ORCID Profile
0000-0002-7165-0735
Current Organisations
Imperial College Healthcare NHS Trust
,
Imperial College London Faculty of Medicine
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Publisher: Research Square Platform LLC
Date: 10-09-2020
DOI: 10.21203/RS.3.RS-73123/V1
Abstract: 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 s led 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 s led. We used metataxonomics to group vaginal swab s les 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 s les 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 .0001 and p=0.0014 respectively) and post-treatment compared to untreated controls (p .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 .0001), however their levels remained lower than controls post-treatment. Conclusions: Women with CIN have increased prevalence of Lactobacillus spp. depleted, high- ersity 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- ersity 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.
Publisher: Research Square Platform LLC
Date: 24-10-2022
DOI: 10.21203/RS.3.RS-2102199/V1
Abstract: Endometrial cancer is a multifactorial disease with inflammatory, metabolic and potentially microbial cues involved in disease pathogenesis. Here we s led different regions of the reproductive tract (vagina, cervix, endometrium, fallopian tubes and ovaries) of 61 patients and showed that the upper genital tract of a subset of women with and without endometrial cancer harbour microbiota quantitatively and compositionally distinguishable from background contaminants. A microbial continuum, defined by detection of common bacterial species along the genital tract, was noted in most women without cancer while the continuum was less cohesive in endometrial cancer patients. Vaginal microbiota were poorly correlated with rectal microbiota in the studied cohorts. Endometrial cancer was associated with reduced cervicovaginal and rectal bacterial load together with depletion of Lactobacillus species relative abundance, including L. crispatus , increased bacterial ersity and enrichment of Porphyromonas , Prevotella, Peptoniphilus and Anaerococcus in the lower genital tract and endometrium. Treatment of benign and malignant endometrial organoids with L. crispatus conditioned media had minimal impact on cytokine and chemokine profiles. Our findings provide evidence that the upper female reproductive tract of some women contains detectable levels of bacteria, the composition of which is associated with endometrial cancer. Whether this is a cause or consequence of cancer pathophysiology remains to be elucidated.
Publisher: Springer Science and Business Media LLC
Date: 24-04-2020
DOI: 10.1038/S41467-020-15856-Y
Abstract: 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 s les 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.
Publisher: Public Library of Science (PLoS)
Date: 03-11-2016
Publisher: Proceedings of the National Academy of Sciences
Date: 16-03-2020
Abstract: Clearance of surgical margins in cervical cancer prevents the need for adjuvant chemoradiation and allows fertility preservation. In this study, we determined the capacity of the rapid evaporative ionization mass spectrometry (REIMS), also known as intelligent knife (iKnife), to discriminate between healthy, preinvasive, and invasive cervical tissue. Cervical tissue s les were collected from women with healthy, human papilloma virus (HPV) ± cervical intraepithelial neoplasia (CIN), or cervical cancer. A handheld diathermy device generated surgical aerosol, which was transferred into a mass spectrometer for subsequent chemical analysis. Combination of principal component and linear discriminant analysis and least absolute shrinkage and selection operator was employed to study the spectral differences between groups. Significance of discriminatory m/z features was tested using univariate statistics and tandem MS performed to elucidate the structure of the significant peaks allowing separation of the two classes. We analyzed 87 s les (normal = 16, HPV ± CIN = 50, cancer = 21 patients). The iKnife discriminated with 100% accuracy normal (100%) vs. HPV ± CIN (100%) vs. cancer (100%) when compared to histology as the gold standard. When comparing normal vs. cancer s les, the accuracy was 100% with a sensitivity of 100% (95% CI 83.9 to 100) and specificity 100% (79.4 to 100). Univariate analysis revealed significant MS peaks in the cancer-to-normal separation belonging to various classes of complex lipids. The iKnife discriminates healthy from premalignant and invasive cervical lesions with high accuracy and can improve oncological outcomes and fertility preservation of women treated surgically for cervical cancer. Larger in vivo research cohorts are required to validate these findings.
Publisher: Springer Science and Business Media LLC
Date: 28-05-2021
DOI: 10.1186/S40168-021-01011-2
Abstract: Obesity and vaginal microbiome (VMB) dysbiosis are each risk factors for adverse reproductive and oncological health outcomes in women. Here, we investigated the relationship between obesity, vaginal bacterial composition, local inflammation and bariatric surgery. Vaginal bacterial composition assessed by high-throughput sequencing of bacterial 16S rRNA genes and local cytokine levels measured using a multiplexed Magnetic Luminex Screening Assay were compared between 67 obese and 42 non-obese women. We further assessed temporal changes in the microbiota and cytokines in a subset of 27 women who underwent bariatric surgery. The bacterial component of the vaginal microbiota in obese women was characterised by a lower prevalence of a Lactobacillus -dominant VMB and higher prevalence of a high ersity ( Lactobacillus spp., and Gardnerella - spp. depleted) VMB, compared with non-obese subjects ( p .001). Obese women had higher relative abundance of Dialister species ( p .001), Anaerococcus vaginalis ( p =0.021), and Prevotella timonensis ( p =0.020) and decreased relative abundance of Lactobacillus crispatus ( p =0.014). Local vaginal IL-1β, IL-4, IL-6, IL-8, IFNγ, MIP-1α and TNFα levels were all higher among obese women, however, only IL-1β and IL-8 correlated with VMB species ersity. In a subset of obese women undergoing bariatric surgery, there were no significant overall differences in VMB following surgery however, 75% of these women remained obese at 6 months. Prior to surgery, there was no relationship between body mass index (BMI) and VMB structure however, post-surgery women with a Lactobacillus -dominant VMB had a significantly lower BMI than those with a high ersity VMB. Obese women have a significantly different vaginal microbiota composition with increased levels of local inflammation compared to non-obese women. Bariatric surgery does not change the VMB however, those with the greatest weight loss 6-month post-surgery are most likely to have a Lactobacillus -dominant VMB.
Publisher: Springer Science and Business Media LLC
Date: 04-11-2021
DOI: 10.1186/S13073-021-00977-W
Abstract: 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. We s led 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 s led. We used metataxonomics to group vaginal swab s les 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. 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 s les before treatment compared to untreated controls, and Prevotella bivia remained significantly higher amongst the treated, with less Lactobacillus crispatus compared to untreated controls. IL-1β 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. Women with CIN have an increased prevalence of Lactobacillus sp. depletion, high- ersity 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- ersity 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.
Publisher: Research Square Platform LLC
Date: 07-12-2020
DOI: 10.21203/RS.3.RS-31292/V3
Abstract: Background: Obesity and vaginal microbiome (VMB) dysbiosis are each risk factors for adverse reproductive and oncological health outcomes in women. Here we investigated the relationship between obesity, vaginal bacterial composition, local inflammation and bariatric surgery. Methods: Vaginal bacterial composition assessed by high-throughput sequencing of bacterial 16S rRNA genes and local cytokine levels measured using a multiplexed Magnetic Luminex Screening Assay were compared between 67 obese and 42 non-obese women. We further assessed temporal changes in the microbiota and cytokines in a subset of 27 women who underwent bariatric surgery. Results: The bacterial component of the vaginal microbiota in obese women was characterised by a lower prevalence of a Lactobacillus -dominant VMB and higher prevalence of a high ersity ( Lactobacillus spp., and Gardnerella - spp. depleted) VMB, compared with non-obese subjects (p .001). Obese women had higher relative abundance of Dialister species (p .001), Anaerococcus vaginalis (p=0.021) and Prevotella timonensis (p=0.020) and decreased relative abundance of Lactobacillus crispatus (p=0.014). Local vaginal IL-1β, IL-4, IL-6, IL-8, IFNγ, MIP-1α, and TNFα levels were all higher among obese women, however only IL-1β and IL-8 correlated with VMB species ersity. In a subset of obese women undergoing bariatric surgery, there were no significant overall differences in VMB following surgery, however 75% of these women remained obese at six months. Prior to surgery there was no relationship between body mass index (BMI) and VMB structure, however post-surgery women with a Lactobacillus -dominant VMB had a significantly lower BMI than those with a high ersity VMB. Conclusions: Obese women have a significantly different vaginal microbiota composition with increased levels of local inflammation compared to non-obese women. Bariatric surgery does not change the VMB, however, those with the greatest weight loss six-months post-surgery are most likely to have a Lactobacillus -dominant VMB.
Publisher: Elsevier BV
Date: 10-2020
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Maria Kyrgiou.