The human gut microbiome in early-onset type 1 diabetes from the TEDDY study

Tommi Vatanen, Eric A. Franzosa, Randall Schwager, Surya Tripathi, Timothy D. Arthur, Kendra Vehik, Åke Lernmark, William A. Hagopian, Marian J. Rewers, Jin-Xiong She, Jorma Toppari, Anette G. Ziegler, Beena Akolkar, Jeffrey P. Krischer, Christopher J. Stewart, Nadim J. Ajami, Joseph F. Petrosino, Dirk Gevers, Harri Lähdesmäki, Hera VlamakisCurtis Huttenhower, Ramnik J. Xavier

Research output: Contribution to journalLetter

54 Citations (Scopus)

Abstract

Type 1 diabetes (T1D) is an autoimmune disease that targets pancreatic islet beta cells and incorporates genetic and environmental factors 1 , including complex genetic elements 2 , patient exposures 3 and the gut microbiome 4 . Viral infections 5 and broader gut dysbioses 6 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 cohorts 7,8 and a T1D mouse model 9 , these data support the protective effects of short-chain fatty acids in early-onset human T1D.

Original languageEnglish (US)
Pages (from-to)589-594
Number of pages6
JournalNature
Volume562
Issue number7728
DOIs
StatePublished - Oct 25 2018

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Microbiota
Type 1 Diabetes Mellitus
Autoimmunity
Metagenome
Volatile Fatty Acids
Islets of Langerhans
Proteobacteria
Bifidobacterium
Gastrointestinal Microbiome
Probiotics
Insulin-Secreting Cells
Human Milk
Virus Diseases
Child Development
Natural History
Oligosaccharides
Genes
Autoimmune Diseases
Fermentation
Breast

ASJC Scopus subject areas

  • General

Cite this

Vatanen, T., Franzosa, E. A., Schwager, R., Tripathi, S., Arthur, T. D., Vehik, K., ... Xavier, R. J. (2018). The human gut microbiome in early-onset type 1 diabetes from the TEDDY study. Nature, 562(7728), 589-594. https://doi.org/10.1038/s41586-018-0620-2

The human gut microbiome in early-onset type 1 diabetes from the TEDDY study. / Vatanen, Tommi; Franzosa, Eric A.; Schwager, Randall; Tripathi, Surya; Arthur, Timothy D.; Vehik, Kendra; Lernmark, Åke; Hagopian, William A.; Rewers, Marian J.; She, Jin-Xiong; Toppari, Jorma; Ziegler, Anette G.; Akolkar, Beena; Krischer, Jeffrey P.; Stewart, Christopher J.; Ajami, Nadim J.; Petrosino, Joseph F.; Gevers, Dirk; Lähdesmäki, Harri; Vlamakis, Hera; Huttenhower, Curtis; Xavier, Ramnik J.

In: Nature, Vol. 562, No. 7728, 25.10.2018, p. 589-594.

Research output: Contribution to journalLetter

Vatanen, T, Franzosa, EA, Schwager, R, Tripathi, S, Arthur, TD, Vehik, K, Lernmark, Å, Hagopian, WA, Rewers, MJ, She, J-X, Toppari, J, Ziegler, AG, Akolkar, B, Krischer, JP, Stewart, CJ, Ajami, NJ, Petrosino, JF, Gevers, D, Lähdesmäki, H, Vlamakis, H, Huttenhower, C & Xavier, RJ 2018, 'The human gut microbiome in early-onset type 1 diabetes from the TEDDY study', Nature, vol. 562, no. 7728, pp. 589-594. https://doi.org/10.1038/s41586-018-0620-2
Vatanen T, Franzosa EA, Schwager R, Tripathi S, Arthur TD, Vehik K et al. The human gut microbiome in early-onset type 1 diabetes from the TEDDY study. Nature. 2018 Oct 25;562(7728):589-594. https://doi.org/10.1038/s41586-018-0620-2
Vatanen, Tommi ; Franzosa, Eric A. ; Schwager, Randall ; Tripathi, Surya ; Arthur, Timothy D. ; Vehik, Kendra ; Lernmark, Åke ; Hagopian, William A. ; Rewers, Marian J. ; She, Jin-Xiong ; Toppari, Jorma ; Ziegler, Anette G. ; Akolkar, Beena ; Krischer, Jeffrey P. ; Stewart, Christopher J. ; Ajami, Nadim J. ; Petrosino, Joseph F. ; Gevers, Dirk ; Lähdesmäki, Harri ; Vlamakis, Hera ; Huttenhower, Curtis ; Xavier, Ramnik J. / The human gut microbiome in early-onset type 1 diabetes from the TEDDY study. In: Nature. 2018 ; Vol. 562, No. 7728. pp. 589-594.
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AU - Vehik, Kendra

AU - Lernmark, Åke

AU - Hagopian, William A.

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AU - She, Jin-Xiong

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AU - Akolkar, Beena

AU - Krischer, Jeffrey P.

AU - Stewart, Christopher J.

AU - Ajami, Nadim J.

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AU - Lähdesmäki, Harri

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N2 - Type 1 diabetes (T1D) is an autoimmune disease that targets pancreatic islet beta cells and incorporates genetic and environmental factors 1 , including complex genetic elements 2 , patient exposures 3 and the gut microbiome 4 . Viral infections 5 and broader gut dysbioses 6 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 cohorts 7,8 and a T1D mouse model 9 , these data support the protective effects of short-chain fatty acids in early-onset human T1D.

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