Research ArticleTOLERANCE

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

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Science Immunology  22 Sep 2016:
Vol. 1, Issue 3, pp. eaai7732
DOI: 10.1126/sciimmunol.aai7732

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Microbes teach tolerance in the gut

The trillions of microbes inhabiting our gut can greatly affect how we respond to infection, but scientists do not fully understand the molecular mechanisms shaping how different microbes interact with the host. Rangan et al. found that both worms and mice harboring Enterococcus faecium can better tolerate Salmonella infection. In both cases, tolerance requires E. faecium to express the enzyme secreted antigen A (SagA). SagA can also exert this probiotic effect when expressed by other bacteria. SagA protects worms by cleaving bacterial peptide fragments so that they can stimulate the tol-1 protein. In mice, Pedicord et al. found that SagA protects against Salmonella and Clostridium difficile pathogenesis in a manner dependent on antimicrobial peptides and multiple innate immune receptors.


Commensal intestinal bacteria can prevent pathogenic infection; however, limited knowledge of the mechanisms by which individual bacterial species contribute to pathogen tolerance has restricted their potential for therapeutic application. We examined how colonization of mice with a human commensal Enterococcus faecium protects against enteric infections. We show that E. faecium improves host intestinal epithelial defense programs to limit Salmonella enterica serotype Typhimurium pathogenesis in vivo in multiple models of susceptibility. E. faecium protection is mediated by a unique peptidoglycan hydrolase, secreted antigen A (SagA), and requires epithelial expression of pattern recognition receptor components and antimicrobial peptides. Ectopic expression of SagA in nonprotective and probiotic bacteria is sufficient to enhance intestinal barrier function and confer tolerance against S. Typhimurium and Clostridium difficile 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.

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