Regulation of intestinal epithelial barrier function: Role of GLP-2 and acetylcholine

The intestinal epithelium forms a critical barrier between the noxious contents of the intestinal lumen and the internal milieu of the body. Penetration of this barrier occurs via two routes: between epithelial cells via the paracellular pathway, or through an epithelial cell via the transcellular pathway. Intestinal barrier dysfunction is thought to play either a primary etiological role or a secondary role in the progression and pathogenesis of intestinal disease.Collectively, these studies identify GLP-2 and acetylcholine as potent regulators of intestinal barrier function and demonstrate the critical role of the epithelial barrier in models of luminal antigen and stress induced gut dysfunction.My studies identified glucagon-like peptide-2 (GLP-2), an intestinotrophic growth hormone, as a novel regulator of intestinal barrier function in mouse intestine. GLP-2 administered subcutaneously, rapidly enhanced epithelial barrier function to reduce permeation of the intestine by both transcellular and paracellular routes. In a model of food allergy, characterized by acute and late phase hypersensitivity reactions, GLP-2 treatment prevented antigen-induced barrier defects and ameliorated secretory and inflammatory responses. In a model of psychological stress, mice exposed to water avoidance stress demonstrated increased intestinal permeability, inflammation and increased bacterial-epithelial interactions. GLP-2 treatment ameliorated stress-induced barrier dysfunction and reduced intestinal inflammation and bacterial interactions. These studies identified that GLP-2 treatment not only enhances baseline barrier function but also protects against barrier dysfunction in models of disease. These studies also identified the critical role of the epithelial barrier in pathological sequelae in response to luminal antigen and psychological stress. My final study examined cholinergic regulation of epithelial barrier function and identified a signaling pathway initiated by cholinergic signaling via M3 receptors and activation of phospholipase A2 and cyclooxygenase to increase transcytosis of intact protein. This pathway was not involved in mediating increased paracellular transport indicating divergent regulation of these two routes of permeation.