Polygonum multiflorum Thunb suppress bile acid synthesis by activating Fxr-Fgf15 signaling in the intestine.

ETHNOPHARMACOLOGICAL RELEVANCE: Polygonum multiflorum Thunb( Heshouwu, HSW) is commonly used in clinical medicine, while the hepatotoxicities of HSW are reported increasingly in recent years. Currently, researchers have demonstrated an essential role of Bile Acids (BAs) in liver diseases. The occurrence of hepatotoxicity cases linked to HSW are characterized by jaundice and cholestasis, suggesting an interaction that between BAs and HSW AIM OF THE STUDY: This study was designed to investigate the HSW-induced liver functional and histological changes in mice and the role of HSW on bile acid synthesis, metabolism, clearance and intestinal absorption.

MATERIALS AND METHODS: The mice were intragastrically (i.g.) given HSW at doses of 1.275and 3.825g/kg (Crude extracts /body weight) once a day for seven days. Liver function was evaluated by measuring the serum levels of enzymes and analyzing the liver histology. The LC/MS analysis was performed to quantify BAs from liver, ileum and serum. Moreover, the expression of bile metabolic-related transporters and metabolic enzymes at both protein and mRNA levels were observed to elucidate the underlying mechanisms.

RESULTS: Oral administration of HSW for 7 days could not cause liver damage. A significant change was observed for the concentrations of liver and serum BAs in treatment groups compared with normal control. The mRNA expression levels of bile acid excretory transporter (Bsep) and basolateral uptake transporter (Ntcp) were increased with the development of HSW. The concentrations of unconjugated BAs increased in mice intestines after the administration of HSW. Western blot and qRT-PCR analyses showed that HSW upregulated the protein and mRNA expression of Shp and Fgf15 in the ileum of the mice.

CONCLUSION: HSW treatment for 7days did not cause liver damage. HSW accelerated bile acid enterohepatic circulation and changed the composition of intestinal BAs, leding to the activation of Fxr-Fgf15 signal in intestines, and further inhibited the expression of Cyp7a1 in the liver.