Protective actions of a luminally acting 5-HT4 receptor agonist in mouse models of colitis

Abstract

Background: 5-hydroxytryptamine 4 receptors (5-HT₄ Rs) are expressed in the colonic epithelium, and previous studies have demonstrated that luminal administration of agonists enhances motility, suppresses nociception, and is protective in models of inflammation. We investigated whether stimulation with a luminally acting 5-HT₄ R agonist is comparable to previously tested absorbable compounds.

Methods: The dextran sodium sulfate (DSS), trinitrobenzene sulfonic acid (TNBS), and interleukin 10 knockout (IL-10KO) models of colitis were used to test the protective effects of the luminally acting 5-HT₄ R agonist, 5HT4-LA1, in the absence and presence of a 5-HT₄ R antagonist. The compounds were delivered by enema to mice either before (prevention) or after (recovery) the onset of active colitis. Outcome measure included disease activity index (DAI) and histological evaluation of colon tissue, and effects on wound healing and fecal water content were also assessed.

Key results: Daily enema of 5HT4-LA1 attenuated the development of, and accelerated recovery from, active colitis. Enema administration of 5HT4-LA1 did not attenuate the development of colitis in 5-HT₄ R knockout mice. Stimulation of 5-HT₄ Rs with 5HT4-LA1 increased Caco-2 cell migration (accelerated wound healing). Daily administration of 5HT4-LA1 did not increase fecal water content in active colitis.

Conclusions and inferences: Luminally restricted 5-HT₄ R agonists are comparable to absorbable compounds in attenuating and accelerating recovery from active colitis. Luminally acting 5-HT₄ R agonists may be useful as an adjuvant to current inflammatory bowel disease (IBD) treatments to enhance epithelial healing.

Keywords: 5-HT4 receptor; colitis; mucosal serotonin signaling.