TThe microbiome has a profound influence on the health of the host, which also affects the host’s young. Studies in mice have shown that maternal gut bacteria play a role in offspring behavior and placental growth during pregnancy.1.2 Nevertheless, the effects of the paternal microbiome on the health of their offspring have remained relatively unexplored.
In a new study, scientists found that altering the gut microbiome of male mice through epigenetic changes in sperm negatively impacts the health and lifespan of their offspring.3 The results, published in Natureprovide insights into a 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 well understood, said study co-author Ayele Argaw-Denboba, a reproductive developmental biologist at the Max Planck Institute for Immunobiology and Epigenetics. “When we started the project, we assumed that the effects on the reproductive system could extend to the next generation,” he said.
To study the influence of the paternal microbiome on offspring health, researchers treated male mice with antibiotics or laxatives to cause gut microbial imbalance, or dysbiosis. They then mated these mice with female mice that had a healthy microbiome. Examination of hundreds of the resulting boys, both male and female, found that they had lower birth weights and a higher chance of premature death compared to offspring of fathers with normal microbiomes. The body weight of the pups remained significantly lower throughout development, and transcriptional analyzes of brain and fat cells revealed differences in several genes related to metabolic processes between offspring of control mice and dysbiotic mice.
The researchers also showed that the paternal microbiome recovered within eight weeks of stopping antibiotic treatment. The offspring produced after this restoration were healthy, suggesting that the effects of dysbiosis are short-lived.
The gut microbiota of the offspring was not disrupted, suggesting that the altered paternal microbiome was not passed on to the pups. Next, the researchers examined whether the effects of disrupted gut bacteria are passed on to the next generation via fathers’ sperm. In vitro Fertilization with sperm isolated from antibiotic-treated mice revealed that the offspring had lower birth weights and impaired development, suggesting a gut-germline axis that impacts offspring health. Further experiments showed that some small RNAs were less abundant in the sperm of dysbiotic mice, suggesting that these epigenetic factors – those that do not change the DNA sequence but can influence gene expression – are involved in the transmission of traits across generations are.
Knowing that sperm passed this epigenetic information to their offspring, researchers wondered how dysbiosis affected the paternal reproductive system. They observed that mice with disrupted microbiomes had significantly smaller testes and lower sperm counts compared to healthy mice.
Metabolic profiling of the testis also revealed that microbiome dysbiosis altered the metabolite landscape, particularly metabolites involved in germ cell function and leptin levels, a hormone essential for maintaining reproductive function.4 Transcriptomic analysis confirmed that an altered microbiome caused dysregulation lEptin Gene expression suggesting that leptin signaling is a key component in the gut-germline axis.
To determine the original cause of the defects in the offspring, the researchers analyzed the transcriptome of mid-pregnancy embryos. When they found no differentially expressed genes between embryos from healthy and dysbiotic mice, they turned to examining the placenta at the same stage of pregnancy.
There were clear differences depending on the paternal microbiome. The placentas from embryos from antibiotic-treated mice had smaller surfaces for nutrient exchange, fewer blood vessels and a lower blood supply compared to placentas from embryos from healthy fathers, indicating a higher risk of placental insufficiency.
“We weren’t particularly surprised by the results,” Argaw-Denboba said, in part because previous studies have shown that paternal stress and diet can influence offspring. “But [it] was very exciting because the study is the first to establish a direct link between the gut flora of future fathers and the health of their offspring.” However, the research did not specifically examine which microbial species are involved in the gut-germline axis, said Argaw-Denboba, however, the lab is continuing to pursue this.
Oliver Rando, who studies paternal epigenetic inheritance at the University of Massachusetts Chan Medical School, said the study was thorough and convincing, in part because of the large number of animals used. He found it impressive that restoring the microbiota in future fathers improved the health of their offspring. “This means that fathers are actually ‘telling’ their children things that are much more relevant to the moment, which is quite surprising,” he said. “It really forced me to change the way I think about my own field.”
However, he added that the study did not reveal the exact molecular changes in sperm that affect the health of offspring. Although Rando suspects that the results would also apply to humans, he is not sure, especially because of the different nature of the human and mouse placentas.
Argaw-Denboba had similar thoughts and cautioned that these results from mice may not necessarily apply to humans. However, if this is the case, Argaw-Denboba said, identifying the microbes involved could provide diagnostic markers to predict or support new therapeutic strategies to prevent adverse birth outcomes.