The nuclear receptor FXR inhibits Glucagon-Like Peptide-1 secretion in response to microbiota-derived Short-Chain Fatty Acids

• Published in: Scientific reports Vol. 10; no. 1; p. 174
• Main Authors: Ducastel, Sarah, Touche, Véronique, Trabelsi, Mohamed-Sami, Boulinguiez, Alexis, Butruille, Laura, Nawrot, Margaux, Peschard, Simon, Chávez-Talavera, Oscar, Dorchies, Emilie, Vallez, Emmanuelle, Annicotte, Jean-Sébastien, Lancel, Steve, Briand, Olivier, Bantubungi, Kadiombo, Caron, Sandrine, Bindels, Laure B., Delzenne, Nathalie M., Tailleux, Anne, Staels, Bart, Lestavel, Sophie
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 13.01.2020; Nature Publishing Group
• Subjects: 631/80/86/2369; 631/80/86/388; 692/163/2743; 692/308/2778; 692/4020/198; Animals; Bile; Biopsy; Cell activation; Cellular Biology; Colon - drug effects; Colon - metabolism; Diabetes mellitus (non-insulin dependent); Dietary fiber; Dietary supplements; Energy balance; Fatty acids; Fatty Acids, Volatile - pharmacology; Fermentation; Fibers; Glucagon; Glucagon-like peptide 1; Glucagon-Like Peptide 1 - antagonists & inhibitors; Glucagon-Like Peptide 1 - metabolism; Homeostasis; Humanities and Social Sciences; Inactivation; Intestinal microflora; Intestine; Inulin; Life Sciences; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Microbiota; mRNA; multidisciplinary; Peptides; Prebiotics; Receptors, Cytoplasmic and Nuclear - physiology; Receptors, G-Protein-Coupled - genetics; Receptors, G-Protein-Coupled - metabolism; Science; Science (multidisciplinary); Secretion
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-019-56743-x

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.