Targeted Restoration of the Intestinal Microbiota with a Simple, Defined Bacteriotherapy Resolves Relapsing Clostridium difficile Disease in Mice

PLoS Pathogens

Taane G. Clark¹  Sylvia H. Duncan²  Harry J. Flint²  Alan W. Walker³  David Goulding³  Gordon Dougan³  Trevor D. Lawley³  Thomas R. Connor³  Claire Raisen³  Roland Rad³  Derek J. Pickard³  Simon Clare³  Laura J. Deakin³  Cordelia Brandt³  Mark D. Stares³  Fernanda Schreiber³  Julian Parkhill³ 

[1] London School of Hygiene and Tropical Medicine, London, United Kingdom;Rowett Institute of Nutrition and Health, Aberdeen, United Kingdom;Wellcome Trust Sanger Institute, Hinxton, United Kingdom

关键词: Clostridium difficile;    Microbiome;    Gastrointestinal tract;    Bacteria;    Anaerobic bacteria;    Animal phylogenetics;    Bacterial pathogens;    Ribosomal RNA;   

DOI  :  10.1371/journal.ppat.1002995

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY