FFA3 Activation Stimulates Duodenal Bicarbonate Secretion and Prevents NSAID-Induced Enteropathy via the GLP-2 Pathway in Rats
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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-dependently augmented duodenal HCO3 − secretion accompanied by increased GLP-2 concentrations in the PV. The effect of FFA3 agonists was inhibited by co-perfusion of the selective FFA3 antagonist CF3-MQC (30 µM). AR-induced augmented HCO3 − secretion was reduced by iv injection of the GLP-2 receptor antagonist GLP-2(3-33) (3 nmol/kg), or by pretreatment with the cystic fibrosis transmembrane conductance regulator (CFTR) inhibitor CFTRinh-172 (1 mg/kg, ip). IND-induced small intestinal ulcers were dose-dependently inhibited by intragastric administration of MQC or AR. GLP-2(3-33) (1 mg/kg, ip) or CF3-MQC (1 mg/kg, ig) reversed AR-associated reduction in IND-induced enteropathy. In contrast, ip injection of AR had no effect on enteropathy.
These results suggest that luminal FFA3 activation enhances mucosal defenses and prevents NSAID-induced enteropathy via the GLP-2 pathway. The selective FFA3 agonist may be a potential therapeutic candidate for NSAID-induced enteropathy.
KeywordsFree fatty acid receptors Short-chain fatty acid Duodenal bicarbonate secretion Glucagon-like peptide-2 NSAID-induced enteropathy
Cystic fibrosis transmembrane conductance regulator
Dipeptidyl peptidase 4
Free fatty acid receptor 3
G protein-coupled receptor
Short-chain fatty acid
We thank Stacey Jung for her assistance with manuscript preparation and Drs. Paul Guth and Eli Engel for their helpful discussion.
This work was supported by a Department of Veterans Affairs Merit Review Award and NIH R01 DK54221.
Y.A. and J.D.K. were responsible for the study concept and design, and for drafting article. Ay.K. and K.I. were responsible for chemical design and synthesis. H.S., Y.A., K.N., and K.M. were responsible for collection, assembly, and analysis of data. Y.A., At.K., and J.D.K. were responsible for data interpretation.
Compliance with ethical standards
Conflict of interest
All authors declare that they have no conflicts of interest.
- 23.Ulven T. Short-chain free fatty acid receptors FFA2/GPR43 and FFA3/GPR41 as new potential therapeutic targets. Front Endocrinol (Lausanne). 2012;3:111.Google Scholar
- 39.Fujiwara K, Inoue T, Yorifuji N, et al. Combined treatment with dipeptidyl peptidase 4 (DPP4) inhibitor sitagliptin and elemental diets reduced indomethacin-induced intestinal injury in rats via the increase of mucosal glucagon-like peptide-2 concentration. J Clin Biochem Nutr. 2015;56:155–162.CrossRefPubMedPubMedCentralGoogle Scholar