[Gly²]-GLP-2(1-5): An ultra-short GLP-2 peptide for intestinal mucosal protection in inflammatory bowel disease

Inflammatory bowel disease (IBD) is a disorder characterized by defective intestinal barrier function, aberrant over-apoptosis of intestinal epithelial cells, and constitutive activation of pro-inflammatory signaling pathways. Glucagon-like peptide-2 (GLP-2), an endogenous gastrointestinal hormone, is known to exert protective effects against IBD by repairing the intestinal barrier and suppressing inflammatory responses. This study used molecular docking and molecular dynamics simulations to discover that [Gly²]-GLP-2(1-5) has a high binding affinity and strong binding stability with GLP-2R. In DSS-induced colitis mouse model, treatment with [Gly²]-GLP-2(1-5)]-GLP-2(1-5) can effectively reverse weight loss in mice, reduce disease activity index, increase colon length, and alleviate inflammatory damage in colon tissues; it also upregulates the expression of tight junction proteins, inhibits epithelial cell apoptosis and release of inflammatory factors, and enhances the regenerative ability of organoids. In LPS-stimulated intestinal epithelial cells, [Gly²]-GLP-2(1-5) can promote intestinal epithelial cell migration, maintain the integrity of tight junctions, and inhibit cell apoptosis. These findings suggest that [Gly²]-GLP-2(1-5) may be the shortest active short peptide of GLP-2 and is expected to be an effective peptide for the treatment of inflammatory bowel disease.