Microbiome in Female Reproductive Health: Implications for Fertility and Assisted Reproductive Technologies

Abstract

The microbiome plays a critical role in the process of conception and the outcomes of pregnancy. Disruptions in microbiome homeostasis in women of reproductive age can lead to various pregnancy complications, which significantly impact maternal and fetal health. Recent studies have associated the microbiome in the female reproductive tract (FRT) with assisted reproductive technology (ART) outcomes, and restoring microbiome balance has been shown to improve fertility in infertile couples. This review provides an overview of the role of the microbiome in female reproductive health, including its implications for pregnancy outcomes and ARTs. Additionally, recent advances in the use of microbial biomarkers as indicators of pregnancy disorders are summarized. A comprehensive understanding of the characteristics of the microbiome before and during pregnancy and its impact on reproductive health will greatly promote maternal and fetal health. Such knowledge can also contribute to the development of ARTs and microbiome-based interventions.

Keywords: Assisted reproductive technology; Female reproductive health; Microbial biomarker; Microbiome; Pregnancy.

Figure 1

Lifestyle influences gut microbiome and is associated with reproductive healthA. The impact of healthy lifestyle on gut microbiome and immunity. Active lifestyles such as regular exercise and a high-fiber diet can balance the gut microbiome homeostasis, maintain the gut barrier integrity, and increase the production of SCFAs, which reduce the production of proinflammatory cytokines and down-regulate immune responses and thereby help maintain reproductive health. B. The impact of unhealthy lifestyle on the gut microbiome and immunity. Unhealthy lifestyles such as sedentariness and a high-fat diet disrupt the gut microbiome, which further impairs the gut barrier integrity. The evasion of pathogens stimulates immune cells to produce more proinflammatory cytokines, which subsequently activates the immune responses and potentially induces various diseases related to reproductive health. C. Persistent inflammation in the intestine at different gestational stages may induce adverse pregnancy outcomes such as fertility impairment, spontaneous abortion, and preterm labor. MAMP, microbe-associated molecular pattern; SCFA, short-chain fatty acid; Th1, T helper type 1; Treg, regulatory T; TLR, Toll-like receptor.

Figure 2

Microbial characteristics in the FRTA. Changes in hormones and microbiome before and during pregnancy. As the follicular phase begins, the levels of estrogen and progesterone rise, though the peaks of the two important hormones occur at different stages. Fluctuations in the hormones lead to changes in the vaginal environment and microbiota: an increase in the abundance of Lactobacillus spp. and a decrease in the vaginal pH and microbial diversity, which gradually makes the vaginal context more favorable for conception. It should be noted that the correct order of a complete menstrual cycle is the follicular phase, ovulation, and the luteal phase. B. The role of Lactobacillus on fertility. The decrease of Lactobacillus is associated with lower lactic acid and H₂O₂ levels in the vagina, which further leads to the rise of environmental pH and overgrowth of pathogenic bacteria. The expansion of pathogenic bacteria in the vagina often induces BV and infertility. C. Five CSTs in the vagina. Each CST is dominated by different strains. Among them, four CSTs (CST I, CST II, CST III, and CST V) are dominated by Lactobacillus spp., while CST IV consists of a diverse microbial community. D. Ethnic variations of Lactobacillus proportions in the vagina based on limited studies. The vaginal microbiota of most healthy Caucasian women from North America is dominated by Lactobacillus spp. [111,117], while Asian and black women appear to have a lower proportion of Lactobacillus spp. [111,117]. Nevertheless, further confirmation of this observation is still needed. FRT, female reproductive tract; BV, bacterial vaginosis; CST, community state type.

Figure 3

Microbiome in ARTs and interventionsA. Difference of microbiomes in FRT. The proportion of Lactobacillus spp. and microbial biomass sharply decrease from LGT to UGT, while the alpha diversity of microbiota and sampling difficulty increase. B. General flow of IVF and the impact of different microbial communities on ART outcomes. The IVF process typically involves retrieving eggs and sperm, fertilizing the eggs, culturing and screening the embryos, and finally transferring an appropriate embryo into the maternal uterus. Different microbial communities are associated with different outcomes. Specifically, an LD community is considered to be related to decreased inflammation and more favorable ART outcomes. C. Restoration of vagina microbiome using VMT. VMT is a novel treatment strategy aiming at modifying vaginal microbiota composition and treating vaginal dysbiosis and related conditions. It involves transferring vaginal fluid from a healthy donor to a recipient to reestablish a normal vaginal microbiome. D. Probiotic intervention and immune interaction between the gut and vagina. Probiotics, especially lactic acid-producing bacteria, can positively modulate immune responses in the gut and vagina. This includes stimulating Th2 cells and suppressing Th1 cells, altering cytokine profiles, and modulating tolerance to commensal bacteria, which helps create an optimal immune environment in the vagina that supports healthy microbiota. ART, assisted reproductive technology; IVF, in vitro fertilization; LD, Lactobacillus-dominated; LGT, lower genital tract; NLD, non-Lactobacillus-dominated; UGT, upper genital tract; Th2, T helper type 2; VMT, vagina microbiota transplantation.