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

Summary

Type 1 diabetes (T1D) is an autoimmune disease targeting pancreatic islet beta cells that 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 predictive of islet autoimmunity (IA) or T1D. We analyzed 10,913 metagenomes from 783 mostly white, non-hispanic children’s stool samples collected monthly from three months of age until the clinical end point (IA or T1D) in the TEDDY (The Environmental Determinants of Diabetes in the Young) study to characterize the natural history of the early gut microbiome in connection to IA, T1D diagnosis, and other common early life events such as antibiotic treatments and probiotics. Microbiomes of control children harbored more genes related to fermentation and short chain fatty acid (SCFA) biosynthesis, but these were not consistently associated with particular taxa across geographically diverse clinical centers, suggesting that microbial factors associated with T1D are taxonomically diffuse but functionally coherent. When investigating the broader establishment and development of the infant microbiome, both taxonomic and functional profiles were dynamic and highly individualized, 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, strain-specific carriage of human milk oligosaccharide utilization genes within a subset of Bifidobacterium longum was present specifically in breast-fed infants. These analyses of TEDDY gut metagenomes provide, to date, the largest and most detailed longitudinal functional profile of the developing gut microbiome in relation to IA, T1D, and other early childhood events. Together with existing evidence from human cohorts ^{7, 8} and T1D mouse model ⁹ , these data support the protective effects of SCFAs on early-onset human T1D.