The intestinal microbiota is a key determinant of gut homeostasis, which is achieved, in part, through regulation of antimicrobial peptide secretion. The aim of this study was to determine the efficiency by which members of the intestinal microbiota induce the antimicrobial peptide REGIII and to elucidate the underlying pathways. We showed that germfree mice have low levels of REGIII-γ in their ileum and colon compared to mice with different intestinal microbiota backgrounds. Colonization with a microbiota of low diversity (altered Schaedler flora) did not induce the expression of REGIII-γ as effectively as a complex community (specific pathogen free). Monocolonization with the probiotic
Bifidobacterium breve, but not with the nonprobiotic commensal Escherichia coliJM83, upregulated REGIII-γ expression. Induction of REGIII-γ by B. brevewas abrogated in mice lacking MyD88 and Ticam1 signaling. Both live and heat-inactivated B. brevebut not spent culture medium from B. breveinduced the expression of REGIII-α, the human ortholog and homolog of REGIII-γ, in human colonic epithelial cells (Caco-2). Taken together, the results suggest that REGIII-γ expression in the intestine correlates with the richness of microbiota composition. Also, specific bacteria such as Bifidobacterium breveNCC2950 effectively induce REGIII production in the intestine via the MyD88-Ticam1pathway. Treatment with this probiotic may enhance the mucosal barrier and protect the host from infection and inflammation.