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 journalArticle

329 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

Cite this

Targeted restoration of the intestinal microbiota with a simple, defined bacteriotherapy resolves relapsing Clostridium difficile disease in mice. / Lawley, Trevor D; Clare, Simon; Walker, Alan W; Stares, Mark D; Connor, Thomas R; Raisen, Claire; Goulding, David; Rad, Roland; Schreiber, Fernanda; Brandt, Cordelia; Deakin, Laura J; Pickard, Derek J; Duncan, Sylvia H; Flint, Harry James; Clark, Taane G; Parkhill, Julian; Dougan, Gordon.

In: PLoS Pathogens, Vol. 8, No. 10, e1002995, 25.10.2012.

Research output: Contribution to journalArticle

Lawley, TD, Clare, S, Walker, AW, Stares, MD, Connor, TR, Raisen, C, Goulding, D, Rad, R, Schreiber, F, Brandt, C, Deakin, LJ, Pickard, DJ, Duncan, SH, Flint, HJ, Clark, TG, Parkhill, J & Dougan, G 2012, 'Targeted restoration of the intestinal microbiota with a simple, defined bacteriotherapy resolves relapsing Clostridium difficile disease in mice', PLoS Pathogens, vol. 8, no. 10, e1002995. https://doi.org/10.1371/journal.ppat.1002995
Lawley, Trevor D ; Clare, Simon ; Walker, Alan W ; Stares, Mark D ; Connor, Thomas R ; Raisen, Claire ; Goulding, David ; Rad, Roland ; Schreiber, Fernanda ; Brandt, Cordelia ; Deakin, Laura J ; Pickard, Derek J ; Duncan, Sylvia H ; Flint, Harry James ; Clark, Taane G ; Parkhill, Julian ; Dougan, Gordon. / Targeted restoration of the intestinal microbiota with a simple, defined bacteriotherapy resolves relapsing Clostridium difficile disease in mice. In: PLoS Pathogens. 2012 ; Vol. 8, No. 10.
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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.",
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AU - Lawley, Trevor D

AU - Clare, Simon

AU - Walker, Alan W

AU - Stares, Mark D

AU - Connor, Thomas R

AU - Raisen, Claire

AU - Goulding, David

AU - Rad, Roland

AU - Schreiber, Fernanda

AU - Brandt, Cordelia

AU - Deakin, Laura J

AU - Pickard, Derek J

AU - Duncan, Sylvia H

AU - Flint, Harry James

AU - Clark, Taane G

AU - Parkhill, Julian

AU - Dougan, Gordon

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N2 - 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.

AB - 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.

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