Murine colitis reveals a disease-associated bacteriophage community

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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Fig. 1: Caudovirales phage abundances are altered during T-cell-mediated colitis.
Fig. 2: Phage community alterations during colitis were identified using a curated VLP contig database.
Fig. 3: Colitic animals share fewer VLP connections relative to healthy animals.
Fig. 4: Phage taxonomy and host bacterial assignments for curated VLP contigs reveal differential abundances of phages that infect both commensals and pathobionts during colitis.
Fig. 5: VLP reads from healthy and colitic animals share identity to human-associated intestinal phages.

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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.

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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.

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

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Supplementary information

Supplementary Information

Supplementary Figures 1–10

Reporting Summary

Supplementary Table 1

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

Supplementary Table 2

VLP contigs determined to be phages using VirSorter

Supplementary Table 3

VLP contigs grouped into genetically related viral clusters

Supplementary Table 4

VLP reads mapped to phage genomes from NCBI

Supplementary Table 5

VLP read mapping abundances against the IMG/VR database

Supplementary Table 6

VLP reads mapped to the curated VLP contig database

Supplementary Table 7

VLP reads mapped to curated VLP contig database at day 42

Supplementary Table 8

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

Supplementary Table 9

Phage taxonomy or host assignment per contig

Supplementary Table 10

P value

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Duerkop, B.A., Kleiner, M., Paez-Espino, D. et al. Murine colitis reveals a disease-associated bacteriophage community. Nat Microbiol 3, 1023–1031 (2018). https://doi.org/10.1038/s41564-018-0210-y

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