Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

The eukaryotic gut virome in hematopoietic stem cell transplantation: new clues in enteric graft-versus-host disease

Nature Medicine volume 23, pages 1080–1085 (2017)Cite this article

Subjects

Abstract

Much attention has been focused on the role of the bacterial microbiome in human health, but the virome is understudied. Although previously investigated in individuals with inflammatory bowel diseases or solid-organ transplants1,2, virome dynamics in allogeneic hematopoietic stem cell transplantation (HSCT) and enteric graft-versus-host disease (GVHD) remain unexplored. Here we characterize the longitudinal gut virome in 44 recipients of HSCT using metagenomics. A viral 'bloom' was identified, and significant increases were demonstrated in the overall proportion of vertebrate viral sequences following transplantation (P = 0.02). Increases in both the rates of detection (P < 0.0001) and number of sequences (P = 0.047) of persistent DNA viruses (anelloviruses, herpesviruses, papillomaviruses and polyomaviruses) over time were observed in individuals with enteric GVHD relative to those without, a finding accompanied by a reduced phage richness (P = 0.01). Picobirnaviruses were detected in 18 individuals (40.9%), more frequently before or within a week after transplant than at later time points (P = 0.008). In a time-dependent Cox proportional-hazards model, picobirnaviruses were predictive of the occurrence of severe enteric GVHD (hazard ratio, 2.66; 95% confidence interval (CI) = 1.46–4.86; P = 0.001), and correlated with higher fecal levels of two GVHD severity markers, calprotectin and α1-antitrypsin. These results reveal a progressive expansion of vertebrate viral infections over time following HSCT, and they suggest an unexpected association of picobirnaviruses with early post-transplant GVHD.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Collection of stool samples for virome analysis according to stage of enteric GVHD.
Figure 2: Microbiome and phage virome dynamics.
Figure 3: Evolution of the enteric virome following transplantation.
Figure 4: Frequency and diversity of PBVs in individuals with or without enteric GVHD.

Similar content being viewed by others

References

  1. De Vlaminck, I. et al. Temporal response of the human virome to immunosuppression and antiviral therapy. Cell 155, 1178–1187 (2013).

    Article  CAS  Google Scholar 

  2. Norman, J.M. et al. Disease-specific alterations in the enteric virome in inflammatory bowel disease. Cell 160, 447–460 (2015).

    Article  CAS  Google Scholar 

  3. Feghoul, L. et al. Adenovirus infection and disease in paediatric haematopoietic stem cell transplant patients: clues for antiviral pre-emptive treatment. Clin. Microbiol. Infect. 21, 701–709 (2015).

    Article  CAS  Google Scholar 

  4. Pichereau, C. et al. The complex relationship between human herpesvirus 6 and acute graft-versus-host disease. Biol. Blood Marrow Transplant. 18, 141–144 (2012).

    Article  Google Scholar 

  5. Zerr, D.M. et al. HHV-6 reactivation and associated sequelae after hematopoietic cell transplantation. Biol. Blood Marrow Transplant. 18, 1700–1708 (2012).

    Article  Google Scholar 

  6. Jenq, R.R. et al. Regulation of intestinal inflammation by microbiota following allogeneic bone marrow transplantation. J. Exp. Med. 209, 903–911 (2012).

    Article  CAS  Google Scholar 

  7. Minot, S. et al. The human gut virome: inter-individual variation and dynamic response to diet. Genome Res. 21, 1616–1625 (2011).

    Article  CAS  Google Scholar 

  8. Schwartz, S. et al. Norovirus gastroenteritis causes severe and lethal complications after chemotherapy and hematopoietic stem cell transplantation. Blood 117, 5850–5856 (2011).

    Article  CAS  Google Scholar 

  9. Yang, J.Y. et al. Enteric viruses ameliorate gut inflammation via Toll-like receptor 3 and Toll-like receptor 7-mediated interferon-β production. Immunity 44, 889–900 (2016).

    Article  CAS  Google Scholar 

  10. Finkbeiner, S.R. et al. Metagenomic analysis of human diarrhea: viral detection and discovery. PLoS Pathog. 4, e1000011 (2008).

    Article  Google Scholar 

  11. Phan, T.G. et al. Acute diarrhea in West African children: diverse enteric viruses and a novel parvovirus genus. J. Virol. 86, 11024–11030 (2012).

    Article  CAS  Google Scholar 

  12. Victoria, J.G. et al. Metagenomic analyses of viruses in stool samples from children with acute flaccid paralysis. J. Virol. 83, 4642–4651 (2009).

    Article  CAS  Google Scholar 

  13. Naccache, S.N. et al. A cloud-compatible bioinformatics pipeline for ultrarapid pathogen identification from next-generation sequencing of clinical samples. Genome Res. 24, 1180–1192 (2014).

    Article  CAS  Google Scholar 

  14. Rodriguez-Otero, P. et al. Fecal calprotectin and alpha-1 antitrypsin predict severity and response to corticosteroids in gastrointestinal graft-versus-host disease. Blood 119, 5909–5917 (2012).

    Article  CAS  Google Scholar 

  15. Alhabbab, R. et al. Diversity of gut microflora is required for the generation of B cell with regulatory properties in a skin graft model. Sci. Rep. 5, 11554 (2015).

    Article  CAS  Google Scholar 

  16. Mathewson, N.D. et al. Gut microbiome-derived metabolites modulate intestinal epithelial cell damage and mitigate graft-versus-host disease. Nat. Immunol. 17, 505–513 (2016).

    Article  CAS  Google Scholar 

  17. Kim, K.S. et al. Dietary antigens limit mucosal immunity by inducing regulatory T cells in the small intestine. Science 351, 858–863 (2016).

    Article  CAS  Google Scholar 

  18. Ganesh, B. et al. Picobirnavirus infections: viral persistence and zoonotic potential. Rev. Med. Virol. 22, 245–256 (2012).

    Article  CAS  Google Scholar 

  19. Bányai, K. et al. Sequence heterogeneity among human picobirnaviruses detected in a gastroenteritis outbreak. Arch. Virol. 148, 2281–2291 (2003).

    Article  Google Scholar 

  20. Bhattacharya, R. et al. Molecular epidemiology of human picobirnaviruses among children of a slum community in Kolkata, India. Infect. Genet. Evol. 6, 453–458 (2006).

    Article  CAS  Google Scholar 

  21. van Leeuwen, M. et al. Human picobirnaviruses identified by molecular screening of diarrhea samples. J. Clin. Microbiol. 48, 1787–1794 (2010).

    Article  CAS  Google Scholar 

  22. Grohmann, G.S. et al. Enteric viruses and diarrhea in HIV-infected patients. N. Engl. J. Med. 329, 14–20 (1993).

    Article  CAS  Google Scholar 

  23. Tamura, K., Stecher, G., Peterson, D., Filipski, A. & Kumar, S. MEGA6: Molecular evolutionary genetics analysis version 6.0. Mol. Biol. Evol. 30, 2725–2729 (2013).

    Article  CAS  Google Scholar 

  24. Bhattacharya, R. et al. Detection of Genogroup I and II human picobirnaviruses showing small genomic RNA profile causing acute watery diarrhoea among children in Kolkata, India. Infect. Genet. Evol. 7, 229–238 (2007).

    Article  CAS  Google Scholar 

  25. Masachessi, G. et al. Maintenance of picobirnavirus (PBV) infection in an adult orangutan (Pongo pygmaeus) and genetic diversity of excreted viral strains during a three-year period. Infect. Genet. Evol. 29, 196–202 (2015).

    Article  Google Scholar 

  26. Smits, S.L. et al. New viruses in idiopathic human diarrhea cases, the Netherlands. Emerg. Infect. Dis. 20, 1218–1222 (2014).

    Article  Google Scholar 

  27. Glucksberg, H. et al. Clinical manifestations of graft-versus-host disease in human recipients of marrow from HL-A-matched sibling donors. Transplantation 18, 295–304 (1974).

    Article  CAS  Google Scholar 

  28. Przepiorka, D. et al. 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant. 15, 825–828 (1995).

    CAS  PubMed  Google Scholar 

  29. Abraham, J. et al. Clinical severity scores in gastrointestinal graft-versus-host disease. Transplantation 97, 965–971 (2014).

    CAS  PubMed  Google Scholar 

  30. O'Meara, A. et al. Fecal calprotectin and α1-antitrypsin dynamics in gastrointestinal GvHD. Bone Marrow Transplant. 50, 1105–1109 (2015).

    Article  CAS  Google Scholar 

  31. Kleiner, M., Hooper, L.V. & Duerkop, B.A. Evaluation of methods to purify virus-like particles for metagenomic sequencing of intestinal viromes. BMC Genomics 16, 7 (2015).

    Article  Google Scholar 

  32. Li, L. et al. Comparing viral metagenomics methods using a highly multiplexed human viral pathogens reagent. J. Virol. Methods 213, 139–146 (2015).

    Article  CAS  Google Scholar 

  33. Chen, E.C., Miller, S.A., DeRisi, J.L. & Chiu, C.Y. Using a pan-viral microarray assay (Virochip) to screen clinical samples for viral pathogens. J. Vis. Exp. 50, 2536 (2011).

    Google Scholar 

  34. Zaharia, M. et al. Faster and more accurate sequence alignment with SNAP. Preprint at arXiv https://arxiv.org/abs/1111.5572 (2011).

  35. Zhao, Y., Tang, H. & Ye, Y. RAPSearch2: a fast and memory-efficient protein similarity search tool for next-generation sequencing data. Bioinformatics 28, 125–126 (2012).

    Article  CAS  Google Scholar 

  36. Lan, Y., Wang, Q., Cole, J.R. & Rosen, G.L. Using the RDP classifier to predict taxonomic novelty and reduce the search space for finding novel organisms. PLoS One 7, e32491 (2012).

    Article  CAS  Google Scholar 

  37. You, F.M. et al. BatchPrimer3: a high throughput web application for PCR and sequencing primer design. BMC Bioinformatics 9, 253 (2008).

    Article  Google Scholar 

  38. Langmead, B. & Salzberg, S.L. Fast gapped-read alignment with Bowtie 2. Nat. Methods 9, 357–359 (2012).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This study was supported by a research grant from Abbott Laboratories to C.Y.C. We would also like to acknowledge funding from the US–France Fulbright Commission, Foundation Monahan and Foundation Phillippe for funding J.L. for a research sabbatical year to perform this research.

Author information

Author notes

  1. Gérard Socié and Charles Y Chiu: These authors contributed equally to this work.

Authors and Affiliations

  1. University of Paris Diderot, Sorbonne Paris Cité, Inserm U941, Microbiology Laboratory, Hôpital Saint-Louis, APHP, Paris, France

    Jérôme Legoff, Séverine Mercier-Delarue & François Simon

  2. UCSF-Abbott Viral Diagnostics and Discovery Center, San Francisco, California, USA

    Jérôme Legoff, Jerome Bouquet, Samia N Naccache, Scot Federman, Erik Samayoa & Charles Y Chiu

  3. University of Paris Diderot, Sorbonne Paris Cité, Inserm U1153, ECSTRA Team, Biostatistics Unit, APHP, Hôpital Saint-Louis, Paris, France

    Matthieu Resche-Rigon & Prescillia Piron

  4. Department of Laboratory Medicine, University of California, San Francisco, California, USA

    Jerome Bouquet, Samia N Naccache, Scot Federman, Erik Samayoa & Charles Y Chiu

  5. University of Paris Descartes, EA4065, Microbiology Laboratory, Hôpital Saint-Louis, APHP, Paris, France

    Marie Robin & Clotilde Rousseau

  6. Laboratoire de Coprologie Fonctionnelle, APHP, GH Pitié-Salpêtrière Charles Foix, EA4065, Université Paris Descartes, Paris, France

    Nathalie Kapel

  7. University of Paris Diderot, Sorbonne Paris Cité, Paris, France, and Hematology and Transplantation, INSERM Unité Mixte de Recherche Scientifique 1160, Paris, France

    Gérard Socié

  8. Department of Medicine, Division of Infectious Diseases, University of California, San Francisco, California, USA

    Charles Y Chiu

Authors
  1. Jérôme Legoff
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Matthieu Resche-Rigon
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jerome Bouquet
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Marie Robin
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Samia N Naccache
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Séverine Mercier-Delarue
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Scot Federman
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Erik Samayoa
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Clotilde Rousseau
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Prescillia Piron
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Nathalie Kapel
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. François Simon
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Gérard Socié
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Charles Y Chiu
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

J.L. conceived of the study, performed the experiments, analyzed the data, designed the figures and wrote the manuscript. M.R.-R. performed the statistical analyses and designed the figures. J.B. ran PCR confirmation for picobirnaviruses and analyzed the data. M.R. collected clinical data. S.M.-D., prepared patient samples for virome analysis and microbiome analysis. S.N.N., S.F. and E.S. contributed to the analysis of patient, microbiome and virome data. C.R. and N.K. contributed to the analysis of microbiome and stool biomarkers. P.P. contributed to statistical analysis. F.S. provided funding and resources and contributed to the discussion. G.S. conceived of the study, analyzed the data and wrote the manuscript. C.Y.C. conceived of the study, analyzed the data, designed the figures and wrote the manuscript. All authors provided feedback on the manuscript. F.S., G.S., J.L. and C.Y.C. supervised the project. J.L. and C.Y.C. secured funding for the study.

Corresponding author

Correspondence to Charles Y Chiu.

Ethics declarations

Competing interests

C.Y.C. is the director of the UCSF–Abbott Viral Diagnostics and Discovery Center and receives research support from Abbott Laboratories.

Supplementary information

Supplementary Text, Tables and Figures

Supplementary Results, Supplementary Tables 1–11 and Supplementary Figures 1–4 (PDF 1303 kb)

Life Sciences Reporting Summary (PDF 158 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Legoff, J., Resche-Rigon, M., Bouquet, J. et al. The eukaryotic gut virome in hematopoietic stem cell transplantation: new clues in enteric graft-versus-host disease. Nat Med 23, 1080–1085 (2017). https://doi.org/10.1038/nm.4380

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm.4380

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing