Abstract

Inflammatory bowel disease (IBD) is a group of chronic diseases of the digestive tract that affects millions of people worldwide. Genetic, environmental and microbial factors have been implicated in the onset and exacerbation of IBD. However, the mechanisms associating gut microbial dysbioses and aberrant immune responses remain largely unknown. The integrative Human Microbiome Project seeks to close these gaps by examining the dynamics of microbiome functionality in disease by profiling the gut microbiomes of >100 individuals sampled over a 1-year period. Here, we present the first results based on 78 paired faecal metagenomes and metatranscriptomes, and 222 additional metagenomes from 59 patients with Crohn’s disease, 34 with ulcerative colitis and 24 non-IBD control patients. We demonstrate several cases in which measures of microbial gene expression in the inflamed gut can be informative relative to metagenomic profiles of functional potential. First, although many microbial organisms exhibited concordant DNA and RNA abundances, we also detected species-specific biases in transcriptional activity, revealing predominant transcription of pathways by individual microorganisms per host (for example, by Faecalibacterium prausnitzii). Thus, a loss of these organisms in disease may have more far-reaching consequences than suggested by their genomic abundances. Furthermore, we identified organisms that were metagenomically abundant but inactive or dormant in the gut with little or no expression (for example, Dialister invisus). Last, certain disease-specific microbial characteristics were more pronounced or only detectable at the transcript level, such as pathways that were predominantly expressed by different organisms in patients with IBD (for example, Bacteroides vulgatus and Alistipes putredinis). This provides potential insights into gut microbial pathway transcription that can vary over time, inducing phenotypical changes that are complementary to those linked to metagenomic abundances. The study’s results highlight the strength of analysing both the activity and the presence of gut microorganisms to provide insight into the role of the microbiome in IBD.

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Acknowledgements

We thank the participants from Massachusetts General Hospital, Emory University, Cedars-Sinai IBD Center and Cincinnati Children’s Hospital Medical Center, who made this study possible. Furthermore, we acknowledge B. Sayoldin for making the data available through the Sequence Read Archive and our collaborators throughout the Integrative Human Microbiome Consortium. This work was supported by the US National Institutes of Health (NIH) grants U54DK102557 (C.H. and R.J.X.), STARR Cancer Consortium (C.H.), CCFA 20144126 (R.J.X.) and R01DK92405 (R.J.X.), U01DK062413 (D.P.B.M.), P01DK046763 (D.P.B.M.), UL1TR001881 (J.B.), and The Leona M. and Harry B. Helmsley Charitable Trust (D.P.B.M.).

Author information

Affiliations

  1. The Broad Institute of MIT and Harvard, Cambridge, MA, USA

    • Melanie Schirmer
    • , Eric A. Franzosa
    • , Jason Lloyd-Price
    • , Lauren J. McIver
    • , Tiffany W. Poon
    • , Hera Vlamakis
    • , Ramnik J. Xavier
    •  & Curtis Huttenhower
  2. Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MA, USA

    • Melanie Schirmer
    • , Eric A. Franzosa
    • , Jason Lloyd-Price
    • , Lauren J. McIver
    • , Randall Schwager
    •  & Curtis Huttenhower
  3. Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Boston, MA, USA

    • Ashwin N. Ananthakrishnan
    • , Elizabeth Andrews
    • , Jenny Sauk
    • , Betsy Stevens
    • , Robin G. Wilson
    •  & Ramnik J. Xavier
  4. The F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA

    • Gildardo Barron
    •  & Dermot P. B. McGovern
  5. Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

    • Kathleen Lake
    •  & Lee A. Denson
  6. Division of Pediatric Gastroenterology, Emory University School of Medicine, Atlanta, GA, USA

    • Mahadev Prasad
    •  & Subra Kugathasan
  7. Vatche and Tamar Manoukian Division of Digestive Disease, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA

    • Jenny Sauk
  8. Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA

    • Jonathan Braun
  9. Children’s Healthcare of Atlanta, Atlanta, GA, USA

    • Subra Kugathasan
  10. Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA, USA

    • Ramnik J. Xavier
  11. Center for Microbiome Informatics and Therapeutics, Massachusetts Institute of Technology, Cambridge, MA, USA

    • Ramnik J. Xavier

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Contributions

M.S., C.H., R.J.X. and H.V. conceived and designed the experiments. A.N.A., E.A., G.B., K.L., M.P., J.S., B.S. and R.G.W. performed the experiments. M.S., C.H. and E.A.F. analysed the data. M.S., C.H., E.A.F., J.L.-P., L.J.M., R.S., T.W.P., E.A., J.B., L.A.D., S.K. and D.P.B.M. contributed materials/analysis tools. M.S., C.H., R.J.X., J.L.-P. and H.V. wrote the paper.

Competing interests

D.P.B.M. is consulting for Cidara. The authors declare no other competing financial interests.

Corresponding authors

Correspondence to Ramnik J. Xavier or Curtis Huttenhower.

Supplementary information

  1. Supplementary Information

    Supplementary Figures 1–6, Supplementary Table 1.

  2. Life Sciences Reporting Summary

  3. Supplementary Table 2

    Description of pathways.