Diet is considered an important trigger in
inflammatory bowel diseases (IBD), as feeding habits can affect intestinal permeability and clearance of
bacterial antigens, consequently influencing the immune system.
Free fatty acid receptors (FFARs), expressed on the intestinal epithelial cells, belong to the family of
luminal-facing receptors that are responsive to nutrients. The objective of this study was to characterize the anti-inflammatory activity and the effect on intestinal barrier function of synthetic FFAR agonists in mouse models of
colitis. Therapeutic activity of
GW9508 (FFAR1 agonist), 4-CMTB (FFAR2 agonist), AR420626 (FFAR3 agonist), and
GSK137647 (FFAR4 agonist) was investigated in two models of semi-chronic
colitis: induced by
trinitrobenzenesulfonic acid (TNBS), mimicking
Crohn's disease, as well as induced by
dextran sulfate sodium (DSS), which recapitulates
ulcerative colitis in humans. Moreover, we assessed the influence of FFARs agonists on epithelial ion transport and measured the ion flow stimulated by
forskolin and
veratridine. Administration of FFAR4 agonist
GSK137647 attenuated both TNBS-induced and DSS-induced
colitis in mice, as indicated by macroscopic parameters and
myeloperoxidase activity. The action of FFAR4 agonist
GSK137647 was significantly blocked by pretreatment with selective FFAR4 antagonist
AH7614. Moreover, FFAR1 and FFAR4 agonists reversed the increase in the colon permeability caused by
inflammation. FFAR4 restored the tight junction genes expression in mouse colon. This is the first evaluation of the anti-inflammatory activity of selective FFAR agonists, showing that pharmacological intervention targeting FFAR4, which is a sensor of medium and long chain
fatty acids, attenuates intestinal
inflammation.