Study: A father's gut microbes affect his future offspring

A recent study shows that disrupting the gut microbiome of male mice increases the risk of their offspring developing the disease in the future.

The gut microbiome is the microbial community that occupies the digestive tract. It is responsible for producing enzymes, metabolites, and other molecules necessary for host metabolism and response to the environment. Thus, a balanced gut microbiome is important for mammalian health in several ways, such as by 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 these gut microbiota on host reproduction, and whether an altered microbiota in the father could influence the fitness of his offspring.

Therefore, researchers at the Hackett Group at the European Molecular Biology Laboratory (EMBL) in Rome, in collaboration with the Bork and Zimmermann groups, tried to answer this question.

The team showed that disrupting the gut microbiota of male mice increases the likelihood that their offspring will be born with a low birth weight, and are more likely to die prematurely.

To study the effects of intestinal microbes on male reproduction and their offspring, researchers modified the composition of the intestinal microbes in male mice by treating them with common antibiotics that do not enter the bloodstream. This leads to a condition called microbiome imbalance, where the gut microbial ecosystem becomes unbalanced.

The team then analyzed changes in the composition of important testicular metabolites. They found that microbiome imbalance in male mice affects testicular physiology, as well as metabolite formation and hormonal signaling.

This effect was modified, at least in part, by changes in levels of the key hormone leptin in the blood and testes of males with induced microbiome imbalance.

These observations suggest that in mammals, the “gut germ line” (sex line is genetic material that can be passed on to offspring) axis exists as an important link between the gut, its microbiota, and the germ line.

To understand the importance of this “gut germline” axis for traits passed down through offspring, the researchers mated males who were not treated with antibiotics or had an imbalanced microbiome to untreated females.

Mice pups sired by microbiome-disrupted parents showed significantly lower birth weights and increased postnatal mortality. Different combinations of antibiotics as well as treatments with microbiome-disrupting laxatives (which also disrupt the microbiota) affected the offspring similarly.

Importantly, this effect is reversible. Once the antibiotics are withdrawn, the parental microbiota recovers.

“We observed that intergenerational effects disappear once the normal microbiota is restored,” said Per Burke, director of the European Molecular Biology Laboratory, who participated in the study. “This means that any change in the gut microbiota capable of causing intergenerational effects can be prevented in parents.” "The next step will be to understand in detail how various environmental factors such as medical drugs, including antibiotics, can affect paternal lineage and thus embryonic development."

The researchers also discovered that placental defects, including poor vascularity and reduced growth, occur more frequently in pregnancies involving an imbalanced male microbiome.

The defective placenta showed hallmarks of a common pregnancy complication in humans known as preeclampsia, which results in poor development of the offspring and is a risk factor for developing a wide range of common diseases later in life.

Jamie Hackett, research project coordinator and group leader at the European Molecular Biology Laboratory in Rome, revealed: “We find that the effect only extends to one generation, and I must point out that further studies are needed to investigate how widespread these effects are and whether they are relevant to humans. There are differences.” "These are essential considerations when translating results from mouse models to humans."