α-Defensins Promote Bacteroides Colonization on Mucosal Reservoir to Prevent Antibiotic-Induced Dysbiosis

In addition to their established functions in host defense, accumulating evidence has suggested an emerging role for antimicrobial proteins (AMPs) in shaping commensal microbiota. However, the role of alpha-defensins, the most abundant AMPs of intestine, in regulating microbial ecology remains inconclusive. Here, we report that alpha-defensins promote commensalBacteroidescolonization by enhancing bacterial adhesion to the mucosal reservoir. Experiments utilizing mice deficient in matrix metalloproteinase 7 (MMP7), the alpha-defensin-activating enzyme, with rigorous littermate controls showed that alpha-defensin deficiency did not significantly influence steady-state intestinal microbiota. In contrast, alpha-defensins are essential for replenishment of commensalBacteroidesfrom the mucosal reservoir following antibiotics-induced dysbiosis, shown by markedly compromised recovery of Bacteroides in Mmp7(-/-) animals. Mechanistically, alpha-defensins promoteBacteroidescolonization on epithelial surfacesin vivoand adhesion to epithelial cellsin vitro. Moreover, alpha-defensins unexpectedly does not show any microbicidal activities againstBacteroides. Together, we propose that alpha-defensins promote commensal bacterial colonization and recovery to maintain microbial diversity upon environmental challenges.