The vaginal microbiota associates with the regression of untreated cervical intraepithelial neoplasia 2 lesions

Mitra, Anita; MacIntyre, David A.; Ntritsos, George; Smith, Ann; Tsilidis, Konstantinos K.; Marchesi, Julian R.; Bennett, Phillip R.; Moscicki, Anna‐Barbara; Kyrgiou, Maria

doi:10.1038/s41467-020-15856-y

Cited by 151 publications

(170 citation statements)

References 82 publications

(92 reference statements)

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“…Therefore, further studies investigating the involvement of the metabolites from Methyloversatilis in the growth and the metabolism of cancer cells may explain its association with prognosis and would be a stepping-stone for the understanding of HNCs. In accordance with previous studies of vaginal microbiota, Lactobacillus, asscociated with the early regressions of cervical intraepithelial neoplasia [39], was found associated with good prognosis of HNCs in our study. Together with the essential role of Lactobacillus in the balance of microbiota, the ndings suggested that Lactobacillus depletion and microbial dysbiosis by antibiotic abuse in clinic might associate with poor prognosis.…”

Section: Discussionsupporting

confidence: 93%

Dysbiotic microbiota to complement TNM staging or HPV status for prognostic indication of head and neck cancer

Wang

et al. 2020

Preprint

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Background: Microbiota has been found associated with the incidence of head and neck cancers (HNCs), however, the association of microbiota with the prognosis of HNCs remains unknown. In the present study, the relationship between tumoral microbiata and survival was examined. The prognosis predictive value of tumoral microbiota to complement classic TNM staging and Human Papillomavirus (HPV) status was also investigated.Results: We conducted a retrospective study including 158 primary tumors using 16S rRNA sequencing. The tumoral microbiota in the HNC patients with poor prognosis were significantly different from that of the patients with good prognosis. A greater abundance of Schlegelella or Methyloversatilis was characterized in HNC patients with poor prognosis and a greater abundance of Lactobacillus or Bacillus was characterized in HNC patients with good prognosis. Strikingly, the microbial dysbiosis index (MDI), the ratio of above poor and good prognosis associated genera, was strongly associated with overall survival [hazard ratio (HR) 3.24; 95% confidence interval (CI), 1.88 to 5.59; P < 0.001] and disease free survival (HR 2.11; 95% CI, 1.34 to 3.34; P = 0.001), independently of age, TNM staging, differentiation and HPV status. Intriguingly, the combination of the MDI and HPV status significantly improved the prognostic performance of HPV status (AUC of 0.719 and 0.581 respectively, P = 0.024). Moreover, the MDI showed higher risk for overall survival in the late stage patients (HR 3.35; 95% CI, 1.73 to 6.49; P < 0.001) compared with the early stage patients (HR 2.41; 95% CI, 1.00 to 5.84; P = 0.051). Conclusion: Together, the MDI could serve as an applicable indicator of the prognosis of HNCs, and complements the predictive values of TNM staging and HPV status. Moreover, the findings of the higher risk of the MDI in the late stage patients supply directions for future studies that microbial modulation might be valuable in survival improvement of HNCs, especially for the late stage patients.

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Section: Discussionsupporting

confidence: 93%

Dysbiotic microbiota to complement TNM staging or HPV status for prognostic indication of head and neck cancer

Wang

et al. 2020

Preprint

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“…Our ndings suggest that women planned for CIN treatment had signi cantly higher levels of a high diversity, Lactobacillus spp.-depleted microbiome pre-treatment compared to a healthy, untreated control group with normal cytology. This nding is in line with previously published cross-sectional data describing associations between the VMB and the presence of CIN [4,8,14,15] with Atopobium, Sneathia, and Prevotella species being consistently associated with higher-grade disease across studies [4,6,8,14,41], the latter two of which were signi cantly overrepresented in our pre-treatment cohort compared to controls. Our analysis further revealed that excision of CIN does not impact on the VMB composition six months after treatment, which remained more diverse with a decreased relative abundance of Lactobacillus crispatus compared to normal controls.…”

Section: Discussionsupporting

confidence: 93%

“…depletion is associated with higher rates of persistent/progressive CIN2 at 12 and 24-month follow-up, whilst Lactobacillus spp. dominance associated with increased rates of regression [6].…”

Section: Introductionmentioning

confidence: 97%

“…Only a fraction of women develops persistence, and ultimately progressive CIN. A number of host, viral genetic and epigenetic factors have been implicated and are currently under investigation, although growing evidence has led to the hypothesis that the vaginal microbiota (VMB) plays a role in the outcome of this virally-induced disease process [3][4][5][6][7][8][9].…”

Section: Introductionmentioning

confidence: 99%

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The Vaginal Microbiota and Innate Immunity After Local Excisional Treatment for Cervical Intraepithelial Neoplasia

Mitra

MacIntyre

Paraskevaidi

et al. 2020

Preprint

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Background: Vaginal microbiota (VMB) are altered in women with cervical intra-epithelial neoplasia (CIN) and associate with disease progression. However, the impact of CIN excision on the VMB and innate immunity is not known. This interventional study aims to explore the impact of CIN excision on the VMB, antimicrobial peptides (AMP) and proinflammatory cytokines. 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 AMPs levels in matched vaginal secretions. Analyses were performed to compare 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-1 and IL-8 remained significantly elevated pre- (p<0.0001 and p=0.0014 respectively) and post-treatment compared to untreated controls (p<0.0001 and p=0.0035 respectively). 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 increased prevalence of Lactobacillus spp. depleted, high-diversity VMB, proinflammatory cytokines and AMPs than 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.

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“…However, much less is known about the role of lectins in shaping microbial niches in the lower female reproductive tract, which play a key role in shaping health and disease throughout a woman's life span (MacIntyre et al, 2017). Colonisation in the vagina by Lactobacillus species has for long been considered a hallmark of health (Ma et al, 2012;van de Wijgert et al, 2014), whereas Lactobacillus deplete, high diversity vaginal microbiomes enriched in potential pathogens are characteristic of bacterial vaginosis and are associated with increased risk of sexually transmitted infections (STIs) (Borgdorff et al, 2014;Reimers et al, 2016), progression of cervical cancer (Mitra et al, 2020) and adverse pregnancy outcomes such as miscarriage and preterm birth (Al-Memar et al, 2019;Brown et al, 2019;Fettweis et al, 2019;Kindinger et al, 2016). A key component of the vaginal mucosa are highly glycosylated mucins that are derived from the mucin-secreting glands of the cervix (Gipson, 2001).…”

Section: Introductionmentioning

confidence: 99%

Proteome-wide prediction of bacterial carbohydrate-binding proteins as a tool for understanding commensal and pathogen colonisation of the vaginal microbiome

Bonnardel

Haslam

Dell

et al. 2020

Preprint

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Lectins, such as adhesins and toxins, are carbohydrate-binding proteins that recognise glycans of cells and their secretions. While mediation of microbe-microbe and microbe-host interactions by lectins has long been recognised in the lung and gut, little is known about those in the vagina, where such interactions are implicated in health and various disease states. These include sexually transmitted infections, cervical cancer and poor pregnancy outcomes such as preterm birth. In this study, the curated UniLectin3D database was used to establish a lectin classification based primarily on taxonomy and protein 3D structure. The resulting 109 lectin classes were characterised by specific Hidden Markov Model (HMM) profiles. Screening of microbial genomes in the UniProt and NCBI NR sequence databases resulted in identification of >100 000 predicted bacterial lectins available at unilectin.eu/bacteria. Screening of the complete genomes of 90 isolates from 21 vaginal bacterial species showed that the predicted lectomes (ensemble of predicted lectins) of Lactobacilli associated with vaginal health are substantially less diverse than those of pathogens and pathobionts. Both the number of predicted bacterial lectins, and their specificities for carbohydrates correlated with pathogenicity. This study provides new insights into potential mechanisms of commensal and pathogen colonisation of the reproductive tract that underpin health and disease states.

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The vaginal microbiota associates with the regression of untreated cervical intraepithelial neoplasia 2 lesions

Cited by 151 publications

References 82 publications

Dysbiotic microbiota to complement TNM staging or HPV status for prognostic indication of head and neck cancer

Dysbiotic microbiota to complement TNM staging or HPV status for prognostic indication of head and neck cancer

The Vaginal Microbiota and Innate Immunity After Local Excisional Treatment for Cervical Intraepithelial Neoplasia

Proteome-wide prediction of bacterial carbohydrate-binding proteins as a tool for understanding commensal and pathogen colonisation of the vaginal microbiome

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