Abstract
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.
Highlights
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 diseases[1,2,3,4,5,6,7,8,9] such as persistent islet autoimmunity and type 1 diabetes[10,11,12]
We show that the developing gut microbiome undergoes three distinct phases of microbiome progression: a developmental phase, a transitional phase, and a stable phase
A companion paper by Vatanen et al.[14] focused exclusively on metagenomic sequencing data. In this cohort of children that are at-risk for developing islet autoimmunity (IA) or type 1 diabetes (T1D), we aimed to (1) characterize definitively the longitudinal gut microbiome development from 3 to 46 months of age; (2) determine selected maternal and postnatal influences on the developing bacterial community during this same time period of early development; and (3) use a nested case–control analysis to investigate the potential of the microbiome as a predictor for the development of IA or T1D
Summary
Metagenomic sequencing taxa (species level), and functional metabolic capacity (Kyoto encyclopedia of genes and genomes (KEGG) modules) (Supplementary Table 1). Several covariates were significantly associated with the genus and species level bacterial community profiles between months 3 and 18 of age, at the first time point of 3 to 6 months (Fig. 2). In the companion manuscript by Vatanen et al.[14], most B. longum strains were found to contain genes from the human milk oligosaccharide (HMO) gene cluster, whereas after the cessation of breast milk, most B. longum strains no longer carried these genes This potentially reflects the ability of B. longum subsp. Vatanen et al.[14] show experimentally that B. breve, B. longum and B. bifidum, which make up DMM clusters 1–3 (Extended Data Fig. 2), have distinct profiles of sugar utilization, suggesting that the different nutrient availability between infants can promote the colonization of specific Bifidobacterium species. The Shannon diversity index between infants receiving some breast milk and infants no longer receiving breast milk began to converge over time, probably as a result of a reduced proportion of breast milk in the
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