Infant Microbiome Develops in Three Stages

By now, we know that the microbiome is important. But, despite all of the attention, exactly what role our commensal bacteria play in human disease remains largely unknown. Two papers were published back-to-back in Nature, the largest clinical microbiome studies done to date, that are trying to answer this question.

In one study, titled “Temporal development of the gut microbiome in early childhood from the TEDDY study,” a team of researchers led by Joseph Petrosino, Ph.D., professor at the Baylor College of Medicine, utilized the dataset available through The Environmental Determinants of Diabetes in the Young (TEDDY) study. The aim of this study is to determine what triggers type 1 diabetes in children at increased genetic risk for the disease.

Sequencing from 12,500 stool samples of 903 children, the team determined that the developing gut microbiome undergoes three distinct phases of microbiome progression: developmental phase (3–14 months of age), transitional phase (15–30 months of age), and stable phase (31–46 months of age.)

“This information is useful for any future microbiome studies looking at an infant cohort for scientific discovery and potential intervention purposes. The idea that we can stratify the development phases in this manner may give researchers additional resolution to reveal differences that could potentially be disease-associated,” Dr. Petrosino says.

Although the overall implications on health still remain unknown, the study found that “receipt of breast milk, either exclusive or partial, was the most significant factor associated with the microbiome structure.” They found an association between at least partial breastfeeding and having a higher abundance of Bifidobacterium breve and Bifidobacterium bifidum. In addition, the cessation of breastfeeding accelerated the maturation of the infant’s microbiome, meaning it proceeded quickly through the other stages to the stable phase, which is hallmarked by higher amounts of the bacteria Firmicutes spp.

“These initial analyses have reinforced previous infant studies and also have revealed additional important microbiome associations during this critical time in life. Future discoveries from this cohort will pave the way for focused mechanistic work to elucidate how the microbiome influences health and disease, particularly type 1 diabetes,” says Christopher Stewart, Ph.D., research fellow at Newcastle University and co-first author of the study.

The TEDDY study includes six clinical research centers in the U.S. and Europe, and has enrolled several thousand newborns with a genetic predisposition for Type 1 Diabetes (T1D) or a first degree relative with T1D. The study allows characterization of microbial, genetic, environmental, immunological, and other factors that may contribute to T1D.

Gut bacteria have been recently linked to the onset of T1D with findings that include increased numbers of Bacteroides species and decreased numbers of bacteria that produce short-chain fatty acids (SCFAs.)

The second paper published in Nature, titled “The human gut microbiome in early-onset type 1 diabetes from the TEDDY study,” was an almost equally large analysis of stool samples that analyzed 10,913 metagenomes in stool samples from 783 children enrolled in the TEDDY study. The samples were collected monthly from three months of age until the clinical endpoint (islet autoimmunity or T1D) 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 research team, led by Ramnik Xavier, M.D., professor of medicine at Harvard Medical School and core institute member of the Broad Institute, found that microbiomes of control children contained more genes that were related to fermentation and the biosynthesis of short-chain fatty acids, even though the type of bacteria varied. This suggests that the function of making short-chain fatty acids may be more important in providing a protective effect in early-onset T1D than the specific type of bacteria.

The authors write that, “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.)” 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.

Taken together, these analyses of TEDDY gut metagenomes are the largest and most detailed longitudinal functional profiles of the developing gut microbiome in relation to islet autoimmunity, T1D, and other early childhood events, and provide a foundation for future work in the role of the microbiome in disease.