One-carbon-derived bioactive peptides improve reproductive performance via regulating placental nutrient transport and offspring glycolipid metabolism

This study aimed to develop novel bioactive peptides from Pichia pastoris (PpBP) as a potential functional ingredient for maternal nutrition. A high-efficiency strain was obtained through generated by ARTP mutagenesis of a winery by-product isolate and optimized via automated fermentation, yielding an enzymatic hydrolysate rich in short-chain peptides (Content = 30.73%). In vitro assays demonstrated that PpBP significantly upregulated the expression of intestinal peptide transporter PEPT1 in IPEC-J2 cells. Molecular docking revealed that dipeptides, especially Leu-Pro, can directly bind to the active site of PEPT1. Maternal PpBP (2 g/kg) supplementation from late gestation through lactation significantly reduced the incidence of IUGR and improved offspring growth performance. Mechanistic investigations indicated that PpBP intake modulated placental nutrient transport function, altering the expression of key glucose and lipid transporters and downregulating p38 MAPK and p-AKT signaling pathways. Placental transcriptomics further highlighted enriched pathways in Ras/Wnt signaling and lipid metabolism. In neonatal piglets, maternal PpBP supplementation shifted hepatic metabolism towards gluconeogenesis while suppressing glycolysis and TCA cycle activity. In conclusion, P. pastoris-derived bioactive peptides improved fetal growth and neonatal development by regulating maternal peptide absorption (via PEPT1 activation) and subsequently optimizing placental nutrient transport and fetal hepatic energy metabolism.