Vancomycin-resistant enterococci exploit antibiotic-induced innate immune deficits

Abstract

Why antibiotic-resistant bacteria are so successful at causing infections in patients being treated with antibiotics is a something of a mystery. One previously unrecognized factor is reported in this issue: treatment with the broad-spectrum antibiotic vancomycin increases infection with resistant bacteria by compromising intestinal innate immunity. In mice receiving the antibiotic, intestinal expression of the antimicrobial protein, RegIIIγ was suppressed. RegIIIγ is notably effective against vancomycin-resistant Enterococcus (VRE), a common infection in hospitalized patients. Therapies that increase levels of this protein, such as orally administered lipopolysaccharide, may therefore be of use in patients receiving broad-spectrum antibiotics. Infection with antibiotic-resistant bacteria, such as vancomycin-resistant Enterococcus (VRE), is a dangerous and costly complication of broad-spectrum antibiotic therapy1,2. How antibiotic-mediated elimination of commensal bacteria promotes infection by antibiotic-resistant bacteria is a fertile area for speculation with few defined mechanisms. Here we demonstrate that antibiotic treatment of mice notably downregulates intestinal expression of RegIIIγ (also known as Reg3g), a secreted C-type lectin that kills Gram-positive bacteria, including VRE. Downregulation of RegIIIγ markedly decreases in vivo killing of VRE in the intestine of antibiotic-treated mice. Stimulation of intestinal Toll-like receptor 4 by oral administration of lipopolysaccharide re-induces RegIIIγ, thereby boosting innate immune resistance of antibiotic-treated mice against VRE. Compromised mucosal innate immune defence, as induced by broad-spectrum antibiotic therapy, can be corrected by selectively stimulating mucosal epithelial Toll-like receptors, providing a potential therapeutic approach to reduce colonization and infection by antibiotic-resistant microbes.