These results suggest that, although FFA2 activation enhances duodenal mucosal defenses, FFA2 overactivation during ulcerogenic cyclooxygenase inhibition may increase the vulnerability of the duodenal mucosa to gastric acid via excessive 5-HT release and 5-HT<sub>3</sub> receptor activation, implicated in foregut-related symptoms such as emesis and epigastralgia.<b>NEW & NOTEWORTHY</b> Luminal free fatty acid receptor 2 agonists stimulate enterochromaffin cells and release serotonin, which enhances mucosal defenses in rat duodenum.