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Title: Differential action of TGR5 agonists on GLP-2 secretion and promotion of intestinal adaptation in piglet short bowel model

Author
item LIN, SEN - Sichuan Agricultural University
item STOLL, BARBARA - Baylor College Of Medicine
item ROBINSON, JASON - Baylor College Of Medicine
item PASTOR, JOSE - Lucta
item MARINI, JUAN - Baylor College Of Medicine
item IPHARRAGUERRE, IGNACIO - Lucta
item HARTMANN, BOLETTE - University Of Copenhagen
item HOLST, JENS - University Of Copenhagen
item CRUZ, STEPHANIE - Baylor College Of Medicine
item LAU, PATRICIO - Baylor College Of Medicine
item OLUTOYE, OLUYINKA - Baylor College Of Medicine
item FANG, ZHENGFENG - Sichuan University
item Burrin, Douglas - Doug

Submitted to: American Journal of Physiology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/20/2019
Publication Date: 3/28/2019
Citation: Lin, S., Stoll, B., Robinson, J., Pastor, J.J., Marini, J.C., Ipharraguerre, I.R., Hartmann, B., Holst, J.J., Cruz, S., Lau, P., Olutoye, O., Fang, Z., Burrin, D.G. 2019. Differential action of TGR5 agonists on GLP-2 secretion and promotion of intestinal adaptation in piglet short bowel model. American Journal of Physiology. https://doi.org/10.1152/ajpgi.00360.2018.
DOI: https://doi.org/10.1152/ajpgi.00360.2018

Interpretive Summary: Infants that experience gut diseases after birth often require surgical remove of part of the intestine, called short bowel syndrome (SBS). The normal process after surgery in infants with SBS involves a period of adaptation during which there is an increase the blood concentration of the gut hormone glucagon-like peptide 2 (GLP-2). The level of GLP-2 in the blood during adaptation is directly linked to the promotion of intestinal growth and development. The goal of this study was to supplement specific plant compounds that activate a cell receptor, the Takeda G-protein-coupled receptor 5, in select intestinal cells that can trigger the release of GLP-2. We first studied neonatal pigs given exclusive intravenous nutrition and that normally have low blood GLP-2 levels, and showed that oral feeding of ursolic acid, a selective TGR5 agonist in plants, we could markedly increase blood GLP-2 levels. We then studied pigs with surgical removal of part of their intestine, to simulate SBS in infants and supplemented ursolic acid and an olive plant extract (OE) to test whether this would increase blood GLP-2 and promote gut growth during the adaptation period after surgery. Our findings showed that dietary supplementation with either ursolic acid or OE did not result in better intestinal growth after surgery in SBS pigs. Thus, ursolic acid may be a good oral agent to increase blood GLP-2 but the doses used in this study are not sufficient to increase blood GLP-2 and promote gut growth during gut adaptation in SBS.

Technical Abstract: 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 these1 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.