Study finds links between human genetic variation, gut mycobiome, and chronic disease risk

Clinicians’ ability to diagnose and treat chronic diseases is limited by scientific uncertainty around factors contributing to disease risk. A study published September 2^nd in the open-access journal PLOS Biology by Drs. Emily Van Syoc, Emily Davenport, and Seth Bordenstein at The Pennsylvania State University, United States, uncovers evidence of the first ternary relationships between human genetic variation, variation in gut mycobiome, and risk of developing chronic disease.

Some gut fungi are implicated in intestinal diseases. However, human-fungi interactions are poorly understood, and scientists have previously thought gut fungi to be determined from diet. To examine the relationship between human genetic variation and variation in gastrointestinal fungal communities, researchers conducted a genome-wide association study on the number and types of human genetic loci influencing gut fungi relative abundance. They accessed paired gut mycobiome and human genome data from 125 individuals via the Human Microbiome Project. After identifying and characterizing fungi-associated genetic variants by which human genomic variation associates with variation in fungal communities, they tested whether relationships between genetic loci and gut fungi affect human disease risk.

The researchers found 148 fungi associated variants (FAVs) across 7 chromosomes that statistically associate with 9 fungal taxa, uncovering several genetic relationships with gut fungi and disease risk. The study was limited by a small cohort, but a key result was validated in an independent larger cohort; future studies can clarify how gut fungi may mediate chronic disease risk and to better understand the mechanism by which genetic variation and gut fungi are connected.

According to the authors, “Determining whether human genetics simultaneously associates with differential microbial abundance and disease risk is a central challenge to resolve with substantive potential for personalized diagnostics and/or biotherapeutics. The findings establish previously unrecognized connections between human genetics, gut fungi, and chronic disease, broadening the paradigm of human-microbe interactions in the gut to the mycobiome. Taken together, this work advances the canonical, two-dimensional focus on human genetics and gut bacteria to the gut fungal biosphere.”

This research is our first major step toward understanding the impacts of human genetic variation on a very understudied group of gut microorganisms – the mycobiome – or community of fungal species that occur in our intestinal tracts.”

Seth Bordenstein, co-corresponding author

Bordenstein says, “We’ve uncovered a surprising number of genetic links to specific gut fungi, and our discovery of a connection between a particular yeast, Kazachstania, and cardiovascular disease risk is particularly interesting for future studies and validation.”

Coauthor Emily Davenport notes, “Gut fungi are greatly understudied compared to other gut microbes like bacteria and archaea. We know much less about what determines the fungi that reside in the gut, and whether they are important for human health. These results demonstrate for the first time that host genetics can influence the fungi that live in the gut, and provide clues about the physiological mechanisms that determine their abundances.”

Davenport adds, “These results offer an exciting first glimpse into host genetic regulation of the mycobiome. Even more exciting, they open up many more questions about how that occurs. Will we see different associations in different populations? Are there interactions between gut fungi and gut bacteria that are modulated by genetics? We are excited to see the new avenues this research opens up.”

First author Emily Van Syoc notes, “This research embarks on a first-in-kind journey to uncover genetic underpinnings of the human gut mycobiome. In a small discovery GWAS cohort, we find that gut fungi, in particular the commensal Kazachstania, are associated with human genetic variants, and in turn, disease states. We are excited to continue pulling at this thread to unravel the forces that shape human gut fungi and contribute to health and disease.”