A novel bifunctional peptide VAMP mined from hemp seed protein hydrolysates improves glucose homeostasis by inhibiting intestinal DPP-IV and increasing the abundance of Akkermansia muciniphila

Discovery of new dipeptidyl peptidase IV (DPP-IV) inhibitory peptides from natural protein resources capable of regulating glucose metabolism in type 2 diabetic populations has been a significant challenge. In this study, we constructed a molecular docking- and machine learning-aided DPP-IV inhibitory peptide library and combined a functional screening approach based on intestinal organoids to discover efficient and new DPP-IV-inhibiting peptides from hemp seed protein hydrolysates. A novel tetrapeptide, VAMP, was then identified to strongly inhibit DPP-IV (IC50=1.00 M in vitro), which competitively binds to DPP-IV and improves glucose metabolism in vivo with high safety by increasing active glucagon-like peptide-1 (GLP-1) levels in obese mouse models. Interestingly, VAMP specifically promoted the growth and abundance of intestinal Akkermansia muciniphila in vivo, at the same time, which was responsible for the improved intestinal barrier function and insulin resistance. Our study demonstrated that the novel bifunctional VAMP can effectively target the DPP-IV-GLP-1 axis and simultaneously regulate the abundance of the gut microbial A. muciniphila, to regulate glucose homeostasis, providing a promising nutraceutical and therapeutic tetrapeptide for hyperglycaemia treatment by targeting the gut-microbiata axis. TeaserVAMP improves glucose metabolism by increasing the active GLP-1 level and promoting the growth of A. muciniphila to improve intestinal barrier function.