Dysregulated Free Fatty Acid Receptor 2 Exacerbates Colonic Adenoma Formation in Apc(Min/+) Mice: Relation to Metabolism and Gut Microbiota Composition

Free fatty acid receptor 2 (FFAR2) has been reported as a tumor suppressor in colon cancer development. The current study investigated the effects of FFAR2 signaling on energy metabolism and gut microbiota profiling in a colorectal cancer mouse model (Apc(Min/+)). Ffar2 deficiency promoted colonic polyp development and enhanced fatty acid oxidation and bile acid metabolism. Gut microbiome sequencing analysis showed distinct clustering among wild-type, Apc(Min/+), and Apc(Min/+)-Ffar2(-/-) mice. The relative abundance of Flavobacteriaceae and Verrucomicrobiaceae was significantly increased in the Apc(Min/+)-Ffar2(-/-) mice compared to the Apc(Min/+) mice. In addition, knocking-down FFAR2 in the human colon cancer cell lines (SW480 and HT29) resulted in increased expression of several key enzymes in fatty acid oxidation, such as carnitine palmitoyltransferase 2, acyl-CoA dehydrogenase, long-chain acyl-CoA dehydrogenase, C-2 to C-3 short chain, and hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase, alpha subunit. Collectively, these results demonstrated that Ffar2 deficiency significantly altered profiles of fatty acid metabolites and gut microbiome, which might promote colorectal cancer development.