Gut bacteria and amino acid imbalance linked to higher miscarriage risk in women with PCOS

A study presented at the 41st Annual Meeting of the European Society of Human Reproduction and Embryology (ESHRE) reveals that women with polycystic ovary syndrome (PCOS) have distinct gut microbiota and metabolic signatures linked to premature endometrial aging and a higher risk of adverse pregnancy outcomes.

The research highlights a sharp reduction in the beneficial gut bacterium Parabacteroides merdae (P. merdae), alongside elevated levels of branched-chain amino acids (BCAAs), particularly isoleucine—an essential amino acid involved in protein production and energy metabolism. Together, these changes may act as potential drivers of poor endometrial function and reproductive complications in women with PCOS.

Affecting up to one in five women of reproductive age globally, PCOS is a major cause of infertility. Although fertility treatments often succeed in helping women with PCOS conceive, they remain at higher risk of complications such as miscarriage, preterm birth, and gestational diabetes. Until now, the mechanisms behind this elevated risk have remained unclear.

“In clinical practice, we noticed that even younger women with PCOS who achieved pregnancy still faced unexpectedly high rates of miscarriage and other complications,” said Dr. Aixia Liu, the lead author of the study.

“Many of these women also had metabolic imbalances and digestive issues, which led us to explore the possible interplay between the gut microbiota, circulating metabolites, and the uterus.”

The prospective study followed 220 women under the age of 35 across 44 cities in China, including 110 PCOS patients and 110 matched controls. Researchers used a combination of gut microbiome sequencing and metabolomics to profile differences between the groups and conducted laboratory studies on endometrial stromal cells (ESCs) to assess aging and decidualization, a process critical for embryo implantation.

Results showed a significant reduction in microbial diversity among PCOS patients, particularly a decrease in P. merdae, a species linked to metabolic health. Serum metabolomics revealed elevated levels of BCAAs, especially isoleucine, and reduced levels of short-chain fatty acids in the PCOS group.

Despite similar pregnancy rates, women with PCOS were nearly twice as likely (1.95 times) to experience at least one adverse pregnancy outcome, including miscarriage, preterm birth, macrosomia, low birth weight, gestational diabetes, hypertensive disorders, and perinatal death.

Further investigation revealed that isoleucine levels were also elevated in endometrial tissue. When researchers exposed ESCs to isoleucine in the lab, they observed increased markers of cellular senescence and reduced capacity for decidualization.

“These findings indicate aging-like changes in the uterus occurring much earlier than expected,” said Dr. Liu. “Our data suggest that high isoleucine levels and the loss of P. merdae may impair endometrial health, even in women under 35.”

The researchers propose that P. merdae and BCAAs could serve as biomarkers for identifying high-risk PCOS patients and may guide personalized treatment approaches in the future.

“The next step is to explore whether dietary interventions, probiotics, or BCAA-restricted diets can reverse these effects and improve pregnancy outcomes,” concludes Dr. Liu.

Professor Dr. Anis Feki, Chair-Elect of ESHRE, added, “The study provides compelling evidence that metabolic and microbial imbalances in PCOS are not only systemic but may directly impair endometrial receptivity, even in younger women. These findings mark a critical step toward personalized reproductive care in PCOS.”

The study abstract will be published in Human Reproduction.