TY - JOUR
T1 - Intestinal virome changes precede autoimmunity in type I diabetes-susceptible children
AU - Zhao, Guoyan
AU - Vatanen, Tommi
AU - Droit, Lindsay
AU - Park, Arnold
AU - Kostic, Aleksandar D.
AU - Poon, Tiffany W.
AU - Vlamakis, Hera
AU - Siljander, Heli
AU - Härkönen, Taina
AU - Hämäläinen, Anu Maaria
AU - Peet, Aleksandr
AU - Tillmann, Vallo
AU - Ilonen, Jorma
AU - Wang, David
AU - Knip, Mikael
AU - Xavier, Ramnik J.
AU - Virgin, Herbert W.
N1 - Funding Information:
We thank Brian Koebbe and Eric Martin from the High-Throughput Computing Facility at the Center for Genome Sciences and Systems Biology for providing high-throughput computational resources and support; Chuck Goss at the Division of Biostatistics, Washington University School of Medicine for statistics consultation (supported by UL1 TR000448 for an Institute of Clinical and Translational Sciences subsidized activity); Jessica Hoisington-Lopez from the DNA Sequencing Innovation Lab at the Center for Genome Sciences and Systems Biology for her sequencing expertise; and Dr. Scott A. Handley for his critical comments. This work was supported by Juvenile Diabetes Research Foundation Grant 2-SRA-2015-305-Q-R and National Institutes of Health Grants R01 DK101354, R24 OD019793, and R01 AI111918. T.V., A.D.K., and R.J.X. are supported by National Institutes of Health Grants DK43351, DK92405, and the Juvenile Diabetes Research Foundation. The DIABIMMUNE study was supported by the European Union Seventh Framework Programme (Grant 202063). M.K. was supported by the Academy of Finland (Centre of Excellence in Molecular Systems Immunology and Physiology Research, Grant 250114, 2012-17).
Publisher Copyright:
© 2017, National Academy of Sciences. All rights reserved.
PY - 2017/7/25
Y1 - 2017/7/25
N2 - 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.
AB - 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.
KW - Bacteriophages
KW - Circoviridae
KW - Microbiome
KW - Type 1 diabetes
KW - Virome
UR - http://www.scopus.com/inward/record.url?scp=85025599680&partnerID=8YFLogxK
U2 - 10.1073/pnas.1706359114
DO - 10.1073/pnas.1706359114
M3 - Article
C2 - 28696303
AN - SCOPUS:85025599680
SN - 0027-8424
VL - 114
SP - E6166-E6175
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 30
ER -