Innate immune functions of α-defensins in the small intestine.

The intestinal mucosa interfaces with a complex, dense community of microorganisms, including hundreds of species of resident microbiota and many transient microbes entering from food- and water-borne sources. In the small intestine, Paneth cells (specialized secretory epithelial cells) produce abundant quantities of α-defensins and several other antibiotic peptides. Human Paneth cells make two α-defensins: HD5 and HD6. Data from in vivo models indicate that Paneth cell α-defensins play a pivotal role in defense from food- and water-borne pathogens in the intestine. The mechanism by which these two α-defensins protect from enteric pathogens is quite distinct. HD5 is a potent antimicrobial that kills target microbes by membrane disruption, whereas HD6 is newly discovered to self-assemble to form fibrils and nanonets that surround and entangle bacteria. Recent data suggest that HD5 also serves to help shape the composition of the colonizing microbiota. Studies in humans suggest that reduced expression of HD5 and HD6 is a fundamental feature of ileal Crohn's disease. Mechanistically, the link between reduced Paneth cell α-defensin expression and ileal Crohn's disease pathogenesis may be a result of the weakened mucosal antimicrobial defense and/or alterations in the composition of commensal microbiota.