Review
Gut and vaginal microbiomes on steroids: implications for women’s health

https://doi.org/10.1016/j.tem.2021.04.014Get rights and content

Highlights

  • Sex steroids modulate the gut and vaginal microbiota, linking their composition and function.

  • The estrobolome and the glycogen-estrogen hypothesis provide a potential pathway linking the gut and vaginal microbiomes through estrogen signaling.

  • The gut and vaginal microbiomes are implicated in a wide range of disorders and disease states affecting women across their lifespan, including polycystic ovary syndrome (PCOS), unexplained infertility, obesity, and endometrial cancer. For example, PCOS is characterized by reduced richness and lower relative abundance of short-chain fatty acid (SCFA)-producing microbes in the gut microbiota, and increased alpha diversity and lower Lactobacillus spp. abundance in the vaginal microbiota.

  • Mounting evidence suggests that steroids and gut microbiota acting via the gut–brain axis influence mental health changes that can occur throughout women’s life phases, including depression, postpartum depression, and anxiety.

This review discusses the interactions of steroids with the gut and vaginal microbiomes within each life phase of adult women and the implications for women’s health. Each phase of a woman’s life is characterized by distinct hormonal states which drive overall physiology of both host and commensal microbes. These host–microbiome interactions underlie disease pathology in disorders that affect women across their lifetime, including bacterial vaginosis, gestational diabetes, polycystic ovary syndrome (PCOS), anxiety, depression, and obesity. Although many associations between host health and microbiome composition are well defined, the mechanistic role of the microbiome in women’s health outcomes is largely unknown. This review addresses potential mechanisms by which the microbiota influences women’s health and highlights gaps in current knowledge.

Section snippets

Estrobolome and the GM

The estrobolome describes the functional collection of all enteric bacterial gene products capable of metabolizing estrogens (Figure 2). In the process of conjugation, estrogens are metabolized in the liver and marked for excretion via urine and feces by the addition of a glucuronic acid moiety [7]. Removal of the glucuronic acid group via deconjugation allows estrogens to remain in the body and exert their effects. Enteric bacteria (e.g., the genera Bifidobacterium, Clostridium, and

Menstrual cycle

E2 and progesterone levels fluctuate across different phases of the menstrual cycle (Figure 1A). The follicular phase is characterized by rising estrogen levels, in particular E2. During the ovulatory phase, E2 peaks when progesterone levels also begin to rise. During the luteal phase the follicle transforms into the corpus which secretes progesterone for stimulation of the secretory endometrium. When pregnancy does not occur, the corpus luteum degenerates and estrogen and progesterone decline

Pregnancy

Endometrial receptivity is guided by progesterone production during the luteal phase. During implantation, progesterone and estrogens regulate important physiologic mechanisms in preparation for embryonic development [57]. Estrogen and progesterone levels increase throughout pregnancy, peak during the third trimester [58], and return to pre-pregnancy values by 5 days postpartum [59] (Figure 1C).

Menopause

Menopause is defined by the permanent cessation of ovarian follicle activity and the lack of a menstrual cycle for 1 year, marking the end of natural reproductive life in women [88]. The period of decline in ovarian function is termed perimenopause and is characterized by increases in follicle-stimulating hormone owing to the lack of follicles and negative feedback from the ovaries [88]. As ovarian activity continues to decrease, the production of E2 and progesterone ceases (Figure 1E). At

Concluding remarks

The interaction between sex steroids and the vaginal and gut microbiomes is a bidirectional axis that profoundly impacts on women’s health across all life stages. The GM modulates circulating estrogens in the estrobolome, and in turn these circulating estrogens help to shape the VM, driving reproductive tract health. The gut and vaginal microbiomes appear to have crucial overlapping functions in various disease states in women’s health. However, there are glaring gaps in our understanding of

Acknowledgments

This work was supported, in part, by Clinical and Translational Science Award (CTSA) grant KL2 TR002379 from the National Center for Advancing Translational Science and a career enhancement award from the National Institutes of Health (NIH; grant P50 CA136393) to M.R.S.W-A., and by Wellesley College Jenkins Distinguished Chair in Neuroscience Funds (to M.J.T.).

Declaration of interests

The Mayo Foundation for Medical Education and Research (inventor M.R.S.W-A.) has been issued a patent 'Methods and Materials for Treating Endometrial Cancer', US10072303B2. The content of the patent relates to the use of the microbiome to address endometrial cancer. M.R.S.W-A. is a member of the scientific advisory board of LUCA Biologics Inc. on research related to urinary tract infections, preterm birth, and reproductive medicine. The other authors declare no conflicts of interest.

Glossary

Bacterial vaginosis (BV)
a state of perturbed bacterial composition in the vagina, often leading to inflammation.
Estradiol (E2)
a major ovarian estrogen steroid hormone.
Gestational diabetes (GD)
the onset of diabetes in pregnancy.
Gut microbiota (GM)
commensal microbes in the gastrointestinal tract, whereas the gut microbiome constitutes all microbes and their associated gene products.
Hypothalamus–pituitary–adrenal (HPA) axis
the primary neuroendocrine pathway comprising the hypothalamus, anterior

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