Neural FFA3 activation inversely regulates anion secretion evoked by nicotinic ACh receptor activation in rat proximal colon

Kaji, Izumi; Akiba, Yasutada; Konno, Kohtarou; Watanabe, Masahiko; Kimura, Shunsuke; Iwanaga, Toshihiko; Kuri, Ayaka; Iwamoto, Kenji; Kuwahara, Atsukazu; Kaunitz, Jonathan D.

doi:10.1113/jp271441

Cited by 45 publications

(61 citation statements)

References 53 publications

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“…In a similar experimental model to that of the present study, it was shown that luminal perfusion of acetate increased duodenal bicarbonate secretion in a dose-dependent manner via dual mechanisms involving the activation of both FFA2 receptors expressed on enterochromaffin cells and FFA3 receptors expressed on endocrine L cells. Supporting this notion is that apical FFA3 receptors expressed by L cells increase duodenal bicarbonate secretion via release of GLP-1/GLP-2 (Tolhurst et al 2012;Akiba et al 2015), and activation of neural FFA3 receptors suppresses nicotinic acetylcholine receptor-stimulated Cl − secretion in rat proximal colon (Kaji et al 2016). An interesting observation of the present study was that the I.V.…”

Section: Discussionsupporting

confidence: 71%

Short‐chain fatty acids augment rat duodenal mucosal barrier function

Saudi

Sjöblom

2017

Experimental Physiology

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Short-chain fatty acids (SCFAs) are produced by bacterial fermentation in the large intestine, particularly from diets containing fibres and carbohydrates. The small intestinal epithelium is exposed toSCFAsderivedmainly fromoral bacteriaor food supplementation. Although luminal nutrients are important in regulation of intestinal functions, the role of SCFAs in regulation of small intestinal mucosal barrier function and motility has not been fully described. The aim of the present study was to elucidate

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Section: Discussionsupporting

confidence: 71%

Short‐chain fatty acids augment rat duodenal mucosal barrier function

Saudi

Sjöblom

2017

Experimental Physiology

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“…FFA3 activation inhibits cholinergic-mediated ion secretion [27] and colonic motility [28] via direct neural FFA3 activation. We thus examined the effect of ip injection of AR420626 on IND-induced intestinal ulcer scores.…”

Section: Resultsmentioning

confidence: 99%

“…FFA3 is expressed on L cells [21], but also on enteric nerves [27,37]. Neural FFA3 activation inversely regulates nicotinic acetylcholine receptor-mediated anion secretion [27] and motility [28] in rat proximal colon.…”

Section: Discussionmentioning

confidence: 99%

“…Neural FFA3 activation inversely regulates nicotinic acetylcholine receptor-mediated anion secretion [27] and motility [28] in rat proximal colon. Since IND-induced enteropathy is reduced by the anti-motility effects of atropine on IND-induced hypermotility [11], it is possible that the prevention of NSAID injury by FFA3 agonists is mediated via neural pathways.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2017

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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.

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“…We recently reported that FFA3 is expressed on cholinergic nerves located in the mucosal and submucosal plexus of rat proximal colon, and that FFA3 activation suppressed nAChR‐mediated anion secretion, possibly through the inhibition of neural ACh release . Myenteric neurons expressed FFA3 more abundantly, suggesting that FFA3 significantly contributes to colonic motility regulation .…”

Section: Introductionmentioning

confidence: 99%