Scientists Reveal Link Between Gut Fungi, Human Genetics, and Disease Susceptibility

In a groundbreaking study poised to reshape our understanding of the intricate relationships within the human gut ecosystem, researchers from The Pennsylvania State University have unveiled compelling evidence linking human genetic variation to the composition of gut fungi—collectively known as the mycobiome—and its association with chronic disease risk. Published September 2nd in PLOS Biology, this pioneering work spearheaded by Drs. Emily Van Syoc, Emily Davenport, and Seth Bordenstein delves into the complex ternary relationship between human DNA, fungal communities inhabiting the gastrointestinal tract, and the incidence of chronic diseases, signaling a notable shift from the traditional binary focus on bacteria and human genetics.

The human microbiome has long captivated scientists, spotlighting the symbiotic bacteria that dwell in our intestines and exert significant influence on health and disease. Yet, fungi—the often-overlooked fungal counterparts in this microbial consortium—have remained largely in the shadows, regarded primarily as dietary contaminants rather than genetically influenced residents. Challenging this paradigm, the new study presents evidence that gut fungi are not random colonizers but are instead modulated in part by one’s genetic makeup. This revelation opens an entirely new frontier in understanding the mycobiome’s role within human physiology.

Utilizing a genome-wide association study (GWAS) approach, the team analyzed data from 125 individuals part of the Human Microbiome Project. This involved the simultaneous interrogation of the participants’ human genomes alongside detailed profiling of their gut fungal communities. By statistically associating specific human genetic loci with variations in the relative abundance of different fungal taxa, the researchers identified 148 fungi-associated variants (FAVs) scattered across seven chromosomes. These loci correlated with changes in nine distinct fungal taxa, illustrating a heretofore unseen genetic influence on the gut mycobiome composition.

Of particular interest was the discovery that some of these genetically influenced fungi correlate with disease risk, bridging a vital gap in our understanding of chronic conditions. While many studies have focused on pathogenic bacteria, this research uncovers fungi, including the commensal genus Kazachstania, as potentially critical players in the etiology of diseases such as cardiovascular ailments. This finding intriguingly aligns with emerging evidence linking microbial dysbiosis to systemic health, suggesting fungi may also enact mechanistic roles in these processes.

Despite the relatively modest sample size, which the authors acknowledge as a limitation, these findings were further substantiated through validation in a more extensive independent cohort. This two-tiered approach strengthens the credibility of the associations and underscores the robustness of the genetic control over gut fungal populations. Further investigations with larger and more diverse samples will undoubtedly clarify how specific fungal taxa contribute to chronic disease phenotypes and how genetic predispositions modulate these effects.

From a mechanistic perspective, this study breaks new ground by implicating host genetics as a determinant of not only bacterial but also fungal ecology within the gut. Historically, fungi have been considered passive inhabitants influenced mainly by environmental factors such as diet. The current findings challenge that notion, highlighting genetic regulation as an essential factor in shaping mycobiome diversity and stability. This insight mandates the integration of fungal components into the broader gut microbiome framework, creating a more holistic understanding of host-microbe interactions.

The lead investigators emphasize the translational potential of these discoveries. The co-corresponding author, Seth Bordenstein, notes that identifying specific human genetic variants that influence fungal colonization patterns can revolutionize personalized medicine. Such knowledge could pave the way for developing targeted diagnostics and therapeutic interventions tailored to an individual’s genetic and microbial landscape, especially for diseases with complex etiologies involving microbial dysbiosis.

Moreover, the association between Kazachstania species and cardiovascular disease risk presents a tantalizing target for future research. This yeast genus, previously unheralded in gut microbiology, may hold keys to understanding how fungal metabolites or immune interactions contribute to disease pathogenesis. Untangling these pathways could inspire novel probiotic or antifungal strategies aimed at mitigating cardiovascular and perhaps other chronic conditions.

Emily Davenport, a coauthor and expert in microbiome biostatistics, highlights the broader implications regarding the multi-kingdom interactions within the gut. She points out the unexplored territory concerning how fungal-bacterial relationships might themselves be subject to host genetic modulation. This opens complex avenues of investigation into tripartite interactions that blend host genetics, bacterial communities, and fungal inhabitants, all influencing one another in a dynamic system.

First author Emily Van Syoc expresses enthusiasm about the nascent stage of this research. She underscores the novelty of uncovering human genetic influences on the mycobiome and their links to disease states—an endeavor that could ultimately redefine prevention and treatment strategies. By “pulling at this thread,” Van Syoc hopes to unravel the biological mechanisms dictating fungal colonization and function in human health.

The implications extend beyond identifying disease risk factors. Understanding genetic regulation of gut fungi could illuminate evolutionary aspects of human-microbial symbiosis. Clarifying whether these associations differ across populations with diverse genetic backgrounds will be crucial in painting a global picture of mycobiome genetics. Furthermore, exploring whether interventions can modulate fungal communities based on genetic predispositions poses exciting possibilities.

This landmark study also carries broader scientific significance by expanding the canonical two-dimensional model of host genetics and bacterial microbiome into a more nuanced three-dimensional construct incorporating fungal members of the gut ecosystem. Recognizing the gut fungal biosphere as a genetically influenced component redefines human-microbe interactions and demands a more integrative research approach.

Funding for this research was provided by grants from Pennsylvania State University and the National Institute of General Medical Sciences, with additional support from the National Institute of Diabetes and Digestive and Kidney Diseases. The authors report no influence from funders on study design, ensuring the independence of the findings.

It is also worth noting that the research team has a pending patent related to this work, signaling potential commercial and clinical applications of their discoveries. This is a testament to the transformative potential held by genetic-mycobiome interfaces in medical science.

In sum, this study introduces a paradigm-shifting narrative that human genetics not only dictate bacterial microbial landscapes but also fundamentally shape the fungal inhabitants of our guts. By forging these genetic links to disease risk and highlighting previously unappreciated fungal players like Kazachstania, the research sparks a new chapter in personalized medicine and gut microbiome research. As investigations expand in scale and scope, the genetic mycobiome frontier promises to illuminate uncharted dimensions of human health and disease.

Subject of Research: People

Article Title: Gut fungi are associated with human genetic variation and disease risk

News Publication Date: September 2, 2025

Web References:
http://plos.io/41twFDB
http://dx.doi.org/10.1371/journal.pbio.3003339

References:
Van Syoc EP, Davenport ER, Bordenstein SR (2025) Gut fungi are associated with human genetic variation and disease risk. PLoS Biol 23(9): e3003339.

Image Credits: Amy Bean (CC BY 4.0)

Keywords: gut mycobiome, human genetics, genome-wide association study, fungal communities, chronic disease risk, Kazachstania, microbiome, host-microbe interactions, personalized medicine, cardiovascular disease, microbiome genetics

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