Disruption of the Murine Glp2r Impairs Paneth Cell Function and Increases Susceptibility to Small Bowel

Exogenous glucagon-like peptide-2 receptor (GLP-2R) activation elicits proliferative and cytopro-tective 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 re-main poorly understood. We studied the importance of the GLP-2R for gut growth, epithelial cell lineage allocation, the response tomucosal injury, and host-bacterial interactions inGlp2r/ and littermatecontrolGlp2r/mice.Glp2r/miceexhibitnormal somaticgrowthandpreservedsmall 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 admin-istration 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 smal