DEFA6 (defensin alpha 6) is an antimicrobial peptide produced by intestinal Paneth cells that functions as a key component of innate immunity at mucosal surfaces 1. The protein forms higher-order oligomers and fibril-like nanonets that capture and entangle both Gram-negative bacteria (E. coli, Salmonella typhimurium) and Gram-positive bacteria (Listeria monocytogenes), preventing bacterial invasion across the epithelial barrier 1. Under reducing conditions mimicking the intestinal environment, DEFA6 exhibits antimicrobial activity against anaerobic bacteria, though its oxidized disulfide-linked form shows negligible activity 1. In inflammatory bowel disease, particularly Crohn's disease affecting the small intestine, DEFA6 expression is specifically reduced, compromising bacterial clearance and contributing to disease pathogenesis 12. Loss of PTPN2 function reduces ileal DEFA6 and DEFA5 expression, increasing susceptibility to adherent-invasive E. coli colonization 3. Lower DEFA6 expression correlates with increased necrotizing enterocolitis risk in neonates 4. In colorectal cancer, DEFA6 expression is elevated and associated with poor prognosis, suggesting dual roles in barrier immunity and oncogenic processes 56. DEFA6 is recognized as a machine-learning-identified biomarker for inflammatory bowel disease diagnosis 7.