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.

The microbiome in the reproductive tract influences both women's and their offspring's health [1][2][3][4]. A highly diverse gut microbiota is considered healthy [5]. However, the vaginal microbiota of a healthy reproductive-aged woman is often dominated by only one or two species of Lactobacillus, such as L. crispatus, L. gasseri, L. iners, and L. jensenii [6]. Interestingly, this property is observed only in humans and not in other primates [7][8][9]. Although some hypotheses have been proposed, the mechanism by which Lactobacillus dominates the human vaginal microbiota remains unknown [7,10,11].Various treatments have been used to modify the vaginal microbiota to a Lactobacillusdominant state against dysbiotic conditions. Probiotic treatment of the vaginal microbiota is promising [12]. However, the indigenous vaginal microbiota frequently surpasses the colonization of the probiotic L. crispatus strain (CTV-05 strain) from the vaginal source [13]. After 24 weeks, approximately 50% of patients who received this probiotic did not retain CTV-05 [12]. Consequently, understanding the mechanism to regulate the vaginal microbiota by the host is crucial for developing novel therapies, including probiotics, to address conditions related to vaginal dysbiosis.Immunoglobulins play important roles in regulating homeostasis and microbiota at mucosal sites. In the intestinal tract, immunoglobulin A (IgA) selectively attaches to microbes that have a close relationship with the host mucosa [14]. IgA appears to serve a dual and context-sensitive function, acting to exclude pathogens while facilitating the colonization of beneficial commensals [14]. Immunoglobulin G (IgG) plays a crucial role in promoting mucosal homeostasis in addition to regulating both non-invasive and invasive mucosal bacteria [15]. In contrast to the gastrointestinal tract and other mucosal tissues, the antibodies found in the vagina are primarily IgG instead of IgA [15]. In vagina, IgA, IgG, and IgM participate in immune defense [16]. Although the function of vaginal IgG remains partially understood, it has been noted to capture viruses and protect the host against viral infections [17].Recent advances in IgA-seq have revealed that the prevalence of IgA-coated vaginal bacteria is elevated in L. crispatus-dominant microbiota compared to other microbiota compositions [18]. Another study also reported that the levels of microbial IgA and IgG coating were lowest in individuals with diverse microbiota, particularly among women from ethnic minority groups [19]. Accumulating evidence suggests that IgA-producing cells in the vagina originate from the intestine [20,21]. Furthermore, although IgG levels in cervicovaginal fluid were higher than those of IgA, it was IgA that predominantly coated the bacteria [22]. Therefore, similar to the gastrointestinal tract, I hypothesize that IgA may regulate the composition of the vaginal microbiota in addition to its role in pathogen clearance. In this article, I discuss the possible regulation of the vaginal microbiota by the gut microbiota via IgA. Here, it is hypothesized that IgA induction for Lactobacillus occurs in the small intestine. Subsequently, Lactobacillus-reactive memory/effector cells migrate from the intestine to the vagina and produce Lactobacillus-specific IgA, increasing the number of IgA-coated Lactobacillus. Finally, these IgA-coated Lactobacillus strains promote stable vaginal colonization, highlighting IgA's role in the gut-vagina axis (Figure 1).Bacterial colonization in host organs is regulated by both direct and indirect mechanisms. Direct mechanisms include spatial nutrients or space competition, active antagonism, and metabolite inhibition [23]. The direct mechanisms in the vagina are beyond the scope of this study and have been discussed elsewhere [11]. Indirect mechanisms include mucus barrier function, oxygen limitation, and microbiota-mediated immune responses [23]. In the gut, some bacterial symbionts stimulate the synthesis of polyreactive low-affinity IgA antibodies that may exhibit cross-reactivity with antigens from other bacterial species, which can affect the composition of the microbiota. Indeed, a significant percentage of commensal gut bacteria are coated with IgA antibodies [23].Recently, IgA-seq has revealed that some microbes in the vagina are also coated with IgA and IgG [18,22,24]. IgA and IgG are present in the cervicovaginal secretions bound to L. crispatus, L. iners, Gardnerella vaginalis, and Prevotella bivia [24]. Interestingly, in a L. crispatus-dominant microbiota, the number of IgA-coated vaginal bacteria was found to be increased compared to other microbiota compositions [18]. Therefore, IgA may regulate the vaginal microbiota, although whether it is polyreactive or species-specific remains unclear.Next, where is IgA produced and how does it bind to Lactobacillus? In humans, IgA is classified into two subclasses, IgA1 and IgA2. The levels of IgA1 and IgA2 in the female genital tract secretions are approximately equal [25]. These observed equal ratios of IgA1 and IgA2, coupled with the predominance of polymeric IgA in cervical secretions, indicates that IgA is synthesized locally in the mucosa [25]. Notably, hysterectomy decreased immunoglobulin levels in the vagina, indicating that immunoglobulins generated locally and transferred from the bloodstream by uterine tissues, to some extent, contribute to humoral immunity in the vagina [26]. While B cells represent a small cell population across all female reproductive tract tissues, plasma cells that produce IgA and IgG are primarily located in the cervix and, to a lesser degree, in the vagina [27]. In vivo, initial infection with herpes simplex virus 2 (HSV2) fails to produce plasma cells within the lamina propria of the female reproductive tract. In contrast, upon secondary challenge with HSV2, circulating memory B cells that migrate into the female reproductive tract act as a source of rapid...

The current COVID‐19 pandemic is a global concern. The recent introduction of vaccines has provided a reason for hope, but new problems, such as vaccine hesitancy, have arisen. One of the most important of these issues is the safety of vaccines for pregnant women. In this article, we collected worldwide indications for vaccination, including women who are pregnant or who wish to become pregnant, and reports of adverse reactions to COVID‐19 vaccination. The Japan Society of Obstetrics and Gynecology and the Japanese Society of Infectious Diseases in Obstetrics and Gynecology have published recommendations for the vaccination of pregnant women with a COVID‐19 vaccine. The guidelines are as follows: (1) pregnant women should not be excluded from vaccination; (2) informed consent should be obtained before vaccination; (3) healthcare workers and pregnant women with complications such as diabetes, hypertension, and obesity should be vaccinated preferentially; (4) vaccination should be avoided until 12 weeks of gestation during organogenesis; (5) spouse and family members should be vaccinated actively; and (6) nursing mothers are not particularly affected. This policy has been adopted in government guidelines. Additional efforts should be made to protect pregnant women from infection and severe illness with COVID‐19 by eliminating vaccine hesitancy.

The Zika virus (ZIKV) is well known for causing congenital Zika syndrome if the infection occurs during pregnancy; however, the mechanism by which the virus infects and crosses the placenta barrier has not been completely understood. In pregnancy, TGF-β1 is abundant at the maternal–fetal interface. TGF-β1 has been reported to enhance rubella virus binding and infection in human lung epithelial cells. Therefore, in this study, we investigate the role of TGF-β1 in ZIKV infection in the immortalized human first-trimester trophoblasts, i.e., Swan.71. The cells were treated with TGF-β1 (10 ng/mL) for two days before being inoculated with the virus (American strain PRVABC59) at a multiplicity of infection of five. The results showed an enhancement of ZIKV infection, as demonstrated by the immunofluorescent assay and flow cytometry analysis. Such enhanced infection effects were abolished using SB431542 or SB525334, inhibitors of the TGF-β/Smad signaling pathway. An approximately 2-fold increase in the virus binding to the studied trophoblasts was found. In the presence of the Smad inhibitors, virus replication was significantly suppressed. An enhancement in Tyro3 and AXL (receptors for ZIKV) expression induced by TGF-β1 was also noted. The results suggest that TGF-β1 promotes the virus infection via the Smad pathway. Further studies should be carried out to clarify the underlying mechanisms of these findings.