The gut microbiome has been studied extensively. However, the impact of the gut microbiome on the germline—and on offspring—remains unexplored. Now, a new study shows that disrupting the gut microbiome of male mice increases the risk of disease in their future offspring. More specifically, the researchers showed that disrupting the gut microbiota in male mice increases the probability that their offspring are born with low birth weight, severe growth restriction, and premature mortality. The authors conclude that the “gut microbiota act as a key interface between paternal preconception environment and intergenerational health in mice.”

This work is published in Nature in the paper, “Paternal microbiome perturbations impact offspring fitness.

To study the effects of the gut microbiota on male reproduction and their offspring, the researchers altered the composition of gut microbes—and created dysbiosis—in male mice by treating them with common antibiotics that do not enter the bloodstream.

“The study originated to understand environmental impacts on fathers by considering the gut microbiota as a nexus of host-environment interactions, thus creating a sufficient-cause model to assess intergenerational health risks in complex ecological systems,” noted Ayele Denboba, PhD, currently a group leader at the Max Planck Institute of Immunobiology and Epigenetics in Freiburg, Germany but formerly worked as a postdoctoral researcher in the lab of Jamie Hackett, PhD, EMBL Rome group leader.

The scientists analyzed changes in the composition of important testicular metabolites. They found that dysbiosis in male mice affects the physiology of the testes, as well as metabolite composition and hormonal signaling. At least part of this effect was mediated by changes in the levels of the key hormone leptin in blood and testes of males with induced dysbiosis. These observations suggest that in mammals, a “gut-germline axis” exists as an important connection between the gut, its microbiota, and the germline.

To understand the relevance of this “gut-germline” axis to traits inherited by offspring, the scientists mated either untreated or dysbiotic males with untreated females. Mouse pups sired by dysbiotic fathers showed significantly lower birth weights and an increased rate of postnatal mortality.  Different combinations of antibiotics as well as treatments with dysbiosis-inducing-laxatives (which also disrupt microbiota) affected offspring similarly.

This effect was shown to be reversible. Once antibiotics are withdrawn, paternal microbiota recover. When mice with recovered microbiota were mated with untreated females, their offspring were born with normal birthweight and developed normally as well.

“We have observed that intergenerational effects disappear once a normal microbiota is restored. That means that any alteration to the gut microbiota able to cause intergenerational effects could be prevented in prospective fathers,” said Peer Bork, PhD, director of EMBL Heidelberg. “The next step will be to understand in detail how different environmental factors such as medicinal drugs including antibiotics can affect the paternal germline and, therefore, embryonic development.”

In their work, Hackett and colleagues also discovered that placental defects, including poor vascularization and reduced growth, occurred more frequently in pregnancies involving dysbiotic males. The defective placentas exhibited hallmarks of pre-eclampsia, which leads to impaired offspring growth and is a risk factor for developing a wide range of common diseases later in life.

Credit: European Molecular Biology Laboratory (EMBL), Morphology LLC Voice over: Jessona Sound 

“Our study demonstrates the existence of a channel of communication between the gut microbiota and the reproductive system in mammals. What’s more, environmental factors that disrupt these signals in prospective fathers increase the risk of adverse health in offspring, through altering placental development” said Hackett, who is also a coordinator of the research project. “This implies that in mice, the environment of a father just prior to conception can influence offspring traits independently of genetic inheritance.”

“At the same time, we find the effect is for one generation only,” continued Hackett, “and I should be clear that further studies are needed to investigate how pervasive these effects are and whether they have relevance in humans. There are intrinsic differences to be considered when translating results from mouse models to humans.”

“But given the widespread prevalence of dietary and antibiotic practices in Western culture that are known to disrupt the gut microbiota,” Hackett noted, “it is important to consider paternal intergenerational effects more carefully—and how they may be affecting pregnancy outcomes and population disease risk.”

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