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.
Subscribe to Journal
Get full journal access for 1 year
only $4.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
De Vlaminck, I. et al. Temporal response of the human virome to immunosuppression and antiviral therapy. Cell 155, 1178–1187 (2013).
Norman, J.M. et al. Disease-specific alterations in the enteric virome in inflammatory bowel disease. Cell 160, 447–460 (2015).
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).
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).
Zerr, D.M. et al. HHV-6 reactivation and associated sequelae after hematopoietic cell transplantation. Biol. Blood Marrow Transplant. 18, 1700–1708 (2012).
Jenq, R.R. et al. Regulation of intestinal inflammation by microbiota following allogeneic bone marrow transplantation. J. Exp. Med. 209, 903–911 (2012).
Minot, S. et al. The human gut virome: inter-individual variation and dynamic response to diet. Genome Res. 21, 1616–1625 (2011).
Schwartz, S. et al. Norovirus gastroenteritis causes severe and lethal complications after chemotherapy and hematopoietic stem cell transplantation. Blood 117, 5850–5856 (2011).
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).
Finkbeiner, S.R. et al. Metagenomic analysis of human diarrhea: viral detection and discovery. PLoS Pathog. 4, e1000011 (2008).
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).
Victoria, J.G. et al. Metagenomic analyses of viruses in stool samples from children with acute flaccid paralysis. J. Virol. 83, 4642–4651 (2009).
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).
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).
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).
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).
Kim, K.S. et al. Dietary antigens limit mucosal immunity by inducing regulatory T cells in the small intestine. Science 351, 858–863 (2016).
Ganesh, B. et al. Picobirnavirus infections: viral persistence and zoonotic potential. Rev. Med. Virol. 22, 245–256 (2012).
Bányai, K. et al. Sequence heterogeneity among human picobirnaviruses detected in a gastroenteritis outbreak. Arch. Virol. 148, 2281–2291 (2003).
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).
van Leeuwen, M. et al. Human picobirnaviruses identified by molecular screening of diarrhea samples. J. Clin. Microbiol. 48, 1787–1794 (2010).
Grohmann, G.S. et al. Enteric viruses and diarrhea in HIV-infected patients. N. Engl. J. Med. 329, 14–20 (1993).
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).
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).
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).
Smits, S.L. et al. New viruses in idiopathic human diarrhea cases, the Netherlands. Emerg. Infect. Dis. 20, 1218–1222 (2014).
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).
Przepiorka, D. et al. 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant. 15, 825–828 (1995).
Abraham, J. et al. Clinical severity scores in gastrointestinal graft-versus-host disease. Transplantation 97, 965–971 (2014).
O'Meara, A. et al. Fecal calprotectin and α1-antitrypsin dynamics in gastrointestinal GvHD. Bone Marrow Transplant. 50, 1105–1109 (2015).
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).
Li, L. et al. Comparing viral metagenomics methods using a highly multiplexed human viral pathogens reagent. J. Virol. Methods 213, 139–146 (2015).
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).
Zaharia, M. et al. Faster and more accurate sequence alignment with SNAP. Preprint at arXiv https://arxiv.org/abs/1111.5572 (2011).
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).
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).
You, F.M. et al. BatchPrimer3: a high throughput web application for PCR and sequencing primer design. BMC Bioinformatics 9, 253 (2008).
Langmead, B. & Salzberg, S.L. Fast gapped-read alignment with Bowtie 2. Nat. Methods 9, 357–359 (2012).
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.
C.Y.C. is the director of the UCSF–Abbott Viral Diagnostics and Discovery Center and receives research support from Abbott Laboratories.
About this article
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
Detection of multiple viruses potentially infecting humans in sewage water from Xinjiang Uygur Autonomous Region, China
Science of The Total Environment (2021)
Integrative Transkingdom Analysis of the Gut Microbiome in Antibiotic Perturbation and Critical Illness
Frontiers in Immunology (2021)
Inflammation Research (2021)
IL-22-dependent dysbiosis and mononuclear phagocyte depletion contribute to steroid-resistant gut graft-versus-host disease in mice
Nature Communications (2021)