Guts, Genes, and Generations: Exploring Stress in the Microbiome

If you’ve ever met a set of identical twins, your initial impressions are likely about their similarities. Their height, facial features, and sometimes their mannerisms look like a reflection of the other. Visual similarities in identical twins can be traced back to genetics. When two people share the exact same set of DNA, their genes encode the same physical characteristics. But take a closer look, and you might notice that twins are not exactly the same. For example, their weight and skin texture may be different. One might develop a disease like cancer that the other never will. This discrepancy can be explained by environmental factors. Environment plays a huge role in shaping a person’s life. It can even affect how somebody’s genes work without ever changing their DNA (Peixoto et. al 2020). The study of the environment’s effect on genes is called epigenetics. Epigenetic changes can be passed down from parent to child (Geraghty et. al 2016).

Genes are not our only characteristic that can be influenced by the environment. Within living things, including humans, there is a whole world of microorganisms that make up something called the microbiome. These microorganisms can include bacteria, archaea, protozoa, fungi, and viruses. These microorganisms are necessary for our health and normal body functions. The gut microbiome is of particular importance. Our understanding of what affects the microbiome is still growing, but scientists know that a person’s microbiome is unique, and can be influenced by a lot of factors (Yang et. al 2021). These can include diet, geographic location, antibiotic use, and more (Yang et. al 2021). There is evidence that the gut microbiome can be affected by environmental factors such as stress (Kemp et al. 2021). The possibility of hereditary microbiome changes is explored in a study by Otaru et. al (2024) titled Transgenerational Effects of Early Life Stress on the Fecal Microbiota in Mice.

Central Question:

This paper explored whether early life stress can change the microbiome and whether those changes can be transmitted across generations.

Evidence:

The researchers used mice as an animal model for their study. In the first generation, the mother and pups were stressed through two methods. The mother underwent a forced swim test, in which the animal was forced to swim in cold water for five minutes. During this time, she was separated from the pups, which induced stress in the offspring as well. This model has the label “unpredictable maternal separation combined with unpredictable maternal stress” (MSUS). The offspring of these stressed mothers are referred to as the MSUS group. This first generation called the F1 generation, was then observed and tested at several points throughout their life to characterize their microbiomes. There was also a parallel group of mice that were exempt from the stress tests and served as a control group. The male F1 MSUS mice as well as the male control mice were bred with new females to create the F2 generation.

The authors examined the difference between the microbiota in the stressed mice and the unstressed control mice. Feces can be used to sample the gut microbiome, because food travels through the gut before the waste is disposed of as feces. So researchers used mouse feces from between 22 days old and 30 weeks out to look for changes in the microbiome. Microbiome research often focuses on looking for similarities and differences. These can be differences within one group. Alpha diversity describes richness, or the amount of “things” in a sample, and how evenly they are found. Beta diversity describes the richness between two groups. The alpha diversity was the same between control and MSUS mice. In other words, the amount of microorganisms found in the gut was similar. However, the composition, or the Beta diversity, of the microbiota was different between the two groups.

The authors continued to examine the alpha and beta diversity in the next two generations. They found that neither the F2 or F3 generations showed a significant difference in alpha diversity. They did observe that for beta diversity, the composition, and the structure of the microbial diversity were significantly different in both F2 and F3. They also found that the microbiota of the offspring was more similar to that of the mother than the father. This evidence supports the idea that the changes in the microbiota caused by stress in the F1 generation continued to affect the microbiota of F2 and F3.

Further Questions:

This paper provided a foundation for transmissible microbiome changes in animal models. However, this study had several limitations that could be explored in further studies. For example, the study only bred three generations of mice. F3, the last generation, was descended from F2 mice that were not directly included in the study. Considering that one of the goals of this project was to examine the inheritance of the microbiota, future studies would benefit from including more generations of direct descendants, as well as recombining the stress vs. control offspring and parents. This would clarify how parental behavior, as opposed to genetics, influences the offspring.

This paper focused on the effect of stress in the early phase of development when the F1 mice were still under the care of a mother and consuming milk. This early postnatal stage is crucial for development. Therefore, the first stage of life is an important topic to focus on in more preliminary studies such as this. Future research could consider how stress throughout life, rather than just at the postnatal stage, can affect the microbiome and explore whether those changes are also inherited.
One limitation that the authors emphasize is that using feces as their main method of sample collection is not an accurate representation of the entire gut. Different sections of the gastrointestinal tract have different communities that may not be reflected in a fecal sample. Outside of the gut, many other microbial communities could be explored between parents and offspring. The gut is only one collection of microorganisms that our bodies hold.

Research involving multiple generations typically used mice or other animals with short lifespans. This reduces the time and resources required for a study. While these mouse models did demonstrate that epigenetic microbial changes can occur, we can’t assume that this knowledge transfers directly to humans. Epigenetic studies on humans are difficult since it is impossible to control for environmental effects, and observing changes over generations would take an extraordinary amount of time. Epigenetic and microbiome research underlines the incredible amount of variables that can impact health. Understanding those factors allows us to treat with a more multifaceted and informed approach.

Further Reading:

Interested in learning more about epigenetics? Check out this video from the BBC to learn about how how lifestyle can influence genes.

For an article providing an overview of the effect of the Microbiota on health, click here.

Check out this article from Stanford Medicine to learn more about how our microbiomes differ, and what a “healthy” gut might look like.

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