Resistin-like molecule β is a bactericidal protein that promotes spatial segregation of the microbiota and the colonic epithelium

Significance The mammalian gastrointestinal tract is home to diverse communities of bacteria that contribute to the metabolic health of their hosts. The epithelial lining of the intestine produces a diverse repertoire of antimicrobial proteins that limit the ability of these microorganisms to enter host tissues and cause disease. We have discovered that resistin-like molecule β (RELMβ) is a previously unknown member of the intestine's antibacterial arsenal. RELMβ is secreted from the intestinal surface and kills Gram-negative bacteria by damaging their membranes, thereby preventing these bacteria from coming into close contact with host tissues. Our findings reveal a new family of endogenous antibiotic proteins and contribute to the understanding of how mammals maintain mutually beneficial relationships with complex communities of intestinal bacteria. The mammalian intestine is colonized by trillions of bacteria that perform essential metabolic functions for their hosts. The mutualistic nature of this relationship depends on maintaining spatial segregation between these bacteria and the intestinal epithelial surface. This segregation is achieved in part by the presence of a dense mucus layer at the epithelial surface and by the production of antimicrobial proteins that are secreted by epithelial cells into the mucus layer. Here, we show that resistin-like molecule β (RELMβ) is a bactericidal protein that limits contact between Gram-negative bacteria and the colonic epithelial surface. Mouse and human RELMβ selectively killed Gram-negative bacteria by forming size-selective pores that permeabilized bacterial membranes. In mice lacking RELMβ, Proteobacteria were present in the inner mucus layer and invaded mucosal tissues. Another RELM family member, human resistin, was also bactericidal, suggesting that bactericidal activity is a conserved function of the RELM family. Our findings thus identify the RELM family as a unique family of bactericidal proteins and show that RELMβ promotes host–bacterial mutualism by regulating the spatial segregation between the microbiota and the intestinal epithelium.