The Father's Gut Microbiota Influences the Next Generation

Researchers altered the composition of the gut microbiota in male mice by common antibiotics, leading to a condition called dysbiosis, and found that mouse pups sired by a dysbiotic father had significantly lower birth weights and an increased risk of growth failure and postnatal mortality.

Gut Microbiota and Offspring Health

The gut microbiota is the microbial community that inhabits the gastrointestinal tract. It is responsible for the production of enzymes, metabolites and other molecules that are critical to the host’s metabolism and response to the environment. Consequently, a balanced gut microbiota is important for mammalian health in many ways, such as regulating the immune and endocrine systems. This in turn affects the physiology of tissues throughout the body. Until now, however, little was known about how the gut microbiota affects the host’s 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 and have now published their results in the journal Nature. The scientists showed that disruption of the gut microbiota in male mice increases the likelihood that their offspring are born with low weight and are more likely to die prematurely.

To investigate the effects of the gut microbiota on male reproduction and their offspring, the researchers altered the composition of the gut microbiota in male mice by treating them with common antibiotics that do not enter the bloodstream. This leads to a so-called dysbiosis, in which the microbial ecosystem in the intestine becomes unbalanced.

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

Influence of Environmental Factors such as Drugs, Including Antibiotics

To understand the importance of this “gut-germline axis” for the inheritance of traits to offspring, the scientists mated either untreated or dysbiotic males with untreated females. Mouse pups sired by dysbiotic fathers had a significantly lower birth weight and a higher postnatal mortality rate. Various combinations of antibiotics and treatments with dysbiosis-inducing laxatives (which also disrupt the microbiota) had a similar effect on the offspring. Importantly, this effect is reversible. As soon as the antibiotics are discontinued, the paternal microbiota recovers. When mice with restored microbiota were mated with untreated females, their offspring were born with normal birth weight and also developed normally.

The researchers observed that the effects between generations disappeared as soon as a normal microbiota was restored. This means that any change in the gut microbiota that could lead to intergenerational effects could be prevented in future fathers. The next step will be to understand in detail how different environmental factors such as drugs, including antibiotics, can affect the paternal germline and therefore embryo development. The study was designed to understand environmental influences on fathers by considering the gut microbiota as a nexus of host-environment interactions, providing a sufficient causal model to assess intergenerational health risks in complex ecological systems.

How the Father Influences the Child’s Risk of Disease

In their work, Hackett and his colleagues also discovered that defects in the placenta, including poor vascularization and reduced growth, were more common in pregnancies with dysbiotic males. The defective placentas showed the characteristics of a common pregnancy complication in humans, known as pre-eclampsia, which impairs the growth of the offspring and is a risk factor for the development of a whole range of common diseases later in life.

The study shows that in mammals there is a communication channel between the gut microbiota and the reproductive system. Furthermore, environmental factors that disrupt these signals in future fathers increase the risk of unfavorable offspring health by altering placental development, the researchers said. This means that in mice, the environment of the father shortly before conception can influence the characteristics of the offspring independently of genetic inheritance.

At the same time, they note that the effect only applies to one generation and that further studies are needed to investigate how far-reaching these effects are and whether they are also significant for humans. Intrinsic differences must be taken into account when extrapolating results from mouse models to humans. Given the widespread prevalence of dietary and antibiotic practices in Western culture that are known to disrupt the gut microbiota, it is important to look more closely at paternal intergenerational effects – and how they might affect pregnancy outcomes and disease risk in the population.