Dysbiosis in male mice affects offspring health and placental development

Gut microflora is the microbial community that occupies the gastrointestinal tract. It is responsible for the production of enzymes, metabolites and other molecules vital to host metabolism and in response to the environment.

Consequently, a balanced gut microbiota is important to mammalian health in many ways, including helping to regulate the immune and endocrine systems. This in turn affects the physiology of tissues throughout the body. However, little was known about the impact of gut microbiota on host reproduction and whether an altered microbiota in a father could affect the fitness of his offspring.

The Hackett group at EMBL Rome, in collaboration with the Bork and Zimmermann groups at EMBL Heidelberg, set out to answer this question, with their results now published in the journal Nature. Scientists have shown that disrupting the gut microbiota in male mice increases the likelihood that their offspring will be born with a low birth weight and are more likely to die prematurely. These findings are illustrated in this cartoon.

What happens to the next generation

To study the effects of gut microbiota on male reproduction and their offspring, the researchers changed the composition of the gut microbes in male mice by treating them with common antibiotics that do not enter the bloodstream. This causes a condition called dysbiosis, where the microbial ecosystem in the gut becomes unbalanced.

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

To understand the relationship of this “gut-germline” axis to the traits inherited by the offspring, the scientists mated either untreated or dysbiotic males with untreated females. Mice pups born to dysbiotic fathers showed significantly lower birth weight and increased postnatal mortality. Different combinations of antibiotics as well as treatments with dysbiotic laxatives (which also disrupt the microflora) affected the offspring in a similar way.

Importantly, this effect is reversible. Once the antibiotics are withdrawn, the paternal microflora recovers. When mice with recovered microbiota were mated with untreated females, their offspring were born with normal birth weight and also developed normally.

“We observed that intergenerational effects disappear as soon as a normal microbiota is restored. This means that any change in the gut microbiota that can cause intergenerational effects could be prevented in prospective fathers,” said Peer Bork, Director of EMBL Heidelberg , who participated in the study. “The next step will be to understand in detail how various environmental factors, such as pharmaceutical drugs, including antibiotics, can affect the paternal germline and thus fetal development.” Ayele Denboba, first author of the paper and former postdoctoral fellow at the Hackett Group, now group leader at the Max Planck Institute for Immunology and Epigenetics in Freiburg, Germany, added: “The study was initiated to understand the environmental effects on fathers by considering the gut microbiota as a nexus of host-environment interactions, thus creating a model of sufficient cause for assessing intergenerational health risks in complex ecological systems’.

Paternal influence on pregnancy disease risk

In their work, Hackett and colleagues also found that placental defects, including poor vascularity and reduced growth, occurred more frequently in pregnancies involving dysbiotic males. The defective placentas showed features of a common complication of pregnancy in humans called preeclampsia, which leads to impaired growth in offspring and is a risk factor for developing a wide range of common diseases later in life.

Our study demonstrates the existence of a communication channel between the gut microbiota and the reproductive system in mammals. Furthermore, environmental factors that disrupt these signals in prospective fathers increase the risk of adverse health in offspring by altering placental development. This means that in mice, a father’s environment just before conception can influence offspring traits independent of genetic inheritance.”

Jamie Hackett, research program coordinator and head of the EMBL Rome Group

“At the same time, we find that the effect is only for one generation and I must be clear that further studies are needed to investigate how widespread these effects are and whether they are relevant to humans. There are inherent differences that must be taken into account when translating results from mouse models to humans.” may affect pregnancy outcomes and disease risk in the population.”