Engineering probiotics to inhibit Clostridioides difficile infection by dynamic regulation of intestinal metabolism
抄録
<jats:title>Abstract</jats:title><jats:p><jats:italic>Clostridioides difficile</jats:italic> infection (CDI) results in significant morbidity and mortality in hospitalised patients. The pathogenesis of CDI is intrinsically related to the ability of <jats:italic>C. difficile</jats:italic> to shuffle between active vegetative cells and dormant endospores through the processes of germination and sporulation. Here, we hypothesise that dysregulation of microbiome-mediated bile salt metabolism contributes to CDI and that its alleviation can limit the pathogenesis of CDI. We engineer a genetic circuit harbouring a genetically encoded sensor, amplifier and actuator in probiotics to restore intestinal bile salt metabolism in response to antibiotic-induced microbiome dysbiosis. We demonstrate that the engineered probiotics limited the germination of endospores and the growth of vegetative cells of <jats:italic>C. difficile</jats:italic> in vitro and further significantly reduced CDI in model mice, as evidenced by a 100% survival rate and improved clinical outcomes. Our work presents an antimicrobial strategy that harnesses the host-pathogen microenvironment as the intervention target to limit the pathogenesis of infection.</jats:p>
収録刊行物
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- Nature Communications
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Nature Communications 13 (1), 2022-07-04
Springer Science and Business Media LLC
