The female reproductive tract microbiotas, inflammation, and gynecological conditions: mechanisms, therapeutic advances, and future perspectives

Dysbiosis of the FRT microbiota disrupts local homeostasis and triggers inflammation through a series of interconnected physical, immune, and metabolic mechanisms. These mechanisms collectively form the pathophysiological basis linking microbial imbalance to various gynecological diseases. The healthy FRT epithelial cells and their surface mucus layer form the first line of defense against pathogens. Symbiotic microbiota, particularly lactobacilli, help maintain tight and adherens junctions between epithelial cells by producing mucins and other substances ( Baker et al., 2018 ; Radtke et al., 2012 ; Figure 1A ). However, microbial dysbiosis can directly damage this physical barrier. Studies have shown that an increased variety of vaginal microbes is associated with an impaired reproductive tract epithelial barrier, high levels of mucosal inflammation, and an elevated risk of contracting sexually transmitted infections, including HIV ( Kenyon et al., 2013 ; van de Wijgert and Jespers, 2017 ; Figures 1B, C ). The loss of barrier integrity thus creates conditions for pathogen invasion and persistent local inflammation. Core mechanisms linking reproductive tract dysbiosis to inflammation. (A) Healthy homeostasis with dominant Lactobacillus , intact epithelium, low diversity. (B) Dysbiosis with loss of Lactobacillus and increased pathogenic diversity. (C) Consequences: mucosal damage, immune activation, and pro-inflammatory cytokine release. When physical barriers are breached, dysregulated microbiota and their products can directly activate the host’s immune recognition system, triggering a cascade of inflammatory responses. Epithelial cells and immune cells lining the FRT express various pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs) and NOD-like receptors ( Carvalho et al., 2012 ; Horne et al., 2008 ; Mitchell and Marrazzo, 2014 ; Usluogullari et al., 2014 ; Witkin et al., 2007 ; Figure 1C ). When microbes trigger these receptors through their pathogen-associated molecular patterns (PAMPs), such as lipopolysaccharides and lipoproteins, it instigates the release of pro-inflammatory cytokines and chemokines ( Gholiof et al., 2022 ). For example, TLR4 is expressed in the cervix, endometrium, and fallopian tubes and may help regulate immune tolerance in the FRT ( Fazeli et al., 2005 ). Anahtar et al. (2015) posited that cervical-vaginal bacteria could stimulate inflammation by being recognized by epithelial and antigen-presenting cells through the NF-κB and Toll-like receptor pathways. The activation of PRRs ultimately leads to the secretion of multiple potent pro-inflammatory cytokines. Studies show that when PRRs on FRT epithelial cells are activated by microbes, they secrete cytokines including IL-1β, TNF-α, IL-6, and IL-8 ( Villa et al., 2020 ; Figure 1C ). Among these, IL-1β is a pivotal inflammatory mediator that not only directly promotes inflammation but also directs the initial CD4+ T cells toward a pro-inflammatory phenotype in vitro and prompts the expression of other pro-inflammatory cytokines ( Hebel et al., 2011 ). Meanwhile, chemokines, such as IL-8, secreted by epithelial cells are responsible for the recruitment and activation of cells of both the innate and adaptive immune systems, including macrophages and CD8+ cytotoxic T cells ( Villa et al., 2020 ). For example, the site of inflammation attracts activated CCR5+ CD4+ T cells, which are the target cells for HIV infection, via a process involving secreted chemokines ( Gholiof et al., 2022 ). Microbiome metabolic activities profoundly influence the local microenvironment, and their dysregulation directly participates in inflammation regulation. In a healthy state, dominant lactobacilli metabolize glycogen to produce lactic acid, maintaining the vaginal acidic environment (pH 2.8–4.2) and inhibiting the growth of harmful bacteria ( Figure 1A ). Dysbiosis leads to a reduction in lactobacilli, decreased lactic acid production, and an increase in vaginal pH (>4.5) ( Figure 1C ). It is noteworthy that vaginal short-chain fatty acids (SCFAs), such as butyrate and succinate, exhibit a pro-inflammatory effect and weaker antimicrobial activity, unlike the gut microbiota, which produces anti-inflammatory SCFAs ( Amabebe and Anumba, 2020 ; Delgado-Diaz et al., 2020 ; Furusawa et al., 2013 ; Klynstra et al., 1967 ). During vaginal microbiota dysbiosis, elevated SCFA levels could facilitate IL-8 and TNF-α production induced by TLR2 and TLR7 ligands in a dose-dependent manner. Additionally, the pro-inflammatory effects of SCFAs are partly driven by their ability to stimulate the production of reactive oxygen species (ROS) ( Gholiof et al., 2022 ; Mirmonsef et al., 2012 ). Moreover, BV-associated anaerobic bacteria could synthesize amines, such as cadaverine and putrescine, which not only cause typical symptoms but also further elevate pH levels, impair epithelial cell function, and potentially stimulate immune responses ( Figure 1C ).

The female reproductive tract (FRT), especially the vagina, has long been considered to be a sterile environment according to traditional views ( Baker et al., 2018 ; Goldenberg et al., 2008 ; Hansen et al., 2014 ). In fact, it is a complex and dynamic ecosystem composed of bacteria, fungi, viruses, and their metabolites, in conjunction with host cells and immune components ( Bradford and Ravel, 2017 ; Happel et al., 2020 ; Madere and Monaco, 2022 ). Among these, the vaginal microbiota is the largest and best-defined constituent of the FRT, typically characterized by the prevalence of Lactobacillus species ( Chen et al., 2017 ; Gholiof et al., 2022 ). These symbiotic microorganisms are not mere “residents”; they play indispensable roles in maintaining local health through close interactions with the reproductive tract epithelial cells. They metabolize glycogen to generate lactic acid, which keeps the vagina acidic (pH 2.8–4.2) and inhibits the proliferation of potential pathogens ( Alakomi et al., 2000 ; Greenbaum et al., 2019 ; O’Hanlon et al., 2011 , 2013 ; Witkin and Linhares, 2017 ); they compete for adhesion sites and produce antimicrobial substances, such as bacteriocins, to directly resist pathogen invasion ( Aroutcheva et al., 2001 ); and they continuously “communicate” with the host immune system, participating in the regulation of local immune responses and maintaining a moderate immune quiescent state, thereby ensuring reproductive tract homeostasis ( Gholiof et al., 2022 ). However, this delicate balance is not static ( Gholiof et al., 2022 ). Microbial dysbiosis is defined as the absence of Lactobacillus dominance, abnormal elevation in microbial diversity, and overgrowth of specific pathogenic genera ( Chee et al., 2020 ). Increasing evidence indicates that dysbiosis of the reproductive tract microbiota is closely associated with local and systemic chronic low-grade inflammation ( Gholiof et al., 2022 ). Dysbiotic microbiota can activate pattern recognition receptors, such as Toll-like receptors, in epithelial cells through their pathogen-associated molecular patterns, triggering signaling pathways such as nuclear factor kappa B (NF-κB), leading to excessive production of pro-inflammatory cytokines, such as interleukin-1β (IL-1β), interleukin-8 (IL-8), tumor necrosis factor-α (TNF-α), and chemokines ( Anahtar et al., 2015 ; Villa et al., 2020 ). This inflammatory state not only damages the integrity of the reproductive tract epithelial barrier, increasing susceptibility to sexually transmitted pathogens, such as HIV, but also creates a persistent pro-inflammatory microenvironment ( Dabee et al., 2021 ; Kenyon et al., 2013 ; van de Wijgert and Jespers, 2017 ). Based on this, we propose the “microbiota-immune-inflammation” axis as a key framework for understanding the occurrence and development of various gynecological diseases. Current research has clearly demonstrated that microbial dysbiosis and its associated inflammatory response constitute a “common soil” linking a range of gynecological diseases ( Gholiof et al., 2022 ). From common bacterial vaginosis to endometriosis, infertility, especially embryo implantation failure in assisted reproduction, and even malignant tumors such as endometrial, ovarian, and cervical cancers, characteristic microbiota disorder and upregulation of inflammatory markers have been observed. For example, in patients with endometriosis, specific pathogenic bacteria are enriched in the reproductive tract microbiota, mutually promoting the peritoneal inflammatory microenvironment ( Jiang et al., 2021 ); in infertile women, a reduced abundance of Lactobacillus bacteria and an increased presence of other species in the endometrium may impede embryo implantation by provoking local inflammatory responses ( Kyono et al., 2018 ; Moreno et al., 2016 ); in gynecological cancers, chronic inflammation associated with dysbiosis may contribute to tumorigenesis through mechanisms such as inducing genomic instability and promoting cell proliferation and angiogenesis ( Gholiof et al., 2022 ). Therefore, in-depth exploration of the specific mechanisms of the “microbiota-immune-inflammation” axis in different gynecological diseases not only helps to elucidate their pathophysiological basis but also provides a highly promising direction for developing novel diagnostic markers and intervention strategies based on microbiota modulation ( Molina et al., 2020 ).

The female genital microbiota plays a central role in maintaining local homeostasis and defending against pathogen invasion ( Gholiof et al., 2022 ). Among these, the vaginal microbiota–the largest in biomass, approximately 10 10 –10 11 bacteria, and most extensively studied–is typically correlated with a “healthy” state, marked by reduced bacterial diversity and predominant colonization by Lactobacillus species ( Chen et al., 2017 ; Gholiof et al., 2022 ). As Gram-positive, anaerobic rod-shaped bacteria, Lactobacillus species convert vaginal glycogen derivatives into lactic acid, maintaining a vaginal pH in the acidic range of 2.8–4.2 ( Greenbaum et al., 2019 ; O’Hanlon et al., 2013 ; Witkin and Linhares, 2017 ). This low pH environment effectively inhibits the growth of various potential pathogens ( Alakomi et al., 2000 ; O’Hanlon et al., 2011 , 2013 ). Beyond acid production, Lactobacillus maintains host health through multiple mechanisms, including attaching to vaginal epithelial cells, forming a physical barrier through competitive occupation of spatial sites, synthesizing bacteriocins and other compounds toxic to other bacteria, and continuously interacting with the host immune system to assist in regulating inflammatory responses and maintaining immune quiescence ( Aroutcheva et al., 2001 ; Gholiof et al., 2022 ). Research indicates that the vaginal microbiota of women of reproductive age could be classified into distinct community state types (CSTs), most of which are dominated by specific Lactobacillus species. Lactobacillus crispatus dominates CST-I, Lactobacillus gasseri dominates CST-II, Lactobacillus iners dominates CST-III, and Lactobacillus jensenii dominates CST-V ( France et al., 2020 ; Ravel et al., 2011 ; Table 1 ). Notably, the protective effect conferred by Lactobacillus iners appears to be lower than that of other Lactobacillus species ( Petrova et al., 2017 ; Table 1 ). However, this traditional definition of “health” is being challenged. Studies indicate that some asymptomatic and clinically healthy women exhibit diverse microbial compositions or anaerobically dominated vaginal microbiomes like CST-IV ( Table 1 ), suggesting that individualized “healthy” baselines may vary and be influenced by multiple factors including ethnicity, geography, and sociodemographic background ( Ravel et al., 2011 ; Zhou et al., 2007 ). Community state types (CSTs) of vaginal microbiota and their dominant Lactobacillus species. Microbiome dysbiosis refers to a state where the balance of the reproductive tract’s microbial community is disrupted. The most common manifestation of dysbiosis in the vaginal environment is the reduction of Lactobacillus dominance and an abnormal increase in microbial diversity ( Chee et al., 2020 ). Bacterial vaginosis (BV), mainly characterized by reduced Lactobacilli and overgrowth of anaerobic and facultative anaerobic bacteria, is the only clinical diagnosis directly associated with the vaginal microbiome and is the most common vaginal disorder in women of reproductive age, including Gardnerella vaginalis , Prevotella spp., Mobiluncus spp., Atopobium spp., and Sneathia sanguinegens ( Gajer et al., 2012 ; Marrazzo et al., 2002 ). BV correlates closely with elevated vaginal pH (>4.5), the presence of clue cells, and increased levels of inflammatory markers ( Aldunate et al., 2015 ; Gholiof et al., 2022 ). Dysregulated vaginal microbiota form biofilms, which the immune system and antibiotics can’t fully clear, leading to prolonged infections and high BV recurrence rates ( Bradshaw et al., 2006 ; Cerca et al., 2005 ). In addition to typical BV, CST-IV also represents a state of vaginal dysbiosis, inherently indicating a lack of Lactobacillus dominance ( Gajer et al., 2012 ). Studies indicate that inflammatory features of the vaginal microbiota correlate strongly with increased microbial diversity, and CST-IV is a stronger predictor of inflammation than BV infections ( Dabee et al., 2021 ; Lennard et al., 2017 ). The female reproductive tract microbiome is not static but undergoes dynamic regulation by multiple intrinsic and extrinsic factors, including the menstrual cycle, hormones, behaviors, and environmental influences. Longitudinal studies indicate that while the vaginal microbiome remains relatively stable overall, its composition undergoes transient alterations in response to physiological states ( Gajer et al., 2012 ; Ravel et al., 2013 ; Santiago et al., 2011 ; Srinivasan et al., 2010 ). Menstrual blood changes the pH and substrates of the vagina, thereby influencing the composition of its microbes ( Eschenbach et al., 2000 ; Moosa et al., 2020 ). During pregnancy, hormonal levels tend to rise, stabilizing the vaginal microbiota and favoring a Lactobacillus -dominant state ( DiGiulio et al., 2015 ; Romero et al., 2014 ). Major hormonal shifts across life stages profoundly influence the microbiota: Prepuberty features a predominantly anaerobic vaginal microbiota; transition to Lactobacillus dominance upon entering reproductive age; post-menopause, declining estrogen levels cause the microbiota to revert to an anaerobic-dominant composition ( Alvarez-Olmos et al., 2004 ; Brotman et al., 2018 ; Shen et al., 2016 ). Behaviors such as sexual intercourse and the use of vaginal douches are linked to a reduction in vaginal lactobacilli ( Gholiof et al., 2022 ; Moosa et al., 2020 ). Antibiotics disrupt endogenous Lactobacilli, potentially causing dysbiosis ( Bradshaw and Sobel, 2016 ; Verwijs et al., 2020 ). Research indicates elevated perceived stress levels correlate with increased BV risk ( Turpin et al., 2021 ). Host genetic factors, such as Toll-like receptor 4 (TLR4) gene polymorphisms, may also influence vaginal microbiota composition ( Genc et al., 2004 ).

The balance between FRT microbiota and the immune system is crucial for maintaining reproductive health, and disruption of this balance and the accompanying inflammatory response are common features in the onset and progression of various gynecological diseases ( Gholiof et al., 2022 ). Microbial dysbiosis first disrupts the epithelial physical barrier, activates PRR-mediated immune signaling, and alters pro-inflammatory metabolites, these three pathways collectively drive the pathogenesis of BV and its progression to PID. BV is a classic manifestation of vaginal microbiota dysbiosis, characterized by a loss of Lactobacillus dominance and overgrowth of anaerobic bacteria ( Gholiof et al., 2022 ). BV is not only a localized condition but also serves as a “bridge” linking lower genital tract infections to upper genital tract inflammation and complications ( Gholiof et al., 2022 ). Traditionally, the upper reproductive tract was regarded as sterile, but this view has been contested ( Baker et al., 2018 ; Goldenberg et al., 2008 ). Studies have shown that bacteria can travel upward from the cervix ( Hansen et al., 2014 ). Transplanting vaginal microbiota from patients with chronic endometritis into rats leads to exacerbated uterine inflammation, manifested by elevated levels of TNF-α and IL-1β ( Gholiof et al., 2022 ). Similarly, when BV-associated bacteria, such as Prevotella bivia , are transplanted into the rat vagina, these bacteria can ascend to the uterus, thereby triggering inflammation and endometritis-like lesions ( Wang et al., 2021 ), providing direct evidence that BV leads to pelvic inflammatory disease (PID). Furthermore, BV-associated microbial dysbiosis disrupts the stability of the reproductive tract environment ( Campisciano et al., 2018 ; Łaniewski et al., 2020 ). In the presence of BV, vaginal epithelial cells are damaged and undergo increased apoptosis, leading to a disruption in the integrity of the epithelial barrier and thereby inducing chronic inflammation, manifested by elevated concentrations of pro-inflammatory cytokines, such as IL-1β and IL-8, in cervical and vaginal secretions ( Aldunate et al., 2015 ; Gholiof et al., 2022 ; O’Hanlon et al., 2020 ; Roselletti et al., 2020 ). The compromised epithelial barrier and persistent inflammatory environment create conditions conducive to the invasion and ascension of other pathogens, such as Chlamydia trachomatis and Neisseria gonorrhoeae , thereby increasing the risk of PID, infertility, and adverse pregnancy outcomes ( Dabee et al., 2021 ). The epithelial barrier damage, immune overactivation, and pro-inflammatory metabolite accumulation caused by microbiota dysbiosis create a chronic inflammatory microenvironment that directly promotes persistent HPV infection and cervical lesion progression. A healthy, Lactobacillus -dominant vaginal microbiota helps maintain immune stability, whereas a dysbiotic microbiota characterized by high diversity and anaerobic bacteria, e.g., CST-IV type, is associated with significant genital tract inflammation ( Anahtar et al., 2015 ; Gholiof et al., 2022 ). This inflammatory environment is a strong predictor of persistent HPV infection and the progression of cervical lesions ( Gholiof et al., 2022 ). The persistent presence of pro-inflammatory cytokines, e.g., IL-1β, TNF-α, may disrupt the tight junctions of the cervical epithelium and recruit large numbers of HIV-susceptible target cells, e.g., CCR5+ CD4+ T cells ( Anahtar et al., 2015 ). Although this research primarily focused on HIV, the mechanism of inflammatory recruitment of target cells it revealed also helps us understand how disruption of the local immune environment impedes HPV clearance. The cervical microbiome in cervical cancer patients undergoes specific changes, such as a decrease in Lactobacillus abundance and an increase in the proportion of anaerobic bacteria ( Gholiof et al., 2022 ). For example, one study found higher abundance of Fusobacterium spp. in cervical cancer samples, accompanied by elevated levels of immunosuppressive cytokines, e.g., IL-4, TGF-β1 ( Audirac-Chalifour et al., 2016 ). These alterations in microbiota and immune profiles collectively create a microenvironment conducive to persistent HPV infection and the progression of cervical intraepithelial neoplasia (CIN) ( Chambers et al., 2021 ). The association between dysbiosis and inflammation is not limited to HPV related cervical cancer, it is also prevalent in other gynecological malignancies. Taking endometrial cancer as an example, compared with women who are healthy or have benign lesions, patients with endometrial cancer exhibit reduced abundance of Lactobacillus in their uterine and vaginal microbiota, while the abundance of Prevotella , Atopobium , Porphyromonas , Anaerococcus , Dialister , and Peptoniphilus ( Aquino et al., 2024 ; Walsh et al., 2019 ; Walther-António et al., 2016 ; Wang et al., 2022 ). Notably, the coexistence of Atopobium and Porphyromonas , along with a higher vaginal pH (>4.5), has been found to be closely associated with an increased risk of endometrial cancer ( Aquino et al., 2024 ; Walther-António et al., 2016 ). Such abnormalities in microbial composition are not merely concomitant phenomena following tumor onset, the chronic inflammation they induce is considered a core driver of endometrial cancer development ( Ganz, 2003 ). This persistent inflammatory state contributes to tumorigenesis and progression by generating free radicals, causing DNA damage, promoting abnormal cell proliferation, and inducing angiogenesis ( Aquino et al., 2024 ; Ganz, 2003 ). Further clinical studies have revealed that the structural characteristics of the vaginal microbiota are even associated with tumor malignancy ( Hakimjavadi et al., 2022 ). Microbiota α-diversity is positively correlated with the pathological grade of endometrial cancer, as lesions progress from benign uterine lesions to low-grade and high-grade endometrial cancer, the species richness and evenness of distribution in patients’ vaginal microbiota also increase ( Aquino et al., 2024 ; Hakimjavadi et al., 2022 ). Different types of vaginal microbiome community states are also associated with tumor histological types and grades. This suggests that microbiome analysis not only aids in distinguishing between benign and malignant diseases but may also serve as a potential biomarker for predicting tumor aggressiveness ( Aquino et al., 2024 ; Hakimjavadi et al., 2022 ). Collectively, these findings indicate that microbiome dysbiosis in the lower genital tract and uterus plays a significant role in the development and progression of gynecological cancers by shaping a persistent pro-inflammatory, pro-oncogenic microenvironment. Endometriosis, as a chronic inflammatory disease arises in part from the epithelial barrier impairment, immune pathway activation, and pro-inflammatory metabolite shifts induced by reproductive tract dysbiosis. Current evidence suggests a bidirectional association between this disease and dysbiosis of the genital and gut microbiota ( Leonardi et al., 2020 ). Compared to healthy controls, the composition of the genital microbiota in patients with endometriosis has undergone significant changes ( Jiang et al., 2021 ). Specifically, in the cervical and vaginal microbiota, the abundance of Gardnerella , Shigella , Streptococcus , Escherichia coli , and Ureaplasma increased, while the abundance of Atopobacter decreased ( Ata et al., 2019 ). In the endometrial microbiota, the Actinobacteria phylum, Oxalobacteraceae and Streptococcaceae families were enriched ( Wessels et al., 2021 ); whereas in ectopic lesions, there was a decrease in Lactobacillus and an increase in Aliishwanella , Enterococcus , and Pseudomonas ( Hernandes et al., 2020 ). Therefore, microbiota dysbiosis is considered a key driver of endometriosis-associated inflammation. An animal study demonstrated that treatment with broad-spectrum antibiotics or metronidazole significantly reduced endometriotic lesions in mice and decreased pro-inflammatory cytokines IL-1β, IL-6, TNF-α, TGF-β1 in peritoneal fluid ( Chadchan et al., 2019 ; Gholiof et al., 2022 ). This directly demonstrates that the microbiota is involved in the inflammatory response and growth processes of the lesions. In humans, specific bacterial species may drive lesion angiogenesis, proliferation, and immune evasion by activating immune cells, such as macrophages, and releasing pro-inflammatory factors, such as IL-1β and TNF-α ( Gholiof et al., 2022 ). The three core inflammatory mechanisms, including epithelial barrier injury, immune disorder, metabolite imbalance, underlie the adverse effects of microbial dysbiosis on endometrial receptivity, embryo implantation, and assisted reproductive outcomes. The composition of the endometrial and vaginal microbiota has a significant impact on embryo implantation and the success rates of assisted reproductive technologies (ART) ( Li et al., 2020 ), as the endometrium is not sterile. A key study demonstrated that, in women undergoing in vitro fertilization (IVF) with an endometrial microbiome dominated by non-lactobacilli have substantially lower rates of implantation, pregnancy, ongoing pregnancy and live birth ( Moreno et al., 2016 ); conversely, an endometrial environment dominated by lactobacilli is more conducive to embryo implantation ( Kyono et al., 2018 ; Moreno et al., 2016 ). Chronic endometritis is a benign, infection-related condition that frequently leads to poor outcomes in assisted reproduction ( Park et al., 2016 ). When researchers transplanted the vaginal microbiota of patients with chronic endometritis into rats, it triggered severe uterine inflammation in the rats, suggesting that specific pathogenic microbial communities may be associated with recurrent implantation failure ( Gholiof et al., 2022 ). Because the vagina is adjacent to the uterus, the state of its microbiota is predictive of the development of endometritis. When vaginal microbiota diversity is high and lactobacilli are absent, e.g., CST-IV type, this is often accompanied by genital tract inflammation, and such an environment may be unfavorable for maintaining pregnancy ( Anahtar et al., 2015 ; Li et al., 2020 ). Additionally, in women with primary ovarian insufficiency (POF), vaginal microbiota diversity is typically higher, and the abundance of Gardnerella , Prevotella , and Bacteroides genera increases ( Wang et al., 2020 ). Microbial dysbiosis triggers adverse pregnancy outcomes mainly through the epithelial barrier disruption, immune inflammatory cascade, and metabolic disturbance pathways. Vaginal microbiota dysbiosis, particularly BV, is an independent risk factor for preterm birth and is associated with adverse pregnancy outcomes, like preterm birth ( Li et al., 2020 ). During pregnancy, a healthy vaginal microbiota typically stabilizes and is dominated by lactobacilli ( DiGiulio et al., 2015 ; Romero et al., 2014 ). However, an imbalanced vaginal microbiome during pregnancy, specifically an elevated level of bacterial diversity and the existence of anaerobic bacteria, could lead to cervical vaginitis, and this inflammatory state is a key step in triggering the preterm birth pathway ( Short et al., 2021 ). It activates pattern recognition receptors on the surface of epithelial cells and immune cells through dysregulated microbiota and their metabolic by-products, thereby leading to elevated levels of pro-inflammatory cytokines, such as IL-1β, IL-6 and IL-8, and chemokines ( Campisciano et al., 2018 ; Łaniewski et al., 2020 ; Villa et al., 2020 ). In HIV-infected pregnant women, vaginal microbiota diversity is higher and the inflammatory response is more pronounced, which is consistent with their increased risk of preterm birth ( Short et al., 2021 ).

The FRT microbiota, dominated by Lactobacillus , is crucial for mucosal defense, immune balance and reproductive health. Disruption to the microbiota could compromise epithelial integrity, activate pro-inflammatory signals and alter metabolic profiles, creating a persistent inflammatory microenvironment that leads to gynecological disorders. The microbiota-immune-inflammation axis provides a common pathological basis for diseases such as BV, PID, persistent HPV infection, cervical malignancies, endometriosis, infertility and preterm birth. Furthermore, physiological, behavioral, and environmental factors dynamically regulate the FRT microbiota, underscoring the necessity of developing personalized health strategies. Modulating the FRT microbiome in targeted ways, such as restoring Lactobacillus dominance, correcting dysbiosis and alleviating chronic inflammation, represents a highly promising approach to improving the diagnosis, prevention and treatment of gynecological diseases. Future research should optimize microbiome-based biomarkers, develop precision interventions, and elucidate their long-term effects on systemic health to advance clinical translation in the field of reproductive medicine. Additionally, in recent years, artificial intelligence and multi-omics technologies have paved the way for the clinical application of the “microbiota-immune-inflammation” axis ( Chen et al., 2025 ). Machine learning could analyze data on the reproductive tract microbiome and inflammation in order to develop models for precisely diagnosing and predicting the progression of gynecological diseases ( Roy and Verma, 2025 ). Interpretable AI could identify the key mechanisms through which the microbiome regulates inflammation, thereby advancing personalized diagnosis and treatment ( Yuan et al., 2024 ). Meanwhile, integrating multi-omics data helps to systematically elucidate host-microbe interaction mechanisms, accelerating the implementation of precision interventions based on microbiome modulation ( Lin et al., 2025 ). Future efforts should focus on advancing the clinical validation of AI models to support the precise prevention and treatment of women’s reproductive health conditions.