Enteric defensins are essential regulators of intestinal microbial ecology. The study shows that Paneth cell α-defensins play a key role in shaping the composition of the small intestinal microbiota. Using two complementary mouse models—DEFA5 transgenic (tg) mice expressing human α-defensin 5 (DEFA5) and MMP7-deficient mice lacking the enzyme needed for processing murine α-defensins—the researchers found significant α-defensin-dependent changes in microbiota composition. DEFA5-expressing mice had striking losses of Segmented Filamentous Bacteria (SFB) and fewer interleukin 17-producing lamina propria T cells. These findings suggest a new homeostatic role for α-defensins in regulating the makeup of the commensal microbiota. The study also found that the loss of SFB in DEFA5 tg mice was due to the absence of maternal transmission of this bacterium. The presence of SFB was associated with higher percentages and absolute numbers of CD4+ IL-17A+ T cells in the small intestine. The results indicate a direct relationship between the host expression of a single Paneth cell α-defensin and the fitness of a specific commensal bacterial species in the intestine. The study also showed that α-defensins do not influence total bacterial numbers, but rather the composition of the microbiota. This is consistent with recent findings that Paneth cells are not involved in regulating total bacterial numbers in the gut. The study supports the hypothesis that α-defensin deficiency may contribute to the host-microbe dysbiosis and enhanced inflammatory responsiveness associated with inflammatory bowel disease (IBD) pathogenesis. The findings highlight the importance of α-defensins in maintaining intestinal homeostasis and suggest that their dysfunction could lead to disease.Enteric defensins are essential regulators of intestinal microbial ecology. The study shows that Paneth cell α-defensins play a key role in shaping the composition of the small intestinal microbiota. Using two complementary mouse models—DEFA5 transgenic (tg) mice expressing human α-defensin 5 (DEFA5) and MMP7-deficient mice lacking the enzyme needed for processing murine α-defensins—the researchers found significant α-defensin-dependent changes in microbiota composition. DEFA5-expressing mice had striking losses of Segmented Filamentous Bacteria (SFB) and fewer interleukin 17-producing lamina propria T cells. These findings suggest a new homeostatic role for α-defensins in regulating the makeup of the commensal microbiota. The study also found that the loss of SFB in DEFA5 tg mice was due to the absence of maternal transmission of this bacterium. The presence of SFB was associated with higher percentages and absolute numbers of CD4+ IL-17A+ T cells in the small intestine. The results indicate a direct relationship between the host expression of a single Paneth cell α-defensin and the fitness of a specific commensal bacterial species in the intestine. The study also showed that α-defensins do not influence total bacterial numbers, but rather the composition of the microbiota. This is consistent with recent findings that Paneth cells are not involved in regulating total bacterial numbers in the gut. The study supports the hypothesis that α-defensin deficiency may contribute to the host-microbe dysbiosis and enhanced inflammatory responsiveness associated with inflammatory bowel disease (IBD) pathogenesis. The findings highlight the importance of α-defensins in maintaining intestinal homeostasis and suggest that their dysfunction could lead to disease.