Intestinal dysbiosis in male mice affects offspring health and placental development

The intestinal flora is the microbial community that occupies the gastrointestinal tract. It is responsible for the production of enzymes, metabolites, and other molecules that are important for host metabolism and response to the environment.

A balanced gut microbiome is therefore important for mammalian health in many ways, including helping to regulate the immune and endocrine systems. This affects the physiology of tissues throughout the body. However, little was known about the influence of the gut microbiota on host reproduction or whether changes in the paternal microbiota influence offspring fitness.

The Hackett Group at EMBL Rome, in collaboration with the Bork Group and the Zimmermann Group at EMBL Heidelberg, worked to answer this question, and the results are now published in the journal. Nature. Scientists have shown that disrupting the gut microbiota of male mice increases the likelihood that their offspring will be born with low body weight and die prematurely. These findings are illustrated in this animation.

What is passed down to the next generation

To study the influence of the gut microbiome on male reproduction and their offspring, researchers investigated the effects of gut bacteria in male mice by treating them with common antibiotics that do not enter the bloodstream. The composition of This causes an imbalance in the microbial ecosystem in the intestines, a condition called dysbiosis.

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

To understand the link between this “gut germline” axis and the traits passed on to offspring, researchers mated untreated or dysbiotic males with untreated females. Mice offspring born to fathers with dysbiosis had significantly lower birth weight and increased postnatal mortality. Treatment with different combinations of antibiotics and laxatives that disrupt the gut microbiome (which also disrupts the microbiome) had similar effects on the offspring.

Importantly, this effect is reversible. When antibiotics are discontinued, the father's microbiome recovers. When mice with restored microbiota were bred with untreated females, their offspring were born with normal birth weight and normal development.

Pia Bork, Director of EMBL Heidelberg, who participated in the study, said: “We observed that when the normal microbiota is restored, the intergenerational effects disappear. “The changes mean there may be protection available for potential fathers.” “The next step is to understand in detail how different environmental factors, such as medicines, including antibiotics, can affect the paternal germline and therefore the development of the fetus.” This publication “This study shows that “We set out to understand the environmental impact on fathers by considering the gut microbiome as a microbiome,” he added. This creates a sufficient cause model for assessing intergenerational health risks in complex ecosystems. ”

Paternal influence on disease risk during pregnancy

In their study, Hackett and colleagues also found that placental abnormalities, such as poor vascularization and reduced growth, occur more frequently in pregnancies of men with internal abnormalities. Placental defects are characteristic of a common pregnancy complication in humans called preeclampsia, which causes impaired growth in offspring and is a risk factor for developing a variety of common diseases later in life.

Our study demonstrates the existence of a communication channel between the mammalian gut microbiota and the reproductive system. Furthermore, environmental factors that disrupt these signals in prospective fathers increase the risk of negative outcomes for offspring health by altering placental development. This means that in mice, the father's environment immediately before conception can influence offspring traits independently of genetics. ”

Jamie Hackett, Research Project Coordinator and EMBL Rome Group Leader

“At the same time, we found that this effect is only one generation. Further research is needed to investigate how pervasive these effects are and whether they are relevant to humans. It must be made clear that there are essential differences that should be considered when translating results from mouse models to humans. '' Hackett continued, “However, given the prevalence of dietary and antibiotic practices in Western culture, which are known to disrupt the gut microbiome, patrilineal intergenerational influences are unlikely.'' “It is important to consider more carefully how these affect pregnancy outcomes and population disease risk.” ”