Milk peptides found in human jejunum induce enteroendocrine hormone secretion and inhibit DPP-IV

The strong effect of protein digestion products on gastrointestinal hormone release is well recognized. However, little is known about the specific characteristics of hormone inducing peptides. A detailed analysis of food-derived peptides remaining in the human intestinal lumen after protein ingestion would constitute a practical strategy for the targeted identification of hormone inducing and DPP-IV inhibitory peptides. In this study, <i>in vivo</i> gastrointestinal resistant peptides derived from casein and whey protein were evaluated in epithelial intestinal cells. The secretion of cholecystokinin (CCK) and glucagon-like peptide-1 (GLP-1) was evaluated in the STC-1 enteroendocrine cell line and the DPP-IV inhibitory potential was assayed <i>in situ</i> using the Caco-2 cell line. Hydrophobic residues at N-terminal positions were crucial for the secretagogue and inhibitory activities, while the presence of multiple glutamic acid residues was shown to be a key trait for CCK secretion. The results appointed the sequence ¹²⁶TPEVDDEALEKFDK¹³⁸ from β-lactoglobulin as a strong CCK inducer. Additionally, ⁹⁴KILDKVGINYWL¹⁰⁵, derived from α-lactalbumin, not only promoted GLP-1 secretion but also demonstrated significant DPP-IV inhibitory activity. These findings provide new insights into the functional potential of food-derived peptides, offering promising therapeutic avenues for regulating gastrointestinal hormones and improving metabolic health.