Non-Toxigenic Clostridioides difficile Strain E4 (NTCD-E4) Prevents Establishment of Primary C. difficile Infection by Epidemic PCR Ribotype 027 in an In Vitro Human Gut Model

Perezimor Etifa, César Rodríguez, Céline Harmanus, Ingrid M. J. G. Sanders, Igor A. Sidorov, Olufunmilayo A. Mohammed, Emily Savage, Andrew R. Timms, Jane Freeman, Wiep Klaas Smits, Mark H. Wilcox, Simon D. Baines, Mehran Monchi (Editor), Michael Samarkos (Editor), Stefano Di Bella (Editor)

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Abstract

Clostridioides difficile infection (CDI) remains a significant healthcare burden. Non-toxigenic C. difficile (NTCD) strains have shown a benefit in preventing porcine enteritis and in human recurrent CDI. In this study, we evaluated the efficacy of metronidazole-resistant NTCD-E4 in preventing CDI facilitated by a range of antimicrobials in an in vitro human gut model. NTCD-E4 spores (at a dose of 107) were instilled 7 days before a clinical ribotype (RT) 027 (at the same dose) strain (210). In separate experiments, four different antimicrobials were used to perturb gut microbiotas; bacterial populations and cytotoxin production were determined using viable counting and Vero cell cytotoxicity, respectively. RT027 and NTCD-E4 proliferated in the in vitro model when inoculated singly, with RT027 demonstrating high-level cytotoxin (3-5-log10-relative units) production. In experiments where the gut model was pre-inoculated with NTCD-E4, RT027 was remained quiescent and failed to produce cytotoxins. NTCD-E4 showed mutations in hsmA and a gene homologous to CD196-1331, previously linked to medium-dependent metronidazole resistance, but lacked other metronidazole resistance determinants. This study showed that RT027 was unable to elicit simulated infection in the presence of NTCD-E4 following stimulation by four different antimicrobials. These data complement animal and clinical studies in suggesting NTCD offer prophylactic potential in the management of human CDI.
Original languageEnglish
Article number435
Pages (from-to)1-15
Number of pages15
JournalAntibiotics
Volume12
Issue number3
Early online date22 Feb 2023
DOIs
Publication statusPublished - 22 Feb 2023

Keywords

  • Article
  • Clostridioides difficile
  • RT027
  • non-toxigenic
  • antibiotics
  • resistance
  • gut model
  • colonisation
  • infection

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