TY - JOUR
T1 - The human gut microbiome in early-onset type 1 diabetes from the TEDDY study
AU - Vatanen, Tommi
AU - Franzosa, Eric A.
AU - Schwager, Randall
AU - Tripathi, Surya
AU - Arthur, Timothy D.
AU - Vehik, Kendra
AU - Lernmark, Åke
AU - Hagopian, William A.
AU - Rewers, Marian J.
AU - She, Jin-Xiong
AU - Toppari, Jorma
AU - Ziegler, Anette G.
AU - Akolkar, Beena
AU - Krischer, Jeffrey P.
AU - Stewart, Christopher J.
AU - Ajami, Nadim J.
AU - Petrosino, Joseph F.
AU - Gevers, Dirk
AU - Lähdesmäki, Harri
AU - Vlamakis, Hera
AU - Huttenhower, Curtis
AU - Xavier, Ramnik J.
N1 - Funding Information:
Acknowledgements This research was performed on behalf of the TEDDY Study Group, which is funded by U01 DK63829, U01 DK63861, U01 DK63821, U01 DK63865, U01 DK63863, U01 DK63836, U01 DK63790, UC4 DK63829, UC4 DK63861, UC4 DK63821, UC4 DK63865, UC4 DK63863, UC4 DK63836, UC4 DK95300, UC4 DK100238, UC4 DK106955, UC4 DK112243, UC4 DK117483, and contract no. HHSN267200700014C from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institute of Allergy and Infectious Diseases (NIAID), National Institute of Child Health and Human Development (NICHD), National Institute of Environmental Health Sciences (NIEHS), Centers for Disease Control and Prevention (CDC), and JDRF. This work supported in part by the NIH/NCATS Clinical and Translational Science Awards to the University of Florida (UL1 TR000064) and the University of Colorado (UL1 TR001082). C.H. was supported by funding from JDRF (3-SRA-2016-141-Q-R) and NIDDK (U54DE023798, R24DK110499). H.V. and R.J.X. were supported by funding from JDRF (2-SRA-2016-247-S-B, 2-SRA-2018-548-S-B).
Funding Information:
Cohort and study design. TEDDY is a prospective cohort study funded by the National Institutes of Health with the primary goal to identify environmental causes of T1D. It includes six clinical research centres—three in the United States (Colorado, Georgia/Florida, Washington) and three in Europe (Finland, Germany and Sweden). Detailed study design and methods have been previously published28,41,42. Written informed consents were obtained for all study participants from a parent or primary caretaker, separately, for genetic screening and participation in a prospective follow-up. The TEDDY study was approved by local US Institutional Review Boards and European Ethics Committee Boards in Colorado’s Colorado Multiple Institutional Review Board, Georgia’s Medical College of Georgia Human Assurance Committee (2004–2010), Georgia Health Sciences University Human Assurance Committee (2011–2012), Georgia Regents University Institutional Review Board (2013–2015), Augusta University Institutional Review Board (2015–present), Florida’s University of Florida Health Center Institutional Review Board, Washington state’s Washington State Institutional Review Board (2004–2012) and Western Institutional Review Board (2013–present), Finland’s Ethics Committee of the Hospital District of Southwest Finland, Germany’s Bayerischen Landesärztekammer (Bavarian Medical Association) Ethics Committee, Sweden’s Regional Ethics Board in Lund, Section 2 (2004–2012) and Lund University Committee for Continuing Ethical Review (2013–present). The study is monitored by External Advisory Board formed by the National Institutes of Health.
Publisher Copyright:
© 2018, Springer Nature Limited.
PY - 2018/10/25
Y1 - 2018/10/25
N2 - Type 1 diabetes (T1D) is an autoimmune disease that targets pancreatic islet beta cells and incorporates genetic and environmental factors1, including complex genetic elements2, patient exposures3 and the gut microbiome4. Viral infections5 and broader gut dysbioses6 have been identified as potential causes or contributing factors; however, human studies have not yet identified microbial compositional or functional triggers that are predictive of islet autoimmunity or T1D. Here we analyse 10,913 metagenomes in stool samples from 783 mostly white, non-Hispanic children. The samples were collected monthly from three months of age until the clinical end point (islet autoimmunity or T1D) in the The Environmental Determinants of Diabetes in the Young (TEDDY) study, to characterize the natural history of the early gut microbiome in connection to islet autoimmunity, T1D diagnosis, and other common early life events such as antibiotic treatments and probiotics. The microbiomes of control children contained more genes that were related to fermentation and the biosynthesis of short-chain fatty acids, but these were not consistently associated with particular taxa across geographically diverse clinical centres, suggesting that microbial factors associated with T1D are taxonomically diffuse but functionally more coherent. When we investigated the broader establishment and development of the infant microbiome, both taxonomic and functional profiles were dynamic and highly individualized, and dominated in the first year of life by one of three largely exclusive Bifidobacterium species (B. bifidum, B. breve or B. longum) or by the phylum Proteobacteria. In particular, the strain-specific carriage of genes for the utilization of human milk oligosaccharide within a subset of B. longum was present specifically in breast-fed infants. These analyses of TEDDY gut metagenomes provide, to our knowledge, the largest and most detailed longitudinal functional profile of the developing gut microbiome in relation to islet autoimmunity, T1D and other early childhood events. Together with existing evidence from human cohorts7,8 and a T1D mouse model9, these data support the protective effects of short-chain fatty acids in early-onset human T1D.
AB - Type 1 diabetes (T1D) is an autoimmune disease that targets pancreatic islet beta cells and incorporates genetic and environmental factors1, including complex genetic elements2, patient exposures3 and the gut microbiome4. Viral infections5 and broader gut dysbioses6 have been identified as potential causes or contributing factors; however, human studies have not yet identified microbial compositional or functional triggers that are predictive of islet autoimmunity or T1D. Here we analyse 10,913 metagenomes in stool samples from 783 mostly white, non-Hispanic children. The samples were collected monthly from three months of age until the clinical end point (islet autoimmunity or T1D) in the The Environmental Determinants of Diabetes in the Young (TEDDY) study, to characterize the natural history of the early gut microbiome in connection to islet autoimmunity, T1D diagnosis, and other common early life events such as antibiotic treatments and probiotics. The microbiomes of control children contained more genes that were related to fermentation and the biosynthesis of short-chain fatty acids, but these were not consistently associated with particular taxa across geographically diverse clinical centres, suggesting that microbial factors associated with T1D are taxonomically diffuse but functionally more coherent. When we investigated the broader establishment and development of the infant microbiome, both taxonomic and functional profiles were dynamic and highly individualized, and dominated in the first year of life by one of three largely exclusive Bifidobacterium species (B. bifidum, B. breve or B. longum) or by the phylum Proteobacteria. In particular, the strain-specific carriage of genes for the utilization of human milk oligosaccharide within a subset of B. longum was present specifically in breast-fed infants. These analyses of TEDDY gut metagenomes provide, to our knowledge, the largest and most detailed longitudinal functional profile of the developing gut microbiome in relation to islet autoimmunity, T1D and other early childhood events. Together with existing evidence from human cohorts7,8 and a T1D mouse model9, these data support the protective effects of short-chain fatty acids in early-onset human T1D.
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U2 - 10.1038/s41586-018-0620-2
DO - 10.1038/s41586-018-0620-2
M3 - Article
C2 - 30356183
AN - SCOPUS:85055415843
SN - 0028-0836
VL - 562
SP - 589
EP - 594
JO - Nature
JF - Nature
IS - 7728
ER -