The role of intestinal fungi on microbiome ecology, host immune development, and susceptibility to airway inflammation

van Tilburg Bernardes, Erik

The role of intestinal fungi on microbiome ecology, host immune development, and susceptibility to airway inflammation

dc.contributor.advisor	Arrieta, Marie-Claire
dc.contributor.advisor	Proud, David
dc.contributor.author	van Tilburg Bernardes, Erik
dc.contributor.committeemember	McCoy, Kathy D.
dc.contributor.committeemember	McDonald, Braedon A.
dc.date	2024-05
dc.date.accessioned	2023-12-05T17:12:10Z
dc.date.available	2023-12-05T17:12:10Z
dc.date.issued	2023-12-04
dc.description.abstract	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.
dc.identifier.citation	van Tilburg Bernardes, E. (2023). The role of intestinal fungi on microbiome ecology, host immune development, and susceptibility to airway inflammation (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca.
dc.identifier.uri	https://hdl.handle.net/1880/117620
dc.identifier.uri	https://doi.org/10.11575/PRISM/42463
dc.language.iso	en
dc.publisher.faculty	Graduate Studies
dc.publisher.institution	University of Calgary
dc.rights	University of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission.
dc.subject	Microbiome
dc.subject	Mycobiome
dc.subject	Host immunity
dc.subject	Fungal microbiome
dc.subject	Antibiotics
dc.subject	Airway Inflammation
dc.subject.classification	Immunology
dc.title	The role of intestinal fungi on microbiome ecology, host immune development, and susceptibility to airway inflammation
dc.type	doctoral thesis
thesis.degree.discipline	Medicine – Immunology
thesis.degree.grantor	University of Calgary
thesis.degree.name	Doctor of Philosophy (PhD)
ucalgary.thesis.accesssetbystudent	I do not require a thesis withhold – my thesis will have open access and can be viewed and downloaded publicly as soon as possible.