How the infant gut microbiome shapes childhood allergic disease : data from the CHILD cohort study

Allergic diseases are typically characterized by a Type 2 immune response, where immune cells are sensitized to an innocuous antigen, often at a compromised epithelial barrier. Re-exposure to the antigen then leads to a pro-inflammatory response. Symptoms can include hives, airway constriction, and dizziness; when this reaction is severe, it can be life-threatening. Therefore, identifying ways to prevent allergic diseases is paramount. Studies demonstrate that microorganisms and their genes in the infant gut (known as the gut microbiome) are associated with childhood allergic diseases. This is thought to be because the expansion of the human immune system during infancy coincides with gut microbial colonization. The gut microbiome may influence epithelial barrier integrity, immune cell gene expression, and the inflammatory state of the gut, potentially priming the immune environment before sensitization. However, the underlying relationship between the gut microbiome and allergies remains unclear. Thus, I hypothesize that the early-life gut microbiome influences the development of allergic outcomes, and that by defining the structure of the early-life stool metagenome, metabolome, and mycobiome, we can predict and ultimately prevent the development of allergic disease. To test this hypothesis, I used shotgun metagenomic and internal transcribed spacer 2 (ITS2) amplicon sequencing, together with metabolomics, to identify early life gut microbiome signatures associated with allergic diseases in the large Canadian Healthy Infant Longitudinal Development (CHILD) study. I discovered that 1-year microbiota maturation was negatively associated with four distinct pediatric allergies. Specifically, a core set of functional imbalances mediated the relationship between 1-year microbiota maturation and 5-year allergic diagnoses (βindirect=−2.28; p=0.0020). Next, in investigating antibiotic-associated perturbation of the gut environment and its link to allergies, I revealed that antibiotics during the first year of life, as opposed to later, were associated with increased atopic dermatitis (AD) risk (p<0.001). Finally, fungi were reliable and consistent biomarkers of the developing gut and a persistently infant-like mycobiome was linked to childhood AD (p=0.007). In conclusion, this thesis suggests that the compositional and functional makeup of the infant gut microbiome can be used to describe microbiome development and provides insight into the associations between the microbiome and childhood allergic disease.

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