The Gut Microbiota as a Therapeutic Target in IBD and Metabolic Disease: A Role for the Bile Acid Receptors FXR and TGR5

Abstract

The gut microbiota plays a crucial role in regulating many physiological systems of the host, including the metabolic and immune system. Disturbances in microbiota composition are increasingly correlated with disease; however, the underlying mechanisms are not well understood. Recent evidence suggests that changes in microbiota composition directly affect the metabolism of bile salts. Next to their role in digestion of dietary fats, bile salts function as signaling molecules for bile salt receptors such as Farnesoid X receptor (FXR) and G protein-coupled bile acid receptor (TGR5). Complementary to their role in metabolism, FXR and TGR5 are shown to play a role in intestinal homeostasis and immune regulation. This review presents an overview of evidence showing that changes in bile salt pool and composition due to changes in gut microbial composition contribute to the pathogenesis of inflammatory bowel disease and metabolic disease, possibly through altered activation of TGR5 and FXR. We further discuss how dietary interventions, such as pro- and synbiotics, may be used to treat metabolic disease and inflammatory bowel disease (IBD) through normalization of bile acid dysregulation directly or indirectly through normalization of the intestinal microbiota.

Keywords: FXR; TGR5; bile acid dysregulation; dysbiosis; gut microbiota; inflammatory bowel disease; metabolic disease; probiotics.

Figure 1

Composition of bile acids in the gallbladder and feces of healthy individuals and their signaling pathways.

Figure 2

Schematic overview of the expression and functions of FXR and TGR5. See Section 3 and Section 4 for details. White on black; Tissue or cellular expression of FXR and TGR5. Black on white; Functions of FXR and TGR5.

Figure 3

Schematic representation of the vicious cycle that follows the pathological perturbation of the intestinal microbiota.