Connection among gut fungi, genetics and disease risk in humans identified

Novel genome-wide association study sheds light on the human genetic determinants of the fungal component of the human microbiome and their relation to chronic disease

Penn State

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UNIVERSITY PARK, Pa. — 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.

At Penn State, researchers are solving real problems that impact the health, safety and quality of life of people across the commonwealth, the nation and around the world. 

For decades, federal support for research has fueled innovation that makes our country safer, our industries more competitive and our economy stronger. Recent federal funding cuts threaten this progress. 

Learn more about the implications of federal funding cuts to our future at Research or Regress.

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Journal

PLOS Biology

DOI

10.1371/journal.pbio.3003339 

Method of Research

Meta-analysis

Subject of Research

People

Article Title

Gut fungi are associated with human genetic variation and disease risk

Article Publication Date

2-Sep-2025

 

Invasive flathead catfish now top predators in Susquehanna River in Pennsylvania

New study suggests that smallmouth bass and channel catfish are changing what they eat to avoid having to compete with or being eaten by the invader

Penn State

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Flatheads grow fast in this river system, attain large body sizes and can eat a variety of prey. Because adult flatheads have few natural predators, they can exert strong control over the ecosystem. 

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Credit: Penn State

UNIVERSITY PARK, Pa. — Flathead catfish, opportunistic predators native to the Mississippi River basin, have the potential to decimate native and recreational fisheries, disrupting ecosystems in rivers where they become established after their introduction or invasion from a nearby river drainage. That concern led a team of researchers from Penn State, the U.S. Geological Survey (USGS), and the Pennsylvania Fish and Boat Commission to assess how flatheads are affecting the food web and energy flow in the Susquehanna River in Pennsylvania, where they were first detected in 1991. Their population has grown rapidly in the decades since.

“Flatheads grow fast in this river system, attain large body sizes and can eat a variety of prey,” said study first author Olivia Hodgson, a master’s degree student in Penn State’s Intercollege Graduate Degree Program in Ecology. “Because adult flatheads have few natural predators, flathead catfish can exert strong control over the ecosystem.”

Hodgson is working with Tyler Wagner, a scientist with the USGS Pennsylvania Cooperative Fish and Wildlife Research Unit Program and a Penn State affiliate professor of fisheries ecology. He is senior author on the study. In findings published Sept. 4 in Ecology, the researchers reported that flathead catfish are apex predators.

Flatheads had the highest trophic position — the level an organism occupies in a food web, based on its feeding relationships — even higher than resident top predators such as smallmouth bass and channel catfish. Channel catfish had a lower trophic position in areas with flathead catfish. This means they now eat lower on the food chain, likely because they are being outcompeted by flatheads or avoiding them, the researchers explained. In areas with flathead catfish, they found, all species showed broader and overlapping diets.

“This suggests that resident species are changing what they eat to avoid competing with or being eaten by the invader,” Hodgson said. “These findings support the ‘trophic disruption hypothesis,’ that says when a new predator enters an ecosystem, it forces existing species to alter their behavior, diets and roles in the food web. This can destabilize ecosystems over time. Our study highlights how an invasive species can do more than just reduce native populations — it can reshape entire food webs and change how energy moves through ecosystems.”

Although the predatory effects of invasive catfishes on native fish communities have been documented — such as in a recent study on the Susquehanna River led by researchers at Penn State — the impacts of invasion on riverine food webs are poorly understood, Hodgson noted. This study quantified the effects of invasive flathead catfish on the food web in the Susquehanna by comparing uninvaded river sections to invaded sections, focusing on several key species: flathead catfish — invader, channel catfish and smallmouth bass — resident predators, and crayfish and minnows — prey.

In addition to evaluating trophic position, the researchers analyzed the isotopic niche occupied by the fish species — the range of carbon and nitrogen markers found within the tissues of an organism, reflecting its diet and habitat, providing insights into its ecological role.

To reach their conclusions, the researchers employed stable isotope analysis, a widely used tool that can explain patterns within a food web, highlighting links between trophic positions, as well as the breadth and overlap of trophic niches. Stable isotope analysis is especially useful for studying invasion ecology, such as investigating trophic reorganization and trophic overlap between introduced and resident species.

When fish eat, their bodies incorporate the isotopic signature of their food. By sampling their tissues, scientists can measure nitrogen isotopes and determine their diet, carbon isotopes to determine habitat use, and compare isotopic signatures across regions to deduce fish migration or habitat shifts. For this study, channel catfish, smallmouth bass, minnows and crayfish were selected as focal species because a previous diet analysis conducted in collaboration with Penn State, USGS, and Pennsylvania Fish and Boat Commission researchers within the Susquehanna River, showed that these species are important prey for flathead catfish.

The researchers collected a total of 279 fish and 64 crayfish for stable isotope analysis, including 79 flathead catfish, 45 smallmouth bass, 113 channel catfish and 42 minnows comprising nine species. All samples were oven dried and ground to a fine powder using a mortar and pestle. Stable isotope samples were sent to Penn State’s Core Facilities and the Michigan State University Stable Isotope Laboratories for isotope determination.

“Stable isotope analysis explained patterns within the Susquehanna food web in habitats invaded and not invaded by the flathead catfish, and it allowed us to understand links between different species in the river food web and how invasive species might lead to changes in how native species interact and compete, what they eat and how their diets overlap, and if they might be displaced from preferred habitats by the invader,” Hodgson said. “We were able to infer resource use, helping us to better understand potential competition for resources and how this changes when flathead catfish become established.”

Contributing to the research were: Sydney Stark, recent Penn State graduate with a master’s degree in wildlife and fisheries science; Megan Schall, associate professor of biology and science at Penn State Hazleton; Geoffrey Smith, Susquehanna River biologist for the Pennsylvania Fish and Boat Commission; and Kelly Smalling, research hydrologist with the U.S. Geological Survey, New Jersey Water Science Center. 

Funding for this research was provided by Pennsylvania Sea Grant and the U.S. Geological Survey.

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Journal

Ecology

DOI

10.1002/ecy.70180 

Method of Research

Observational study

Subject of Research

Animals

Article Title

Invasive predatory fish occupies highest trophic position leading to expansion of isotopic niches in a riverine food web

Article Publication Date

4-Sep-2025

Study coauthor Geoffrey Smith, Susquehanna River biologist for the Pennsylvania Fish and Boat Commission, with a big flathead catfish. 

Study coauthor Sydney Stark, who recently graduated from Penn State with a master’s degree in wildlife and fisheries science, lifts a 40-pound flathead catfish. 

Credit

Penn State

Broken bones regrow quickly with help of biodegradable implant

Penn State

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From left to right, biomedical engineering doctoral student Ethan Gerhard; co-corresponding author and Assistant Research Professor of Biomedical Engineering Su Yan; first author and biomedical engineering doctoral student Hui Xu; and biomedical engineering doctoral student Yuqi Wang pose in the lab. The team worked together to create the bone growth scaffold CitraBoneQMg. 

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Credit: Caleb Craig/Penn State

UNIVERSITY PARK, Pa. — For most broken bones, bone cells regrow on their own while patients wear a cast or brace to keep the injury steady. But for complex or severe fractures, surgeons may intervene by placing grafts or scaffolds made of biocompatible materials, or by using metal fixation devices to ensure proper bone healing and alignment. Collaborating with orthopedic surgeons, a team led by biomedical engineering researchers at Penn State created CitraBoneQMg, an implantable biodegradable scaffold to support bone regrowth made by combining magnesium and glutamine with citric acid. They published research on their implant, for which they filed a U.S. patent application, in Science Advances.

“By integrating magnesium and glutamine — two small molecules found naturally in the body and in food — with citric acid, we found that the molecules work together to promote bone growth by encouraging increased intracellular energy metabolism,” said first author Hui Xu, a doctoral student in biomedical engineering, who is advised by co-corresponding author Su Yan, assistant research professor of biomedical engineering.

The researchers found that adding magnesium and glutamine to a traditional citric acid-only based implant, which was approved by the U.S. Food and Drug Administration and on the market, increased intracellular energy and helped regulate two energy pathways that are essential for bone growth, AMPK and mTORC1. The pathways act as control systems inside the cell, balancing fuel use so cells have the energy to make new bone.

“The molecules concurrently regulate the two energy pathways, which is different than what normally happens – usually they act as a seesaw, one speeding up while the other slows down,” Xu said. “The scaffold essentially powers up a bone cell: both nutrients act in a synergistic relationship with the citric acid to give stem cells more energy to grow and differentiate to bone cells, leading to better bone regrowth.”

To test CitraBoneQMg, the researchers implanted their experimental scaffold into a cranial defect of the skull of rats and compared its resulting bone growth to rats with a citric acid only-based scaffold implant and one with a traditional bone material implant.

They found that after 12 weeks, CitraBoneQMg had increased the bone growth surrounding the cranial injury by 56% as compared to the animals with the citric acid only-based scaffold and 185% compared to the animals with a traditional bone material implant.

“The three molecules work as a healing recipe for the bone, paving the way for a new way of thinking of bone repair,” Yan said. “Alongside rapid bone growth, we also saw nerve regeneration and antiinflammation properties at the site of the scaffold, two elements that are important to long-term healing of the bone.”

Releasing the molecules directly at the site of the injury via the scaffold helps transport a high concentration of nutrients directly to where they are most needed, the researchers explained, rather than relying on oral ingestion, where only a small percentage reaches the injury site.

Additionally, the researchers discovered that the polymer scaffold contains inherent photoluminescent and photoacoustic properties, which allows it to be easily imaged after it is implanted at the injury site.

“With photoacoustic properties, CitraBoneQMg has great potential for in vivo tracking, where it can be detected by ultrasound underneath deep tissue,” Xu said.

In addition to Xu and Yan, the Penn State-affiliated co-authors include Ethan Gerhard, Rohitraj Ray and Yuqi Wang, doctoral students in biomedical engineering; Sri-Rajasekhar Kothapalli, associate professor of biomedical engineering; and April D. Armstrong, the C. McCollister Evarts Professor and chair of the Department of Orthopaedics and Rehabilitation and chief of the Shoulder and Elbow Service, Penn State Health. For a full list of authors and their affiliations, as well as the funding agencies that supported this research, see Science Advances. 

A test tube contains the CitraBoneQMg bone implants researchers used in the study. 

Credit

Caleb Craig/Penn State

Journal

Science Advances

DOI

10.1126/sciadv.ady2862 

Method of Research

Experimental study

Subject of Research

Animals

Article Title

Metabotissugenic citrate biomaterials orchestrate bone regeneration via citrate-mediated signaling pathways

New research highlights critical role of

movement in lifelong bone health

Reducing sedentary behaviour and increasing physical activity found to protect against bone loss and fractures across all ages.

International Osteoporosis Foundation

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A new review by the International Osteoporosis Foundation (IOF) Rehabilitation Working Group underscores the powerful impact of lifestyle behaviours—specifically physical activity and sedentary behaviour —on bone health across the human lifespan. 

While exercise has long been recognized for its role in strengthening bones and reducing fracture risk, emerging evidence reveals that prolonged sitting and inactivity can harm skeletal health, even among individuals who engage in regular physical activity. 

The study 'The Impact of Sedentary Behavior and Physical Activity on Bone Health: A Narrative Review from the Rehabilitation Working Group of the International Osteoporosis Foundation' synthesizes findings from epidemiological studies, systematic reviews, and meta-analyses, examining how physical activity and sedentary behaviour influence bone mineral density (BMD) and fracture risk in children, adolescents, adults, and older populations.

Key findings include:

• Physical activity – especially weight-bearing and resistance training – improves bone mineral density and helps reduce fracture risk in both younger and older populations.
• Sedentary behaviour – independent of overall activity levels – has harmful effects on bone health, increasing fracture risk, particularly in frail or pre-frail individuals.
• Even light-intensity activity can yield measurable benefits when it replaces sedentary time, especially in older adults and postmenopausal women.
• Early and continuous promotion of physical activity, aligned with World Health Organization (WHO) guidelines, provides an effective strategy for maintaining skeletal health and preventing osteoporotic fractures.

The evidence demonstrates that physical activity and sedentary behaviour are independent, modifiable factors influencing skeletal health. Clinical practice and public health policy should address both — not only encouraging physical activity, but also actively reducing prolonged sedentary time.

Professor Olivier Bruyère, Co-chair of the IOF Rehabilitation Working Group and Lead Author of the publication, stated:  

“This review highlights a critical message for populations worldwide: bone health depends not only on engaging in regular physical activity, but also on reducing the hours we spend in sedentary behaviour. In children and adolescents, too much sitting time can undermine bone development, while in adults and older individuals, inactivity accelerates bone loss and fracture risk. Importantly, even light daily activity—such as walking—can provide measurable benefits, particularly for older adults and postmenopausal women.”

IOF President Professor Nicholas Harvey and IOF CSA Chairman Professor Eugene McCloskey jointly underscore the significance of the study’s clinical and policy implications: 

“The findings highlight the imperative for early intervention and sustained promotion of physical activity throughout the life course, in alignment with WHO recommendations. We therefore urge governments, healthcare providers, and policymakers to implement comprehensive public health strategies that not only encourage active lifestyles but also systematically reduce sedentary behaviours across all populations and age groups, in order to ensure optimal skeletal health and fracture prevention.”

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Reference: Bruyère, O., Scott, D., Papaioannou, A. et al. The Impact of Sedentary Behavior and Physical Activity on Bone Health: A Narrative Review from the Rehabilitation Working Group of the International Osteoporosis Foundation. Calcif Tissue Int 116, 109 (2025). https://doi.org/10.1007/s00223-025-01421-6
 

About IOF
The International Osteoporosis Foundation (IOF) is the world’s largest nongovernmental organization dedicated to the prevention, diagnosis, and treatment of osteoporosis and related musculoskeletal diseases. IOF’s membership committees include leading scientific experts, 340 patient organizations and medical societies in more than 150 countries, as well as universities worldwide. The IOF Capture the Fracture® initiative counts over 1,200 Fracture Liaison Services across all regions of the world. Together, this global network works to prioritize bone health and fracture prevention, sharing a vision of a world free from fragility fractures, where healthy mobility is a reality for all. @iofbonehealth
Websites: www.osteoporosis.foundation ; www.capturethefracture.org ; www.worldosteoporosisday.org ; www.buildbetterbones.org ; https://www.iofacademy.org/ 

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Journal

Calcified Tissue International

DOI

10.1007/s00223-025-01421-6 

Method of Research

Literature review

Subject of Research

People

Article Title

The Impact of Sedentary Behavior and Physical Activity on Bone Health: A Narrative Review from the Rehabilitation Working Group of the International Osteoporosis Foundation