The Early-Life Intestinal Mycobiome in Obesity Development and Metabolic Inflammation
Creators: name: Gutierrez, Mackenzie
Publisher: name: Graduate Studies
Year: 2024
Subjects: subject: Microbiome
subject: Mycobiome
subject: Obesity
subject: Early Life
subject: Adipose Tissue
subject: Microbiology
subject: FOS: Biological sciences
subject: Immunology
subject: FOS: Clinical medicine

description: The intestinal microbiome plays a critical role in host metabolism and contributes to the development of obesity. Thus far, research has mainly focused on bacteria, overlooking the role of other microbial groups, including fungi. Recent efforts have begun to explore the role of fungi in obesity development; however, this has been restricted to adulthood. With the alarming growing rates of obesity across the globe in children, it is critical to explore the understudied role of intestinal fungi in obesity development in the context of early life. Gut-resident fungi have an important role in early-life immune development, which may be an avenue by which fungi contribute to host metabolic regulation. Therefore, this project aims to determine the role of the early-life mycobiome in obesity development and metabolic inflammation. In a subcohort of Canadian infants enrolled in the Canadian Healthy Infant Longitudinal Development (CHILD) Study, we found mycobiome maturation patterns and specific fungal taxa to be associated with early-life BMI z-scores (BMIz). An atypical increase in fungal richness over the first year of life was associated with infant BMIz, maternal BMI and diet, and bacterial diversity. The abundance of common fungal colonizers, including Rhodotorula, Malassezia and Candida, was found to be associated with BMIz from 1 to 5 years of age, prompting us to further evaluate the role of these fungal taxa in obesity development. We evaluated causality between these three fungal taxa and metabolic health in a gnotobiotic diet induced obesity (DIO) model. Both Rhodotorula mucilaginosa and Malassezia restricta drove increased adiposity while only R. mucilaginosa colonization exacerbated the development of metabolic disease. We found a striking resistance to DIO with early-life Candida albicans colonization. Interestingly, this phenotype was paired with broad white adipose tissue (WAT) inflammation, suggestive of dysregulated energy storage. Further exploration of the mechanisms underlying the phenotype driven by C. albicans focused on WAT mitochondrial respiration and adaptive thermogenesis. We found that C. albicans colonization increased the expression of thermogenesis-associated genes and elevated mitochondrial respiration in WAT. This was accompanied by elevated gdT cells that had an increased capacity to produce prothermogenic cytokines, suggesting that C. albicans colonization drives WAT-specific immune regulation to influence energy storage. This project used a translational approach to demonstrate the causal influence of core gut mycobiome members in the early-life regulation of host energy metabolism and metabolic inflammation. With childhood obesity continuing to rise, holistic microbiome based preventative strategies must be prioritized. The inclusion of fungi in microbiome-centered approaches to mitigate the development of obesity may provide new insights that have been previously overlooked.