Penetration of the gut epithelial barrier by intact luminal antigen is necessary for immunologically-mediated pathophysiology in the context of food allergy. We investigated if glucagon-like peptide-2 (GLP-2) could affect immediate hypersensitivity and late phase allergic inflammation in a murine model. Mice were sensitized to horseradish peroxidase (HRP); studies were conducted 14 days later. Mice were treated with 5 µg of GLP-2 sc 4h before antigen challenge. For immediate hypersensitivity, jejunal segments in Ussing chambers were challenged by luminal HRP antigen. GLP-2 treatment reduced the uptake of HRP and the antigen-induced secretory response after luminal challenge. GLP-2 appears to reduce macromolecular uptake independent of the CD23 mediated enhanced antigen uptake pathway. For the late phase, mice were gavaged with antigen and 48 h later the function and histology of the jejunum was examined. GLP-2 prevented the usual prolonged permeability defect and reduced the number of inflammatory cells in the mucosa. Our studies demonstrate that a single treatment of sensitized mice with GLP diminishes both immediate and late phase hypersensitivity reactions characteristic of food allergy by inhibiting transepithelial uptake of antigen.