Digestive Diseases and Sciences

, Volume 62, Issue 8, pp 1944–1952 | Cite as

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

  • Hyder Said
  • Yasutada Akiba
  • Kazuyuki Narimatsu
  • Koji Maruta
  • Ayaka Kuri
  • Ken-ichi Iwamoto
  • Atsukazu Kuwahara
  • Jonathan D. Kaunitz
Original Article



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.


Free 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


Glucagon-like peptide






Portal vein


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.

Author’s contribution

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.


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Copyright information

© Springer Science+Business Media New York (Outside the USA) 2017

Authors and Affiliations

  1. 1.College of Arts and Sciences, University of CaliforniaLos AngelesUSA
  2. 2.Greater Los Angeles Veterans Affairs Healthcare SystemLos AngelesUSA
  3. 3.Department of MedicineUniversity of California Los Angeles, School of MedicineLos AngelesUSA
  4. 4.Brentwood Biomedical Research InstituteLos AngelesUSA
  5. 5.Graduate School of Integrated Pharmaceutical and Nutritional SciencesUniversity of ShizuokaShizuokaJapan
  6. 6.Department of SurgeryUniversity of California Los Angeles, School of MedicineLos AngelesUSA

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