The microbiome has a profound impact on host health, and this impact extends to the host’s younger generations. Studies in mice have shown that maternal gut bacteria play a role in child behavior and placental growth during pregnancy. However, the influence of the father’s microbiome on offspring health has remained relatively unexplored.
In a new study, scientists found that altering the gut microbiome of male mice negatively impacts the health and longevity of their offspring through epigenetic changes in sperm. 3 The results, published in Nature, provide insight into the gut germline axis that mediates the gut microbiome. The impact of the microbiome on health and disease across generations.
Although the microbiome can affect nearly every organ system, its effects on the reproductive system were not well understood, said study co-author and researcher at the Max Planck Institute for Immunobiology and Epigenetics. said developmental biologist Aire Argo-Dembova. “When we started the project, we hypothesized that effects on the reproductive system could extend to the next generation,” he says.
To study the influence of a father’s microbiome on his child’s health, researchers treated male mice with antibiotics or laxatives, leading to an imbalance of gut microbes, or dysbiosis. . These mice were then bred with female mice with healthy microbiomes. A study of hundreds of resulting puppies (male and female) revealed that they had lower birth weights and were more likely to die prematurely compared to offspring of fathers with normal microbiomes. . Pup body weight remains significantly lower throughout development, and transcriptional analysis of brain cells and adipocytes reveals differences in several genes related to metabolic processes between offspring of control and dysbiosis mice It became.
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The researchers further showed that the father’s microbiome recovered within eight weeks after stopping antibiotic treatment. Offspring born after this repair were healthy, indicating that the influence of the gut microbiota is short-lived.
The child’s intestinal flora was not destroyed. This suggests that the altered paternal microbiome was not passed on to the puppies. The researchers then investigated whether the effects of disrupted gut bacteria could be passed on to the next generation via the father’s sperm. In vitro fertilization using sperm isolated from mice treated with antibiotics revealed low birth weight and impaired growth in offspring, suggesting that the gut-germline axis influences offspring health. Shown. Further experiments showed that some small RNAs were less present in the sperm of mice with dysbiosis, indicating that these epigenetic factors (which do not change the DNA sequence but may affect gene expression) It was suggested that a certain factor) is involved in the transmission of traits across generations.
Knowing that sperm transmit this epigenetic information to offspring led researchers to wonder how dysbiosis might affect the father’s reproductive system. They observed that mice with disrupted microbiomes had significantly smaller testes and lower sperm counts compared to healthy mice.
Metabolic profiling of testes further reveals that microbiome imbalance alters the metabolite landscape, particularly those involved in germ cell function, and levels of leptin, a hormone essential for maintaining reproductive function It has become. 4 Transcriptomic analysis confirmed that microbiome changes lead to dysregulation, suggesting that leptin signaling is an important component of the gut-germline axis.
To identify the initial cause of the defect in the offspring, the researchers analyzed the transcriptomes of mid-gestation embryos. When they couldn’t find any genes that were differentially expressed in embryos fathered by healthy and dysbiotic mice, they turned to studying placentas at the same stage of pregnancy.
This revealed significant differences depending on the father’s microbiome. Placentas from mouse fetuses treated with antibiotics have a smaller surface area for nutrient exchange, fewer blood vessels, and a reduced blood supply compared to placentas from fetuses with healthy fathers, which may lead to placental insufficiency. Indicates high risk.
“We were not really surprised by this result,” Argo Demboba said. This is also because previous research has shown that fathers’ stress and diet can affect their offspring. “But this study was very exciting because it’s the first to directly link the future father’s gut microbiome to the child’s health.” However, this study did not know which microbial species were aligned along the gut-germline axis. Whether this is the case has not been specifically investigated, Professor Argo Demboba said, but the lab is pursuing this further.
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Oliver Rand, who studies paternal epigenetic inheritance at the University of Massachusetts Chan School of Medicine, said the study was thorough and convincing, in part because of the large number of animals used. He said he was impressed that restoring the future father’s microbiome improves the health of his offspring. “This means that fathers are actually ‘telling’ their children something more real, which is quite surprising,” he says. “It really forced me to think about my field differently.”
However, he added that the study did not reveal the exact molecular changes in sperm that affect the health of the offspring. Rand suspects the results also apply to humans, but he can’t be sure, especially because human and mouse placentas have different properties.
Argaw-Denboba had similar thoughts, cautioning that these results in mice do not necessarily translate to humans. However, if so, identifying the microorganisms involved may provide diagnostic markers to predict or inform new therapeutic strategies to prevent adverse birth outcomes. said Professor Argo Demboba.
