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. 2025 Jan 8;33(1):30-41.e6.
doi: 10.1016/j.chom.2024.12.002. Epub 2024 Dec 27.

Commensal-pathogen dynamics structure disease outcomes during Clostridioides difficile colonization

Skye R S Fishbein  1 , Anna L DeVeaux  2 , Sakshi Khanna  1 , Aura L Ferreiro  1 , James Liao  1 , Wesley Agee  2 , Jie Ning  1 , Bejan Mahmud  2 , Miranda J Wallace  1 , Tiffany Hink  3 , Kimberly A Reske  3 , Candice Cass  3 , Janaki Guruge  1 , Sidh Leekha  2 , Sunaina Rengarajan  4 , Erik R Dubberke  3 , Gautam Dantas  5
Affiliations

Commensal-pathogen dynamics structure disease outcomes during Clostridioides difficile colonization

Skye R S Fishbein et al. Cell Host Microbe. .

Abstract

Gastrointestinal colonization by Clostridioides difficile is common in healthcare settings and ranges in presentation from asymptomatic carriage to lethal C. difficile infection (CDI). We used a systems biology approach to investigate why patients colonized with C. difficile have a range of clinical outcomes. Microbiota humanization of germ-free mice with fecal samples from toxigenic C. difficile carriers revealed a spectrum of virulence among clinically prevalent clade 1 lineages and identified candidate taxa, including Blautia, as markers of stable colonization. Using gnotobiotic mice engrafted with defined human microbiota, we validated strain-specific CDI severity across clade 1 strains isolated from patients. Mice engrafted with a community broadly representative of colonized patients were protected from severe disease across all strains without suppression of C. difficile colonization. These results underline the capacity of gut community structure to attenuate a diversity of pathogenic strains without inhibiting colonization, providing insight into determinants of stable C. difficile carriage.

Keywords: Clostridioides difficile; gastrointestinal infection; gut microbiome.

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Conflict of interest statement

Declaration of interests E.R.D. has served as a consultant for Seres Therapeutics, Ferring Pharmaceuticals, AstraZeneca, Summit, Merck, Recursion, and Abbott and has received research support from Theriva Biologics, Ferring Pharmaceuticals, and Pfizer, all unrelated to this study.

Update of

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