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Proc Natl Acad Sci U S A. 2017 Jul 25;114(30):E6166-E6175. doi: 10.1073/pnas.1706359114. Epub 2017 Jul 10.

Intestinal virome changes precede autoimmunity in type I diabetes-susceptible children.

Author information

1
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110; gzhao@wustl.edu virgin@wustl.edu.
2
Infectious Disease and Microbiome Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142.
3
Department of Information and Computer Science, Aalto University School of Science, 02150 Espoo, Finland.
4
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110.
5
Children's Hospital, University of Helsinki and Helsinki University Central Hospital, 00290 Helsinki, Finland.
6
Research Programs Unit, Diabetes and Obesity, University of Helsinki, 00290 Helsinki, Finland.
7
Jorvi Hospital, Helsinki Hospital, 02740 Espoo, Finland.
8
Children's Clinic of Tartu University Hospital, 50406 Tartu, Estonia.
9
Department of Pediatrics, University of Tartu, 50090 Tartu, Estonia.
10
Immunogenetics Laboratory, University of Turku and Turku University Hospital, FI-20520 Turku, Finland.
11
Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110.
12
Folkhälsan Research Center, 00290 Helsinki, Finland.
13
Tampere Center for Child Health Research, Tampere University Hospital, 33520 Tampere, Finland.
14
Center for Computational and Integrative Biology and Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114.

Abstract

Viruses have long been considered potential triggers of autoimmune diseases. Here we defined the intestinal virome from birth to the development of autoimmunity in children at risk for type 1 diabetes (T1D). A total of 220 virus-enriched preparations from serially collected fecal samples from 11 children (cases) who developed serum autoantibodies associated with T1D (of whom five developed clinical T1D) were compared with samples from controls. Intestinal viromes of case subjects were less diverse than those of controls. Among eukaryotic viruses, we identified significant enrichment of Circoviridae-related sequences in samples from controls in comparison with cases. Enterovirus, kobuvirus, parechovirus, parvovirus, and rotavirus sequences were frequently detected but were not associated with autoimmunity. For bacteriophages, we found higher Shannon diversity and richness in controls compared with cases and observed that changes in the intestinal virome over time differed between cases and controls. Using Random Forests analysis, we identified disease-associated viral bacteriophage contigs after subtraction of age-associated contigs. These disease-associated contigs were statistically linked to specific components of the bacterial microbiome. Thus, changes in the intestinal virome preceded autoimmunity in this cohort. Specific components of the virome were both directly and inversely associated with the development of human autoimmune disease.

KEYWORDS:

Circoviridae; bacteriophages; microbiome; type 1 diabetes; virome

PMID:
28696303
PMCID:
PMC5544325
DOI:
10.1073/pnas.1706359114
[Indexed for MEDLINE]
Free PMC Article

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