Inhibitory Effect of Vaginal Lactobacillus Supernatants on Cervical Cancer Cells

Wang, Kedi; Xu, Dong-Jiang; Wang, Baoya; Yan, Donghui; Lv, Zhi; Su, Jianrong

doi:10.1007/s12602-017-9339-x

Cited by 77 publications

(48 citation statements)

References 35 publications

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“…The results of this study show that L. crispatus protects the cervical epithelial barrier in the presence of an inflammatory stimulus; however, the mechanisms regulating this interaction will need further investigation as these experiments are not able to identify if L. crispatus bacteria-free supernatants have the ability to block LPS binding to the TLR4 receptor or activate the host immune response to prevent the inflammatory insult. While there are previous studies that have shown a protective effect of L. crispatus in the face of Prevotella bivia and G. vaginalis (BV-associated bacteria) ( Atassi et al, 2006 ), E. coli ( Ghartey et al, 2014 ), HIV acquisition ( Gosmann et al, 2017 ), and cervical cancer (human papillomavirus oncogenes) ( Wang et al, 2017 ), none have investigated the direct protective effects of L. crispatus on either the cervical epithelial barrier or the biological mechanisms involved in this effect. In the presence of L. crispatus bacteria-free supernatants, the G. vaginalis -induced increase in miRNA expression was robustly reduced, suggesting that L. crispatus bacteria-free supernatants are able to mitigate the G. vaginalis -mediated disruption of the cervical epithelial barrier through a reduction in miRNA expression.…”

Section: Discussionmentioning

confidence: 99%

Common Cervicovaginal Microbial Supernatants Alter Cervical Epithelial Function: Mechanisms by Which Lactobacillus crispatus Contributes to Cervical Health

et al. 2018

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Cervicovaginal (CV) microbiota is associated with vaginal health and disease in non-pregnant women. Recent studies in pregnant women suggest that specific CV microbes are associated with preterm birth (PTB). While the associations between CV microbiota and adverse outcomes have been demonstrated, the mechanisms regulating the associations remain unclear. As the CV space contains an epithelial barrier, we postulate that CV microbiota can alter the epithelial barrier function. We investigated the biological, molecular, and epigenetic effects of Lactobacillus crispatus, Lactobacillus iners, and Gardnerella vaginalis on the cervical epithelial barrier function and determined whether L. crispatus mitigates the effects of lipopolysaccharide (LPS) and G. vaginalis on the cervical epithelial barrier as a possible mechanism by which CV microbiota mitigates disease risk. Ectocervical and endocervical cells treated with L. crispatus, L. iners, and G. vaginalis bacteria-free supernatants alone or combined were used to measure cell permeability, adherens junction proteins, inflammatory mediators, and miRNAs. Ectocervical and endocervical permeability increased after L. iners and G. vaginalis exposure. Soluble epithelial cadherin increased after exposure to L. iners but not G. vaginalis or L. crispatus. A Luminex cytokine/chemokine panel revealed increased proinflammatory mediators in all three bacteria-free supernatants with L. iners and G. vaginalis having more diverse inflammatory effects. L. iners and G. vaginalis altered the expression of cervical-, microbial-, and inflammatory-associated miRNAs. L. crispatus mitigated the LPS or G. vaginalis-induced disruption of the cervical epithelial barrier and reversed the G. vaginalis-mediated increase in miRNA expression. G. vaginalis colonization of the CV space of a pregnant C57/B6 mouse resulted in 100% PTB. These findings demonstrate that L. iners and G. vaginalis alter the cervical epithelial barrier by regulating adherens junction proteins, cervical immune responses, and miRNA expressions. These results provide evidence that L. crispatus confers protection to the cervical epithelial barrier by mitigating LPS- or G. vaginalis-induced miRNAs associated with cervical remodeling, inflammation, and PTB. This study provides further evidence that the CV microbiota plays a role in cervical function by altering the cervical epithelial barrier and initiating PTB. Thus, targeting the CV microbiota and/or its effects on the cervical epithelium may be a potential therapeutic strategy to prevent PTB.

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Section: Discussionmentioning

confidence: 99%

Common Cervicovaginal Microbial Supernatants Alter Cervical Epithelial Function: Mechanisms by Which Lactobacillus crispatus Contributes to Cervical Health

et al. 2018

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“…Furthermore, in-vitro studies suggested that vaginal microbiota may increase the apoptosis of cancer cells or may provoke the anti-inflammatory cells like dendritic, Treg and cytokines. [66][67][68][69] The lack of efficient treatment to counter antibiotic resistance to bacterial infections and the intravaginal application of lactobacilli and lactoferrin may be the narrative and capable therapeutic approach to reinstate the mucosal immune homeostasis. 25…”

Section: Probiotic Therapymentioning

confidence: 99%

<p>Vaginal Microbiota and HPV Infection: Novel Mechanistic Insights and Therapeutic Strategies</p>

Li¹,

Yu²,

Yan³

et al. 2020

IDR

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Cervical cancer is a global public health concern. The complex interaction of genetic and environmental factors is critical for the progress of cervical cancer. Growing evidence suggests that microbes, human papillomavirus (HPV), and the immune system interact closely with each other to govern homeostasis of the vaginal environment and the health of the lower genital tract of females. Certain vaginal microbial strains may play either a protective or a pathogenic role in carcinogenesis of the cervix after HPV persistent infection. Probiotics can therefore present a putative therapeutic approach for cervical cancer. However, work in this field remains limited. Recent technological developments have allowed us to identify microbes and their products using culture-independent molecular detection techniques. In this review, we discuss the composition of the vaginal bacterial community, its commensal flora and the protective impact this has on the health of the female genital tract. This review will also describe critical immune factors in lower genital tract health and summarize the role of the vaginal microbiota in cervical carcinogenesis. Knowledge in this field has provided researchers with the clues and tools to propose the use of probiotics as a potential line of treatment for cervical cancer and has provided valuable insights into host-pathogen interaction dynamics within the female genital tract.

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“…Lactobacillus spp. is able to outcompete growth of Gardnerella and Prevotella species [48] and has been shown to inhibit growth of cervical cancer cell lines [49]. Further in vitro studies have demonstrated that L. crispatus in particular is protective against in ammationmediated increases in ectocervical cell permeability, as the endocervical production of IL-6 and IL-8 signi cantly decreased after exposure to L. crispatus bacteria-free supernatants [50].…”

Section: Discussionmentioning

confidence: 99%

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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Inhibitory Effect of Vaginal Lactobacillus Supernatants on Cervical Cancer Cells

Cited by 77 publications

References 35 publications

Common Cervicovaginal Microbial Supernatants Alter Cervical Epithelial Function: Mechanisms by Which Lactobacillus crispatus Contributes to Cervical Health

Common Cervicovaginal Microbial Supernatants Alter Cervical Epithelial Function: Mechanisms by Which Lactobacillus crispatus Contributes to Cervical Health

<p>Vaginal Microbiota and HPV Infection: Novel Mechanistic Insights and Therapeutic Strategies</p>

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

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