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

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 cohorts^7,8 and a T1D mouse model⁹, these data support the protective effects of short-chain fatty acids in early-onset human T1D.

SUBMITTER: Vatanen T

PROVIDER: S-EPMC6296767 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The development of the microbiome from infancy to childhood is dependent on a range of factors, with microbial-immune crosstalk during this time thought to be involved in the pathobiology of later life diseases1-9 such as persistent islet autoimmunity and type 1 diabetes10-12. However, to our knowledge, no studies have performed extensive characterization of the microbiome in early life in a large, multi-centre population. Here we analyse longitudinal stool samples from 903 children between 3 and 46 months of age by 16S rRNA gene sequencing (n = 12,005) and metagenomic sequencing (n = 10,867), as part of the The Environmental Determinants of Diabetes in the Young (TEDDY) study. We show that the developing gut microbiome undergoes three distinct phases of microbiome progression: a developmental phase (months 3-14), a transitional phase (months 15-30), and a stable phase (months 31-46). Receipt of breast milk, either exclusive or partial, was the most significant factor associated with the microbiome structure. Breastfeeding was associated with higher levels of Bifidobacterium species (B. breve and B. bifidum), and the cessation of breast milk resulted in faster maturation of the gut microbiome, as marked by the phylum Firmicutes. Birth mode was also significantly associated with the microbiome during the developmental phase, driven by higher levels of Bacteroides species (particularly B. fragilis) in infants delivered vaginally. Bacteroides was also associated with increased gut diversity and faster maturation, regardless of the birth mode. Environmental factors including geographical location and household exposures (such as siblings and furry pets) also represented important covariates. A nested case-control analysis revealed subtle associations between microbial taxonomy and the development of islet autoimmunity or type 1 diabetes. These data determine the structural and functional assembly of the microbiome in early life and provide a foundation for targeted mechanistic investigation into the consequences of microbial-immune crosstalk for long-term health.

Project description:INTRODUCTION:Diabetes remains a growing public health concern in Egypt, as prevalence of Type II diabetes (TIID) has nearly tripled there in the last two decades. Egypt was ranked ninth worldwide in number of diabetes cases, with prevalence of 15.56% among adults. Recent studies have proposed that disturbance of gut microbiota could influence TIID development and indicated associations between a reduced diversity in microbiomes and Type I diabetes (TID). In the present study, we investigated the composition and abundance of the bacterial microbiome in disease state (TID and TIID) of Egyptian patients. Our goal in this study was to characterize features of the gut microbiota and possible differences associated with TID and TIID in this population. METHODS:DNA was extracted from fecal samples taken from 22 TID and 18 TIID outpatients of Al-Hussein hospital, Cairo, Egypt. 16S rRNA amplicon sequencing was used to characterize the bacterial taxa and these reads were processed using the software mothur with analysis utilizing packages vegan, phyloseq and metagenomSeq in R. RESULTS AND CONCLUSIONS:Our results highlighted a significant increase in abundance of Gram negative, potentially opportunistic pathogenic taxa (Pseudomonas, Prevotella) in all diabetic groups, compared to the control. Lipopolysccharide (LPS), a component of the gram-negative bacterial wall, can activate local immune response and may result in low-grade systemic inflammation contributing to insulin resistance. The gram-positive Gemella, which is associated with increased risk to diabetes, also had a significant increase in abundance in all diabetic groups, compared to the control. In contrast, the commensal bacterial taxa Turicibacter, Terrisporobacter and Clostridium were found to be more abundant in the control group than in TID. Further studies are needed to understand the role of these taxa in health and disease. Lower Richness and low Shannon diversity, though not statistically significant, were observed for TID subjects with no glucose control and with onset of liver disease or hypertension compared to other subjects. In addition, large variation in alpha diversity within the control group could also be observed. Future studies will include larger samples sizes to further elucidate these findings, as well as possible metagenomic studies to examine the intriguing function of significant microbes.

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

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