RESUMO
The microbiota in the female genital tract is an intricate assembly of diverse aerobic, anaerobic, and microaerophilic microorganisms, which share the space within the reproductive tract and engage in complex interactions. Microbiome dysbiosis may disrupt the symbiotic relationship between the host and microorganisms and play a pivotal role in the pathogenesis of various diseases, including its involvement in the establishment of human papillomavirus (HPV)-associated cervical cancer (CC). Interventions to restore microbiota homeostasis (e.g., probiotics) and bacterial-vector HPV therapeutic vaccines have been reported to be potentially effective in clearing HPV infection and ameliorating cytological abnormalities. In this review, we place emphasis on elucidating the alterations within the cervical-vaginal microbiota as well as the intratumoral microbiota in the context of high-risk HPV (HR-HPV) infection and its subsequent progression to cervical intraepithelial neoplasia/CC. Furthermore, we explore the mechanisms by which these microbial communities exert potential pathogenic or protective effects, including modulating genital inflammation and immune responses, affecting HR-HPV oncogene expression and oncoprotein production, regulating oxidative stress and deoxyribonucleic acid (DNA) damage, and inducing metabolic rewiring. Lastly, we summarize the latest evidence in human trials regarding the efficacy of probiotics, prebiotics and probiotic-vector HPV therapeutic vaccines. This review aims to foster a deeper understanding of the role of the microbiota in HR-HPV infection-related cervix cancer development, and further provide a theoretical basis for the development of preventive and therapeutic strategies based on microbial modulation.
Assuntos
Disbiose , Microbiota , Infecções por Papillomavirus , Probióticos , Neoplasias do Colo do Útero , Vagina , Humanos , Feminino , Neoplasias do Colo do Útero/virologia , Neoplasias do Colo do Útero/microbiologia , Neoplasias do Colo do Útero/terapia , Infecções por Papillomavirus/virologia , Infecções por Papillomavirus/terapia , Vagina/microbiologia , Vagina/virologia , Probióticos/uso terapêutico , Probióticos/administração & dosagem , Papillomaviridae/patogenicidade , Papillomaviridae/fisiologia , Colo do Útero/microbiologia , Colo do Útero/virologia , Vacinas contra Papillomavirus/administração & dosagem , Displasia do Colo do Útero/virologia , Displasia do Colo do Útero/microbiologia , Displasia do Colo do Útero/terapia , Prebióticos/administração & dosagemRESUMO
The cervicovaginal microbiome may contribute to human papillomavirus (HPV)-associated cervical carcinogenesis, but studies have been limited by low-resolution analysis methods. Using a high-resolution bioinformatics pipeline, we evaluated the relationship of the cervicovaginal microbiome with HPV and cervical intraepithelial neoplasia (CIN). The cervicovaginal microbiome of 186 women was characterized by sequencing 16S rRNA regions (V3-V4 and V5-V6) and annotated with the high-resolution ANCHOR pipeline. Samples were genotyped for HPV using the Roche-Cobas 4800 assay. We fitted logistic regression models using stepwise forward selection to select species (presence/absence) as correlates of CIN1+ and constructed a linear microbiome-based score using the regression coefficients. An HPV-based score was calculated from a separate logistic regression model to detect CIN1+ . Receiver operating characteristic curve analyses were performed; the area under the curve (AUC) and 95% confidence intervals (CI) were compared between scores. Overall, 66.7% of participants were HPV-positive. 77 unique species were identified: 8 using V3-V4, 48 using V5-V6, and 21 shared. Twelve species were retained via stepwise selection. The AUCs for the microbiome-, and HPV-based scores were 0.7656 (95% CI 0.6885-0.8426), and 0.7529 (95% CI 0.6855-0.8204), respectively. Bacterial species may be involved in cervical carcinogenesis as the microbiome- and HPV-based scores performed similarly for CIN1+ detection.
Assuntos
Carcinogênese , Colo do Útero , Microbiota , Papillomaviridae , Infecções por Papillomavirus , RNA Ribossômico 16S , Displasia do Colo do Útero , Neoplasias do Colo do Útero , Vagina , Humanos , Feminino , Infecções por Papillomavirus/virologia , Infecções por Papillomavirus/microbiologia , Infecções por Papillomavirus/complicações , Adulto , Vagina/microbiologia , Vagina/virologia , Colo do Útero/microbiologia , Colo do Útero/virologia , Neoplasias do Colo do Útero/virologia , Neoplasias do Colo do Útero/microbiologia , Displasia do Colo do Útero/microbiologia , Displasia do Colo do Útero/virologia , Papillomaviridae/genética , Papillomaviridae/isolamento & purificação , Papillomaviridae/classificação , RNA Ribossômico 16S/genética , Pessoa de Meia-Idade , Genótipo , Bactérias/classificação , Bactérias/isolamento & purificação , Bactérias/genética , Adulto Jovem , Papillomavirus HumanoRESUMO
Alterations in the vaginal microbiota, including both species composition and functional pathways, have been associated with HPV infection and progression of dysplasia to cervical cancer. To further explore this, shotgun metagenomic sequencing was used to taxonomically and functionally characterize the vaginal microbiota of women with and without cervical dysplasia. Women with histologically verified dysplasia (n = 177; low grade dysplasia (LSIL) n = 81, high-grade dysplasia (HSIL) n = 94, cancer n = 2) were compared with healthy controls recruited from the cervical screening programme (n = 177). Women with dysplasia had a higher vaginal microbial diversity, and higher abundances of Gardnerella vaginalis, Aerococcus christensenii, Peptoniphilus lacrimalis and Fannyhessea vaginae, while healthy controls had higher relative abundance of Lactobacillus crispatus. Genes involved in e.g. nucleotide biosynthesis and peptidoglycan biosynthesis were more abundant in women with dysplasia. Healthy controls showed higher abundance of genes important for e.g. amino acid biosynthesis, (especially L-lysine) and sugar degradation. These findings suggest that the microbiota may have a role in creating a pro-oncogenic environment in women with dysplasia. Its role and potential interactions with other components in the microenvironment deserve further exploration.
Assuntos
Microbiota , Displasia do Colo do Útero , Vagina , Humanos , Feminino , Vagina/microbiologia , Adulto , Displasia do Colo do Útero/microbiologia , Displasia do Colo do Útero/patologia , Pessoa de Meia-Idade , Estudos de Casos e Controles , Metagenômica/métodos , Bactérias/genética , Bactérias/classificaçãoRESUMO
The presence of dysbiotic cervicovaginal microbiota has been observed to be linked to the persistent development of cervical carcinogenesis mediated by the human papillomavirus (HPV). Nevertheless, the characteristics of the cervical microbiome in individuals diagnosed with cervical cancer (CC) are still not well understood. Comprehensive analysis was conducted by re-analyzing the cervical 16S rRNA sequencing datasets of a total of 507 samples from six previously published studies. We observed significant alpha and beta diversity differences in between CC, cervical intraepithelial neoplasia (CIN) and normal controls (NC), but not between HPV and NC in the combined dataset. Meta-analysis revealed that opportunistic pernicious microbes Streptococcus, Fusobacterium, Pseudomonas and Anaerococcus were enriched in CC, while Lactobacillus was depleted compared to NC. Members of Gardnerella, Sneathia, Pseudomonas, and Fannyhessea have significantly increased relative abundance compared to other bacteria in the CIN group. Five newly identified bacterial genera were found to differentiate CC from NC, with an area under the curve (AUC) of 0.8947. Moreover, co-occurrence network analysis showed that the most commonly encountered Lactobacillus was strongly negatively correlated with Prevotella. Overall, our study identified a set of potential biomarkers for CC from samples across different geographic regions. Our meta-analysis provided significant insights into the characteristics of dysbiotic cervicovaginal microbiota undergoing CC, which may lead to the development of noninvasive CC diagnostic tools and therapeutic interventions.
Assuntos
Disbiose , Microbiota , RNA Ribossômico 16S , Neoplasias do Colo do Útero , Humanos , Feminino , Neoplasias do Colo do Útero/microbiologia , Neoplasias do Colo do Útero/virologia , RNA Ribossômico 16S/genética , Disbiose/microbiologia , Microbiota/genética , Bactérias/genética , Bactérias/classificação , Bactérias/isolamento & purificação , Carcinogênese , Displasia do Colo do Útero/microbiologia , Displasia do Colo do Útero/virologia , Vagina/microbiologia , Colo do Útero/microbiologia , Colo do Útero/patologiaRESUMO
High-risk Human Papillomavirus (HR-HPV) genotypes, specifically HPV16 and HPV18, pose a significant risk for the development of cervical intraepithelial neoplasia and cervical cancer. In the multifaceted cervical microenvironment, consisting of immune cells and diverse microbiota, Lactobacillus emerges as a pivotal factor, wielding significant influence in both stabilizing and disrupting the microbiome of the reproductive tract. To analyze the distinction between the cervical microbiota and Lactobacillus-dominant/non-dominant status of HR-HPV and non-infected healthy women, sixty-nine cervical swab samples were analyzed, included 44 with HR-HPV infection and healthy controls. All samples were recruited from Human Papillomavirus-based cervical cancer screening program and subjected to 16s rRNA sequencing analysis. Alpha and beta diversity analyses reveal no significant differences in the cervical microbiota of HR-HPV-infected women, including 16 and 18 HPV genotypes, and those with squamous intraepithelial lesion (SIL), compared to a control group. In this study we identified significantly lower abundance of Lactobacillus mucosae in women with HR-HPV infection compared to the control group. Furthermore, changes in bacterial diversity were noted in Lactobacillus non-dominant (LND) samples compared to Lactobacillus-dominant (LD) in both HR-HPV-infected and control groups. LND samples in HR-HPV-infected women exhibited a cervical dysbiotic state, characterized by Lactobacillus deficiency. In turn, the LD HR-HPV group showed an overrepresentation of Lactobacillus helveticus. In summary, our study highlighted the distinctive roles of L. mucosae and L. helveticus in HR-HPV infections, signaling a need for further research to demonstrate potential clinical implications of cervical microbiota dysbiosis.
Assuntos
Colo do Útero , Disbiose , Lactobacillus , Microbiota , Infecções por Papillomavirus , RNA Ribossômico 16S , Humanos , Feminino , Infecções por Papillomavirus/virologia , Infecções por Papillomavirus/microbiologia , Infecções por Papillomavirus/complicações , Disbiose/microbiologia , Disbiose/virologia , Adulto , Colo do Útero/microbiologia , Colo do Útero/virologia , Lactobacillus/isolamento & purificação , Lactobacillus/genética , RNA Ribossômico 16S/genética , Pessoa de Meia-Idade , Neoplasias do Colo do Útero/microbiologia , Neoplasias do Colo do Útero/virologia , Papillomavirus Humano 16/genética , Papillomavirus Humano 16/isolamento & purificação , Estudos de Casos e Controles , Papillomavirus Humano 18/genética , Papillomavirus Humano 18/isolamento & purificação , Displasia do Colo do Útero/microbiologia , Displasia do Colo do Útero/virologiaRESUMO
BACKGROUND: Latina women experience disproportionately higher rates of HPV infection, persistence, and progression to cervical dysplasia and cancer compared to other racial-ethnic groups. This systematic review explores the relationship between the cervicovaginal microbiome and human papillomavirus infection, cervical dysplasia, and cervical cancer in Latinas. METHODS: The review abides by the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. PubMed, EMBASE, and Scopus databases were searched from January 2000 through November 11, 2022. The review included observational studies reporting on the cervicovaginal microbiota in premenopausal Latina women with human papillomavirus infection, cervical dysplasia, and cervical cancer. RESULTS: Twenty-five articles were eligible for final inclusion (N = 131,183). Forty-two unique bacteria were reported in the cervicovaginal microbiome of Latinas. Seven bacteria: Lactobacillus crispatus, Lactobacillus iners, Chlamydia trachomatis, Prevotella spp., Prevotella amnii, Fusobacterium spp. and Sneathia spp. were enriched across multiple stages of cervical carcinogenesis in Latinas. Therefore, the total number of reported bacteria includes four bacteria associated with the healthy state, 16 bacteria enriched in human papillomavirus outcomes, 24 unique bacteria associated with abnormal cytology/dysplasia, and five bacteria associated with cervical cancer. Furthermore, three studies reported significantly higher alpha and beta diversity in Latinas with cervical dysplasia and cancer compared to controls. Lactobacillus depletion and an increased abundance of L. iners in Latinas compared to non-Latinas, regardless of human papillomavirus status or lesions, were observed. CONCLUSIONS: The identification of 42 unique bacteria and their enrichment in cervical carcinogenesis can guide future cervicovaginal microbiome research to better inform cervical cancer prevention strategies in Latinas.
Assuntos
Hispânico ou Latino , Microbiota , Infecções por Papillomavirus , Neoplasias do Colo do Útero , Vagina , Humanos , Feminino , Infecções por Papillomavirus/etnologia , Neoplasias do Colo do Útero/virologia , Neoplasias do Colo do Útero/microbiologia , Hispânico ou Latino/estatística & dados numéricos , Vagina/microbiologia , Displasia do Colo do Útero/microbiologia , Displasia do Colo do Útero/virologia , Displasia do Colo do Útero/etnologia , CarcinogêneseRESUMO
BACKGROUND: Convincing studies demonstrated that cervicovaginal microbiota disorder and toll-like receptor 9 (TLR9) high expression were related to cervical carcinogenesis. However, the effects of cervicovaginal microbiota integration TLR9 in cervical cancerization are unclear. Based on the biological basis that unmethylated cytosine-phosphate-guanine (CpG) motifs of bacteria could activate TLR9, we explored the effects of cervicovaginal microbiota disorder and CpG motif-TLR9 axis change in cervical carcinogenesis. METHODS: A total of 341 participants, including 124 normal cervical (NC), 90 low-grade cervical intraepithelial neoplasia (CIN1), 78 high-grade cervical intraepithelial neoplasia (CIN2/3) and 49 squamous cervical cancer (SCC), diagnosed by pathology were enrolled in the study. Here, metagenomic shotgun sequencing was used to reveal cervicovaginal microbiota characteristics, and TLR9 protein was detected by western blotting. RESULTS: Our results showed that the diversity of cervicovaginal microbiota gradually increased along with the poor development of cervical lesions, showing the abundance of Lactobacillus crispatus and Lactobacillus iners decreased, while the abundance of pathogenic bacteria gradually increased. The level of TLR9 expression was gradually increased with cervicovaginal microbiota diversity increasing, the abundance of Lactobacillus decreasing, and we found a positive correlation dependency relationship (r = 0.384, P = 0.002) between TLR9 and GTCGTT motif content. Stratified analysis based on HPV16 infection, we found that the characteristics of cervicovaginal microbiota and increased TLR9 expression were also closely related to HPV16 infection. CONCLUSIONS: Cervicovaginal microbiota dysbiosis might lead to the CpG motif increased, which was closely associated with TLR9 high expression, and ultimately might promote the progression of cervical lesions.
Assuntos
Carcinogênese , Colo do Útero , Microbiota , Receptor Toll-Like 9 , Displasia do Colo do Útero , Neoplasias do Colo do Útero , Vagina , Feminino , Humanos , Bactérias , Fosfatos , Receptor Toll-Like 9/genética , Receptor Toll-Like 9/metabolismo , Displasia do Colo do Útero/genética , Displasia do Colo do Útero/microbiologia , Displasia do Colo do Útero/patologia , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/microbiologia , Neoplasias do Colo do Útero/patologia , Vagina/microbiologia , Colo do Útero/microbiologiaRESUMO
Cervical cancer (CC) continues to be one of the most common cancers among females worldwide. It takes a few years or even decades for CC to arise in a minority of women with cervical precancers. An increasing corpus of studies today indicates that local microecology and carcinogenesis are intimately related. To investigate the changes in cericovaginal microecology with the development of cervical cancer, we performed 16S rDNA sequencing and metabolomic analysis in cericovaginal fluid from 10 LSIL patients, 10 HSIL patients, 10 CC patients and 10 healthy controls to reveal the differential flora and metabolites during cervical carcinogenesis. Carcinogenesis is associated with alterations in microbiome diversity, individual taxa, and functions with notable changes in Lactobacillus, Prevotella and Aquabacterium, as well as in cervicovaginal metabolites that correlate with cervicovaginal microbial patterns. Increased bacterial diversity and a decline in the relative abundance of Lactobacillus, the dominant species in the cericovaginal flora, are observed when cervical lesions advance. According to KEGG pathway enrichment analysis, lipids and organic acids change as cervical cancer progresses, and the phenylalanine, tyrosine, and tryptophan biosynthesis pathway is essential for the development of cervical cancer. Our results reveal that microbic and metabolomic profiling is capable of distinguishing CC from precancer and highlights potential biomarkers for the early detection of cervical dysplasia. These differential microorganisms and metabolites are expected to become a potential tool to assist in the diagnosis of cervical cancer.
Assuntos
Microbiota , Displasia do Colo do Útero , Neoplasias do Colo do Útero , Humanos , Feminino , Neoplasias do Colo do Útero/patologia , Displasia do Colo do Útero/microbiologia , Displasia do Colo do Útero/patologia , Metaboloma , CarcinogêneseRESUMO
Cervical intraepithelial neoplasia (CIN) is a precancerous condition inducing local lesions on the surface of the squamocolumnar junction of the cervix. Despite the role of vaginal microbiota having been under-discussed, the role of the cervical microbiome and the microbial migration across the reproductive tract involved in CIN was limitedly studied. We aimed to synchronously characterize the dysbiosis associated with CIN in both the cervix and vagina in a Chinese population. Profiling of cervical and vaginal microbiota from 60 CIN women and 60 healthy women was conducted. 16S rRNA sequencing was adopted. By comparing the microbial profiles between different parts of the reproductive tract, our results demonstrated an increased shift of microbial diversity in the cervix compared with that in the vagina for the CIN patients, specifically in CIN 1. Less dysbiosis was found between the CIN patients and controls, in either the vagina or cervix. The microbial community may be modulated by the onset of sexual activity, a known clinical risk factor for cervical neoplasia. Distinct patterns of perturbated bacteria were found in the vaginal and cervical microbiota, in which reduced Actinobacteria-related operational taxonomic units (OTUs) and increased Proteobacteria-related OTUs were found in the vagina and cervix, respectively. A good agreement between the direction of the top-significant perturbated OTUs was observed between the vaginal and cervical microbiome, suggesting a potential microbial migration in the reproductive tract. Enriched genera such as Sphingomonas and Stenotrophomonas were found in cervical microbiota-associated CIN. Multivariate analysis revealed Comamonas, Rhizobium, and Pseudomonas as independent genera contributing to CIN in the cervix. In summary, this study revealed the perturbation of microbiota in the presence of CIN and demonstrated a distinct pattern of characteristic bacteria community between the vagina and cervix involved in the development of CIN.
Assuntos
Microbiota , Displasia do Colo do Útero , Colo do Útero/microbiologia , Disbiose/microbiologia , Feminino , Humanos , Microbiota/genética , RNA Ribossômico 16S/genética , Vagina/microbiologia , Displasia do Colo do Útero/epidemiologia , Displasia do Colo do Útero/microbiologia , Displasia do Colo do Útero/patologiaRESUMO
This study aimed to explore the changes of the vaginal microbiota and enzymes in the women with high-risk human papillomavirus (HR-HPV) infection and cervical lesions. A total of 448 participants were carried out HPV genotyping, cytology tests, and microecology tests, and 28 participants were treated as sub-samples, in which vaginal samples were characterized by sequencing the bacterial 16S V4 ribosomal RNA (rRNA) gene region. The study found the prevalence of HR-HPV was higher in patients with BV (P = 0.036). The HR-HPV infection rate was 72.73% in G. vaginalis women, which was significantly higher than that of women with lactobacillus as the dominant microbiota (44.72%) (P = 0.04). The positive rate of sialidase (SNA) was higher in women with HR-HPV infection (P = 0.004) and women diagnosed with cervical intraepithelial neoplasia (CIN) (P = 0.041). In HPV (+) women, the α-diversity was significantly higher than that in HPV (-) women. The 16S rRNA gene-based amplicon sequencing results showed that Lactobacillus was the dominant bacteria in the normal vaginal microbiota. However, the proportion of Gardnerella and Prevotella were markedly increased in HPV (+) patients. Gardnerella and Prevotella are the most high-risk combination for the development of HPV (+) women. The SNA secreted by Gardnerella and Prevotella may play a significant role in HPV infection progress to cervical lesions.
Assuntos
Microbiota/genética , Infecções por Papillomavirus/microbiologia , Displasia do Colo do Útero/microbiologia , Vagina/microbiologia , Alphapapillomavirus/genética , Alphapapillomavirus/patogenicidade , Bactérias/classificação , Bactérias/genética , Feminino , Humanos , Lactobacillus/genética , Neuraminidase/genética , Infecções por Papillomavirus/genética , Infecções por Papillomavirus/patologia , Infecções por Papillomavirus/virologia , RNA Ribossômico 16S/genética , Vagina/virologia , Displasia do Colo do Útero/genética , Displasia do Colo do Útero/patologia , Displasia do Colo do Útero/virologiaRESUMO
BACKGROUND: Vaginal microbiota (VMB) composition is altered in women with cervical intra-epithelial neoplasia (CIN) compared to healthy controls and is associated with disease progression. However, the impact of CIN excision on the VMB and innate immunity is not known. This observational study aims to explore the impact of CIN excision on the VMB, antimicrobial peptides (AMP) and proinflammatory cytokines. METHODS: We sampled 103 non-pregnant, premenopausal women at the time of excisional treatment for CIN and at their 6-month follow-up visit. A further 39 untreated controls with normal cytology were also sampled. We used metataxonomics to group vaginal swab samples into community state types (CSTs) and ELISA to quantify cytokine and AMP levels in matched vaginal secretions. Analyses were performed to compare the bacterial composition and immune analyte levels before and after CIN excision and in healthy controls. RESULTS: Women with CIN had significantly higher rates of Lactobacillus species depletion pre-treatment compared to healthy controls (CST IV 21/103, 20% vs 1/39, 3%, p = 0.0081). Excision did not change the VMB composition, with CST IV remaining significantly more prevalent after excision compared to untreated, healthy controls (CST IV 19/103, 20% vs 1/39, 3%, p = 0.0142). Prevotella bivia and Sneathia amnii were significantly higher in samples before treatment compared to untreated controls, and Prevotella bivia remained significantly higher amongst the treated, with less Lactobacillus crispatus compared to untreated controls. IL-1ß and IL-8 remained significantly elevated pre- (p < 0.0001 and p = 0.0014, respectively) and post-treatment (p < 0.0001 and p = 0.0035, respectively) compared to untreated controls. Levels of human beta-defensin-1 and secretory leukocyte protease inhibitor were both significantly reduced following CIN excision (p < 0.0001); however, their levels remained lower than controls post-treatment. CONCLUSIONS: Women with CIN have an increased prevalence of Lactobacillus sp. depletion, high-diversity VMB composition, and higher levels of proinflammatory cytokines and AMPs compared to normal controls. Surgical excision of the disease reduces levels of vaginal AMPs but does not alter VMB composition or cytokine levels. These findings suggest that women with CIN have an inherent predisposition to a high-diversity proinflammatory environment that is not corrected by disease excision. The failure to re-establish a Lactobacillus-enriched CST may explain why women remain at high risk of pre-invasive and invasive disease recurrence.
Assuntos
Imunidade Inata , Microbiota , Displasia do Colo do Útero/imunologia , Displasia do Colo do Útero/microbiologia , Neoplasias do Colo do Útero/imunologia , Vagina/imunologia , Vagina/microbiologia , Peptídeos Antimicrobianos , Progressão da Doença , Feminino , Genótipo , Humanos , Lactobacillus/genética , Prevotella , RNA Ribossômico 16S , Neoplasias do Colo do Útero/microbiologiaRESUMO
Cervical cancer is an important health concern worldwide and is one of the leading causes of death in Mexican women. Previous studies have shown changes in the female genital tract microbe community related to human papillomavirus (HPV) infection and cervical cancer; yet, this link remains unexplored in many human populations. This study evaluated the vaginal bacterial community among Mexican women with precancerous squamous intraepithelial lesions (SIL). We sequenced the V3 region of the 16S rRNA gene in cervical samples from 228 Mexican women, including 121 participants with SIL, most of which were HPV positive, and 107 healthy women without HPV infection or SIL. The presence of SIL was associated with changes in composition (beta diversity) and with a higher species richness (Chao1). A comparison of HPV-positive women with and without SIL showed that microbiota changes occurred even in the absence of SIL. Multivariate association with linear models (MaAsLin) analysis yielded independent associations between HPV infection and an increase in the relative abundance of Brachybacterium conglomeratum and Brevibacterium aureum as well as a decrease in two Lactobacillus iners operational taxonomic units (OTUs). We also identified a positive independent association between HPV-16, the most common HPV subtype linked to SIL, and Brachybacterium conglomeratum. Our work indicates that HPV infection leading to SIL is primarily associated with shifts in vaginal microbiota composition, some of which may be specific to this human population. IMPORTANCE Human papillomavirus (HPV) plays a critical role in cervical carcinogenesis but is not sufficient for cervical cancer development, indicating the involvement of other factors. The vaginal microbiota is an important factor in controlling infections caused by HPV, and, depending on its composition, it can modulate the microenvironment in vaginal mucosa against viral infections. Ethnic and sociodemographic factors influence differences in vaginal microbiome composition, which underlies the dysbiotic patterns linked to HPV infection and cervical cancer across different populations of women. Here, we provide evidence for associations between vaginal microbiota patterns and HPV infection linked to ethnic and sociodemographic factors. To our knowledge, this is the first report of the species Brevibacterium aureum and Brachybacterium conglomeratum linked to HPV infection or squamous intraepithelial lesions (SIL).
Assuntos
Bactérias/classificação , Microbiota/genética , Displasia do Colo do Útero/patologia , Neoplasias do Colo do Útero/patologia , Vagina/microbiologia , Actinobacteria/genética , Actinobacteria/isolamento & purificação , Adulto , Alphapapillomavirus , Bactérias/genética , Bactérias/isolamento & purificação , Brevibacterium/genética , Brevibacterium/isolamento & purificação , Disbiose/microbiologia , Células Epiteliais/patologia , Feminino , Humanos , Lactobacillus/genética , Lactobacillus/isolamento & purificação , México , Infecções por Papillomavirus/patologia , RNA Ribossômico 16S/genética , Determinantes Sociais da Saúde , Fatores Sociodemográficos , Neoplasias do Colo do Útero/microbiologia , Neoplasias do Colo do Útero/virologia , Displasia do Colo do Útero/microbiologia , Displasia do Colo do Útero/virologiaRESUMO
Gardnerella vaginalis (GV) and Trichomonas vaginalis (TV) infections have been proposed as risk factors for persistence or progression of low-grade precancerous cervical lesions (CIN1/L-SIL). However, their role is still undefined. We aimed to assess if GV and TV infections affect the risk of persistence/progression of CIN1/L-SIL. A retrospective cohort study was performed to assess the risk of CIN1/L-SIL persistence or progression, persistence alone and progression alone in patients with GV and/or TV infections (GV + and/or TV+), only GV (GV+), only TV (TV+), or GV and TV coinfections compared to patients without these infections. Relative risk (RR) with 95 % confidence intervals (CI) was adopted (significant p-value>0.05). Two hundred and seventy patients were included. RR for CIN1/L-SIL persistence or progression was 1.63 in GV + and/or TV+ (p = 0.02), 1.99 in GV+ (p = 0.0008), 0.25 in TV+ (p = 0.32), 1.78 in coinfection (p = 0.26). RR for persistence was 1.55 in GV + and/or TV+ (p = 0.1), 2.179 in GV+ (p = 0.0013), 0.32 in TV+ (p = 0.41), 0.45 in coinfection (p = 0.55). RR for progression was 1.92 in GV + and/or TV+ (p = 0.22), 1.34 in GV+ (p = 0.68), 1.16 in TV+ (p = 0.91), 8.39 in coinfection (p = 0.0002). In conclusion, GV infection may be a risk factor for CIN1/L-SIL persistence. TV infection alone does not significantly affect the risk of persistence or progression of such lesions, while it may greatly increase the risk of progression when associated with GV infection.
Assuntos
Gardnerella vaginalis/patogenicidade , Infecções por Bactérias Gram-Positivas/microbiologia , Vaginite por Trichomonas/parasitologia , Trichomonas vaginalis/patogenicidade , Displasia do Colo do Útero , Neoplasias do Colo do Útero , Vaginose Bacteriana/microbiologia , Adulto , Progressão da Doença , Feminino , Infecções por Bactérias Gram-Positivas/diagnóstico , Humanos , Pessoa de Meia-Idade , Gradação de Tumores , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Vaginite por Trichomonas/diagnóstico , Neoplasias do Colo do Útero/microbiologia , Neoplasias do Colo do Útero/parasitologia , Neoplasias do Colo do Útero/patologia , Vaginose Bacteriana/diagnóstico , Displasia do Colo do Útero/microbiologia , Displasia do Colo do Útero/parasitologia , Displasia do Colo do Útero/patologiaRESUMO
BACKGROUND: The vaginal microbiota has been reported to be associated with HPV infection and cervical cancer. This study was performed to compare the vaginal microbiota at two timepoints in women performing self-sampling and had a persistent or transient HPV16 infection. The women were tested for 12 high-risk HPV (hrHPV) types but only women with single type (HPV16) were included to reduce confounding variables. METHODS: In total 96 women were included in this study. Of these, 26 were single positive for HPV16 in the baseline test and HPV negative in the follow-up test and 38 were single positive for HPV16 in both tests and diagnosed with CIN2+ in histology. In addition, 32 women that were negative for all 12 HPV tested were included. The samples of vaginal fluid were analyzed with the Ion 16S™ Metagenomics Kit and Ion 16S™ metagenomics module within the Ion Reporter™ software. RESULTS: K-means clustering resulted in two Lactobacillus-dominated groups, one with Lactobacillus sp. and the other specifically with Lactobacillus iners. The two remaining clusters were dominated by a mixed non-Lactobacillus microbiota. HPV negative women had lower prevalence (28%) of the non-Lactobacill dominant cluster in the baseline test, as compared to women with HPV16 infection (42%) (p value = 0.0173). Transition between clusters were more frequent in women with persistent HPV16 infection (34%) as compared in women who cleared the HPV16 infection (19%) (p value = 0.036). CONCLUSIONS: The vaginal microbiota showed a higher rate of transitioning between bacterial profiles in women with persistent HPV16 infection as compared to women with transient infection. This indicate an instability in the microenvironment in women with persistent HPV infection and development of CIN2+.
Assuntos
Microbiota , Infecções por Papillomavirus/etiologia , Infecções por Papillomavirus/microbiologia , Displasia do Colo do Útero/etiologia , Displasia do Colo do Útero/microbiologia , Vagina/virologia , Esfregaço Vaginal/métodos , Adulto , Detecção Precoce de Câncer , Feminino , Papillomavirus Humano 16/genética , Papillomavirus Humano 16/isolamento & purificação , Humanos , Pessoa de Meia-Idade , Infecções por Papillomavirus/diagnóstico , Manejo de Espécimes/métodos , Neoplasias do Colo do Útero/diagnóstico , Neoplasias do Colo do Útero/etiologia , Neoplasias do Colo do Útero/microbiologia , Displasia do Colo do Útero/diagnósticoRESUMO
INTRODUCTION: We characterized the cervical 16S rDNA microbiome of patients in Botswana with high-grade cervical dysplasia and locally advanced cervical cancer. METHODS: This prospective study included 31 patients: 21 with dysplasia and 10 with cancer. The Shannon diversity index was used to evaluate alpha (intra-sample) diversity, while the UniFrac (weighted and unweighted) and Bray-Curtis distances were employed to evaluate beta (inter-sample) diversity. The relative abundance of microbial taxa was compared among samples using linear discriminant analysis effect size. RESULTS: Alpha diversity was significantly higher in patients with cervical cancer than in patients with cervical dysplasia (P<0.05). Beta diversity also differed significantly (weighted UniFrac Bray-Curtis, P<0.01). Neither alpha diversity (P=0.8) nor beta diversity (P=0.19) varied by HIV status. The results of linear discriminant analysis effect size demonstrated that multiple taxa differed significantly between patients with cervical dysplasia vs cancer. Lachnospira bacteria (in the Clostridia class) were particularly enriched among cervical dysplasia patients, while Proteobacteria (members of the Firmicutes phyla and the Comamonadaceae family) were enriched in patients with cervical cancer. DISCUSSION: The results of our study suggest that differences exist in the diversity and composition of the cervical microbiota between patients with cervical dysplasia and patients with cervical cancer in Botswana. Additional studies are warranted to validate these findings and elucidate their clinical significance among women living in sub-Saharan Africa, as well as other regions of the world.
Assuntos
Carcinoma de Células Escamosas/microbiologia , Colo do Útero/microbiologia , Displasia do Colo do Útero/microbiologia , Neoplasias do Colo do Útero/microbiologia , Adulto , Botsuana , Carcinoma de Células Escamosas/patologia , Clostridiales , Comamonadaceae , Feminino , Gardnerella , Humanos , Lactobacillus , Microbiota , Pessoa de Meia-Idade , Gradação de Tumores , Estudos Prospectivos , Proteobactérias , Displasia do Colo do Útero/patologia , Neoplasias do Colo do Útero/patologiaRESUMO
OBJECTIVES: Although persistent human papillomavirus (HPV) infection is a major cause of cervical squamous intra-epithelial neoplasia, the relationship between vaginal microbiota and different grades of squamous intra-epithelial neoplasia is not well established. We explored the possible relationship between the vaginal microbiota and the progression of cervical squamous intra-epithelial neoplasia. METHODS: We evaluated 69 women who attended the Obstetrics and Gynecology Hospital of Fudan University. The vaginal bacterial composition of three groups of women was characterized by deep sequencing of bar-coded 16S rRNA gene fragments (V3-4) using Illumina MiSeq. Exclusion criteria were any previous hysterectomy, history of cervical or other lower genital cancer, and/or destructive therapy of the cervix. Women who had autoimmune disorders, who were HIV positive, who received antibiotics within 15 days of sampling, or who had engaged in sexual intercourse or douching within 48 hours prior to sampling were also excluded. P values for age and proportions of organisms were calculated using one-way ANOVA and p values for HPV status and community state types (CSTs) were calculated using a χ2 test. RESULTS: The vaginal bacterial composition of three groups of women, those without an intra-epithelial lesion or malignancy (n=31), those with a low-grade squamous intra-epithelial lesion (LSIL) (n=22), and those with a high-grade squamous intra-epithelial lesion (HSIL) (n=16) were analyzed. Lactobacillus was the most dominant genus overall. Prevotella and Streptococcus were increased in the HSIL group. Cervical disease progression was associated with the prevalence of high-risk HPV infection. Squamous intra-epithelial neoplasia converted the vaginal bacterial community structure from CSTs IV to II. Microbiota diversity was more pronounced in CST types II and IV (p<0.001), especially in type II. We found a significant enrichment in the Peptostreptococcaceae family, Pseudomonadales order, and other types of bacteria in the group of women without intra-epithelial lesions or malignancy compared with women with squamous intra-epithelial neoplasia. We found enrichment in Delftia in the LSIL and HSIL groups compared with the group without an intra-epithelial lesion or malignancy. CONCLUSIONS: Our results show that the vaginal microbiota is directly or indirectly related to the progression of squamous intra-epithelial neoplasia, and Delftia might be a microbiological hallmark of cervical pre-cancerous lesions.
Assuntos
Microbiota , Displasia do Colo do Útero/microbiologia , Vagina/microbiologia , Adulto , Estudos de Casos e Controles , China , Progressão da Doença , Feminino , Humanos , Pessoa de Meia-Idade , Infecções por Papillomavirus/diagnóstico , Displasia do Colo do Útero/patologiaRESUMO
The cervical microbiome is associated with cervical cancer risk, but how microbial diversity and functional profiles change in cervical cancer remains unclear. Herein, we investigated microbial-compositional and functional differences between a control group and a high-grade cervical intraepithelial neoplasia and cervical cancer (CIN2/3-CC) group. After retrospective collection of 92 cervical swab samples, we carried out 16S rRNA amplicon sequencing on 50 and 42 samples from the control and CIN2/3-CC groups, respectively. The EzBioCloud pipeline was applied to identify the genomic features associated with the groups using 16S rRNA data. A linear discriminant analysis effect size (LEfSe) was performed to assess the enrichment in the assigned taxonomic and functional profiles. We found a lower richness in the control group relative to the CIN2/3-CC group; however, the ß-diversity tended to be similar between the groups. The LEfSe analysis showed that a phylum Sacchaaribacteria_TM7, 11 genera, and 21 species were more abundant in the CIN2/3-CC group and that one uncharacterized Gardnerella species was more abundant only in the control group. Further characterization of the functional pathways using EzBioCloud showed that the 4 KEGG orthologs (Phosphotransferase system [PTS] sucrose-specific IIA, IIB, IIC components and PTS cellubiose-specific IIC component) were involved in the KEGG pathway of starch and sucrose metabolism. The two pathways of folate biosynthesis and oxidative phosphorylation were more abundant in the CIN2/3-CC group. Further confirmation of these results in larger samples can help to elucidate the potential association between the cervical microbiome and cervical cancer.
Assuntos
Colo do Útero/microbiologia , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/microbiologia , Adulto , Feminino , Genômica/métodos , Humanos , Microbiota/genética , Pessoa de Meia-Idade , RNA Ribossômico 16S , República da Coreia , Estudos Retrospectivos , Displasia do Colo do Útero/genética , Displasia do Colo do Útero/microbiologiaRESUMO
Emerging evidence suggests associations between the vaginal microbiota (VMB) composition, human papillomavirus (HPV) infection, and cervical intraepithelial neoplasia (CIN); however, causal inference remains uncertain. Here, we use bacterial DNA sequencing from serially collected vaginal samples from a cohort of 87 adolescent and young women aged 16-26 years with histologically confirmed, untreated CIN2 lesions to determine whether VMB composition affects rates of regression over 24 months. We show that women with a Lactobacillus-dominant microbiome at baseline are more likely to have regressive disease at 12 months. Lactobacillus spp. depletion and presence of specific anaerobic taxa including Megasphaera, Prevotella timonensis and Gardnerella vaginalis are associated with CIN2 persistence and slower regression. These findings suggest that VMB composition may be a future useful biomarker in predicting disease outcome and tailoring surveillance, whilst it may offer rational targets for the development of new prevention and treatment strategies.
Assuntos
Microbiota/imunologia , Infecções por Papillomavirus/microbiologia , Displasia do Colo do Útero/microbiologia , Neoplasias do Colo do Útero/microbiologia , Vagina/microbiologia , Adolescente , Adulto , Colo do Útero/patologia , Colo do Útero/virologia , Estudos de Coortes , DNA Bacteriano/isolamento & purificação , Feminino , Seguimentos , Gardnerella vaginalis/genética , Gardnerella vaginalis/imunologia , Gardnerella vaginalis/isolamento & purificação , Humanos , Lactobacillus/genética , Lactobacillus/imunologia , Lactobacillus/isolamento & purificação , Microbiota/genética , Estadiamento de Neoplasias , Papillomaviridae/imunologia , Papillomaviridae/isolamento & purificação , Infecções por Papillomavirus/imunologia , Infecções por Papillomavirus/patologia , Prevotella/genética , Prevotella/imunologia , Prevotella/isolamento & purificação , RNA Ribossômico 16S/genética , Fatores de Risco , Neoplasias do Colo do Útero/imunologia , Neoplasias do Colo do Útero/patologia , Adulto Jovem , Displasia do Colo do Útero/imunologia , Displasia do Colo do Útero/patologiaRESUMO
BACKGROUND: Human papillomavirus (HPV) infection is one of the most common sexually transmitted infections. However, only a small percentage of high-risk (HR) HPV infections progress to cervical precancer and cancer. In this study, we investigated the role of the cervicovaginal microbiome (CVM) in the natural history of HR-HPV. METHODS: This study was nested within the placebo arm of the Costa Rica HPV Vaccine Trial that included women aged 18-25 years of age. Cervical samples from two visits of women with an incident HR-HPV infection (n = 273 women) were used to evaluate the prospective role of the CVM on the natural history of HR-HPV. We focus specifically on infection clearance, persistence, and progression to cervical intraepithelial neoplasia grade 2 and 3 (CIN2+). The CVM was characterized by amplification and sequencing the bacterial 16S V4 rRNA gene region and the fungal ITS1 region using an Illumina MiSeq platform. OTU clustering was performed using QIIME2. Functional groups were imputed using PICRUSt and statistical analyses were performed using R. RESULTS: At Visit 1 (V1) abundance of Lactobacillus iners was associated with clearance of incident HR-HPV infections (Linear Discriminant Analysis (LDA)>4.0), whereas V1 Gardnerella was the dominant biomarker for HR-HPV progression (LDA>4.0). At visit 2 (V2), increased microbial Shannon diversity was significantly associated with progression to CIN2+ (p = 0.027). Multivariate mediation analysis revealed that the positive association of V1 Gardnerella with CIN2+ progression was due to the increased cervicovaginal diversity at V2 (p = 0.040). A full multivariate model of key components of the CVM showed significant protective effects via V1 genus Lactobacillus, OR = 0.41 (0.22-0.79), V1 fungal diversity, OR = 0.90 (0.82-1.00) and V1 functional Cell Motility pathway, OR = 0.75 (0.62-0.92), whereas V2 bacterial diversity, OR = 1.19 (1.03-1.38) was shown to be predictive of progression to CIN2+. CONCLUSION: This study demonstrates that features of the cervicovaginal microbiome are associated with HR-HPV progression in a prospective longitudinal cohort. The analyses indicated that the association of Gardnerella and progression to CIN2+ may actually be mediated by subsequent elevation of microbial diversity. Identified features of the microbiome associated with HR-HPV progression may be targets for therapeutic manipulation to prevent CIN2+. TRIAL REGISTRATION: ClinicalTrials.gov NCT00128661.
Assuntos
Colo do Útero , Gardnerella , Lactobacillus , Microbiota , Papillomaviridae/metabolismo , Infecções por Papillomavirus , Displasia do Colo do Útero , Neoplasias do Colo do Útero , Vagina , Adolescente , Adulto , Colo do Útero/metabolismo , Colo do Útero/microbiologia , Colo do Útero/patologia , Colo do Útero/virologia , Feminino , Gardnerella/classificação , Gardnerella/genética , Gardnerella/metabolismo , Humanos , Lactobacillus/classificação , Lactobacillus/genética , Lactobacillus/metabolismo , Estudos Longitudinais , Infecções por Papillomavirus/metabolismo , Infecções por Papillomavirus/microbiologia , Infecções por Papillomavirus/patologia , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/microbiologia , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/virologia , Vagina/metabolismo , Vagina/microbiologia , Vagina/patologia , Vagina/virologia , Displasia do Colo do Útero/metabolismo , Displasia do Colo do Útero/microbiologia , Displasia do Colo do Útero/patologia , Displasia do Colo do Útero/virologiaRESUMO
BACKGROUND: Persistent infection with high-risk human papillomavirus can lead to cervical dysplasia and cancer. Recent studies have suggested associations between the composition of the vaginal microbiota, infection with human papillomavirus (HPV) and progression to cervical dysplasia and cancer. OBJECTIVE: To assess how specific cervico-vaginal microbiota compositions are associated with HPV infection, cervical dysplasia and cancer, we conducted a systematic review and network meta-analysis (registered in PROSPERO: CRD42018112862). SEARCH STRATEGY: PubMed, Web of science, Embase and Cochrane database. SELECTION CRITERIA: All original studies describing at least two community state types of bacteria (CST), based on molecular techniques enabling identification of bacteria, and reporting the association with HPV infection, cervical dysplasia and/or cervical cancer. DATA COLLECTION AND ANALYSIS: For the meta-analysis, a network map was constructed to provide an overview of the network relationships and to assess how many studies provided direct evidence for the different vaginal microbiota compositions and HPV, cervical dysplasia or cancer. Thereafter, the consistency of the model was assessed, and forest plots were constructed to pool and summarise the available evidence, presenting odds ratios and 95% confidence intervals. MAIN RESULTS: Vaginal microbiota dominated by non-Lactobacilli species or Lactobacillus iners were associated with three to five times higher odds of any prevalent HPV and two to three times higher for high-risk HPV and dysplasia/cervical cancer compared with Lactobacillus crispatus. CONCLUSIONS: These findings suggest an association between certain bacterial community types of the vaginal microbiota and HPV infection and HPV-related disease. This may be useful for guiding treatment options or serve as biomarkers for HPV-related disease. TWEETABLE ABSTRACT: This network meta-analysis suggests an association between different vaginal bacterial community types and the risk of HPV.