The Microbiome as a Key Regulator of Female Genital Tract Barrier Function

Abstract

The microbiome, the collection of microbial species at a site or compartment, has been an underappreciated realm of human health up until the last decade. Mounting evidence suggests the microbiome has a critical role in regulating the female genital tract (FGT) mucosa's function as a barrier against sexually transmitted infections (STIs) and pathogens. In this review, we provide the most recent experimental systems and studies for analyzing the interplay between the microbiome and host cells and soluble factors with an influence on barrier function. Key components, such as microbial diversity, soluble factors secreted by host and microbe, as well as host immune system, all contribute to both the physical and immunologic aspects of the FGT mucosal barrier. Current gaps in what is known about the effects of the microbiome on FGT mucosal barrier function are compared and contrasted with the literature of the gut and respiratory mucosa. This review article presents evidence supporting that the vaginal microbiome, directly and indirectly, contributes to how well the FGT protects against infection.

Keywords: barrier; female genital tract (FGT); host factors; microbial factors; microbiome; sexually transmitted infection (STI); tissue explant; vagina.

Figure 1

Overview of FGT anatomy and components of barrier function. The FGT is divided generally into an upper (endometrium and endocervix) and a lower (vagina and ectocervix) tract. The lower FGT is considered the primary point of contact for pathogens, and harbors multiple innate immune mechanisms, such as AMPs, mucus, and immunoglobulins that prevent transmission across the epithelial barrier. The epithelium itself is composed of a stratified squamous epithelium that arises from a basement membrane and terminates in fully keratinized, senescent, cells. Microbiota, primarily Lactobacillus, can be found in high abundance within the lower FGT, but have also been shown to be resident within the upper FGT in lower numbers. As the epithelium progresses to the upper FGT it changes to a single columnar epithelium at a junction known as the ‘transformation zone’ between the ectocervix and endocervix. The upper FGT harbors unique uNK populations, as well as lymphoid aggregates consisting of B cells surrounded by CD8⁺ T cells and macrophage. These immune gatekeepers balance immune surveillance and response with the need to maintain a fertile environment for pregnancy. FGT, Female genital tract; IgA, Immunoglobulin A; IgG, Immunoglobulin G; DC, Dendritic cell; NK, Natural killer; uNK, Uterine natural killer; AMP, Antimicrobial peptide.

Figure 2

Different types of models to study cervicovaginal mucosal barrier function. 2D, Two dimensional; 3D, Three dimensional; ECM, Extracellular matrix; ALI, Air-liquid interface; CVL, Cervicovaginal liquid; RWV, Rotating well vessel; CE-OOC, Organ-on-chip cervical epithelial.