Abstract
The gut microbiota participates in the control of energy homeostasis partly through fermentation of dietary fibers hence producing short-chain fatty acids (SCFAs), which in turn promote the secretion of the incretin Glucagon-Like Peptide-1 (GLP-1) by binding to the SCFA receptors FFAR2 and FFAR3 on enteroendocrine L-cells. We have previously shown that activation of the nuclear Farnesoid X Receptor (FXR) decreases the L-cell response to glucose. Here, we investigated whether FXR also regulates the SCFA-induced GLP-1 secretion. GLP-1 secretion in response to SCFAs was evaluated ex vivo in murine colonic biopsies and in colonoids of wild-type (WT) and FXR knock-out (KO) mice, in vitro in GLUTag and NCI-H716 L-cells activated with the synthetic FXR agonist GW4064 and in vivo in WT and FXR KO mice after prebiotic supplementation. SCFA-induced GLP-1 secretion was blunted in colonic biopsies from GW4064-treated mice and enhanced in FXR KO colonoids. In vitro FXR activation inhibited GLP-1 secretion in response to SCFAs and FFAR2 synthetic ligands, mainly by decreasing FFAR2 expression and downstream Gαq-signaling. FXR KO mice displayed elevated colonic FFAR2 mRNA levels and increased plasma GLP-1 levels upon local supply of SCFAs with prebiotic supplementation. Our results demonstrate that FXR activation decreases L-cell GLP-1 secretion in response to inulin-derived SCFA by reducing FFAR2 expression and signaling. Inactivation of intestinal FXR using bile acid sequestrants or synthetic antagonists in combination with prebiotic supplementation may be a promising therapeutic approach to boost the incretin axis in type 2 diabetes.
Highlights
In addition to its major role in digestion and dietary nutrient absorption, the intestine plays a role in glucose homeostasis through the interaction of nutrients and gut microbiota with enteroendocrine cells, modulating the secretion of numerous neuro-endocrine signals
These results show that Farnesoid X Receptor (FXR) regulates short-chain fatty acids (SCFAs)-induced Glucagon-Like Peptide-1 (GLP-1) secretion in the murine colon
The aim of the present study was to examine the role of the nuclear receptor FXR in the colonic L-cell response to gut microbiota-derived SCFAs
Summary
In addition to its major role in digestion and dietary nutrient absorption, the intestine plays a role in glucose homeostasis through the interaction of nutrients and gut microbiota with enteroendocrine cells, modulating the secretion of numerous neuro-endocrine signals. Enteroendocrine L-cells respond to various secretagogues through a range of sensing and signaling pathways including G-protein coupled receptors, ion channels and transporters[1] Digested nutrients, such as glucose, amino acids and long-chain fatty acids, which are mostly absorbed in the small intestine, are GLP-1 secretagogues acting primarily in the small intestine[1,3]. FXR activation in L-cells decreases glucose-induced proglucagon gene expression and GLP-1 secretion through inhibition of the transcription factor ChREBP and the inhibition of glycolysis[12] It is unknown whether FXR in L-cells modulates the response to other secretagogues and especially the metabolites produced by the gut microbiota in the colon such as the SCFAs. GLP-1 secretion in response to SCFAs was evaluated ex vivo in intestinal biopsies from mice treated with GW4064, a synthetic FXR agonist, in murine WT and FXR KO colonoids and in vitro in murine and human L cells activated with GW4064. To assess in vivo the response to SCFAs, GLP-1 levels were measured in WT and FXR KO mice supplemented with prebiotics (inulin-type fructans) to increase SCFA production in the colon
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