Studies in mice have shown that early life exposure to persistent organic pollutants significantly disrupts the gut microbiota, influencing the development of metabolic disorders in adulthood.
A new Penn State-led study finds that early life exposure to “forever chemicals” in the environment can permanently disrupt the gut microbiome in mice, leading to the development of metabolic diseases later in life. The findings, published in Environmental Health Perspectives, suggest that similar exposures in early life may contribute to higher rates of metabolic diseases such as obesity and type 2 diabetes in adults.
The researchers focused specifically on 2,3,7,8-tetrachlorodibenzofuran (TCDF), a widespread persistent organic pollutant (POP) that is a by-product of waste incineration, metals production, and fossil fuel and wood combustion. TCDF accumulates in the food chain, and humans are primarily exposed to TCDF through the consumption of high-fat foods such as meat, dairy products, and some fish. Infants may be exposed to TCDF through the consumption of breast milk.
“POPs are widespread in the environment and are exposed to nearly all living organisms,” said Andrew Patterson, the John T. and Paige S. Smith Professor of Molecular Toxicology and Biochemistry and Molecular Biology at Penn State. “The adverse health effects of these chemicals are well documented and include birth defects and cancer. Our study is the first to suggest that exposure to a specific POP, called TCDF, during childhood disrupts the gut microbiome, leading to metabolic disorders later in life.”
Methodology and initial findings
The research team studied the effects of TCDF in two groups of mice: a test group that received TCDF, and a control group that received no treatment. They fed four-week-old mice tablets containing 0.46 micrograms (µg) of TCDF or a control tablet without TCDF for five days. 0.46 µg is higher than the amount typically found in the human diet, but not high enough to cause toxic illness.
“In our study, we used relatively high doses compared to typical human exposure, but we can use this information to identify new high points of toxicity involving the gut microbiome and begin to infer what might happen at even lower doses. Of course, we also need to consider how complex mixtures of these POPs interact with us and our microbial partners, because no single exposure can fully mimic a real-life scenario.”
The researchers then looked at several indicators of the animals’ health, including indicators of metabolic disease, such as their gut microbiome, body weight, glucose tolerance, the amount of triglycerides in their livers, and the amount of mucus in their feces. They collected these data immediately after the five-day TCDF treatment and again three months after the last treatment. In humans, these time points correspond to infants and young adults.
“We found that early life exposure to TCDF permanently disrupted the gut microbiome in wild-type mice,” said lead author Yuan Tian, an associate research professor at Penn State, “and we also found that these mice gained weight and had impaired glucose tolerance at four months of age.”
Further Experiments and Conclusions
To further investigate the impact of TCDF on the gut microbiome, the scientists transplanted gut microbiomes from mice whose microbiomes had been disrupted by TCDF into mice without a microbiome and measured their health. The transplanted mice developed metabolic disorders, indicating that the altered microbiome is the cause of metabolic disease.
“These results suggest that exposure to TCDF during childhood may affect gut microbiota dysfunction and health in old age, even after TCDF has been cleared from the body,” Tian said.
She explained that a disrupted gut microbiome is characterized by a decline in certain bacteria. seedThis includes Akkermansia muciniphila, a bacterium also commonly found in the human gut microbiome.
“This is important because Akkermansia is recognised as important for overall gut health, but we now know that it can be negatively affected by TCDF,” Tian said.
To investigate the importance of A. muciniphila’s impact on health, the team administered the bacteria as a probiotic to mice treated with TCDF, which restored the microbiome to a normal state.
“Our findings suggest that these bacteria are affected by exposure to toxic substances and play an important role in determining health outcomes,” Patterson said. “With further research, it may one day be possible to restore an optimal human microbiome through pre- and probiotic supplementation.”
Reference: Yuan Tian, Bipin Rimal, Jordan E. Bisanz, Wei Gui, Trenton M. Wolfe, Imhoi Koo, Iain A. Murray, Shaneice K. Nettleford, Shigetoshi Yokoyama, Fangcong Dong, Sergei Koshkin, K. Sandeep Prabhu, Peter J. Turnbaugh, Seth T. Walk, Gary H. Perdew, Andrew D. Patterson, “Early exposure to the aryl hydrocarbon receptor ligand TCDF impacts gut microbiota and host metabolic homeostasis in C57BL/6J mice,” August 14, 2024, Environmental Health Perspectives.
Posted on: 2010/03/28
Other authors from Penn State include Jordan Bisanz, assistant professor of biochemistry and molecular biology, Imhoi Koo, research assistant professor, Ian Murray, research assistant professor, Shigetoshi Yokoyama, research assistant professor, Sergey Koshkin, research assistant professor, Vipin Rimal, graduate student, Wei Gui, research technician, Shane Nettleford, graduate student, Fancong Dong, postdoctoral researcher, Sandeep Prabhu, chair of the Department of Veterinary Medicine and Biomedical Sciences, and Gary Perdue, the H. Thomas and Dorothy Willits Hallowell Professor of Agricultural Sciences. Other authors include Trenton Wolf, graduate student at Montana State University, Peter Turnbaugh, professor of microbiology and immunology at the University of California, San Francisco, and Seth Walk, professor of microbiology and immunology at Montana State University.
US National Institutes of HealthThe research was supported by the National Institute of Food and Agriculture and the Pennsylvania Department of Health.