Bile acids (BA) are synthesized from cholesterol in the pericentral hepatocytes and play an important role in several biological functions. Recent experiments show that BA supplementation modulates energy expenditure in mice; this effect is mediated by the G protein-coupled receptor called TGR5. This receptor is also expressed in the small bowel and is able, upon BA binding, to regulate the intestinal secretion of the incretin Glucagon-like peptide-1 (GLP-1). Thomas et al. (1) and other authors have shown that TGR5 agonist stimulate GLP-1 release in intestinal cell lines which could enhance glucose tolerance and improve liver and pancreatic function. Aims: to assess the effect of BA administration on portal and systemic GLP-1 levels in vivo and to explore the role of TGR5 deficiency in this process. Methods: Wild type(wt) TGR5 and TGR5 knockout (ko) mice (kindly provided by Dr. J. Auwerx, Strasbourg, France), were fed with standard rodent chow (control group) or supplemented with ursodeoxycholic acid (UDCA) 1% or cholic acid (CA) 0.5%, during 2 weeks. Mice were anesthetized with a mixture of xylazine (10 mg/kg) and ketamine (100 mg/kg) administered i.p. Animal experiments were approved by the local ethic review committee on animals experiments (2). We assessed portal and systemic GLP-1 levels (ELISA Millipore kit, MA, USA), liver histology and serum alanine-aminotransferase levels (ALT). Results were expressed as mean±SD and p values <0.05 were considered statistically significant (t student). Bayesian analysis was carried out in order to test the statistical significance of the observed increment of GLP-1 levels. Results: In wt mice, portal GLP-1 levels were significantly higher than systemic levels (6.2±0.7 vs 5.2±0.5 pM;p<0.05). CA feeding significantly increased portal but not systemic GLP-1 levels. UDCA, a known weak activator of TGR5, modestly increased portal GLP-1 levels. TGR5 ko mice fed with the same diets exhibited an increase in portal GLP1 levels that was significantly less than that observed in wt mice with no differences among both BA treatments (Figure 1). No liver histological differences were observed in control or treated animals. ALT serum levels increased with CA feeding but not with UDCA feeding. Conclusions: These data indicate for first time in vivo that CA is able to stimulate intestinal GLP-1 secretion. Our results suggest that this effect is mainly mediated through the action of CA on the TGR5 although additional mechanism may operate. Since CA has a significantly higher affinity for TGR5 compared to UDCA, the latter exerts a weaker stimulation of GLP-1 release. Pharmacological targeting of TGR5 may constitute a promising incretin-based strategy for the treatment of diabetes and associated glucose metabolic disorders (FONDECYT#1110455).