Abstract

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 CO2 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 HCO3- secretion. The PA1-associated reductions of GAS were significantly reversed by the IV injection of the 5-HT3 antagonist ondansetron, whereas atropine, the 5-HT1/5-HT2 antagonist pizotifen, or a somatostatin receptor antagonist cyclosomatostatin had no effect. These results suggest that FFA2 activation suppresses GAS via 5-HT3 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-HT3-related functional dyspepsia symptoms. Supported by VA Merit Review, NIH R01 DK54221

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