FFA2 activation suppresses gastric acid secretion via 5‐HT 3 receptor activation in rats in vivo

The observation that exogenous 5‐HT inhibits stimulated gastric acid secretion (GAS) implicates endogenous, locally released 5‐HT in the regulation of GAS. We have reported that the short‐chain fatty acid (SCFA) receptor FFA2 (GRP43) is expressed in duodenal 5‐HT containing enterochromaffin (EC) cells. We thus hypothesized that FFA2 activation alters gastric acid secretion (GAS) via 5‐HT release. We measured GAS in the perfused stomach in vivo using back‐titration and flow‐through pH and CO 2 electrodes, with or without luminal application of the selective FFA2 agonist phenylacetamide‐1 (PA1), followed by IV pentagastrin infusion. Immunostaining localized FFA2 to 5‐HT‐positive fundic EC cells. Luminal perfusion of PA1 reduced basal and pentagastrin‐induced GAS, without changing the rate of HCO 3 ‐ secretion. The PA1‐associated reductions of GAS were significantly reversed by the IV injection of the 5‐HT 3 antagonist ondansetron, whereas atropine, the 5‐HT 1 /5‐HT 2 antagonist pizotifen, or a somatostatin receptor antagonist cyclosomatostatin had no effect. These results suggest that FFA2 activation suppresses GAS via 5‐HT 3 activation, unmasking a previously undescribed GAS regulatory system. The presence of the SCFA receptor FFA2 in gastric EC cells implicate ingested or microbially‐produced SCFA in the genesis of 5‐HT 3 ‐related functional dyspepsia symptoms. Supported by VA Merit Review, NIH R01 DK54221