title: Targeted restoration of the intestinal microbiota with a simple, defined bacteriotherapy resolves relapsing Clostridium difficile disease in mice.
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.
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, United Kingdom. tl2@sanger.ac.uk
authors.forename: Trevor D
authors.initials: TD
authors.lastname: Lawley
authors.forename: Simon
authors.initials: S
authors.lastname: Clare
authors.forename: Alan W
authors.initials: AW
authors.lastname: Walker
authors.forename: Mark D
authors.initials: MD
authors.lastname: Stares
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Connor
authors.forename: Claire
authors.initials: C
authors.lastname: Raisen
authors.forename: David
authors.initials: D
authors.lastname: Goulding
authors.forename: Roland
authors.initials: R
authors.lastname: Rad
authors.forename: Fernanda
authors.initials: F
authors.lastname: Schreiber
authors.forename: Cordelia
authors.initials: C
authors.lastname: Brandt
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Deakin
authors.forename: Derek J
authors.initials: DJ
authors.lastname: Pickard
authors.forename: Sylvia H
authors.initials: SH
authors.lastname: Duncan
authors.forename: Harry J
authors.initials: HJ
authors.lastname: Flint
authors.forename: Taane G
authors.initials: TG
authors.lastname: Clark
authors.forename: Julian
authors.initials: J
authors.lastname: Parkhill
authors.forename: Gordon
authors.initials: G
authors.lastname: Dougan
mesh_terms: D000818:Animals; D016360:Clostridioides difficile / Q000187:drug effects / Q000472:pathogenicity*; D024881:Drug Resistance, Bacterial; D004761:Enterocolitis, Pseudomembranous / Q000188:drug therapy / Q000382:microbiology / Q000628:therapy*; D005243:Feces / Q000382:microbiology*; D005260:Female; D007422:Intestines / Q000382:microbiology*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D059013:Microbial Consortia; D056265:Microbial Interactions; D008969:Molecular Sequence Data; D019936:Probiotics / Q000627:therapeutic use*; D012008:Recurrence; D014640:Vancomycin / Q000494:pharmacology
chemical_list: D014640:Vancomycin