Infant gut fungal dysbiosis drives asthma onset and severity

Global asthma prevalence has reached epidemic proportions, emphasizing an urgent need for research into the causes of this burdensome and incurable early-onset disease. A growing body of evidence implicates the early life gut microbiota in immunomodulation relevant to asthma, and suggests that an imbalanced (dysbiotic) gut microbiota may precede disease onset. Notably, fungal communities of the infant gut microbiota (the mycobiota) are understudied, but have recently been shown in two birth cohorts to differ strikingly according to atopy/asthma risk in association with bacterial dysbiosis. I hypothesized that fungal dysbiosis in the infant gut contributes to asthma development through interactions with the host and immunomodulatory bacteria to alter key early-life immune mechanisms involved in this disease. To address this hypothesis, I first generated additional evidence supporting associations between bacterial dysbiosis at three months of age with atopic outcomes in Canadian children from the CHILD Cohort Study. I then examined the fungal communities of the gut microbiota in these infants at three months and one year of age and characterized features of early life gut fungal dysbiosis associated with atopic disease outcomes at age five years. Replicating our lab’s findings in Ecuadorian infants, these analyses revealed that overgrowth of the yeast Pichia kudriavzevii in the infant gut was associated with atopic outcomes at age five years. Using a mouse model of allergic airway disease, I then established a causal role for overgrowth of P. kudriavzevii within the infant gut in increasing allergic airway disease severity later in life. Finally, I used in vitro microbiology techniques to determine how bacterial-fungal interactions shape asthma-associated gut microbiota community structures. I found that bacterial-derived short-chain fatty acids (SCFAs), which we found to be reduced in abundance in stool from infants at risk of atopic disease, inhibit the growth of P. kudriavzevii and the ability of this yeast to adhere to gut epithelial cells. Using biologically relevant experimental systems that broadly address the role of early life fungal dysbiosis in asthma, I provide mechanistic insights into gut microbiota bacterial-fungal interactions, mycobiota-immune interactions, and the gut-lung axis. This work may ultimately inform the development of novel microbiota-based therapeutics.Science, Faculty ofMicrobiology and Immunology, Department ofGraduat