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Differential action of TGR5 agonists on GLP-2 secretion and promotion of intestinal adaptation in a piglet short bowel model.
Am J Physiol Gastrointest Liver Physiol. 2019 05 01; 316(5):G641-G652.AJ

Abstract

Enteroendocrine L cells and glucagon-like peptide 2 (GLP-2) secretion are activated in the intestinal adaptation process following bowel resection in patients with short bowel syndrome. 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; 10 or 50 mg/kg), or ursolic acid (UA; 10 mg/kg), and plasma GLP-2 was measured for 6 h. In study 2, neonatal pigs (n = 6-8/group) were subjected to transection or 80% mid-small intestine resection and, after 2 days, assigned to treatments for 10 days as follows: 1) transection + vehicle (sham), 2) resection + vehicle (SBS), 3) resection + 30 mg UA (SBS + UA), and 4) resection + 180 mg/kg OE (SBS + OE). We measured plasma GLP-2, intestinal histology, cell proliferation, and 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 to be increased by 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 farnesoid X receptor 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 is not capable of augmenting GLP-2 secretion or the intestinal adaptation response after massive small bowel resection. NEW & NOTEWORTHY Therapeutic activation of endogenous glucagon-like peptide 2 (GLP-2) secretion is a promising strategy to improve intestinal adaptation in patients with short bowel syndrome. This study in neonatal pigs showed that oral supplementation with a selective Takeda G protein-coupled receptor 5 (TGR5) agonist is an effective approach to increase GLP-2 secretion. The results warrant further study to establish a more potent oral TGR5 agonist that can effectively improve intestinal adaptation in pediatric patients with SBS.

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Authors+Show Affiliations

Lin S
Institute of Animal Nutrition, Sichuan Agricultural University , Chengdu, Sichuan , People's Republic of China.
Stoll B
US Department of Agriculture/Agricultural Research Service Children's Nutrition Research Center , Houston, Texas.
Robinson J
US Department of Agriculture/Agricultural Research Service Children's Nutrition Research Center , Houston, Texas.
Pastor JJ
Lucta S.A., Montornès del Vallès, Spain.
Marini JC
US Department of Agriculture/Agricultural Research Service Children's Nutrition Research Center , Houston, Texas. Section of Critical Care Medicine, Department of Pediatrics, Baylor College of Medicine , Houston, Texas.
Ipharraguerre IR
Lucta S.A., Montornès del Vallès, Spain. Institute of Human Nutrition and Food Science, University of Kiel , Kiel , Germany.
Hartmann B
Department of Biomedical Sciences and Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen , Copenhagen , Denmark.
Holst JJ
Department of Biomedical Sciences and Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen , Copenhagen , Denmark.
Cruz S
Division of Pediatric Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Texas Children's Hospital , Houston, Texas.
Lau P
Division of Pediatric Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Texas Children's Hospital , Houston, Texas.
Olutoye O
Division of Pediatric Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Texas Children's Hospital , Houston, Texas.
Fang Z
Institute of Animal Nutrition, Sichuan Agricultural University , Chengdu, Sichuan , People's Republic of China.
Burrin DG
US Department of Agriculture/Agricultural Research Service Children's Nutrition Research Center , Houston, Texas. Section of Gastroenterology, Hepatology and Nutrition, Baylor College of Medicine, Houston, Texas.

MeSH

Adaptation, PhysiologicalAnimalsAnimals, NewbornCell ProliferationDisease Models, AnimalEnteroendocrine CellsGlucagon-Like Peptide 2Intestinal MucosaIntestine, SmallParenteral NutritionReceptors, G-Protein-CoupledShort Bowel SyndromeSwineTreatment Outcome

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

Language

eng

PubMed ID

30920308

Citation

Lin, Sen, et al. "Differential Action of TGR5 Agonists On GLP-2 Secretion and Promotion of Intestinal Adaptation in a Piglet Short Bowel Model." American Journal of Physiology. Gastrointestinal and Liver Physiology, vol. 316, no. 5, 2019, pp. G641-G652.
Lin S, Stoll B, Robinson J, et al. Differential action of TGR5 agonists on GLP-2 secretion and promotion of intestinal adaptation in a piglet short bowel model. Am J Physiol Gastrointest Liver Physiol. 2019;316(5):G641-G652.
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 a piglet short bowel model. American Journal of Physiology. Gastrointestinal and Liver Physiology, 316(5), G641-G652. https://doi.org/10.1152/ajpgi.00360.2018
Lin S, et al. Differential Action of TGR5 Agonists On GLP-2 Secretion and Promotion of Intestinal Adaptation in a Piglet Short Bowel Model. Am J Physiol Gastrointest Liver Physiol. 2019 05 1;316(5):G641-G652. PubMed PMID: 30920308.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Differential action of TGR5 agonists on GLP-2 secretion and promotion of intestinal adaptation in a piglet short bowel model. AU - Lin,Sen, AU - Stoll,Barbara, AU - Robinson,Jason, AU - Pastor,Jose J, AU - Marini,Juan C, AU - Ipharraguerre,Ignacio R, AU - Hartmann,Bolette, AU - Holst,Jens J, AU - Cruz,Stephanie, AU - Lau,Patricio, AU - Olutoye,Oluyinka, AU - Fang,Zhengfeng, AU - Burrin,Douglas G, Y1 - 2019/03/28/ PY - 2019/3/29/pubmed PY - 2020/2/13/medline PY - 2019/3/29/entrez KW - GLP-2 KW - TGR5 KW - bile acids KW - short bowel syndrome KW - ursolic acid SP - G641 EP - G652 JF - American journal of physiology. Gastrointestinal and liver physiology JO - Am J Physiol Gastrointest Liver Physiol VL - 316 IS - 5 N2 - Enteroendocrine L cells and glucagon-like peptide 2 (GLP-2) secretion are activated in the intestinal adaptation process following bowel resection in patients with short bowel syndrome. 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; 10 or 50 mg/kg), or ursolic acid (UA; 10 mg/kg), and plasma GLP-2 was measured for 6 h. In study 2, neonatal pigs (n = 6-8/group) were subjected to transection or 80% mid-small intestine resection and, after 2 days, assigned to treatments for 10 days as follows: 1) transection + vehicle (sham), 2) resection + vehicle (SBS), 3) resection + 30 mg UA (SBS + UA), and 4) resection + 180 mg/kg OE (SBS + OE). We measured plasma GLP-2, intestinal histology, cell proliferation, and 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 to be increased by 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 farnesoid X receptor 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 is not capable of augmenting GLP-2 secretion or the intestinal adaptation response after massive small bowel resection. NEW & NOTEWORTHY Therapeutic activation of endogenous glucagon-like peptide 2 (GLP-2) secretion is a promising strategy to improve intestinal adaptation in patients with short bowel syndrome. This study in neonatal pigs showed that oral supplementation with a selective Takeda G protein-coupled receptor 5 (TGR5) agonist is an effective approach to increase GLP-2 secretion. The results warrant further study to establish a more potent oral TGR5 agonist that can effectively improve intestinal adaptation in pediatric patients with SBS. SN - 1522-1547 UR - https://www.unboundmedicine.com/medline/citation/30920308/Differential_action_of_TGR5_agonists_on_GLP_2_secretion_and_promotion_of_intestinal_adaptation_in_a_piglet_short_bowel_model_ DB - PRIME DP - Unbound Medicine ER -