title: Disruption of the murine Glp2r impairs Paneth cell function and increases susceptibility to small bowel enteritis.
abstract: Exogenous glucagon-like peptide-2 receptor (GLP-2R) activation elicits proliferative and cytoprotective responses in the gastrointestinal mucosa and ameliorates experimental small and large bowel gut injury. Nevertheless, the essential physiological role(s) of the endogenous GLP-2R remain poorly understood. We studied the importance of the GLP-2R for gut growth, epithelial cell lineage allocation, the response to mucosal injury, and host-bacterial interactions in Glp2r(-/-) and littermate control Glp2r(+/+) mice. Glp2r(-/-) mice exhibit normal somatic growth and preserved small and large bowel responses to IGF-I and keratinocyte growth factor. However, Glp2r(-/-) mice failed to up-regulate intestinal epithelial c-fos expression in response to acute GLP-2 administration and do not exhibit changes in small bowel conductance or small or large bowel growth after administration of GLP-2R agonists. The crypt and villus compartment and the numbers and localization of Paneth, enteroendocrine, and goblet cells were comparable in Glp2r(+/+) vs. Glp2r(-/-) mice. Although the severity and extent of colonic mucosal injury in response to 3% oral dextran sulfate was similar across Glp2r genotypes, Glp2r(-/-) mice exhibited significantly increased morbidity and mortality and increased bacterial translocation after induction of enteritis with indomethacin and enhanced mucosal injury in response to irinotecan. Moreover, bacterial colonization of the small bowel was significantly increased, expression of Paneth cell antimicrobial gene products was reduced, and mucosal bactericidal activity was impaired in Glp2r(-/-) mice. Although the Glp2r is dispensable for gut development and the response to colonic injury, Glp2r(-/-) mice exhibit enhanced sensitivity to small bowel injury, and abnormal host-bacterial interactions in the small bowel.
authors.affiliation: Department of Medicine, Mt. Sinai Hospital, Samuel Lunenfeld Research Institute, 600 University Avenue, TCP5-1004, Toronto, Ontario, Canada.
authors.forename: Seung-Jun
authors.initials: SJ
authors.lastname: Lee
authors.forename: Jennifer
authors.initials: J
authors.lastname: Lee
authors.forename: Karen K
authors.initials: KK
authors.lastname: Li
authors.forename: Dianne
authors.initials: D
authors.lastname: Holland
authors.forename: Heather
authors.initials: H
authors.lastname: Maughan
authors.forename: David S
authors.initials: DS
authors.lastname: Guttman
authors.forename: Bernardo
authors.initials: B
authors.lastname: Yusta
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Drucker
mesh_terms: D000818:Animals; D001835:Body Weight; D004751:Enteritis / Q000473:pathology*; D005091:Exons; D005260:Female; D051523:Fibroblast Growth Factor 7 / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D000067758:Glucagon-Like Peptide-2 Receptor; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism; D007421:Intestine, Small / Q000378:metabolism; D007422:Intestines / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019879:Paneth Cells / Q000166:cytology*; D010539:Permeability; D012336:RNA, Ribosomal, 16S / Q000378:metabolism; D018027:Receptors, Glucagon / Q000235:genetics* / Q000502:physiology*
chemical_list: D000067758:Glucagon-Like Peptide-2 Receptor; D012336:RNA, Ribosomal, 16S; D018027:Receptors, Glucagon; D051523:Fibroblast Growth Factor 7; D007334:Insulin-Like Growth Factor I