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

We previously showed that feeding bile acids can induce glucagon-like peptide 2 (GLP-2) secretion and intestinal growth in parenteral nutrition-fed (PN) piglets. We hypothesize that bile acids function as agonist for the G protein-coupled bile acid receptor 1 (TGR5) expressed in enteroendocrine L cells to induce GLP-2 secretion. Our in this study was to test whether natural TGR5 agonists can increase GLP-2 secretion and intestinal adaptation in piglet short bowel model. In study 1, 24 neonatal piglets were PN-fed and given oral gavage with one of four TGR5 treatments to measure acute GLP-2 secretion. In study 2, neonatal piglets underwent either 80% midjejunoileal resection or transection surgery and receive either 1) transection, 2) resection, 3) resection + 10 mg ursolic acid (UA), 4) resection + 60 mg compound R071. In study 1, oral gavage with UA, but not R071, increased GLP-2 secretion (P < 0.05). In study 2, compared to transection, remnant ileum villus height, crypt cell proliferation, and plasma GLP-2 secretion was increased (P < 0.05) by resection but not further stimulated by UA or R071. Bile acid profiling showed that UA and R071 increased (P < 0.05) conjugated HCA and HDCA level in liver and decreased (P < 0.05) conjugated HCA, HDCA and CDCA level in ileum. Resection tended (p=0.08) to increase, while UA decreased liver IL-1β expression. We conclude that oral TGR5 agonists differentially increased GLP-2 secretion in healthy PN-fed pigs, but did not augment GLP-2 secretion or intestinal adaptation after resection in short-bowel piglets. We found that TGR5 agonists altered bile acid homeostasis and had anti-inflammatory actions in liver in short-bowel piglets.