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An important area of research is understanding how lifetime exposures to various factors affect fetal and placental development. While maternal influences during pregnancy are direct and varied, paternal impacts are primarily genetic or epigenetic, influenced by factors like stress and diet. Epigenetics refers to heritable traits, or a stable change of cell function, that happen without changes to the DNA sequence. These epigenetic changes are on top of the traditional genetic mechanisms of inheritance.

“The vast community of gut microbes living in our gut functions as a critical interface between us and … the environment…”

The vast community of gut microbes living in our gut functions as a critical interface between us and many influences from the environment (the so called exposome) on our health and disease. This interaction influences human homeostasis, including metabolic and immune networks with widespread consequences on many aspects of health. An extensive body of scientific evidence has demonstrated that environmental factors that unbalance gut microbial ecosystems, in particular diet, lifestyle and antibiotics and environmental toxins can therefore shape physiological and disease-associated responses across different organs.

“…the majority of such research has been performed in rodent models, and has dealt with the prenatal maternal influences on brain development and the immune system.”

While the majority of studies have focused on such influences occurring after birth and in adult individuals, a growing number of publications has reported the ability of prenatal factors affecting the microbiome of the pregnant mother, with downstream effects on the health of the offspring. As previously addressed in this newsletter and in my Mind Gut Conversation podcast episode with Dr. Tracy Bale, the majority of such research has been performed in rodent models, and has dealt with the prenatal maternal influences on brain development and the immune system. For example poor diet, obesity and metabolic syndrome and viral infections in the pregnant mother have all been shown to increase low grade immune activation which can be transmitted via the placenta to the fetus leading to compromised fetal brain development.

However, the systemic impact of the gut microbiome on the germline—and consequently on the first generation offspring it gives rise to—is largely unexplored. Germ line refers to the sex cells (eggs and sperm) that sexually reproducing organisms use to pass on their genomes from one generation to the next (parents to first generation offspring). Egg and sperm cells are called germ cells, in contrast to the other cells of the body, which are called somatic cells.

“Recent research …has expanded the focus on microbiomes from the traditional mother-newborn interaction to a more comprehensive mother-father-newborn model…”

Recent research by Ayele Argaw-Denboba from the European Molecular Biology Laboratory, Epigenetics & Neurobiology Unit, Rome, Italy and colleagues from several European Universities and published in the journal Nature has expanded the focus on microbiomes from the traditional mother-newborn interaction to a more comprehensive mother-father-newborn model, examining how the gut microbiome of male mice influences their offspring’s health through changes in the paternal germline tissue.

“The study found that alterations in the father’s gut microbiome …led to changes in sperm that negatively impacted offspring development…”

The study found that alterations in the father’s gut microbiome, induced by administering non absorbable, gut-specific antibiotics or laxatives, led to changes in sperm that negatively impacted offspring development, resulting in lower birth weights and higher mortality rates. These paternal gut microbiome changes were not associated with compromised health in the fathers. The investigators demonstrated that these effects were conveyed not through genetic inheritance (e.g. via permanent changes in the DNA) but via epigenetic modifications in the sperm, with the negative consequences being reversible once the microbiome returned to normal prior to conception.

“…the potential for the father’s preconception microbiome to affect offspring health, suggesting that fathers contribute more than just genetic material to their progeny…”

As discussed by two editorials to the Argaw-Denboba paper, these findings highlight the potential for the father’s preconception microbiome to affect offspring health, suggesting that fathers contribute more than just genetic material to their progeny. The study highlights the gut microbiota’s role in integrating environmental signals to affect epigenetic components, such as small RNAs and chromatin states, which are crucial for inheritance and phenotype of the next generation. The study also points to the need for further research to understand the specific molecular pathways involved and whether similar effects occur in humans.

In addition, as only laxatives and antibiotics were used to alter the paternal microbiome in the Argaw-Denboba study, and considering the many other factor known to negatively affect the adult gut microbiome including diet, stress and environmental toxins, the study emphasizes the need to evaluate additional environmental factors in males that could lead to negative health outcomes in the offspring. Finally, the research suggest that the paternal microbiome might be a modifiable factor influencing pregnancy health, a novel concept in the biology of human pregnancy.