Novel GPR43 Agonists Exert an Anti-Inflammatory Effect in a Colitis Model

Abstract

Inflammation is a type of defense response activated to protect organisms from detrimental factors, such as pathogens and tissue damage. Imbalance in inflammatory mechanisms can lead to chronic disorders, such as inflammatory bowel disease (IBD). The adaptive immune system is mainly involved in the pathogenesis of IBD, but some innate immune cells are also implicated (de Mattos et al., 2015). While many small-molecule drugs, such as aminosalicylates and corticosteroids, and biological molecules, for instance, infliximab and adalimumab, induce clinical remission in around 50% of the 48 GPR43 (also known as FFAR2), a metabolite-sensing G-protein-coupled receptor stimulated by short-chain fatty acid (SCFA) ligands is involved in innate immunity and metabolism. GPR43 couples with Gαi/o and Gαq/11 heterotrimeric proteins and is capable of decreasing cyclic AMP and inducing Ca 2+ flux. The GPR43 receptor has additionally been shown to bind β-arrestin 2 and inhibit inflammatory pathways, such as NF-κB. However, GPR43 shares the same ligands as GPR41, including acetate, propionate, and butyrate, and determination of its precise functions in association with endogenous ligands, such as SCFAs alone, therefore remains a considerable challenge. In this study, we generated novel synthetic agonists that display allosteric modulatory effects on GPR43 and downregulate NF-κB activity. In particular, the potency of compound 187 was significantly superior to that of preexisting compounds in vitro. However, in the colitis model in vivo, compound 110 induced more potent attenuation of inflammation. These novel allosteric agonists of GPR43 clearly display anti-inflammatory potential, supporting their clinical utility as therapeutic drugs.

The Role of Short Chain Fatty Acids in Irritable Bowel Syndrome

“…[96][97][98] In addition, a series of agonists of SCFA receptors can affect gut function through different mechanisms (Table 2). 66,71,[99][100][101][102] Selective GPR41 agonists are expected to become promising targets for the treatment of neurogenic diarrheal disorders because of their anti-dynamic and anti-secretory functions. 66 Selective GPR43 agonists inhibit gut transit via the PYY pathways.…”

Gut Microflora Modulates Th17/Treg Cell Differentiation in Experimental Autoimmune Prostatitis via the Short-Chain Fatty Acid Propionate

“…It has been exquisitely reported that SCFA propionate could regulate immune cell differentiation through G-protein-coupled receptors (GPRs) and histone deacetylases (HDACs) ( 30 ). To explore whether propionic acid regulated Th17 and Treg cell differentiation in a GPR-dependent manner, we detected the expressions of GPR43, one of the GPRs that play an important role in the immunity and metabolism, and intracellular signaling HDAC6 ( 31 ). First, the expressions of GPR43 were increased by propionic acid stimulation under Th17 and Treg cell conditions but suppressed by using LV-shGPR43 ( Figure 7A ).…”

Gut microbiota short-chain fatty acids and their impact on the host thyroid function and diseases

“…SCFAs can facilitate signaling events involving G protein-coupled receptors (GPRs), on the cell surface ( 150 , 151 ). Acetate, propionate, and butyrate are among the ligands shared by some GPRs ( 152 , 153 ). Within these receptors, we can find GPR109a (also known as hydroxycarboxylic acid receptor 2 or HCA2) expressed in the apical side of intestinal cells, adipose tissue, and immune cells ( 154 ), and in different tissues and cells of mammals can be found the free fatty acid receptor 2 (FFAR2; also known as GPR43) and the free fatty acid receptor 3 (FFAR3; also known as GPR41) ( 155 , 156 ).…”

“…The production of SCFAs by the gut microbiota can modulate immune cell responses ( 157 ). Different immune cells, such as neutrophils and leukocytes, predominate the expression of FFAR2 ( 158 , 159 ) and have been described to be involved in the inhibition of inflammatory pathways ( 152 , 153 ), and protective effects by diminishing the susceptibility to bacterial infections with Klebsiella pneumoniae , Citrobacter rodentium , and Staphylococcus aureus , but also by viruses such as respiratory syncytial and influenza viruses ( 159 ). Its protective effects can be compromised by inadequate fiber intake or a deficiency of FFAR2 ( 160 ).…”