Dual-action peptide KWH2 protects against Salmonella choleraesuis diarrhea in weaned piglets by enhancing intestinal barrier integrity and modulating GSK-3β/Myc signaling

Bioactive peptides with dual antimicrobial and immune-regulatory functions offer promising strategies for managing infections and immune dysregulation in livestock. KWH 2 , a novel peptide demonstrating potent antimicrobial activity, holds translational potential for enteric disease control. This study evaluated KWH 2 ’s therapeutic efficacy in weaned piglets challenged with Salmonella choleraesuis —a clinically relevant model of intestinal infection and immunity. KWH 2 supplementation significantly improved clinical outcomes during infection, including restoring growth performance, reducing diarrhea severity, and enhancing intestinal barrier integrity. Transcriptomic analysis revealed KWH 2 ’s modulation of key pathways in intestinal immunity, inflammation, and cellular stress responses. Mechanistically, KWH 2 targeted the GSK-3β signaling axis, suppressing inflammatory activation and promoting epithelial repair through GSK-3β phosphorylation. These results establish KWH 2 as a dual-function therapeutic candidate that enhances intestinal resilience against infection by integrating antimicrobial activity with host-directed immunometabolic regulation. Its efficacy in a production-relevant porcine model supports KWH 2 ’s potential for developing veterinary therapeutics targeting enteric pathogens.