GPR41/FFAR3 and GPR43/FFAR2 as Cosensors for Short-Chain Fatty Acids in Enteroendocrine Cells vs FFAR3 in Enteric Neurons and FFAR2 in Enteric Leukocytes

Abstract

The expression of short-chain fatty acid receptors GPR41/FFAR3 and GPR43/ free fatty acid receptor 2 (FFAR2) was studied in the gastrointestinal tract of transgenic monomeric red fluorescent protein (mRFP) reporter mice. In the stomach free fatty acid receptor 3 (FFAR3)-mRFP was expressed in a subpopulation of ghrelin and gastrin cells. In contrast, strong expression of FFAR3-mRFP was observed in all cholecystokinin, glucose-dependent insulinotropic peptide (GIP), and secretin cells of the proximal small intestine and in all glucagon-like peptide-1 (GLP-1), peptide YY, and neurotensin cells of the distal small intestine. Throughout the colon and rectum, FFAR3-mRFP was strongly expressed in the large population of peptide YY and GLP-1 cells and in the neurotensin cells of the proximal colon. A gradient of expression of FFAR3-mRFP was observed in the somatostatin cells from less than 5% in the stomach to more than 95% in the rectum. Substance P-containing enterochromaffin cells displayed a similar gradient of FFAR3-mRFP expression throughout the small intestine. Surprisingly, FFAR3-mRFP was also expressed in the neuronal cells of the submucosal and myenteric ganglia. Quantitative PCR analysis of fluorescence-activated cell sorting (FACS) purified FFAR3-mRFP positive cells confirmed the coexpression with the various peptide hormones as well as key neuronal marker proteins. The FFAR2-mRFP reporter was strongly expressed in a large population of leukocytes in the lamina propria of in particular the small intestine but surprisingly only weakly in a subpopulation of enteroendocrine cells. Nevertheless, synthetic ligands specific for either FFAR3 or FFAR2 each released GLP-1 from colonic crypt cultures and the FFAR2 agonist mobilized intracellular Ca²⁺ in FFAR2 positive enteroendocrine cells. It is concluded that FFAR3-mRFP serves as a useful marker for the majority of enteroendocrine cells of the small and large intestine and that FFAR3 and FFAR2 both act as sensors for short-chain fatty acids in enteroendocrine cells, whereas FFAR3 apparently has this role alone in enteric neurons and FFAR2 in enteric leukocytes.

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

“…Similar to K þ efflux, we found that acetate mediated hyperpolarization through GPR43 and activated the inflammasome in colonic epithelial cells. As described for neutrophils 12,33 , acetate induced an increase in intracellular Ca 2 þ in colonic epithelial cells, which is in accordance with other reports showing enteroendocrine cells expressing GPR43 mobilize Ca 2 þ when stimulated with agonist 34 . An increase of intracellular Ca 2 þ has been shown to promote K þ efflux in HT29 cells, suggesting that the hyperpolarizing effects of acetate might be due indirectly to a rise in intracellular Ca 2 þ (ref.…”

Gut/brain axis and the microbiota

“…Signaling through GPCRs, as well as transport of SCFAs by SLC5A8 and the resultant physiological effects, are affected by dietary intake of fermentable fiber (128). Different types of SCFA receptors have been identified on enteroendocrine cells and on neurons of the submucosal and myenteric ganglia (129). A diet supplemented with Bifidobacterium breve was associated with increased fatty acid concentrations in the brain; however, the mechanisms underlying these effects are not known (75).…”

Gut chemosensing mechanisms

“…They have been identified as ligands for two GPCRs, free fatty acid receptor 2 (FFAR2, previously known as GPR43) and FFAR3 (previously known as GPR41) (102,103), both of which are detectable in rat and human colonic mucosa (104)(105)(106) and in murine L cells (106)(107)(108). FFAR2 couples to G q and G i pathways, whereas FFAR3 is presumed to couple exclusively to the pertussis toxin-sensitive G i pathway (102,103).…”