title: Precision microbiome reconstitution restores bile acid mediated resistance to Clostridium difficile.
abstract: The gastrointestinal tracts of mammals are colonized by hundreds of microbial species that contribute to health, including colonization resistance against intestinal pathogens. Many antibiotics destroy intestinal microbial communities and increase susceptibility to intestinal pathogens. Among these, Clostridium difficile, a major cause of antibiotic-induced diarrhoea, greatly increases morbidity and mortality in hospitalized patients. Which intestinal bacteria provide resistance to C. difficile infection and their in vivo inhibitory mechanisms remain unclear. Here we correlate loss of specific bacterial taxa with development of infection, by treating mice with different antibiotics that result in distinct microbiota changes and lead to varied susceptibility to C. difficile. Mathematical modelling augmented by analyses of the microbiota of hospitalized patients identifies resistance-associated bacteria common to mice and humans. Using these platforms, we determine that Clostridium scindens, a bile acid 7α-dehydroxylating intestinal bacterium, is associated with resistance to C. difficile infection and, upon administration, enhances resistance to infection in a secondary bile acid dependent fashion. Using a workflow involving mouse models, clinical studies, metagenomic analyses, and mathematical modelling, we identify a probiotic candidate that corrects a clinically relevant microbiome deficiency. These findings have implications for the rational design of targeted antimicrobials as well as microbiome-based diagnostics and therapeutics for individuals at risk of C. difficile infection.
authors.affiliation: 1] Infectious Diseases Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA [2] Lucille Castori Center for Microbes, Inflammation and Cancer, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Charlie G
authors.initials: CG
authors.lastname: Buffie
authors.affiliation: 1] Computational Biology Program, Sloan-Kettering Institute, New York, New York 10065, USA [2] Department of Biology, University of Massachusetts Dartmouth, North Dartmouth, Massachusetts 02747, USA.
authors.forename: Vanni
authors.initials: V
authors.lastname: Bucci
authors.affiliation: Computational Biology Program, Sloan-Kettering Institute, New York, New York 10065, USA.
authors.forename: Richard R
authors.initials: RR
authors.lastname: Stein
authors.affiliation: 1] Infectious Diseases Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA [2] Lucille Castori Center for Microbes, Inflammation and Cancer, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Peter T
authors.initials: PT
authors.lastname: McKenney
authors.affiliation: Lucille Castori Center for Microbes, Inflammation and Cancer, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Lilan
authors.initials: L
authors.lastname: Ling
authors.affiliation: Lucille Castori Center for Microbes, Inflammation and Cancer, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Asia
authors.initials: A
authors.lastname: Gobourne
authors.affiliation: Lucille Castori Center for Microbes, Inflammation and Cancer, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: No
authors.affiliation: Donald B. and Catherine C. Marron Cancer Metabolism Center, Sloan-Kettering Institute, New York, New York 10065, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Liu
authors.affiliation: 1] Infectious Diseases Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA [2] Lucille Castori Center for Microbes, Inflammation and Cancer, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Melissa
authors.initials: M
authors.lastname: Kinnebrew
authors.affiliation: Genomics Core Laboratory, Sloan-Kettering Institute, New York, New York 10065, USA.
authors.forename: Agnes
authors.initials: A
authors.lastname: Viale
authors.affiliation: Lucille Castori Center for Microbes, Inflammation and Cancer, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Littmann
authors.affiliation: 1] Bone Marrow Transplant Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA [2] Immunology Program, Sloan-Kettering Institute, New York, New York 10065, USA.
authors.forename: Marcel R M
authors.initials: MR
authors.lastname: van den Brink
authors.affiliation: Bone Marrow Transplant Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Robert R
authors.initials: RR
authors.lastname: Jenq
authors.affiliation: 1] Infectious Diseases Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA [2] Lucille Castori Center for Microbes, Inflammation and Cancer, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Taur
authors.affiliation: Computational Biology Program, Sloan-Kettering Institute, New York, New York 10065, USA.
authors.forename: Chris
authors.initials: C
authors.lastname: Sander
authors.affiliation: Donald B. and Catherine C. Marron Cancer Metabolism Center, Sloan-Kettering Institute, New York, New York 10065, USA.
authors.forename: Justin R
authors.initials: JR
authors.lastname: Cross
authors.affiliation: 1] Lucille Castori Center for Microbes, Inflammation and Cancer, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA [2] Computational Biology Program, Sloan-Kettering Institute, New York, New York 10065, USA.
authors.forename: Nora C
authors.initials: NC
authors.lastname: Toussaint
authors.affiliation: 1] Lucille Castori Center for Microbes, Inflammation and Cancer, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA [2] Computational Biology Program, Sloan-Kettering Institute, New York, New York 10065, USA.
authors.forename: Joao B
authors.initials: JB
authors.lastname: Xavier
authors.affiliation: 1] Infectious Diseases Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA [2] Lucille Castori Center for Microbes, Inflammation and Cancer, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA [3] Immunology Program, Sloan-Kettering Institute, New York, New York 10065, USA.
authors.forename: Eric G
authors.initials: EG
authors.lastname: Pamer
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001647:Bile Acids and Salts / Q000378:metabolism*; D005075:Biological Evolution; D016360:Clostridioides difficile / Q000187:drug effects / Q000502:physiology*; D003013:Clostridium / Q000378:metabolism; D003092:Colitis / Q000378:metabolism / Q000382:microbiology / Q000517:prevention & control / Q000628:therapy; D004198:Disease Susceptibility / Q000382:microbiology*; D005243:Feces / Q000382:microbiology; D005260:Female; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000187:drug effects / Q000382:microbiology*; D054892:Metagenome / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D064307:Microbiota / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D013559:Symbiosis
chemical_list: D000900:Anti-Bacterial Agents; D001647:Bile Acids and Salts