DIFFERENTIAL 1 ACTION OF TGR5 AGONISTS ON GLP-2 SECRETION AND PROMOTION OF INTESTINAL ADAPTATION IN PIGLET SHORT BOWEL MODEL

Enteroendocrine L cells and GLP-2 secretion are activated in the intestinal adaptation process following bowel resection in short bowel patients. We hypothesized that enteral activation of Takeda G-protein-coupled receptor 5 (TGR5) expressed in enteroendocrine L cells could augment endogenous GLP-2 secretion and the intestinal adaptation response. Our aim was to assess the efficacy of different TGR5 agonists to stimulate GLP-2 secretion and intestinal adaptation in a piglet short-bowel model. In study 1, parenterally-fed, neonatal pigs (n=6/group) were gavaged with vehicle, olive extract (OE) at 10 or 50 mg/kg, or ursolic acid (UA) 10 mg/kg and plasma GLP-2 were measured for 6 hr. In study 2, neonatal pigs (n=6-8/group) received either transection or 80% mid-small intestine resection and after 2 d assigned to treatments for 10 d as follows: 1) transection + vehicle (Sham), 2) resection + vehicle (SBS), 3) resection + (30 mg UA)(SBS-UA), 4) resection + (180 mg/kg OE)(SBS-OE). We measured plasma GLP-2, intestinal histology, cell proliferation, gene expression as well as whole body citrulline-arginine kinetics and bile acid profiles. In study 1, GLP-2 secretion was increased by UA and tended be with OE. In study 2, SBS alone but not additional treatment with either TGR5 agonist resulted in increased mucosal thickness and crypt cell proliferation in remnant jejunum and ileum sections. SBS increased biliary and ileal concentration of bile acids and expression of inflammatory and FXR-target genes, but these measures were suppressed by UA treatment. In conclusion, UA is an effective oral GLP-2 secretagogue in parenterally-fed pigs but was not capable of augmenting GLP-2 secretion nor the intestinal adaptation response after massive small bowel resection.