Free Fatty Acid Receptors 2 and 3 as Microbial Metabolite Sensors to Shape Host Health: Pharmacophysiological View

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.

Keywords: FFAR2; FFAR3; SCFA; gut; immune; microbiota.

Figure 1

Phylogenetic tree depicting genetic closeness and differences in Free fatty acid receptor 2 (FFAR2) (A) and Free fatty acid receptor 3 (FFAR3) (B) among different animal species.

Figure 2

(A) Diagrammatic representation of FFAR2 and FFAR3 expression in human tissues/cells and their comparison with mouse tissues/cells. (B–E) Homolgy structure of mouse (B,D) and human (C,E) FFAR2 (A,B) and pFFAR3 (D,E) protein. (a,b) Depicts the rainbow (a) and pipes and plank (b) structures.

Figure 3

Superposition of mice and human FFAR2 and FFAR3 receptors (A–F) Pipes and Plank model (A,D); Rainbow Ribbon Model (B,E); and root-mean-square deviation (RMSD) pairwise alignments of mouse and human FFAR2 (A–C) and FFAR3 (D–F) receptor sequence.

Figure 4

Structural analyses of FFAR2 protein-ligand bindings with agonists–acetate (A–D) and butyrate (E–H) and an FFAR2 antagonist-CATPB ((S)-3-(2-(3-chlorophenyl)acetamido)-4-(4-(trifluoromethyl)phenyl)butanoic acid) (I–L) in the ribbon models (A,C,E,G,I,K) and two dimensional Ligplot images (B,D,F,H,J,K)) and of mice (A,B,E,F,I,J) and human (C,D,G,H,K,L).

Figure 5

Mice (A) and human (B,C) FFAR2 (A,B) and FFAR3 (C) Protein-ligand interaction at orthosteric and allosteric sites. (A) Mice FFAR2 protein-ligand interaction (a) Hydrophobic model; (b) Ball and stick model with (c) Orthosteric binding site of C3 (Propionate), (d) Allosteric binding site of Cmp1; (B) Human FFAR2 protein-ligand interaction (a) Hydrophobic model, (b) Ball and stick model with (c) Orthosteric binding site of 4-CMTB, (d) Critical binding sites, (e) Allosteric binding site of 4-CMTB; and (C) Human FFAR3 protein-ligand Interaction (a) Hydrophobic model, (b) Ball and stick model, (c) Critical active sites for ligand binding, (d) Binding mode of 1-MCPC.

Figure 6

Biological function of FFAR2/3 as short chain fatty acid (SCFA)’s receptors at different body parts.

Figure 7

Role of diet-derived SCFAs activated FFAR2/3 signaling in regulation of energy balance through (A) Regulating the food intake by modulating gut-brain axis (B) Maintaining homeostasis by decreasing the fat accumulation and increasing the energy expenditure in adipose tissues, manipulating rate of gluconeogenesis in liver, and increasing insulin secretion and beta-cell function in the pancreas (C) Maintaining intestinal cellular homeostasis by increasing gut transit, mucus production, tight junction protein expression, and gut hormone synthesis and secretion.