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Clostridioides difficile pathogenesis and control

Nature Reviews Microbiology (2025)Cite this article

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Abstract

Clostridioides difficile infection (CDI) continues to be a notable burden worldwide, both in terms of patient mortality and morbidity, and the economic costs associated with treatment, diagnosis and management. The epidemiology of C. difficile has changed markedly over the decades, with high CDI rates driven by clinical pressures exacerbated by the severe acute respiratory syndrome coronavirus 2 pandemic, antibiotic resistance and selective pressures caused by antimicrobial use. C. difficile is challenging to diagnose and treat as it forms spores and can persist asymptomatically within the gut. Some strains express multiple virulence factors, including adhesins and toxins. The gut microbiota is crucially important in CDI, as a healthy microbiota is resistant to colonization with C. difficile. Dysbiosis, often caused by antimicrobial exposure, enables C. difficile spores to germinate and produce toxin, causing symptoms that can range from mild diarrhoea to fulminant colitis and death. This Review describes changes in epidemiology and effects on diagnosis, discusses recent breakthroughs in the understanding of pathogenesis and antibiotic resistance and explores the role of microbiota dysbiosis in CDI and novel microbiota therapies in CDI treatment.

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Fig. 1: Most common C. difficile ribotypes reported according to published data.
Fig. 2: The CDI cycle.
Fig. 3: Summary of pathogenicity factors during CDI and recurrent disease.
Fig. 4: The microbiota in C. difficile infection.

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Acknowledgements

C.H.C., C.N., I.B.M., J.F., K.D. and M.H.W. acknowledge the support of the National Institute for Health and Care Research (NIHR) Leeds Biomedical Research Centre (grant no. NIHR203331). The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, the UK Health Security Agency (UKHSA) or the Department of Health and Social Care. M.H.W., K.D. and J.F acknowledge the support of the NIHR Health Protection Research Unit in Healthcare Associated Infections and Antimicrobial Resistance (grant no. NIHR207397), a partnership between the UKHSA and the University of Oxford. M.H.W. and V.V. acknowledge the support of the NIHR Oxford Biomedical Research Centre and the NIHR Health Protection Research Unit in Healthcare Associated Infections and Antimicrobial Resistance (grant no. NIHR200915), a partnership between the UKHSA and the University of Oxford. K.D. acknowledges the support of the NIHR HealthTech Research Centre in Accelerated Surgical Care.

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Authors and Affiliations

  1. Leeds Institute of Medical Research, University of Leeds, Leeds, UK

    Caroline H. Chilton, Virginie Viprey, Charmaine Normington, Ines B. Moura, Jane Freeman, Kerrie Davies & Mark H. Wilcox

  2. NIHR Leeds Biomedical Research Centre, Leeds, UK

    Caroline H. Chilton, Charmaine Normington, Ines B. Moura, Jane Freeman, Kerrie Davies & Mark H. Wilcox

  3. NIHR Health Protection Research Unit in Healthcare Associated Infections and Antimicrobial Resistance, Oxford, UK

    Virginie Viprey, Jane Freeman, Kerrie Davies & Mark H. Wilcox

  4. School of Food Science and Nutrition, University of Leeds, Leeds, UK

    Anthony M. Buckley

  5. Leeds Teaching Hospitals NHS Trust, Leeds, UK

    Jane Freeman, Kerrie Davies & Mark H. Wilcox

  6. NIHR HealthTech Research Centre in Accelerated Surgical Care, Leeds, UK

    Kerrie Davies

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  1. Caroline H. Chilton
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Contributions

C.H.C. led the review and edit process of this article. The other authors contributed equally to all other aspects of the article.

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Correspondence to Caroline H. Chilton or Mark H. Wilcox.

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Competing interests

In the past 3 years, C.H.C. has received research funding from Debiopharm International and the MRC. I.B.M. has received research funding from GSK, Seres Therapeutics and the European Tissue Symposium. A.M.B. has received research funding from Seres Therapeutics. J.F. has received honorarium from Tillotts Pharma UK and grants from ACT-IVD, AJ Biosciences, Crestone, ESCMID, the MRC, the National Institute for Health and Care Research (NIHR), Pfizer and the UK Health Security Agency (UKHSA). K.D. has received honorarium from BD, Tillotts Pharma UK and Tillotts Pharma Europe, and grants from AJ Biosciences, ACT-IVD, AJ Biosciences, the MRC, the NIHR and Pfizer. M.H.W. has received consulting fees from AstraZeneca, Debiopharm, Ferring Pharmaceuticals, GSK, Nestlé, Paion, Pfizer, Phico Therapeutics, Qpex Biopharma, Seres Therapeutics, Summit, The European Tissue Symposium, Tillotts and Vedanta; lecture fees from GSK, Pfizer, Seres Therapeutics and Tillotts; and grant support from Debiopharm, GSK, Pfizer, Seres Therapeutics, Summit, the European Tissue Symposium and Tillotts. The other authors declare no competing interests.

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Nature Reviews Microbiology thanks Dena Lyras, who co-reviewed with Steven Mileto; Joseph Zackular; and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Chilton, C.H., Viprey, V., Normington, C. et al. Clostridioides difficile pathogenesis and control. Nat Rev Microbiol (2025). https://doi.org/10.1038/s41579-025-01242-2

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