A new genome-wide study uncovers evidence of the first three-way relationships between human genetic variation, variation in the fungal component of the human microbiome - known as the mycobiome - and risk of developing chronic disease. 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 include the mycobiome.
"Gut fungi are greatly understudied compared to other gut microbes like bacteria and archaea," said Emily Davenport, assistant professor of biology in the Eberly College of Science at Penn State and an author of the paper. "We know much less about what determines the fungi that reside in the gut and whether they are important for human health. Our 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."
A paper describing the study, by a team of scientists at Penn State's One Health Microbiome Center (OHMC), appeared Sept. 2 in the open-access journal PLOS Biology.
"Clinicians' ability to diagnose and treat chronic diseases is limited by scientific uncertainty around factors contributing to disease risk," said study author Seth Bordenstein, Dorothy Foehr Huck and J. Lloyd Huck Endowed Chair in Microbiome Sciences, director of OHMC and professor of biology and entomology at Penn State. "Determining whether disease risk and onset occur because of interactions between human genes and microorganisms is a central challenge to resolve with substantive potential for personalized diagnostics and biotherapeutics."
Some gut fungi have been implicated in intestinal diseases, however, human-fungi interactions are poorly understood, and scientists had previously thought gut fungi were determined by diet, according to the research team. To examine the relationship between human genetic variation and variation in gastrointestinal fungal communities, the researchers conducted a genome-wide association study (GWAS). They focused on the number and types of human genes influencing gut fungi abundance and the development of major chronic diseases.
"This research embarks on a first-in-kind journey to uncover the genetic underpinnings of the human gut mycobiome," said Emily Van Syoc, a postdoctoral researcher at Penn State at the time of the research and first author of the paper. "In a small discovery GWAS cohort that was validated in two larger datasets, we find that gut fungi, 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."
The team accessed paired gut mycobiome and human genome data from 125 individuals via the Human Microbiome Project, an NIH initiative to study of the microbial communities that live in and on our bodies and the roles they play in human health and disease. After identifying and characterizing human genes that associate with variation in the abundance of specific gut fungi, they tested whether relationships between locations in the human genome and gut fungi affect human disease risk.
"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," Bordenstein said. "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."
The researchers found a total of 148 fungi-associated genetic variants across seven chromosomes that statistically associate with nine fungal taxa, uncovering several genetic relationships with gut fungi and disease risk. The study was limited by a small cohort assessed for gut fungi in the Human Microbiome Project, but the connection with cardiovascular disease was validated in data from larger cohorts in the United Kingdom and a global consortium focused on coronary artery disease. Future studies may clarify if and how gut fungi mediate chronic disease risk, as well as reveal the mechanism by which genetic variation and gut fungi are connected, Bordenstein said.
"These results offer an exciting first glimpse into host genetic regulation of the mycobiome," Davenport said. "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."
The U.S. National Institutes of Health and Penn State funded the research.
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