Journal
CELL HOST & MICROBE
Volume 29, Issue 11, Pages 1693-+Publisher
CELL PRESS
DOI: 10.1016/j.chom.2021.09.007
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Funding
- BWH Precision Medicine Institute from the National Institute of Allergy and Infectious Diseases (NIAID) [R01AI153605]
- National Institute of Diabetes, Digestive and Kidney Diseases [P30DK034854]
- NIAID [U19AI135976, R01AI128215, R01AI141953]
- National Science Foundation [IIBR-2042948]
- Intramural Research Program of the National Library of Medicine, National Institutes of Health
- Institut Pasteur (Bourse ROUX)
- [T32 HL007627]
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Different species of Clostridia can protect against or worsen Clostridioides difficile infection in mice by modulating the pathogen's colonization, growth, and virulence through altering the gut-nutrient environment. This research lays the groundwork for mechanistically informed therapies to counter C. difficile disease using systems biology approaches to define host-commensal-pathogen interactions in vivo.
Leveraging systems biology approaches, we illustrate how metabolically distinct species of Clostridia protect against or worsen Clostridioides difficile infection in mice by modulating the pathogen's colonization, growth, and virulence to impact host survival. Gnotobiotic mice colonized with the amino acid fermenter Paraclostridium bifermentans survive infection with reduced disease severity, while mice colonized with the butyrate-producer, Clostridium sardiniense, succumb more rapidly. Systematic in vivo analyses revealed how each commensal alters the gut-nutrient environment to modulate the pathogen's metabolism, gene regulatory networks, and toxin production. Oral administration of P. bifermentans rescues conventional, clindamycin-treated mice from lethal C. difficile infection in a manner similar to that of monocolonized animals, thereby supporting the therapeutic potential of this commensal species. Our findings lay the foundation for mechanistically informed therapies to counter C. difficile disease using systems biology approaches to define host-commensal-pathogen interactions in vivo.
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