Abstract

Background:

The homeostasis of gut microbiota is pivotal to maintaining the physiological liver-gut axis. In cholestatic diseases, impaired bile flow changes the composition of gut bacteria and subsequently dysregulates the bile acids metabolisms. Beneficial roles of vancomycin (VCM) in treating patients with sclerosing cholangitis have been reported; yet the mechanism is not clear. The therapeutic values of the intestinal microbiome restoration in cholestatic disease are less explored.

Methods:

Adult male Bsep (abcb11) knockout mice with genetic variants in Plec demonstrated a more severe jaundiced phenotype named Bsep-ko-JD (KO). This intrahepatic cholestatic model treated with vancomycin (VCM) exhibited decreased serum bilirubin levels, improved liver bile acid profiles, and ameliorated damages in the biliary ductal structures. This study aims to explore the potential therapeutic gut microbe of the cholestatic liver disease model.

Results:

Using next generation sequencing to profile the intestinal microbiota, the weighted UniFrac principal co-ordinates analysis (PCoA) showed that VCM largely changed gut microbiota in the wild type (WT)-VCM and the KO mice compared to control (Ctrl). (Figure) Parabacteroides goldsteinii (PG) was the most abundant species in this intrahepatic cholestasis model. We treated the KO mice with 1*10^9 PG or phosphate buffered saline by intragastric gavage 3 times per week for a total of 4 weeks. Significant improvement in the PG-treated mice was noted as evidenced by decreased levels of serum bile acids, direct-bilirubin, alkaline phosphatase, as well as reduced levels of hepatic chenodeoxycholic acid, lithocholic acid, and lymphocyte infiltration in the liver.

Conclusion:

Our results suggested that the PG identified from a therapeutic model of intrahepatic cholestasis may modulate bile flow and/or bile acid metabolisms, and may direct future investigations of the treatment of cholestatic liver diseases.