Letter | Published:

Precision microbiome reconstitution restores bile acid mediated resistance to Clostridium difficile

Nature volume 517, pages 205208 (08 January 2015) | Download Citation

This article has been updated


The gastrointestinal tracts of mammals are colonized by hundreds of microbial species that contribute to health, including colonization resistance against intestinal pathogens1. Many antibiotics destroy intestinal microbial communities and increase susceptibility to intestinal pathogens2. Among these, Clostridium difficile, a major cause of antibiotic-induced diarrhoea, greatly increases morbidity and mortality in hospitalized patients3. 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.

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Change history

  • 07 January 2015

    A minor change was made to the author list.


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Sequence Read Archive

Data deposits

Study sequence data are deposited in the National Center for Biotechnology Information Sequence Read Archive under accession number SRP045811.


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E.G.P. received funding from US National Institutes of Health (NIH) grants RO1 AI42135 and AI95706, and from the Tow Foundation. J.B.X. received funding from the NIH Office of the Director (DP2OD008440), NCI (U54 CA148967), and from a seed grant from the Lucille Castori Center for Microbes, Inflammation, and Cancer. C.G.B. was supported by a Medical Scientist Training Program grant from the National Institute of General Medical Sciences of the NIH (award number T32GM07739, awarded to the Weill Cornell/Rockefeller/Sloan-Kettering Tri-Institutional MD-PhD Program).

Author information


  1. Infectious Diseases Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA

    • Charlie G. Buffie
    • , Peter T. McKenney
    • , Melissa Kinnebrew
    • , Ying Taur
    •  & Eric G. Pamer
  2. Lucille Castori Center for Microbes, Inflammation and Cancer, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA

    • Charlie G. Buffie
    • , Peter T. McKenney
    • , Lilan Ling
    • , Asia Gobourne
    • , Daniel No
    • , Melissa Kinnebrew
    • , Eric Littmann
    • , Ying Taur
    • , Nora C. Toussaint
    • , Joao B. Xavier
    •  & Eric G. Pamer
  3. Computational Biology Program, Sloan-Kettering Institute, New York, New York 10065, USA

    • Vanni Bucci
    • , Richard R. Stein
    • , Chris Sander
    • , Nora C. Toussaint
    •  & Joao B. Xavier
  4. Department of Biology, University of Massachusetts Dartmouth, North Dartmouth, Massachusetts 02747, USA

    • Vanni Bucci
  5. Donald B. and Catherine C. Marron Cancer Metabolism Center, Sloan-Kettering Institute, New York, New York 10065, USA

    • Hui Liu
    •  & Justin R. Cross
  6. Genomics Core Laboratory, Sloan-Kettering Institute, New York, New York 10065, USA

    • Agnes Viale
  7. Bone Marrow Transplant Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA

    • Marcel R. M. van den Brink
    •  & Robert R. Jenq
  8. Immunology Program, Sloan-Kettering Institute, New York, New York 10065, USA

    • Marcel R. M. van den Brink
    •  & Eric G. Pamer


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C.G.B. and E.G.P. designed the experiments and wrote the manuscript with input from co-authors. C.G.B. performed animal experiments and most analyses. V.B., R.R.S., J.B.X., C.S. and C.G.B. performed microbiota time-series inference modelling and analysis. P.T.M. and C.G.B designed and performed ex vivo experiments. L.L., A.G., A.V. D.N. and M.K. performed 16S amplicon quantification and multiparallel sequencing (454, MiSeq) and contributed to data analysis. M.R.M.v.d.B., R.R.J., Y.T., E.L., C.G.B. and E.G.P. assessed clinical parameters and supervised patient cohort analysis. N.C.T. and C.G.B. performed metagenomic shotgun sequencing analysis. J.R.C. and H.L. developed the metabolomics analysis platform and performed quantification of bile acid species.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Eric G. Pamer.

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