Short‐chain fatty acid sensing in rat duodenum

Abstract

Key pointsr Luminal lipid in the duodenum modulates gastroduodenal functions via the release of gut hormones and mediators such as cholecystokinin and 5-HT. Abstract Intraduodenal fatty acids (FA) and bacterial overgrowth, which generate short-chain FAs (SCFAs), have been implicated in the generation of functional dyspepsia symptoms. We studied the mechanisms by which luminal SCFA perfusion affects duodenal HCO 3 − secretion (DBS), a measure of mucosal neurohumoral activation. Free fatty acid receptor (FFAR) 1 (FFA1), which binds long-chain FA (LCFA), and SCFA receptors FFA2 and FFA3 were immunolocalised to duodenal enteroendocrine cells. FFA3 colocalised with glucagon-like peptide (GLP)-1, whereas FFA2 colocalised with 5-HT. Luminal perfusion of the SCFA acetate or propionate increased DBS, enhanced by dipeptidyl peptidase-IV (DPPIV) inhibition, at the same time as increasing GLP-2 portal blood concentrations. Acetate-induced DBS was partially inhibited by monocarboxylate/HCO 3 − exchanger inhibition without affecting GLP-2 release, implicating acetate absorption in the partial mediation of DBS. A selective FFA2 agonist dose-dependently increased DBS, unaffected by DPPIV inhibition or by cholecystokinin or 5-HT 3 receptor antagonists, but was inhibited by atropine and a 5-HT 4 antagonist. By contrast, a selective FFA1 agonist increased DBS accompanied by GLP-2 release, enhanced by DPPIV inhibition and inhibited by a GLP-2 receptor antagonist. Activation of FFA1 by LCFA and presumably FFA3 by SCFA increased DBS via GLP-2 release, whereas FFA2 activation stimulated DBS via muscarinic and 5-HT 4 receptor activation. SCFA/HCO 3 − exchange also appears to be present in the duodenum. The presence of duodenal fatty acid sensing receptors that signal hormone

The Pharmacology and Function of Receptors for Short-Chain Fatty Acids

“…In accordance with the expression profile of FFA2 and FFA3, stimulation of enteroendocrine cells with SCFAs can trigger GLP-1 (Reimer and McBurney, 1996;Lin et al, 2012;Tolhurst et al, 2012;Nøhr et al, 2013;Psichas et al, 2015), GLP-2 (Akiba et al, 2015), peptide tyrosine tyrosine (Lin et al, 2012;Psichas et al, 2015), and GIP (Lin et al, 2012) release. However, reports as to whether oral SCFAs can increase enteroendocrine hormones in vivo are mixed.…”

“…One study found oral SCFAs had no effect on GLP-1, but decreased the plasma GIP response to glucose challenge (Tang et al, 2015). FFA2 agonists may also act on enterochromaffin cells to trigger 5-hydroxytryptamine release, which together with GLP-2 would help prevent mucosal injury (Akiba et al, 2015), suggesting a mechanism for the benefits to adding SCFAs to total parenteral nutrition. Finally, there is a link between SCFAs and decreased intestinal motility, which is FFA3-and neuroendocrine-independent (Dass et al, 2007).…”

“…In PMNs/peripheral blood mononuclear cells (PBMCs), FFA2 causes chemotaxis down an SCFA gradient, and elicits changes in ROS signaling and cytokine release (Säemann et al, 2000;Cavaglieri et al, 2003;Sina et al, 2009;Vinolo et al, 2009Vinolo et al, , 2011. In enteroendocine cells, FFA2 and FFA3 cause secretion of a variety of gut hormones (Lin et al, 2012;Tolhurst et al, 2012;Akiba et al, 2015;Psichas et al, 2015). FFA2 promotes adipogenesis, decreases lipolysis, and possibly increases leptin secretion from adipocytes (Xiong et al, 2004;Hong et al, 2005;Ge et al, 2008;Zaibi et al, 2010).…”

An Enteral Formula Containing Fermented Milk Products and Prebiotics Promotes Glucagon-Like Peptide-1 Secretion via Short Chain Fatty Acid Signaling

“…Propionic acid produced by propionic acid bacteria is also present in BGS [22]. SCFA receptors, especially GPR41, are expressed in gastrointestinal hormone-producing endocrine cells of the stomach and duodenum as well as the jejunum, ileum and colon [23,24]. Propionic acid and/or butyric acid derived from fermented milk products and BGS in PF may promote GLP-1 production in the upper gastrointestinal tract via GPR41.…”

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*].…”