Short-chain fatty acid receptors involved in epithelial acetylcholine release in rat caecum

Jasmin Ballout; Yasutada Akiba; Jonathan D Kaunitz; Martin Diener

doi:10.1016/j.ejphar.2021.174292

Short-chain fatty acid receptors involved in epithelial acetylcholine release in rat caecum

Eur J Pharmacol. 2021 Sep 5:906:174292. doi: 10.1016/j.ejphar.2021.174292. Epub 2021 Jun 30.

Authors

Jasmin Ballout¹, Yasutada Akiba², Jonathan D Kaunitz³, Martin Diener⁴

Affiliations

¹ Institute for Veterinary Physiology and Biochemistry, Justus Liebig University Giessen, Germany.
² Greater Los Angeles Veterans Affairs Healthcare System, University of California Los Angeles, School of Medicine, CA, 90073, USA; Department of Medicine, University of California Los Angeles, School of Medicine, CA, 90073, USA.
³ Greater Los Angeles Veterans Affairs Healthcare System, University of California Los Angeles, School of Medicine, CA, 90073, USA; Department of Medicine, University of California Los Angeles, School of Medicine, CA, 90073, USA; Department of Surgery, University of California Los Angeles, School of Medicine, CA, 90073, USA.
⁴ Institute for Veterinary Physiology and Biochemistry, Justus Liebig University Giessen, Germany. Electronic address: Martin.Diener@vetmed.uni-giessen.de.

PMID: 34216575
DOI: 10.1016/j.ejphar.2021.174292

Abstract

Short-chain fatty acids (SCFAs) produced by the microbial fermentation of carbohydrates are important energy substrates for mammals. Intestinal epithelia respond to these metabolites by stimulation of anion secretion via the release of epithelial acetylcholine. The present experiments were performed to discover which of the known receptors for SCFAs are expressed in rat caecum, the most important site of fermentation within the intestine of non-ruminant mammals. Using the increase in short-circuit current (I_sc) induced by anion secretion as the readout, the order of efficiency of the tested SCFAs in rat caecum was propionate > butyrate > acetate. Both synthetic high-affinity selective free fatty acid (FFA) receptor agonists 4-CMTB (FFA2 receptor) and AR420626 (FFA3 receptor) partially mimicked the effect of propionate on I_sc (I_Prop). I_Prop was concentration-dependently inhibited by the FFA3 receptor antagonist β-OH-butyrate. Although no antagonist of rat FFA2 receptor is available, coadministration of the allosteric FFA2 receptor agonist 4-CMTB together with a low concentration of propionate potentiated I_Prop, suggesting that FFA2 receptor is involved in sensing of short-chain fatty acids as well. The expression of both receptor types was confirmed by qPCR (with FFA2 > FFA3 receptor). Immunohistochemical staining revealed the localization of FFA2 receptor in the surface epithelium and the FFA3 receptor expression predominantly in enteroendocrine cells and subepithelial nerve-like fibers. Taken together, the present results demonstrate that the anion secretion induced by the microbial metabolite propionate in rat caecum is enhanced by activation of FFA2 and FFA3 receptor expressed in different cell types within the caecal epithelium.

Keywords: Caecum; Epithelium; FFA2 receptor; FFA3 receptor; Rat; Short-chain fatty acids.

MeSH terms

Acetylcholine / metabolism*
Animals
Cecum / drug effects
Cecum / metabolism*
Fatty Acids, Volatile / metabolism
Female
Intestinal Mucosa / drug effects
Intestinal Mucosa / metabolism*
Male
Models, Animal
Rats
Receptors, G-Protein-Coupled / agonists
Receptors, G-Protein-Coupled / metabolism*

Substances

Fatty Acids, Volatile
Ffar2 protein, rat
Receptors, G-Protein-Coupled
Acetylcholine