Targeted restoration of the intestinal microbiota with a simple, defined bacteriotherapy resolves relapsing Clostridium difficile disease in mice

Trevor D Lawley, Simon Clare, Alan W Walker, Mark D Stares, Thomas R Connor, Claire Raisen, David Goulding, Roland Rad, Fernanda Schreiber, Cordelia Brandt, Laura J Deakin, Derek J Pickard, Sylvia H Duncan, Harry James Flint, Taane G Clark, Julian Parkhill, Gordon Dougan

Research output: Contribution to journalArticlepeer-review

373 Citations (Scopus)
4 Downloads (Pure)

Abstract

Relapsing C. difficile disease in humans is linked to a pathological imbalance within the intestinal microbiota, termed dysbiosis, which remains poorly understood. We show that mice infected with epidemic C. difficile (genotype 027/BI) develop highly contagious, chronic intestinal disease and persistent dysbiosis characterized by a distinct, simplified microbiota containing opportunistic pathogens and altered metabolite production. Chronic C. difficile 027/BI infection was refractory to vancomycin treatment leading to relapsing disease. In contrast, treatment of C. difficile 027/BI infected mice with feces from healthy mice rapidly restored a diverse, healthy microbiota and resolved C. difficile disease and contagiousness. We used this model to identify a simple mixture of six phylogenetically diverse intestinal bacteria, including novel species, which can re-establish a health-associated microbiota and clear C. difficile 027/BI infection from mice. Thus, targeting a dysbiotic microbiota with a defined mixture of phylogenetically diverse bacteria can trigger major shifts in the microbial community structure that displaces C. difficile and, as a result, resolves disease and contagiousness. Further, we demonstrate a rational approach to harness the therapeutic potential of health-associated microbial communities to treat C. difficile disease and potentially other forms of intestinal dysbiosis.

Original languageEnglish
Article numbere1002995
Number of pages14
JournalPLoS Pathogens
Volume8
Issue number10
DOIs
Publication statusPublished - 25 Oct 2012

Keywords

  • transplantation
  • susceptibility
  • epidemic
  • strain
  • infection
  • antibiotic perturbation
  • diarrhea
  • transmission
  • inflammation
  • enterica serovar typhimurium
  • vancomycin
  • animals
  • clostridium difficile
  • drug resistance
  • bacterial
  • enterocolitis
  • pseudomembranous
  • feces
  • female
  • intestines
  • mice
  • mice, inbred C3H,
  • microbial consortia
  • microbial interactions
  • molecular sequence data
  • probiotics
  • recurrence

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