While a disrupted gut microbiome has been linked to an altered function of multiple body systems, little is known about its impact on host reproduction and offspring’s well-being. Now a team of scientists at the European Molecular Biology Laboratory (EMBL) in Rome, in collaboration with EMBL Heidelberg, has found that disrupting the gut microbiome in male mice changes the testes and sperm, which increases the risk that their offspring are born with low weight, have growth issues, and die prematurely.
To explore the connection between the gut microbiome and the reproductive system of male progenitors and the health of their offspring, scientists altered the gut microbiome of male mice with non-absorbable antibiotics or osmotic laxatives (polyethylene glycol). As expected, both treatments led to a marked reduction in gut microbiome diversity and abundance.
The mice with disrupted gut microbiomes also had reduced testes size and sperm counts, accompanied by altered metabolite profiles and hormones. Part of this effect was explained by a marked reduction in leptin levels in blood and testes, which could have implications for energy metabolism and reproduction. The other change linked to a disrupted male gut microbiome included placental defects, such as poor vascularization and reduced growth. Sperm from the treated male mice negatively impacted placental development and exhibited hallmarks of pre-eclampsia, leading to restricted normal fetal growth.
To establish a direct link between paternal gut microbiome-induced dysbiosis and traits inherited by offspring, both treated and untreated male mice were paired with untreated female mice for mating. Some of the offspring from treated fathers had lower birth weights, -which is a predictor of metabolic diseases such as diabetes in adulthood-, increased susceptibility to severe growth restriction, and a greater risk of premature death than did offspring of fathers with a normal microbiome. These findings show that different combinations of antibiotics and osmotic laxatives affected offspring similarly, and male mice’s gut microbiome at the time of conception influenced offspring health. The connection between the gut, its microbiome, and the germline was termed the ‘gut-germline axis’ and could also operate in other mammals.
Interestingly, these negative intergenerational effects were reversible once the paternal microbiome was restored naturally after eight weeks of the perturbation. The offspring of mice with recovered microbiomes that were mated with untreated females were born with normal birth weights and developed without growth issues.
These findings suggest that the gut microbiome of male mice could affect their offspring’s health through changes in the paternal germline tissue, highlighting a new mother-father-newborn communication system that complements the current model in which gut colonization takes place mainly after birth. Although it remains to be seen whether similar findings would affect subsequent generations and would be seen in humans, this research suggests that the microbiome could play a role in the intergenerational transmission of disease susceptibility. It is also plausible that the future discovery of molecular pathways by which the disrupted gut microbiome affects the male germline could help to prevent some birth complications in humans.
References:
Argaw-Denboba A, Schmidt TSB, Di Giacomo M, et al. Paternal microbiome perturbations impact offspring fitness. Nature. 2024; 629(8012):652-659. doi: 10.1038/s41586-024-07336-w.
Veerus L, Blaser MJ, Sadovsky Y, et al. Dad’s gut microbes matter for pregnancy health and baby’s growth. Nature news & views forum. 1 May 2024. Available: https://www.nature.com/articles/d41586-024-01191-5
