FFA3 Activation Stimulates Duodenal Bicarbonate Secretion and Prevents NSAID-Induced Enteropathy via the GLP-2 Pathway in Rats

Digestive Diseases and Sciences
Hyder SaidJonathan D Kaunitz

Abstract

Therapy with nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with enteropathy in humans and experimental animals, a cause of considerable morbidity. Unlike foregut NSAID-associated mucosal lesions, most treatments for this condition are of little efficacy. We propose that the endogenously released intestinotrophic hormone glucagon-like peptide-2 (GLP-2) prevents the development of NSAID-induced enteropathy. Since the short-chain fatty acid receptor FFA3 is expressed on enteroendocrine L cells and on enteric nerves in the gastrointestinal tract, we further hypothesized that activation of FFA3 on L cells protects the mucosa from injury via GLP-2 release with enhanced duodenal HCO3- secretion. We thus investigated the effects of synthetic selective FFA3 agonists with consequent GLP-2 release on NSAID-induced enteropathy. We measured duodenal HCO3- secretion in isoflurane-anesthetized rats in a duodenal loop perfused with the selective FFA3 agonists MQC or AR420626 (AR) while measuring released GLP-2 in the portal vein (PV). Intestinal injury was produced by indomethacin (IND, 10 mg/kg, sc) with or without MQC (1-10 mg/kg, ig) or AR (0.01-0.1 mg/kg, ig or ip) treatment. Luminal perfusion with MQC or AR (0.1-10 µM) dose-...Continue Reading

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Citations

Aug 21, 2018·Current Opinion in Gastroenterology·Mari IwasakiJonathan D Kaunitz
Jul 11, 2019·Current Gastroenterology Reports·Mari IwasakiJonathan D Kaunitz
Aug 29, 2019·Physiological Reviews·John F CryanTimothy G Dinan
Sep 6, 2019·Physiological Reviews·Ikuo KimuraMiki Igarashi
Aug 15, 2017·Current Opinion in Gastroenterology·Izumi Kaji, Jonathan D Kaunitz
May 19, 2021·Neurotoxicity Research·Yousef TizabiMichael Aschner
Mar 7, 2020·Journal of Medicinal Chemistry·Elisabeth Rexen UlvenTrond Ulven

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