Xue Feng1,2†
Chaoyang Li
Min Feng
Nan Wang- 1Department of Clinical Laboratory Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
- 2College of Laboratory Medicine, Dalian Medical University, Dalian, Liaoning, China
- 3Institute of Pulmonology, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
Microbial communities play a vital role in the human defense system, existing symbiotically with us, contributing to metabolic processes, and strengthening immune defenses against pathogens. A diverse bacterial population in the vagina contributes to maintaining dynamic homeostasis, with their interactions playing a critical role in determining health or disease status. The balanced vaginal microbiota, dominated by Lactobacilli, helps maintain vaginal pH, converts glycogen to lactic acid, and produces bacteriocins and hydrogen peroxide (H2O2), all contributing to its protective functions. On the other hand, an abnormal vaginal microbial composition, characterized by a decrease in beneficial microorganisms, heightens the risk of gynecological diseases such as bacterial vaginosis (BV), sexually transmitted infections, human papillomavirus (HPV) infections, and cervical cancer due to persistent infections. Variation in microbial composition is influenced by factors such as racial background, ethnicity, pregnancy, hormonal fluctuations, sexual behavior, personal hygiene practices, and various physiological conditions. This review aims to offer a detailed overview of the existing literature, focusing on the complex interplay between vaginal microbiota and gynecological conditions such as HPV infection. Our goal is to provide valuable insights that can inform future clinical strategies and interventions.
1 Introduction
The human microbiome comprises many microorganisms, spanning bacteria, archaea, protozoa, fungi, and viruses. Together, their collective genetic material forms the “microbiome,” and they inhabit various body regions in staggering numbers (Schirmer et al., 2018). Their colonization within the human body stems from intricate interactions with multiple facets of host physiology and metabolism, reflecting a finely tuned relationship. They aid in nutrient absorption and the development of the host’s immune system, playing a vital role in safeguarding the host against infections. In essence, human rely on microbes to maintain their health, while microbes, in turn, depend on the distinctive environment provided by the human body to thrive and coexist in a mutually beneficial relationship.
Based on findings from numerous recent studies utilizing microbiome and omics approaches, alongside data from diverse cohorts of women, it’s evident that the female genital tract harbors a distinct microbial community. Notably, the vaginal microbiome is typically dominated by Lactobacilli (Ravel et al., 2011), maintaining a low-pH environment that protects against pathogens (Miller et al., 2016). Disruption of this community-marked by reduced Lactobacilli abundance and increased microbial diversity-has been associated with inflammation and a heightened risk of persistent HPV infection, ultimately contributing to the development of cervical lesions. However, several knowledge gaps persist. The vaginal microbiota, a key component of the reproductive tract microbiota, is influenced by changes in the gut microbiota (Xu, Mageswaran, et al., 2025). Moreover, the causal relationships among dysbiosis, HPV persistence, and cervical carcinogenesis remain incompletely understood.
This review aims to clarify these concepts and highlight how microbial ecology contributes to HPV susceptibility and disease progression. By distinguishing key microbial niches and emphasizing unresolved mechanisms, the review provides conceptual clarification and points toward areas for future study.
2 Vaginal microbiota
2.1 Composition and ecological characteristics of the vaginal microbiota
The vaginal microbiota represents a dynamic and intricately balanced ecosystem, with continual shifts in composition and interactions among its microbial members. In healthy women, it typically comprises six major phyla: Firmicutes, Bacteroidetes, Fusobacteria, Actinobacteria, Tenericutes and Proteobacteria (Lee et al., 2013), with Firmicutes predominating due to the abundance of Lactobacilli. While the healthy vaginal environment is inherently variable, it is typically characterized by a Lactobacilli-rich community that maintains ecological stability and epithelial protection.
2.2 Protective roles of lactobacilli in vaginal homeostasis
In the vaginal flora of most women, Lactobacilli are usually dominant at the species level and are commonly found in the vaginal epithelium. Lactobacilli protect by several mechanisms: (1) preventing pathogenic bacteria from adhering to the vaginal epithelium. Free glycogen is produced as the vaginal epithelium proliferates, sheds, and reattaches, providing a source of nutrients and energy for the growth of Lactobacilli, which in turn helps prevent the attachment of harmful bacteria. (2) Lactobacillus metabolizes glycogen via anaerobic glycolysis to produce lactic acid, which helps maintain a low pH environment in the vagina. Both protonated forms, D-lactate and L-lactate, exhibit bactericidal properties (O'hanlon et al., 2011). Lactic acid can cause the breakdown of bacteria apart from Lactobacilli, acidifies cell membranes, disrupts intracellular functions, and increases the permeability of cell membranes to H2O2, diacetyls, and other compounds, thereby strengthening its antimicrobial properties within the vaginal environment (Alakomi et al., 2000). (3) It produces these metabolites including H2O2, reactive oxygen species (ROS), bacteriocins, bacteriocin-like antagonistic substances, and bioemulsifiers. These metabolic derivatives prevent the growth of harmful bacteria and break down the biofilms produced by these harmful bacteria (Lee et al., 2013; Molina et al., 2024; Boskey et al., 2001). (4) Certain strains of Lactobacilli attenuate the proinflammatory response triggered by Toll-like receptors (TLRs) and exert immunomodulatory effects, partially due to the presence of lactic acid. Collectively, these functions position Lactobacilli as the primary regulator of vaginal microbial homeostasis.
2.3 Community state types and microbial transitions
According to species composition and the relative abundance of bacteria, the vaginal microbiota can be sorted into five distinct CSTs, initially introduced in 2011 (Ravel et al., 2011; Lee et al., 2020). These CSTs aid in research-driven interpretations of the health status, diversity, and transitional phases within the vaginal microbiome (Ravel et al., 2011). Lactobacilli (Lactobacillus crispatus, Lactobacillus gasseri and Lactobacillus iners) were the main features of CST I-III. In contrast, CST IV is a diverse group distinguished by a lower presence of Lactobacilli, typically with the highest pH median. The predominant bacteria in CST IV are anaerobes, including Gardnerella, Prevotella, Atopobium, and Aerococcus, which are frequently linked with BV (Figure 1). This cluster is labeled CST IV-BV, whereas another cluster lacking anaerobic bacteria is termed CST IV-AV (Di Paola et al., 2017; Brotman et al., 2014b). Both CST IV-AV and CST IV-BV are microbial communities characterized by reduced Lactobacilli, with CST IV-BV exhibiting even fewer Lactobacilli. In short, CST IV-AV is dominated by Lactobacilli and anaerobic bacteria, while CST IV-BV is characterized by BV-associated bacteria and high anaerobic diversity (Shen-Gunther et al., 2025). Conversely, vaginal dysbiosis is marked by reduced levels of Lactobacilli and elevated levels of CST IV microbiota (Auriemma et al., 2021).
Figure 1. CSTs of the vaginal microbiota and the protective mechanisms of Lactobacilli. The figure shows the different CSTs of the vaginal microbiota and highlights how Lactobacilli contribute to vaginal health through mechanisms such as lactic acid production and pathogen inhibition.
2.4 Vaginal pH and its role in microbial and mucosal stability
The composition of the vaginal microbiota is closely intertwined with the vaginal pH. The indigenous flora is critical to the balance of the local microbiota, with a specific average pH for the entire biological response chain of 4–4.5. A vaginal pH below 4.5 provides a protective shield against pathogens, which struggle to thrive in such a low pH condition. When the pH level increases, it provides an opportunity for harmful bacteria to enter and disturb the balance of the vaginal environment (Borgogna et al., 2020; Mangieri et al., 2023). Thus, local homeostatic disorders and any pH alteration directly impair the integrity of the mucosa, which has a functional role in the internal and external adaptable slope (Borgogna et al., 2020; Mangieri et al., 2023). If ever disrupted, mucous membranes and tissues turn susceptible to invasive microbes and the process of inflammation. As a result, this hastens the degradation of the endothelial wall and the protective function of the microbiota, leading to increased accumulation of pro-inflammatory endotoxins and the prolonged spread of pathogens (Borgogna et al., 2020; Mangieri et al., 2023).
2.5 Determinants of vaginal microbiota composition
Various factors contribute to shaping the composition of the vaginal microbiota, such as race (Borgdorff et al., 2017), hormone levels (Krog et al., 2022; Adapen et al., 2022; María Fosch et al., 2022; Clabaut et al., 2021; Kaur et al., 2020), smoking history, vaginal douching practices, sexual activity frequency, persistent stress, and indiscriminate antibiotic use. In a cross-sectional survey comprising 396 women who are sexually active among four self-reported racial backgrounds, it was observed that the vaginal microbiota was not predominantly dominated by Lactobacilli among black and Hispanic women, a pattern considered normal and prevalent within these populations. These findings imply that genetic factors could play a notable role in shaping the makeup of the vaginal microbiota (Ravel et al., 2011). The vaginal microbiota has been shown to undergo cyclical fluctuations corresponding to different phases of the menstrual cycle (Chen et al., 2017). Additionally, the administration of external hormones, either orally or via injections, can alter its composition (Balle et al., 2020). Research demonstrated that following menopause, the percentage of indigenous bacteria, such as Lactobacilli declines (Lee et al., 2013). Furthermore, evidence indicates that individuals who smoke exhibit reduced levels of Lactobacilli (Brotman et al., 2014a).
3 Dysbiosis of vaginal flora
In the typical intestinal microenvironment, an increase in microbiome diversity is a sign of health, while the opposite trend is observed in the female vagina. The vaginal microbiota is a central component of vaginal microbiological ecology. Vaginal dysbiosis is distinguished as a decrease in the number of Lactobacilli and an increase in anaerobic bacteria, resulting in later metabolic and immunological alterations (Mckenzie et al., 2021). Typically, the components of vaginal microecology uphold a dynamic equilibrium. However, when the dominance of Lactobacilli is disturbed and microbial variety escalates, it initiates a sequence of metabolic alterations. Normal vaginal flora and dysbiosis are shown in Figure 2. The resulting increase in vaginal pH disrupts the suppressive role of the vaginal microbiota against additional pathogenic bacteria. Establishment by pathogenic bacteria triggers the secretion of various abnormal metabolites, such as sialidase, β-glucuronidase, coagulase, and neuraminidase, which diminish the thickness of the cervicovaginal fluid (CVF) and impair its protective role. In addition, mucosal immune and inflammatory responses are altered.
Figure 2. Female genital tract microbiota in health and disease. This illustration depicts the microbial composition and equilibrium of the female genital tract in healthy states, and shows how disruptions to this balance are linked to disease.
BV is a condition caused by multiple types of microorganisms and an exact microbiological definition remains elusive. It is featured by a decrease in Lactobacilli and an elevation in other bacteria typically associated with BV (Pramanick et al., 2019). Nevertheless, these causative organisms are capable of residing in the vaginal flora of healthy women. Meanwhile, individuals with BV typically do not show a notable inflammation. The vaginal mucosa is usually not inflamed or sensitive. Complaints of discomfort or pain are not often heard from female counterparts. Hence, BV is generally categorized as BV rather than vaginitis, and it’s regarded as a significant bacterial imbalance disorder. As depicted in Figure 2, in a healthy vagina during the probiotic phase, the lactic acid colony produces lactic acid. This lactic acid production helps maintain a vaginal pH below 4.5, establishing an acidic condition where acid-resistant bacteria can thrive while inhibiting the growth of pathogenic bacteria. Furthermore, lactic acid exhibits anti-inflammatory properties and serves to protect the epithelial cells. Additionally, it helps maintain the viscoelasticity of the mucus. In contrast, during dysbiosis and BV, there is a restriction in the population of Lactobacilli, leading to a reduction in lactic acid levels. This creates an environment where other pathogenic bacteria, such as Prevotella, Gardnerella, Atopobium, and Mobiluncus, can proliferate. These pathogens produce significant amounts of short-chain fatty acids (SCFAs) from glucose, maltose, and certain amino acids. SCFAs induces the activation of nodular lupus-like receptor protein 3 (NLRP3) inflammatory vesicles and IL-18 secretion in epithelial cells, promoting neutrophil recruitment to inflammatory sites. It also enhances the differentiation and suppressive function of FOXP3 + regulatory T (Treg) cells to mediate inflammation (Yu et al., 2025). In such instances, the integrity of the epithelium is compromised due to bacterial virulence factors, leading to impaired viscoelasticity of the mucus. This creates a pro-inflammatory environment characterized by a foul odor.
4 Association of vaginal microbiota with HPV infection and cervical cancer
4.1 HPV infection
The environment in which our bodies live is rich in microbiota, and the resident microbiota is considered to be an inseparable component of the human body. Research into the human microbiota has consistently shown its importance in preserving health and warding off a range of ailments, including gastrointestinal disorders and cancer. Research on vaginal microbiota and its functions is crucial because it is closely linked to various gynecological cancers (Liu et al., 2020). Lactobacilli in the healthy vaginal help immunocytes to clear HPV infections, prevent viral evasion, and reestablish immune balance. Certainly, dysbiosis of the vaginal flora has been linked to increased susceptibility to HPV infection (Nicolò et al., 2021; Cheng L. et al., 2020; Chao et al., 2019) and has been correlated with the persistence of HPV infection as well as the presence of HPV-associated lesions (Usyk et al., 2020; Brusselaers et al., 2019; Kwasniewski et al., 2018; Dareng et al., 2016; Audirac-Chalifour et al., 2016; Godoy-Vitorino et al., 2018). According to a meta-analysis conducted by Norenhag, it was found that having a vaginal microbiota dominated by non-Lactobacilli or even by Lactobacilli increased the chance of getting HPV significantly, by 3–5 times. Furthermore, research indicates that women who test positive for HPV tend to exhibit significantly higher microbial diversity in their vaginal microbiota and a decreased presence of Lactobacilli compared to those who test negative for HPV (Lee et al., 2013). Increased prevalence and incidence rates of HPV infection are closely associated with BV characterized by reduced Lactobacilli and increased anaerobic bacteria (Guo et al., 2012). The most prominent one is the increase of Prevotella bacteria associated with the recurrence of cervical cancer (Tsementzi et al., 2025). Additionally, genital infections such as Chlamydia trachomatis, Mycoplasma genitalium, and concurrent infections are associated with promoted HPV infection and hindered clearance of high-risk HPV (hr-HPV) strains (Cheng W. et al., 2020; Yang et al., 2020). Vaginal dysbiosis increases susceptibility to HPV infection. However, evidence suggests that transient HPV infection can reduce the richness and diversity of the vaginal microbiome, resulting in dysbiosis (Guo et al., 2025; Kumari and Bhor, 2021). Overall, HPV infection and vaginal dysbiosis appear to influence each other in a dynamic and reciprocal manner.
HPV infection is frequently encountered among sexually active women, with over 80% expected to acquire HPV at some phase of their life. While the majority can clear HPV infection naturally within 1–2 years, around 10–20% of women experience persistent HPV infection. The HPV virus is classified into two types based on its oncogenic potential: hr-HPV and low-risk (lr-HPV) types. The hr-HPV types include 16, 18, 31, 33, 35, 39, 45, 51, 52, 53, 56, 58, 59, 66, and 68, while the remaining types are classified as lr-HPV. The hr-HPV 16 and 18 types are detected in approximately 70% of cervical cancer cases. Continued HPV infection is considered a key factor in the development of cervical intraepithelial neoplasia and ultimately cervical cancer. Moreover, the lr-HPV can contribute to the development of genital warts, which can manifest as either benign growths or less aggressive lesions.
Furthermore, HPV impacts the maturation and differentiation of monocytes (Song et al., 2015), as well as inhibits the activity and role of TLRs, which play an essential role in recognizing pathogens (Daud et al., 2011). The expression of HPV-related tumor proteins (E6/E7) hamper the recruitment of macrophages along with other immune cells and suppresses the production of interferons (IFNs) by natural killer (NK) cells. IFNs are vital for curbing replication of the virus and activation of immune cells (Lee et al., 2001). In the realm of acquired immune responses, studies indicate that HPV 16 E6 and E7 diminish the expression of IFNs and human leukocyte antigen (HLA) (Tamadonfar et al., 2023) class I molecules, leading to a deficiency of cytotoxic T lymphocyte (CTL) feedback to HPV. Meanwhile, HPV controls the expression of a range of cytokines with anti-inflammatory and pro-inflammatory properties, influencing the roles of immune cells such as antigen-presenting cells (APCs) and CD4 + T cells (Cho et al., 2001). The ability of HPV to circumvent the immune response contributes to persistent infection and the advancement of cervical lesions. Acute HPV infection is characterized by the virus invading cells, viral genetic replication, and the production of virus particles, which may ultimately be eliminated by the immune system. Indeed, in certain instances of acute HPV infection, the virus is eliminated superficially, but the viral genome remains persistently within the infected cells and is difficult to detect, leading to a state of latent infection. Latent HPV infection has the potential to be reactivated by various factors, including immunosuppression. Chronic HPV infection is characterized as an untreated acute infection leading to sustained viral activity.
4.2 Cervical cancer
While most HPV infections are transient, a fraction persists and, over time, can initiate a carcinogenic cascade. The progression from persistent hr-HPV infection to cervical cancer is a multi-step process, and the vaginal microbiome is increasingly implicated in driving this progression. Cervical cancer stands as one of the most prevalent and deadliest cancers affecting women globally, with its morbidity and mortality rates on the rise. In the majority of patients, the immune system clears HPV infection within 6–18 months. However, when hr-HPV infection persists, it can lead to the development of cervical cancer. Multiple factors, including smoking, the amount and type of virus, age, as well as immune status, are strongly linked to the prolonged presence of HPV infection. The main treatment remains a combination of surgery procedure and chemotherapy. Certainly, long-lasting HPV infection and the resulting abnormalities in the cervix not only cause considerable physical distress but also place substantial psychological and economic strain on affected individuals. Indeed, previous research has indicated that the vaginal microenvironment plays a crucial role in shaping the progression of HPV infection and the development of cervical lesions. A dysregulated and functionally impaired microbiome tend to promote chronic low-grade inflammation, immune dysregulation, oxidative stress, DNA damage and metabolic rewiring, contributing to the carcinogenic effects of hr-HPV integrating oncogenes into the host genome. Vaginal inflammation increases the risk of cervical cancer (Huang et al., 2024). Lately, there has been growing attention to investigating the impact of vaginal microbiome dysbiosis on the persistence of HPV infection and the formation of cervical lesions (Qingqing et al., 2021; Santella et al., 2022).
Cervical cancer generally develops across four stages: the spread of HPV, persistent viral infection, the formation of cervical precancerous lesions within persistently infected epithelial cells, and eventual invasion of the epithelial basal membrane. Throughout the differentiation of basal cells, the HPV virus undergoes proliferation and sheds viral particles from the outer epithelial cells. Indeed, as HPV DNA becomes integrated into the host cell genome, it prompts elevated synthesis of E6 and E7 proteins. These viral tumor proteins play crucial roles in reactivating the synthesis of host cell DNA, fostering ongoing cell cycle processes, and inducing genetic changes, thus promoting the development of cancer. Moreover, HPV can alter glucose metabolism and promote glycolysis, creating a conducive microenvironment for cancer proliferation.
However, the immune system demonstrates the ability to clear most HPV infections, with only a minor fraction developing into precancerous or cervical lesions. Most patients either remain asymptomatic or exhibit transient positivity for the virus (Mosmann et al., 2021; Bhatla et al., 2013; Sangpichai et al., 2019). Certainly, recent findings affirm that the mere occurrence of HPV is insufficient to elucidate the onset and development of cervical cancer. Other factors, including host immune response, viral genotype, and environmental influences, likely play crucial roles in determining disease outcomes. There appears to be a consensus regarding the influence of immunity and hormones, but there is limited agreement on the role of the microbiota and changes in its composition. Some studies suggest a shift toward Lactobacillus liners dominance over Lactobacillus crispatus, while others indicate decreases in Bifidobacterium bifidum, Enterobacter, Atopobium, and Streptococcus species (Ochoa-Repáraz et al., 2017). Recent studies have firmly established that the vaginal microbiome plays a key role in the natural history of HPV infection and its development toward cervical tumors (Bautista et al., 2025). These changes have led to the belief that oncogenic mutations are a multistep process with multiple factors involved over time. This scenario is characterized by the fact that pathogen-infected cells are undergoing overlapping conditions of DNA alteration, which allows genetic and epigenetic alterations that enable viral replication and establish ideal conditions for oncogenic transformations (Ochoa-Repáraz et al., 2017; Hochreiter et al., 2000; Alagarasu et al., 2021; Paul and Grossman, 2014; Higgins et al., 2002; Collinson et al., 2002).
4.3 Mechanistic pathways linking vaginal microbiota, HPV persistence, and cervical carcinogenesis
4.3.1 Microbial metabolic pathways
Research has demonstrated that alterations in the microbiome, instead of the influence of a solitary pathogen, are responsible for the majority of microbial carcinogenesis cases (Sobhani et al., 2019). A decline in Lactobacilli dominance decreases lactic acid production, disrupts pH homeostasis, and weakens the natural antimicrobial barrier. This favors the survival of anaerobes associated with HPV persistence. These anaerobes produce metabolites, including short-chain fatty acids, polyamines, ammonia, and volatile amines, that can irritate the epithelium, damage DNA, and cause oxidative stress.
These metabolic disturbances also interact with host cellular pathways. Increased levels of oxidative and nitrative metabolites promote lipid peroxidation, protein modification and genotoxic lesions. These processes impair epithelial defense and facilitate viral integration. Microbial enzymes that degrade mucins or generate reactive metabolites further compromise barrier function, thereby enhancing susceptibility to viral entry. Additionally, shifts in microbial metabolism can modulate host immune responses by altering cytokine profiles and pattern recognition receptors (PRRs) activation.
4.3.2 Immunological interactions
The formation of tumors is closely associated with immune regulatory mechanisms within the vaginal epithelium. The vaginal epithelium of the host contains cell surface or intracellular receptors, known as PRRs, including TLRs and nucleotide-binding domain (NOD)-containing proteins. These receptors recognize and bind to pathogen-associated molecular patterns (PAMPs). In immune cells, TLR activation triggers a canonical signaling cascade beginning with the recruitment of the adaptor protein myeloid differentiation primary response 88 (MyD88). This process leads to the activation of the B-cell nuclear factor-κB (NF-κB) complex, which in turn promotes the transcription of cytokines and inflammatory genes (Crespo-Quiles and Femenía, 2025). Persistent HPV infection increases the expression of TLRs 2, 4 and 5 in the cytoplasm, leading to dysregulation of cytokine signaling. Inflammatory mediators such as IL-6, IL-8 and IL-1β promote tumor cell proliferation and drive cervical cancer progression (Schäfer et al., 2013). Beyond innate immune activation, HPV employs multiple immune-evasion strategies. A key mechanism is the downregulation of MHC-I molecules mediated by the viral protein E5, which retains MHC-I within the Golgi and endoplasmic reticulum, reducing antigen presentation to CD8+ T cells and facilitating persistent infection (Miyauchi et al., 2023).
Additionally, the abnormal activation of specific immune signaling cascades promotes carcinogenesis. The Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway facilitates immune evasion, while STAT3 promotes the production of inhibitory cytokines, such as transforming growth factor beta (TGF-β), IL-6 and IL-10. This encourages the recruitment of regulatory T cells and inhibits dendritic cell maturation. Together, these changes create an immunosuppressive environment that encourages tumor growth.
HPV further promotes cervical carcinogenesis through its E6 and E7 oncoproteins. E6 recruits E6AP to target p53 for proteasomal degradation, impairing apoptosis and DNA-damage responses. E7 binds and inactivates the retinoblastoma protein (pRb), releasing E2F transcription factors and driving uncontrolled cell-cycle progression. HPV E6/E7 oncoproteins also disrupt host immune surveillance by modulating transcription factor expression and perturbing NF-κB signaling (Zhang et al., 2025). This ultimately promotes abnormal cell proliferation, inflammation, angiogenesis, immune escape and tissue infiltration. Cervicovaginal dysbiosis is thought to exacerbate this process by potentially facilitating HPV acquisition and persistence, and promoting viral transformation (including E6/E7 expression, viral integration, and genomic instability), and supporting secondary infections, such as those caused by Chlamydia trachomatis (Figure 3). These immune disturbances together sustain a pro-inflammatory microenvironment that accelerates tumor formation.
Figure 3. Role of cervicovaginal dysbiosis and co-infection in cervical tumor development. Cervicovaginal dysbiosis and HPV co-infection with other bacteria and viruses cause associated immune dysregulation leading to cervical tumors.
4.3.3 HPV–microbiota molecular mechanisms
There is increasing evidence that oxidative and nitric stress are key microbial factors that drive inflammation-mediated carcinogenesis (Nelson et al., 2015). Oxidative stress impairs the function of immune cells, while nitric stress increases the production of biogenic amines and nitrosamines, thereby strengthening the resilience of pathogens and supporting the formation of biofilms (Nelson et al., 2015). However, high concentrations of Lactobacillus species can counteract these effects by inhibiting amine-producing bacteria and exhibiting cytotoxicity toward cervical cancer cells.
At a molecular level, the interactions between HPV and the microbiome influence the expression of viral oncogenes and downstream tumor-promoting pathways. For example, the regulation of HPV16 E7 by miR-27b enhances the proliferation and invasion of cervical cancer cells (Zhang et al., 2015). Furthermore, E6/E7 activation stimulates the PD-1/PD-L1 axis, thereby driving tumor progression. Immune checkpoint inhibitors that target this pathway have shown promise as a treatment for metastatic cervical cancer.
4.3.4 Barrier integrity and inflammation
Chronic HPV infection disrupts the normal cervical-vaginal microbiota and mucosal metabolism, triggering persistent inflammatory signalling. Activation of local mucosal immunity, including hyperactivity of NK cells and macrophages, promotes persistent tissue damage. However, HPV infection alone is not enough to cause malignant transformation. Additional factors, such as reduced Lactobacilli abundance, increased production of mucosal injury mediators and recurrent mixed microbial infections, all play a role in compromising epithelial barrier integrity.
Barrier dysfunction increases epithelial permeability, enabling inflammatory cytokines to penetrate deeper tissues and exacerbate intraepithelial damage. These processes promote HPV replication, transcription and modification, thereby advancing cervical intraepithelial neoplasia (Norenhag et al., 2020; So et al., 2020). Persistent inflammation further induces cytotoxic effects in healthy cells, causing DNA damage and activating autocrine and paracrine signalling loops that are influenced by epigenetic and microbial factors.
5 Interrelationships between the vaginal microbiota and the immune-endocrine system
During acute HPV infection, the initial immune response is driven by cells with antiviral and bactericidal properties, including mucosal NK cells, macrophages (M1 type during the acute phase and M2 type during the repair phase), and epithelial cells. Inflammatory patterns are infrequently observed due to the evolutionary development of molecular strategies by HPV, enabling them to evade both innate and adaptive immune responses. The HPV16 E7 oncoprotein suppresses TLR9 expression through the NF-κB signaling pathway, inducing an immunosuppressive state that impedes interferon production. This mechanism obstructs immune surveillance via cytokine responses, thereby enabling HPV to achieve immune escape (Mohammed et al., 2025). Infections typically exhibit a notable presence of CD4+/CD25 + regulatory T cells, activated T helper 2 (Th2) cells, and suppression of cytotoxic function, resulting in T cell anergy (Koskela et al., 2000).
The interplay between the vaginal microbiota and the host endocrine system is complex and bidirectional. The vaginal microbiota can metabolize and modulate the local availability of hormones. For instance, certain bacteria express enzymes like β-glucuronidase, which can deconjugate estrogen metabolites, potentially influencing the local hormonal milieu. Conversely, host sex hormones are pivotal regulators of the vaginal ecosystem. Estrogen, in particular, promotes the proliferation of vaginal epithelial cells and glycogen deposition. Animal studies provide insights into the potential depth of microbiota-endocrine interactions. Studies have shown that transferring microbiota from adult male mice to immature females results in shifts in hormone levels (notably elevated testosterone), as well as changes in the metabolome and autoantibody production. For example, one study found no significant differences in bacterial DNA sequencing results obtained from the caecal contents of 4-week-old and 10-13-week-old mice. However, they observed α-diversity discrepancies between the sexes in prepubertal mice. Sequencing of the 16S rRNA gene in the male microbiome, female, and neutered male mice revealed some “unusual” characteristics: the microbiota of female mice was very similar to that of castrated males, with comparable composition and androgen levels (Yurkovetskiy et al., 2013). Similarly, samples collected during pregnancy demonstrated that the composition of the vaginal microbiota tended to shift, mirroring changes in hormone levels and microbial communities. From pregnancy I to pregnancy III, an increase in the solidified bacterial phylum was observed, which is characteristic of the vaginal microbiome of normal women (Amin et al., 2023). On the other hand, during BV, vaginal microbiota dysbiosis has been defined by a variety of bacterial taxa from specific phyla, including Fusarium, Actinobacteria, Pseudomonas, and Bacillus-like phyla (Chaban et al., 2014). Likewise, the vaginal microbiota in premenopausal and perimenopausal women is primarily dominated by the fungal phylum, whereas in postmenopausal women, it is chiefly comprised of Pseudomonas, Bacteroidetes, and Actinobacteria phyla (Amin et al., 2023; Chaban et al., 2014).
It is well-known that there is an interaction between the immune system and the microbiome, involving hormone receptors, various immune mediators, stem cells, different subpopulations of leukocytes, plasma cells, and antibodies such as IgG, IgM, and IgA, along with interleukins and inflammatory proteins. Lactobacilli can directly influence the production of interleukins (IL-1β, IL-6, IL-8, IL-2, IL-10, and IL-17) and play a role in balancing inflammation and anti-inflammation. In terms of immunology, hormones play a pivotal role by actively controlling the synthesis of antimicrobial peptides (such as β-defensins) and cytokines that promote inflammation. These molecules are locally produced by epithelial cells, particularly to protect spermatozoa and prevent infections. Estrogen significantly influences the composition of microbial populations at different life stages. For example, before puberty, the vaginal microbiota is predominantly composed of anaerobic species from the Enterobacteriaceae and Staphylococcaceae families. During puberty, estrogen promotes the accumulation of glycogen in mature epithelial cells (Yurkovetskiy et al., 2013). The digestion of glycogen produces maltotriose and α-dextrin, which serve as essential nutrients for Lactobacilli and facilitate the production of lactic acid (Yurkovetskiy et al., 2013).
As shown in Figure 4, these multifactorial influences highlight the complex interplay between host, viral, microbial, and environmental determinants in shaping cervical disease risk. The microbiota, immune, and endocrine systems form a uniquely specialized unit that ensures vital bodily functions and coordinates essential processes. The microbiota and the immune system collaborate to defend the body against harmful pathogens. Meanwhile, the microbiota and endocrine system ensure normal metabolic activities in organs by managing systemic balance.
Figure 4. Factors affecting HPV progression. Host immunity, vaginal microbiota, viral characteristics, and lifestyle influence whether HPV infection is cleared, persists, or develops into precancerous lesions and cervical cancer.
6 Microbiome-based biomarkers and diagnostic technologies
Advances in sequencing and multi-omics technologies have enabled the identification of microbiome-based biomarkers to assist with the diagnosis and risk stratification of HPV persistence and cervical lesion progression, as well as predicting them. Technologies such as 16S rRNA sequencing, metagenomics, metatranscriptomics and metabolomics now enable high-resolution profiling of cervicovaginal communities and their functional outputs. This transformation turns the microbiome from a descriptive ecological feature into a clinically relevant diagnostic tool.
Microbial metabolites in the female reproductive system are the end products of metabolic reactions triggered by the interaction between nutrients and microbiota. These metabolites can alter the status of the host through multiple pathways by coordinating physiological functions and response mechanisms. They also serve as key regulatory factors in inflammation of the female reproductive tract, malignant tumors, and pregnancy (Ghartey et al., 2015; Mcmillan et al., 2015). Typical vaginal microbial metabolites, such as lactic acid, hydrogen peroxide, ethanol and SCFAs, are emerging as functional biomarkers that reflect the health of the cervix and vagina (Liu et al., 2022). Increased SCFAs in the female reproductive system lead to a mixed anaerobic flora and induce inflammation (Aldunate et al., 2015; Amabebe and Anumba, 2020). These mixed anaerobic flora include Streptococcus, Bacteroides, Gardnerella, Prevotella, Mycoplasma, and Mobiluncus, which are commonly found in female genital tract diseases such as BV and vulvovaginal candidiasis (VVC) (Aldunate et al., 2015, Ceccarani et al., 2019, Vitali et al., 2015). Anaerobes associated with BV can produce SCFAs in the female reproductive system through carbohydrate fermentation and amino acid catabolism. The most common SCFAs found in the female reproductive tract include propionate, acetate, isovalerate, isobutyrate, and n-butyrate (Dandona et al., 2004). In vaginal dysbiosis, acetate and propionate often reach elevated millimolar concentrations (10–50 mM), markedly higher than levels observed in Lactobacillus-dominant states. In addition, SCFAs signal through G-protein coupled receptors such as GPR41 and GPR43, which are expressed on cervical epithelial and immune cells (Ceccarani et al., 2019). Activation of these receptors modulates cytokine secretion, epithelial permeability, and neutrophil recruitment, suggesting a direct pathway by which dysbiotic metabolic profiles influence local immunity. High concentrations of acetate and butyrate have been shown to alter tight-junction proteins and histone acetylation patterns in cervical epithelial cells, potentially facilitating viral entry and supporting HPV persistence. Taken together, the composition of the microbiome and its metabolic outputs provide a rich source of biomarkers for the early diagnosis, prognosis and prediction of risk. Based on this concept, several microbial taxa and multi-omics signatures have been suggested as potential clinical biomarkers.
Changes in the vaginal microbiome can be used to screen for precancerous lesions of cervical cancer. Certain bacteria can serve as biomarkers to help us determine whether HPV infection can develop into cervical cancer. Traditional biomarkers include immune markers and HPV genotyping. Hr-HPV can integrate into the host genome and, through its multi-copy presence in cells, be released in the form of circulating tumor DNA (ctDNA). Therefore, ctHPV DNA is a potential biomarker for cervical cancer (Sivars et al., 2023). Type-specific total viral load may serve as a robust diagnostic indicator for High-grade squamous intraepithelial lesion (HSIL) in HPV types 16, 18, and 58 (Kim et al., 2020). However, these markers alone are insufficient for accurate risk stratification. Recently, increasing attention has been directed toward microbial biomarkers, particularly those from the gastrointestinal and vaginal microbiota, due to their close association with the pathogenesis of HPV infection and cervical lesions. Numerous studies have shown that alterations in vaginal microbiome diversity may serve as early indicators for the diagnosis and prevention of various HPV-related conditions. It has been reported that Gardnerella vaginalis can disrupt cervical-vaginal microbial homeostasis and may serve as a key biomarker for the progression of HPV infection to HSIL (Kudela et al., 2021). Likewise, other studies have indicated that Streptococcus sanguinis, anaerobic cocci, and anaerobic digestible streptococci may also function as potential biomarkers for HSIL (Mitra et al., 2015). Continued advancements in this field have the potential to improve current diagnostic frameworks.
In recent years, the vast amount of information and data about the microbiome has revolutionized the field of microbiology. Multi-omics approaches provide a more comprehensive understanding of the vaginal microbiome and its interactions with HPV. Metagenomics identifies the composition of microbes and their functional genes. Metatranscriptomics captures the expression of genes in microbes and hosts (Jiang et al., 2019). Metabolomics quantifies bioactive metabolites, such as SCFAs and lactate, that influence mucosal immunity. Each “omics” layer provides different, yet complementary, information. Combining them provides a more complete view of HPV-microbiome interactions. Recent studies illustrate the value of this approach. Multi-omics profiling has revealed that HPV-positive women exhibit increased microbial diversity and an enrichment of Gardnerella-related metabolic pathways. There are also shifts toward pro-inflammatory metabolites, such as acetate and propionate. Furthermore, metatranscriptomic analyzes have demonstrated that HPV infection alters the expression of host epithelial immune genes, including those in interferon-related pathways. Meanwhile, metabolomic signatures have been shown to distinguish cervical intraepithelial neoplasi (CIN)1 from high-grade CIN lesions with high accuracy. Together, these findings emphasize that multi-omics integration can reveal biomarkers of HPV persistence and identify molecular pathways linking dysbiosis to cervical carcinogenesis.
7 Treatment: probiotics and prebiotics
The World Health Organization (WHO) characterizes probiotics as live microorganisms that, when consumed in appropriate quantities, offer advantageous effects on the host’s health. Metronidazole and lincomycin are commonly used antibiotics to treat BV. The efficacy of antibiotics in treating bacterial vaginosis or antifungals in addressing VVC is not always optimal, and recurrence rates tend to be high. While antibiotics may effectively inhibit anaerobic overgrowth, they often fail to restore Lactobacilli to their optimal levels. Extended use of antibiotics is also linked to numerous adverse effects and an increased risk of bacterial resistance. Hence, with the growing recognition of the role of Lactobacilli in maintaining vaginal health, vaginal probiotics containing Lactobacillus strains have become increasingly popular as both preventive and therapeutic interventions for vaginal dysbiosis. Vaginal probiotics containing Lactobacilli have been extensively researched and developed for the treatment of BV and VVC. Pregnant women with VVC have shown promising efficacy and safety after using probiotics, significantly improving their quality of life. Furthermore, probiotics show promise in offering some potential benefits to individuals experiencing constipation (Ang et al., 2022a; Ang et al., 2022b). For pregnant patients experiencing recurrent staphylococcal infections, probiotic preparations are a promising therapeutic option if antifungal drugs are contraindicated. Besides their therapeutic benefits, long-term oral probiotics offer protection for healthy women as well (Reid et al., 2003). Most probiotics play a key role in restoring the composition of the vaginal microbiota (Van De Wijgert and Verwijs, 2020; Lagenaur et al., 2021).
By replenishing diminished Lactobacilli, probiotics can offer protective functions comparable to natural Lactobacilli. These functions encompass establishing a robust physical barrier, stimulating the immune system, and decreasing the expression of E6 and E7 proteins. Studies have demonstrated that the Lactobacillus strain LH23 can reduce the expression of E6 and E7 proteins, thereby inhibiting cervical cancer cell proliferation and inducing apoptosis (Hu et al., 2023). Additionally, recent findings indicate that taurine produced by Lactobacillus rhamnosus markedly decreases endometrial cancer cell viability, highlighting its targeted anticancer effects (Lawore et al., 2024). Our research findings indicate that women are more likely to develop vaginal dysbiosis in cases of persistent HPV infection. In this context, using probiotics might promote HPV clearance and is associated with a reduced incidence of uterine lesions in some studies (Medina-Rivero et al., 2025). Women experiencing persistent vaginal dysbiosis should consider using probiotics, reduce sexual frequency, and employ protective measures such as condom use to further mitigate the risk of complications (Figure 5).
Figure 5. Probiotics and prebiotics in restoring the vaginal microbiota and reducing HPV-related risk. Probiotics help replenish beneficial Lactobacilli and support their growth. By improving the local microenvironment, these interventions may reduce HPV persistence and lower the risk of related cervical disease.
Another method to restore vaginal microbiota is by using probiotics. Prebiotics are organic compounds that remain undigested or unabsorbed by the host, yet they selectively foster the metabolism and growth of beneficial bacteria within the body, consequently enhancing host health. Probiotics can enhance HPV clearance through immune regulation, competitive elimination of pathogens, and production of protective metabolites (Porcaro et al., 2025). We summarized some studies on the treatment of HPV infection and the prevention of cervical cancer with probiotics using Table 1. In cases of intestinal diseases, oral intake of prebiotics can improve intestinal conditions and promote the activity of Lactobacilli. Likewise, in the vaginal environment rich in Lactobacilli, prebiotics can exert comparable function. A large number of researchers have found that the disaccharide lactofructose broadly and specifically stimulates the growth of vaginal Lactobacilli, including Bacteroides fragilis, without promoting the growth of bacteria associated with bacterial vaginosis (Collins et al., 2018). Studies have additionally shown that probiotic maltose gel facilitates the transition of vaginal microbiota in rhesus monkeys from domination by BV-associated bacteria to a prevalence of Lactobacilli (Zhang et al., 2020). According to clinical studies, the combination of Lactobacillus rhamnosus BMX54 with lactose can restore the vaginal microbiota and regulate vaginal pathological pathways (Baldacci et al., 2020). However, due to the lack of relevant clinical and preclinical studies, whether this combination can benefit patients with HPV infection needs to be further explored in the future. Despite these positive signals, the clinical evidence remains limited by several key factors: small sample sizes, heterogeneity in probiotic strains, dosages, and administration routes, short follow-up periods, and a primary focus on BV and VVC rather than HPV clearance as the primary endpoint. Consequently, while certain probiotic regimens show promise, they cannot yet be recommended as a standard clinical intervention for preventing or treating HPV-related cervical disease.
Table 1. Research on probiotics in the treatment of HPV infection and prevention of cervical cancer.
8 Conclusion, limitations, and future directions
Numerous studies have shown that changes in microbial diversity and disturbances in microbiome composition can be linked to the onset of various diseases. Our assessment indicates that a reduction in Lactobacilli within the vaginal microbiota is linked to sustained HPV infection and the advancement of cervical lesions. The use of probiotics and prebiotics can aid in reestablishing the normal vaginal microbiota, thereby potentially impeding the progression of cervical lesions (Figure 6).
Figure 6. Progression of the vaginal microenvironment from homeostasis to dysbiosis, HPV invasion, and cancerous transformation. The vaginal environment shifts across four stages. Normal: The microbiota is dominated by Lactobacilli, which help protect the epithelium. Dysbiosis: Overgrowth of Gardnerella and other bacteria reduces Lactobacilli and disrupts the normal balance. HPV invasion: The damaged environment becomes more vulnerable to HPV infection, and continued microbial imbalance further harms the epithelium. Cervical cancer: With ongoing injury and viral persistence, lesions may progress and eventually invade beyond the basement membrane, leading to cancer development.
Despite extensive research on the relationship between the vaginal microbiome and HPV infection, most of the available data are derived from cross-sectional designs, which limit the scope for interpretation to correlations rather than causations. Additionally, inconsistent findings across studies are due to heterogeneity in sequencing platforms, CST classification methods and analytical pipelines. The dynamic and unstable nature of CSTs, coupled with hormonal fluctuations, sexual behavior and behavioral confounders, makes interpreting microbiome-HPV interactions even more challenging. These variables complicate the exclusion of external influences and often result in inconsistent or non-reproducible findings. However, it should be noted that it is unclear whether dysbiosis leads to persistent HPV infection or is a consequence of viral suppression of mucosal immunity. There is also insufficient mechanistic insight into how microbial metabolites (such as SCFAs) alter epithelial junctions and modulate inflammation. The intricate interplay between the microbiome, immune responses and HPV oncogene expression requires further investigation.
To address these challenges, future research should prioritize longitudinal cohort designs to clarify the temporal sequence between microbiome alterations and HPV infection. Integrating multi-omics platforms, which encompass metagenomics, metatranscriptomics, metabolomics and immunoassays, could help to identify the microbial metabolites and host pathways that drive HPV persistence or tumor formation. In future clinical trials, standardized microbiome-related markers such as SCFAs, lactate enantiomers and mucosal immune biomarkers could be used as secondary endpoints alongside HPV clearance rates. Well-designed, controlled clinical trials are needed to determine the therapeutic potential of probiotics, prebiotics, vaginal microbiota transplantation and metabolite-targeted therapies. Addressing these challenges will help future research clarify the clinical utility of microbiome modulation in preventing HPV persistence and cervical disease progression.
Author contributions
XF: Formal analysis, Validation, Methodology, Conceptualization, Writing – original draft. WS: Validation, Methodology, Writing – review & editing, Conceptualization. XR: Writing – review & editing, Resources. ZX: Writing – review & editing, Data curation. CL: Software, Writing – review & editing. MF: Writing – review & editing, Visualization, Funding acquisition. NW: Supervision, Project administration, Writing – review & editing, Investigation.
Funding
The author(s) declared that financial support was received for this work and/or its publication. This work was supported by grants from the Basic research project of Liaoning Provincial Department of Education (grant no. LJ222510161007).
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.
Generative AI statement
The author(s) declared that Generative AI was not used in the creation of this manuscript.
Any alternative text (alt text) provided alongside figures in this article has been generated by Frontiers with the support of artificial intelligence and reasonable efforts have been made to ensure accuracy, including review by the authors wherever possible. If you identify any issues, please contact us.
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
References
Adapen, C., RéOT, L., Nunez, N., Cannou, C., Marlin, R., Lemaître, J., et al. (2022). Local innate markers and vaginal microbiota composition are influenced by hormonal cycle phases. Front. Immunol. 13:841723. doi: 10.3389/fimmu.2022.841723,
Alagarasu, K., Kaushal, H., Shinde, P., Kakade, M., Chaudhary, U., Padbidri, V., et al. (2021). TNFA and IL10 polymorphisms and IL-6 and IL-10 levels influence disease severity in influenza a(H1N1)pdm09 virus infected patients. Genes 12. doi: 10.3390/genes12121914,
Alakomi, H. L., SKYTTä, E., Saarela, M., Mattila-Sandholm, T., Latva-Kala, K., and Helander, I. M. (2000). Lactic acid permeabilizes gram-negative bacteria by disrupting the outer membrane. Appl. Environ. Microbiol. 66, 2001–2005. doi: 10.1128/AEM.66.5.2001-2005.2000,
Aldunate, M., Srbinovski, D., Hearps, A. C., Latham, C. F., Ramsland, P. A., Gugasyan, R., et al. (2015). Antimicrobial and immune modulatory effects of lactic acid and short chain fatty acids produced by vaginal microbiota associated with eubiosis and bacterial vaginosis. Front. Physiol. 6:164. doi: 10.3389/fphys.2015.00164,
Amabebe, E., and Anumba, D. O. C. (2020). Female gut and genital tract microbiota-induced crosstalk and differential effects of short-chain fatty acids on immune sequelae. Front. Immunol. 11:2184. doi: 10.3389/fimmu.2020.02184,
Amin, M. E., Azab, M., Hanora, A., Atwa, K., and Shabayek, S. (2023). Compositional changes in the vaginal bacterial microbiome of healthy pregnant women across the three gestational trimesters in Ismailia, Egypt. Microorganisms 11. doi: 10.3390/microorganisms11010139,
Ang, X. Y., Chung, F. Y., Lee, B. K., Azhar, S. N. A., Sany, S., Roslan, N. S., et al. (2022a). Lactobacilli reduce recurrences of vaginal candidiasis in pregnant women: a randomized, double-blind, placebo-controlled study. J. Appl. Microbiol. 132, 3168–3180. doi: 10.1111/jam.15158,
Ang, X. Y., Mageswaran, U. M., Chung, Y. L. F., Ang, X., Mageswaran, U., Chung, Y., et al. (2022b). Probiotics reduce vaginal candidiasis in pregnant women via modulating abundance of Candida and Lactobacillus in vaginal and cervicovaginal regions. Microorganisms 10. doi: 10.3390/microorganisms10020285,
Audirac-Chalifour, A., Torres-Poveda, K., Bahena-Román, M., Téllez-Sosa, J., Martínez-Barnetche, J., Cortina-Ceballos, B., et al. (2016). Cervical microbiome and cytokine profile at various stages of cervical cancer: a pilot study. PLoS One 11:e0153274. doi: 10.1371/journal.pone.0153274,
Auriemma, R. S., Scairati, R., Del Vecchio, G., Liccardi, A., Verde, N., Pirchio, R., et al. (2021). The vaginal microbiome: a long urogenital colonization throughout woman life. Front. Cell. Infect. Microbiol. 11:686167. doi: 10.3389/fcimb.2021.686167,
Baldacci, F., Baldacci, M., and Bertini, M. (2020). Lactobacillus rhamnosus BMX 54 + lactose, a symbiotic long-lasting vaginal approach to improve women's health. Int. J. Women's Health 12, 1099–1104. doi: 10.2147/IJWH.S259311,
Balle, C., Konstantinus, I. N., Jaumdally, S. Z., Havyarimana, E., Lennard, K., Esra, R., et al. (2020). Hormonal contraception alters vaginal microbiota and cytokines in south African adolescents in a randomized trial. Nat. Commun. 11:5578. doi: 10.1038/s41467-020-19382-9,
Bautista, J., Altamirano-Colina, A., and López-Cortés, A. (2025). The vaginal microbiome in HPV persistence and cervical cancer progression. Front. Cell. Infect. Microbiol. 15:1634251. doi: 10.3389/fcimb.2025.1634251,
Bhatla, N., Puri, K., Joseph, E., Kriplani, A., Iyer, V. K., and Sreenivas, V. (2013). Association of Chlamydia trachomatis infection with human papillomavirus (HPV) & cervical intraepithelial neoplasia - a pilot study. Indian J. Med. Res. 137, 533–539,
Borgdorff, H., Van Der Veer, C., Van Houdt, R., Alberts, C. J., de Vries, H. J., Bruisten, S. M., et al. (2017). The association between ethnicity and vaginal microbiota composition in Amsterdam, the Netherlands. PLoS One 12:e0181135. doi: 10.1371/journal.pone.0181135,
Borgogna, J. C., Shardell, M. D., Santori, E. K., Nelson, T. M., Rath, J. M., Glover, E. D., et al. (2020). The vaginal metabolome and microbiota of cervical HPV-positive and HPV-negative women: a cross-sectional analysis. BJOG 127, 182–192. doi: 10.1111/1471-0528.15981,
Boskey, E. R., Cone, R. A., Whaley, K. J., and Moench, T. R. (2001). Origins of vaginal acidity: high D/L lactate ratio is consistent with bacteria being the primary source. Hum. Reprod. 16, 1809–1813. doi: 10.1093/humrep/16.9.1809,
Brotman, R. M., He, X., Gajer, P., Fadrosh, D., Sharma, E., Mongodin, E. F., et al. (2014a). Association between cigarette smoking and the vaginal microbiota: a pilot study. BMC Infect. Dis. 14:471. doi: 10.1186/1471-2334-14-471,
Brotman, R. M., Shardell, M. D., Gajer, P., Tracy, J. K., Zenilman, J. M., Ravel, J., et al. (2014b). Interplay between the temporal dynamics of the vaginal microbiota and human papillomavirus detection. J. Infect. Dis. 210, 1723–1733. doi: 10.1093/infdis/jiu330,
Brusselaers, N., Shrestha, S., VAN DE Wijgert, J., and Verstraelen, H. (2019). Vaginal dysbiosis and the risk of human papillomavirus and cervical cancer: systematic review and meta-analysis. Am. J. Obstet. Gynecol. 221, 9–18.e8. doi: 10.1016/j.ajog.2018.12.011,
Ceccarani, C., Foschi, C., Parolin, C., D’Antuono, A., Gaspari, V., Consolandi, C., et al. (2019). Diversity of vaginal microbiome and metabolome during genital infections. Sci. Rep. 9:14095. doi: 10.1038/s41598-019-50410-x,
Cha, M. K., Lee, D. K., An, H. M., Lee, S.-W., Shin, S.-H., Kwon, J.-H., et al. (2012). Antiviral activity of Bifidobacterium adolescentis SPM1005-a on human papillomavirus type 16. BMC Med. 10:72. doi: 10.1186/1741-7015-10-72,
Chaban, B., Links, M. G., Jayaprakash, T. P., Wagner, E. C., Bourque, D. K., Lohn, Z., et al. (2014). Characterization of the vaginal microbiota of healthy Canadian women through the menstrual cycle. Microbiome 2:23. doi: 10.1186/2049-2618-2-23,
Chao, X. P., Sun, T. T., Wang, S., Fan, Q.-B., Shi, H.-H., Zhu, L., et al. (2019). Correlation between the diversity of vaginal microbiota and the risk of high-risk human papillomavirus infection. Int. J. Gynecol. Cancer 29, 28–34. doi: 10.1136/ijgc-2018-000032,
Chen, C., Song, X., Wei, W., Zhong, H., Dai, J., Lan, Z., et al. (2017). The microbiota continuum along the female reproductive tract and its relation to uterine-related diseases. Nat. Commun. 8:875. doi: 10.1038/s41467-017-00901-0,
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, W., Xu, F., Gao, L., and Liu, J. (2020). The correlation between the determination of vaginal micro-ecological composition and the outcome of HPV infection by high-throughput metagene sequencing information technology on the Illumina platform. J. Infect. Public Health 13, 1961–1966. doi: 10.1016/j.jiph.2020.05.024,
Cho, Y. S., Kang, J. W., Cho, M., Cho, C.-W., Lee, S. J., Choe, Y.-K., et al. (2001). Down modulation of IL-18 expression by human papillomavirus type 16 E6 oncogene via binding to IL-18. FEBS Lett. 501, 139–145. doi: 10.1016/S0014-5793(01)02652-7,
Clabaut, M., Suet, A., Racine, P. J., Tahrioui, A., Verdon, J., Barreau, M., et al. (2021). Effect of 17β-estradiol on a human vaginal Lactobacillus crispatus strain. Sci. Rep. 11:7133. doi: 10.1038/s41598-021-86628-x,
Collins, S. L., Mcmillan, A., Seney, S., van der Veer, C., Kort, R., Sumarah, M. W., et al. (2018). Promising prebiotic candidate established by evaluation of lactitol, lactulose, raffinose, and oligofructose for maintenance of a Lactobacillus-dominated vaginal microbiota. Appl. Environ. Microbiol. 84. doi: 10.1128/AEM.02200-17,
Collinson, E. J., Wheeler, G. L., Garrido, E. O., Avery, A. M., Avery, S. V., and Grant, C. M. (2002). The yeast glutaredoxins are active as glutathione peroxidases. J. Biol. Chem. 277, 16712–16717. doi: 10.1074/jbc.M111686200,
Crespo-Quiles, C., and Femenía, T. (2025). Toll-like receptors in immuno-metabolic regulation of emotion and memory. Cells 14. doi: 10.3390/cells14120933,
Dandona, P., Aljada, A., and Bandyopadhyay, A. (2004). Inflammation: the link between insulin resistance, obesity and diabetes. Trends Immunol. 25, 4–7. doi: 10.1016/j.it.2003.10.013,
Dareng, E. O., Ma, B., Famooto, A. O., Akarolo-Anthony, S. N., Offiong, R. A., Olaniyan, O., et al. (2016). Prevalent high-risk HPV infection and vaginal microbiota in Nigerian women. Epidemiol. Infect. 144, 123–137. doi: 10.1017/S0950268815000965,
Daud, I. I., Scott, M. E., Ma, Y., Shiboski, S., Farhat, S., and Moscicki, A. B. (2011). Association between toll-like receptor expression and human papillomavirus type 16 persistence. Int. J. Cancer 128, 879–886. doi: 10.1002/ijc.25400,
Di Paola, M., Sani, C., Clemente, A. M., Iossa, A., Perissi, E., Castronovo, G., et al. (2017). Characterization of cervico-vaginal microbiota in women developing persistent high-risk human papillomavirus infection. Sci. Rep. 7:10200. doi: 10.1038/s41598-017-09842-6,
Gao, Q., Fan, T., Luo, S., Zheng, J., Zhang, L., Cao, L., et al. (2023). Lactobacillus gasseri LGV03 isolated from the cervico-vagina of HPV-cleared women modulates epithelial innate immune responses and suppresses the growth of HPV-positive human cervical cancer cells. Transl. Oncol. 35:101714. doi: 10.1016/j.tranon.2023.101714,
Ghartey, J., Bastek, J. A., Brown, A. G., Anglim, L., and Elovitz, M. A. (2015). Women with preterm birth have a distinct cervicovaginal metabolome. Am. J. Obstet. Gynecol. 212, 776.e1–776.e12. doi: 10.1016/j.ajog.2015.03.052,
Godoy-Vitorino, F., Romaguera, J., Zhao, C., Vargas-Robles, D., Ortiz-Morales, G., Vázquez-Sánchez, F., et al. (2018). Cervicovaginal fungi and bacteria associated with cervical intraepithelial neoplasia and high-risk human papillomavirus infections in a Hispanic population. Front. Microbiol. 9:2533. doi: 10.3389/fmicb.2018.02533,
Guo, M., Feng, X., Ma, J., Zhu, K., and Niyazi, M. (2025). Differential study on the relationship between HPV infection and vaginal microbiota composition in Uygur and Han women. Microb. Pathog. 198:107149. doi: 10.1016/j.micpath.2024.107149
Guo, Y. L., You, K., Qiao, J., Zhao, Y.-m., and Geng, L. (2012). Bacterial vaginosis is conducive to the persistence of HPV infection. Int. J. STD AIDS 23, 581–584. doi: 10.1258/ijsa.2012.011342,
Higgins, V. J., Alic, N., Thorpe, G. W., Breitenbach, M., Larsson, V., and Dawes, I. W. (2002). Phenotypic analysis of gene deletant strains for sensitivity to oxidative stress. Yeast 19, 203–214. doi: 10.1002/yea.811,
Hochreiter, W. W., Duncan, J. L., and Schaeffer, A. J. (2000). Evaluation of the bacterial flora of the prostate using a 16S rRNA gene based polymerase chain reaction. J. Urol. 163, 127–130. doi: 10.1016/S0022-5347(05)67987-6,
Hu, S., Hao, Y., Zhang, X., Yang, Y., Liu, M., Wang, N., et al. (2023). Lacticaseibacillus casei LH23 suppressed HPV gene expression and inhibited cervical cancer cells. Probiotics Antimicrob. Proteins 15, 443–450. doi: 10.1007/s12602-021-09848-7,
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,
Jiang, D., Armour, C. R., Hu, C., Mei, M., Tian, C., Sharpton, T. J., et al. (2019). Microbiome multi-omics network analysis: statistical considerations, limitations, and opportunities. Front. Genet. 10:995. doi: 10.3389/fgene.2019.00995,
Kaur, H., Merchant, M., Haque, M. M., and Mande, S. S. (2020). Crosstalk between female gonadal hormones and vaginal microbiota across various phases of women's gynecological lifecycle. Front. Microbiol. 11:551. doi: 10.3389/fmicb.2020.00551,
Kim, J., Kim, B. K., Jeon, D., Lee, C. H., Roh, J.-W., Kim, J.-Y., et al. (2020). Type-specific viral load and physical state of HPV type 16, 18, and 58 as diagnostic biomarkers for high-grade squamous intraepithelial lesions or cervical cancer. Cancer Res. Treat. 52, 396–405. doi: 10.4143/crt.2019.152,
Koskela, P., Anttila, T., BJøRGE, T., Brunsvig, A., Dillner, J., Hakama, M., et al. (2000). Chlamydia trachomatis infection as a risk factor for invasive cervical cancer. Int. J. Cancer 85, 35–39. doi: 10.1002/(SICI)1097-0215(20000101)85:1<>3.0.CO;2-A,
Krog, M. C., Hugerth, L. W., Fransson, E., Bashir, Z., Nyboe Andersen, A., Edfeldt, G., et al. (2022). The healthy female microbiome across body sites: effect of hormonal contraceptives and the menstrual cycle. Hum. Reprod. 37, 1525–1543. doi: 10.1093/humrep/deac094,
Kudela, E., Liskova, A., Samec, M., Koklesova, L., Holubekova, V., Rokos, T., et al. (2021). The interplay between the vaginal microbiome and innate immunity in the focus of predictive, preventive, and personalized medical approach to combat HPV-induced cervical cancer. EPMA J. 12, 199–220. doi: 10.1007/s13167-021-00244-3,
Kumari, S., and Bhor, V. M. (2021). Association of cervicovaginal dysbiosis mediated HPV infection with cervical intraepithelial neoplasia. Microb. Pathog. 152:104780. doi: 10.1016/j.micpath.2021.104780,
Kwasniewski, W., Wolun-Cholewa, M., Kotarski, J., Warchol, W., Kuzma, D., Kwasniewska, A., et al. (2018). Microbiota dysbiosis is associated with HPV-induced cervical carcinogenesis 16, 7035–7047. doi: 10.3892/ol.2018.9509,
Lagenaur, L. A., Hemmerling, A., Chiu, C., Miller, S., Lee, P. P., Cohen, C. R., et al. (2021). Connecting the dots: translating the vaginal microbiome into a drug. J. Infect. Dis. 223, S296–s306. doi: 10.1093/infdis/jiaa676,
Lawore, D. C., Jena, S., Berard, A. R., Birse, K., Lamont, A., Mackelprang, R. D., et al. (2024). Computational microbiome pharmacology analysis elucidates the anti-cancer potential of vaginal microbes and metabolites. bioRxiv 2024:351. doi: 10.1101/2024.10.10.616351,
Lee, S. J., Cho, Y. S., Cho, M. C., Shim, J. H., Lee, K. A., Ko, K. K., et al. (2001). Both E6 and E7 oncoproteins of human papillomavirus 16 inhibit IL-18-induced IFN-gamma production in human peripheral blood mononuclear and NK cells. J. Immunol. 167, 497–504. doi: 10.4049/jimmunol.167.1.497,
Lee, J. E., Lee, S., Lee, H., Song, Y.-M., Lee, K., Han, M. J., et al. (2013). Association of the vaginal microbiota with human papillomavirus infection in a Korean twin cohort. PLoS One 8:e63514. doi: 10.1371/journal.pone.0063514,
Lee, S., Oh, K. Y., Hong, H., Jin, C. H., Shim, E., Kim, S. H., et al. (2020). Community state types of vaginal microbiota and four types of abnormal vaginal microbiota in pregnant Korean women. Front. Public Health 8:507024. doi: 10.3389/fpubh.2020.507024,
Liu, J., Luo, M., Zhang, Y., Cao, G., and Wang, S. (2020). Association of high-risk human papillomavirus infection duration and cervical lesions with vaginal microbiota composition. Ann. Transl. Med. 8:1161. doi: 10.21037/atm-20-5832,
Liu, J., Tan, Y., Cheng, H., Zhang, D., Feng, W., and Peng, C. (2022). Functions of gut microbiota metabolites, current status and future perspectives. Aging Dis. 13, 1106–1126. doi: 10.14336/AD.2022.0104,
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 (Albany NY) 16, 11446–11459. doi: 10.18632/aging.206032,
Mangieri, L. F. L., Cezar-Dos-Santos, F., Trugilo, K. P., Watanabe, M. A. E., de Jaime Curti, R. R., Castilha, E. P., et al. (2023). Cross-sectional analysis of human papillomavirus infection and cytological abnormalities in Brazilian women. Pathogens 12. doi: 10.3390/pathogens12010148,
María Fosch, S. E., Trossero, M. L., Grosso, O. A., Reyes, A. P., Cocucci, S. E., Payalef, S. N., et al. (2022). Vaginal states: detection of conversion processes in women using contraception and characterization of vaginal Lactobacillus species. Infect. Dis. 22:531. doi: 10.2174/1871526522666220126154731,
Mckenzie, R., Maarsingh, J. D., Łaniewski, P., and Herbst-Kralovetz, M. M. (2021). Immunometabolic analysis of Mobiluncus mulieris and Eggerthella sp. reveals novel insights into their pathogenic contributions to the hallmarks of bacterial vaginosis. Front. Cell. Infect. Microbiol. 11:759697. doi: 10.3389/fcimb.2021.759697,
Mcmillan, A., Rulisa, S., Sumarah, M., Macklaim, J. M., Renaud, J., Bisanz, J. E., et al. (2015). A multi-platform metabolomics approach identifies highly specific biomarkers of bacterial diversity in the vagina of pregnant and non-pregnant women. Sci. Rep. 5:14174. doi: 10.1038/srep14174,
Medina-Rivero, A. S., Ratkovich-Gonzalez, S., Ruiz-Briseño, M. D. R., and Rosas-González, V. C. (2025). The role of cervicovaginal microbiota and probiotics in modulating HPV persistence and preventing cervical cancer. ACS Infect. Dis. 2025:385. doi: 10.1021/acsinfecdis.5c00385
Miller, E. A., Beasley, D. E., Dunn, R. R., and Archie, E. A. (2016). Lactobacilli dominance and vaginal pH: why is the human vaginal microbiome unique? Front. Microbiol. 7:1936. doi: 10.3389/fmicb.2016.01936,
Mitra, A., Macintyre, D. A., Lee, Y. S., Smith, A., Marchesi, J. R., Lehne, B., et al. (2015). Cervical intraepithelial neoplasia disease progression is associated with increased vaginal microbiome diversity. Sci. Rep. 5:16865. doi: 10.1038/srep16865,
Miyauchi, S., Kim, S. S., Jones, R. N., Zhang, L., Guram, K., Sharma, S., et al. (2023). Human papillomavirus E5 suppresses immunity via inhibition of the immunoproteasome and STING pathway. Cell Rep. 42:112508. doi: 10.1016/j.celrep.2023.112508,
Mohammed, M. M., Al-Khafaji, Z. A. I., and Al-Hilli, N. M. (2025). An exploration of the natural and acquired immunological mechanisms to high-risk human papillomavirus infection and unmasking immune escape in cervical cancer: a concise synopsis. Tzu Chi Med. J. 37, 28–41. doi: 10.4103/tcmj.tcmj_134_24,
Molina, M. A., Leenders, W. P. J., Huynen, M. A., Melchers, W. J. G., and Andralojc, K. M. (2024). Temporal composition of the cervicovaginal microbiome associates with hrHPV infection outcomes in a longitudinal study. BMC Infect. Dis. 24:552. doi: 10.1186/s12879-024-09455-1,
Mosmann, J. P., Zayas, S., Kiguen, A. X., Venezuela, R. F., Rosato, O., and Cuffini, C. G. (2021). Human papillomavirus and Chlamydia trachomatis in oral and genital mucosa of women with normal and abnormal cervical cytology. BMC Infect. Dis. 21:422. doi: 10.1186/s12879-021-06118-3,
Nelson, T. M., Borgogna, J. L., Brotman, R. M., Borgogna, J.-L. C., Ravel, J., Walk, S. T., et al. (2015). Vaginal biogenic amines: biomarkers of bacterial vaginosis or precursors to vaginal dysbiosis? Front. Physiol. 6:253. doi: 10.3389/fphys.2015.00253,
NICOLò, S., Tanturli, M., Mattiuz, G., Antonelli, A., Baccani, I., Bonaiuto, C., et al. (2021). Vaginal lactobacilli and vaginal dysbiosis-associated bacteria differently affect cervical epithelial and immune homeostasis and anti-viral defenses. Int. J. Mol. Sci. 22. doi: 10.3390/ijms22126487,
Norenhag, J., Du, J., Olovsson, M., Verstraelen, H., Engstrand, L., and Brusselaers, N. (2020). The vaginal microbiota, human papillomavirus and cervical dysplasia: a systematic review and network meta-analysis. BJOG 127, 171–180. doi: 10.1111/1471-0528.15854,
OCHOA-REPáRAZ, J., Magori, K., and Kasper, L. H. (2017). The chicken or the egg dilemma: intestinal dysbiosis in multiple sclerosis. Ann. Transl. Med. 5:145. doi: 10.21037/atm.2017.01.18,
O'hanlon, D. E., Moench, T. R., and Cone, R. A. (2011). In vaginal fluid, bacteria associated with bacterial vaginosis can be suppressed with lactic acid but not hydrogen peroxide. BMC Infect. Dis. 11:200. doi: 10.1186/1471-2334-11-200,
Palma, E., Recine, N., Domenici, L., Giorgini, M., Pierangeli, A., and Panici, P. B. (2018). Long-term Lactobacillus rhamnosus BMX 54 application to restore a balanced vaginal ecosystem: a promising solution against HPV-infection. BMC Infect. Dis. 18:13. doi: 10.1186/s12879-017-2938-z,
Paul, W. E., and Grossman, Z. (2014). Pathogen-sensing and regulatory T cells: integrated regulators of immune responses. Cancer Immunol. Res. 2, 503–509. doi: 10.1158/2326-6066.CIR-14-0046,
Porcaro, G., Calcagno, M., and Tinelli, A. (2025). Medicinal mushrooms, probiotics and combination of natural compounds in the management of HPV: a comparative look at viral clearance and lesion resolution. Viruses 17. doi: 10.3390/v17070942,
Pramanick, R., Mayadeo, N., Warke, H., Begum, S., Aich, P., and Aranha, C. (2019). Vaginal microbiota of asymptomatic bacterial vaginosis and vulvovaginal candidiasis: are they different from normal microbiota? Microb. Pathog. 134:103599. doi: 10.1016/j.micpath.2019.103599,
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,
Ravel, J., Gajer, P., Abdo, Z., Schneider, G. M., Koenig, S. S., McCulle, S. L., et al. (2011). Vaginal microbiome of reproductive-age women. Proc. Natl. Acad. Sci. U. S. A. 108, 4680–4687. doi: 10.1073/pnas.1002611107,
Reid, G., Charbonneau, D., Erb, J., Kochanowski, B., Beuerman, D., Poehner, R., et al. (2003). Oral use of Lactobacillus rhamnosus GR-1 and L. fermentum RC-14 significantly alters vaginal flora: randomized, placebo-controlled trial in 64 healthy women. FEMS Immunol. Med. Microbiol. 35, 131–134. doi: 10.1016/S0928-8244(02)00465-0,
Sangpichai, S., Patarapadungkit, N., Pientong, C., Ekalaksananan, T., Chaiwiriyakul, S., Thongbor, R., et al. (2019). Chlamydia Trachomatis infection in high-risk human papillomavirus based on cervical cytology specimen. Asian Pac. J. Cancer Prev. 20, 3843–3847. doi: 10.31557/APJCP.2019.20.12.3843,
Santella, B., Schettino, M. T., Franci, G., De Franciscis, P., Colacurci, N., Schiattarella, A., et al. (2022). Microbiota and HPV: the role of viral infection on vaginal microbiota. J. Med. Virol. 94, 4478–4484. doi: 10.1002/jmv.27837,
Schäfer, G., Kabanda, S., Van Rooyen, B., Marušič, M. B., Banks, L., and Parker, M. I. (2013). The role of inflammation in HPV infection of the oesophagus. BMC Cancer 13:185. doi: 10.1186/1471-2407-13-185,
Schirmer, M., Franzosa, E. A., Lloyd-Price, J., McIver, L. J., Schwager, R., Poon, T. W., et al. (2018). Dynamics of metatranscription in the inflammatory bowel disease gut microbiome. Nat. Microbiol. 3, 337–346. doi: 10.1038/s41564-017-0089-z,
Shen-Gunther, J., Xia, Q., Cai, H., and Wang, Y. (2025). Cervicovaginal microbiome and HPV: a standardized approach to 16S/ITS NGS and microbial community profiling for viral association. Int. J. Mol. Sci. 26. doi: 10.3390/ijms26168090,
Sivars, L., Palsdottir, K., Crona Guterstam, Y., Falconer, H., Hellman, K., and Tham, E. (2023). The current status of cell-free human papillomavirus DNA as a biomarker in cervical cancer and other HPV-associated tumors: a review. Int. J. Cancer 152, 2232–2242. doi: 10.1002/ijc.34333,
So, K. A., Yang, E. J., Kim, N. R., Hong, S. R., Lee, J. H., Hwang, C. S., et al. (2020). Changes of vaginal microbiota during cervical carcinogenesis in women with human papillomavirus infection. PLoS One 15:e0238705. doi: 10.1371/journal.pone.0238705,
Sobhani, I., Bergsten, E., Couffin, S., Amiot, A., Nebbad, B., Barau, C., et al. (2019). Colorectal cancer-associated microbiota contributes to oncogenic epigenetic signatures. Proc. Natl. Acad. Sci. U. S. A. 116, 24285–24295. doi: 10.1073/pnas.1912129116,
Song, D., Li, H., Li, H., Song, D., Li, H., and Dai, J. (2015). Effect of human papillomavirus infection on the immune system and its role in the course of cervical cancer. Oncol. Lett. 10, 600–606. doi: 10.3892/ol.2015.3295,
Tamadonfar, K. O., Di Venanzio, G., Pinkner, J. S., Dodson, K. W., Kalas, V., Zimmerman, M. I., et al. (2023). Structure-function correlates of fibrinogen binding by Acinetobacter adhesins critical in catheter-associated urinary tract infections. Proc. Natl. Acad. Sci. USA 120:e2212694120. doi: 10.1073/pnas.2212694120,
Tsementzi, D., Meador, R., Eng, T., Shelton, J., Scott, I., Konstantinidis, K. T., et al. (2025). Associations among HPV persistence, the vaginal microbiome, and cervical cancer recurrence. J. Transl. Med. 23:858. doi: 10.1186/s12967-025-06811-w,
Usyk, M., Zolnik, C. P., Castle, P. E., Porras, C., Herrero, R., Gradissimo, A., et al. (2020). <article-title update="added">Cervicovaginal microbiome and natural history of HPV in a longitudinal study. PLoS Pathog. 16:e1008376. doi: 10.1371/journal.ppat.1008376,
Van De Wijgert, J., and Verwijs, M. C. (2020). Lactobacilli-containing vaginal probiotics to cure or prevent bacterial or fungal vaginal dysbiosis: a systematic review and recommendations for future trial designs. BJOG 127, 287–299. doi: 10.1111/1471-0528.15870,
Vitali, B., Cruciani, F., Picone, G., Parolin, C., Donders, G., and Laghi, L. (2015). Vaginal microbiome and metabolome highlight specific signatures of bacterial vaginosis. Eur. J. Clin. Microbiol. Infect. Dis. 34, 2367–2376. doi: 10.1007/s10096-015-2490-y,
Xu, P., Mageswaran, U. M., Nisaa, A. A., Balasubramaniam, S. D., Rajendran, D., Ismail, E. H. B. E., et al. (2025). Roles of probiotics against HPV through the gut-vaginal axis. Int. J. Gynaecol. Obstet. 169, 1–8. doi: 10.1002/ijgo.16005,
Xu, P., Mageswary, U., Nisaa, A. A., Balasubramaniam, S. D., Samsudin, S. B., Rusdi, N. I. B. M., et al. (2025). Probiotic reduces vaginal HPV abundance, improves immunity and quality of life in HPV-positive women: a randomised, placebo-controlled and double-blind study. Benef Microbes 16, 667–684. doi: 10.1163/18762891-bja00079,
Yang, M., Li, L., Jiang, C., Qin, X., Zhou, M., Mao, X., et al. (2020). Co-infection with trichomonas vaginalis increases the risk of cervical intraepithelial neoplasia grade 2-3 among HPV16 positive female: a large population-based study. BMC Infect. Dis. 20:642. doi: 10.1186/s12879-020-05349-0,
Yu, W., Sun, S., and Fu, Q. (2025). The role of short-chain fatty acid in metabolic syndrome and its complications: focusing on immunity and inflammation. Front. Immunol. 16:1519925. doi: 10.3389/fimmu.2025.1519925,
Yurkovetskiy, L., Burrows, M., Khan, A. A., Khan, A. . A., Graham, L., Volchkov, P., et al. (2013). Gender bias in autoimmunity is influenced by microbiota. Immunity 39, 400–412. doi: 10.1016/j.immuni.2013.08.013,
Zhang, Q. Q., Liu, Z. H., Liu, L. L., Hu, G., Lei, G. L., Wang, Y., et al. (2020). Prebiotic maltose gel can promote the vaginal microbiota from BV-related bacteria dominant to Lactobacillus in rhesus macaque. Front. Microbiol. 11:594065. doi: 10.3389/fmicb.2020.594065,
Zhang, S., Liu, F., Mao, X., Huang, J., Yang, J., Yin, X., et al. (2015). Elevation of miR-27b by HPV16 E7 inhibits PPARγ expression and promotes proliferation and invasion in cervical carcinoma cells. Int. J. Oncol. 47, 1759–1766. doi: 10.3892/ijo.2015.3162,
Keywords: cervical cancer, community state types, human papillomavirus, lactobacilli, vaginal microbiota
Citation: Feng X, Song W, Ren X, Xu Z, Li C, Feng M and Wang N (2025) Microbial influences on HPV infection and cervical carcinogenesis: emerging evidence from the vaginal microbiome. Front. Microbiol. 16:1733315. doi: 10.3389/fmicb.2025.1733315
Edited by:
Xiaoyuan Wei, University of South Florida, United StatesReviewed by:
Chung-Yao Yang, Hygeia Touch Inc., TaiwanMilena Camargo, Centro de Tecnología en Salud (CETESA)-Innovaseq SAS, Colombia
Jhommara Bautista, University of the Americas, Ecuador
Copyright © 2025 Feng, Song, Ren, Xu, Li, Feng and Wang. 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: Nan Wang, d2FuZ25hbmxhYkAxNjMuY29t; Min Feng ZmVuZ2ZlbmcwNzE2QDE2My5jb20=
†These authors have contributed equally to this work