The Effect of Paternal Microbiome on Mice Offspring

The Hackett group at the European Molecular Biology Laboratory (EMBL) have uncovered a link between paternal gut microbiota and offspring health. Results from their study show perturbations (slightly negative alterations) to paternal mice gut microbiota result in low birth weight, growth restriction and premature mortality in their offspring. 

The microbiota

In your gut alone, there are trillions of bacteria, archaea, and eukarya. In fact, the number of these microorganisms in the body has been estimated to be approximately equal to the number of human cells (while some other estimates suggest ten times the number of microorganisms). A majority of this vast population exists in the gastrointestinal tract and is known as the gut microbiota. The gut microbiota are responsible for a range of internal functions, such as helping with digestion, protecting against harmful bacteria, and controlling your immune system. 

Studying gut microbiota offers insights into how these microbes influence digestion, immune function, and even mental health. Research has shown that an imbalanced gut microbiome is linked to various conditions, from obesity to depression. By understanding the gut microbiome, scientists can develop targeted therapies and probiotics to restore balance, improve health outcomes, and potentially prevent or treat a range of diseases. This burgeoning field underscores the intricate connection between our microbial inhabitants and overall well-being.

Dysbiosis, having an altered gut microbiota, has also been associated with the development of inflammatory diseases and infections; previous studies have found that the maternal microbiome can have an effect on offspring health. However, the effect of paternal microbiome perturbations on the germline and mammalian offspring health is unclear. EMBL’s recent study published in Nature sheds some light on the link between the paternal environment and his offspring using mice. 

Epigenetic experiments

Sperm carry information to the next generation through both genetic (DNA) and epigenetic (non-DNA sequence-based) material. Researchers have hypothesised that the epigenetic information carried on to offspring has the potential to be modified by the preconception environment, and therefore could influence offspring phenotype. Such epigenetic material can be affected by the gut microbiome. 

Given the modern diet and the plausible reduction in human gut microbiota diversity, richness, or abundance as a result of food modifications or a less varied diet, these potential changes to our microbiota may impact the health of future generations.

By altering the gut bacterial composition of paternal mice, Jamie Hackett and colleagues at EMBL have explored the impact of the paternal gut microbiome on the health of successive generations, and so the effect of the germline on the next generation. 

Using antibiotics which reduce abundance, diversity and richness of mice gut microbiota, they found the offspring of these mice are smaller, less healthy, and show increased premature mortality compared to the offspring of mice whose gut microbiota has not been antibiotically ‘perturbed’.

Results also showed that leptin, a hormone with a key role in energy homeostasis and reproduction, was especially ‘dysregulated’ as a result of nABX (non-absorbable antibiotics) medication. Perturbation to paternal leptin before conception—as a result of dysbiosis—has an intergenerational effect on offspring gene expression programmes.

Fortunately, the study showed that restoration of gut microbiota (stopping antibiotic supplements and allowing 8 weeks recovery time) rescued emergent F1 (dominant) phenotypes—the effect of nABX-induced dysbiosis is reversible and treatable. 

Using IVF the Hackett group showed that these F1 phenotypes were transmitted specifically through paternal gametes and copurifying molecules—dysbiotic sperm donors produced offspring with similarly significantly reduced neonatal birth weight, postnatal growth and serious growth restriction.

Comparing mice and men

Human and mice microbiota are largely distinct: despite a 62% overlap of mouse microbiota genome and human gastrointestinal genomes at the genus, there is only 10% overlap at the species level. So, there are likely to be variations in the effect of reduced microbiota richness, abundance and diversity in humans compared to mice. This 90% discrepancy may mean drawing a link between the data observed in mice and applying it to human heritable epigenetic material is not applicable. 

The group plans to investigate the relevant inherited phenotypes further, and how these results may be applied beyond mice. However, this microbiota germline link may prove to be of interest in mitigating against unwanted pregnancy outcomes.