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. KWH2, a novel peptide demonstrating potent antimicrobial activity, holds translational potential for enteric disease control. This study evaluated KWH2's therapeutic efficacy in weaned piglets challenged with Salmonella choleraesuis-a clinically relevant model of intestinal infection and immunity. KWH2 supplementation significantly improved clinical outcomes during infection, including restoring growth performance, reducing diarrhea severity, and enhancing intestinal barrier integrity. Transcriptomic analysis revealed KWH2's modulation of key pathways in intestinal immunity, inflammation, and cellular stress responses. Mechanistically, KWH2 targeted the GSK-3β signaling axis, suppressing inflammatory activation and promoting epithelial repair through GSK-3β phosphorylation. These results establish KWH2 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 KWH2's potential for developing veterinary therapeutics targeting enteric pathogens.