Do Microbiota and T Cells Influence Epigenetic Inheritance of Phenotypes?

New findings reveal the microbiome and immune system play a key role in the non-genetic transfer of phenotypes to offspring.

The findings

Researchers conducted a basic science study that found the microbiome and immune system control epigenetic information in the gametes – reproductive cells – of both sexes that impact the phenotypes of barrier and metabolic tissues of following generations of offspring, or progeny, non-genetically. They identified defects in sebum secretion of germ-free and T cell-deficient animal models that persisted transgenerationally, suggesting that T cells and the microbiome influence inheritance of certain phenotypes non-genetically.

Why it matters

Barrier sites like the skin, gut, and lungs offer protection from pathogens by responding to changes in the environment, which affects an organism's ability to adapt and survive. An organism's ability to hone these adaptions to maximize fitness was previously thought to solely occur through natural selection over long periods of time (many generations). These findings demonstrate that mammals have the ability to generate phenotypic diversity in a single generation through the microbiome and immune system, relaying information to the germline to alter epigenetic information in the gametes that transmit non-genetically inherited phenotypes to succeeding generations of progeny.

This study also helps contextualize how past environments, experiences, and decisions impact the state of human health. As an example, a major emphasis on hygiene over the last several years has led to a rise in immune overreaction in the form of allergies and autoimmune diseases, which has the potential to alter the microbiome and immune systems, and subsequently inherited information in sperm and eggs.

Who conducted the study

Researchers from Children's Hospital of Philadelphia and the University of Pennsylvania Perelman School of Medicine conducted the study, including corresponding authors Colin Conine, PhD, assistant professor of Pediatrics and Genetics in the Division of Neonatology; Taku Kambayashi, MD, PhD, professor of Pathology and Laboratory Medicine at Penn; and Elizabeth Grice, PhD, associate professor of Dermatology at Penn. Co-authors Adele Harman, technical director of the Transgenic Core at CHOP, and Natalie Trigg, PhD, a postdoc at CHOP in the Conine Lab, contributed to this work.

How they did it

Researchers mated mice models lacking a functional microbiome (germ free) or without any T cells to normal animal models to determine that the microbiome and immune system of parents affect the phenotypes of progeny, grand progeny, and great-grand progeny. They measured inherited phenotypes by RNA-sequencing to quantitate gene expression. Biochemical assays also measured sebum secretion.

To determine that non-genetically transmitted phenotypes were the result of altered epigenetic information in the germline, the study team used in vitro fertilization with the gametes of animal models without a microbiome or T cells. Using these assays, researchers also demonstrated that the sperm and eggs of animals without a microbiome or T cells produced early preimplantation embryos that exhibited altered gene expression. These data provide evidence that microbiota and immune system are responsible for acute changes to skin barrier function and influence phenotypes persistent through generations through altered embryonic development.

Quick thoughts

"While we've known for some time now that the environment experienced by parents prior to conception can influence the phenotypes of offspring non-genetically," Dr. Conine said, "these findings demonstrate that the microbiome and immune system can convey environmental information to the germline to facilitate this transmission of inherited information."

What's next

Future studies will determine the specific mechanisms that control microbe- and immune-related transgenerational non-genetic inheritance of phenotypes. Researchers are interested in understanding how the microbiome and immune system signal the germline to alter epigenetic information in the gametes, learning what epigenetic information is regulated, and how information is programmed in development to encode a non-genetically inherited phenotype.

In addition, future research will help scientists understand what types of more subtle perturbations to the microbiome and immune system trigger signaling to the germline and the transmission of phenotypic diversity to the next generation.

Where the study was published

The study appears in Cell Reports.