Frontiers in Cellular and Infection Microbiology

Vaginal dysbiosis seems associated with hrHPV infection in women attending the Dutch Cervical Cancer Screening Program

Human papillomavirus (HPV) is a sexually transmitted virus, which infects approximately 80% of all men and women at some time in their lives. Usually, the infection is resolved successfully by the body’s immune system. Persistent infection with high-risk HPV (hrHPV) is necessary but not sufficient for cervical cancer development, and additional factors, such as the vaginal microbiome (vaginome), are thought to be involved. The aim of this study is to investigate whether either vaginal dysbiosis (imbalance in vaginal bacterial composition) or sexually transmitted pathogens, e.g., Chlamydia trachomatis (CT), are possible cofactors for hrHPV infection and HPV-induced cervical dysplasia in asymptomatic women attending the Dutch Cervical Cancer Screening Program. In this study, 492 hrHPV-positive and 500 hrHPV-negative cervical smears from women attending the Screening Program were included. Age and cytology were known for the hrHPV-positive samples. All cervical smears were diluted in Aptima® specimen transfer medium and tested with Aptima® transcription-mediated amplification assays targeting CT, Neisseria gonorrhoeae (NG), Mycoplasma genitalium (MG), Candida spp. (CS), C. glabrata (CG), Trichomonas vaginalis (TV), and bacterial vaginosis (BV). The prevalences of CT, NG, MG, CS, CG, TV, and BV in this cohort were found to be 1.9%, 0.0%, 1.7%, 5.4%, 1.4%, 0.1%, and 27.2%, respectively. When comparing HPV groups, it was found that CT, MG, and BV had a significantly higher prevalence in hrHPV-positive smears as compared with hrHPV-negative samples (for all p < 0.001). No significant differences were found when comparing different age groups and cytology outcomes. In conclusion, vaginal dysbiosis seems associated with hrHPV infection in women attending the Dutch Cervical Cancer Screening Program.

A prospective cohort study on the association between cervical microenvironmental factors and the efficacy of treating high-risk human papillomavirus infection comorbid with cervical diseases

Objective Interferon-based local therapy is an intervention for high-risk human papillomavirus (HR-HPV)-associated low-grade squamous intraepithelial lesions (LSIL) or lower-grade cervical abnormalities. This study sought to delineate the differences in clinical outcomes following interferon-based local drug treatment and elucidate the microenvironmental factors driving these disparities. Methods Cervical secretions, cell brush specimens, and cervical tissue samples were collected from patients with persistent HR-HPV infection and LSIL/lower-grade lesions at Shanghai First Maternity and Infant Hospital. Follow-up samples were obtained at 3 months post-treatment. Cervical secretions were subjected to 16S rRNA sequencing (to profile the microbiota) and cytokine quantification. Cell brush specimens were analyzed via transcriptome sequencing, while cervical tissue samples underwent immunohistochemical staining. Efficacy-related markers were assessed through both inter-group (independent comparisons) and intra-patient (self-paired) analyses. Results At the transcriptome level, the HR-HPV clearance group exhibited lower enrichment in pathways related to differentiation, keratinization, and development but higher enrichment in immune activation pathways compared to the persistence group at baseline (with a reversed pattern observed at follow-up). Baseline expression of TRAF3IP3, ZBP1 , and IFI35 was higher in the clearance group, and ZDHHC11 expression remained consistently elevated. Immunohistochemical findings further demonstrated that the percentage of TRAF3IP3- and ZBP1-positive cells at baseline was significantly higher in the clearance group than in the persistence group. At the microbial level, treatment failure was associated with reduced Lactobacillus abundance, increased Gardnerella , Streptococcus anginosus , Schaalia turicensis , and Comamonadaceae abundance, alongside higher alpha diversity. Among cervical secretory cytokines, IL-2, IL-8, IL-12p70 showed inter-group differences, while IL-4 and IL-5 were barely detectable. Conclusions This study characterizes the cervical microenvironmental differences underlying divergent responses to interferon-based therapy, highlighting that coordinated changes in the microenvironment and immune status modulate treatment outcomes. The upregulated mRNA and protein levels of TRAF3IP3 and ZBP1 in the baseline period favor HR-HPV clearance, suggesting their potential as promising therapeutic targets.

Mechanistic pathways predictive modeling and translational interventions for radiation enteritis in cervical cancer radiotherapy

Radiation enteritis remains a major dose-limiting toxicity in cervical cancer radiotherapy, significantly impairing treatment continuity, long-term gastrointestinal function, and patient quality of life. Despite advances in radiation techniques, the biological heterogeneity of intestinal radiosensitivity continues to challenge effective prevention and management. This review synthesizes current evidence on the core mechanistic axes underlying radiation enteritis, with a focus on DNA damage response failure, oxidative stress amplification, immune dysregulation, and microbiota disruption. We further summarize emerging predictive frameworks integrating clinical variables, dosimetric parameters, radiomics, and circulating biomarkers to enable individualized risk stratification. Particular attention is given to translational therapeutic strategies, including antioxidant pathway modulation, inflammasome targeting, microbiota engineering, and tissue-protective agents, highlighting both their mechanistic rationale and clinical feasibility. By linking molecular pathophysiology with predictive modeling and intervention development, this review provides an integrated roadmap for precision prevention and management of radiation enteritis in cervical cancer radiotherapy. Such a framework may facilitate risk-adapted treatment planning, mitigate gastrointestinal toxicity, and ultimately improve therapeutic outcomes.

Vaginal microbiome distinction in women with HPV+, cervical intraepithelial neoplasia, and cervical cancer, a retrospective study

IntroductionThe vaginal microbiota is a complex and dynamic micro-ecosystem that plays a pivotal role in protecting the host from various pathogens. Previous studies have investigated the diversity of the vaginal microbiome and its association with health outcomes, particularly the development of HPV-related disorders. This study aimed to investigate the correlation between the vaginal microbiota, HPV infection, cervical intraepithelial neoplasias (CINs), and cervical cancers in 69 women.MethodsDNA was extracted from vaginal samples, followed by HPV genotyping through PCR and sequenced of the16S rRNA gene.ResultsOur results revealed that Lactobacillus was the predominant bacterium across all groups, with prevalence rates of 60.2% in women with HPV+, 63.9% in CINI, 97.7% in CINII, 52.0% in CINIII, 36.9% in cervical cancer, and 70.9% in NILM (normal cytology). Additionally, an elevated proportion of Gardnerella was identified as a high-risk bacterium associated with HPV infection, potentially contributing to the progression of cervical lesions. High-risk HPV genotypes, particularly HPV16, 52, and 33, were found to be more prevalent among women with HPV+, CIN, and cervical cancer. We also observed significantly higher alpha diversity in the vaginal microbiome of women with HPV+ and CIN, as indicated by increased Sobs, Shannon, Ace, and Chao indices, compared to the NILM group.ConclusionThese findings suggest that HPV infection and its associated pathological conditions are closely linked to alterations in the vaginal microbiome. This underscores the need for further research to unravel the intricate relationship between HPV genotype infections and vaginal microbiota, which could pave the way for new diagnostic and therapeutic approaches.

The interplay between HPV, other Sexually Transmissible Infections and genital microbiome on cervical microenvironment (MicroCervixHPV study)

BackgroundThe importance of Cervicovaginal Microbiota in protecting against infections (such as HPV) is already well established, namely through Lactobacillus spp., as well as the mechanism through which HPV leads to Cervical Neoplasia. However, it is not possible to classify HPV as a complete carcinogen. Thus, the importance of exploring Cervicovaginal dysbiosis with the intention of deciphering this interaction with HPV, takes on greater relevance. The main objectives of this study were: 1) Comparison of the MCV composition of women with or without HPV and women with ASCUS or LSIL; 2) Characterization of cytokines present in the vaginal microenvironment; 3) Evaluation of the blood count ratios as prognostic systemic inflammatory biomarkers; 4) Correlation between MCV, HPV serotypes and cytokines.MethodsThis was a retrospective, observational, multicenter, cross-sectional study. CVM analysis was performed by isolation RNA and sequencing on a NGS platform. Cytokine concentrations of CVM were obtained through Multiplex platform. Statistical analysis was performed in SPSS v 26.0. An α of 0.05 was considered statistically significant.ResultsHighlighting the core of the study, CVM types of CST I and CST IV were found to influence the emergence of cervical lesions. Neutrophil-to-Lymphocyte ratio was found to impact the prognosis of ASCUS. Within CVM, Lactobacillus prevent the growth of other CST IV species, while the latter express symbiotic relationships with each other and show affinity for specific HPV serotypes. At last, RANTES chemokine is significantly elevated in cervicovaginal infections.ConclusionThe importance of using vaginal cytokine profiles and CVM is highlighted in the hypothesis of prevention of Cervical Neoplasia development, as well as in its use as a prognostic biomarker. Taken together, these insights are one step closer to personalized medicine.

Characteristics of the vaginal microbiota and vaginal metabolites in women with cervical dysplasia

IntroductionEmerging evidence suggests that the vaginal microbiota is closely associated with cervical cancer. However, little is known about the relationships among the vaginal microbiota, vaginal metabolites, and cervical lesion progression in women undergoing cervical dysplasia.MethodsIn this study, to understand vaginal microbiota signatures and vaginal metabolite changes in women with cervical lesions of different grades and cancer, individuals with normal or cervical dysplasia were recruited and divided into healthy controls (HC) group, low-grade squamous intraepithelial lesions (LSIL) group, high-grade squamous intraepithelial lesions (HSIL) group, and cervical cancer (CC) group. Vaginal secretion samples were collected for 16S rRNA gene sequencing, liquid chromatography coupled with mass spectrometry (LC–MS)-based metabolomics, and integrated analysis.ResultsThe results demonstrated that bacterial richness and diversity were greater in the CC group than the other three groups. Additionally, Lactobacillus was found to be negatively associated with bacterial diversity and bacterial metabolic functions, which increased with the degree of cervical lesions and cancer. Metabolomic analysis revealed that distinct metabolites were enriched in these metabolite pathways, including tryptophan metabolism, retinol metabolism, glutathione metabolism, alanine, aspartate, and glutamate metabolism, as well as citrate cycle (TCA cycle). Correlation analysis revealed positive associations between CC group-decreased Lactobacillus abundance and CC group-decreased metabolites. Lactobacillus iners was both negative to nadB and kynU genes, the predicted abundance of which was significantly higher in the CC group. The linear regression model showed that the combination of the vaginal microbiota and vaginal metabolites has good diagnostic performance for cervical cancer.DiscussionOur results indicated a clear difference in the vaginal microbiota and vaginal metabolites of women with cervical dysplasia. Specifically altered bacteria and metabolites were closely associated with the degree of cervical lesions and cancer, indicating the potential of the vaginal microbiota and vaginal metabolites as modifiable factors and therapeutic targets for preventing cervical cancer.

Detection of Alpha, Beta, Gamma, and Unclassified Human Papillomaviruses in Cervical Cancer Samples From Mexican Women

How the Cervical Microbiota Contributes to Cervical Cancer Risk in Sub-Saharan Africa

Despite ongoing efforts, sub-Saharan Africa faces a higher cervical cancer burden than anywhere else in the world. Besides HPV infection, definitive factors of cervical cancer are still unclear. Particular states of the cervicovaginal microbiota and viral infections are associated with increased cervical cancer risk. Notably, HIV infection, which is prevalent in sub-Saharan Africa, greatly increases risk of cervicovaginal dysbiosis and cervical cancer. To better understand and address cervical cancer in sub-Saharan Africa, a better knowledge of the regional cervicovaginal microbiome is required This review establishes current knowledge of HPV, HIV, cervicovaginal infections, and the cervicovaginal microbiota in sub-Saharan Africa. Because population statistics are not available for the region, estimates are derived from smaller cohort studies. Microbiota associated with cervical inflammation have been found to be especially prevalent in sub-Saharan Africa, and to associate with increased cervical cancer risk. In addition to high prevalence and diversity of HIV and HPV, intracellular bacterial infections such as Chlamydia, Gonorrhea, and

HPV16-LINC00393 Integration Alters Local 3D Genome Architecture in Cervical Cancer Cells

High-risk human papillomavirus (hrHPV) infection and integration were considered as essential onset factors for the development of cervical cancer. However, the mechanism on how hrHPV integration influences the host genome structure remains not fully understood. In this study, we performed in situ high-throughput chromosome conformation capture (Hi-C) sequencing, chromatin immunoprecipitation and sequencing (ChIP-seq), and RNA-sequencing (RNA-seq) in two cervical cells, 1) NHEK normal human epidermal keratinocyte; and 2) HPV16-integrated SiHa tumorigenic cervical cancer cells. Our results reveal that the HPV-LINC00393 integrated chromosome 13 exhibited significant genomic variation and differential gene expression, which was verified by calibrated CTCF and H3K27ac ChIP-Seq chromatin restructuring. Importantly, HPV16 integration led to differential responses in topologically associated domain (TAD) boundaries, with a decrease in the tumor suppressor KLF12 expression downstream of LINC00393. Overall, this study provides significant insight into the understanding of HPV16 integration induced 3D structural changes and their contributions on tumorigenesis, which supplements the theory basis for the cervical carcinogenic mechanism of HPV16 integration.

The ovarian cancer-associated microbiome contributes to the tumor’s inflammatory microenvironment

A growing body of research has established a correlation between tumors and persistent chronic inflammatory infiltration. As a primary instigator of inflammation, the majority of microbiomes naturally residing within our bodies engage in a mutually beneficial symbiotic relationship. Nevertheless, alterations in the microbiome's composition or breaches in the normal barrier function can disrupt the internal environment's homeostasis, potentially leading to the development and progression of various diseases, including tumors. The investigation of tumor-related microbiomes has contributed to a deeper understanding of their role in tumorigenesis. This review offers a comprehensive overview of the microbiome alterations and the associated inflammatory changes in ovarian cancer. It may aid in advancing research to elucidate the mechanisms underlying the ovarian cancer-associated microbiome, providing potential theoretical support for the future development of microbiome-targeted antitumor therapies and early screening through convenient methods.

Gut and genital tract microbiomes: Dysbiosis and link to gynecological disorders

Every year, millions of women are affected by genital tract disorders, such as bacterial vaginosis (BV), endometrial cancer, polycystic ovary syndrome (PCOS), endometriosis, and uterine fibroids (UFs). These disorders pose a significant economic burden on healthcare systems and have serious implications for health and fertility outcomes. This review explores the relationships between gut, vaginal, and uterine dysbiosis and the pathogenesis of various diseases of the female genital tract. In recent years, reproductive health clinicians and scientists have focused on the microbiome to investigate its role in the pathogenesis and prevention of such diseases. Recent studies of the gut, vaginal, and uterine microbiomes have identified patterns in bacterial composition and changes across individuals’ lives associated with specific healthy and diseased states, particularly regarding the effects of the estrogen–gut microbiome axis on estrogen-driven disorders (such as endometrial cancer, endometriosis, and UFs) and disorders associated with estrogen deficiency (such as PCOS). Furthermore, this review discusses the contribution of vitamin D deficiency to gut dysbiosis and altered estrogen metabolism as well as how these changes play key roles in the pathogenesis of UFs. More research on the microbiome influences on reproductive health and fertility is vital.

Multi-cohort ensemble learning framework for vaginal microbiome-based endometrial cancer detection

Introduction Endometrial cancer is the most common gynecological malignancy in high-income countries and lacks an established strategy for early detection. Prior studies suggest that the vaginal microbiome may hold diagnostic potential, but inconsistent findings have limited clinical translation. Methods We conducted a systematic review to collect and analyze vaginal 16S rRNA sequencing data from five independent cohorts (n = 265). These studies included women with histologically confirmed endometrial cancer and controls with benign gynecologic conditions. We used these datasets to identify microbial signatures associated with endometrial cancer and to develop a predictive machine learning model. Results Microbial diversity was significantly higher in endometrial cancer samples, and host characteristics influenced community composition. Peptoniphilus was reproducibly enriched in cancer samples across cohorts. An ensemble classifier accurately identified endometrial cancer in a held-out test set, achieving an area under the receiver operating characteristic curve of 0.93 (95% CI: 0.71–0.93), sensitivity of 1.0 (95% CI: 0.74–1.0), and a negative predictive value of 1.0 (95% CI: 0.59–1.0). Discussion These findings support the potential of vaginal microbiome profiling as a minimally invasive approach for early detection of endometrial cancer.

Research progress of probiotics intervention on reconstruction of intestinal flora and improvement of quality of life in patients after endometrial cancer surgery

ObjectiveThis study aims to comprehensively assess the impact of probiotic supplementation on gut microbiota composition and quality of life in endometrial cancer (EC) patients, offering clinical insights supported by empirical data.MethodsA systematic search was conducted across multiple databases, including PubMed, EMBASE, Cochrane Library, Web of Science, and CNKI, covering literature up to mid-2023. Only randomized controlled trials (RCTs) investigating probiotic administration in EC surgery patients were selected. Key evaluation metrics encompassed gut microbial diversity indices, shifts in specific bacterial populations, quality of life assessments, gastrointestinal symptom severity, and immune response indicators. Statistical analyses were performed using RevMan 5.4 and Stata 16.0 software.ResultsThe meta-analysis incorporated 18 RCTs with a total of 1,246 participants. Findings revealed that probiotic supplementation significantly enhanced α-diversity (SMD = 0.68, 95% CI: 0.41–0.95, p < 0.001) and increased the prevalence of beneficial microbes, including Bifidobacterium (SMD = 1.12, 95% CI: 0.78–1.46, p < 0.001) and Lactobacillus (SMD = 0.93, 95% CI: 0.65–1.21, p < 0.001). Conversely, opportunistic pathogens like Bacteroidetes exhibited reduced abundance (SMD = -0.54, 95% CI: -0.82 to -0.26, p < 0.001). Clinically, probiotic use led to notable improvements in overall quality of life (MD = 8.74, 95% CI: 5.12–12.36, p < 0.001) and alleviated gastrointestinal disturbances, such as diarrhea (RR = 0.45, 95% CI: 0.32–0.63, p < 0.001) and constipation (RR = 0.57, 95% CI: 0.42–0.78, p < 0.001). Additionally, inflammatory markers, including IL-6 (SMD = -0.76, 95% CI: -1.05 to -0.47, p < 0.001) and TNF-α (SMD = -0.64, 95% CI: -0.93 to -0.35, p < 0.001), were significantly lowered. Subgroup analyses indicated superior efficacy with multi-strain formulations, higher dosages (≥1010 CFU/day), and extended treatment durations (≥8 weeks).ConclusionCurrent evidence supports the beneficial role of probiotics in restoring gut microbiota balance, enhancing patient well-being, mitigating digestive complications, and reducing systemic inflammation following EC surgery. Further high-quality research is warranted to refine optimal probiotic strains, dosing strategies, and intervention timing.

A comprehensive analysis of the uterine microbiome in endometrial cancer patients - identification of Anaerococcus as a potential biomarker and carcinogenic cofactor

IntroductionEndometrial cancer (EC) is a significant gynecological malignancy with increasing incidence worldwide. Emerging evidence highlights the role of the uterine microbiome in the pathogenesis of EC. This study aims to characterize the uterine microbiome in EC patients and identify potential microbial biomarkers, with a focus on Anaerococcus as a differentiating taxon.MethodsThe endocervical canal swabs from patients with EC (n=16) and non-cancerous patients (EM, n=13) were collected. The V3-V4 region of the 16S rRNA gene was sequenced using the Illumina platform. Bioinformatic analyses were performed with QIIME2, and statistical comparisons were conducted to assess differences in microbial composition and diversity. In vitro experiments were conducted to assess the functional impact of Anaerococcus on human uterine fibroblasts, including its ability to adhere to the human cells and induce oxidative stress.ResultsThe α-diversity metrics, including Shannon entropy and observed amplicon sequence variants (ASVs), revealed significantly higher microbial diversity in EC samples compared to EM. Anaerococcus was identified as a key taxon differentiating EC from EM groups, showing a higher relative abundance in EC samples. Functional predictions and in vitro assays indicated that Anaerococcus may contribute to carcinogenesis by inducing reactive oxygen species (ROS) production, and has the high ability to adhere to the human endometrial fibroblasts.DiscussionThe study provides evidence of distinct microbial signatures in EC, with Anaerococcus emerging as a potential biomarker. The in vitro findings suggest its role in endometrial carcinogenesis, underscoring its potential as a target for future diagnostic and therapeutic applications.

Analysis of endometrial lavage microbiota reveals an increased relative abundance of the plastic-degrading bacteria Bacillus pseudofirmus and Stenotrophomonas rhizophila in women with endometrial cancer/endometrial hyperplasia

The pathogenic influences of uterine bacteria on endometrial carcinogenesis remain unclear. The aim of this pilot study was to compare the microbiota composition of endometrial lavage samples obtained from women with either endometrial hyperplasia (EH) or endometrial cancer (EC) versus those with benign uterine conditions. We hypothesized that specific microbiota signatures would distinguish between the two groups, possibly leading to the identification of bacterial species associated with endometrial tumorigenesis. A total of 35 endometrial lavage specimens (EH, n = 18; EC, n = 7; metastatic EC, n = 2; benign endometrial lesions, n = 8) were collected from 32 women who had undergone office hysteroscopy. Microbiota composition was determined by sequencing the V3−V4 region of 16S rRNA genes and results were validated by real-time qPCR in 46 patients with EC/EH and 13 control women. Surprisingly, we found that Bacillus pseudofirmus and Stenotrophomonas rhizophila – two plastic-degrading bacterial species – were over-represented in endometrial lavage specimens collected from patients with EC/EH. Using computational analysis, we found that the functional profile of endometrial microbiota in EC/EH was associated with fatty acid and amino acid metabolism. In summary, our hypothesis-generating data indicate that the plastic-degrading bacteria Bacillus pseudofirmus and Stenotrophomonas rhizophila are over-represented within the endometrial lavage microbiota of women with EC/EH living in Taiwan. Whether this may be related to plastic pollution deserves further investigation.

Integrated Analysis of Microbiome and Transcriptome Data Reveals the Interplay Between Commensal Bacteria and Fibrin Degradation in Endometrial Cancer

The gut-uterus axis plays a pivotal role in the pathogenesis of endometrial cancer (EC). However, the correlations between the endometrial microbiome and endometrial tumor transcriptome in patients with EC and the impact of the endometrial microbiota on hematological indicators have not been thoroughly clarified. In this prospective study, endometrial tissue samples collected from EC patients (n = 30) and healthy volunteers (n = 10) were subjected to 16S rRNA sequencing of the microbiome. The 30 paired tumor and adjacent nontumor endometrial tissues from the EC group were subjected to RNAseq. We found thatPelomonasandPrevotellawere enriched in the EC group with a high tumor burden. By integrating the microbiome and hematological indicators, a correlation was observed betweenPrevotellaand elevated serum D-dimer (DD) and fibrin degradation products (FDPs). Further transcriptome analysis identified 8 robust associations betweenPrevotellaand fibrin degradation-related genes expressed within ECs. Finally, the microbial marker ofPrevotellaalong with DD and FDPs showed a high potential to predict the onset of EC (AUC = 0.86). Our results suggest that the increasing abundance ofPrevotellain endometrial tissue combined with high serum DD and FDP contents may be important factors associated with tumor burden. The microbe-associated transcripts of host tumors can partly explain howPrevotellapromotes DD and FDPs.

Distinct cervical microbiome and metabolite profiles before and after menopause: implications for cervical cancer progression

IntroductionCervical cancer is the fourth most common malignancy in women and is primarily caused by persistent infection with high-risk human papillomavirus (HPV). In addition, host immune responses, genetic factors, and lifestyle habits also have etiological roles. The cervicovaginal microbiome undergoes dynamic changes during menopause, which may be involved in the progression of cervical neoplasia. We aimed to elucidate the association between cervical microenvironmental changes and the progression of cervical neoplasia before and after menopause by integrating analyses of the cervical microbiome, related metabolites, cytokines, and microRNAs.MethodsA total of 248 HPV-positive women with cervical neoplasia, including 17 with cervical intraepithelial neoplasia (CIN1), 80 with CIN2, 82 with CIN3, and 69 with squamous cell carcinoma (SCC), were enrolled. As normal controls, 48 HPV-negative healthy women were included. Each group was stratified based on the mean menopausal age of 50 years. Cervical mucus was analyzed according to the methods outlined below. The microbiota was profiled by 16S rRNA gene sequencing, metabolites were analyzed by ultra-HPLC-tandem mass spectrometry, RT-qPCR was used for miRNA expression analysis, and RANTES levels were quantified by multiplex bead array. Data analysis was performed using MicrobiomeAnalyst and MetaboAnalyst.ResultsIn the SCC group, Prevotella and Atopobium were the key bacterial genera among the younger group, while Peptoniphilus, Fusobacterium, and Porphyromonas were more prevalent in elderly group (LDA score > 4.5). We observed a consistent positive correlation between Atopobium and xanthine in younger groups with CIN2 or worse (p < 0.0001). However, no such correlations were detected in elderly women. In addition, Atopobium, Adlercreutzia, and Gardnerella showed significant positive correlation with nicotinic acid in younger women with SCC compared to the elderly women (p < 0.0001). In the younger SCC women, several metabolites were significantly elevated in groups with high expression levels of RANTES, miR-20b-5p, and miR-155-5p.ConclusionThe cervical microbiome undergoes changes during menopause, and may influence disease progression by interacting with metabolites, cytokines, and miRNAs. These results highlight the potential for personalized medicine for cervical cancer that is tailored to different age groups.

A potential association between the characteristics of the multi-organ microbiota and lymph node metastasis in cervical cancer

Introduction Microbiota alterations at multiple sites are associated with cervical cancer (CC). However, it is unclear whether CC lymph node metastasis (LNM) is indeed associated with microbiota alterations, whether the microbiota is generally suitable for screening CC LNM-related taxa. Materials and methods We performed 16S rDNA sequencing of samples from oral swabs, feces, urine, and vaginal secretions from CC patients to clarify microbiota characteristics of LNM group. And we constructed a LNM prediction model for CC based on specific flora at each site. Results The α-diversity of the urinary microbiota ( P Sob = 0.0272, P Pielou = 0.0278, P Shannon = 0.0209 and P Simpson = 0.0465) was reduced in the LNM group compared to the non-LNM group, and significant differences were observed in the structure of the gut (R² = 0.0266, P  = 0.033) and urine (R² = 0.0379, P  = 0.002) microbiota between the two groups. The establishment of a predictive model based on oral specific flora, including Erysipelotrichaceae UCG-003 sp., Eubacterium halli group , and Staphylococcus has enabled the differentiation of CC lymph node status. The area under the ROC curve was 0.798. The Yoden index, sensitivity and specificity of this prediction model were 0.520, 57.9% and 94.1%, respectively. Conclusion CC patients with LNM have significant microbiological changes at multiple sites. The predictive model based on oral bacteria can provide a noninvasive and simple method for assessing LNM in CC.

Evolving HPV diagnostics: current practice and future frontiers

Human papillomavirus (HPV) infection serves as a primary causative agent of cervical cancer, highlighting the importance of early screening and detection in mitigating the incidence and mortality rates of HPV-related diseases. Over the past decades, HPV detection technologies have evolved considerably, transitioning from traditional methods to more advanced, patient-centered approaches. This review provides a comprehensive overview of both established and emerging HPV detection strategies, with a particular focus on their clinical applicability, technical advantages, and limitations. Conventional methods such as hybrid capture and PCR-based assays remain the backbone of clinical screening, offering robust sensitivity and specificity. However, their reliance on invasive sampling and centralized laboratory infrastructure limits accessibility and patient compliance, particularly in low-resource settings. To address these limitations, emerging technologies—including CRISPR/Cas systems, droplet digital PCR (ddPCR), next-generation sequencing (NGS), isothermal amplification techniques (IAT) and artificial intelligence (AI) combined with hpv screening offer enhanced accuracy, rapid turnaround, and the potential for point-of-care deployment. In parallel, innovations in sampling such as self-collected vaginal swabs and liquid biopsy using urine, blood, or extracellular vesicles are improving test acceptability and broadening screening coverage. By summarizing current progress and highlighting ongoing challenges, this review aims to guide the development of more precise, non-invasive, and scalable HPV detection strategies to reduce the global burden of HPV-related disease, support global prevention efforts, and guide public health policies.

Human papillomavirus infection and disease recurrence/persistence after treatment for women of high-grade cervical intraepithelial neoplasia with coexisting vaginal intraepithelial neoplasia

BackgroundCoexistent cervical intraepithelial neoplasia (CIN) and vaginal intraepithelial neoplasia (VaIN) is problematic, posing challenges for patient management. This study focused on the clinical characteristics of coexistent CIN 2/3 and VaIN (all degrees), evaluating the proclivity for disease recurrence/persistence at 6 months after treatment.MethodsA retrospective case–control study of women treated for coexistent CIN 2/3 and VaIN (CE group) was undertaken between January 2018 and December 2020. During the same period, women with CIN 2/3 only were selected chronologically (1:2 ratio) for comparison (sCIN group). A loop electrosurgical excision procedure (LEEP) was the standard treatment for CIN 2/3, performing electrofulguration of VaIN in tandem. First follow-up visits at 6 months thereafter entailed testing for human papillomavirus (HPV). Univariate and multivariate analyses served to assess pertinent risk factors.ResultsThere were 91 CE group members, each treated for coexistent CIN 2/3 and VaIN (VaIN 1, 35; VaIN 2/3, 56). Age ≥50 years (OR = 3.362, 95% CI: 1.421–7.954) emerged as an independent risk factor for coexistent disease. Positive margins and persistent high-risk HPV (HR-HPV) infection after treatment were more common in the CE (vs. sCIN) group (p = 0.012 and p < 0.001, respectively), as was recurrent/persistent high-grade disease (17.6% vs. 2.2%; p < 0.001). In the CE group, persistent HR-HPV infection 6 months after treatment (OR = 21.320, 95% CI: 2.509–181.188) was the sole independent risk factor for disease recurrence/persistence at 6 months.ConclusionsComprehensive vaginal wall examinations are warranted for women with CIN 2/3, particularly those >50 years old. Close follow-up by HPV test is also indicated if CIN 2/3 and VaIN coexist, given a heightened incidence of recurrent/persistent disease.

The vaginal microbiome in HPV persistence and cervical cancer progression

Persistent infection with high-risk human papillomaviruses (HR-HPV) is the primary cause of cervical cancer, but its progression depends on host and environmental factors beyond viral presence. The vaginal microbiome, particularly the transition from Lactobacillus crispatus–dominated communities to dysbiotic states enriched in Gardnerella, Fannyhessea, and Sneathia, has emerged as a key modulator of HPV persistence, local inflammation, and epithelial transformation. First, community state type IV (CST IV) microbiota strongly predict persistent HR-HPV infection and progression to high-grade lesions, highlighting their potential as non-invasive biomarkers for early risk stratification. Second, cervicovaginal dysbiosis alters mucosal immunity and promotes epigenetic reprogramming of both host and viral genomes, facilitating immune evasion and oncogenesis. Third, restoring Lactobacillus dominance through probiotics or microbial engineering holds translational promise for enhancing HPV vaccine efficacy and reducing cervical cancer burden. These findings position the vaginal microbiome not as a passive bystander, but as an active determinant of HPV-driven carcinogenesis and underscore its diagnostic and therapeutic potential in cervical cancer prevention.

Advances in the interrelated nature of vaginal microecology, HPV infection, and cervical lesions

Vaginal microecology serves as a crucial defense mechanism in women’s reproductive health. It encompasses vaginal anatomy, microbial flora, endocrine regulation, and immune responses. Lactobacillus species dominate this ecosystem, maintaining a dynamic balance essential for vaginal health. Studies have highlighted a strong association between vaginal microecology, human papillomavirus (HPV) infection, and cervical lesions. A well-balanced vaginal microenvironment enhances mucosal barriers and immune function, aiding in HPV prevention and clearance. Conversely, disruptions in vaginal microecology compromise these defenses, increasing susceptibility to HPV infection. Persistent high-risk HPV (HR-HPV) infections are key contributors to cervical lesions and may further destabilize the vaginal microbiota(VMB). Additionally, cervical lesion progression is influenced by local immune responses, with HPV infection potentially accelerating disease development by suppressing cervical immunity. This review explores the intricate association between vaginal microecology, HPV infection, and cervical lesions, offering insights into early diagnosis, prevention, and treatment strategies.

Knowledge and attitudes of medical students regarding human papilloma virus infection and vaccine: cross-sectional study from Jordan

BackgroundAs of the present moment, Jordan is yet to incorporate cervical cancer screening in its cancer control program nor advocates for vaccines. This paper aims to examines the perceptions and attitudes of medical students towards HPV and its vaccine.MethodsWe conducted a cross-examination of HPV knowledge and vaccine uptake among medical students across the period between January and March 2024. Participants completed a questionnaire developed and validated by the existing literature. The questionnaire was composed of 4 domains pertaining to sociodemographic, knowledge of HPV, knowledge of HPV vaccine, and attitudes. Medical students were conveniently sampled from Jordan’s six public medical schools. Predictors to self-vaccinate, recommending vaccination to friends/family, and recommending vaccination to patients were examined using a binary logistic regression model. All analyses were conducted on R version (4.3.3).ResultsA total of 473 medical students were included in the final analysis. On a scale of 12 and 8, mean HPV and vaccine knowledge scores were 5.4 ± 3.1 and 2.9 ± 1.9, respectively. Knowledge of HPV and its vaccine were significantly higher among females, students in their clinical years, and those with self-perceived understanding of HPV (all p <0.05). Intention to self-vaccinate against HPV was predicted by higher HPV and vaccine knowledge scores. Male participants were significantly less likely to self-vaccinate compared to females (OR: 0.61; 95%CI: 0.40 – 0.91). Similarly, higher HPV and vaccine knowledge scores were associated a higher likelihood to recommend the vaccine to family or patients. On the other hand, male participants were significantly less likely to recommend the vaccine to patients compared to their female counterparts (OR: 0.62; 95%CI: 0.40 – 0.95).ConclusionThe study implies that the overall awareness and attitudes regarding HPV and its vaccine is alarmingly poor among medical students. Moreover, there exists a gender difference in the knowledge and attitudes favoring females. Concerned policy makers and institutions should strive to improve vaccine awareness and uptake through informational, behavioral, and environmental interventions. Moreover, medical students should be well equipped to tackle HPV vaccine hesitancy through curricular reforms, targeted training, and increased exposure to public vaccine promotional efforts.

The intratumoral microbiota heterogenicity is related to the prognosis and tumorigenesis of cervical cancer

BackgroundThe intratumoral microbe-host interaction plays crucial role in the development of cancer. The microbiome can influence cancer development by modulating inflammation, immune responses and metabolic pathways. Therefore, we aim to delineate the landscape and role of intratumoral microbiota in cervical cancer (CC).MethodsThe presence of bacterial community in CC tissues was confirmed by fluorescence in situ hybridization (FISH). Then 16s rRNA and RNA-Seq were used to characterize the composition of intratumoral microbiota. Combined with cervical squamous cell carcinoma (CESC) data from the Tumor Cancer Genome Atlas (TCGA), the clinical signatures of intratumoral microbiota and DEGs were further analyzed. Finally, the effect of the up-regulated Fibrinogen beta chain (FGB) expressed fragment peptide on the biological behavior of cancer was verified in vitro.ResultsWe found the composition heterogeneity of bacteria in CC tumors. Pseudomonas was most highly enriched in CC tissues and grouped according to the relative abundance level. The clinical characteristics of patients with relatively high abundance of Pseudomonas had the higher levels of fibrinogen and lower levels of white blood cell (WBC) and albumin (ALB) expression. Combining transcriptome data from the two our collective CC and TCGA-CESC cohorts, we found that Pseudomonas abundance was significantly associated with fibrinogen beta peptide expression and worse overall survival in CC patients. In vitro experiment revealed that Pseudomonas could promote the proliferation and migration of cervical cancer cells through overexpression of FGB.ConclusionsWe characterized the composition of the intratumoral microbiota in CC tissues and identified the most significantly differentially abundant bacteria between cancerous and non-cancerous tissues. Our findings provide novel insights into the relationship between intratumoral Pseudomonas and the tumorigenesis of CC. A deeper understanding of the tumor microenvironment and its associated microbiota may reveal new potential therapeutic targets and improve clinical outcomes.

Integrated analysis of microbiome and metabolome reveals insights into cervical neoplasia aggravation in a Chinese cohort

IntroductionCervical carcinoma (CC) remains one of the significant cancers threatening women's health globally. Increasing evidence suggests that alterations in the microbiota are closely associated with cancer development. However, the understanding of reliable biomarkers and underlying mechanisms during the aggravation of cervical neoplasia such as cervical intraepithelial neoplasia (CIN) and CC is still relatively limited.MethodsIn this study, cervical swab samples from 53 healthy controls, 51 high-grade squamous intraepithelial lesion (HSIL), and 52 CC patients were subjected to 16S rDNA sequencing and metabolomics analysis.ResultsWe observed significant differences in the cervical microbiota between CC patients and healthy controls or HSIL groups. Compared to the healthy controls, CC patients exhibited increased microbial diversity, decreased abundance of Lactobacillus, and notable changes in microbial composition. Metabolomics analysis revealed significantly elevated levels of the inflammatory mediator Prostaglandin E2 (PGE2) in CC samples. Through random forest modeling and ROC curve analysis, we identified a combination of key microbiota (Porphyromonas, Pseudofulvibacter) and metabolites (Cellopentaose, PGE2) as diagnostic biomarkers with high diagnostic value for CC. Furthermore, we found a significant correlation between the cervical microbiota Porphyromonas and the metabolite PGE2, suggesting a potential role of key microbiota in inducing inflammation.DiscussionThese findings indicate that alterations in cervical microbiota and metabolites may be closely associated with the occurrence and aggravation of cervical neoplasia, providing new insights for further understanding the mechanisms of cervical neoplasia progression and developing novel diagnostic markers and therapeutic approaches.

Alternative splicing in the genome of HPV and its regulation

Persistent infection with high-risk human papillomavirus (HR-HPV) is the main cause of cervical cancer. These chronic infections are characterized by high expression of the HPV E6 and E7 oncogenes and the absence of the L1 and L2 capsid proteins. The regulation of HPV gene expression plays a crucial role in both the viral life cycle and rare oncogenic events. Alternative splicing of HPV mRNA is a key mechanism in post-transcriptional regulation. Through alternative splicing, HPV mRNA is diversified into various splice isoforms with distinct coding potentials, encoding multiple proteins and influencing the expression of HPV genes. The spliced mRNAs derived from a donor splicing site within the E6 ORF and one of the different acceptor sites located in the early mRNA contain E6 truncated mRNAs, named E6*. E6* is one of the extensively studied splicing isoforms. However, the role of E6* proteins in cancer progression remains controversial. Here, we reviewed and compared the alternative splicing events occurring in the genomes of HR-HPV and LR-HPV. Recently, new HPV alternative splicing regulatory proteins have been continuously discovered, and we have updated the regulation of HPV alternative splicing. In addition, we summarized the functions of known splice isoforms from three aspects: anti-tumorigenic, tumorigenic, and other cancer-related functions, including not only E6*, but also E6^E7, E8^E2, and so on. Comprehending their contributions to cancer development enhances insights into the carcinogenic mechanisms of HPV and explores the potential utility of alternative splicing in the diagnosis and treatment of cervical cancer.

Recombinant adenoviruses expressing HPV16/18 E7 upregulate the HDAC6 and DNMT3B genes in C33A cells

ObjectiveHigh-risk human papillomavirus (HPV) is a carcinogenic virus associated with nearly all cases of cervical cancer, as well as an increasing number of anal and oral cancers. The two carcinogenic proteins of HPV, E6 and E7, can immortalize keratinocytes and are essential for HPV-related cellular transformation. Currently, the global regulatory effects of these oncogenic proteins on the host proteome are not fully understood, and further exploration of the functions and carcinogenic mechanisms of E6 and E7 proteins is needed.MethodsWe used a previously established platform in our laboratory for constructing recombinant adenoviral plasmids expressing the HPV16 E7 gene to further construct recombinant virus particles expressing HPV16/18 E6, E7, and both E6 and E7 genes. These recombinant viruses were used to infect C33A cells to achieve sustained expression of the HPV16/18 E6/E7 genes. Subsequently, total RNA was extracted and RNA-Seq technology was employed for transcriptome sequencing to identify differentially expressed genes associated with HPV infection in cervical cancer.ResultsRNA-Seq analysis revealed that overexpression of the HPV16/18 E6/E7 genes upregulated GP6, CD36, HDAC6, ESPL1, and DNMT3B among the differentially expressed genes (DEGs) associated with cervical cancer. Spearman correlation analysis revealed a statistically significant correlation between the HDAC6 and DNMT3B genes and key pathways, including DNA replication, tumor proliferation signature, G2M checkpoint, p53 pathways, and PI3K/AKT/mTOR signaling pathways. Further, qRT-PCR and Western blot analyses indicated that both HPV16/18 E7 can upregulate the expression of HDAC6 and DNMT3B, genes associated with HPV infection-related cervical cancer.ConclusionThe successful expression of HPV16/18 E6/E7 in cells indicates that the recombinant viruses retain the replication and infection capabilities of Ad4. Furthermore, the recombinant viruses expressing HPV16/18 E7 can upregulate the HDAC6 and DNMT3B genes involved in cervical cancer pathways, thereby influencing the cell cycle. Additionally, HDAC6 and DNMT3B are emerging as important therapeutic targets for cancer. This study lays the foundation for further exploration of the oncogenic mechanisms of HPV E6/E7 and may provide new directions for the treatment of HPV-related cancers.

Head-to-head comparison of two human papillomavirus vaccines for efficacy against cervical intraepithelial neoplasia grade 3 and adenocarcinoma in situ—population-based follow-up of two cluster-randomized trials

IntroductionWe report head-to-head comparison of the bivalent and quadrivalent HPV vaccine efficacies against immediate precursors of cervical cancer from 15 years’ country-wide cancer registry follow-up of phase III trial cohorts and an age-aligned cohort of unvaccinated women.MethodsThese individually and/or clusterrandomized cohorts of HPV6/11/16/18- and HPV16/18-vaccinated and unvaccinated women were enrolled, respectively, in 2002, 2004, and 2003/2005. The trial cohorts comprised initially 16- to 17-year-old HPV6/11/16/18-vaccinated FUTURE II (NCT00092534) participants (866) and HPV16/18-vaccinated PATRICIA (NCT00122681) and 012 trial (NCT00169494) participants (2,465), and 16,526 initially 16- to 19-year-old unvaccinated controls. After active 4-year clinical follow-up, passive, country-wide Finnish Cancer Registry (FCR) follow-up for cervical intraepithelial neoplasia grade 3 (CIN3) and adenocarcinoma in situ (AIS) was based on consented use of unique personal identifiers and started 6 months after the end of the FUTURE II and PATRICIA trials in 2007 and 2009, and ended at the end of 2019. The follow-up with altogether 229,020 follow-up years was age-aligned to ensure that similarly aged cohorts were passively followed up for 15 years post=vaccination for the intention-to-treat analyses of vaccine efficacy.ResultsOverall, we identified 5 and 16 CIN3 (no AIS) cases in the HPV6/11/16/18 and HPV16/18 cohorts, respectively, during the FCR-based follow-up. In the unvaccinated cohort, we identified 281 CIN3 cases, 20 AIS cases, and 13 cases with invasive cervical cancer. Vaccine efficacies against CIN3+ were 68.4% and 64.5% for the quadrivalent and the bivalent vaccines, respectively, with overlapping confidence intervals.DiscussionLong-term follow-up of randomized, initially adolescent HPV-vaccinated and unvaccinated cohorts shows, in this head-to-head setting, that the bivalent and quadrivalent HPV vaccines are equally effective against immediate precursors of cervical cancer.

Age-specific performance of human papillomavirus E6/E7 mRNA assay versus cytology for primary cervical cancer screening and triage: community-based screening in China

BackgroundIn the general population, primary human papillomavirus (HPV) testing is advocated for cervical cancer (CC) screening. HPV E6/E7 mRNA (Aptima HPV, AHPV) assays have garnered considerable traction due to their higher specificity when compared with HPV DNA assays. Here, we investigated age-specific primary AHPV screening assays and different triage strategies versus cytology to identify the best approach.MethodsBetween April 2018 and December 2021, we recruited female participants from 34 communities across Liaoning province and Qingdao City, China. Primary cervical screening protocols included liquid-based cytology (LBC) and AHPV assays, with females positive for any assays undergoing colposcopy. Genotyping (AHPV-GT) was conducted on all HPV-positive samples. Our primary outcomes were the identification of age-specific detection rates, colposcopy referral rates, and sensitivity and specificity values for high-grade squamous intraepithelial lesions or worse (HSIL+). AHPV and different triage strategy performances were also examined across different age cohorts.ResultsOur investigation included 9911 eligible females. Age-specific abnormal cytology rates were in the 6.1%–8.0% range, and were highest in 45–54-year olds. When compared with 35–44-or 45–54-year olds, HPV prevalence was highest in 55–64-year olds (12.2% or 11.6% vs.14.1%, P = 0.048 and P = 0.002, respectively). In 35–44-year olds, AHPV sensitivity for detecting HSIL+ was 96.6 (95% confidence interval [CI]: 89.7–100) - significantly higher than LBC sensitivity (65.5 [95% CI: 48.3–82.8], P < 0.001). When compared with LBC, HSIL+ detection rates by AHPV-GT using reflex LBC triage increased by 31.5% (9.6‰ vs. 7.3‰), and colposcopy referral rates decreased by 16.4% (5.1% vs. 6.1%). In 45–54-year olds, HSIL+ detection rates for AHPV-GT using reflex LBC triage were lower than LBC rates (6.2‰ vs. 6.6‰). In 55–64-year olds, AHPV sensitivity (97.2 [95% CI: 91.7–100.0]) was higher than LBC sensitivity (66.7 [95% CI: 50.0–80.6], P = 0.003). The area under the curve (AUC) value was not significantly different between AHPV-GT with reflex LBC triage and LBC (0.845 [95% CI: 0.771–0.920] vs. 0.812 [95% CI: 0.734–0.891], P = 0.236).ConclusionsPrimary AHPV screening using different triage strategies were different across different age cohorts. Thus, AHPV may be an appropriate primary screening method for 35–44 and 55–64 year old females, while AHPV-GT with reflex LBC triage may be more apt for 35–44 year old females.

Analysis of the correlation between cervical HPV infection, cervical lesions and vaginal microecology

BackgroundVaginal microbiota is involved in human papillomavirus (HPV) infection and cervical cancer (CC) progression, and the specific changes in vaginal microbial composition during this process remains uncertain.ObjectiveThis study aimed to observe the changes in the specific composition of vaginal microorganisms in different cervical lesions and identify biomarkers at different stages of lesions.MethodsIn this study we used the illumina high-throughput gene sequencing technology to determine the V4 region of 16SrRNA and observed the vaginal microbial composition in different cervical lesions.ResultsThe vaginal microbiota of patients with high-risk HPV infection and cervical lesions is significantly different from that of the normal population, but there is no significant difference in the richness of vaginal microbes. The diversity of vaginal species in CC patients is higher than that in high-risk HPV infection or CIN patients. The main manifestation is an increase in the diversity of vaginal microbes, a decrease in the relative abundance of cyanobacteria and Lactobacillus, and an increase in the relative abundance of dialister, peptonephila and other miscellaneous bacteria. There are characteristic vaginal biomarker in normal women, high risk HPV patients and CC patients. In detail, the biomarker in the normal group was varibaculum, the biomarker in the high-risk HPV group was saccharopolyspora, the biomarker of the CC group was the Proteobacteria, Corynebacterium, Coprococcus, Peptococcus and Ruminococcus.ConclusionsThe study indicated that the compositions of vaginal microbes in different cervical lesions is different. The vaginal microbial composition has a certain diagnostic effect on healthy women, patients with high-risk HPV infection and cervical lesions. These microbes may serve as potential biomarkers for CC. It also provided an effective way for the treatment of HPV infections and cervical lesions.

Diagnostic and prognostic potential of the intra-tumoral microbiota profile in HPV-independent endocervical adenocarcinoma

BackgroundMicrobial community dynamics have been involved in numerous diseases, including cancer. The diversity of intertumoral microbiota in human papillomavirus independent endocervical adenocarcinoma (HPVI ECA) is not well-characterized.ObjectiveOur objective is to delineate the intratumoral microbiota profile in HPVI ECA and investigate its potential influence on oncogenesis.MethodsWe analyzed 45 HPVI ECA cases, comprising 36 gastric-type ECA (GEA) and 9 clear cell carcinomas (CCC). We compared the microbial composition within cancerous and adjacent noncancerous tissue samples using 5R-16S ribosomal DNA sequencing. Further, we investigated the correlation between specific microbes and clinical-pathological metrics as well as patient outcomes.ResultsOur findings demonstrate notable differences in the microbial spectra between cancerous and adjacent noncancerous tissues. Amongst HPVI ECA subtypes, GEAs exhibit more microbial variations compared to CCCs. Using the Random Forest algorithm, we identified two distinct microbial signatures that could act as predictive biomarkers for HPVI ECA and differentiate between GEA and CCC. Varied microbial abundances was related to clinical characteristics of HPVI ECA patients. In addition, high levels of Micrococcus and low levels of unknown genus75 from the Comamonadaceae family were associated with poorer outcomes in HPVI ECA patients. Similarly, an abundance of Microbacterium correlated with reduced overall survival (OS), and a high presence of Streptococcaceae family microbes was linked to reduced recurrence-free survival (RFS) in GEA patients. Intriguingly, a high abundance of Micrococcus was also associated with a worse OS in GEA patients.ConclusionThe study reveals distinct microbial signatures in HPVI ECA, which have potential as biomarkers for disease prognosis. The correlation between these tumor-associated microbiota features and clinicopathological characteristics underscores the possibility of microbiome-based interventions. Our research provides a foundation for more in-depth studies into the cervical microbiome’s role in HPVI ECA.

PAD-mediated citrullination is a novel candidate diagnostic marker and druggable target for HPV-associated cervical cancer

Citrullination is an emerging post-translational modification catalyzed by peptidyl-arginine deiminases (PADs) that convert peptidyl-arginine into peptidyl-citrulline. In humans, the PAD family consists of five isozymes (PADs 1-4, 6) involved in multiple diseases, including cancer. Given that high-risk (hr) human papillomaviruses (HPVs) are the etiological agents of cervical cancer, in this study, we sought to determine whether PAD-mediated protein citrullination would play a functional role in the HPV-driven transformation of epithelial cells. Here we show that both total protein citrullination and PAD4 expression levels are significantly associated with cervical cancer progression. Specifically, epithelial immunostaining for PAD4 revealed an increasingly higher histoscore from low-grade (CIN1) to high-grade (CIN2, CIN3) cervical intraepithelial neoplasia, and invasive squamous cell carcinoma (SCC) lesions, raising the attractive possibility that PAD4 may be used as tumor staging markers. Furthermore, taking advantage of the epidermoid cervical cancer cell line CaSki, which harbors multiple copies of the integrated HPV16 genome, we show that the expression of E6 and E7 HPV oncoproteins is impaired by treatment with the pharmacological pan-PAD inhibitor BB-Cl-amidine. Consistently, p53 and p21, two targets of HPV oncoproteins, are upregulated by the PAD inhibitor, which undergoes cell growth arrest and apoptosis. Altogether, these findings highlight a novel mechanism by which hrHPVs alter host regulatory pathways involved in cell cycle and survival to gain viral fitness, raising the possibility that PADs may represent an attractive target for developing novel host-targeting antivirals effective in preventing cervical cancer progression.

Portable, and ultrasensitive HR-HPV tests based on nucleic acid biosensors

Cervical cancer is the third most common cancer threatening women’s health globally, and high-risk human papillomavirus (HR-HPV) infection is the main cause of cervical cancer worldwide. Given the recurrent nature of HR-HPV infection, accurate screening is essential for its control. Since the commonly used polymerase chain reaction (PCR) technique is limited by professional equipment and personnel, convenient and ultrasensitive detection methods for HR-HPV are still highly needed. As new molecular detection methods, nucleic acid amplification-based biosensors have the advantages of high sensitivity, rapid operation, and portability, which are helpful for point-of-care testing in rural and remote areas. This review summarized nucleic acid biosensors for HR-HPV screening based on a variety of nucleic acid amplification strategies involved in improved PCR, loop-mediated isothermal amplification, recombinase polymerase amplification, hybridization chain reaction, catalyzed hairpin assembly, and CRISPR/Cas systems. In combination with microfluidic technology, lateral flow assays, electrochemical analysis and other sensing technologies, HR-HPV nucleic acid biosensors have the advantages of high throughput, short response time, high sensitivity and easy operation in the field. Although there are still shortcomings, such as high cost and poor reproducibility, this approach will be suitable for on-site screening of HR-HPV infection or cervical cancer and for auxiliary clinical diagnosis in complex environments and poor areas in the future.

Human papillomavirus and cervical cancer in the microbial world: exploring the vaginal microecology

The vaginal microbiota plays a crucial role in female reproductive health and is considered a biomarker for predicting disease outcomes and personalized testing. However, its relationship with human papillomavirus (HPV) infection and cervical cancer is not yet clear. Therefore, this article provides a review of the association between the vaginal microbiota, HPV infection, and cervical cancer. We discuss the composition of the vaginal microbiota, its dysbiosis, and its relationship with HPV infection, as well as potential mechanisms in the development of cervical cancer. In addition, we assess the feasibility of treatment strategies such as probiotics and vaginal microbiota transplantation to modulate the vaginal microbiota for the prevention and treatment of diseases related to HPV infection and cervical cancer. In the future, extensive replication studies are still needed to gain a deeper understanding of the complex relationship between the vaginal microbiota, HPV infection, and cervical cancer, and to clarify the role of the vaginal microbiota as a potential biomarker for predicting disease outcomes, thus providing a theoretical basis for personalized testing.

Revealing the Disturbed Vaginal Micobiota Caused by Cervical Cancer Using High-Throughput Sequencing Technology

Cervical cancer is the fourth most prevalent cancer type among all malignancies, so it is of great significance to find its actual pathogenesis mechanisms. In the present study, 90 women were enrolled, and high-throughput sequencing technology was firstly used to analyze the vaginal microbiota of healthy women (C group), cervical intraepithelial neoplasia patients (CIN group) and cervical cancer patients (CER group). Our results indicates that compared with C group, a higher HPV infection rate as well as increased Neutrophil ratio and tumor marker squamous cell carcinoma antigen (SCCA) were obtained, and a decrease in Lymphocyte ratio and Hemoglobin were also present. In addition, the cervical cancer showed a strong association with reduced probiotics Lactobacillus, increased pathogens Prevotella spp., Sneathia spp. and Pseudomonas spp. These results prove that the immunological changes generated by the cervical cancer and the vaginal microbiota can interact with each other. However, further study investigating the key bacteria for cervical cancer is still needed, which can be a clue for the diagnosis or treatment of cervical cancer.

Genotype Distribution Change After Human Papillomavirus Vaccination in Two Autonomous Communities in Spain

ContextIt has been more than 10 years since the human papillomavirus (HPV) vaccination program was initiated in most advanced countries. Thus, it seems necessary to change the uterine cervical cancer screening strategy. Molecular-based tests are considered essential in this scenario.ObjectiveWe aimed to review the distribution of the HPV genotypes after the introduction of the vaccination program with Cervarix® and Gardasil 4® in two autonomous communities in Spain, looking for possible changes in distribution and the occurrence of a herd effect.DesignA cross-sectional study was performed in 45,362 samples that were processed in the Cantabria and Aragon communities during the period from 2002 to 2016. We compared the genotype distribution before and after the vaccination program was initiated.ResultsGenotypes HPV6 and HPV11 have decreased significantly after the introduction of the vaccine. HPV16 has had a decrease, but not a significant one in the statistical analysis. However, HPV31, HPV52, and HPV45 have increased in percentage. A replacement phenomenon with other genotypes not included in the vaccine has been observed in our population.ConclusionsContinued surveillance is needed to provide further indication of any changes over time in the genotypes in circulation. This will be facilitated by monitoring the genotyping results from the new model of cervical screening using primary HPV DNA testing.

Dysregulation of Stemness Pathways in HPV Mediated Cervical Malignant Transformation Identifies Potential Oncotherapy Targets

Human papillomavirus (HPV) infection is associated with a range of malignancies that affect anogenital and oropharyngeal sites. α-HPVs dominantly infect basal epithelial cells of mucosal tissues, where they dysregulate cell division and local immunity. The cervix is one of the mucosal sites most susceptible to HPV infections. It consists of anatomically diverse regions, and the majority of cervical intraepithelial neoplasia and cancers arise within the cervical squamo-columnar junction where undifferentiated basal progenitor cells with stem cell properties are found. The cancer stem cell theory particularly associates tumorigenesis, invasion, dissemination, and metastasis with cancer cells exhibiting stem cell properties. In this perspective, we discuss evidence of a cervical cancer stem cell niche and explore the association of stemness related genes with 5-year survival using a publicly available transcriptomic dataset of a cervical cancer cohort. We report that poor prognosis in this cohort correlates with overexpression of a subset of stemness pathway genes, a majority of which regulate the central Focal Adhesion pathway, and are also found to be enriched in the HPV infection pathway. These observations support therapeutic targeting of stemness genes overexpressed by mucosal cells infected with high-risk HPVs.

Cervicovaginal microbiota significantly changed for HPV-positive women with high-grade squamous intraepithelial lesion

Lower female genital tract is colonized by a variety of microbes (cervicovaginal microbiota, CVM) which associate with the risk of genital infection. This study characterized CVM for 149 Chinese women with different status of human papillomavirus (HPV) infection and squamous intraepithelial lesion (SIL): no HPV infection (HPV-), HPV infection without significant SIL (HPV+NoSIL), HPV infection with low-grade SIL (HPV+LSIL) and HPV infection with high-grade SIL (HPV+HSIL). Analysis results showed CVM has dramatically changed in HPV+HSIL group when compared to HPV+LSIL group, but it exhibited no significant differences between HPV- and HPV+NoSIL groups as well as between HPV+NoSIL and HPV+LSIL groups. In consistence, random forest analysis found more notable differences in HPV+HSIL vs HPV+LSIL comparison than in other comparisons. In addition, depletion of Lactobacillus in CVM was more to be frequently identified in SIL-positive women as compared to SIL-negative individuals. Our findings suggested that significant CVM differences occurred when SIL developed to HSIL which was caused by persistent HPV infection.

Editorial: HPV and Host Interaction

Bacterial DNA involvement in carcinogenesis

The incidence of cancer is high worldwide, and biological factors such as viruses and bacteria play an important role in the occurrence of cancer. Helicobacter pylori, human papillomavirus, hepatitis B viruses and other organisms have been identified as carcinogens. Cancer is a disease driven by the accumulation of genome changes. Viruses can directly cause cancer by changing the genetic composition of the human body, such as cervical cancer caused by human papillomavirus DNA integration and liver cancer caused by hepatitis B virus DNA integration. Recently, bacterial DNA has been found around cancers such as pancreatic cancer, breast cancer and colorectal cancer, and the idea that bacterial genes can also be integrated into the human genome has become a hot topic. In the present paper, we reviewed the latest phenomenon and specific integration mechanism of bacterial DNA into the human genome. Based on these findings, we also suggest three sources of bacterial DNA in cancers: bacterial DNA around human tissues, free bacterial DNA in bacteremia or sepsis, and endogenous bacterial DNA in the human genome. Clarifying the theory that bacterial DNA integrates into the human genome can provide a new perspective for cancer prevention and treatment.

A systematic assessment of stress insomnia as the high-risk factor for cervical cancer and interplay of cervicovaginal microbiome

Cervical cancer is a dreaded form of cancer in women, the fourth most common cancer, with around 0.3 million females suffering from this disease worldwide. Over the past several decades, global researches have focused on the mitigation of cervical lesions and cancers and have explored the impact of physiological and psychological stress and insomnia on cervical pathogenesis. Furthermore, disruption of the cervicovaginal microbiome profiles is identified as an added high-risk factor for the occurrence of cervical cancer. The physiological regulation of stress has an underlying mechanism controlled via hypothalamic pituitary adrenal (HPA) and sympatho-adrenal medullary (SAM) axes. Disruptions in these axes have been identified as the factors responsible for maintaining the homeostasis balance. Recent studies on microbiomes have offered novel ways to combat cervical cancer and cervix infection by exploring the interplay of the cervicovaginal microbiome. Moreover, the integration of various immune cells and microbiome diversity is known to act as an effective strategy to decipher the cervix biological activity. Cytokine profiling and the related immune competence, and physiological stress and insomnia impart to the regulatory networks underlying the mechanism which may be helpful in designing mitigation strategies. This review addressed the current progress in the research on cervical cancer, HPV infection, immune cell interaction, and physiological stress and insomnia with the cervicovaginal microbiome to decipher the disease occurrence and therapeutic management.

Prevention and treatment of human papillomavirus in men benefits both men and women

Men should not be overlooked in research on human papillomavirus (HPV) and its associated genital diseases. This is because men infected with HPV are not only at higher risk of genital cancers, but also increase their partners’ risk of HPV infection and reinfection through sexual contact. Herein, we summarized the state of knowledge regarding the prevention and treatment of HPV infection in men as well as the possible effects of the prevention and treatment of HPV in men on their female partners. Condom use, smoking cessation, male circumcision, and HPV vaccination for men each play an important role in preventing HPV infection within heterosexual couples. Additionally, men could choose to test for certain types of HPV, such as the oncogenic HPV16 or HPV18 strains, as part of a routine screening program when their partner is positive for HPV. Although there is no recognized treatment for HPV infection as of yet, immunotherapy drugs, such as toll-like receptor agonists, therapeutic HPV vaccines, and immune checkpoint inhibitors, have shown promising results in clinical trials and in actual clinical practice. HPV infection in men also increases the risk of cervical cancer in their female partners. Because of the high partner concordance for HPV demonstrated in prior research, the prevention and treatment of HPV in men should be explored more comprehensively in future research.

Gastric-type mucinous endocervical adenocarcinomas: A case report and literature review

Gastric-type mucinous endocervical adenocarcinomas (GAS) are new variant types of cervical adenocarcinomas according to the 2014 World Health Organization (WHO) classification. GAS is a unique disease that can be differentiated from typical adenocarcinomas—it is less common and more aggressive and likely to have deep invasion and horizontal diffusion, invasion of the uterus and vagina, early distant metastases, and a lower 5-year survival rate compared to the usual-type cervical cancer. At present, initial treatment and postoperative adjuvant therapy are not conclusive, but early detection and early treatment are a consensus that can improve prognosis. Most of its occurrence has nothing to do with human papillomavirus (HPV) infection. Whether it is only negative for the subtypes that can be detected at present and whether it may be an unknown subtype of infection need to be further explored in the future. The clinical symptoms commonly include aqueous secretion, lower abdominal pain, and elevated serum carbohydrate antigen-19-9 (CA19-9) levels, which may be helpful for diagnosis. MRI and PET-CT can help to describe the characteristics of lesions and judge the state of the systemic metastasis. We believe that early detection and surgical treatment will give patients more benefits. Looking for potential gene and molecular changes and establishing biomarkers to identify molecular targets will be the key to early identification and target therapy.

Performance of human papillomavirus E6/E7 mRNA assay for primary cervical cancer screening and triage: Population-based screening in China

ObjectiveCervical cancer screening is very important in the prevention and treatment of cervical cancer. In China, the cervical screening strategy needs to be improved. To explore a suitable cervical screening strategy in China, we evaluated the performance of the human papillomavirus (HPV) E6/E7 mRNA (Aptima HPV (AHPV)) assay in primary screening and different triage strategies for women undergoing routine cervical screening.MethodsA total of 10,002 women aged 35 to 65 years of age were recruited in Liaoning Province and Qingdao City, China. Specimens were tested by liquid-based cytology (LBC) and the AHPV assay, and women who tested positive on any test were referred for colposcopy. Genotyping was performed on all high-risk HPV (HR-HPV)-positive samples. Test characteristics were calculated based on histological review.ResultsWe identified 109 women with high-grade squamous intraepithelial lesion or worse (HSIL+), including six with cervical cancer. The sensitivity of AHPV was clearly higher than that of LBC (92.7 [95% CI: 87.2, 97.2] vs. 67.9 [95% CI: 59.6, 76.1], p < 0.001). The specificity of AHPV was 93.0 (95% CI: 92.5, 93.5), which was lower than that of LBC (95.2 [95% CI: 94.8, 95.6], p < 0.001). There was no statistical difference between the positive predictive value of AHPV and LBC (13.5 [95% CI: 11.2, 16.2] vs. 14.3 [95% CI: 11.4, 17.6], p = 0.695). The difference of area under the curve (AUC) values between the AHPV test (0.928 [95% CI: 0.904, 0.953]) and LBC test (0.815 [95% CI: 0.771, 0.860]) in detecting HSIL+ was statistically significant (p < 0.001). Finally, among the three triage strategies, both the sensitivity (73.4 [95% CI: 65.1, 81.7]) and AUC (0.851 [95% CI: 0.809, 0.892]) of AHPV genotyping with reflex LBC triage were the greatest.ConclusionIn summary, the AHPV assay is both specific and sensitive for detecting HSIL+ and may be suitable for use in primary cervical cancer screening in China. AHPV genotyping with reflex LBC triage may be a feasible triage strategy.

Small Cell (Neuroendocrine) Carcinoma of the Cervix: An Analysis for 19 Cases and Literature Review

Cervical SCNEC is a rare and highly malignant invasive tumor. The incidence is low, at less than 5% of all cervical cancers. Moreover, most patients with small cell carcinoma are interrelated with high risk HPV (more familiar HPV 18). Compared to squamous cell carcinoma or adenocarcinoma, patients of cevical SCNEC are more prone to lymph node invasion early, so the clinical manifestation is usually local or distant metastasis. We summarized the clinical features of 19 patients with cervical small cell carcinoma in the Second Affiliated Hospital of Dalian Medical University from 2012 to 2021, and retrospectively analyzed data from 1576 patients in 20 related studies and more than 50 pieces of literature in recent years by searching PubMed, Google schalor, Cochrane Library, Clinicalkey, and other databases. The collected patient data included age, clinical manifestation, TCT, HPV detection, the size and morphology of the tumor, local invasion depth, stage, lymph node status, initial treatment method, tumor-free survival, and so on. The positive rates of CGA, SYN, and CD56 in our cases were high, and NSE was a moderately sensitive index. P16 and Ki67 were the most sensitive, and all patients were positive. We found that multimodal treatment can indeed improve tumor-free survival (DFS), but the prognosis of patients is still very poor. For the early stages, our treatment principles refer to the guidelines of SGO, international gynecological cancer Cooperation (GCIG), and NCCN. We suggest a combination of surgery, radiotherapy, and chemotherapy. However, the general state of advanced patients is poor, whether they can tolerate the operation after neoadjuvant chemotherapy, whether the operation area can remain tumor-free, and whether this treatment will prolong the survival time of patients still need to be further discussed. In order to better prolong the tumor-free survival and prognosis of patients, we need to find gene changes suitable for targeted therapy, so as to complete the clinical application of these treatment methods. Further works are needed to explore more effective therapy for cervical SCNEC.

Prophylactic and Therapeutic HPV Vaccines: Current Scenario and Perspectives

Persistent human papillomavirus (HPV) infection is recognized as the main cause of cervical cancer and other malignant cancers. Although early detection and treatment can be achieved by effective HPV screening methods and surgical procedures, the disease load has not been adequately mitigated yet, especially in the underdeveloped areas. Vaccine, being regarded as a more effective solution, is expected to prevent virus infection and the consequent diseases in the phases of both prevention and treatment. Currently, there are three licensed prophylactic vaccines for L1-VLPs, namely bivalent, quadrivalent and nonavalent vaccine. About 90% of HPV infections have been effectively prevented with the implementation of vaccines worldwide. However, no significant therapeutic effect has been observed on the already existed infections and lesions. Therapeutic vaccine designed for oncoprotein E6/E7 activates cellular immunity rather than focuses on neutralizing antibodies, which is considered as an ideal immune method to eliminate infection. In this review, we elaborate on the classification, mechanism, and clinical effects of HPV vaccines for disease prevention and treatment, in order to make improvements to the current situation of HPV vaccines by provoking new ideas.

Role of Immunity and Vaginal Microbiome in Clearance and Persistence of Human Papillomavirus Infection

Cervical cancer disproportionately affects women of reproductive age, with 80% of cases occurring in low- and middle-income countries. Persistent infection with high-risk human papillomavirus (HPV) genotypes has been described as the most common non-systemic biological risk factor for the development of cervical cancer. The mucosal immune system plays a significant role in controlling HPV infection by acting as the first line of host defense at the mucosal surface. However, the virus can evade host immunity using various mechanisms, including inhibition of the antiviral immune response necessary for HPV clearance. Pro-inflammatory cytokines and the vaginal microbiome coordinate cell-mediated immune responses and play a pivotal role in modulating immunity. Recently, diverse vaginal microbiome (associated with bacterial vaginosis) and genital inflammation have emerged as potential drivers of high-risk HPV positivity and disease severity in women. The potential role of these risk factors on HPV recurrence and persistence remains unclear. This article reviews the role of cellular or cytokine response and vaginal microbiome dysbiosis in the clearance, persistence, and recurrence of HPV infection.

Identification of Peptoniphilus vaginalis-Like Bacteria, Peptoniphilus septimus sp. nov., From Blood Cultures in a Cervical Cancer Patient Receiving Chemotherapy: Case and Implications

A 39-year-old woman with a 3-year human papillomavirus (HPV) 18 infection history was admitted to the hospital for a 16-day history of vaginal bleeding after sex. She was diagnosed with cervical cancer based on the results of the electronic colposcopy, cervical cytology, microscopy, and magnetic resonance imaging (MRI). Then, she received chemotherapy, with paclitaxel 200 mg (day 1), cisplatin 75 mg (day 2), and bevacizumab 700 mg (day 3) twice with an interval of 27 days. During the examination for the diagnosis and treatment, many invasive operations, including removal of intrauterine device, colposcopy, and ureteral dilatation, were done. After that, the patient was discharged and entered the emergency department about 2.5 months later with a loss of consciousness probably caused by septic shock. The patient finally died of multiple organ failure and bacterial infection, although she has received antimicrobial therapy. The blood cultures showed a monobacterial infection with an anaerobic Gram-positive bacterial strain, designated as SAHP1. Matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI–TOF MS) indicated that the patient was infected with Peptoniphilus asaccharolyticus, while molecular analysis and genome-based taxonomy confirmed the infection with a novel Peptoniphilus species that has a close genetic relationship with Peptoniphilus vaginalis and proposed provisionally as Peptoniphilus septimus sp. nov., which may also act as a commensal of the human vagina. Genomic features of SAHP1 have been fully described, and comparative genomic analysis reveals the known prokaryote relative of Peptoniphilus septimus sp. nov. in the genus Peptoniphilus. The invasive operations on the genital tract during the diagnosis and treatment of the patient and the tumor tissue damage and bleeding may have a certain role in the bloodstream infection. This study casts a new light on the Peptoniphilus bacteria and prompts clinicians to include anaerobic blood cultures as part of their blood culture procedures, especially on patients with genital tract tumors. Furthermore, due to the incomplete database and unsatisfying resolution of the MALDI–TOF MS for Peptoniphilus species identification, molecular identification, especially whole-genome sequencing, is required for those initially identified as bacteria belonging to Peptoniphilus in the clinical laboratory.

Bioinformatics Analysis Highlights Five Differentially Expressed Genes as Prognostic Biomarkers of Cervical Cancer and Novel Option for Anticancer Treatment

Cervical cancer is one of the most common gynecological malignancies and is related to human papillomavirus (HPV) infection, especially high-risk type HPV16 and HPV18. Aberrantly expressed genes are involved in the development of cervical cancer, which set a genetic basis for patient prognosis. In this study, we identified a set of aberrantly expressed key genes from The Cancer Genome Atlas (TCGA) database, which could be used to accurately predict the survival rate of patients with cervical squamous cell carcinoma (CESC). A total of 3,570 genes that are differentially expressed between normal and cancerous samples were analyzed by the algorithm of weighted gene co-expression network analysis (WGCNA): 1,606 differentially expressed genes (DEGs) were upregulated, while 1,964 DEGs were downregulated. Analysis of these DEGs divided them into 7 modules including 76 hub genes. Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment analysis revealed a significant increase of genes related to cell cycle, DNA replication, p53 signaling pathway, cGMP-PKG signaling pathway, and Fanconi anemia (FA) pathway in CESC. These biological activities are previously reported to associate with cervical cancer or/and HPV infection. Finally, we highlighted 5 key genes (EMEMP2, GIMAP4, DYNC2I2, FGF13-AS1, and GIMAP1) as robust prognostic markers to predict patient’s survival rate (p = 3.706e-05) through univariate and multivariate regression analyses. Thus, our study provides a novel option to set up several biomarkers for cervical cancer prognosis and anticancer drug targets.

Preliminary Identification of the Aerobic Cervicovaginal Microbiota in Mexican Women With Cervical Cancer as the First Step Towards Metagenomic Studies

Cervical cancer (CC) is considered a public health problem. Recent studies have evaluated the possible relationship between the cervicovaginal microbiome and gynecologic cancer but have not studied the relationship between aerobic bacterial communities and neoplasia. The study aimed to identify the cultivable aerobic bacterial microbiota in women with cervical cancer as a preliminary approach to the metagenomic study of the cervicovaginal microbiome associated with cervical cancer in Mexican women. An observational cross-sectional study was conducted, including 120 women aged 21-71 years, divided into two study groups, women with locally advanced CC (n=60) and women without CC (n=60). Sociodemographic, gynecological-obstetric, sexual, and habit data were collected. Cervicovaginal samples were collected by swabbing, from which standard microbiological methods obtained culturable bacteria. The strains were genetically characterized by PCR-RFLP of the 16S rRNA gene and subsequently identified by sequencing the same gene. Variables regularly reported as risk factors for the disease were found in women with CC. Differences were found in the prevalence and number of species isolated in each study group. Bacteria commonly reported in women with aerobic vaginitis were identified. There were 12 species in women with CC, mainly Corynebacterium spp. and Staphylococcus spp.; we found 13 bacterial species in the group without cancer, mainly Enterococcus spp. and Escherichia spp. The advanced stages presented a more significant number of isolates and species. This study provided a preliminary test for cervicovaginal metagenomic analysis, demonstrating the presence of aerobic cervicovaginal dysbiosis in women with CC and the need for more in-depth studies.

Genetically predicted blood metabolites mediate relationships between gut microbiota and ovarian cancer: a Mendelian randomization study

Background and purposeWhile there is evidence that gut microbiota (GM) and blood metabolites are associated with ovarian cancer (OC), the precise mechanisms underlying this relationship are still unclear. This study used Mendelian randomization (MR) to elucidate the causal connections between GM, blood metabolite biomarkers, and OC.MethodsIn this study, we leveraged summary data for GM (5,959 individuals with genotype-matched GM), blood metabolites (233 circulating metabolic traits with 136,016 participants), and OC (63,702 participants with 23,564 cases and 40,138 controls) from genome-wide association studies (GWASs). We performed MR analysis to explore the causal relationship between GM and OC. Further, we harnessed univariable MR (UVMR) analysis to evaluate the causal associations between GM and circulating metabolites. Finally, we employed a two-step approach based on multivariable MR (MVMR) to evaluate the total genetic prediction effect of metabolites mediating the GM on the risk of OC to discover a potential causal relationship.ResultsIn the MR analysis, 24 gut bacteria were causally associated with the pathogenesis of OC, including 10 gut bacteria (Dorea phocaeense, Succinivibrionaceae, Raoultella, Phascolarctobacterium sp003150755, Paenibacillus J, NK4A144, K10, UCG-010 sp003150215, Pseudomonas aeruginosa, and Planococcaceae) that were risk factors, and 14 gut bacteria (CAG-177 sp002438685, GCA-900066135 sp900066135, Enorma massiliensis, Odoribacter laneus, Ruminococcus E sp003521625, Streptococcus sanguinis, Turicibacter sp001543345, Bacillus velezensis, CAG-977, CyanobacteriaStaphylococcus A fleurettii, Caloranaerobacteraceae, RUG472 sp900319345, and CAG-269 sp001915995) that were protective factors. The UVMR analysis showed that these 24 positive gut bacteria were causally related to lipoproteins, lipids, and amino acids. According to the MVMR analysis, Enorma massiliensis could reduce the risk of OC by raising the total cholesterol to total lipids ratio in large low-density lipoprotein (LDL) and cholesteryl esters to total lipids ratio in intermediate-density lipoprotein (IDL). Turicibacter sp001543345, however, could reduce the risk of OC by lowering free cholesterol in small high-density lipoprotein (HDL) and increasing the ratios of saturated fatty acids to total fatty acids, total cholesterol to total lipids ratio in very small very-low-density lipoprotein (VLDL), and cholesteryl esters to total lipids ratio in very small VLDL.ConclusionThe current MR study provides evidence that genetically predicted blood metabolites can mediate relationships between GM and OC.

Tripterygium glycosides sensitizes cisplatin chemotherapeutic potency by modulating gut microbiota in epithelial ovarian cancer

Epithelial ovarian cancer (EOC) is a fatal gynecological malignancy with limited therapeutic options. Previous research has demonstrated that Tripterygium glycosides (GTW) can enhance effectiveness of cisplatin (DDP) chemotherapy against EOC. However, the underlying mechanism of GTW alleviating EOC still remains unclear. In this article, an ID8 cell-derived xenograft mouse model was established to evaluate the anti-tumor efficacy of GTW combined with DDP. Consistent with previous findings, the results suggested that GTW combined with DDP can exhibit a stronger tumor suppressive effect than DDP alone. Additionally, GTW was found can further exert gastrointestinal protection against DDP by reducing pathological damage on colon tissue. Secondly, to verify whether gut microbiota play an instrumental role in GTW’s anticancer effect, we treated mice models with antibiotic to eliminate gut microbiota. And our experimental results indicated that all drug groups showed a weaker tumor suppressive effect and more severe gastrointestinal damage post antibiotic supplement. At genus level, the relative abundance of Lactobacillus was dramatically diminished by the antibiotic treatment, while combined treatment of GTW and DDP can significantly restore the level. Moreover, we performed Lactobacillus acidophilus transplantation and healthy mice fecal microbiota transplantation experiments to further investigate the link between the anticancer effect of GTW and gut microbiota. Our results suggested that both cisplatin-sensitizing and intestinal barrier-protecting effects of GTW can be recovered to a different extent. In conclusion, our results indicated that GTW is a promising chemosensitization and intestinal barrier repair drug for EOC, and the potential mechanism may corelate with the restoration of the compromised intestinal microbial balance.