Genipin ameliorates cholestatic liver injury in Mdr2−/− mice: the role of gut microbiota modulation by its dialdehyde intermediates

Abstract

Cholestasis causes severe hepatobiliary diseases with poor prognosis and limited therapeutic drugs. Under cholestatic conditions, impairment of the bile acid (BA)-metabolizing function of gut microbiota, along with abnormal BA profiles, exacerbates disease progression. Interventions targeting the composition and function of gut microbiota represent promising strategies for alleviating cholestatic liver injury. Genipin (GP) is the aglycone of geniposide, the primary bioactive compound in the choleretic herbal medicine Gardenia jasminoides Ellis. The hemiacetal group in GP can generate reactive dialdehyde intermediates that covalently modify intestinal proteins. This study investigates the protective effect of GP against cholestatic liver injury in Mdr2^−/− mice and explores the role of these dialdehyde intermediates in this process. Methylated GP (MGP) was synthesized by methylating the hemiacetal hydroxyl group of GP. The mice received intragastric gavage of GP or MGP at 100 mg/kg for 14 days. GP exhibited significant ameliorative effects on cholestatic liver injury in Mdr2^−/− mice. GP treatment generated dialdehyde intermediates that covalently modified intestinal proteins and restored the gut microbiota composition along with bile salt hydrolase and 7α-dehydroxylase activities, leading to increased levels of intestinal unconjugated BAs and decreased levels of conjugated BAs. These changes activated intestinal farnesoid X receptor (FXR)-FGF15-hepatic CYP7A1 pathway. The ameliorative effect of GP on cholestasis was abolished by co-administration of a specific intestinal FXR inhibitor. In contrast, MGP did not exhibit these beneficial effects. In conclusion, the gut microbiota modulation by dialdehyde intermediates generated from GP contributes to its amelioration of cholestatic liver injury in Mdr2^−/− mice.