What are the implications of microbial ecosystems for women’s reproductive health?

In a recent study published in Pathogensresearchers reviewed the current understanding of the composition and temporal dynamics of microbial niches in the female reproductive tract.

Study: The Continuum of Microbial Ecosystems Along the Female Reproductive Tract: Implications for Health and Fertility. Image credit: Orawan Pattarawimonchai/Shutterstock

Background

The microbiota is the sum of microbial populations in a particular environment, while the microbiome represents the entire ecosystem, including bacterial and host genomes and environmental factors. These factors contribute to the resulting ecosystem functionality/dysfunctionality and influence metabolic pathways that facilitate cross-talk between organ systems.

Several disorders, such as diabetes, obesity, preterm birth, bacterial vaginosis (BV), and irritable bowel disease (IBD), have been found to be associated with altered microbiota. Increasing research interest has focused on the relationship of intestinal metabolic activity to urogenital health. In the present study, researchers discussed the composition, temporal dynamics and characterization of microbes in the female reproductive tract.

Vaginal microbiome

A healthy vaginal microbiome has been described as compositionally dominated by members of Lactobacillaceae family. They are well adapted and act as a first line of defense against pathogen colonization. The byproduct of fermentation, lactic acid, helps maintain a low vaginal pH between 3.5 and 4.2, inhibiting many invading microbes.

In addition, lactobacilli produce bacteriocins that function as narrow-spectrum antibiotics and protect the vaginal environment. The researchers identified five different types of community states (CSTs I to V) of the vaginal microbiota. CST-I, -II, -III and -V are dominated by lactobacilli, while CST-IV has both obligate and facultative anaerobes. Of the two CST-IV subtypes, only CST-IV-B is dysbiotic.

Women cycle between CSTs during the menstrual cycle. Various studies have examined CST to understand the dynamics of the vaginal microbiome and show that healthy women are likely to maintain CST for two to three weeks. One study concluded that frequent CST shifts and specific bacterial species strongly predicted dysbiosis and symptomatic disorders.

In addition, interspecies variation in microbial composition has been documented across races/ethnicities. African-American and Hispanic women preferred CST-IV-A, while Asian and Caucasian women were Lactobacillus-dominant. CSTs can also be altered by cyclic changes in estrogen, pH, menstruation, glycogen content, and the introduction of exogenous bacterial species.

Factors contributing to vaginal dysbiosis

Estrogen increases Lactobacillus levels by increasing the availability of free glycogen in the vaginal mucosa. Decreased estrogen levels and increased pH and iron levels due to menstrual blood along the vaginal canal cause changes in the microbial composition, which can increase vulnerability to pathogens. Estrogen levels also drop after menopause, and postmenopausal women are at increased risk for urinary tract infections, BV, and other dysbiosis-related complications.

Sperm causes complex changes in the vaginal microbiome. Seminal fluid contains immunoactive molecules that promote/inhibit inflammatory responses of the female genital organs and cause mucosal changes to increase pregnancy changes. In turn, females have an immunosuppressive mechanism to prevent inflammatory reactions to sperm. Women release oxytocin during orgasm, reducing the likelihood of inflammatory reactions to sperm.

Nevertheless, immunosuppression can make women susceptible to harmful growth of commensals and pathogenic microbes, possibly leading to sexually transmitted infections (STIs). In addition, contraception can also affect a woman’s microbial environment. Hormonal intrauterine devices (IUDs) cause changes in estrogen levels leading to protective effects in the vaginal microbiome, while oral hormonal birth control may negatively affect the relationship between estrogen and gut bacteria.

Bacterial vaginosis

BV is common in women of reproductive and menopausal age and is associated with foul odor and discharge. It is characterized by a decreasing vaginal pH, loss/reduction of lactic acid-producing microbes, and increased levels of facultative microbes and opportunistic anaerobes. One study reported an inverse relationship between symptomatic BV and urobiome diversity. Serious reproductive health outcomes are associated with BV, such as salpingitis, adenomyosis, endometritis, and pelvic inflammatory disease (PID).

Additionally, chronic/recurrent BV may increase the risk of infertility and adverse pregnancy outcomes. The recommended first-line therapy for BV is metronidazole/clindamycin. However, after treatment with metronidazole, BV was found to recur in 58% of women, highlighting the need to improve current therapeutic approaches to BV.

Immune responses and redox potential

Pathogenic bacteria/viruses bind to a toll-like receptor (TLR), triggering type 1 helper T cells (Th1) or Th17 responses. The Th1 response involves macrophages, the cluster of differentiation 8 (CD8+) T cells and interferon (IFN)-γ, while the Th17 response is characterized by interleukin (IL)-17A, IL-17F and IL-22. Pathogenic bacteria cause neutrophils and macrophages to generate reactive oxygen species (ROS), which affect the redox potential and pH in the uterus and vagina.

One study found that women with BV had a lower redox potential and therefore a more reduced vaginal environment than healthy women. Short-chain fatty acids affect the vaginal redox potential. The reduced environment can lead to immunological changes and overgrowth of BV-associated anaerobes in the vaginal ecosystem, leading to BV pathogenesis.

Concluding remarks

Defining a eubiotic/healthy microbiome is elusive. Although correlations have been observed between disease states and specific bacterial species, the causality of disease pathogenesis and the factors influencing the return to homeostasis are complex.

Although compositional classification is valuable for categorizing the microbiome, reports indicate that microbial composition is individualized and sometimes shows correlations with disease states. The authors proposed to examine current scientific concepts/hypotheses through a holistic ecosystem approach to understand what determines health in the urogenital microbiome.

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