Functional Characterization of Human Receptors for Short Chain Fatty Acids and Their Role in Polymorphonuclear Cell Activation*

By E. Le Poul, Cécile Loison, S. Struyf, J. Springael, V. Lannoy, Marie-Eve Decobecq, S. Brézillon, V. Dupriez, G. Vassart, J. Van Damme and 2 more. Journal of Biological Chemistry, 2003

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Short chain fatty acids (SCFAs), including acetate, propionate, and butyrate, are produced at high concentration by bacteria in the gut and subsequently released in the bloodstream. Basal acetate concentrations in the blood (about 100 μm) can further increase to millimolar concentrations following alcohol intake. It was known previously that SCFAs can activate leukocytes, particularly neutrophils. In the present work, we have identified two previously orphan G protein-coupled receptors, GPR41 and GPR43, as receptors for SCFAs. Propionate was the most potent agonist for both GPR41 and GPR43. Acetate was more selective for GPR43, whereas butyrate and isobutyrate were more active on GPR41. The two receptors were coupled to inositol 1,4,5-trisphosphate formation, intracellular Ca2+ release, ERK1/2 activation, and inhibition of cAMP accumulation. They exhibited, however, a differential coupling to G proteins; GPR41 coupled exclusively though the Pertussis toxin-sensitive Gi/o family, whereas GPR43 displayed a dual coupling through Gi/o and Pertussis toxin-insensitive Gq protein families. The broad expression profile of GPR41 in a number of tissues does not allow us to infer clear hypotheses regarding its biological functions. In contrast, the highly selective expression of GPR43 in leukocytes, particularly polymorphonuclear cells, suggests a role in the recruitment of these cell populations toward sites of bacterial infection. The pharmacology of GPR43 matches indeed the effects of SCFAs on neutrophils, in terms of intracellular Ca2+ release and chemotaxis. Such a neutrophil-specific SCFA receptor is potentially involved in the development of a variety of diseases characterized by either excessive or inefficient neutrophil recruitment and activation, such as inflammatory bowel diseases or alcoholism-associated immune depression. GPR43 might therefore constitute a target allowing us to modulate immune responses in these pathological situations.

Subfields: Cellular and Molecular Neuroscience, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/7fd9a68572a92945c708e63eb0b99b377e7f25c6

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Citations in the corpus

Regulation of intestinal epithelial permeability by tight junctions (2012, background): “Recently, two functional receptors for SCFAs, GPCR41, and 43, have been identified [207, 208].”
Olfactory receptor responding to gut microbiota-derived signals plays a role in renin secretion and blood pressure regulation (2013, background): “Importantly, Gpr41 responds in vitro to much lower doses of propionate (EC50 = ∼11 μM) (11, 29) than does Olfr78 (EC50 = ∼0.”
Gut microbiome, obesity, and metabolic dysfunction. (2011, background): “Propionate and acetate are ligands for two G protein–coupled receptors (GPCRs), Gpr41 and Gpr43, mainly expressed by intestinal epithelial cells (66, 67).”
International Union of Basic and Clinical Pharmacology. LXXIX. Cannabinoid Receptors and Their Ligands: Beyond CB1 and CB2 (2010, background): “…GPR41 and GPR43, were identified by three independent research groups as receptors for short-chain fatty acids (C1-C6; Table 3) (Brown et al., 2003; Le Poul et al., 2003; Nilsson et al., 2003) and these receptors have now been renamed FFA 3 and FFA 2 , respectively (Stoddart et al., 2008).”
Regulation of Inflammation by Short Chain Fatty Acids (2011, background): “Chemotaxis of neutrophils induced by formyl-Met-Leu-Phe (fMLP) or KC (CXCL1), an important chemokine for mouse neutrophils, has been shown to be either increased [24] or not affected by SCFAs [20,22].”
The microbial metabolites, short chain fatty acids, regulate colonic Treg cell homeostasis (2013, methodology): “To determine if Ffar2 contributes to cTreg homeostasis, we treated Ffar2−/− mice and Ffar2+/+ littermates with propionate, which has the highest affinity for Ffar2 (17), and measured cTreg numbers.”
Microbiota metabolite short chain fatty acids, GCPR, and inflammatory bowel diseases (2016, background): “GPR109a are coupled with Gi/0 and their activation by SCFA inhibits cAMP production [42].”