Enteric defensins, specifically α-defensins, are antimicrobial peptides that play a crucial role in host defense against enteric pathogens. This study investigates whether α-defensins also regulate the intestinal microbial ecology. Using two complementary mouse models—*DEFA5* transgenic mice expressing human α-defensin 5 (DEFA5) and MMP7-deficient mice lacking the enzyme required for processing murine α-defensins—the authors found significant α-defensin-dependent changes in the composition of the intestinal microbiota, particularly in the abundance of Segmented Filamentous Bacteria (SFB) and the number of interleukin 17-producing lamina propria T cells. These findings suggest that α-defensins have a homeostatic role in regulating the composition of the commensal microbiota, which may influence mucosal immune responsiveness. The study also highlights the potential implications of α-defensin deficiency in conditions like inflammatory bowel disease (IBD), where dysbiosis and enhanced inflammatory responses may contribute to disease pathogenesis.Enteric defensins, specifically α-defensins, are antimicrobial peptides that play a crucial role in host defense against enteric pathogens. This study investigates whether α-defensins also regulate the intestinal microbial ecology. Using two complementary mouse models—*DEFA5* transgenic mice expressing human α-defensin 5 (DEFA5) and MMP7-deficient mice lacking the enzyme required for processing murine α-defensins—the authors found significant α-defensin-dependent changes in the composition of the intestinal microbiota, particularly in the abundance of Segmented Filamentous Bacteria (SFB) and the number of interleukin 17-producing lamina propria T cells. These findings suggest that α-defensins have a homeostatic role in regulating the composition of the commensal microbiota, which may influence mucosal immune responsiveness. The study also highlights the potential implications of α-defensin deficiency in conditions like inflammatory bowel disease (IBD), where dysbiosis and enhanced inflammatory responses may contribute to disease pathogenesis.