1. In vivo commensal control of Clostridioides difficile virulence.
- Author
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Girinathan BP, DiBenedetto N, Worley JN, Peltier J, Arrieta-Ortiz ML, Immanuel SRC, Lavin R, Delaney ML, Cummins CK, Hoffman M, Luo Y, Gonzalez-Escalona N, Allard M, Onderdonk AB, Gerber GK, Sonenshein AL, Baliga NS, Dupuy B, and Bry L
- Subjects
- Amino Acids metabolism, Animals, Arginine metabolism, Butyrates metabolism, Cecum metabolism, Cecum microbiology, Clostridiales growth & development, Clostridioides difficile genetics, Clostridioides difficile physiology, Clostridium growth & development, Fermentation, Gene Expression Profiling, Gene Expression Regulation, Bacterial, Gene Regulatory Networks, Germ-Free Life, Mice, Severity of Illness Index, Systems Biology, Virulence, Clostridiales physiology, Clostridioides difficile pathogenicity, Clostridium physiology, Clostridium Infections microbiology, Clostridium Infections therapy, Symbiosis
- Abstract
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., Competing Interests: Declaration of interests L.B. and G.K.G. are co-inventors on patents for C. difficile microbiota therapeutics. L.B., G.K.G., and A.L.S. are SAB members and hold stock in ParetoBio. G.K.G.is an SAB member and holds stock in Kaleido, Inc. A.L.S. is a co-owner of ExArca Pharmaceuticals. The remaining authors declare no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)
- Published
- 2021
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