For women trying to conceive later in life, the uterus itself can be just as much of an obstacle as egg quality. Even with the best fertility treatments available, including donor eggs from younger women, older mothers still face higher rates of failed implantation and pregnancy loss. Scientists have long suspected the aging uterus plays a major role, but the biological reasons behind it have been frustratingly hard to pin down. Now, a new study points to a surprising association that hides in plain sight: the gradual disappearance of beneficial bacteria from the uterus as women age.
Researchers from Peking University Third Hospital, writing in the journal Cell Host & Microbe, found that in this study’s cohort, as women grew older, a group of protective bacteria called Lactobacillus declined in the lining of the uterus. That loss was associated with the uterine lining becoming less hospitable to embryos. The scientists also identified a specific member of that bacterial family, Lactobacillus gasseri, and found that treating aged mice with it reduced signs of uterine cellular aging and improved embryo implantation.
Its active ingredient appears to be not the bacterium itself, but a coating-like substance the microbe secretes, called an exopolysaccharide, or EPS. In lab-grown human uterine cells and in mouse tissue, EPS reduced markers of cellular aging, and experiments using a strain engineered to lack EPS showed the substance was responsible for much of the bacterium’s benefit. Researchers describe EPS as an early-stage experimental candidate, one they suggest could eventually be worth exploring as a postbiotic approach, while emphasizing that further pharmacological and translational work would be needed before any clinical use becomes realistic.
What Researchers Found About Age-Related Fertility Decline
To build their case, the team combined human patient data, cell-based lab experiments, and mouse tests. They enrolled 149 women being seen for infertility at a single hospital in Beijing between 2021 and 2022. Participants were divided into three age groups: women under 30, women between 30 and 35, and women 35 and older. During a routine surgical procedure, small tissue samples were collected from the uterine lining of each participant.
Using genetic sequencing techniques that identify bacteria by their unique DNA signatures, the researchers mapped the microbial communities living in each woman’s uterus. They then tracked embryo transfer outcomes over the following year for the subset of women who went on to attempt in vitro fertilization.
At the broader group level, clinical pregnancy rates after embryo transfer did not differ significantly across the three age groups, coming in at 65.0%, 57.1%, and 61.3% respectively, a pattern the researchers attributed to factors such as embryo selection and the limited size of the follow-up group. But when they looked within each age group, women who became pregnant consistently showed higher levels of Lactobacillus in their uterine lining than women who did not. Women who conceived also tended to have higher levels of the species L. crispatus, while those who did not conceive more often had higher levels of L. iners and another bacterium, Gardnerella vaginalis.
Zeroing In on the Right Bacteria
With an association established between uterine bacteria and fertility outcomes, the team set out to identify which specific strain would be most therapeutically useful. They isolated five different Lactobacillus species from the reproductive tracts of healthy women and put each through a series of head-to-head tests, measuring how well each fought off harmful bacteria, how strongly it attached to uterine cells, and how effectively it neutralized the cellular damage associated with aging.
L. gasseri emerged as the strongest overall candidate across multiple measures, particularly in its ability to counteract oxidative stress, essentially the cellular equivalent of rust. Oxidative stress, caused by an accumulation of unstable molecules called free radicals, is one of the main drivers of cellular aging. L. gasseri also produced the highest amount of EPS compared to the other strains tested. The other strains were not without merit: L. delbrueckii showed strong pathogen inhibition and biofilm activity, and L. crispatus demonstrated anti-inflammatory effects in co-culture experiments with uterine cells.
To test whether L. gasseri could actually slow down uterine aging, the researchers treated older female mice with the bacteria delivered directly into the vagina over 28 days. Compared to untreated older mice, the treated animals showed significant reductions in biological markers of cellular aging in their uterine tissue. The treated mice also showed improved embryo implantation rates.
How a Bacterial Substance Appears to Turn Back the Clock
When the team stripped away the bacteria and tested purified EPS alone on lab-grown human uterine cells, the substance reproduced many of the same anti-aging effects. It reduced the proportion of cells showing signs of aging, lowered levels of an inflammatory signaling cluster associated with aging cells, and reduced oxidative stress markers.
Gene expression analysis in mouse uterine tissue pointed to a specific biological pathway as a likely explanation. A communication network inside cells called the Hippo-YAP pathway, which helps regulate how cells grow, age, and respond to stress, was found to be overactive in older uteri. L. gasseri and its EPS appeared to dial that activity back down to healthier levels in the mouse model. When the researchers blocked the key protein in this pathway, called YAP, the protective effects of both the bacteria and their EPS were eliminated, showing that YAP is required for these effects and that Hippo-YAP signaling is at least part of the mechanism at work.
To confirm the link between EPS and these effects, the team also engineered a version of L. gasseri that could not produce EPS. That modified strain lost much of its protective power in mice. When EPS was added back externally, the beneficial effects were largely restored.