Gut and genital tract microbiomes: Dysbiosis and link to gynecological disorders

Abstract

Every year, millions of women are affected by genital tract disorders, such as bacterial vaginosis (BV), endometrial cancer, polycystic ovary syndrome (PCOS), endometriosis, and uterine fibroids (UFs). These disorders pose a significant economic burden on healthcare systems and have serious implications for health and fertility outcomes. This review explores the relationships between gut, vaginal, and uterine dysbiosis and the pathogenesis of various diseases of the female genital tract. In recent years, reproductive health clinicians and scientists have focused on the microbiome to investigate its role in the pathogenesis and prevention of such diseases. Recent studies of the gut, vaginal, and uterine microbiomes have identified patterns in bacterial composition and changes across individuals' lives associated with specific healthy and diseased states, particularly regarding the effects of the estrogen-gut microbiome axis on estrogen-driven disorders (such as endometrial cancer, endometriosis, and UFs) and disorders associated with estrogen deficiency (such as PCOS). Furthermore, this review discusses the contribution of vitamin D deficiency to gut dysbiosis and altered estrogen metabolism as well as how these changes play key roles in the pathogenesis of UFs. More research on the microbiome influences on reproductive health and fertility is vital.

Keywords: PCOS; endometrium; fibroid; gut microbiome; vaginal microbiome.

Figure 1

Factors affecting the gut microbiota composition. Figure created using BioRender.com.

Figure 2

Estrobolome and estrogen metabolism. (A) Healthy condition. Estrogens are mainly produced by the ovaries, adipose tissue, and adrenal glands and distributed via the bloodstream in a free or protein-bound state. Estrogens and their metabolites can then be conjugated in the liver. Conjugated estrogens are excreted from the liver after metabolic transformation to water-soluble molecules and passed in the bile to the gut. The conjugated estrogens eliminated in the bile can be deconjugated by gut bacteria that have β-glucuronidase activity, leading to estrogen reabsorption into the bloodstream. Circulating estrogens impact target tissues, including the uterus, stimulating cell proliferation. The estrobolome affects estrogen elimination and circulation by regulating the enterohepatic circulation of estrogens. (B) Pathological condition. Altering the estrobolome by increasing the Firmicutes/Bacteroidetes ratio leads to more deconjugated estrogen and more circulating estrogen, impacting specific organs and contributing to multiple diseases such as endometriosis and uterine fibroids. Figures are created using BioRender.com.

Figure 3

Comorbid endometriosis and uterine fibroids that are (A) untreated and (B) treated with gonadotropin-releasing hormone agonist (GnRHa). Excess estrogen exposure is associated with both endometriosis and uterine fibroids (UFs), so estrogen is a target of multiple treatments (e.g., GnRHa and aromatase inhibitors). However, these treatments have local immunosuppressive effects, increasing susceptibility to uterine dysbiosis and subsequent endometriosis (Khan et al., 2014; Qu et al., 2021). Figures are created using BioRender.com.

Figure 4

Effects of vitamin D on the gut and estrogen metabolism. (A) Effect of vitamin D sufficiency: healthy gut. Dominant gut bacteria (including Bacteroidetes) are anti-inflammatory, preserve gut homeostasis, and maintain estrogen metabolite levels, decreasing the incidence of uterine diseases. (B) Effect of vitamin D deficiency: pathological gut. Lower vitamin D level leads to gut inflammation with increased release of interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, and IL-21, which causes gut dysbiosis (involving an increase in the Firmicutes/Bacteroidetes ratio) followed by an increase in the release of unbound estrogen into the circulation. This increases the incidence of uterine fibroids (UFs). Figure created using BioRender.com.