Scientists at Pennsylvania State University and their colleagues report that early exposure to “forever chemicals” in the environment permanently disrupts the gut microbiome of mice, contributing to the development of metabolic diseases later in life.

The team that published their study, “Effects of Early Life Exposures to the Aryl Hydrocarbon Receptor Ligand TCDF on Gut Microbiota and Host Metabolic Homeostasis in C57BL/6J Mice,” Environmental health perspectivessuggests that human exposure to these chemicals in early childhood may be contributing to the recent epidemic of metabolic diseases, including obesity and type 2 diabetes in adults.

The researchers focused in particular on 2,3,7,8-tetrachlorodibenzofuran (TCDF), a common persistent organic pollutant (POP) that is produced as a byproduct of waste incineration, metal production, and the combustion of fossil fuels and wood. TCDF accumulates in the food chain, and humans are exposed to it primarily through the consumption of fatty foods such as meat, dairy products, and some types of fish. Babies can be exposed to it through the consumption of breast milk.

“POPs are ubiquitous in the environment, and nearly every living organism is exposed to them,” said Andrew Patterson, PhD, John T. and Paige S. Smith Professor of Molecular Toxicology and Biochemistry and Molecular Biology at Penn State. “The negative health effects of these chemicals are well documented and include birth defects and cancer. Our study is the first to indicate that early exposure to a specific POP, called TCDF, also disrupts the gut microbiome and is associated with metabolic disorders later in life.”

The team studied the effects of TCDF in two groups of mice – a test group, those treated with TCDF, and a control group, those that received no treatment. The team fed four-week-old mice tablets containing either 0.46 micrograms (µg) of TCDF or a control tablet that did not contain TCDF for five days. Although 0.46 µg is more than the typical level in the human diet, this level is not high enough to cause toxic disease.

“This study used metagenomics, nuclear magnetic resonance (NMR) and mass spectrometry (MS)-based metabolomics and biochemical assays to characterize the composition and function of the gut microbiome and the physiological and metabolic effects of early exposure to 2,3,7,8-tetrachlorodibenzofuran (TCDF) in conventional, germ-free (GF) and Ahr-null mice. The influence of TCDF on Akkermansia muciniphila (A. muciniphila) in vitro was assessed by optical density (OD 600), flow cytometry, transcriptomics and MS-based metabolomics,” the researchers write.

“TCDF-exposed mice showed lower levels of A. muciniphilalower levels of cecal short-chain fatty acids (SCFAs) and indole-3-lactic acid (ILA), and lower levels of the gut hormones glucagon-like peptide 1 (GLP-1) and peptide YY (PYY). These findings suggest a disruption in the structure and function of the gut microbiome community.

“Importantly, microbial and metabolic phenotypes associated with early life POP exposure were transferable to GF recipients in the absence of POP transfer. Furthermore, AHR-independent interactions between POPs and the microbiota were observed that were significantly associated with growth, physiology, gene expression, and metabolic activity outcomes of A. muciniphilawhich supports suppressed activity along the ILA signaling pathway.

“These data, obtained in a mouse model, indicate the complex effects of POPs on the host and microbiota and provide strong evidence that short-term and self-limiting POP exposure in early life can negatively impact the microbiome, with effects that persist into later life and result in associated health consequences.”

In the study, “we used a dose that is relatively high compared to typical human exposures. However, we can use this information to identify new peaks of toxicity, including in the gut microbiome, and extrapolate what might happen at even lower doses,” Patterson continued. “Of course, we also need to consider how complex mixtures of these POPs interact with us and our microbial partners, as a single exposure does not perfectly mimic real-world scenarios.”

Examined the intestinal microbiome

Next, the researchers examined the animals’ gut microbiome as well as several health indicators, including body weight, glucose tolerance, and the amount of triglycerides in their liver and mucus in their feces, among other markers of metabolic disease. They collected this data immediately after the five-day TCDF treatment, as well as three months after the last dose. In humans, these time points correspond to an infant and a young adult.

“We found that early exposure to TCDF permanently disrupted the gut microbiomes of the wild-type mice,” said Yuan Tian, ​​PhD, lead author and associate research professor at Penn State. “We also found that these mice had higher body weight and glucose intolerance at four months of age.”

To further explore the effects of TCDF on the gut microbiome, the scientists administered gut microbiome transplants from mice with TCDF-disrupted microbiomes to mice without a microbiome and measured their health. They found that the mice with the transplants developed metabolic disorders, suggesting that the altered microbiome is the cause of the metabolic disease.

“These results suggest that early TCDF exposure may impair gut microbiome function and lead to health problems later in life, even long after TCDF has been eliminated from the body,” Tian said.

She explained that the disturbances of the gut microbiome are characterized by a decline in certain types of bacteria, including Akkermansia muciniphilaa bacterium that is also typically found in the human intestinal microbiome.

“This is important because Akkermansia is considered important for overall gut health, but now we know that it can be negatively affected by TCDF,” noted Tian.

To understand the importance of Akkermansia muciniphila To influence the health effects, the team experimented with administering the bacteria as a probiotic to mice treated with TCDF. The probiotic restored the microbiome to normal.

“Our results suggest that these bacteria are affected by toxic exposures and play an important role in mediating health outcomes,” Patterson said. “It’s possible that with further research, we may one day be able to restore a person’s microbiome to its optimal state by supplementing with prebiotics and probiotics.”