Host-defense peptide that contributes to intestinal innate immunity and mediates homeostasis at mucosal surfaces by forming higher-order oligomers that capture bacteria and prevent microbial invasion of the epithelium (By similarity). After binding to bacterial surface proteins, undergoes ordered self-assembly to form fibril-like nanonets that surround and entangle bacteria and thereby prevent bacterial invasion across the epithelial barrier (By similarity). Entangles and agglutinates Gram-negative bacteria, such as E.coli, S.typhimurium and Y.enterocolitica, and Gram-positive bacteria such as L.monocytogenes, thereby protecting the intestine against invasion by enteric bacterial pathogens (By similarity). Blocks adhesion of C.albicans to intestinal epithelial cells and thereby suppresses fungal invasion of epithelial cells and biofilm formation (By similarity). Under reducing conditions and in an acidic environment similar to the intestinal milieu, exhibits inhibitory activity against anaerobic bacteria such as B.adolescentis, L.acidophilus, and B.breve, as well as B.longum and S.thermophilus, possibly by leading to alterations in bacterial cell envelope structures (By similarity). The disulfide-linked oxidized form exhibits negligible antimicrobial activity against Gram-negative and Gram-positive bacteria, as compared to the enteric defensin DEFA5 (By similarity). Homodimer (By similarity). Self-assembles into higher-order oligomers termed nanonets, fibril-like structures that entrap microbes (By similarity). Self-assembly into nanonets seems to protect against proteolytic digestion in duodenal fluid (By similarity). Interacts with Y.enterocolitica invasin and S.typhimurium fliC/flagellim; the interaction creates an anchoring site for progressive DEFA6 self-assembly into nanonets (By similarity). Stored as propeptide in secretory granules of small intestinal Paneth cells and found in the ileum lumen as mature peptide. Proteolytically cleaved by trypsin at Arg-68; the propeptide is stored in the tissue of the small intestine and the mature peptide is found in the luminal fluid; cleavage may occur during or after release into the lumen (By similarity). The N-terminal propeptide region suppresses self-assembly and renders DEFA6 propeptide unable to agglutinate bacteria and protect human epithelial cells from bacterial invasion (By similarity). Under reducing conditions, naturally present in the gut owing to the low redox potential or enzymatically generated by the thioredoxin system, the disulfide bridges are opened leading to a conformational change of DEF6, thereby changing its antimicrobial spectrum (By similarity). The reduced form exhibits inhibitory activity against anaerobic bacteria, in contrast to the minimal antimicrobial activity of the disulfide-linked oxidized form (By similarity). The formation of higher-order nanonets and bacterial entrapment is independent of the redox state (By similarity). Belongs to the alpha-defensin family.