Experimental human colonisation with non-toxigenic Clostridioides difficile: a placebo-controlled randomised clinical trial

Nature Communications, vol. 17

Abstract

Clostridioides difficile infections remain a major global healthcare burden, underscoring the need for novel therapies. Human colonisation models provide mechanistic insight into C. difficile colonisation and facilitate identification of novel intervention targets. We conducted a placebo-controlled, randomised clinical trial (NCT05693077) administering non-toxigenic C. difficile (NTCD) capsules to healthy participants to assess safety and colonisation as primary endpoints, and microbiota susceptibility as a secondary endpoint. A total of 69 healthy participants (18-45 years), not previously colonised with C. difficile and without recent antibiotic use, were enrolled following a health assessment. NTCD capsules administered for five consecutive days at low or high dose, was safe with no dose-response relationship in colonisation outcomes. Vancomycin pretreatment induced colonisation success: with 5% colonisation without, 32% after one day, and 84% after five days vancomycin pretreatment. Some participants that cleared vancomycin rapidly acquired non-challenge C. difficile strains prior to NTCD challenge. Microbiota profiling (using shotgun metagenomics) revealed reduced α-diversity and pronounced community restructuring. These findings highlight the impact of antibiotic-mediated microbiota disruption, the widespread environmental presence of C. difficile, and the feasibility of meaningful microbiota assessment in small-scale intervention trials, thereby providing a robust tool to investigate this globally impactful infection.

Authors 21

1. Annefleur D. O. Hensen Aachen

   Leiden University · Leiden University Medical Center

   Affiliation as printed

   Leiden University Center for Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands

2. Céline Harmanus Aachen

   Leiden University · Leiden University Medical Center

   Affiliation as printed

   Leiden University Center for Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands

3. P. H. Verbeek-Menken Aachen

   Leiden University · Leiden University Medical Center

   Affiliation as printed

   Leiden University Center for Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands

4. Jan Pieter R. Koopman Aachen

   Leiden University · Leiden University Medical Center

   Affiliation as printed

   Leiden University Center for Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands

5. O. A. C. Lamers Aachen

   Leiden University · Leiden University Medical Center

   Affiliation as printed

   Leiden University Center for Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands

6. Geert V.T. Roozen Aachen

   Leiden University · Leiden University Medical Center

   Affiliation as printed

   Leiden University Center for Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands

7. Jacqueline J. Janse Aachen

   Leiden University · Leiden University Medical Center

   Affiliation as printed

   Leiden University Center for Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands

8. M. Balke-Buijs Aachen

   Leiden University · Leiden University Medical Center

   Affiliation as printed

   Leiden University Center for Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands

9. M. Y. E. C. van der Stoep Aachen Center for Cell and Gene Therapy Clinical Pharmacy and Toxicology

   Leiden University · Leiden University Medical Center

   Affiliation as printed

   Center for Cell and Gene Therapy, Leiden University Medical Center, Leiden, The Netherlands

   Clinical Pharmacy and Toxicology, Leiden University Medical Centre, Leiden, The Netherlands

10. Pauline Meij Aachen Center for Cell and Gene Therapy

    Leiden University Medical Center

    Affiliation as printed

    Center for Cell and Gene Therapy, Leiden University Medical Center, Leiden, The Netherlands

11. I.M. van Amerongen-Westra Aachen Center for Cell and Gene Therapy

    Leiden University Medical Center

    Affiliation as printed

    Center for Cell and Gene Therapy, Leiden University Medical Center, Leiden, The Netherlands

12. P. Schipper Aachen Center for Cell and Gene Therapy

    Leiden University Medical Center

    Affiliation as printed

    Center for Cell and Gene Therapy, Leiden University Medical Center, Leiden, The Netherlands

13. C. Crul Aachen

    Leiden University · Leiden University Medical Center

    Affiliation as printed

    Leiden University Center for Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands

14. L. Pattacini Aachen

    Leiden University · Leiden University Medical Center

    Affiliation as printed

    Leiden University Center for Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands

15. Katharina Rox

    German Center for Infection Research · Helmholtz Centre for Infection Research

    Affiliation as printed

    Department of Chemical Biology, Helmholtz Center for Infection Research (HZI), Braunschweig, Germany

    German Centre for Infection Research (DZIF), partner site Hannover, Braunschweig, Braunschweig, Germany

16. F. Farowski

    University Hospital Cologne

    Affiliation as printed

    Department I of Internal Medicine, University Hospital of Cologne, Cologne, Germany

17. Anastasia Tsakmaklis

    University Hospital Cologne

    Affiliation as printed

    Department I of Internal Medicine, University Hospital of Cologne, Cologne, Germany

18. M.J.G.T. Vehreschild

    Goethe University Frankfurt · German Center for Infection Research · University Hospital Frankfurt · University Hospital Cologne

    Affiliation as printed

    Department I of Internal Medicine, University Hospital of Cologne, Cologne, Germany

    German Center for Infection Research, partner site Bonn-, Cologne, Germany

    Goethe University Frankfurt, University Hospital Frankfurt, Department II of Internal Medicine, Frankfurt am Main, Germany

19. Ed J. Kuijper Aachen

    Leiden University · Leiden University Medical Center

    Affiliation as printed

    Leiden University Center for Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands

20. Wiep Klaas Smits Aachen

    Leiden University · Leiden University Medical Center

    Affiliation as printed

    Leiden University Center for Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands

21. Meta Roestenberg corresponding Aachen

    Leiden University · Leiden University Medical Center

    Affiliation as printed

    Leiden University Center for Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands. m.roestenberg@lumc.nl