What are the implications of microbial ecosystems for female reproductive health?

By Tarun Sai LomteOct 31 2022Reviewed by Aimee Molineux

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

Background

Microbiota is the sum of microbial populations in a particular environment, whereas the microbiome represents the entire ecosystem, including bacterial and host genomes and environmental factors. These factors contribute to the resultant functionality/dysfunctionality of the ecosystem and affect the metabolic pathways that facilitate crosstalk between organ systems.

It has been revealed that several disorders, such as diabetes, obesity, preterm labor, bacterial vaginosis (BV), and irritable bowel disease (IBD), are associated with an altered microbiota. A growing research interest is focused on the association of gut metabolic activity with 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 microbiome of the vagina has been described as one dominated compositionally by members of the Lactobacillaceae family. They are well-adapted and act as the first line of defense against pathogen colonization. The fermentation by-product, lactic acid, helps maintain a low vaginal pH between 3.5 and 4.2, inhibiting many invading microbes.

Further, lactobacilli produce bacteriocins that function as narrow-spectrum antibiotics and protect the vaginal environment. Researchers identified five distinct community state types (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 sub-types, only CST-IV-B is dysbiotic.

Females shift between CSTs during the menstrual cycle. Various studies have explored CSTs to understand the dynamics of the vaginal microbiome and indicated that healthy women likely maintain a CST for two to three weeks. One study concluded that frequent CST shifts and specific bacterial species strongly predict dysbiosis and symptomatic disorders.

Moreover, inter-species microbial composition variations have been documented across races/ethnicities. African American and Hispanic females favor CST-IV-A, whereas Asian and Caucasian females are Lactobacillus-dominant. CSTs can also change with cyclical changes in estrogen, pH, menses, glycogen content, and the introduction of exogenous bacterial species.

Contributing factors of vaginal dysbiosis

Estrogen increases Lactobacillus levels by increasing the availability of free glycogen in the vaginal mucosa. Declining levels of estrogen and increased pH and iron levels due to menstrual blood along the vaginal canal cause microbial compositional changes, which may increase the vulnerability to pathogens. Estrogen levels also fall after menopause, and post-menopausal females are at an elevated risk of UTIs, BV, and other dysbiosis-related complications.

Semen causes complex changes in the vaginal microbiome. The seminal fluid contains immune-active molecules that promote/inhibit female genital inflammatory reactions and induces changes in the mucosa to increase pregnancy changes. In turn, females have an immunosuppressive mechanism to avert inflammatory responses to semen. Females secrete oxytocin during orgasms, reducing the odds of inflammatory reactions to semen.

Nevertheless, immunosuppression may make women susceptible to deleterious growth of commensals and pathogenic microbes, possibly leading to sexually-transmitted infections (STIs). Besides, contraception can also impact the female microbial environment. Hormonal intra-uterine devices (IUDs) cause changes in estrogen levels leading to protective effects in the vaginal microbiome, whereas oral hormonal birth control can negatively influence the association between estrogen and gut bacteria.

Bacterial vaginosis

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

Moreover, chronic/recurrent BV may increase the risk of infertility and adverse pregnancy outcomes. The first-line therapy recommended for BV is metronidazole/clindamycin. However, it was found that after metronidazole treatment, BV recurred in 58% of females, 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-cell (Th1) or Th17 responses. 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 lead neutrophils and macrophages to generate reactive oxygen species (ROS), which affect the redox potential and pH in the uterus and vagina.

A study observed that women with BV had lower redox potential and, thus, a more reduced environment of the vagina than healthy women. Short-chain fatty acids affect the vaginal redox potential. A reduced environment may result in immunologic changes and overgrowth of BV-related anaerobes in the vaginal ecosystem leading to BV pathogenesis.

Concluding remarks

Defining a eubiotic/healthy microbiome has been elusive. Although correlations are observed between disease states and specific bacterial species, the causal reasons for disease pathogenesis and the factors influencing return to homeostasis are complex.

Though compositional classification is valuable for categorizing the microbiome, reports suggest that the composition of microbes is individualized and occasionally shows correlations with disease states. The authors suggested exploring the current scientific notions/hypothesis through a holistic ecosystem approach to understand what defines health in the urogenital microbiome.