Browsing by Author "McDonald, Braedon A."

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    The role of intestinal fungi on microbiome ecology, host immune development, and susceptibility to airway inflammation
    (2023-12-04) van Tilburg Bernardes, Erik; Arrieta, Marie-Claire; Proud, David; McCoy, Kathy D.; McDonald, Braedon A.
    Early-life microbiome alterations can lead to immune dysregulation and increase susceptibility to asthma. Bacterial changes often precede asthma development in humans and have been causally linked to heightened airway inflammation in mice. Prospective infant studies have also identified fungal microbiome (mycobiome) alterations associated with asthma risk. However, it remains unknown if fungi contribute to the pathogenesis of atopy and asthma. My Ph.D. thesis project aimed to determine the causal role of early-life fungal colonization in immune development and susceptibility to allergic airway inflammation. We determined the role of intestinal fungi on microbiome structure, function, and host immune development in gnotobiotic mice colonized with defined communities of 12 bacteria and/or five fungi. Gut fungi exerted significant ecological pressures to the coexisting bacterial microbiome, and vice versa. Early-life fungal colonization also induced robust host systemic immune changes and influenced the immune phenotype of lung’s inflammatory response to ovalbumin allergen. Antibiotic use also impacts the gut microbiome, leading to an increased risk of asthma. However, the impact of antibiotics on the infant mycobiome is unknown. To investigate mycobiome changes associated with antibiotic treatment we conducted an observational, prospective clinical study of 47 infants (under 6 months of age) who received antibiotics. Antibiotic use decreased bacterial and increased fecal fungal DNA and induced the expansion of Malassezia spp. in infants. To evaluate the effect of colonization with Malassezia spp. on immune development and airway inflammation, we assessed early-life immune readouts and susceptibility to a house-dust mite (HDM) model in mice colonized with or without Malassezia restricta. M. restricta colonization increased intestinal immune responses deemed critical in atopy development, and elevated airway inflammation in HDM-challenged mice. Further evaluation in eosinophil-deficient mice revealed that the observed immune response is partially dependent on this cell type. This translational work demonstrates that fungi are integral components of the intestinal microbiome, causally implicated in host immune development and susceptibility to airway inflammation. Fungal overgrowth and expansion of Malassezia spp. are previously overlooked collateral effects of infant antibiotic use, which may offer a potential strategy to prevent or mitigate pediatric asthma and related conditions.