Xiaoyuan Zhang
Juanwen Ma- Department of Gynecology, Lanzhou Maternal and Child Health Care Hospital, Lanzhou, Gansu, China
Persistent infection with human papillomavirus (HPV) is a major pathogenic factor in the development of cervical lesions and cervical cancer. Its occurrence is not only related to the virus itself but also closely associated with the stability of the host vaginal microecological environment. In particular, microbial dysbiosis caused by vaginal infections such as bacterial vaginosis (BV), trichomoniasis (TV), and vulvovaginal candidiasis (VVC) may facilitate HPV acquisition and persistence. Among these factors, VVC has drawn special attention due to its unique bidirectional role: it may promote persistent HPV infection by inducing local inflammation and disrupting epithelial barrier function, while under certain conditions, it may also activate immune responses that suppress viral activity. This dual nature offers novel mechanistic insights into HPV-related cervical pathogenesis. This review systematically summarizes current evidence on the interplay between persistent HPV infection and vaginal microecological imbalance, with a particular focus on the dual regulatory role of VVC and its potential influence on the expression of the HPV oncogenes E6 and E7 oncogenes. By integrating recent mechanistic findings, the review aims to provide a theoretical foundation and clinical reference for microecology-based interventions to improve HPV-related outcomes and prevent cervical lesions.
1 Introduction
The relationship between vaginal microecological dysbiosis and persistent human papillomavirus (HPV) infection, as well as cervical lesions, has attracted growing attention in recent years. Persistent high-risk HPV infection, particularly with types 16 and 18, is a key risk factor for cervical intraepithelial neoplasia (CIN) and cervical cancer (Balasubramaniam et al., 2019). These oncogenic viruses can lead to significant pathological changes in cervical tissues, resulting in a spectrum of lesions ranging from low-grade squamous intraepithelial lesions (LSIL) to high-grade squamous intraepithelial lesions (HSIL) and invasive cervical cancer (Brăila et al., 2025). The interplay between HPV and the vaginal microbiome is complex, as a balanced microbiota is crucial for maintaining vaginal health and preventing infections. Disruptions in this ecosystem, characterized by an overgrowth of pathogenic bacteria or fungi, can create an environment conducive to persistent HPV infections and subsequent cervical lesions (Shen et al., 2024).
The vaginal microbiota is predominantly composed of Lactobacillus species, which play a protective role against infections by maintaining an acidic pH and producing antimicrobial substances (France et al., 2022). However, factors such as hormonal changes, sexual behaviors, and antibiotic usage can disrupt this balance and lead to dysbiosis, characterized by a reduction in both the abundance and diversity of Lactobacillus (Chee et al., 2020). Notably, bacterial vaginosis (BV) and vulvovaginal candidiasis (VVC) often coexist with HPV infection, potentially affecting viral persistence and lesion progression (Liu H. M. et al., 2024). Different vaginal infections may exert distinct influences on the course of HPV infection.
Several studies suggest that VVC has a dual role in HPV infection: it may promote viral persistence by inducing inflammation and disrupting the mucosal barrier, but under certain conditions, VVC-induced immune responses can enhance viral clearance. In contrast, BV is consistently linked to a higher prevalence of HPV infection (Long et al., 2023). Mechanistically, vaginal microecological dysbiosis may promote persistent HPV infection and alter E6/E7 oncogene expression, which can disrupt local immune function and cervical epithelial integrity, facilitating virus–host interaction and cervical lesion development (Huang J. et al., 2023; Pagar et al., 2024).
This review focuses on the association between vaginal microecological dysbiosis, persistent HPV infection, and cervical lesions, with particular attention to the potential bidirectional regulatory role of VVC in this process. Building on this, it further examines how imbalances in the vaginal microbiota may influence the expression of HPV oncogenes E6 and E7, and explores microecological intervention strategies—such as the use of probiotics—as potential approaches for the prevention and management of HPV-related cervical lesions. Overall, a deeper understanding of the interplay between HPV infection and the vaginal microbiome will help advance the development of personalized prevention and treatment strategies and improve the scientific basis for cervical health management in women.
2 Main body
2.1 The relationship between persistent HPV infection and cervical lesions
2.1.1 Classification and distinct pathogenicity of human papillomavirus
High-risk genotypes such as HPV16 and HPV18 are most strongly associated with high-grade CIN and invasive cervical cancer. Persistent high-risk HPV infection drives carcinogenesis through E6 and E7 oncogenes that inactivate tumor suppressor pathways (Wagh et al., 2019).
Persistent infection with HPV16 and HPV18 is strongly linked to high-grade cervical lesions, and co-infection with multiple high-risk types may further increase the risk of progression (Kim et al., 2025; Dickey et al., 2021).
The immune response is crucial in determining HPV infection outcomes; individuals with impaired immunity are more likely to develop persistent infection and cervical lesions (Dom-Chima et al., 2023). Co-infection with pathogens such as Chlamydia trachomatis can exacerbate HPV's effects and further increase dysplasia risk (Mbulawa et al., 2022). Together, these factors highlight persistent HPV infection as the central biological prerequisite upon which additional modulators—such as vaginal microecological disturbances—exert their influence on cervical disease development (Leão et al., 2025).
In summary, persistent high-risk HPV infection, together with host immune dysfunction and co-infections, contributes to the development of precancerous and cancerous cervical lesions (Hong et al., 2025).
2.1.2 Mechanisms of persistent HPV infection
Persistent HPV infection is a key driver of cervical cancer (Jain et al., 2023). HPV evades immune detection through multiple strategies, notably via E6 and E7 proteins that disrupt immune surveillance and inactivate tumor suppressor pathways, promoting infected cell survival and the development of precancerous lesions (Zhao et al., 2024; Pan et al., 2022; Chen et al., 2024).
Beyond viral immune evasion, host immunity critically determines HPV infection outcomes. Individuals with impaired immune function, including older women and those with HIV infection, exhibit higher rates of persistent HPV because of reduced T-cell–mediated viral clearance (Tounkara et al., 2021). Co-infections such as Chlamydia trachomatis and other STIs can further impair immunity and promote HPV persistence, reflecting the combined influence of microbial and host factors (Zhao et al., 2023; Lozar and Carchman, 2025).
Overall, persistent HPV infection reflects the interplay between viral immune-evasion mechanisms and host immune competence, forming the biological basis on which vaginal microecological disturbances—including those induced by VVC—may further influence HPV persistence.
2.1.3 The role of HPV oncogenes E6/E7 in carcinogenesis
E6 and E7 are critical drivers of cervical carcinogenesis. They disrupt cell cycle regulation by inactivating the tumor suppressors p53 and Rb, enabling the survival and proliferation of HPV-infected epithelial cells (Hoppe-Seyler et al., 2021; Liu et al., 2022).
Sustained E6/E7 expression is crucial for maintaining malignancy in HPV-positive cervical cancer. Their continuous activity supports cancer cell survival and proliferation, highlighting E6/E7 as essential biomarkers of disease progression (Liu et al., 2022; Inturi and Jemth, 2021). Moreover, E6 and E7 expression is tightly regulated by multiple factors, including the cellular environment and interactions with viral or host elements (Schichl and Doorbar, 2025). These regulatory influences are particularly relevant when considering how vaginal microecological disturbances—such as those caused by VVC—may indirectly affect HPV oncogene activity.
In summary, E6 and E7 promote HPV-driven carcinogenesis by sustaining the proliferation and survival of infected cells, forming a critical mechanistic basis for understanding factors—including VVC-related dysbiosis—that may modulate HPV persistence and progression (Hoppe-Seyler et al., 2021; Liu et al., 2022).
2.2 Composition and function of the vaginal microecological environment
2.2.1 Composition of normal vaginal microecology
The vaginal microecology, dominated by Lactobacillus species such as L. crispatus, L. gasseri, and L. iners, maintains a protective environment through acid production and antimicrobial activity that suppress pathogenic overgrowth and support local immune homeostasis (Deka et al., 2021). Recent high-throughput sequencing studies have shown that the vaginal microbiota can be classified into community state types (CSTs), with Lactobacillus-dominant CSTs (I, II, III, and V) being associated with low inflammation and reduced susceptibility to persistent HPV infection (Musa et al., 2023; Zhang Y. et al., 2024). In contrast, CST IV—characterized by reduced Lactobacillus abundance and increased microbial diversity—has been consistently linked to epithelial barrier impairment, heightened inflammatory cytokines, and increased risk of persistent high-risk HPV infection (Zhang Y. et al., 2024; Lin et al., 2022; Shen et al., 2022).
Maintaining vaginal microbiome balance is vital for sustaining epithelial barrier integrity. Loss of Lactobacillus dominance predisposes women to dysbiosis, including BV and VVC, and may alter mucosal immunity in ways relevant to HPV persistence (Huang J. L. et al., 2023). Understanding these CST-based ecological patterns is essential for interpreting how VVC-associated disruptions of normocenosis may facilitate HPV persistence through inflammation, immune modulation, and loss of Lactobacillus-mediated antiviral mechanisms (Laghi et al., 2021; Garmendia et al., 2024).
In summary, Lactobacillus-dominant communities therefore serve as a key protective ecological state against HPV persistence, providing the foundational microenvironment on which VVC-induced dysbiosis may exert downstream effects on HPV-related disease (Laghi et al., 2021; Garmendia et al., 2024).
2.2.2 Manifestations and diagnosis of vaginal microbial dysbiosis
Vaginal microbial dysbiosis, marked by an imbalance in the microbiota, often manifests as abnormal discharge linked to BV or VVC. Symptoms such as abnormal discharge and irritation reflect alterations in microbial composition and mucosal inflammation.
Diagnosis of vaginal microbial dysbiosis combines clinical assessment and laboratory testing. Amsel's criteria and the Nugent score are commonly used, with the latter—based on Gram-stained smears—serving as the gold standard; scores ≥7 indicate reduced Lactobacillus and increased anaerobes. Vaginal pH >4.5 also suggests dysbiosis. Molecular methods such as 16S rRNA sequencing now provide finer-resolution profiling of the vaginal microbiota, supporting more precise characterization of dysbiosis relevant to HPV and VVC interactions (Bennett et al., 2020; Li et al., 2025; Wei and Chen, 2021). Beyond sequencing-based approaches, fluorescence in situ hybridization (FISH) has become a useful complementary tool for identifying biofilm-associated BV. Building on the work of Swidsinski's group, recent studies show that FISH can directly visualize dense Gardnerella biofilms on the vaginal epithelium—structural details not captured by Gram staining or 16S profiling (Swidsinski et al., 2023). These findings reinforce BV as a biofilm-driven condition and help clarify its link to persistent HPV infection.
In summary, the diagnosis of dysbiosis provides essential context for understanding how VVC-related microbial shifts may alter susceptibility to HPV acquisition and persistence (Łaniewski et al., 2024; Mazinani et al., 2025; Lee et al., 2022).
2.3 The relationship between vaginal microecological disorder and HPV infection
2.3.1 BV and HPV infection
BV is a major disruption of the vaginal microbiome, marked by reduced Lactobacillus and overgrowth of anaerobes, and is associated with greater susceptibility to high-risk HPV infection. Beyond this compositional shift, BV also features a dense Gardnerella-dominated biofilm adherent to the vaginal epithelium, which protects resident bacteria from immune clearance and sustains chronic low-grade inflammation. This biofilm structure provides protection against host immune clearance and maintains chronic low-grade inflammation, further weakening epithelial tight junctions and amplifying HPV entry opportunities (Shang et al., 2024; Ma et al., 2022). It disrupts the vaginal ecosystem and immune balance, creating inflammation that facilitates HPV entry and persistence, while impaired epithelial integrity and altered immunity further increase infection risk and hinder viral clearance (Long et al., 2023; Martins et al., 2023). Furthermore, inflammatory cytokines released during BV can promote HPV replication and persistence, contributing to the progression of cervical lesions over time.
Statistical data from various studies corroborate the association between BV and increased HR-HPV infection rates. A meta-analysis has shown women with BV are 2.68 times more likely to have HR-HPV (Martins et al., 2023), and a study of 14,679 women found BV is more prevalent in those with cytological abnormalities, suggesting it may also be linked to lesion severity (Long et al., 2023). Additional research has highlighted that the prevalence of BV is notably higher in women with CIN, further establishing BV as a potential co-factor in HPV-related pathogenesis (Zhou et al., 2023). These findings highlight the need to screen for BV in women with HPV, as treating BV may help reduce HPV persistence and the risk of cervical disease progression.
In summary, BV increases susceptibility to HPV and may worsen HPV-related clinical outcomes. Understanding this interaction is vital for developing strategies to prevent and treat cervical cancer, especially in high-risk populations. Targeted management of BV could help reduce HPV persistence and disease progression, underscoring the importance of integrated women's health approaches that consider the vaginal microbiome's role in HPV infection.
2.3.2 Trichomonas vaginalis (TV) and HPV infection
TV is the most common non-viral sexually transmitted infection globally and causes marked disruption of the vaginal microenvironment, promoting HPV persistence. TV infection also produces direct epithelial microabrasions and disrupts tight-junction proteins, creating physical entry portals for HPV (Hinderfeld et al., 2019). In addition, parasite-secreted proteases intensify mucosal inflammation and impair epithelial repair, thereby enhancing HPV's ability to establish persistent infection (Zimmann et al., 2022). It reduces beneficial Lactobacillus populations, impairs local immunity, and creates conditions that enhance pathogen survival and increase susceptibility to HPV infection (Heikal et al., 2023). The inflammatory response to TV increases epithelial HPV receptor expression and also upregulates CD151 and HSPG2, which mediate viral entry (Sheng et al., 2025). Additionally, inflammatory cytokines induced by Trichomonas vaginalis infection create a microenvironment that promotes HPV replication and persistence, increasing the risk of CIN and cervical cancer (Hamar et al., 2023).
Moreover, co-infection with Trichomonas vaginalis and HPV exacerbates cervical lesion severity, with studies showing a higher prevalence of HSIL in women harboring both infections than in those with HPV alone (Idrak et al., 2024). Thus, Trichomonas vaginalis facilitates HPV infection and lesion progression through immune evasion and inflammation. The interaction between TV and HPV highlights the need for comprehensive STI screening and management to reduce cervical cancer risk. Given the high co-infection rates, further studies are warranted to clarify their molecular interplay and guide targeted therapies to improve outcomes in affected women (Hamar et al., 2023).
In conclusion, the complex relationship between Trichomonas vaginalis infection and HPV persistence underscores the need for integrated prevention and treatment strategies.
2.3.3 VVC and HPV infection: a dual perspective
Vulvovaginal candidiasis (VVC), mainly caused by Candida albicans albicans, significantly influences HPV infection dynamics. Candida albicans overgrowth disrupts the vaginal microenvironment and induces inflammation that may promote HPV persistence. A defining pathogenic feature of VVC is the release of Candida albicanslysin, a pore-forming toxin that induces epithelial cell lysis and stimulates a strong IL-1β-dominated inflammatory response (Valentine et al., 2024; Cheng K. O. et al., 2024). This mucosal damage increases exposure of basal keratinocytes—the primary HPV target cells—thereby promoting viral persistence under conditions of dysbiosis. Studies have shown that women with concurrent VVC have a higher likelihood of persistent HPV infection, suggesting that the inflammation caused by fungal infection creates conditions favorable for viral survival (Chen et al., 2025). Furthermore, Candida albicans overgrowth disrupts Lactobacillus dominance, weakening natural defenses against HPV and increasing viral load and cervical lesion risk (Li et al., 2024b). Additionally, the inflammatory cytokines released during VVC further enhance HPV immune evasion, promoting persistence. This dual effect highlights the complex interaction between fungal and viral pathogens and underscores the need to better understand how VVC contributes to HPV-related cervical disease.
Conversely, Candida albicans may also inhibit HPV activity and protect against initial infection under certain conditions. A cross-sectional study found that women with VVC had a lower likelihood of concurrent HPV detection (Gao et al., 2021), possibly due to immune responses induced by Candida albicans that enhance local defenses or through antifungal metabolites that alter the vaginal environment to hinder viral establishment. These effects may vary with host health, hormonal status, and microbiota composition. Thus, while VVC can promote HPV persistence via inflammation, it may also offer transient protection against infection, underscoring the complex, context-dependent nature of VVC–HPV interactions and the need for personalized management strategies.
2.4 The dual role mechanism of VVC and HPV infection
2.4.1 Mechanisms by which VVC promotes persistent HPV infection
VVC, primarily caused by Candida albicans albicans, is increasingly recognized as a factor influencing HPV infection dynamics. It promotes persistent HPV infection by inducing local inflammation and immune modulation. Candida albicans triggers immune cell recruitment, disrupting the epithelial barrier and enhancing HPV entry and persistence. Inflammatory cytokines released during infection can alter receptor expression and co-factors essential for HPV replication, while changes in vaginal pH and microbiome composition further create a favorable environment for viral survival (Long et al., 2023).
Beyond inflammation, virulence factors produced by C. albicans—including secreted aspartyl proteases (SAPs) and Candida albicanslysin—directly damage epithelial tight junctions (e.g., E-cadherin, occludin), increasing the exposure of basal keratinocytes, the primary targets of HPV infection (Bras et al., 2024; Kumar et al., 2022). These structural disruptions facilitate viral access to deeper epithelial layers and promote persistent HPV colonization. VVC-associated dysbiosis with reduced Lactobacillus dominance can weaken lactic-acid–mediated antiviral defense and increase vaginal pH, forming a microenvironment that supports HPV persistence (Bautista et al., 2025). These microecological shifts are consistent with clinical evidence that women with chronic C. albicans infection exhibit higher rates of persistent rather than incident HPV infection (Chen et al., 2025).
An additional mechanism linking VVC to HPV persistence is the formation of Candida albicans biofilms. Biofilm-embedded C. albicans displays enhanced resistance to immune clearance and antifungal therapy, leading to chronic mucosal inflammation (Yan et al., 2025; David and Solomon, 2023). Such persistent inflammation—frequently observed in recurrent VVC—impairs epithelial repair, maintains elevated cytokines, and sustains dysbiosis (Yan et al., 2025). These biofilm-driven alterations favor a shift toward CST IV–like microbiota with reduced Lactobacillus dominance, an ecological profile strongly associated with persistent high-risk HPV infection (Mei et al., 2022). Although direct clinical evidence remains limited, biofilm-associated immune modulation and barrier disruption provide a plausible pathway by which VVC may facilitate prolonged HPV survival.
Furthermore, VVC-induced inflammation may potentiate HPV oncogenic activity. Pro-inflammatory cytokines (e.g., IL-1β, IL-6, TNF-α) activated via NF-κB and JAK/STAT signaling during C. albicans infection have been shown to enhance HPV long control region (LCR) promoter activity, leading to increased E6/E7 transcription (Williams et al., 2011). Oxidative stress generated in inflamed mucosa further augments HPV early gene expression and may promote viral DNA integration. These mechanisms provide the biological basis for subsequent discussions on how VVC-related inflammation may act as an upstream regulator of HPV E6/E7 expression.
In summary, VVC promotes persistent HPV infection through epithelial barrier disruption, inflammatory cytokine activation, oxidative stress, and microecological imbalance, all of which create a permissive environment for HPV survival and oncogene expression. Understanding these mechanisms is essential for developing targeted therapies to restore vaginal microbiota balance and reduce HPV-related risks.
2.4.2 Potential mechanisms of VVC in suppressing HPV infection
VVC exhibits a dual role in HPV infection, although the evidence for a suppressive effect remains much weaker than that for its promoting role. It stimulates innate and adaptive immunity, recruiting macrophages and neutrophils that release cytokines to clear fungi and create conditions less favorable for HPV persistence. Candida albicans-induced activation of Toll-like receptors enhances IFN-γ and TNF-α expression, promoting antiviral defense and, in some cases, reducing HPV load. However, these findings are based on limited and largely cross-sectional evidence, and their reproducibility across populations remains unclear. This effect is context-dependent, influenced by co-infections and host immune status. While VVC may confer transient and modest protection, other infections such as BV show a stronger association with HPV, suggesting that VVC's protective role is minor, inconsistent, and not comparable in strength to its HPV-promoting mechanisms (Long et al., 2023; Wang et al., 2020).
Interactions between Candida albicans and other vaginal microorganisms critically influence HPV dynamics. Under normal conditions, Lactobacillus species maintain microbial balance and protect against pathogens, including HPV. During VVC, Candida albicans overgrowth disrupts this balance, creating a dysbiotic state that may favor HPV and other pathogens. Although some ecological interactions could theoretically reduce the abundance of certain bacteria, such effects have not been shown to meaningfully suppress HPV activity. Instead, VVC-associated increases in pH and microenvironmental changes can promote HPV survival and replication. Given the imbalance in evidence, the HPV-suppressive effect of VVC should be regarded as hypothetical and secondary to its well-established role in supporting HPV persistence (Li et al., 2024b; Fu and Zhang, 2023).
In conclusion, although VVC-related immune activation may exert limited inhibitory effects on HPV under certain conditions, the current evidence is insufficient to place this mechanism on equal footing with the extensively documented pathways through which VVC promotes HPV persistence. Further longitudinal and mechanistic studies are required to clarify the true extent and significance of this proposed suppressive role.
2.4.3 Host factors influencing the interaction between VVC and HPV
The interplay between vaginal microbiota—particularly VVC—and HPV infection is strongly shaped by host immune and hormonal factors. A healthy, Lactobacillus-dominant microbiota supports robust immune responses that facilitate HPV clearance, whereas dysbiosis in VVC can weaken local defenses, promoting viral persistence and cervical lesion development (Kazlauskaite et al., 2025). Hormonal fluctuations from menstruation, pregnancy, or contraceptive use further influence microbiome composition and immunity; while estrogen favors Lactobacillus growth, other hormonal shifts may increase susceptibility to both VVC and HPV (Cui et al., 2025). These combined effects create conditions that can sustain HPV infection and drive progression toward cervical dysplasia and cancer.
Individual factors, including genetic predisposition and lifestyle, further influence the dual role of VVC in HPV interactions. Variations in immune-related genes can alter host responses to HPV, with certain polymorphisms linked to increased risk of persistent infection and cervical lesion development (Na et al., 2025). Additionally, lifestyle factors, including smoking, diet, and sexual behavior, affect the vaginal microbiome and immunity, and smoking is a notable risk factor for persistent HPV, likely via immunosuppression that worsens dysbiosis and HPV-related complications (Zukiene et al., 2025). Furthermore, individual variations in vaginal microbiota, shaped by factors such as sexual activity and hygiene practices, also affect susceptibility to VVC and HPV co-infections. These differences underscore the need for personalized approaches to understanding host–microbiome interactions, which could guide targeted prevention and treatment strategies for cervical cancer (Ventura et al., 2024).
In summary, the relationship between VVC and HPV is shaped by host factors such as immune status, hormonal balance, and individual variability. Understanding these influences is crucial for reducing the risks of HPV persistence and cervical lesions, especially in women with VVC. Future research should clarify how host factors interact with the vaginal microbiome and HPV to inform personalized prevention and treatment strategies that enhance women's reproductive health.
2.5 The association between HPV oncogenes E6/E7 expression and vaginal microecological disorder
2.5.1 E6/E7 gene expression and correlation with HR-HPV infection
E6 and E7 expression is central to cervical carcinogenesis, as E6 degrades p53 and E7 inactivates pRb, disrupting cell cycle control and promoting uncontrolled proliferation. Elevated E6/E7 mRNA levels serve as biomarkers of HPV oncogenic potential. In a study of 1,327 women, those with HR-HPV showed significantly higher E6/E7 expression than those with low-risk types. Increased E6/E7 levels correlate with precancerous lesions and cervical cancer, while BV may act as an independent HR-HPV risk factor by inducing microecological changes that enhance E6/E7 expression (Huang J. et al., 2023).
Beyond cervical carcinogenesis, E6/E7 mRNA expression is also implicated in other HR-HPV–related malignancies, including head and neck cancers. Expression patterns vary by HPV genotype, with HPV16 and HPV18 showing the highest oncogenic potential. Mutations within E6 and E7 can alter expression levels and influence cancer aggressiveness; for instance, specific E7 variants are linked to increased risk of high-grade cervical lesions (Evande et al., 2023). Moreover, E6/E7 mRNA detection offers greater sensitivity and specificity for identifying HSIL than traditional HPV DNA testing, highlighting its value in clinical diagnostics (Evande et al., 2023; Plisko et al., 2024).
The regulation of E6/E7 expression is intricately linked to host cellular pathways and the tumor microenvironment. E6 and E7 can modulate the immune landscape, fostering tumor progression and immune evasion (Pandey et al., 2025). Additionally, their interactions with key signaling pathways, such as Wnt/β-catenin, further contribute to HPV-driven tumorigenesis (Donmez et al., 2022).
In conclusion, E6 and E7 mRNA expression serves as a key indicator of HR-HPV carcinogenic potential, closely correlating with cervical cancer progression and high-grade lesions. Incorporating E6/E7 mRNA testing into clinical practice could enhance early detection and risk assessment. Further elucidation of the regulatory mechanisms controlling their expression may guide the development of targeted therapies to mitigate HR-HPV–driven carcinogenesis.
2.5.2 The impact of dysbiosis on E6/E7 expression
The relationship between vaginal dysbiosis and HPV oncogene expression is key to understanding microbial influences on cervical carcinogenesis. Dysbiosis—marked by reduced Lactobacillus and increased pathogenic bacteria—creates conditions favorable for persistent HR-HPV infection. In HPV-16–transformed SiHa cells, specific Lactobacillus species, particularly L. crispatus and L. gasseri, were shown to modulate and suppress basal E6/E7 expression and oncoprotein production, highlighting their potential protective role against HPV-driven malignancy (Nicolò et al., 2023). In contrast, dysbiosis-associated bacteria such as Gardnerella vaginalis and Megasphaera micronuciformis enhance E6/E7 expression and oncoprotein production. M. micronuciformis further decreases p53 and pRb levels, promoting S-phase progression and potential malignant transformation of cervical epithelial cells. These findings illustrate the dual role of the vaginal microbiota—Lactobacillus species mitigate oncogenic risk, whereas dysbiotic bacteria exacerbate it. Maintaining a healthy, Lactobacillus-dominant microbiome may thus help prevent HPV-related cervical lesions, and probiotic interventions show promise in counteracting dysbiosis-induced upregulation of E6/E7 expression and associated cancer risk (Bi et al., 2023). Thus, understanding how specific bacterial species regulate HPV oncogene expression is crucial for developing targeted therapies and preventive strategies against HPV-related cervical cancer.
2.5.3 Influence of VVC and Candida albicans albicans on HPV E6/E7 expression
Recent evidence indicates that Candida albicans albicans–induced inflammation and epithelial injury may modulate HPV oncogene expression, offering a mechanistic link between VVC and cervical carcinogenesis. C. albicans stimulates strong IL-1β, IL-6, and TNF-α responses via NF-κB and JAK/STAT activation, generating an inflammatory milieu that can enhance HPV early promoter activity and upregulate E6/E7 transcription (Moyes et al., 2015; Valand and Girija, 2021).
Moreover, Candida albicans secretes aspartyl proteases (SAPs) that disrupt epithelial tight junctions and compromise barrier integrity, increasing exposure of basal keratinocytes—the primary HPV target cells—and potentially facilitating early viral gene expression, including E6/E7 (Bras et al., 2024). Metabolic byproducts such as ethanol and short-chain organic acids further alter vaginal pH and oxidative stress, factors known to affect HPV replication and early gene transcription (Hickey et al., 2025).
Conversely, acute VVC can activate strong innate immune responses, particularly TLR2/TLR4 pathways and IFN-γ production, which may exert antiviral effects and suppress E6/E7 mRNA expression. This bidirectional influence aligns with epidemiologic findings showing that VVC may either promote HPV persistence or, in certain contexts, reduce HPV detectability through enhanced immune clearance (Chen et al., 2025; Miró et al., 2017).
2.5.4 Application value of E6/E7 gene testing in clinical diagnosis
E6/E7 gene testing has become a key tool in the clinical diagnosis of HPV infections, especially in cervical cancer. E6/E7 mRNA testing demonstrates high specificity and sensitivity for HR-HPV associated with CIN and cervical cancer, outperforming HPV DNA testing in predicting high-grade lesions (Pankaj et al., 2024). The detection of E6/E7 mRNA also reflects active viral replication and oncogenic potential, making it essential for evaluating disease progression risk in HPV-infected patients (He et al., 2021).
However, E6/E7 gene testing has several limitations. False positives can occur, particularly in low HPV prevalence settings, leading to unnecessary anxiety and procedures such as colposcopy or biopsy (Zhang et al., 2023). Additionally, the interpretation of E6/E7 results can be complicated by the presence of multiple HPV types, as co-infections may influence the expression levels of these oncogenes (Dust et al., 2022). Moreover, factors such as immune status and comorbidities can affect test accuracy and influence cervical cancer risk assessment (Kotian et al., 2024).
In conclusion, E6/E7 gene testing shows great potential as an auxiliary diagnostic tool for HPV-related diseases, but its benefits must be weighed against inherent limitations. Continued advances in molecular diagnostics are essential to improve its accuracy and clinical utility. Integrating E6/E7 testing into routine practice—supported by patient education and counseling—will help maximize its diagnostic value while minimizing potential drawbacks, ultimately improving outcomes in HPV management.
2.6 Clinical intervention of vaginal microecological repair and HPV infection
2.6.1 Microecological regulation treatment strategies
Probiotic therapy has gained attention as a strategy to restore vaginal microecology, particularly for BV and VVC. Lactobacillus strains maintain microbiota balance by producing lactic acid, lowering pH, and inhibiting pathogens such as Gardnerella and Atopobium (Han et al., 2025; Jawanda et al., 2024). Clinical trials, including those using Lactobacillus crispatus, have shown that probiotics can restore vaginal flora, reduce Nugent scores, and increase Lactobacillus abundance, improving outcomes in recurrent infections (Jawanda et al., 2024). By enhancing anti-inflammatory cytokines and suppressing pro-inflammatory pathways, probiotics reduce inflammation and may strengthen mucosal immunity, potentially lowering HPV persistence and cervical lesion risk (Han et al., 2025; Jawanda et al., 2024; Schuster et al., 2024). Overall, integrating probiotics into treatment protocols offers a promising approach to restoring vaginal health and preventing recurrence.
Antibiotics and antifungal agents remain central to managing vaginal infections but can disrupt the vaginal microbiota balance. Drugs such as metronidazole and clindamycin effectively treat BV yet often deplete beneficial Lactobacillus, leading to dysbiosis and frequent relapse (Schuster et al., 2024; Muzny and Sobel, 2022). Similarly, antifungals clear Candida albicans infections but may alter microbial composition, foster resistance, and contribute to recurrence (Bradfield Strydom et al., 2023). Combining antibiotics with probiotics may mitigate antibiotic-induced microbiota disruption, improve efficacy, and reduce recurrence while preserving beneficial microbes essential for vaginal health (Han et al., 2025; Jawanda et al., 2024).
2.6.2 The impact of microecological restoration on HPV clearance rates
Recent research has highlighted the pivotal role of vaginal microbiota in HPV infection and clearance. A Lactobacillus-dominant microbiome is associated with reduced risk of persistent HPV and cervical lesions. In a pilot study of 100 women, those with persistent HR-HPV had lower Lactobacillus and higher pathogenic bacteria than those who cleared the virus (Mei et al., 2022). A longitudinal study further showed that higher baseline Lactobacillus iners abundance correlated with reduced HPV clearance within 1 year (Shi et al., 2022). These findings emphasize that vaginal microbiota composition influences immune responses and viral persistence, suggesting that restoring a healthy microbiome may promote HPV clearance.
Microecological restoration, especially through probiotic therapy, shows promise in enhancing HPV clearance. In a controlled study, intravaginal Lactobacillus crispatus significantly reduced HPV viral load and improved clearance compared with placebo (Liu Y. et al., 2024). These findings suggest that probiotics may restore the vaginal microbiota and enhance local immunity, promoting HPV clearance; a systematic review further confirmed that Lactobacillus dominance is linked to lower HPV persistence and cervical dysplasia rates (Pai et al., 2025).
Moreover, the mechanisms by which microecological restoration aids in HPV clearance are becoming clearer. Lactobacillus can increase antimicrobial substance production, modulate immunity, reduce inflammation, and improve epithelial barrier integrity, collectively creating conditions unfavorable for HPV persistence (Papamentzelopoulou and Pitiriga, 2025). In this context, the role of vaginal probiotics is not merely to restore microbial balance but also to enhance the host's immunological defenses against viral infections.
In conclusion, restoring vaginal microecology through probiotics and related interventions shows strong potential for enhancing HPV clearance. Clinical evidence indicates that a Lactobacillus-dominant microbiome is associated with reduced HPV persistence and fewer cervical lesions. As understanding of vaginal microbiota–HPV interactions deepens, microecological restoration may become an effective strategy for reducing cervical cancer risk. Further large-scale studies are needed to confirm these findings and refine microbiota-based prevention and treatment approaches.
2.6.3 The significance of VVC treatment in HPV infection management
Treating VVC is important for supporting HPV infection management. As a common fungal infection, VVC can disrupt vaginal microecology and alter the dynamics of HPV persistence and progression (Dovnik et al., 2015). Although VVC does not significantly increase the risk of HPV-related cytological abnormalities, its treatment helps restore vaginal microecology, strengthen local immunity, thereby improving the host environment related to HPV clearance rather than directly modifying lesion risk (Long et al., 2023). The interplay between VVC and other infections such as BV underscores the need for comprehensive vaginal health management; notably, BV may protect against cytological abnormalities in HPV-infected women, highlighting the importance of a balanced and Lactobacillus-dominant microbiome in modulating HPV persistence (Holali Ameyapoh et al., 2021). Thus, treating VVC not only relieves symptoms but also contributes to overall microecological stability, which is relevant to broader HPV management strategies.
Preventive strategies should integrate VVC management with HPV screening, vaccination, and probiotic-based microbiome modulation to maintain vaginal health and reduce HPV risk (Brennan et al., 2024). Addressing VVC and other infections can improve outcomes in women susceptible to HPV-related complications. Education on sexual health further supports prevention. Overall, effective VVC treatment is a key component of HPV management by supporting microecological and immunological homeostasis, highlighting the need for continued research into vaginal microecology–HPV interactions.
2.7 Microecological-viral interaction model in the development of cervical cancer
2.7.1 Pathways by which microbial dysbiosis promotes cervical cancer development
Microbial dysbiosis in the female reproductive tract contributes to cervical cancer through chronic inflammation and immune suppression (Huang et al., 2024). A Lactobacillus-dominant microbiome protects against infection, while reduced Lactobacilli and increased pathogens are linked to persistent HPV infection (Huang et al., 2024). Dysbiosis disrupts immune balance and elevates IL-6 and TNF-α levels, creating a pro-inflammatory, oncogenic microenvironment (Shen et al., 2024).
Moreover, immune suppression caused by dysbiosis further hinders HPV clearance. A dysbiotic microbiome alters local immunity, promoting recruitment of regulatory T cells and myeloid-derived suppressor cells that weaken antiviral responses (Qingqing et al., 2021). This immune evasion enables HPV persistence and progression to CIN and cervical cancer. Thus, maintaining a balanced vaginal microbiome is essential for preventing HPV-related malignancy.
Dysbiosis and chronic inflammation form a self-reinforcing cycle that hinders HPV management, highlighting the need for microbiota-restoring therapies. Probiotics can rebalance the microbiome, reduce inflammation, and promote HPV clearance, potentially lowering cervical cancer risk (Mazinani et al., 2025). Integrating microbiome analysis into clinical practice may enable personalized prevention and treatment strategies targeting both microbial imbalance and inflammation.
2.7.2 HPV virus and microbiome's synergistic carcinogenic mechanism
The interaction between HPV and the vaginal microbiome plays a key role in cervical carcinogenesis. Certain microbial communities influence cellular signaling pathways exploited by high-risk HPV types such as HPV-16 and HPV-18, which integrate into the host genome and upregulate E6/E7, disrupting p53 and Rb pathways (Sims et al., 2021). Reduced Lactobacillus dominance increases HPV persistence, while anaerobes like Gardnerella and Prevotella induce inflammation that promotes viral integration and tumor development (Nieves-Ramírez et al., 2021; Lebeau et al., 2022).
Furthermore, dysbiosis of the vaginal microbiome alters local immune responses and weakens host defenses against HPV. Reduced Lactobacillus and increased pathogenic bacteria elevate inflammatory cytokines such as IL-6 and TNF-α, which are associated with CIN progression, suggesting that chronic inflammation synergizes with HPV in driving carcinogenesis (Li X. et al., 2024; Leon-Gomez and Romero, 2024; Kamzayeva et al., 2025).
Moreover, HPV can also modify the vaginal microbiome, creating a feedback loop that worsens dysbiosis and enhances oncogenic potential. The E7 oncoprotein downregulates antimicrobial peptides essential for microbial balance, enabling pathogenic bacteria to proliferate (Lebeau et al., 2022). This shift not only facilitates HPV persistence but also promotes pro-inflammatory mediator expression, further driving carcinogenesis.
In conclusion, the interplay between HPV and the vaginal microbiome synergistically regulates cellular signaling pathways that drive cervical carcinogenesis. Understanding this relationship may enable the development of therapeutic strategies—such as probiotic interventions—to restore microbial balance, strengthen host defenses, and reduce cervical cancer risk (Uysal et al., 2022; Gutierrez Salmean et al., 2024). Future research should identify microbial signatures linked to HPV persistence and clarify how these microorganisms influence oncogenic signaling mechanisms.
2.7.3 Latest theoretical models and future research directions
The interplay between the vaginal microbiome and HPV infection has gained increasing attention, especially with the use of multi-omics technologies that enable a deeper understanding of their interactions. By integrating genomics, transcriptomics, proteomics, and metabolomics, multi-omics approaches offer a comprehensive view of vaginal microbial communities and their functions in HPV infection. A Lactobacillus-dominated microbiome is essential for maintaining homeostasis and protecting against HPV and other infections (Kyrgiou and Moscicki, 2022). Dysbiosis, marked by reduced Lactobacillus and increased pathogens such as Gardnerella vaginalis, is linked to greater susceptibility to HPV infection and cervical lesion progression (Zukiene et al., 2025; Ye and Vaginal, 2024). Shotgun metagenomic studies reveal that HPV-associated microbiome changes extend beyond composition, involving alterations in metabolic pathways, suggesting that specific microbial taxa may drive HPV persistence and CIN development (Yang et al., 2025; Valentine et al., 2025).
HPV and the vaginal microbiome interact bidirectionally, with HPV worsening dysbiosis in a self-perpetuating cycle that promotes cervical disease (Li M. et al., 2024). Elucidating the molecular mechanisms underlying this interaction—such as how bacterial metabolites affect HPV gene expression and immune responses—may reveal therapeutic targets. Additionally, identifying microbial biomarkers linked to HPV persistence and lesion progression could also enable novel diagnostic and preventive strategies (Shen et al., 2024; Yang et al., 2024).
As research advances, it is crucial to examine these interactions across diverse populations, given that vaginal microbiome composition varies with ethnicity, age, and environmental factors (Mbabazi et al., 2025). Future studies should also investigate how host genetics and immune responses shape the microbiome–HPV relationship. A comprehensive, personalized approach—integrating microbiome profiling, immune status, and multi-omics data with clinical outcomes—will be key to developing precision strategies for HPV-related disease management and improving prevention and treatment of cervical cancer.
2.8 Future research hotspots and challenges
2.8.1 Development prospects of precision microbiota regulation technologies
Precision microbiota regulation technologies, particularly microbiome editing, hold promise for managing HPV infection and cervical lesions. Using CRISPR-Cas9, synthetic biology, and advanced sequencing, microbiome editing enables targeted modification of microbial genes and functions to restore balance and enhance host health. Specific Lactobacillus species have been shown to protect against HPV persistence and cervical cancer by modulating local immunity and maintaining vaginal homeostasis (Papamentzelopoulou and Pitiriga, 2025). Microbiome editing could increase beneficial bacteria, reduce harmful species, and create a microenvironment that strengthens immune defense against HPV.
Beyond gynecological health, microbiome editing holds promise for broader clinical applications. The gut microbiota plays a key role in systemic diseases such as obesity, diabetes, and inflammatory bowel disease, highlighting the value of targeted microbial modulation for therapeutic benefit (Yang et al., 2025). Strategies such as dietary intervention, probiotic supplementation, and fecal microbiota transplantation have demonstrated potential to improve metabolic function and reduce inflammation (Wang et al., 2025). Integrating precision microbiota regulation into clinical practice could enable treatments tailored to individual microbiome profiles, improving efficacy and reducing adverse effects.
Despite its promise, microbiome editing faces several challenges. Ethical concerns about genetic modification, the need for comprehensive safety evaluations, and the complexity of host–microbiome interactions hinder clinical translation. Individual variability in microbiome composition also demands deeper insight into the mechanisms linking microbiota to health and disease. Future research should clarify these mechanisms, refine editing technologies, and establish clinical standards to ensure the safe and effective implementation of microbiome editing in healthcare.
In conclusion, precision microbiota regulation technologies, especially microbiome editing, offer a transformative approach to managing dysbiosis-related and infectious diseases such as HPV. These advanced tools enable personalized interventions that restore microbial balance and improve overall patient health. Continued interdisciplinary research and collaboration will be vital to fully realize the clinical potential of microbiome editing and develop innovative solutions for complex health challenges.
2.8.2 Investigating the molecular mechanisms of HPV infection and microbiota interaction: key molecular targets and signaling pathways
The complex interplay between HPV infection and the vaginal microbiota is now recognized as a key factor in cervical lesion and cancer development. Recent studies have identified molecular targets and signaling pathways underlying this interaction. Vaginal dysbiosis—marked by reduced Lactobacillus and increased Gardnerella and Prevotella—is linked to persistent HPV infection and CIN progression (Cheng et al., 2020; Chen et al., 2021). These microbial shifts elevate IL-6 and TNF-α levels, inducing chronic inflammation and creating a microenvironment that supports HPV persistence (Qingqing et al., 2021; Leon-Gomez and Romero, 2024). Moreover, key signaling pathways such as NF-κB and JAK/STAT play central roles in mediating inflammation and facilitating HPV immune evasion, thereby contributing to viral persistence and disease progression (Kazlauskaite et al., 2025; Zhang Z. et al., 2024).
Furthermore, the interaction between HPV and the vaginal microbiota may also regulate the expression of viral oncogenes E6 and E7, which drive cellular transformation and cancer progression (Uysal et al., 2022; Fang et al., 2022). Dysbiotic microbiota can alter the local immune microenvironment by impairing antigen-presenting cells, such as Langerhans cells, reducing the host's ability to clear HPV (Dai et al., 2022). Microbiota-targeted therapies, including probiotics, may help restore microbial balance and enhance immune defenses against HPV (Dahlstrom et al., 2023; Cheng L. et al., 2024).
In summary, the interaction between HPV and the vaginal microbiota involves a complex network of microbial dysbiosis, immune modulation, and signaling pathways that promote HPV persistence and cervical lesion development. Elucidating these molecular mechanisms could inform novel therapeutic strategies for preventing HPV-related diseases and improving women's health. Future research should aim to identify specific microbial biomarkers and their functional roles in HPV infection, enabling personalized approaches to cervical cancer prevention and management.
2.8.3 The necessity of large-scale clinical cohort studies
Investigating the relationship between vaginal microbiota, HPV persistence, and cervical lesions requires large, multi-center longitudinal cohort studies encompassing diverse populations. Such designs enhance the generalizability of findings, as vaginal microbiota composition varies with genetic, environmental, and lifestyle factors. Evidence indicates that Lactobacillus-dominant microbiota confers protection against HPV persistence, whereas a shift toward a diverse, dysbiotic community increases the risk of cervical lesions (Kazlauskaite et al., 2025). Multi-center longitudinal studies enable the capture of diverse microbiota profiles and HPV genotypes, allowing researchers to track temporal changes in microbiota–HPV interactions, infection dynamics, and lesion progression. For instance, longitudinal analyses have shown that Lactobacillus-dominated community state types are linked to higher HPV clearance rates (Shi et al., 2022). This temporal approach is essential for understanding how microbiota shifts influence HPV persistence and CIN development. Including diverse demographic samples can also help identify microbial biomarkers predictive of disease progression or regression (Lavitola et al., 2020). The intricate relationship between the vaginal microbiome and HPV highlights the need for comprehensive, multi-center cohort studies to clarify these interactions and guide clinical practice. Such studies should account for confounding factors—including sexual behavior, hormonal status, and co-infections—that influence microbiota composition and HPV dynamics. Large-scale cohorts are vital for generating reliable evidence, identifying key risk modifiers, and informing targeted prevention and therapeutic strategies to improve outcomes in women at risk of HPV-related cervical disease.
2.9 Comprehensive overview of vaginal microecology and prevention strategies for HPV-related cervical lesions
2.9.1 Comprehensive microbial regulation combined with HPV vaccination strategies
The interaction between the vaginal microbiome and HPV infection is a key focus for advancing prevention and treatment strategies. Studies, including a cross-sectional survey of young Swedish women, show that Lactobacillus-dominated microbiota protect against HPV and cervical lesions, while non-Lactobacillus dominance correlates with oncogenic HPV types (Cheng et al., 2020). These findings support integrating microbiota modulation with HPV vaccination. Probiotics and prebiotics can restore microbial balance, reduce inflammation and oxidative stress, and strengthen antiviral immunity (Huang et al., 2024). Furthermore, therapeutic HPV vaccines employing bacterial vectors may leverage microbiome-driven immune modulation to enhance vaccine efficacy and promote HPV clearance (Vargas-Robles et al., 2023).
The synergistic effects of combining microbiome regulation with HPV vaccination could be particularly beneficial in populations with high HPV prevalence and associated cervical cancer risk, such as women living with HIV (McClymont et al., 2022). Populations with altered immunity and higher susceptibility to HPV-related diseases, such as women living with HIV, require innovative approaches that integrate microbial health with vaccination. Mucosal vaccines that elicit both systemic and local immune responses, combined with probiotics that strengthen the vaginal microbiota, could provide a comprehensive, multi-layered defense against HPV infection and disease progression (Gong et al., 2023). Additionally, identifying microbial signatures linked to HPV infection may enable targeted interventions and personalized vaccination strategies tailored to high-risk populations (Fraszczak et al., 2022).
Emerging evidence indicates that vaginal microbiome composition can affect HPV vaccine efficacy, with specific bacterial taxa linked to stronger vaccine-induced immune responses (Giraldo et al., 2021). A dysbiotic microbiome may impair vaccine immunogenicity, emphasizing the need to understand microbial influences on immunity. Optimizing the vaginal microbiota before vaccination could enhance immune protection against HPV and reduce the risk of cervical cancer.
In conclusion, combining microbiome modulation with HPV vaccination offers a promising strategy to strengthen prevention and treatment of HPV-related diseases. Promoting a balanced vaginal microbiota and harnessing the immune-enhancing effects of probiotics and therapeutic vaccines may reduce HPV persistence and improve women's health globally. Future research should clarify how the microbiome shapes HPV infection and vaccine responses and develop tailored interventions that meet the needs of diverse populations.
2.9.2 Early screening and individualized interventions
The link between vaginal microecological disturbances and persistent HPV infection has become a key focus in early screening and personalized intervention research. Monitoring vaginal microecology is essential for evaluating HPV infection risk and cervical lesion development (Fan et al., 2024). A Lactobacillus-dominant microbiome supports local immunity and protects against pathogens, whereas dysbiosis—marked by reduced Lactobacillus and increased pathogenic bacteria—is associated with greater HPV susceptibility and cervical cancer progression (Nittala et al., 2024).
Recent advances in genomic medicine and precision medicine have created new opportunities for early detection and personalized intervention in cervical cancer prevention. Precision Population Medicine (PPM) integrates individual risk factors—such as microbiome composition, genetic susceptibility, and environmental exposures—into tailored health strategies. Leveraging big data analytics, wearable monitoring devices, and telemedicine enables more accurate identification of women at risk for HPV infection and cervical disease, promoting timely and targeted screening and intervention (Nittala et al., 2024).
Furthermore, individualized interventions guided by vaginal microecological assessments can strengthen preventive strategies. Women with dysbiotic microbiomes may benefit from targeted probiotic therapy to restore Lactobacillus-dominant flora, potentially reducing HPV infection risk and enhancing cervical health. Personalized education and counseling on sexual health, HPV vaccination, and regular screening further empower women to actively manage and protect their reproductive health (Nittala et al., 2024).
Integrating microecological monitoring into routine gynecological care marks a paradigm shift in assessing and managing HPV risk. As understanding of the vaginal microbiome–HPV interplay deepens, these insights can inform more precise screening and personalized interventions. Such a proactive approach improves early detection of HPV-related cervical lesions and supports the broader goal of reducing cervical cancer incidence and mortality, especially in underserved populations (Nittala et al., 2024).
In conclusion, monitoring vaginal microecology is a vital element of early screening and personalized intervention for HPV infection and cervical disease. Integrating microbiome assessment within precision medicine frameworks can improve risk stratification, strengthen prevention, and advance efforts toward cervical cancer elimination. Continued research on the vaginal microbiome's role in HPV dynamics will refine these strategies, bringing us closer to a future where cervical cancer is no longer a major public health threat.
2.9.3 Public health strategies and health education promotion
The link between vaginal microbiota, HPV infection, and cervical lesions highlights the need for public health initiatives that promote awareness of vaginal health and HPV prevention. A Lactobacillus-dominant microbiome protects against HPV persistence, whereas dysbiosis increases susceptibility to infection and lesion development (Kazlauskaite et al., 2025; Cui et al., 2025). Educational programs should emphasize the importance of maintaining microbial balance, which is influenced by sexual behavior, hygiene, and antibiotic use. Notably, women with BV have a significantly higher risk of persistent HPV infection and cervical lesion progression (Na et al., 2025).
Health education campaigns should stress the importance of regular gynecological check-ups, HPV vaccination, and awareness of vaginal infection symptoms. Educating women about lifestyle factors—such as smoking, which is linked to persistent HPV infection—can encourage healthier choices (Na et al., 2025). Additionally, the integration of microbiota education into routine healthcare can help women recognize the impact of their vaginal health on overall reproductive health. For example, promoting the use of probiotics and prebiotics as potential adjunct therapies to restore healthy vaginal flora could be beneficial (Papamentzelopoulou and Pitiriga, 2025).
Addressing cultural stigmas and misconceptions is essential, as discomfort in discussing vaginal health often leads to delayed diagnosis and treatment. Community outreach, educational workshops, and social media campaigns can provide accessible platforms to share information on vaginal health, HPV prevention, and the importance of maintaining microbiota balance.
Integrating these educational strategies into public health initiatives can greatly improve women's understanding of reproductive health and promote proactive care. Empowering women to take charge of their vaginal health can reduce HPV infection rates and cervical disease incidence, ultimately enhancing overall health and quality of life.
3 Discussion
Although this review discusses the potential “dual role” of VVC in HPV infection, the current evidence supporting these two effects is clearly imbalanced. The HPV-promoting role of VVC—mediated by inflammation, epithelial disruption, and microecological imbalance—is supported by multiple mechanistic and epidemiologic studies. In contrast, the proposed suppressive effect relies on limited cross-sectional findings and theoretical immune-activation pathways, with inconsistent results across studies. Therefore, this inhibitory effect should be interpreted as preliminary and context-dependent, whereas the available evidence more strongly supports VVC as a contributor to HPV persistence. Further longitudinal and mechanistic research is required to clarify whether VVC genuinely confers meaningful antiviral effects.
4 Conclusion
The strong association between persistent HPV infection and cervical disease underscores the pivotal role of high-risk HPV types in cervical carcinogenesis. This review highlights the growing recognition of the vaginal microbiome's influence on HPV dynamics, showing that microecological disruptions—particularly from BV, TV, and VVC—affect HPV infection and persistence. The dual role of VVC, which can both promote and inhibit HPV infection, further emphasizes the complexity of host–microbiota–virus interactions and the need for continued in-depth research.
Notably, disturbances in the vaginal microbiota have been linked to increased expression of HPV oncogenes E6 and E7. The detection of E6/E7 mRNA as an auxiliary diagnostic tool offers promise for improving early identification and management of high-risk HPV infections. These insights underscore the importance of understanding HPV–microbiome interactions to refine diagnostic approaches and optimize patient care..
The restoration and regulation of vaginal microecology emerge as pivotal components in the prevention and treatment of HPV infections. Integrating microbiome modulation strategies with HPV vaccination could significantly enhance the efficacy of cervical disease prevention efforts. This multifaceted approach not only addresses the viral aspect of HPV but also acknowledges the importance of the host's microenvironment in influencing disease outcomes.
Looking ahead, future research should focus on elucidating the molecular mechanisms underlying the interactions between the vaginal microbiome and HPV. Large-scale clinical studies are needed to clarify these complex relationships and guide the development of tailored interventions that account for individual microbiome variations and HPV susceptibility. These efforts could advance precision medicine in cervical cancer prevention and treatment, enabling more effective, personalized strategies for diverse patient populations.
In conclusion, the intersection of HPV infection, vaginal microbiome dynamics, and cervical disease presents a compelling area for ongoing research and clinical focus. By balancing the various research perspectives and findings, we can foster a comprehensive understanding that not only informs clinical practice but also guides public health initiatives aimed at reducing the burden of cervical cancer globally. Integrating microbiome research into HPV-related studies will be critical for informing future guidelines and advancing effective strategies against this preventable disease.
Author contributions
XZ: Supervision, Conceptualization, Writing – original draft, Writing – review & editing, Methodology. MY: Formal analysis, Data curation, Supervision, Writing – original draft. YH: Supervision, Data curation, Writing – original draft, Formal analysis. HW: Formal analysis, Data curation, Writing – original draft, Supervision. HL: Writing – original draft, Supervision, Data curation, Formal analysis. JM: Methodology, Conceptualization, Supervision, Writing – review & editing.
Funding
The author(s) declared that financial support was received for this work and/or its publication. This study was supported by Gansu Provincial Science and Technology Plan Project (25JRRA786).
Conflict of interest
The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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The author(s) declared that generative AI was not used in the creation of this manuscript.
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References
Balasubramaniam, S. D., Balakrishnan, V., Oon, C. E., and Kaur, G. (2019). Key molecular events in cervical cancer development. Medicina 55:384. doi: 10.3390/medicina55070384
Bautista, J., Altamirano-Colina, A., and Lopez-Cortes, A. (2025). The vaginal microbiome in HPV persistence and cervical cancer progression. Front. Cell Infect. Microbiol. 15:1634251. doi: 10.3389/fcimb.2025.1634251
Bennett, P. R., Brown, R. G., and MacIntyre, D. A. (2020). Vaginal microbiome in preterm rupture of membranes. Obstet. Gynecol. Clin. North Am. 47, 503–521. doi: 10.1016/j.ogc.2020.08.001
Bi, Z., Wang, Q., Yang, T., Liu, Y., Yuan, J., Li, L., et al. (2023). Effect of Lactobacillus delbrueckii subsp. Lactis on vaginal radiotherapy for gynecological cancer. Sci. Rep. 13:10105. doi: 10.1038/s41598-023-37241-7
Bradfield Strydom, M., Khan, S., Walpola, R. L., Ware, R. S., and Tiralongo, E. (2023). Interplay of the microbiome and antifungal therapy in recurrent vulvovaginal candidiasis (RVVC): a narrative review. J. Med. Microbiol. 72:001705. doi: 10.1099/jmm.0.001705
Brăila, A. D., Poalelungi, C. V., Albu, C. C., Damian, C. M., Dîră, L. M., Bănăţeanu, A. M., et al. (2025). The relationship between cervicovaginal infection, human papillomavirus infection and cervical intraepithelial neoplasia in Romanian women. Diseases 13:18. doi: 10.3390/diseases13010018
Bras, G., Satala, D., Juszczak, M., Kulig, K., Wronowska, E., Bednarek, A., et al. (2024). Secreted aspartic proteinases: key factors in candida infections and host-pathogen interactions. Int. J. Mol. Sci. 25:4775. doi: 10.3390/ijms25094775
Brennan, C., Chan, K., Kumar, T., Maissy, E., Brubaker, L., Dothard, M. I., et al. (2024). Harnessing the power within: engineering the microbiome for enhanced gynecologic health. Reprod. Fertil. 5:e230060. doi: 10.1530/RAF-23-0060
Chee, W. J. Y., Chew, S. Y., and Than, L. T. L. (2020). Vaginal microbiota and the potential of Lactobacillus derivatives in maintaining vaginal health. Microb. Cell Fact. 19:203. doi: 10.1186/s12934-020-01464-4
Chen, M., Chen, R., Zhang, Y., Qing, W., Zhou, Z., Song, X., et al. (2025). Dual effects of vaginal Candida albicans on human papillomavirus infection: a large-scale multicenter study in Chinese women. J. Adv. Res. 473, 154–160. doi: 10.1016/j.jare.04.049
Chen, M. X., Zhou, Z. Y., Qing, W., Li, H., and Zhou, H. W. (2021). [The cervical microbiota characteristics in patients with human papillomavirus infection]. Zhonghua Yu Fang Yi Xue Za Zhi. 55, 867–874. doi: 10.13345/j.cjb.210163
Chen, Z., Li, X., Tian, D., Liu, J., Bai, X., Feng, T., et al. (2024). Study on the clinical characteristics, persistent infection capability and viral load of human papillomavirus type 26 single infection. Virol. J. 21:301. doi: 10.1186/s12985-024-02582-w
Cheng, K. O., Montano, D. E., Zelante, T., Dietschmann, A., and Gresnigt, M. S. (2024). Inflammatory cytokine signalling in vulvovaginal candidiasis: a hot mess driving immunopathology. Oxf. Open Immunol. 5:iqae010. doi: 10.1093/oxfimm/iqae010
Cheng, L., Norenhag, J., Hu, Y. O. O., Brusselaers, N., Fransson, E., Ährlund-Richter, A., et al. (2020). Vaginal microbiota and human papillomavirus infection among young Swedish women. NPJ Biofilms Microbiomes 6:39. doi: 10.1038/s41522-020-00146-8
Cheng, L., Yan, C., Yang, Y., Hong, F., and Du, J. (2024). Exploring the clinical signatures of cervical dysplasia patients and their association with vaginal microbiota. Cancer Med. 13:e70440. doi: 10.1002/cam4.70440
Cui, M., Wu, Y., Liu, Z., Liu, Y., and Fan, L. (2025). Advances in the interrelated nature of vaginal microecology, HPV infection, and cervical lesions. Front. Cell Infect. Microbiol. 15:1608195. doi: 10.3389/fcimb.2025.1608195
Dahlstrom, K. R., Sikora, A. G., Liu, Y., Chang, C. C., Wei, P., Sturgis, E. M., et al. (2023). Characterization of the oral microbiota among middle-aged men with and without human papillomavirus infection. Oral Oncol. 142:106401. doi: 10.1016/j.oraloncology.2023.106401
Dai, W., Gui, L., Du, H., Li, S., and Wu, R. (2022). The association of cervicovaginal Langerhans cells with clearance of human papillomavirus. Front. Immunol. 13:918190. doi: 10.3389/fimmu.2022.918190
David, H., and Solomon, A. P. (2023). Molecular association of Candida albicans and vulvovaginal candidiasis: focusing on a solution. Front. Cell Infect. Microbiol. 13:1245808. doi: 10.3389/fcimb.2023.1245808
Deka, N., Hassan, S., Seghal Kiran, G., and Selvin, J. (2021). Insights into the role of vaginal microbiome in women's health. J. Basic Microbiol. 61, 1071–1084. doi: 10.1002/jobm.202100421
Dickey, B. L., Fan, W., Bettampadi, D., Reich, R. R., Sirak, B., Abrahamsen, M., et al. (2021). Sequential acquisition of human papillomavirus infection between genital and oral anatomic sites in males. Int. J. Cancer 149, 1483–1494. doi: 10.1002/ijc.33732
Dom-Chima, N., Ajang, Y. A., Dom-Chima, C. I., Biswas-Fiss, E., Aminu, M., and Biswas, S. B. (2023). Human papillomavirus spectrum of HPV-infected women in Nigeria: an analysis by next-generation sequencing and type-specific PCR. Virol. J. 20:144. doi: 10.1186/s12985-023-02106-y
Donmez, H. G., Akgor, U., Onder, S., Tanacan, A., Kuru, O., Ozgul, N., et al. (2022). Impact of human papillomavirus on Wnt/beta-catenin signaling in morphological inconspicuous cervicovaginal cells. Acta Cytol. 66, 409–419. doi: 10.1159/000522635
Dovnik, A., Golle, A., Novak, D., Arko, D., and Takac, I. (2015). Treatment of vulvovaginal candidiasis: a review of the literature. Acta Dermatovenerol. Alp Pannonica Adriat. 24, 5–7. doi: 10.15570/actaapa.2015.2
Dust, K., Carpenter, M., Chen, J. C., Grant, C., McCorrister, S., Westmacott, G. R., et al. (2022). Human papillomavirus 16 E6 and E7 oncoproteins alter the abundance of proteins associated with DNA damage response, immune signaling and epidermal differentiation. Viruses 14:1764. doi: 10.3390/v14081764
Evande, R., Rana, A., Biswas-Fiss, E. E., and Biswas, S. B. (2023). Protein-DNA interactions regulate human papillomavirus DNA replication, transcription, and oncogenesis. Int. J. Mol. Sci. 24:8493. doi: 10.3390/ijms24108493
Fan, Z., Han, D., Fan, X., Zeng, Y., and Zhao, L. (2024). Analysis of the correlation between cervical HPV infection, cervical lesions and vaginal microecology. Front. Cell Infect. Microbiol. 14:1405789. doi: 10.3389/fcimb.2024.1405789
Fang, B., Li, Q., Wan, Z. OuYang, Z., and Zhang, Q. (2022). Exploring the association between cervical microbiota and HR-HPV infection based on 16S rRNA gene and metagenomic sequencing. Front. Cell Infect. Microbiol. 12:922554. doi: 10.3389/fcimb.2022.922554
France, M., Alizadeh, M., Brown, S., Ma, B., and Ravel, J. (2022). Towards a deeper understanding of the vaginal microbiota. Nat. Microbiol. 7, 367–378. doi: 10.1038/s41564-022-01083-2
Fraszczak, K., Barczynski, B., and Kondracka, A. (2022). Does lactobacillus exert a protective effect on the development of cervical and endometrial cancer in women? Cancers 14:4909. doi: 10.3390/cancers14194909
Fu, J., and Zhang, H. (2023). Meta-analysis of the correlation between vaginal microenvironment and HPV infection. Am. J. Transl. Res. 15, 630–640.
Gao, B., Liou, Y. L., Yu, Y., Zou, L., Li, W., Huang, H., et al. (2021). The characteristics and risk factors of human papillomavirus infection: an outpatient population-based study in Changsha, Hunan. Sci. Rep. 11:15128. doi: 10.1038/s41598-021-94635-1
Garmendia, J. V., De Sanctis, C. V., Hajduch, M., and de Sanctis, J. B. (2024). Microbiota and recurrent pregnancy loss (RPL); more than a simple connection. Microorganisms 12:1641. doi: 10.3390/microorganisms12081641
Giraldo, P. C., Sanches, J. M., Sparvolli, L. G., Amaral, R., Migliorini, I., Gil, C. D., et al. (2021). Relationship between Papillomavirus vaccine, vaginal microbiome, and local cytokine response: an exploratory research. Braz. J. Microbiol. 52, 2363–2371. doi: 10.1007/s42770-021-00616-x
Gong, X., Chi, H., Xia, Z., Yang, G., and Tian, G. (2023). Advances in HPV-associated tumor management: therapeutic strategies and emerging insights. J. Med. Virol. 95:e28950. doi: 10.1002/jmv.28950
Gutierrez Salmean, G., Delgadillo Gonzalez, M., Rueda Escalona, A. A., Leyva Islas, J. A., and Castro-Eguiluz, D. (2024). Effects of prebiotics, probiotics, and synbiotics on the prevention and treatment of cervical cancer: Mexican consensus and recommendations. Front. Oncol. 14:1383258. doi: 10.3389/fonc.2024.1383258
Hamar, B., Teutsch, B., Hoffmann, E., Hegyi, P., Váradi, A., Nyirády, P., et al. (2023). Trichomonas vaginalis infection is associated with increased risk of cervical carcinogenesis: a systematic review and meta-analysis of 470,000 patients. Int. J. Gynaecol. Obstet. 163, 31–43. doi: 10.1002/ijgo.14763
Han, X., Liu, H., Zhang, K., Zeng, Y., Liu, P., Gan, L., et al. (2025). Lactiplantibacillus plantarum MH-301 reduces Helicobacter pylori treatment-related adverse events via gut-vaginal axis: a randomized, double-blind, placebo-controlled trial. J. Infect. 91:106539. doi: 10.1016/j.jinf.2025.106539
He, J., Li, T., Wang, Y., Song, Z., Li, Q., Liu, Y., et al. (2021). Genetic variability of human papillomavirus type 39 based on E6, E7 and L1 genes in Southwest China. Virol. J. 18:72. doi: 10.1186/s12985-021-01528-w
Heikal, E. A., Elamir, A. M., Hegazi, M. A., Salem, H. S., Tawfeik, A. M., Bosilah, A. H., et al. (2023). Signature of real-time PCR in detection of Trichomonas vaginalis infection and its association with human papillomavirus genotype 16. Eur. Rev. Med. Pharmacol. Sci. 27, 501–510. doi: 10.26355/eurrev_202301_31050
Hickey, E., Leaves, I., Pradhan, A., Ma, Q., Yuecel, R., Gow, N. A. R., et al. (2025). Effects of short-chain fatty acid combinations relevant to the healthy and dysbiotic gut upon Candida albicans. Curr. Microbiol. 82:420. doi: 10.1007/s00284-025-04400-0
Hinderfeld, A. S., Phukan, N., Bar, A. K., Roberton, A. M., and Simoes-Barbosa, A. (2019). Cooperative interactions between Trichomonas vaginalis and associated bacteria enhance paracellular permeability of the cervicovaginal epithelium by dysregulating tight junctions. Infect. Immun. 87, e00141–19. doi: 10.1128/IAI.00141-19
Holali Ameyapoh, A., Katawa, G., Ritter, M., Tchopba, C. N., Tchadié, P. E., Arndts, K., et al. (2021). Hookworm infections and sociodemographic factors associated with female reproductive tract infections in rural areas of the Central Region of Togo. Front. Microbiol. 12:738894. doi: 10.3389/fmicb.2021.738894
Hong, D. D., Shang, T. T., Guo, H. Y., Zuo, W. T., Sun, R., Xu, W. W., et al. (2025). [Role of Toll-like receptors in persistent infection of cervical high-risk human papillomavirus based on “latent pathogen theory”]. Zhongguo Zhong Yao Za Zhi 50, 1974–1979. doi: 10.19540/j.cnki.cjcmm.20250109.501
Hoppe-Seyler, K., Herrmann, A. L., Däschle, A., Kuhn, B. J., Strobel, T. D., Lohrey, C., et al. (2021). Effects of metformin on the virus/host cell crosstalk in human papillomavirus-positive cancer cells. Int. J. Cancer 149, 1137–1149. doi: 10.1002/ijc.33594
Huang, J., Yin, C., and Wang, J. (2023). Relationship between vaginal microecological changes and oncogene E6/E7 and high-risk human papillomavirus infection. J. Obstet. Gynaecol. 43:2161349. doi: 10.1080/01443615.2022.2161349
Huang, J. L., Wang, X., Yu, F., Li, M. Y., and Tang, Y. T. (2023). [Vaginal microbiota abnormalities in women with unexplained infertility and its treatment]. Zhonghua Yu Fang Yi Xue Za Zhi 57, 1813–1819. doi: 10.3760/cma.j.cn112150-20230322-00217
Huang, R., Liu, Z., Sun, T., and Zhu, L. (2024). Cervicovaginal microbiome, high-risk HPV infection and cervical cancer: Mechanisms and therapeutic potential. Microbiol. Res. 287:127857. doi: 10.1016/j.micres.2024.127857
Idrak, S., Zaki, S., Rasheed, F., Javed, M., Khalid, H., Niaz, S., et al. (2024). Cervical cancer screening practices in HIV positive females - a missing link in health care delivery in Pakistan. J. Pak. Med. Assoc. 74, 631–640. doi: 10.47391/JPMA.8211
Inturi, R., and Jemth, P. (2021). CRISPR/Cas9-based inactivation of human papillomavirus oncogenes E6 or E7 induces senescence in cervical cancer cells. Virology 562, 92–102. doi: 10.1016/j.virol.2021.07.005
Jain, M., Yadav, D., Jarouliya, U., Chavda, V., Yadav, A. K., Chaurasia, B., et al. (2023). Epidemiology, molecular pathogenesis, immuno-pathogenesis, immune escape mechanisms and vaccine evaluation for HPV-associated carcinogenesis. Pathogens 12:1380. doi: 10.3390/pathogens12121380
Jawanda, I. K., Soni, T., Kumari, S., and Prabha, V. (2024). The evolving facets of vaginal microbiota transplantation: reinvigorating the unexplored frontier amid complex challenges. Arch. Microbiol. 206:306. doi: 10.1007/s00203-024-04024-1
Kamzayeva, N., Bapayeva, G., Terzic, M., Primbetov, B., Imankulova, B., Kim, Y., et al. (2025). Enhancing cervical cancer screening: new diagnostic methodologies, triage, and risk stratification in prevention and treatment. Life 15:367. doi: 10.3390/life15030367
Kazlauskaite, J., Zukiene, G., Rudaitis, V., and Bartkeviciene, D. (2025). The vaginal microbiota, human papillomavirus, and cervical dysplasia-a review. Medicina 61:847. doi: 10.3390/medicina61050847
Kim, J. M., Song, H. S., Hwang, J., and Kim, J. K. (2025). The prevalence of multi-type infections among human papillomavirus types in Korean women. Pathogens 14:369. doi: 10.3390/pathogens14040369
Kotian, S., Ramesh, P. S., Shetty, J., Laxminarayana, K. P. H., Shetty, V., and Devegowda, D. (2024). Detection of transcriptionally active high-risk human papillomavirus in patients with oesophageal carcinoma by real-time PCR. J. Cancer Res. Ther. 20, 1440–1445. doi: 10.4103/jcrt.jcrt_1226_22
Kumar, R., Rojas, I. G., and Edgerton, M. (2022). Candida albicans Sap6 initiates oral mucosal inflammation via the protease activated receptor PAR2. Front. Immunol. 13:912748. doi: 10.3389/fimmu.2022.912748
Kyrgiou, M., and Moscicki, A. B. (2022). Vaginal microbiome and cervical cancer. Semin Cancer Biol. 86, 189–198. doi: 10.1016/j.semcancer.2022.03.005
Laghi, L., Zagonari, S., Patuelli, G., Zhu, C., Foschi, C., Morselli, S., et al. (2021). Vaginal metabolic profiles during pregnancy: changes between first and second trimester. PLoS One 16:e0249925. doi: 10.1371/journal.pone.0249925
Łaniewski, P., Joe, T. R., Jimenez, N. R., Eddie, T. L., Bordeaux, S. J., Quiroz, V., et al. (2024). Viewing native american cervical cancer disparities through the lens of the vaginal microbiome: a pilot study. Cancer Prev. Res. 17, 525–538. doi: 10.1158/1940-6207.CAPR-24-0286
Lavitola, G., Della Corte, L., De Rosa, N., Nappi, C., and Bifulco, G. (2020). Effects on vaginal microbiota restoration and cervical epithelialization in positive HPV patients undergoing vaginal treatment with carboxy-methyl-beta-glucan. Biomed Res. Int. 2020:5476389. doi: 10.1155/2020/5476389
Leão, S. L., Parente da Silva, G. R., Dos Santos, D. L., São Marcos, B. F., Bezerra Fontes, P. H., de Oliveira Isídio, B. E., et al. (2025). The differential expression of the JAK/STAT pathway in breast cancer cells transfected with human papillomavirus oncogenes. Viruses 17:880. doi: 10.3390/v17070880
Lebeau, A., Bruyere, D., Roncarati, P., Peixoto, P., Hervouet, E., Cobraiville, G., et al. (2022). HPV infection alters vaginal microbiome through down-regulating host mucosal innate peptides used by Lactobacilli as amino acid sources. Nat. Commun. 13:1076. doi: 10.1038/s41467-022-28724-8
Lee, J. Y., Seo, S., Shin, B., Hong, S. H., Kwon, E., Park, S., et al. (2022). Development of a new biomarker model for predicting preterm birth in cervicovaginal fluid. Metabolites 12:734. doi: 10.3390/metabo12080734
Leon-Gomez, P., and Romero, V. I. (2024). Human papillomavirus, vaginal microbiota and metagenomics: the interplay between development and progression of cervical cancer. Front. Microbiol. 15:1515258. doi: 10.3389/fmicb.2024.1515258
Li, D., Yang, C., Yang, H., Cao, J., and Wang, S. (2025). Dynamic changes of vaginal microbiota in healthy Chinese women from pre-pregnancy to the postpartum period. Int. J. Gynaecol. Obstet. 170, 1267–1276. doi: 10.1002/ijgo.70309
Li, J., Jin, H., Sun, Y., Wang, C., Chen, H., Gong, S., et al. (2024b). Reconnoitering correlation between human papillomavirus infection-induced vaginal microecological abnormality and squamous intraepithelial lesion (SIL) progression. BMC Womens Health 24:5. doi: 10.1186/s12905-023-02824-z
Li, M., Zhao, C., Zhang, X., Li, J., Zhao, Y., Zhang, W., et al. (2024). PAX1/JAM3 methylation and HPV viral load in women with persistent HPV infection. Cancers 16:1430. doi: 10.3390/cancers16071430
Li, X., Xiang, F., Liu, T., Chen, Z., Zhang, M., Li, J., et al. (2024). Leveraging existing 16S rRNA gene surveys to decipher microbial signatures and dysbiosis in cervical carcinogenesis. Sci. Rep. 14:11532. doi: 10.1038/s41598-024-62531-z
Lin, W., Zhang, Q., Chen, Y., Dong, B., Xue, H., Lei, H., et al. (2022). Changes of the vaginal microbiota in HPV infection and cervical intraepithelial neoplasia: a cross-sectional analysis. Sci. Rep. 12:2812. doi: 10.1038/s41598-022-06731-5
Liu, H., Liang, H., Li, D., Wang, M., and Li, Y. (2022). Association of cervical dysbacteriosis, HPV oncogene expression, and cervical lesion progression. Microbiol. Spectr. 10:e0015122. doi: 10.1128/spectrum.00151-22
Liu, H. M., Zhang, F., Cai, H. Y., Lv, Y. M., and Pi, M. Y. (2024). Cross-sectional study on the correlation between vaginal microecology and high-risk human papillomavirus infection: establishment of a clinical prediction model. Int. J. Womens Health. 16, 1765–1774. doi: 10.2147/IJWH.S479836
Liu, Y., Zhao, X., Wu, F., Chen, J., Luo, J., Wu, C., et al. (2024). Effectiveness of vaginal probiotics Lactobacillus crispatus chen-01 in women with high-risk HPV infection: a prospective controlled pilot study. Aging 16, 11446–11459. doi: 10.18632/aging.206032
Long, T., Zhang, C., He, G., Hu, Y., Lin, Z., and Long, L. (2023). Bacterial vaginosis decreases the risk of cervical cytological abnormalities. Cancer Prev. Res. 16, 109–117. doi: 10.1158/1940-6207.CAPR-22-0288
Lozar, T., and Carchman, E. (2025). Pathophysiology of anal cancer. Surg. Oncol. Clin. N. Am. 34, 21–35. doi: 10.1016/j.soc.2024.07.003
Ma, X., Wang, X., Ye, S., Liu, J., Yuan, H., and Wang, N. (2022). Biofilm and pathogenic factor analysis of Gardnerella vaginalis associated with bacterial vaginosis in Northeast China. Front. Microbiol. 13:1033040. doi: 10.3389/fmicb.2022.1033040
Martins, B. C. T., Guimaraes, R. A., Alves, R. R. F., and Saddi, V. A. (2023). Bacterial vaginosis and cervical human papillomavirus infection in young and adult women: a systematic review and meta-analysis. Rev Saude Publica. 56:113. doi: 10.11606/s1518-8787.2022056004412
Mazinani, S., Aghazadeh, M., Poortahmasebi, V., Arafi, V., and Hasani, A. (2025). Cervical cancer pathology and vaginal and gut microbiota: conception of the association. Lett. Appl. Microbiol. 78:ovaf088. doi: 10.1093/lambio/ovaf088
Mbabazi, E., Munyemana, J. B., Mukashema, J., Bazimaziki, E., Ndayisaba, M. C., Adegboyega, T. T., et al. (2025). Prevalence of human papillomavirus and genotype correlation with cervical lesions at the university teaching hospital of Kigali. Am. J. Trop. Med. Hyg. 112, 1335–1340. doi: 10.21203/rs.3.rs-5348722/v1
Mbulawa, Z. Z. A., Phohlo, K., Garcia-Jardon, M., Williamson, A. L., and Businge, C. B. (2022). High human papillomavirus (HPV)-35 prevalence among South African women with cervical intraepithelial neoplasia warrants attention. PLoS One 17:e0264498. doi: 10.1371/journal.pone.0264498
McClymont, E., Albert, A. Y., Wang, C., Dos Santos, S. J., Coutlée, F., Lee, M., et al. (2022). Vaginal microbiota associated with oncogenic HPV in a cohort of HPV-vaccinated women living with HIV. Int. J. STD AIDS 33, 847–855. doi: 10.1177/09564624221109686
Mei, L., Wang, T., Chen, Y., Wei, D., Zhang, Y., Cui, T., et al. (2022). Dysbiosis of vaginal microbiota associated with persistent high-risk human papilloma virus infection. J. Transl. Med. 20:12. doi: 10.1186/s12967-021-03201-w
Miró, M. S., Rodríguez, E., Vigezzi, C., Icely, P. A., García, L. N., Peinetti, N., et al. (2017). Contribution of TLR2 pathway in the pathogenesis of vulvovaginal candidiasis. Pathog. Dis. 75:fty050. doi: 10.1093/femspd/ftx096
Moyes, D. L., Richardson, J. P., and Naglik, J. R. (2015). Candida albicans-epithelial interactions and pathogenicity mechanisms: scratching the surface. Virulence 6, 338–346. doi: 10.1080/21505594.2015.1012981
Musa, J., Maiga, M., Green, S. J., Magaji, F. A., Maryam, A. J., Okolo, M., et al. (2023). Vaginal microbiome community state types and high-risk human papillomaviruses in cervical precancer and cancer in North-central Nigeria. BMC Cancer 23:683. doi: 10.1186/s12885-023-11187-5
Muzny, C. A., and Sobel, J. D. (2022). The role of antimicrobial resistance in refractory and recurrent bacterial vaginosis and current recommendations for treatment. Antibiotics 11:500. doi: 10.20944/preprints200042.v1
Na, J., Li, Y., Lu, Q., Wang, Y., Han, S., and Wang, J. (2025). Investigating the impact of persistent HPV infection on recurrence of lesions post-surgery for early-stage cervical cancer and related influencing factors. Front. Oncol. 15:1506521. doi: 10.3389/fonc.2025.1506521
Nicolò, S., Antonelli, A., Tanturli, M., Baccani, I., Bonaiuto, C., Castronovo, G., et al. (2023). Bacterial species from vaginal microbiota differently affect the production of the E6 and E7 oncoproteins and of p53 and p-Rb oncosuppressors in HPV16-infected cells. Int. J. Mol. Sci. 24:7173. doi: 10.3390/ijms24087173
Nieves-Ramírez, M. E., Partida-Rodríguez, O., Moran, P., Serrano-Vázquez, A., Pérez-Juárez, H., Pérez-Rodríguez, M. E., et al. (2021). Cervical squamous intraepithelial lesions are associated with differences in the vaginal microbiota of Mexican women. Microbiol. Spectr. 9:e0014321. doi: 10.1128/Spectrum.00143-21
Nittala, M. R., Yang, J., Velazquez, A. E., Salvemini, J. D., Vance, G. R., Grady, C. C., et al. (2024). Precision population cancer medicine in cancer of the uterine cervix: a potential roadmap to eradicate cervical cancer. Cureus 16:e53733. doi: 10.7759/cureus.53733
Pagar, R., Deshkar, S., Mahore, J., Patole, V., Deshpande, H., Gandham, N., et al. (2024). The microbial revolution: Unveiling the benefits of vaginal probiotics and prebiotics. Microbiol. Res. 286:127787. doi: 10.1016/j.micres.2024.127787
Pai, H. D., Baid, R., Palshetkar, N. P., Pai, R., Pai, A., and Palshetkar, R. (2025). Role of vaginal and gut microbiota in human papillomavirus (HPV) progression and cervical cancer: a systematic review of microbial diversity and probiotic interventions. Cureus 17:e85880. doi: 10.7759/cureus.85880
Pan, S., Wei, W., Du, X., Li, Z., Tuo, J., Zhang, M., et al. (2022). Factors associated with persistence and clearance of HPV16/18 among rural Chinese women: a cohort study in Wufeng, Hubei province. Women Health 62, 276–286. doi: 10.1080/03630242.2022.2056283
Pandey, P., Ramniwas, S., Pandey, S., Lakhanpal, S., Ballal, S., Kumar, S., et al. (2025). Elucidating the anticancerous efficacy of genistein via modulating HPV (E7 and E6) oncogenes expression and apoptotic induction in cervical cancer cells. Biotechnol. Appl. Biochem. 72, 709–717. doi: 10.1002/bab.2691
Pankaj, S., Rani, J., Kumari, P., Abhilashi, K., Choudhary, V., Kumari, S., et al. (2024). Efficacy of HPV E6/E7 mRNA assay, HPV DNA test and cytology in detection of high grade cervical lesions and invasive cancer at a tertiary care center in India. Malawi Med. J. 36, 120–127. doi: 10.4314/mmj.v36i2.9
Papamentzelopoulou, M., and Pitiriga, V. C. (2025). Unlocking the interactions between the whole-body microbiome and hpv infection: a literature review. Pathogens 14:293. doi: 10.20944/preprints201667.v1
Plisko, O., Zodzika, J., Jermakova, I., Pcolkina, K., Prusakevica, A., Liepniece-Karele, I., et al. (2024). Prediction of high-grade cervical precancerous abnormalities: the role of personal factors, vaginal microflora, sexually transmitted infections, and high-risk human papillomavirus. PLoS One 19:e0313004. doi: 10.1371/journal.pone.0313004
Qingqing, B., Jie, Z., Songben, Q., Juan, C., Lei, Z., and Mu, X. (2021). Cervicovaginal microbiota dysbiosis correlates with HPV persistent infection. Microb. Pathog. 152:104617. doi: 10.1016/j.micpath.2020.104617
Schichl, K., and Doorbar, J. (2025). Regulation and deregulation of viral gene expression during high-risk HPV infection. Viruses 17:937. doi: 10.3390/v17070937
Schuster, H. J., Bos, A. M., Himschoot, L., van Eekelen, R., Matamoros, S. P. F., de Boer, M. A., et al. (2024). Vaginal microbiota and spontaneous preterm birth in pregnant women at high risk of recurrence. Heliyon 10:e30685. doi: 10.1016/j.heliyon.2024.e30685
Shang, X., Bai, H., Fan, L., Zhang, X., Zhao, X., and Liu, Z. (2024). In vitro biofilm formation of Gardnerella vaginalis and Escherichia coli associated with bacterial vaginosis and aerobic vaginitis. Front. Cell Infect. Microbiol. 14:1387414. doi: 10.3389/fcimb.2024.1387414
Shen, J., Sun, H., Chu, J., Gong, X., and Liu, X. (2024). Cervicovaginal microbiota: a promising direction for prevention and treatment in cervical cancer. Infect. Agent Cancer. 19:13. doi: 10.1186/s13027-024-00573-8
Shen, L., Zhang, W., Yuan, Y., Zhu, W., and Shang, A. (2022). Vaginal microecological characteristics of women in different physiological and pathological period. Front. Cell Infect. Microbiol. 12:959793. doi: 10.3389/fcimb.2022.959793
Sheng, W., Zhou, J., Zhang, H., Tian, W., Zhang, Y., Yang, Z., et al. (2025). Trichomonas vaginalis adhesion protein 33 (TvAP33) promotes HPV infection by upregulating the expression of HPV membrane receptor molecules. Acta. Trop. 264:107578. doi: 10.1016/j.actatropica.2025.107578
Shi, W., Zhu, H., Yuan, L., Chen, X., Huang, X., Wang, K., et al. (2022). Vaginal microbiota and HPV clearance: a longitudinal study. Front. Oncol. 12:955150. doi: 10.3389/fonc.2022.955150
Sims, T. T., Colbert, L. E., and Klopp, A. H. (2021). The role of the cervicovaginal and gut microbiome in cervical intraepithelial neoplasia and cervical cancer. J. Immunother. Precis. Oncol. 4, 72–78. doi: 10.36401/JIPO-20-17
Swidsinski, S., Moll, W. M., and Swidsinski, A. (2023). Bacterial vaginosis-vaginal polymicrobial biofilms and dysbiosis. Dtsch Arztebl Int. 120, 347–354. doi: 10.3238/arztebl.m2023.0090
Tounkara, F. K., Téguété, I., Guédou, F. A., Talbot, D., Traoré, C. B., Béhanzin, L., et al. (2021). Type-specific incidence, persistence and factors associated with human papillomavirus infection among female sex workers in Benin and Mali, West Africa. Int. J. Infect. Dis. 106, 348–357. doi: 10.1016/j.ijid.2021.04.008
Uysal, I. B., Boué, V., Murall, C. L., Graf, C., Selinger, C., Hirtz, C., et al. (2022). Concomitant and productive genital infections by HSV-2 and HPV in two young women: a case report. IDCases 30:e01604. doi: 10.1016/j.idcr.2022.e01604
Valand, N., and Girija, U. V. (2021). Candida pathogenicity and interplay with the immune system. Adv. Exp. Med. Biol. 1313, 241–272. doi: 10.1007/978-3-030-67452-6_11
Valentine, M., Rosati, D., Dietschmann, A., Schille, T. B., Netea, M. G., Hube, B., et al. (2025). Probiotic Lactobacillus species modulate immune responses during vaginal epithelial cell colonization. J. Infect. Dis. 232, e403–e415. doi: 10.1093/infdis/jiaf221
Valentine, M., Rudolph, P., Dietschmann, A., Tsavou, A., Mogavero, S., Lee, S., et al. (2024). Nanobody-mediated neutralization of candidalysin prevents epithelial damage and inflammatory responses that drive vulvovaginal candidiasis pathogenesis. mBio 15:e0340923. doi: 10.1128/mbio.03409-23
Vargas-Robles, D., Romaguera, J., Alvarado-Velez, I., Tosado-Rodríguez, E., Dominicci-Maura, A., Sanchez, M., et al. (2023). The cervical microbiota of Hispanics living in Puerto Rico is nonoptimal regardless of HPV status. mSystems 8:e0035723. doi: 10.1128/msystems.00357-23
Ventura, P. M., Guimarães, I. C. C. D. V., Velarde, L. G. C., Fialho, S. C. A. V., Ferreira, D. G., Fernandes, M. M., et al. (2024). Analysis of vaginal microbiota before and after treatment of high-grade squamous intraepithelial lesions of the uterine cervix. Rev. Bras. Ginecol. Obstet. 46:e-rbgo86. doi: 10.61622/rbgo/2024rbgo86
Wagh, P., Kulkarni, P., Kerkar, S., Tongaonkar, H., Deodhar, K., Rekhi, B., et al. (2019). Types of human papillomavirus observed in hospital-based population. Indian J. Med. Microbiol. 37, 557–562. doi: 10.4103/ijmm.IJMM_19_451
Wang, W., Zhang, X. H., Li, M., Hao, C. H., and Liang, H. P. (2020). Association between vaginal infections and the types and viral loads of human papillomavirus: a clinical study based on 4,449 cases of gynecologic outpatients. Can. J. Infect. Dis. Med. Microbiol. 2020:9172908. doi: 10.1155/2020/9172908
Wang, Y. T., Wu, H., Wu, J. J., Yu, Y. S., Wen, J., Zou, B., et al. (2025). The hypoglycemic effect of mulberry (Morus atropurpurea) fruit lacking fructose and glucose by regulation of the gut microbiota. Food Funct. 16, 2444–2460. doi: 10.1039/D4FO02781G
Wei, K., and Chen, T. (2021). [Vaginal microbiota transplantation for treatment of bacterial vaginosis: a review]. Sheng Wu Gong Cheng Xue Bao 37, 3820–3827.
Williams, V. M., Filippova, M., Soto, U., and Duerksen-Hughes, P. J. (2011). HPV-DNA integration and carcinogenesis: putative roles for inflammation and oxidative stress. Future Virol. 6, 45–57. doi: 10.2217/fvl.10.73
Yan, C., Zhang, J., Yang, Y., Zeng, X., and Xiao, G. (2025). Virulence factors, biofilm formation and antifungal resistance in Candida albicans from recurrent vulvovaginal candidiasis patients: a comparative study. Sci Rep. 15:37557. doi: 10.1038/s41598-025-21846-1
Yang, C. Y., Chang, T. C., Lee, Y. T., Shih, T. Y., Li, C. W., and Cheng, C. M. (2025). Exploring the interplay between cervicovaginal microbiome, HPV infection, and cervical intraepithelial neoplasia in Taiwanese women. J. Med. Virol. 97:e70190. doi: 10.1002/jmv.70190
Yang, Y., Zhu, J., Feng, R., Han, M., Chen, F., and Hu, Y. (2024). Altered vaginal cervical microbiota diversity contributes to HPV-induced cervical cancer via inflammation regulation. PeerJ 12:e17415. doi: 10.7717/peerj.17415
Ye, J., and Vaginal, Q. i. X. (2024). microecology and its role in human papillomavirus infection and human papillomavirus associated cervical lesions. APMIS 132, 928–947. doi: 10.1111/apm.13356
Zhang, W., Che, Q., Tan, H., Qi, X., Li, D., Zhu, T., et al. (2023). A novel antimycin analogue antimycin A2c, derived from marine Streptomyces sp., suppresses HeLa cells via disrupting mitochondrial function and depleting HPV oncoproteins E6/E7. Life Sci. 330:121998. doi: 10.1016/j.lfs.2023.121998
Zhang, Y., Wu, X., Li, D., et al. (2024). HPV-associated cervicovaginal microbiome and host metabolome characteristics. BMC Microbiol. 24:94. doi: 10.1186/s12866-024-03244-1
Zhang, Z., Ma, Q., Zhang, L., Ma, L., Wang, D., Yang, Y., et al. (2024). Human papillomavirus and cervical cancer in the microbial world: exploring the vaginal microecology. Front. Cell Infect. Microbiol. 14:1325500. doi: 10.3389/fcimb.2024.1325500
Zhao, M., Kang, P., Zhu, L., Zhou, D., Cui, M., Zhang, M., et al. (2024). Global pattern of persistent human papillomavirus infection in female genital tract: an update system review and meta-analysis. iScience 27:110991. doi: 10.1016/j.isci.2024.110991
Zhao, M., Zhou, D., Zhang, M., Kang, P., Cui, M., Zhu, L., et al. (2023). Characteristic of persistent human papillomavirus infection in women worldwide: a meta-analysis. PeerJ. 11:e16247. doi: 10.7717/peerj.16247
Zhou, Y. X., Wang, L., Wang, T. T., Qu, X. L., and Zhang, X. Q. (2023). Analysis of HPV prevalence among individuals with reproductive tract infections in a Chinese population. Medicine 102:e34989. doi: 10.1097/MD.0000000000034989
Zimmann, N., Rada, P., Žárský, V., Smutná, T., Záhonová, K., Dacks, J., et al. (2022). Proteomic analysis of trichomonas vaginalis phagolysosome, lysosomal targeting, and unconventional secretion of cysteine peptidases. Mol. Cell Proteomics 21:100174. doi: 10.1016/j.mcpro.2021.100174
Keywords: persistent human papillomavirus infection, vaginal microecology, vulvovaginal candidiasis, E6/E7 oncogenes, cervical cancer
Citation: Zhang X, Yao M, Huang Y, Wang H, Li H and Ma J (2026) The dual role of vulvovaginal candidiasis in HPV infection: implications for vaginal microecology and cervical lesions. Front. Microbiol. 16:1724735. doi: 10.3389/fmicb.2025.1724735
Received: 14 October 2025; Revised: 24 November 2025;
Accepted: 08 December 2025; Published: 12 January 2026.
Edited by:
Samantha Flores-Treviño, Autonomous University of Nuevo León, MexicoReviewed by:
Hong-Yu Zhang, The Fourth Hospital of Harbin Medical University, ChinaTatiana Priputnevich, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V. I. Kulakov of Ministry of Healthcare of Russian Federation, Russia
Copyright © 2026 Zhang, Yao, Huang, Wang, Li and Ma. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Juanwen Ma, MTM5OTMxNTg0MjdAMTYzLmNvbQ==