concept art depicts a cross-section of the intestine, its folds interwoven with leafy forms symbolizing the complex and dynamic microbial ecosystem within. Surrounding the gut are ovarian histology images spanning different ages, representing the progressive structural changes that accompany ovarian aging. Together, the imagery reflects the bidirectional dialogue between the gut and the ovary and highlights the potential of the microbiome as a lever to reshape the trajectory of reproductive aging.
Illustration Credit: Rapheal Williams, Benayoun Laboratory
Scientific Frontline: "At a Glance" Summary: Fecal Transplants and Ovarian Health
- Main Discovery: Fecal transplants from older, estropausal female mice significantly improve ovarian function, reduce tissue inflammation, and enhance overall fertility in younger female mice.
- Methodology: Researchers administered antibiotics to young adult female mice to clear their existing gut bacteria, subsequently remodeling their microbiomes via fecal transplants from either young or older female mouse donors.
- Key Data: One hundred percent of the mice receiving the older microbiome successfully produced pups at an accelerated rate, whereas a portion of the mice receiving the younger microbiome failed to reproduce entirely.
- Significance: Findings demonstrate a dynamic, bidirectional communication between the gut microbiome and the ovaries, revealing that older estrobolome microbes may compensate for aging by increasing molecular signals that boost reproductive vitality in younger, responsive tissue.
- Future Application: Targeted manipulation of gut bacteria and related metabolites could lead to novel microbiome-based therapies to treat infertility, delay menopause, and mitigate age-associated risks like osteoporosis and cardiovascular disease in women.
- Branch of Science: Gerontology, Reproductive Biology, and Microbiology.
- Additional Detail: The research team established a standardized composite ovarian health index that integrates follicle counts and circulating hormone levels to measure and compare ovarian aging rates across future studies.
A new USC study published in Nature Aging 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 Associate Professor Bérénice Benayoun, the study’s senior author.
Microbiome transplants have 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.
To establish a baseline, the researchers first compared the normal microbiomes of young (4-month-old) female mice to those of older (20-month-old) estropausal mice. There were very clear differences in both the relative amounts of various bacteria species and the levels of metabolites involved in hormonal pathways affected by gut bacteria, said Min Hoo Kim, a postdoctoral researcher in the Benayoun lab and the study’s first author.
Kim noted that in recent years, other studies have suggested that microbial transplants from human polycystic ovarian syndrome (PCOS) patients, or from mice with a PCOS-like condition, into healthy mice resulted in decreases in both ovarian health and fertility. This early-stage research plus the team’s baseline findings raised the question of how transplanting an “older” microbiome into a younger animal might affect fertility and ovarian health, she explained.
“Our original hypothesis was that we would see damaging effects of the older microbiome on ovarian function, but surprisingly, we found the opposite,” Kim said.
Benayoun recalled her initial disbelief at the unexpected findings: “When Kim first brought these results to me, I wondered if the labels had been swapped!” But after extensive retesting and replication, the striking results persisted.
“We’ve done multiple different assays from different perspectives,” Kim said. “We did a fertility assay, we looked at serum hormone levels, follicle counts … All of them indicated improvement in ovarian health in the mice that received the fecal transplants from older mice.”
Older microbiomes linked to reproductive rejuvenation
Benayoun and Kim explained that the improvements in ovarian function are readily apparent even on a molecular level. 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. “Even when ignoring the mice that never had pups, the mice that received the older transplants produced pups more quickly than the mice that received the younger microbiome transplants.”
One hypothesis as to why the older microbiome produces these dramatic improvements in health and fertility involves the hormonal interactions between ovaries and gut bacteria, she explained.
A subset of the microbiome called the estrobolome – gut microbes that are involved in estrogen metabolism – 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. It could be a compensatory phenomenon such as this that provides the potent reproductive boost when the older microbiome is transplanted into a younger animal with ovaries that are more responsive to signaling, Benayoun explained.
New treatment hopes and research tools
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. For now, the study adds to a growing body of evidence that the gut microbiome is not merely a bystander in aging but an active participant in shaping how tissues and organs age across the body.
Future research will be needed to determine whether similar mechanisms operate in humans and whether microbiome-based therapies could one day support fertility and healthy aging in women, Benayoun said.
“I feel like we’ve opened a positive can of worms with this study; there are so many new questions,” she said. “If these effects are also seen in humans, it could provide new treatment targets for infertility or menopause symptoms based on which bacteria species and metabolites are most responsible for this rejuvenation.”
During the study, the team also developed a composite “ovarian health index” that integrates follicle counts as well as circulating hormone levels to provide a standardized, integrative measure of ovarian function. The initial baseline findings established both a microbial and physiological signature of ovarian aging; as expected, estropausal mice show significantly reduced ovarian health compared to younger mice. Both Benayoun and Kim said they hope the new composite index will be useful for other researchers and serve as a more comprehensive way to describe and compare ovarian aging rates (and potential rejuvenation strategies) across studies.
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,” Benayoun said. “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.”
Reference material: What Is: Human Microbiome
Funding: The study was supported by the GCRLE-2020 post-doctoral fellowship from the Global Consortium for Reproductive Longevity and Equality at the Buck Institute, made possible by the Bia-Echo Foundation (Min Hoo Kim), USC Provost’s Undergraduate Research Fellowship (Wang), National Institute on Aging T32 AG052374 predoctoral fellowship and Diana Jacobs Kalman/AFAR Scholarships for Research in the Biology of Aging (Lu), and Pew Biomedical Scholar award #00034120 from the Pew Charitable Trust (Benayoun). Other study resources were supported by the National Cancer Institute (P30 CA014089), Eunice Kennedy Shriver National Institute of Child Health and Human Development (R24HD102061), and the USDA Agricultural Research Service (cooperative agreement 58-1950-7-707).
Published in journal: Nature Aging
Title: Estropausal gut microbiota transplant improves measures of ovarian function in adult mice
Authors: Minhoo Kim, Justin Wang, Steven E. Pilley, Ryan J. Lu, Alan Xu, Younggyun Kim, Minying Liu, Xueyan Fu, Sarah L. Booth, Peter J. Mullen, and Bérénice A. Benayoun
Source/Credit: Leonard Davis School of Gerontology | Beth Newcomb
Reference Number: bio030326_01
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