The Pharmacology and Function of Receptors for Short-Chain Fatty Acids

Abstract

Despite some blockbuster G protein-coupled receptor (GPCR) drugs, only a small fraction (∼15%) of the more than 390 nonodorant GPCRs have been successfully targeted by the pharmaceutical industry. One way that this issue might be addressed is via translation of recent deorphanization programs that have opened the prospect of extending the reach of new medicine design to novel receptor types with potential therapeutic value. Prominent among these receptors are those that respond to short-chain free fatty acids of carbon chain length 2-6. These receptors, FFA2 (GPR43) and FFA3 (GPR41), are each predominantly activated by the short-chain fatty acids acetate, propionate, and butyrate, ligands that originate largely as fermentation byproducts of anaerobic bacteria in the gut. However, the presence of FFA2 and FFA3 on pancreatic b-cells, FFA3 on neurons, and FFA2 on leukocytes and adipocytes means that the biologic role of these receptors likely extends beyond the widely accepted role of regulating peptide hormone release from enteroendocrine cells in the gut. Here, we review the physiologic roles of FFA2 and FFA3, the recent development and use of receptor-selective pharmacological tool compounds and genetic models available to study these receptors, and present evidence of the potential therapeutic value of targeting this emerging receptor pair.

The Neutrophil Response Induced by an Agonist for Free Fatty Acid Receptor 2 (GPR43) Is Primed by Tumor Necrosis Factor Alpha and by Receptor Uncoupling from the Cytoskeleton but Attenuated by Tissue Recruitment

“…Signaling by the Cmp1/FFA2R complex is also rapidly terminated by swift receptor desensitization, but the mechanism for how signaling is turned off differs from that of the FPRs. The fact that short-chain fatty acids are produced by gut microbes during anaerobic metabolism has suggested that receptors for such molecules expressed on innate immune cells are of prime importance for regulating inflammatory reactions in the gut (67), but the fact that the tissue-recruited neutrophils were nonresponding to the FFA2R agonist suggests a role for the receptor also in other organs and that the role of FFA2Rs is complex and needs further analysis.…”

Cross-feeding interactions of gut symbionts driven by human milk oligosaccharidesand mucins

“…Physiologically, butyrate is associated with the enhancement of colonic barrier function and it could regulate host immune and metabolic state by signalling through G-protein-coupled receptors (GPR) and by inhibiting histone deacetylase (HDAC) (Bolognini et al 2016, Fellows et al 2018, Koh et al 2016.…”

“…It is used as the preferred energy source for colonic epithelial cells (Donohoe et al 2011). Physiologically, butyrate is associated with the enhancement of colonic barrier function, increase satiety, pain relief, anti-inflammation, and protection against colorectal cancer (Banasiewicz et al 2013, Bolognini et al 2016, Donohoe et al 2011, Furusawa et al 2013, Goncalves and Martel 2013. Also, it can regulate host immune and metabolic states by signalling through G-protein-coupled receptors (GPR) and by inhibiting histone deacetylase (HDAC) (Bolognini et al 2016, Fellows et al 2018, Koh et al 2016.…”

“…While all SCFAs are vital for maintaining gut homeostasis, butyrate is of particular interest because it has been attributed to a range of health-promoting functions. Butyrate is the primary energy source for colonic epithelial cells and is associated with the enhancement of colonic barrier function, increase of satiety, pain relief, anti-inflammatory responses, and protection against colorectal cancer (Banasiewicz et al 2013, Bolognini et al 2016, Donohoe et al 2011, Furusawa et al 2013, Goncalves and Martel 2013.…”

“…While all SCFAs are vital for maintaining gut homeostasis, butyrate is of particular interest because it has been attributed to a range of health-promoting functions. Butyrate is the primary energy source for colonic epithelial cells and is associated with the enhancement of colonic barrier function, increase of satiety, pain relief, anti-inflammatory responses, and protection against colorectal cancer (Banasiewicz et al 2013, Bolognini et al 2016, Donohoe et al 2011, Furusawa et al 2013, Goncalves and Martel 2013.Considering the physiological benefits of butyrate to human health, this thesis investigates the microbial interaction of gut symbionts that support butyrate production driven primarily by the host produced glycans in human milk and mucus. Glycans are compounds consisting of an array of glycosidically linked monosaccharides (monosaccharides and disaccharides are collectively termed sugars) such as human milk oligosaccharides (HMOS) and mucins (Varki and Kornfeld 2017).…”