The underexplored mycobiome: insights from Drosophila into human health and disease.

Drosophila melanogaster serves as a powerful and experimentally tractable genetic model for microbiome research due to its relatively simple gut community, ease of genetic manipulation, and the ability to generate germ-free flies. Despite extensive research on bacterial components of the human microbiome, the role of the mycobiome in host health and disease remains largely underexplored, presenting a significant knowledge gap. Although yeasts form a minor component of the Drosophila gut microbiome, they serve as a critical dietary source of essential micronutrients that drive larval development, growth, and metabolic rate. Furthermore, live yeasts directly shape adult fly behaviour, including oviposition, mating, and aggression, while interacting with gut bacteria to regulate lipid metabolism. Drosophila can be used as an invaluable tool for modelling neurodegenerative disorders, offering platforms for high-throughput screening and dissecting disease mechanisms. Despite these advantages, translation to human clinical contexts requires careful consideration of the fly's evolutionary limitations, including its exclusive reliance on the innate immune system, the absence of an adaptive immune system, the absence of certain vertebrate-specific genes and physiological pathways, and fundamental differences in brain architecture, neuronal organisation, and neurotransmission. Nevertheless, Drosophila provides essential mechanistic insights that are accelerating our understanding and guiding the development of novel therapeutic strategies against mycobiome-associated, metabolic, and neurological disorders. It also advances our understanding of the mycobiome's integral role in shaping insect behaviours, development, ecology, and overall health. These studies can significantly influence the understanding of fungi in human health and their roles in various disease conditions.