Gut microbiome in liver pathophysiology and cholestatic liver disease

Abstract

An increasing amount of evidence has shown critical roles of gut microbiome in host pathophysiology. The gut and the liver are anatomically and physiologically connected. Given the critical role of gut-liver axis in the homeostasis of the liver, gut microbiome interplays with a diverse spectrum of hepatic changes, including steatosis, inflammation, fibrosis, cholestasis, and tumorigenesis. In clinic, cholestasis manifests with fatigue, pruritus, and jaundice, caused by the impairment in bile formation or flow. Studies have shown that the gut microbiome is altered in cholestatic liver disease. In this review, we will explore the interaction between the gut microbiome and the liver with a focus on the alteration and the role of gut microbiome in cholestatic liver disease. We will also discuss the prospect of exploiting the gut microbiome in the development of novel therapies for cholestatic liver disease.

Keywords: Cholestatic liver disease; Gut microbiome; Liver pathophysiology.

Fig. 1

Roles of gut microbiome in cholestatic liver disease and potential therapies. Gut microbiome is altered in cholestatic liver disease and in turn contributes to the pathogenesis of cholestatic liver disease. Modulation of the gut microbiota is feasible via a diverse array of strategies, including antibiotics, fecal microbiota transplantation (FMT), and probiotics. Gut dysbiosis increases gut permeability, which enhances bacterial translocation and transportation of microbial products like lipopolysaccharide (LPS) to the liver, thereby causing hepatic immune response. Inhibition of Toll-like receptors (TLRs) may be a potential therapy. Changes in microbial metabolites, particularly bile acids, by gut dysbiosis affect physiological functions of both the intestine and the liver. Altered bile acid profile in the intestine can alter intestinal farnesoid X receptor (FXR) activity and the expression of fibroblast growth factor (FGF)15/19, which are critical for bile acid homeostasis. In the liver, altered bile acid composition is associated with cholestatic liver disease. Interventions specifically targeted to microbial metabolism in cholestatic liver disease include ursodeoxycholic acid (UDCA) treatment, bile acid sequestrants, and agents targeting to bile acid metabolism. Abbreviations: FGF, fibroblast growth factor; FMT, fecal microbiota transplantation; FXR, farnesoid X receptor; LPS, lipopolysaccharide; TLR, Toll-like receptor; UDCA, ursodeoxycholic acid.