Temporal development of the gut microbiome in early childhood from the TEDDY study

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.

Environmental exposures and child and maternal gut microbiota in rural Malawi

“…Especially in early life while the microbiota is developing, changes in its composition can be influential and contribute to undernutrition in resource‐poor environments . The human gut changes considerably during the first 2 years of life as children progress from breast milk‐dominated diets and are exposed to greater numbers of bacterial species . Undernourished children have been reported to have gut microbiota that appear less mature than those of chronologically age‐matched healthy children .…”

The Environmental Determinants of Diabetes in the Young (TEDDY) Study: 2018 Update

“…These phases correlated with diet, especially with breast-feeding which was the most significant factor associated with the microbiome structure. While a number of factors were identified to determine the development of gut bacteriome in early childhood, no association was found with IA [62, 63]. However, genes mapping to bacterial fermentation pathways, including the production of short-chain fatty acids (SCFA), were decreased in cases of IA, supporting previously postulated protective effects of SCFA on early-onset human T1D.…”

Commentary: Microbial panaceas: does development have the answer? – reflections on Cowan, Dinan, & Cryan (2020)

“…Evidence now suggests that the microbiota–gut–brain axis continues to mature across middle childhood (Hollister et al, ) and into adolescence (Agans et al, ; Flannery et al, ). In the target review paper, Cowan and colleagues outline the multitude of factors within the developmental environment that are known to influence microbiota, including genetics (Goodrich et al, ; Rothschild et al, ), diet (Subramanian et al, ), mode of birth (Dominguez‐Bello et al, ; Stewart et al, ), and early environmental stress (Callaghan, Fields et al, ; D’Agata et al, ; Hantsoo et al, ). Though limited, together these data support the assertion that the microbiota, its structure and function, is fundamentally a developmental phenomenon.…”