Targeting the Gut Microbiota-FXR Signaling Axis for Glycemic Control: Does a Dietary Supplement Work Magic?

Abstract

Glucose-dependent organs such as the brain are sustained through periods of fasting by glucose production in the liver, called hepatic gluconeogenesis. Normally, rising blood glucose levels homeostatically suppress gluconeogenesis. In obesity-related type 2 diabetes, however, insulin resistance and elevated glucagon inhibit the suppression of gluconeogenesis, contributing to hyperglycemia. Therapeutic intervention to suppress hepatic gluconeogenesis is therefore clinically important for controlling glucose in type 2 diabetes. Recent studies have suggested that the bile acid−farnesoid X receptor (FXR) signaling axis is a potential therapeutic target for metabolic disorders, including hyperglycemia caused by elevated hepatic gluconeogenesis (1,2). Bile acids are synthesized in the liver from cholesterol as conjugates of taurine (in mice) or glycine (in humans) and delivered to the gut to facilitate solubilization of dietary lipids and vitamins. Bile acids and their metabolites also function as endogenous ligands of FXR, a ligand-activated transcription factor highly expressed in the liver and the intestine. Bile acid−FXR signaling provides negative feedback control of bile acid production and transport to maintain bile acid homeostasis (3). Moreover, the bile acid−FXR signaling axis has been shown to regulate fat and glucose metabolism (4–7). Comparative analysis of global, liver-specific, and intestine-specific FXR knockout mice revealed a complex signaling network, wherein activation of the liver FXR and intestinal FXR result in distinct metabolic outcomes in diet-induced or genetic obesity models (6,8–12). In particular, several recent studies indicate that selective inhibition of intestinal FXR improves metabolic phenotypes in obese animals (9 …