Letter | Published:

Moving beyond microbiome-wide associations to causal microbe identification

Nature volume 552, pages 244247 (14 December 2017) | Download Citation

  • An Erratum to this article was published on 17 January 2018

This article has been updated

Abstract

Microbiome-wide association studies have established that numerous diseases are associated with changes in the microbiota1,2. These studies typically generate a long list of commensals implicated as biomarkers of disease, with no clear relevance to disease pathogenesis1,2,3,4,5. If the field is to move beyond correlations and begin to address causation, an effective system is needed for refining this catalogue of differentially abundant microbes and to allow subsequent mechanistic studies1,4. Here we demonstrate that triangulation of microbe–phenotype relationships is an effective method for reducing the noise inherent in microbiota studies and enabling identification of causal microbes. We found that gnotobiotic mice harbouring different microbial communities exhibited differential survival in a colitis model. Co-housing of these mice generated animals that had hybrid microbiotas and displayed intermediate susceptibility to colitis. Mapping of microbe–phenotype relationships in parental mouse strains and in mice with hybrid microbiotas identified the bacterial family Lachnospiraceae as a correlate for protection from disease. Using directed microbial culture techniques, we discovered Clostridium immunis, a previously unknown bacterial species from this family, that—when administered to colitis-prone mice—protected them against colitis-associated death. To demonstrate the generalizability of our approach, we used it to identify several commensal organisms that induce intestinal expression of an antimicrobial peptide. Thus, we have used microbe–phenotype triangulation to move beyond the standard correlative microbiome study and identify causal microbes for two completely distinct phenotypes. Identification of disease-modulating commensals by microbe–phenotype triangulation may be more broadly applicable to human microbiome studies.

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Change history

  • 17 January 2018

    Please see accompanying Erratum (http://doi.org/10.1038/nature25471). In Fig. 2c, the labels for the green, blue and red lines were corrected from: ‘MMb’, ‘MMbHMb−1d’ and ‘MMbHMb−3d’ to ‘HMb’, ‘HMbMMb−1d’ and ‘HMbMMb−3d’, respectively.

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NCBI Reference Sequence

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Acknowledgements

We thank C. Couter for technical assistance; S. Edwards, J. Ramos, and T. Sherpa for assistance with gnotobiotic mice; R. Bronson for review of histology; J. McCoy for editorial assistance; and members of the Kasper laboratory for discussions. Support for this work was provided by a Career Development Award from Boston Children’s Hospital (N.K.S.) and National Institutes of Health grants K08 AI108690 (N.K.S.) and U19 AI109764 (N.K.S. and D.L.K.).

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Affiliations

  1. Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts 02115, USA

    • Neeraj K. Surana
    •  & Dennis L. Kasper
  2. Division of Infectious Diseases, Department of Medicine, Boston Children’s Hospital, Boston, Massachusetts 02115, USA

    • Neeraj K. Surana

Authors

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Contributions

N.K.S. conceived the study, designed and performed experiments, and analysed all data. D.L.K. supervised all aspects of the project. N.K.S. and D.L.K. wrote the paper.

Competing interests

N.K.S. and D.L.K. are inventors on patent application numbers 17/38680, 62/581372 and 62/523330 submitted by Harvard University that cover the therapeutic use of C. immunis.

Corresponding authors

Correspondence to Neeraj K. Surana or Dennis L. Kasper.

Reviewer Information Nature thanks J. Faith, M. Lathrop, A. Macpherson and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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https://doi.org/10.1038/nature25019

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