Abstract
The role of the gut microbiome in human health is becoming apparent. The major functional impact of the gut microbiome is transmitted through the microbial metabolites that are produced in the gut and interact with host cells either in the local gut environment or are absorbed into circulation to impact distant cells/organs. Short-chain fatty acids (SCFAs) are the major microbial metabolites that are produced in the gut through the fermentation of non-digestible fibers. SCFAs are known to function through various mechanisms, however, their signaling through free fatty acid receptors 2 and 3 (FFAR2/3; type of G-coupled protein receptors) is a new therapeutic approach. FFAR2/3 are widely expressed in diverse cell types in human and mice, and function as sensors of SCFAs to change several physiological and cellular functions. FFAR2/3 modulate neurological signaling, energy metabolism, intestinal cellular homeostasis, immune response, and hormone synthesis. FFAR2/3 function through Gi and/or Gq signaling, that is mediated through specific structural features of SCFAs-FFAR2/3 bindings and modulating specific signaling pathway. In this review, we discuss the wide-spread expression and structural homologies between human and mice FFAR2/3, and their role in different human health conditions. This information can unlock opportunities to weigh the potential of FFAR2/3 as a drug target to prevent human diseases.
Highlights
The gut microbiome and its contribution to human health is an emerging area and much remains to be learned about the interactions between microbial cells with a host
NCI-H716 cells through downregulation of extracellular signal-regulated kinase (ERK), p38 mitogen-activated protein kinase (MAPK), and NF-κB pathways [144]. These results profoundly indicate that fattyfatty acidacid receptor 2 receptor 2 (FFAR2) signaling regulates glucagon-like peptide 1 (GLP-1) and Peptide YY (PYY) secretion and may pave the way to consider FFAR2 as a therapeutic target against diabetes, because GLP-1 increase is beneficial in regulation of blood glucose levels
The novel FFAR2 antagonists such as CATPB, BTI-A-404, and BTI-A-292 decreases the GLP-1 hormonal synthesis from NCI-H716 cells through downregulation of ERK, p38 MAPK, and NF-κB pathways [144]
Summary
The gut microbiome and its contribution to human health is an emerging area and much remains to be learned about the interactions between microbial cells with a host. FFAR2/3 are cell surface receptors that can play a very significant role in intracellular cell signaling [46,47] Both FFAR2/3 receptors activate the heterotrimeric G-coupled protein intracellularly, by binding with endogenous SCFAs at the cell surface of any specific tissues. Both FFAR2 and FFAR3 are characterized as seven transmembrane (7TM) spanning proteins and consist of ~2% of the whole human and mice genome sequence respectively [46], and are coupled with Gαi/o coupled signaling [22,48]. Based on expression pattern, structural importance, and activation of FFAR2/3 receptors by gut microbiota metabolites at different tissue levels provide a new scope to investigate the importance of these receptors on human diseases. Sources of information about detailed expression patterns, structural and functional analyses, and their biological functions in different human diseases and health conditions is obscure
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