A koumiss-derived bioactive peptide MP-4 mitigates Escherichia coli–induced infectious diarrhea by combining direct antimicrobial action with host metabolic-transcriptional reprogramming

The increasing prevalence of antibiotic-resistant Escherichia coli underscores the need for alternative antimicrobial strategies derived from natural food sources. Koumiss, a traditional fermented dairy product, represents a promising reservoir of bioactive peptides. This study evaluated the antibacterial activity and biological effects of a novel koumiss-derived peptide, MP-4, against E. coli-induced infectious diarrhea. Antibacterial efficacy was assessed in vitro using MIC, minimum bactericidal concentration (MBC), growth kinetics, scanning electron microscopy, and ion leakage analyses, while protective effects were further examined in a murine infection model. The MP-4 exhibited pronounced antibacterial activity against E. coli, accompanied by morphological changes consistent with altered membrane integrity. In vivo administration of MP-4 was associated with reduced BW loss, attenuation of intestinal villus damage, and reduction of epithelial apoptosis in infected mice. Integrated metabolomic and transcriptomic analyses revealed broad alterations in host metabolic profiles and gene expression patterns following MP-4 treatment, with differentially regulated metabolites mainly associated with AA and lipid metabolism and altered gene expression enriched in circadian rhythm-related pathways. Notably, lysine degradation emerged as a central pathway, showing coordinated changes at both the metabolic and transcriptional levels. Collectively, these findings suggest that MP-4 is a food-derived bioactive peptide with antibacterial activity and host-associated biological effects during intestinal infection, highlighting the potential of traditional fermented dairy products as functional resources for dietary intervention against enteric pathogens.