GPR43 activation with COX inhibition induces duodenal injury via 5‐HT pathway (905.1)

The reason why NSAIDs injure the small intestinal mucosa, but spare the duodenal mucosa is unknown. The short‐chain fatty acid receptor GRP43 is expressed in 5‐HT containing enterochromaffin cells, and a selective GPR43 agonist phenylacetamide‐1 (PA1) increases duodenal HCO 3 ‐ secretion (DBS) via 5HT 4 receptor activation. We hypothesized that GPR43 activation modulates duodenal mucosal defenses via 5‐HT release in an NSAID‐induced intestinal injury model. We measured DBS with pH and CO 2 electrodes in vivo through a duodenal loop, perfused with PA1 (0.1 ‐ 10 µM) while measuring released 5‐HT in the portal vein (PV). Intestinal injury was induced by indomethacin (IND, 10 mg/kg, sc) with or without PA1 (0.1 ‐ 1 mg/kg, ig), the 5HT 3 antagonist ondansetron (Ond, 3 mg/kg, ip), omeprazole (OPZ, 10 mg/kg, ig), or atropine (10 mg/kg, ig). Luminal perfusion with PA1 dose‐dependently increased DBS accompanied by 5‐HT release into PV. IND induced small intestinal ulcers with duodenal sparing. PA1 + IND dose‐dependently induced duodenal lesions, whereas PA1 alone had no effect. PA1 + IND‐induced duodenal lesions were inhibited by Ond or OPZ, but not by atropine. Non‐duodenal intestinal lesions were reduced by Ond or atropine, but not by OPZ as previously reported. These results suggest that although GPR43 activation enhances mucosal defenses by increased DBS via 5HT 4 activation, GPR43 activation combined with COX inhibition may increase the vulnerability of the duodenal mucosa to gastric acid via 5HT 3 activation. Grant Funding Source : Supported by VA Merit Review, NIH R01 DK54221