The impact of microbiota and their metabolites on women's reproductive health.

The gut microbiota affects various organs and metabolic pathways in the gut environment and is also considered a mature endocrine organ. By interacting with estrogen, androgen, insulin, and other hormones, the microbiota plays an important role in the reproductive endocrine system throughout a woman's life. An imbalance in the composition of the gut microbiota can lead to various diseases and conditions, such as pregnancy complications, adverse pregnancy outcomes, polycystic ovary syndrome (PCOS), endometriosis, and cancer.

Increasing evidence obtained in recent years suggests that these microorganisms act almost as an additional organ by actively participating in shaping and maintaining our physiological functions. Many host and environmental factors, including diet, host genes, and hormones, are associated with changes in the gut microbiome. Sex hormones (such as progestogens, estradiol, and androgens) also participate in the communication between the microbiota and its host, playing many important physiological roles in reproduction, differentiation, cell proliferation, apoptosis, inflammation, metabolism, homeostasis, and brain function.

The human microbiome can influence various stages and levels of female reproduction, including follicle and oocyte maturation in the ovaries, fertilization and embryo migration, implantation, and throughout pregnancy, even during childbirth. Changes in the microbiome, particularly the gut microbiome, have specific effects on the reproductive endocrine system, and correcting an abnormal microbiome can improve reproductive outcomes.

Interaction between estrogen and the gut microbiome

The gut microbiota is not only influenced by estrogen but also actively affects estrogen levels. Estrogen is a major regulator of the gut microbiome, and the gene pool of gut microbes that can metabolize estrogen is referred to as the 'estrogenome.'

The expression of estrogen receptor beta (ERβ) and serum concentrations of steroid hormones (especially estradiol) are known to change throughout the life cycle of the organism. Therefore, regulating estrogen is crucial for women's health. Gut bacteria play an important role in estrogen metabolism, and this observation supports the idea that the use of antibiotics can lower estrogen levels. Microbial secreted β-glucuronidase can metabolize estrogen from its conjugated form to its unconjugated form. Malnutrition and reduced gut microbiota diversity can decrease the activity of β-glucuronidase, leading to a reduced ability to decouple estrogen and phytoestrogens into circulating and active forms. A decrease in circulating estrogen can alter the activation of estrogen receptors and may lead to pathological causes of obesity: obesity, metabolic syndrome, cardiovascular diseases, and cognitive decline.

The gut microbiota diversity in postmenopausal women is positively correlated with the ratio of estrogen metabolites in urine. It has been reported that total fat mass and abdominal fat (key factors for the future development of insulin resistance and type 2 diabetes) are increased in postmenopausal women compared to premenopausal women. The gut microbiota plays an important role in regulating estrogen levels and metabolism during menopause. Additionally, the gut microbiota can metabolize estrogen-like compounds from foods such as soy isoflavones, promoting the growth of certain specific bacteria, and supplementation with soy isoflavones can increase the concentration of bifidobacteria, inhibiting the non-classified fusobacteria in postmenopausal women, which plays a beneficial role in promoting gut absorption, immunity, and preventing infections.

The gut microbiota and its products may influence the entire embryonic development, from gamete formation to fertilization, conceptual implantation, placental implantation, miscarriage, delivery of newborns, and metabolic programming and reprogramming during critical periods. Many bacteria present in the digestive tract are also found in the female reproductive tract, including the vagina, endometrium, and placenta. Functionally, the microbiota is a continuum of the reproductive tract and can be disrupted at multiple sites of disease.

Products of the gut microbiota may circulate and affect the female reproductive tract (for example, potentially leading to menstrual cycle disruptions, reproductive tract diseases, and endometriosis), ovarian function, embryonic development, and the health of both mother and fetus. The gut influences gamete formation, embryonic development, and the fertilization process, and changes in the gut microbiota can lead to ovarian dysfunction, PCOS, infertility, and poor IVF outcomes. In pregnant women, the gut microbiota can impact the placenta, pregnancy outcomes, delivery of newborns, infant microbiomes, live birth rates, and fetal growth, development, and survival.

The vaginal microbiome is dynamic and appears to be influenced by the menstrual cycle, dominant microbiota, and sexual activity. Women who experience preterm labor show significantly reduced levels of fragile lactobacilli in the vagina, while levels of amniotic Candida are significantly increased, which is associated with pro-inflammatory cytokines in vaginal fluid. A meta-analysis of five independent studies involving 3,201 samples indicated significant differences in microbial samples between preterm women compared to those with full-term deliveries. Additionally, differences were observed in mid-pregnancy and were consistent across different racial or ethnic backgrounds. The vaginal microbiome of pregnant women can alter the composition of the microbiota that colonizes the newborn's gut. Compared to offspring born via vaginal delivery, the microbiota diversity, structure, and composition in offspring born via cesarean section without prior exposure are significantly reduced. Prenatal stress is also associated with changes in the fetal gut transcriptome and niche, as well as changes in the adult gut, which are caused by additional exposure to stress after adulthood.

Recently, molecular identification of bacterial species in the endometrium has confirmed that the uterine cavity is not sterile. Additionally, the endometrial community also originates from the colonization of specific large colonies, with a significant presence of Bacteroides and Proteobacteria related to the gastrointestinal tract. Several differing opinions suggest that the presence of the uterine microbiome may reflect bacterial invasion rather than a resident microbiome that contributes to health and homeostasis. The presence of bacterial species in the uterine cavity of patients undergoing in vitro fertilization (IVF) negatively impacts implantation and pregnancy rates. The presence of a non-lactobacillus-dominated microbiome in the recipient's endometrium is associated with a significant reduction in implantation rates, pregnancy, ongoing pregnancy, and live birth rates, but the pathogens and their mechanisms interfering with embryo implantation remain unclear. The gut microbiome and its metabolites may influence the immune response of the endometrium and uterus during implantation and placentation, which may be a potential interaction partner of the local microbiome. For example, T cells constitute a large portion of immune cells in the human endometrium, and an appropriate ratio of Th1 and Th2 cells in the endometrium is required to prepare for implantation. The gut microbiome and its metabolites can provide immune-stimulating signals and activate innate and downstream adaptive immune responses, and the differentiation of various T cell subsets in mice with disrupted gut microbiota is impaired. Because T cells reside too much in the deep layers of the endometrium, they are more likely to play a role in early placentation after implantation.

The establishment and maintenance of placental integrity and function are crucial for fetal growth, development, and survival. There is still controversy over whether the placenta has its own colonizing microbiome. A recent report indicated that there is no evidence of bacteria in most complex and uncomplicated pregnancy placental samples. However, in about 5% of pregnant women, a significant pathogen, non-lactose fermenting Streptococcus, was found in the placenta before labor. Another study showed that the microbial content in the placenta is low but metabolically rich, and variations in the placental microbiome are associated with a history of prenatal infections, which may have profound implications for intrauterine infections and preterm birth. According to a recent study on newborns, Escherichia coli is highly present in meconium and is a significant factor in early-onset sepsis in extremely low birth weight newborns, with the placenta potentially being a source of Escherichia coli in newborn meconium. In a recent study, SCFAs in the blood were able to cross the placenta from the maternal gut microbiota into the developing embryo. The regulation of embryonic insulin in embryos from germ-free (GF) mothers is impaired, and insulin levels in adulthood are significantly elevated, providing evidence for the important contribution of the maternal gut environment to the metabolic programming of offspring.

Overall, the gut microbiota is closely related to the health of the female reproductive tract, and the driving force for future research will be to identify targets for therapeutic improvement of reproductive endocrine diseases in women's fertility.

Reference: [1] Qi X, Yun C, Pang Y, et al. The impact of the gut microbiota on the reproductive and metabolic endocrine system[J]. Gut Microbes, 2021.