Cited by 114Clostridium difficile and Clostridium perfringens researchGut microbiota and healthEscherichia coli research studies

In vivo commensal control of Clostridioides difficile virulence

Open access
Girinathan, Brintha P., DiBenedetto, Nicholas, Worley, Jay N., Peltier, Johann, Arrieta-Ortiz, Mario L., Immanuel, Selva Rupa Christinal, Lavin, Richard, Delaney, Mary L. +11 more·2021·Cell Host & Microbe

Published version of a preprint

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.

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Authors
Girinathan, B. P., DiBenedetto, N., Worley, J. N., Peltier, J., Arrieta-Ortiz, M. L., Immanuel, S. R. C., Lavin, R., Delaney, M. L., Cummins, C. K., Hoffman, M., Luo, Y., Gonzalez-Escalona, N., Allard, M., Onderdonk, A. B., Gerber, G. K., Sonenshein, A. L., Baliga, N. S., Dupuy, B., & Bry, L.
Affiliations
  • Brigham and Women's Hospital (US)
  • Institute for Systems Biology (US)
  • Center for Food Safety and Applied Nutrition (US)
  • Tufts University (US)
  • Centre National de la Recherche Scientifique (FR)
Corresponding author
Bry, Lynn
Venue
Cell Host & Microbe
Publisher
Elsevier BV
Published
2021-11
Volume
29
Issue
11
Pages
1693-1708.e7
ISSN
1931-3128 (ISSN-L)
OpenAlex
W3207286353
Cited by
114
References
97
Citations by year
2026: 14 · 2025: 20 · 2024: 21 · 2023: 31 · 2022: 21 · 2021: 7
FWCI
6.32
Type
journal article
Language
en
Open access
Locations
  • Cell Host & Microbe (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
  • HAL (submittedVersion)
Funders
  • NIAID (R01AI141953, R01AI128215, U19AI135976)
  • NHLBI
  • Institut Pasteur
  • National Institute of Diabetes and Digestive and Kidney Diseases (P30DK034854, IIBR-2042948)
  • BWH
  • U.S. National Library of Medicine
  • National Science Foundation (IIBR-2042948)
  • National Institutes of Health
Topics
  • Health Sciences › Medicine › Infectious Diseases › Clostridium difficile and Clostridium perfringens research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Endocrinology › Escherichia coli research studies
Keywords
Clostridium difficile infection, commensal bacteria, gut microbiota, Paraclostridium bifermentans, amino acid fermentation, butyrate production, toxin production, clindamycin, gnotobiotic mice, bacterial metabolism, gene regulatory networks
MeSH terms
Eubacteriales, Amino Acids, Animals, Arginine, Butyrates, Cecum, Clostridium, Clostridium Infections, Fermentation, Germ-Free Life, Severity of Illness Index, Symbiosis, Virulence, Gene Expression Regulation, Bacterial, Clostridioides difficile, Gene Expression Profiling, Systems Biology, Mice, Gene Regulatory Networks

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