Abstract

The dysregulation of intestinal microbial communities is associated with inflammatory bowel diseases (IBD). Studies aimed at understanding the contribution of the microbiota to inflammatory diseases have primarily focused on bacteria, yet the intestine harbours a viral component dominated by prokaryotic viruses known as bacteriophages (phages). Phage numbers are elevated at the intestinal mucosal surface and phages increase in abundance during IBD, suggesting that phages play an unidentified role in IBD. We used a sequence-independent approach for the selection of viral contigs and then applied quantitative metagenomics to study intestinal phages in a mouse model of colitis. We discovered that during colitis the intestinal phage population is altered and transitions from an ordered state to a stochastic dysbiosis. We identified phages specific to pathobiotic hosts associated with intestinal disease, whose abundances are altered during colitis. Additionally, phage populations in healthy and diseased mice overlapped with phages from healthy humans and humans with IBD. Our findings indicate that intestinal phage communities are altered during inflammatory disease, establishing a platform for investigating phage involvement in IBD.

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Acknowledgements

We would like to thank C. Boyd, T. Leal and K. Ruhn for assistance with animals and X. Dong and F. Santoriello for bioinformatics assistance. This work was supported by NIH R01DK070855 (L.V.H.), the Howard Hughes Medical Institute (L.V.H.), NIH K01DK102436 (B.A.D.), start-up funds from the University of Colorado School of Medicine (B.A.D.), the Government of Canada’s Banting Postdoctoral Fellowship (M.K.) and the NC State Chancellor’s Faculty Excellence Program Cluster on Microbiomes and Complex Microbial Communities (M.K.). This work was partly conducted by the US Department of Energy Joint Genome Institute, a DOE Office of Science User Facility, under contract number DE-AC02-05CH11231.

Author information

Author notes

  1. These authors contributed equally to this work: Breck A. Duerkop, Manuel Kleiner.

Affiliations

  1. Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO, USA

    • Breck A. Duerkop
  2. Department of Plant and Microbial Biology, North Carolina State University, Raleigh, NC, USA

    • Manuel Kleiner
  3. Department of Energy, Joint Genome Institute, Walnut Creek, CA, USA

    • David Paez-Espino
    • , Brian Bushnell
    •  & Nikos C. Kyrpides
  4. Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX, USA

    • Wenhan Zhu
    •  & Sebastian E. Winter
  5. Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX, USA

    • Brian Hassell
    •  & Lora V. Hooper
  6. Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA

    • Lora V. Hooper

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Contributions

B.A.D., M.K. and L.V.H. designed the study. B.A.D., M.K., D.P.E. and B.H. performed experiments. B.A.D., M.K., D.P.E. and B.B. performed bioinformatic analyses. B.A.D., M.K., D.P.E., W.Z., S.E.W., N.C.K. and L.V.H. analysed data. B.A.D., M.K. and L.V.H. wrote the paper with input from all of the authors.

Competing interests

The authors declare no competing interests.

Corresponding authors

Correspondence to Breck A. Duerkop or Manuel Kleiner or Lora V. Hooper.

Supplementary information

  1. Supplementary Information

    Supplementary Figures 1–10

  2. Reporting Summary

  3. Supplementary Table 1

    VLP contigs containing virus-like genes determined using a VPF database

  4. Supplementary Table 2

    VLP contigs determined to be phages using VirSorter

  5. Supplementary Table 3

    VLP contigs grouped into genetically related viral clusters

  6. Supplementary Table 4

    VLP reads mapped to phage genomes from NCBI

  7. Supplementary Table 5

    VLP read mapping abundances against the IMG/VR database

  8. Supplementary Table 6

    VLP reads mapped to the curated VLP contig database

  9. Supplementary Table 7

    VLP reads mapped to curated VLP contig database at day 42

  10. Supplementary Table 8

    Contigs with high read recruitment in T-cell-treated animals

  11. Supplementary Table 9

    Phage taxonomy or host assignment per contig

  12. Supplementary Table 10

    P value

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DOI

https://doi.org/10.1038/s41564-018-0210-y