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

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 acid2farnesoid 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 acid2FXR signaling provides negative feedback control of bile acid production and transport to maintain bile acid homeostasis (3). Moreover, the bile acid2FXR signaling axis has been shown to regulate fat and glucose metabolism (4–7). Comparative analysis of global, liverspecific, 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 (9–11). Although mechanisms underlying the tissue-specific FXR metabolic effects remain to be unraveled, these studies suggest that tissuespecific manipulations of FXR signaling may be exploited to combat obesity-related metabolic syndrome and type 2 diabetes (1,8,13). The gut microbiota serves as a metabolic “organ” that actively participates in host metabolism (14), in part by regulating bile acid metabolism and FXR signaling (15,16). Critically, primary bile acids are liberated from their conjugated amino acids by microbe-derived bile salt hydrolase (BSH), a necessary step prior to further modification by additional microbial enzymes that generate diverse bile acid metabolites and influence host physiology. Profiling of bile acid metabolites in germ-free and conventionally raised mice revealed tauro-b-muricholic acid (T-b-MCA) as a major bile acid that is elevated in germ-free mice and also showed that T-b-MCA is normally metabolized to b-MCA through the action of BSH produced by the gut microbiota (15). T-b-MCA is a strong FXR antagonist. Thus, conversion of T-b-MCA to b-MCA by gut microbiota relieves FXR inhibition and favors FXR agonism (15). The effect of gut microbiota on FXR signaling appears to be restricted to the intestine, leaving hepatic FXR signaling relatively unchanged (11,15). Interestingly, in germ-free mice fed a high-fat diet (HFD), FXR antagonism due to elevated T-b-MCA rendered the mice less prone to obesity and metabolic disorders (16). These studies point to BSH and microbiota as therapeutic targets to help contain metabolic disorders through intestine-specific FXR inhibition. In this issue of Diabetes, Xie et al. (17) took advantage of a recent chemical screening study showing that the dietary supplement caffeic acid phenethyl ester (CAPE) inhibits bacterial BSH (18). Using CAPE to elevate levels of intestinal T-b-MCA for intestinal FXR inhibition, they found that CAPE reduced hepatic gluconeogenesis and alleviated hyperglycemia in mice fed an HFD. In contrast, CAPE had no effect on intestine-specific Fxr knockout