The female reproductive tract microbiotas, inflammation, and gynecological conditions

Abstract

The intricate interactions between the host cells, bacteria, and immune components that reside in the female reproductive tract (FRT) are essential in maintaining reproductive tract homeostasis. Much of our current knowledge surrounding the FRT microbiota relates to the vaginal microbiota, where 'health' has long been associated with low bacterial diversity and Lactobacillus dominance. This concept has recently been challenged as women can have a diverse vaginal microbial composition in the absence of symptomatic disease. The structures of the upper FRT (the endocervix, uterus, Fallopian tubes, and ovaries) have distinct, lower biomass microbiotas than the vagina; however, the existence of permanent microbiotas at these sites is disputed. During homeostasis, a balance exists between the FRT bacteria and the immune system that maintains immune quiescence. Alterations in the bacteria, immune system, or local environment may result in perturbances to the FRT microbiota, defined as dysbiosis. The inflammatory signature of a perturbed or "dysbiotic" FRT microbiota is characterized by elevated concentrations of pro-inflammatory cytokines in cervical and vaginal fluid. It appears that vaginal homeostasis can be disrupted by two different mechanisms: first, a shift toward increased bacterial diversity can trigger vaginal inflammation, and second, local immunity is altered in some manner, which disrupts the microbiota in response to an environmental change. FRT dysbiosis can have negative effects on reproductive health. This review will examine the increasing evidence for the involvement of the FRT microbiotas and inflammation in gynecologic conditions such as endometriosis, infertility, and endometrial and ovarian cancer; however, the precise mechanisms by which bacteria are involved in these conditions remains speculative at present. While only in their infancy, the use of antibiotics and probiotics to therapeutically alter the FRT microbiota is being studied and is discussed herein. Our current understanding of the intimate relationship between immunity and the FRT microbiota is in its early days, and more research is needed to deepen our mechanistic understanding of this relationship and to assess how our present knowledge can be harnessed to assist in diagnosis and treatment of gynecologic conditions.

Keywords: female reproductive tract (FRT); gynecological diseases; immune response; inflammation; microbiome.

Figure 1

Anatomy of the female reproductive tract. A visual depiction of the female reproductive tract (FRT), further subdivided into the upper and lower reproductive tract. The lower reproductive tract consists of the vagina and ectocervix, lined by a stratified squamous epithelium. The endocervix, lined by a monolayer columnar epithelium, and the uterus, Fallopian tubes and ovaries comprise the upper reproductive tract. Adapted from “Female Reproductive System Anatomy,” by BioRender.com (2022). Retrieved from https://app.Biorender.com/Biorender-templates.

Figure 2

Potential mechanism of immune homeostasis with the female reproductive tract microbiotas. (A) Commensal bacteria likely maintain homeostasis by interacting with the epithelial cells via pattern recognition receptors (PRRs) and promoting induction of T-reg cells through different pathways: (1) commensal bacteria play an important role in preserving the epithelial barrier through antimicrobial peptide (AMP) and mucin production, (2&3) commensal bacteria or bacterial metabolites can induce antigen presenting cells, such as dendritic cells (DCs) that favor T-reg selection through production of retinoic acid (RA) and TGF-β, (4) commensals can also facilitate tolerance through signaling and triggering toll-like receptors (TLRs). (B) The loss of commensal bacteria can lead to increased microbial diversity and changes in immune and epithelial homeostasis likely through multiple mechanisms including: (1) production of pro-inflammatory cytokines and chemokines, (2) decrease in T-reg frequency and increase in T-helper cells; ultimately resulting in (3,4&5) cytokine imbalance, barrier disruption, and immune cell recruitment. Created with BioRender.com.

Figure 3

Summary of the female reproductive tract microbiota, inflammation, and therapeutics and diagnostics. (A) An illustration depicting a summary of the vaginal microbiota in homeostasis vs. a dysbiotic state (as in Bacterial vaginosis). In homeostasis, the native bacteria are tolerated by the host immune system, while in a dysbiotic state the bacteria and/or metabolites induce an immune response and inflammation in the host. Barrier disruption can occur as a result. (B) An overview of how the female reproductive microbiotas might be harnessed as potential therapeutics and diagnostics for gynecological conditions involving inflammation and/or dysbiosis in the female reproductive tract. BV, Bacterial vaginosis; STI, sexually transmitted infections. Created with BioRender.com.