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

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 knockout (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.

The triterpenoid sapogenin (2α-OH-Protopanoxadiol) ameliorates metabolic syndrome via the intestinal FXR/GLP-1 axis through gut microbiota remodelling

“…Intestinal FXR inhibition regulates glucose and lipid homoeostasis partly through the gut–liver axis and gut–adipose axis 20 – 22 . Recent studies indicated FXR inhibition in L cells stimulates GLP-1 production and glucose-induced GLP-1 secretion 14 , 21 , 23 , 24 . Therefore, de-activation of intestinal FXR may be the potential strategy for metabolic syndrome treatment 14 , 18 , 19 .…”

Role of Bile Acids in the Regulation of Food Intake, and Their Dysregulation in Metabolic Disease

“…These observations have been replicated in studies with different L-cell lines (i.e., NCI-H736 [ 28 ] and STC-1 [ 29 ]). In a similar manner, GW4064 blunted the GLP-1 response to short-chain fatty acids (SCFA) in both GLUTag and NCI-H716 cell lines [ 30 ]. Consistent with these observations, FXR-deficient mice exhibited increased GLP-1 secretion in response to both dietary fiber, which increases colonic SCFA [ 30 ], and oral glucose [ 31 ].…”

“…In a similar manner, GW4064 blunted the GLP-1 response to short-chain fatty acids (SCFA) in both GLUTag and NCI-H716 cell lines [ 30 ]. Consistent with these observations, FXR-deficient mice exhibited increased GLP-1 secretion in response to both dietary fiber, which increases colonic SCFA [ 30 ], and oral glucose [ 31 ]. Oral intake of GW4064 (10 mg/kg, 2 doses over 12 h) also decreased active GLP-1 levels in the plasma of mini-pigs [ 28 ].…”

Microbial regulation of enteroendocrine cells

“…In contrast, FXR agonism was shown to downregulate GPR43 expression and attenuate SCFAinduced GLP-1 response both in ex vivo colonoids and in vivo, an effect that could be reversed by FXR deficiency. 89 Thus, FXR is an important factor that, through regulation of expression or activation of other receptors and through cross-talk with the gut microbiota, serves to regulate GLP-1 levels. However, the effects mediated by FXR are complex, as it can up-or downregulate expression of hormones, depending on interaction with other receptors.…”