Mechanisms of Glucagon-like Peptide-2-mediated Effects on Intestinal Barrier Function in Health and Irinotecan-induced Enteritis

Glucagon-like peptide-2 (GLP-2) is an intestinal hormone that promotes gut growth through an insulin-like growth factor (IGF)-1 and intestinal epithelial (IE)-IGF-1 receptor (R)-dependent pathway. GLP-2 also promotes epithelial barrier function by as yet unknown mechanisms. I hypothesized that GLP-2-mediated effects on barrier function requires the IE-IGF-1R. Chronic GLP-2 treatment enhanced barrier function by decreasing gastrointestinal permeability in vivo and increasing jejunal resistance ex vivo. These responses were abolished in inducible IE-IGF-1R knockout (KO) animals. Additionally, epithelial sealing tight junctional proteins claudin-3 and -7 were upregulated by GLP-2 in control but not KO mice. Moreover, IE-IGF-1R deletion induced a shift in occludin localization from apical to intracellular domains. In contrast, in irinotecan-induced enteritis, GLP-2 normalized epithelial barrier function in control animals, but continued to be ineffective in KO mice. Collectively, the effects of GLP-2 on barrier function are dependent on the IE-IGF-1R and involve modulation of the tight junctional complex.MAS