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Cited by 23Inflammatory mediators and NSAID effectsGastrointestinal motility and disordersInflammatory Bowel Disease

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

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Said, Hyder, Akiba, Yasutada, Narimatsu, Kazuyuki, Maruta, Koji, Kuri, Ayaka, Iwamoto, Ken-ichi, Kuwahara, Atsukazu, Kaunitz, Jonathan D.·2017·Digestive Diseases and Sciences
DOI 10.1007/s10620-017-4600-4PMC PMC5511769
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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 HCO 3- secretion. We thus investigated the effects of synthetic selective FFA3 agonists with consequent GLP-2 release on NSAID-induced enteropathy. Methods We measured duodenal HCO 3- 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 HCO 3- 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 HCO 3- 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 CFTR inh-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.

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Metadata

Authors
Said, H., Akiba, Y., Narimatsu, K., Maruta, K., Kuri, A., Iwamoto, K.-I., Kuwahara, A., & Kaunitz, J. D.
Affiliations
  • University of California, Los Angeles (US)
  • Shizuoka University (JP)
Corresponding author
Kaunitz, Jonathan D.
ORCID
Venue
Digestive Diseases and Sciences
Publisher
Springer Science and Business Media LLC
Published
2017-05-18
Volume
62
Issue
8
Pages
1944-1952
ISSN
  • 0163-2116 (ISSN-L)
  • 1573-2568
DOI
10.1007/s10620-017-4600-4
PMC
PMC5511769
OpenAlex
W2576993281
Cited by
23
References
0
Citations by year
2025: 1 · 2024: 4 · 2023: 4 · 2022: 1 · 2021: 2 · 2020: 4 · 2019: 4 · 2018: 2 · 2017: 1
FWCI
2.10
Type
journal article
Language
en
Open access
Licence
Locations
  • Digestive Diseases and Sciences (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • U.S. Department of Veterans Affairs
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK54221)
Topics
  • Health Sciences › Medicine › Pharmacology (medical) › Inflammatory mediators and NSAID effects
  • Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
  • Health Sciences › Medicine › Gastroenterology › Inflammatory Bowel Disease
Keywords
glucagon-like peptide-2, NSAID-induced enteropathy, duodenal bicarbonate secretion, indomethacin, CFTR, enteroendocrine L cells, intestinal mucosal protection, CFTRinh-172
MeSH terms
Animals, Anti-Inflammatory Agents, Non-Steroidal, Bicarbonates, Duodenum, Fatty Acids, Nonesterified, Indomethacin, Intestinal Diseases, Intestinal Mucosa, Male, Ulcer, Quinolones, Signal Transduction, Rats, Sprague-Dawley, Cystic Fibrosis Transmembrane Conductance Regulator, Receptors, G-Protein-Coupled, Rats, Glucagon-Like Peptide 2

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CoChat. (2026). Citation check: FFA3 Activation Stimulates Duodenal Bicarbonate Secretion and Prevents NSAID-Induced Enteropathy via the GLP-2 Pathway in Rats. https://app.cochat.ai/papers/10.1007/s10620-017-4600-4
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Said, H., Akiba, Y., Narimatsu, K., Maruta, K., Kuri, A., Iwamoto, K.-I., Kuwahara, A., & Kaunitz, J. D. (2017). FFA3 Activation Stimulates Duodenal Bicarbonate Secretion and Prevents NSAID-Induced Enteropathy via the GLP-2 Pathway in Rats. Digestive Diseases and Sciences. https://doi.org/10.1007/s10620-017-4600-4