target. In this study, oral administration of gentamicin (GEN) decreased the serum and hepatic levels of total bile acid in 17 alpha-ethynylestradiol (EE)-induced cholestatic male rats, signifi-cantly improved the serum levels of hepatic biomarkers and reversed the histopathological changes in the liver. In healthy male rats, the serum and hepatic levels of total bile acid were also decreased by GEN, the ratio of primary to secondary bile acids, and conjugated to unconjugated bile acids was significantly increased, and the urinary excretion of total bile acid was elevated. 16S rDNA sequencing of the ileal contents revealed that GEN treatment substantially reduced the abundance of Lactobacillus and Bacteroides both of which expressed BSH. Consistently, BSH activity analysis by the generation of d5-chenodeoxycholic acid from d5-taurochenodeoxycholic acid in situ showed BSH was significantly inhibited in the ileal contents of rats treated with GEN. This finding led to an increased proportion of hydrophilic conjugated bile acids and facilitated the urinary excretion of total bile acids, thereby decreasing serum and hepatic total bile acids and reversing liver injury related to cholestasis. Our results provide important evidence that BSH can be a potential drug target for treating cholestasis.

Automated summary

This study found that oral administration of gentamicin (GEN) can reduce the levels of bile acids in male rats and improve liver pathology, indicating that GEN may be a potential therapeutic drug for cholestasis. Furthermore, GEN was found to significantly inhibit bile salt hydrolase activity in lactobacillus and bacteroides, promote urinary excretion of bile acids, and decrease serum and hepatic levels of bile acids.