GPR109A is a G-protein-coupled receptor for the bacterial fermentation product butyrate and functions as a tumor suppressor in colon

By M. Thangaraju, G. Cresci, Kebin Liu, S. Ananth, Jaya P. Gnanaprakasam, D. Browning, J. Mellinger, Sylvia B. Smith, Gregory J. Digby, N. Lambert and 2 more. Cancer Research, 2009

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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.

Subfields: Food Science, Molecular Biology, Surgery

View Paper: https://www.semanticscholar.org/paper/1608c1e2163bdaa559af0a858aeb0b08d75438d9

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Citations in the corpus

Butyrate and Propionate Protect against Diet-Induced Obesity and Regulate Gut Hormones via Free Fatty Acid Receptor 3-Independent Mechanisms (2012, background): “The niacin receptor GPR109A can also be activated by butyrate in the mM range and is expressed on the apical surface of colonic epithelium [29].”
The role of short-chain fatty acids in the interplay between gut microbiota and diet in cardio-metabolic health (2021, background): “FFAR2 prefers binding to acetate and propionate, whereas FFAR3 binds propionate, butyrate, and acetate with a lower affinity,(99) and GPR109a mainly binds butyrate.(100) Moreover, butyrate and propionate play an important role in transcriptional regulations and post-translational modifications, as t”
The Human Gut Microbiome – A Potential Controller of Wellness and Disease (2018, background): “…signaling, via intracellular action of butyrate as HDAC inhibitor that could epigenetically regulate gene expression, and/or its extracellular action as a ligand that targets G-protein coupled receptor GPR109A-expressing cancer cell (Hassig et al., 1997; Thangaraju et al., 2009; Wei et al., 2016).”
The Microbiome in Infectious Disease and Inflammation (2012, positive): “The defect in NF-κB activation leads to apoptosis of IECs, impaired expression of antimicrobial proteins, and translocation of bacteria into the mucosa.”
Short-Chain Fatty Acids and Their Association with Signalling Pathways in Inflammation, Glucose and Lipid Metabolism (2020, background): “GPR109A KO mice were more susceptible to dss-induced colitis than the control group, and GPR109A was found to be downregulated in human colon cancer cell lines (along with mouse models of colon cancer) [42,67,78].”
Diet, metabolites, and "western-lifestyle" inflammatory diseases. (2014, neutral): “, 2009), GPR109A (Lukasova et al., 2011; Singh et al., 2014; Thangaraju et al., 2009), GPR40 (Fujita et al.”