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.