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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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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.

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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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Acknowledgments

We thank Stacey Jung for her assistance with manuscript preparation and Drs. Paul Guth and Eli Engel for their helpful discussion.

Funding

This work was supported by a Department of Veterans Affairs Merit Review Award and NIH R01 DK54221.

Author information

Authors and Affiliations

  1. College of Arts and Sciences, University of California, Los Angeles, CA, USA

    Hyder Said

  2. Greater Los Angeles Veterans Affairs Healthcare System, 11301 Wilshire Boulevard, Bldg 115, Suite 217, Los Angeles, CA, 90073, USA

    Yasutada Akiba & Jonathan D. Kaunitz

  3. Department of Medicine, University of California Los Angeles, School of Medicine, Los Angeles, CA, USA

    Yasutada Akiba, Kazuyuki Narimatsu, Koji Maruta & Jonathan D. Kaunitz

  4. Brentwood Biomedical Research Institute, Los Angeles, CA, USA

    Yasutada Akiba & Jonathan D. Kaunitz

  5. Graduate School of Integrated Pharmaceutical and Nutritional Sciences, University of Shizuoka, Shizuoka, Japan

    Ayaka Kuri, Ken-ichi Iwamoto & Atsukazu Kuwahara

  6. Department of Surgery, University of California Los Angeles, School of Medicine, Los Angeles, CA, USA

    Jonathan D. Kaunitz

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  1. Hyder Said
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Contributions

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.

Corresponding author

Correspondence to Jonathan D. Kaunitz.

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Said, H., Akiba, Y., Narimatsu, K. et al. FFA3 Activation Stimulates Duodenal Bicarbonate Secretion and Prevents NSAID-Induced Enteropathy via the GLP-2 Pathway in Rats. Dig Dis Sci 62, 1944–1952 (2017). https://doi.org/10.1007/s10620-017-4600-4

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  • DOI: https://doi.org/10.1007/s10620-017-4600-4

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