GPR109A Is a G-protein–Coupled Receptor for the Bacterial Fermentation Product Butyrate and Functions as a Tumor Suppressor in Colon

Abstract

Short-chain fatty acids, generated in colon by bacterial fermentation of dietary fiber, protect against colorectal cancer and inflammatory bowel disease. Among these bacterial metabolites, butyrate is biologically most relevant. GPR109A is a G-protein-coupled receptor for nicotinate, but recognizes butyrate with low affinity. Millimolar concentrations of butyrate are needed to activate the receptor. Although concentrations of butyrate in colonic lumen are sufficient to activate the receptor maximally, there have been no reports on the expression/function of GPR109A in this tissue. Here we show that GPR109A is expressed in the lumen-facing apical membrane of colonic and intestinal epithelial cells and that the receptor recognizes butyrate as a ligand. The expression of GPR109A is silenced in colon cancer in humans, in a mouse model of intestinal/colon cancer, and in colon cancer cell lines. The tumor-associated silencing of GPR109A involves DNA methylation directly or indirectly. Re-expression of GPR109A in colon cancer cells induces apoptosis, but only in the presence of its ligands butyrate and nicotinate. Butyrate is an inhibitor of histone deacetylases, but apoptosis induced by activation of GPR109A with its ligands in colon cancer cells does not involve inhibition of histone deacetylation. The primary changes in this apoptotic process include downregulation of Bcl-2, Bcl-xL, and cyclin D1, and upregulation of death receptor pathway. In addition, GPR109A/butyrate suppresses NF-κB activation in normal and cancer colon cell lines as well as in normal mouse colon. These studies show that GPR109A mediates the tumor-suppressive effects of the bacterial fermentation product butyrate in colon.

Metabolite-sensing receptors GPR43 and GPR109A facilitate dietary fibre-induced gut homeostasis through regulation of the inflammasome

“…Similarly, absence of GPR109A in the non-haematopoeitic compartment abrogated the protective effects of fibre in DSS colitis ( Supplementary Fig. 5), presumably in the epithelium, a site of GPR109A expression 22 .…”

“…3b). Because GPR43 did not account for 100% of the beneficial effects of a high-fibre diet, at least by clinical score, we next tested GPR109A, a receptor expressed by colonic epithelial cells 22 that binds the SCFA butyrate and the fatty acid-derived ketone body (D)-beta-hydroxybutyrate 23 . We found that protection in the DSS model provided by high-fibre diet was GPR109A dependent, at least by clinical scores (Fig.…”

Daikenchuto (TU‐100) shapes gut microbiota architecture and increases the production of ginsenoside metabolite compound K

“…Short‐chain fatty acids have potent immunomodulatory activities on intestinal dendritic cells and lymphocytes as shown by the enhancement of gut T‐regulatory cell development with mixtures or specific species of Clostridiales that decreased colitis and systemic IgE responses in an experimental animal models (Thangaraju et al. 2009; Berdnt et al. 2012; Furusawa et al.…”

Blockade of Dendritic Cell Development by Bacterial Fermentation Products Butyrate and Propionate through a Transporter (Slc5a8)-dependent Inhibition of Histone Deacetylases

“…SLC5A8 has been shown to function as a tumor suppressor in the colon (17) and other tissues (13,18,19); the ability of this transporter to mediate the Na ϩ -coupled entry of HDAC inhibitors (butyrate, propionate, and pyruvate) into cells underlies the tumor-suppressive function of this transporter (15,16). While SLC5A8 is necessary for the intracellular actions of butyrate, butyrate also elicits biologic effects on colon cells extracellularly by serving as an agonist for the cell surface G-protein-coupled receptor GPR109A, but without involving HDAC inhibition (20). GPR109A was originally described as the receptor for nicotinate, and the acti-vation of the receptor by nicotinate provided the molecular basis for the anti-lipolytic actions of this vitamin (21,22).…”

“…Subsequent studies have shown that the ketone body ␤-hydroxybutyrate is the physiologic ligand for the receptor (23). Butyrate is also able to activate the receptor but with a low affinity; millimolar concentrations of butyrate are needed to activate the receptor (20,23). This indicates that butyrate might serve as a ligand for GPR109A in the colon under physiologic conditions because of the presence of high levels of this fatty acid in the colonic lumen (ϳ20 mM) due to bacterial fermentation of dietary fiber.…”