In vivo commensal control of Clostridioides difficile virulence
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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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Fully restricting C. difficile may require sequestering key nutrients or amino acids in addition to producing inhibitory BAs.
“Moreover, fully restricting C. difficile may require sequestering key nutrients or amino acids in addition to producing inhibitory BAs48.”
From Bile salt hydrolases shape the bile acid landscape and restrict Clostridioides difficile growth in the murine gut (2023) · cites this paper as [48]
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Foley, M. H., Walker, M. E., Stewart, A. K., O’Flaherty, S., Gentry, E. C., Patel, S., Beaty, V. V., Allen, G., Pan, M., Simpson, J. B., et al. (2023) · Nature Microbiology · doi:10.1038/s41564-023-01337-7 · Cited by 181 · see citing works
Ying, X., Rongjiong, Z., Kahaer, M., Chunhui, J., & Wulasihan, M. (2023) · Frontiers in Microbiology · doi:10.3389/fmicb.2023.1088187 · Cited by 47 · see citing works
- 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
- ORCID
- Venue
- Cell Host & Microbe
- Publisher
- Elsevier BV
- Published
- 2021-11
- Volume
- 29
- Issue
- 11
- Pages
- 1693-1708.e7
- ISSN
- 1931-3128 (ISSN-L)
- PMC
- PMC8651146
- 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
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 374 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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