Figure 6.

Customizing our approach for resolution of the roles of short chain fatty acid receptors. Evidence connects short chain fatty acid receptors to gut inflammatory responses. For reasons like shared endogenous ligands, differences in ligand efficacy for species orthologs (and others, enumerated in the text) there are hurdles in assigning selective physiological roles to these receptors. Their actual therapeutic potential thus remains unappreciated. These blocks can be overcome by customized approaches like, development of selective and potent agonists and antagonists for these receptors and their use in in vitro and ex vivo models (A and D); use of designer receptors with modified ligand binging sites, allowing activation of a particular member from the family which also contains a fluorescent tag (if attached to the receptor) (B); minimizing discrepancies by determining receptor expression along the course of cell/tissue differentiation (C); several different mouse models can be used to ascertain specific physiological effects of these receptors (E), including use of mice lacking two or more members of the family (multiple receptor KO), tissue specific KO or mice with gene of a human receptor replacing the mouse ortholog (tissue specific human receptor knock-in). These mouse models can then be used in combination with gut microbiota knockdown approaches (germ free), colonized with human microbiota, or fed SCFAs alone or in combination to determine the interrelationship of these receptors with gut microbiota (44,73,94,120,122,123,132,206,218).