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

“A Koumiss-derived bioactive peptide MP-4 mitigates Escherichia coli-induced infectious diarrhea by combining direct antimicrobial action with host metabolic-transcriptional reprogramming. Zhang M(1), Fan Y(2), Gao J(2), Zhang H(3), Shuang Q(4), Ji Z(2), Zhao J(1), Guo K(5), Zhang F(6), Tian X(7). Author information: (1)College of Life and Food, Inner Mongolia University for Nationalities, Tongliao, 028000, P. R. China; Inner Mongolia Autonomous Region Engineering Technology Research Center for Prevention and Control of Pathogenic Bacteria in Milk, Tongliao, Inner Mongolia, 028000, P. R. China; College of Food Science and Engineering, Inner Mongolia Agricultural University, Hohhot, 010018, P. R. China. (2)College of Life and Food, Inner Mongolia University for Nationalities, Tongliao, 028000, P. R. China; Inner Mongolia Autonomous Region Engineering Technology Research Center for Prevention and Control of Pathogenic Bacteria in Milk, Tongliao, Inner Mongolia, 028000, P. R. China. (3)College of Life Science, Inner Mongolia University, Hohhot, 010030, P.R. China. (4)Inner Mongolia Autonomous Region Engineering Technology Research Center for Prevention and Control of Pathogenic Bacteria in Milk, Tongliao, Inner Mongolia, 028000, P. R. China. (5)Inspection Division of Food and Grain & Oil Products, Ordos City Inspection and Testing Center, Ordos, 017000, P.R. China. (6)College of Food Science and Engineering, Inner Mongolia Agricultural University, Hohhot, 010018, P. R. China. Electronic address: zfm1997@aliyun.com. (7)College of Life and Food, Inner Mongolia University for Nationalities, Tongliao, 028000, P. R. China. Electronic address: tianxun@imun.edu.cn. 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, the concentration at which no bacterial growth is observed (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. The Authors. Published by Elsevier Inc. on behalf of the American Dairy Science Association®. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).”