Study links gut microbiome health directly to ovarian aging processes

A new study details how fecal transplants from older female mice significantly improve ovarian function and fertility in young mice. The surprising results reveal a direct link between the microbiome (the collection of all bacteria and other microbes present) of the gut and ovarian health and function.

"These findings suggest that there is two-way communication between the ovary and the microbiome and that this communication changes throughout life with age," said USC Leonard Davis School of Gerontology Associate Professor Bérénice Benayoun, the study's senior author.

The study, which appears in the journal Nature Aging, joins a growing body of research on the microbiome and how it interacts with mental health, metabolism, cardiovascular disease and many other conditions in humans.

Future research will be needed to determine whether microbiome-based therapies could one day support fertility and healthy aging in women, Benayoun said.

Unexpected effects on ovarian function

In the study, young adult female mice were first treated with antibiotics to clear their existing gut bacteria, then received fecal transplants to essentially "remodel" their microbiome from the ground up, said Benayoun, who also has appointments in cancer biology and pharmacology and pharmaceutical sciences at USC. The donor microbiomes came from either other young female mice, or older mice that were estropausal, a post-reproductive state akin to human menopause.

"Our original hypothesis was that we would see damaging effects of the older microbiome on ovarian function, but surprisingly, we found the opposite," said Min Hoo Kim, a postdoctoral researcher in the Benayoun lab and the study's first author.

After receiving older microbiome transplants, recipient mice's transcriptomes – the range of messenger RNA transcribed from DNA during the protein-making process – in ovarian cells resembled those of much younger animals. Overall, recipient ovaries also showed substantially reduced markers of inflammation, a well-established marker of tissue aging.

This rejuvenation was reflected not only in the health of ovarian tissue, but also in fertility outcomes. When compared to mice that received younger microbiome transplants, mice that received transplants from older mice showed higher reproductive success. When paired with male mice, "Some of the mice that received the younger microbiome never produced pups, while all of the mice that received the older microbiome did," Benayoun said.

One hypothesis as to why the older microbiome produces these dramatic improvements involves a subset of the microbiome called the estrobolome. This collection of gut microbes is involved in estrogen metabolism and works in tandem with signaling from the reproductive system to maintain hormone balance. However, as ovaries age and respond less to signals originating in the estrobolome, the bacteria involved may increase expression of these molecular signals to compensate, resulting in a reproductive boost when the older microbiome is transplanted into a younger animal with ovaries that are more responsive to signaling, Benayoun said.

New treatment hopes for ovarian aging

In the paper, Benayoun and her coauthors highlight a handful of bacteria species and related metabolic pathways that may be key to the communication taking place between ovaries and gut bacteria. While the findings are based only on mouse models at this time, they point to a potentially transformative idea: that targeted manipulation of the gut microbiome could influence reproductive aging.

Ovarian aging is not only central to fertility but is also associated with increased risks of osteoporosis, cardiovascular disease, and dementia in women. Earlier menopause has been linked to shorter lifespan, making ovarian health a critical factor in overall aging, Benayoun noted.

Menopause isn't just about no longer being fertile."

Bérénice Benayoun, Associate Professor, Leonard Davis School of Gerontology, University of Southern California

"It has dramatic negative effects on women's overall health and is associated with huge increases in risks of diseases ranging from osteoporosis and diabetes to heart disease and dementia. If we could effectively delay menopause, it would help women live longer, healthier lives."