Antimicrobial peptides are important effectors of innate immunity throughout the plant and animal kingdoms. In the mammalian small intestine, Paneth cell α-defensins are antimicrobial peptides that contribute to host defense against enteric pathogens. To determine if α-defensins also govern intestinal microbial ecology, we analyzed the intestinal microbiota in mice expressing a human α-defensin (DEFA5) and in mice lacking an enzyme required for processing of murine α-defensins. We detected significant α-defensin-dependent changes in microbiota composition, but not in total bacterial numbers, in these complementary models. Furthermore, DEFA5-expressing mice had striking losses of Segmented Filamentous Bacteria and fewer interleukin 17-producing lamina propria T cells. These data ascribe a new homeostatic role for α-defensins in regulating the makeup of the commensal microbiota.

The pathogenesis of Crohn s disease (CD), an idiopathic inflammatory bowel disease, is attributed, in part, to intestinal bacteria that may initiate and perpetuate mucosal inflammation in genetically susceptible individuals. Paneth cells (PC) are the major source of antimicrobial peptides in the small intestine, including human ␣-defensins HD5 and HD6. We tested the hypothesis that reduced expression of PC ␣-defensins compromises mucosal host defenses and predisposes patients to CD of the ileum. We report that patients with CD of the ileum have reduced antibacterial activity in their intestinal mucosal extracts. These specimens also showed decreased expression of PC ␣-defensins, whereas the expression of eight other PC products either remained unchanged or increased when compared with controls. The specific decrease of ␣-defensins was independent of the degree of inflammation in the specimens and was not observed in either CD of the colon, ulcerative colitis, or pouchitis. The functional consequence of ␣-defensin expression levels was examined by using a transgenic mouse model, where we found changes in HD5 expression levels, comparable to those observed in CD, had a pronounced impact on the luminal microbiota. Thus, the specific deficiency of PC defensins that characterizes ileal CD may compromise innate immune defenses of the ileal mucosa and initiate and͞or perpetuate this disease.innate immunity ͉ intestine ͉ bacteria ͉ inflammatory bowel disease