Exploiting a host-commensal interaction to promote intestinal barrier function and enteric pathogen tolerance

Abstract

Commensal intestinal bacteria can prevent pathogenic infection; however, limited knowledge of the mechanisms by which individual bacterial species contribute to pathogen resistance has restricted their potential for therapeutic application. Here, we examined how colonization of mice with a human commensal <i>Enterococcus faecium</i> protects against enteric infections. We show that <i>E. faecium</i> improves host intestinal epithelial defense programs to limit <i>Salmonella enterica</i> serotype Typhimurium pathogenesis <i>in vivo</i> in multiple models of susceptibility. <i>E. faecium</i> protection is mediated by a unique peptidoglycan hydrolase, SagA, and requires epithelial expression of pattern recognition receptor components and antimicrobial peptides. Ectopic expression of SagA in non-protective and probiotic bacteria is sufficient to enhance intestinal barrier function and confer resistance against <i>S.</i> Typhimurium and <i>Clostridium difficile</i> pathogenesis. These studies demonstrate that specific factors from commensal bacteria can be used to improve host barrier function and limit the pathogenesis of distinct enteric infections.