TThe microbiome has a profound impact on the health of the host, extending into the host’s juveniles. Studies in mice have shown that the mother’s gut bacteria play a role. puppy behavior And placental enlargement during pregnancy.^1,2 However, the effects of the paternal microbiome on offspring health have remained relatively unstudied.

In a new study, scientists Gut microbiome of male mice negatively affected the health and longevity of their offspring through epigenetic changes in sperm.³ The results were published on: Natureoffers insights into the gut-germline axis that mediates the effects of the microbiome on health and disease across generations.

The microbiome can influence almost all organ systems, but its effects on the reproductive system are not fully understood, one of the study’s authors said. Ayele Argaw-DenbobaReproductive developmental biologist at the Max Planck Institute for Immunobiology and Epigenetics. “When we started the project, we assumed that the impact on the reproductive system could extend to future generations,” he said.

To examine the impact of the paternal microbiome on offspring health, researchers treated male mice with antibiotics or laxatives, causing a gut microbial imbalance, or dysbiosis. They then mated these mice with female mice with healthy microbiomes. A study of hundreds of the resulting offspring, both male and female, found that they had lower birth weights and were more likely to die prematurely compared to offspring of fathers with normal microbiomes. The body weights of the offspring remained significantly low throughout development, and transcriptional analyzes of brain and fat cells revealed differences in several genes related to metabolic processes between control offspring and dysbiotic mice.

The researchers also showed that the paternal microbiome improved within eight weeks of stopping antibiotic treatment. The fact that the offspring conceived after this restoration were healthy indicates that the effect of dysbiosis was short-lived.

The fact that the intestinal microbiota of the offspring was not disrupted suggests that the altered paternal microbiome was not transmitted to the offspring. The researchers then investigated whether the effects of disrupted gut bacteria were transmitted to future generations through fathers’ sperm. in vitro Fertilization using sperm isolated from antibiotic-treated mice revealed that offspring had lower birth weight and impaired development; This points to a gut-germline axis influencing offspring health. Further experiments showed that some small RNAs were less abundant in the sperm of dysbiotic mice; This revealed that these epigenetic factors (factors that do not change the DNA sequence but can affect gene expression) play a role in the transmission of traits across generations.

After learning that sperm carry this epigenetic information to their offspring, researchers wondered how dysbiosis affects the father’s reproductive system. They observed that mice with disrupted microbiomes had significantly smaller testicles and lower sperm counts compared to healthy mice.

Metabolic profiling of the testis also revealed that microbiome dysbiosis alters metabolite structure, particularly metabolites and levels involved in germ cell function. leptinIt is a hormone necessary to maintain reproductive function.⁴ Transcriptomic analysis reveals that an altered microbiome Ieptin Gene expression indicates that leptin signaling is a key component in the gut-germline axis.

To identify the initial source of the defects in the offspring, the researchers analyzed the transcriptome of the embryos halfway through the pregnancy. When they failed to find differentially expressed genes between embryos fathered by healthy and dysbiotic mice, they turned to examining placentas at the same gestational stage.

This revealed significant differences depending on the father’s microbiome. Placentas from embryos from antibiotic-treated mice had smaller surface areas for nutrient exchange, fewer blood vessels, and less blood flow than placentas from embryos with healthy fathers; This indicates a higher risk of placental insufficiency.

“We weren’t particularly surprised by the results,” Argaw-Denboba said, because previous studies had shown that the father’s stress and diet could affect the offspring. “But this was very exciting because this was the first study directly linking the gut microbiota of expectant fathers to offspring health.” However, Argaw-Denboba said that while the study did not specifically investigate which microbial species are involved in the gut-germline axis, the lab is taking this topic further.

Oliver RandoThe study was comprehensive and convincing, in part because of the large number of animals used, said the scientist who studies paternal epigenetic inheritance at the University of Massachusetts Chan School of Medicine. He found it impressive that repairing the microbiota in expectant fathers improved the health of their offspring. “This actually means that fathers are ‘telling’ their children a lot more in the moment, which is quite surprising,” he said. “This really forced me to change the way I thought about my field.”

However, he added that the study did not fully reveal the molecular changes in sperm that affect offspring health. Although Rando suspects the results will hold true in humans, he is unsure, especially given the different nature of human and mouse placentas.

Argaw-Denboba had similar thoughts and cautioned that these results from mice may not necessarily apply to humans. But if they do, identifying the microbes involved could provide diagnostic markers to predict or inform new therapeutic strategies to prevent adverse birth outcomes, Argaw-Denboba said.