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

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.

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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.

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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.

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Authors

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.

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Competing interests

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

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

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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

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