Female reproductive tract-organ axes

Abstract

The female reproductive tract (FRT) and remote/versatile organs in the body share bidirectional communication. In this review, we discuss the framework of the "FRT-organ axes." Each axis, namely, the vagina-gut axis, uterus-gut axis, ovary-gut axis, vagina-bladder axis, vagina-oral axis, uterus-oral axis, vagina-brain axis, uterus-brain axis, and vagina-joint axis, is comprehensively discussed separately. Each axis could be involved in the pathogenesis of not only gynecological diseases but also diseases occurring apart from the FRT. Although the microbiota is clearly a key player in the FRT-organ axes, more quantitative insight into the homeostasis of the microbiota could be provided by host function measurements rather than current microbe-centric approaches. Therefore, investigation of the FRT-organ axes would provide us with a multicentric approach, including immune, neural, endocrine, and metabolic aspects, for understanding the homeostatic mechanism of women's bodies. The framework of the FRT-organ axes could also provide insights into finding new therapeutic approaches to maintain women's health.

Keywords: brain; female reproductive tract; gut; microbiota; oral cavity; ovary; uterus; vagina.

Figure 1

Anatomical overview of the FRT-organ axes. Each axis can be characterized by proximal or distal interactions. Trafficking of bacterial species is a unique aspect of proximal axes compared to other distal axes. However, distal bacterial translocation might occur systemically via the bloodstream, especially in pathological conditions accompanied by the dysregulation of epithelial barrier function.

Figure 2

Proposed mechanisms of vaginal microbiota shaping via the vagina-gut axis. Many factors, such as age, ethnicity, menstrual cycle, lifestyle, immune system, infection, and probiotics, are known to affect the composition of the vaginal microbiota. However, why the human vaginal microbiota is often dominated by a single or a few strains of Lactobacillus is still unknown. Tolerance and promotion of Lactobacillus dominance in the vagina might be regulated via the vagina-gut axis. Immunization with Lactobacillus might occur both in the vagina and the gut. The collection of microorganisms that can metabolize estrogens (coined the estrobolome) can deconjugate hepatically conjugated estrogens in the gastrointestinal tract. Deconjugated estrogen is then reabsorbed to the systemic circulation. Circulating estrogen will affect the distal epithelia of the vagina, resulting in glycogen and mucus production. Then, increased glycogen supports Lactobacillus dominance in the vagina because glycogen can serve as an energy source for lactobacilli. AMPs: antimicrobial peptides and proteins. The established pathways are represented by solid lines. The proposed mechanisms are represented by dotted lines. The estrobolome-driven pathway is represented by green lines.

Figure 3

FRT-organ axes and diseases. Dysregulation of immune, neural, endocrine, or metabolic functions in the FRT-organ axes implicates its involvement in the pathogenesis of not only gynecological diseases but also diseases occurring apart from the FRT. PCOS, polycystic ovary syndrome; UTI, urinary tract infection; BV, bacterial vaginosis; IBD, inflammatory bowel disease; IBS, irritable bowel syndrome.