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

Abstract

Background

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.

Methods

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.

Results

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.

Conclusion

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.

Keywords

Free fatty acid receptors Short-chain fatty acid Duodenal bicarbonate secretion Glucagon-like peptide-2 NSAID-induced enteropathy 

Abbreviations

5-HT

5-Hydroxytryptamine

CF3-MQC

N-(2-methylphenyl)-4-[5-(2-trifluoromethoxy-phenyl)-furan-2-yl)-2-methyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxamide

CFTR

Cystic fibrosis transmembrane conductance regulator

DPP4

Dipeptidyl peptidase 4

FFA3

Free fatty acid receptor 3

GPCR

G protein-coupled receptor

GLP

Glucagon-like peptide

IND

Indomethacin

MQC

N-[2-methylphenyl]-[4-furan-3-yl]-2-methyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxamide

PV

Portal vein

SCFA

Short-chain fatty acid

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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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