DEFA5 (defensin alpha 5) is an antimicrobial peptide produced by Paneth cells in the small intestine that functions as a key component of innate intestinal immunity 1. As an enteric alpha-defensin, DEFA5 exerts potent antibacterial activity against both Gram-positive and Gram-negative bacteria, and demonstrates antiviral effects against non-enveloped viruses 2. However, DEFA5 has a paradoxical dual role: while providing defense against microbes, it can also enhance pathogen infectivity. Specifically, DEFA5 binds to the purinergic receptor P2Y11 on colonic epithelial cells, inducing filopodial extensions that facilitate Shigella adhesion and invasion 3. Additionally, DEFA5 serves as a target for Shigella flexneri, augmenting bacterial infectivity through enhanced epithelial cell invasion. Deficient DEFA5 expression is a hallmark of small intestinal Crohn's disease 1 and correlates with ulcerative colitis severity 4. DEFA5 levels are reduced in colitis-associated dysplasia and serve as a biomarker for distinguishing inflammatory bowel disease subtypes 56. Loss of intestinal epithelial PTPN2 reduces DEFA5 expression, increasing susceptibility to adherent-invasive E. coli colonization 7. These findings identify DEFA5 as both a critical antimicrobial effector and a disease-relevant marker in IBD pathogenesis.