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

Abstract

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 (SCFA) 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 of 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.

Luminal chemosensing in the gastroduodenal mucosa

“…We recently reported that the rat proximal duodenum possesses an active short-chain fatty acid (SCFA) absorption mechanism and that luminal SCFAs stimulate duodenal bicarbonate secretion via SCFA receptors (FFA2 and FFA3) and SCFA transporter-dependent pathways (Figure 2) [65;66]. Luminal SCFA acetate increases the secretory rate of bicarbonate through FFA2-mediated 5-HT release and FFA3-mediated GLP-2 release, consistent with results of studies in which selective FFA agonists were used singly [23;67*]. Since the response to acetate is significantly reduced by SCFA transporter inhibition or by capsaicin deafferentation [66], afferent nerves may detect SCFA directly after absorption and potentiate EEC transmitter release to increase duodenal mucosal protection.…”

Control of Intestinal Epithelial Proliferation and Differentiation: The Microbiome, Enteroendocrine L Cells, Telocytes, Enteric Nerves, and GLP, Too

“…These observations, repeated many times, have been mostly unexplained, but more recently data have emerged that these changes are likely due to the production of bacterial fermentative metabolites, in particular short-chain fatty acids (SCFAs), by the gut microbiota [24][25][26]. Since L cells express the G-proteincoupled receptors (GPCR), GPR 41 and 43 also termed free fatty acid (FFA)3 and FFA2, and since L cells in rats release GLP-2 into the portal vein in response to luminal perfusion with FFA3 ligands [27], it is likely that microbial fermentation products such as SCFAs release GLP-2 from L cells, increasing the rate of epithelial proliferation [27,28], helping to explain the effects of high-fiber diets and starvation on the rate of intestinal proliferation.…”

Duodenal Chemosensing of Short-Chain Fatty Acids: Implications for GI Diseases

“…These results suggest that exogenous GLP-2 or luminal nutrients that enhance endogenous GLP-2 release combined with DPP4 inhibition may be therapeutic for NSAID-induced enteropathy. Furthermore, oral administration of AR420626 prevents the formation of NSAID-induced small intestinal ulcers [8]. FFA3 is also expressed on myenteric neurons.…”

“…DPP4 inhibitors are clinically used to treat diabetes, since DPP4 inhibition enhances the insulinotropic effect of GLP-1 [33]. The DPP4 inhibitor NVP-728 enhances amino acid-and bile acid-augmented HCO 3 − secretion in rat duodenum via prolonging the t 1/2 of GLP-2 [34], suggesting that enhanced endogenous GLP-2 signaling by the luminal GPCR agonist such as amino acids, bile acids, and FFA3 ligands [8,34], acting at L cells, combined with DPP4 inhibition augments duodenal defense mechanisms.…”

“…Intraperitoneal treatment or serosal application of AR420626 inhibits nicotinic acetylcholine receptormediated colonic motility and ion secretion [30,37]. Nevertheless, intraperitoneal AR420626 has no effect on NSAID-induced enteropathy [8], suggesting that enhanced release of GLP-2 via luminal FFA3 activation may be a novel therapeutic for prevention of NSAID-induced enteropathy.…”