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 Ϫ/Ϫ and littermate control Glp2r ϩ/ϩ mice. Glp2r Ϫ/Ϫ mice exhibit normal somatic growth and preserved small and large bowel responses to IGF-I and keratinocyte growth factor. However, Glp2r Ϫ/Ϫ 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 ϩ/ϩ vs. Glp2r Ϫ/Ϫ mice.Although the severity and extent of colonic mucosal injury in response to 3% oral dextran sulfate was similar across Glp2r genotypes, Glp2r Ϫ/Ϫ 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 Ϫ/Ϫ mice. Although the Glp2r is dispensable for gut development and the response to colonic injury, Glp2r Ϫ/Ϫ mice exhibit enhanced sensitivity to small bowel injury, and abnormal host-bacterial interactions in the small bowel. (Endocrinology 153: 1141-1151, 2012)

GLP-1R Agonists Modulate Enteric Immune Responses Through the Intestinal Intraepithelial Lymphocyte GLP-1R

“…Conversely, disruption of GLP-2R signaling was associated with increased bacterial colonization of the small bowel, reduced bactericidal activity, impaired Paneth cell responses (43), and enhanced susceptibility to gut injury and inflammation (43). The anti-inflammatory actions of GLP-2 are indirect, mediated through reduction of gut permeability (44,45).…”

Glucagon-like peptide 2 and its beneficial effects on gut function and health in production animals

“…In addition, Chen et al [76] showed that GLP-2 increases secretory Immunoglobulin A (IgA), an important factor for reducing bacterial translocation through the intestinal barrier, in intestinal crypts of obstructive jaundiced rats. In the study by Lee et al [73], GLP-2R knockouts were more susceptible to bacterial overgrowth in the jejunum and ileum, bacterial septicemia, and changes in the microbial population of the cecum compared with wild-type mice. Paneth cells also produce factors that support the intestinal epithelial stem and progenitor cells [74], but it is not known whether GLP-2 or activation of its receptor has effects on the expression of these factors.…”

“…In addition to reducing inflammation, GLP-2 exhibits antioxidant activity, reduces inflammation-induced oxidative stress in intestinal tissues [71], and provides protection from gut ischemia and reperfusion injury [72]; although the mechanisms of these actions have not been fully investigated to date. Using GLP-2R knockout mice, Lee et al [73] showed that GLP-2R activation contributes to the synthesis and activity of antimicrobial peptides produced by Paneth cells in the small intestine needed to maintain normal host-bacterial balance. Antimicrobial peptides produced by Paneth cells include lysozyme, a-defensins, secretory phospholipase A2, cathelicidins, and regenerating islet-derived protein IIIA, which provide a biochemical barrier of protection to the intestinal epithelial cells [74,75].…”

Glucagon-like peptides 1 and 2

“…However, the response was not completely blocked because of either incomplete immunoneutralization or the fact that GLP-2 is not the only factor implicated in intestinal adaptation. Mice in which the GLP-2 receptor (GLP-2R) was disrupted showed no response to exogenous GLP-2 but displayed normal growth and development of the small and large intestines, which supports the hypothesis that multiple factors are involved in intestinal adaptation [45]. Experimental and clinical studies indicated that the GLP-2 has several nontrophic effects such as decreasing proximal motility and gastric emptying [46][47][48], inhibiting gastric acid secretion [49], and increasing nutrient absorption [50,51].…”