Short-chain free-fatty acid G protein-coupled receptors in colon cancer

The dietary role of macronutrients and their metabolites in cancer has been evident for many decades. Dietary ingestion of fat, carbohydrates, protein, and fiber, as well as probiotics that influence gut microbiota, have all been linked to gastrointestinal (GI) tract health and disease, particularly in the colon, where it has long been known that fat and fiber can regulate inflammation and carcinogenesis. Short-chained fatty acids (SCFA), including acetate, propionate, and butyrate, which are biosynthesized by microbiota-mediated metabolism of dietary fiber, have previously been shown to play important roles in colorectal health, including decreasing inflammation and oxidative stress. Since the 1980s, a growing number of studies have also demonstrated a link between SCFA and colon epithelial cell carcinogenesis and prevention of colorectal cancers (CRC). While the effects of SCFA have historically been associated with their intracellular metabolism and function, the discovery of a family of G protein-coupled free-fatty acid receptors in the early 2000s suggests that many effects of SCFA are cell-surface receptor mediated. Indeed, the SCFA GPCRs FFA2 (previously termed GPR43), FFA3 (previously termed GPR41), and GPR109A are now well established to be expressed within the GI tract, where they modulate a variety of functions in response to luminal SCFA. While the role of SCFA in cancers, including CRC, has been reviewed in detail elsewhere, the goal of this report is to provide a review on the current body of evidence in regard to the effects of SCFA on FFA2, FFA3, and GPR109A in colon cancers.