Abstract
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.
Highlights
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]
Common findings include increased numbers of Bacteroides species, and deficiency of bacteria that produce short-chain fatty acids (SCFAs)[7,8] in cases of T1D or islet autoimmunity (IA)[8,11,15,18]. Corroborating these findings, decreased levels of SCFA-producing bacteria were found in adults with type 2 diabetes (T2D)[19]
Studies using the nonobese diabetic (NOD) mouse model have determined immune mechanisms that mediate the protective effects of SCFAs9 and the microbiome-linked sex bias in autoimmunity[20]
Summary
Additional metadata analysed for subjects and samples included the status of breastfeeding, birth mode, probiotics, antibiotics, formula feeding, and other dietary covariates. b, Overview of stool samples collected and microbiome development as summarized by Shannon’s alpha diversity and stratified by end point. Using cross-sectional analysis to test for associations between taxonomic beta diversities and other collected metadata, we found that in addition to subject ID and age, geographical location and breastfeeding had strong and systematic effects on the composition of the microbial community (Supplementary Table 1, Extended Data Fig. 2a–d, Supplementary Note 1). This suggests that the early life microbiome is relatively well-covered by current microbial reference genomes, less functional and biochemical characterization has been carried out on gene families within these microorganisms, which will benefit from future work. We observed that several bacterial pathways that contribute to the biosynthesis of short-chain fatty acids were increased in healthy controls
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