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Article ; Online: The Vaginal Microbiota, Human Papillomavirus Infection, and Cervical Carcinogenesis: A Systematic Review in the Latina Population.

Mancilla, Vianney / Jimenez, Nicole R / Bishop, Naomi S / Flores, Melissa / Herbst-Kralovetz, Melissa M

Journal of epidemiology and global health

2024

Abstract: 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 ... ...

Abstract	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.
Language	English
Publishing date	2024-02-26
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2645324-1
ISSN	2210-6014 ; 2210-6014
ISSN (online)	2210-6014
ISSN	2210-6014
DOI	10.1007/s44197-024-00201-z
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Connecting microbiome and menopause for healthy ageing.

Łaniewski, Paweł / Herbst-Kralovetz, Melissa M

Nature microbiology

2022 Volume 7, Issue 3, Page(s) 354–358

MeSH term(s)	Female ; Healthy Aging ; Humans ; Menopause ; Microbiota
Language	English
Publishing date	2022-02-16
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	2058-5276
ISSN (online)	2058-5276
DOI	10.1038/s41564-022-01071-6
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Article ; Online: Immunometabolic and potential tumor-promoting changes in 3D cervical cell models infected with bacterial vaginosis-associated bacteria.

Maarsingh, Jason D / Łaniewski, Paweł / Herbst-Kralovetz, Melissa M

Communications biology

2022 Volume 5, Issue 1, Page(s) 725

Abstract: Specific bacteria of the human microbiome influence carcinogenesis at diverse anatomical sites. Bacterial vaginosis (BV) is the most common vaginal disorder in premenopausal women that is associated with gynecologic sequelae, including cervical cancer. ... ...

Abstract	Specific bacteria of the human microbiome influence carcinogenesis at diverse anatomical sites. Bacterial vaginosis (BV) is the most common vaginal disorder in premenopausal women that is associated with gynecologic sequelae, including cervical cancer. BV-associated microorganisms, such as Fusobacterium, Lancefieldella, Peptoniphilus, and Porphyromonas have been associated with gynecologic and other cancers, though the pro-oncogenic mechanisms employed by these bacteria are poorly understood. Here, we integrated a multi-omics approach with our three-dimensional (3-D) cervical epithelial cell culture model to investigate how understudied BV-associated bacteria linked to gynecologic neoplasia influence hallmarks of cancer in vitro. Lancefieldella parvulum and Peptoniphilus lacrimalis elicited robust proinflammatory responses in 3-D cervical cells. Fusobacterium nucleatum and Fusobacterium gonidiaformans modulated metabolic hallmarks of cancer corresponding to accumulation of 2-hydroxyglutarate, pro-inflammatory lipids, and signs of oxidative stress and genotoxic hydrogen sulfide. This study provides mechanistic insights into how gynecologic cancer-associated bacteria might facilitate a tumor-promoting microenvironment in the human cervix.
MeSH term(s)	Bacteria/classification ; Bacteria/pathogenicity ; Cervix Uteri/cytology ; Cervix Uteri/microbiology ; Female ; Humans ; Microbiota ; Tumor Microenvironment ; Uterine Cervical Neoplasms/etiology ; Uterine Cervical Neoplasms/microbiology ; Vaginosis, Bacterial/complications ; Vaginosis, Bacterial/immunology ; Vaginosis, Bacterial/metabolism ; Vaginosis, Bacterial/microbiology
Language	English
Publishing date	2022-07-22
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	2399-3642
ISSN (online)	2399-3642
DOI	10.1038/s42003-022-03681-6
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Article ; Online: Commensal Lactobacilli Metabolically Contribute to Cervical Epithelial Homeostasis in a Species-Specific Manner.

Jimenez, Nicole R / Maarsingh, Jason D / Łaniewski, Paweł / Herbst-Kralovetz, Melissa M

mSphere

2023 Volume 8, Issue 1, Page(s) e0045222

Abstract: In reproductive-age women, the vaginal microbiome is typically dominated by one or a ... ...

Abstract	In reproductive-age women, the vaginal microbiome is typically dominated by one or a few
MeSH term(s)	Female ; Humans ; Phylogeny ; Lactobacillus ; Homeostasis ; Lactic Acid/metabolism
Chemical Substances	Lactic Acid (33X04XA5AT)
Language	English
Publishing date	2023-01-11
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ISSN	2379-5042
ISSN (online)	2379-5042
DOI	10.1128/msphere.00452-22
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Article ; Online: Bacterial vaginosis and health-associated bacteria modulate the immunometabolic landscape in 3D model of human cervix.

Łaniewski, Paweł / Herbst-Kralovetz, Melissa M

NPJ biofilms and microbiomes

2021 Volume 7, Issue 1, Page(s) 88

Abstract: Bacterial vaginosis (BV) is an enigmatic polymicrobial condition characterized by a depletion of health-associated Lactobacillus and an overgrowth of anaerobes. Importantly, BV is linked to adverse gynecologic and obstetric outcomes: an increased risk of ...

Abstract	Bacterial vaginosis (BV) is an enigmatic polymicrobial condition characterized by a depletion of health-associated Lactobacillus and an overgrowth of anaerobes. Importantly, BV is linked to adverse gynecologic and obstetric outcomes: an increased risk of sexually transmitted infections, preterm birth, and cancer. We hypothesized that members of the cervicovaginal microbiota distinctly contribute to immunometabolic changes in the human cervix, leading to these sequelae. Our 3D epithelial cell model that recapitulates the human cervical epithelium was infected with clinical isolates of cervicovaginal bacteria, alone or as a polymicrobial community. We used Lactobacillus crispatus as a representative health-associated commensal and four common BV-associated species: Gardnerella vaginalis, Prevotella bivia, Atopobium vaginae, and Sneathia amnii. The immunometabolic profiles of these microenvironments were analyzed using multiplex immunoassays and untargeted global metabolomics. A. vaginae and S. amnii exhibited the highest proinflammatory potential through induction of cytokines, iNOS, and oxidative stress-associated compounds. G. vaginalis, P. bivia, and S. amnii distinctly altered physicochemical barrier-related proteins and metabolites (mucins, sialic acid, polyamines), whereas L. crispatus produced an antimicrobial compound, phenyllactic acid. Alterations to the immunometabolic landscape correlate with symptoms and hallmarks of BV and connected BV with adverse women's health outcomes. Overall, this study demonstrated that 3D cervical epithelial cell colonized with cervicovaginal microbiota faithfully reproduce the immunometabolic microenvironment previously observed in clinical studies and can successfully be used as a robust tool to evaluate host responses to commensal and pathogenic bacteria in the female reproductive tract.
MeSH term(s)	Bacteria ; Cervix Uteri ; Female ; Gardnerella vaginalis ; Humans ; Infant, Newborn ; Premature Birth ; Vaginosis, Bacterial
Language	English
Publishing date	2021-12-13
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2817021-0
ISSN	2055-5008 ; 2055-5008
ISSN (online)	2055-5008
ISSN	2055-5008
DOI	10.1038/s41522-021-00259-8
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Article ; Online: The microbiome and gynaecological cancer development, prevention and therapy.

Łaniewski, Paweł / Ilhan, Zehra Esra / Herbst-Kralovetz, Melissa M

Nature reviews. Urology

2020 Volume 17, Issue 4, Page(s) 232–250

Abstract: The female reproductive tract (FRT), similar to other mucosal sites, harbours a site-specific microbiome, which has an essential role in maintaining health and homeostasis. In the majority of women of reproductive age, the microbiota of the lower FRT ( ... ...

Abstract	The female reproductive tract (FRT), similar to other mucosal sites, harbours a site-specific microbiome, which has an essential role in maintaining health and homeostasis. In the majority of women of reproductive age, the microbiota of the lower FRT (vagina and cervix) microenvironment is dominated by Lactobacillus species, which benefit the host through symbiotic relationships. By contrast, the upper FRT (uterus, Fallopian tubes and ovaries) might be sterile in healthy individuals or contain a low-biomass microbiome with a diverse mixture of microorganisms. When dysbiosis occurs, altered immune and metabolic signalling can affect hallmarks of cancer, including chronic inflammation, epithelial barrier breach, changes in cellular proliferation and apoptosis, genome instability, angiogenesis and metabolic dysregulation. These pathophysiological changes might lead to gynaecological cancer. Emerging evidence shows that genital dysbiosis and/or specific bacteria might have an active role in the development and/or progression and metastasis of gynaecological malignancies, such as cervical, endometrial and ovarian cancers, through direct and indirect mechanisms, including modulation of oestrogen metabolism. Cancer therapies might also alter microbiota at sites throughout the body. Reciprocally, microbiota composition can influence the efficacy and toxic effects of cancer therapies, as well as quality of life following cancer treatment. Modulation of the microbiome via probiotics or microbiota transplant might prove useful in improving responsiveness to cancer treatment and quality of life. Elucidating these complex host-microbiome interactions, including the crosstalk between distal and local sites, will translate into interventions for prevention, therapeutic efficacy and toxic effects to enhance health outcomes for women with gynaecological cancers.
MeSH term(s)	Anti-Infective Agents/therapeutic use ; Bacteria, Anaerobic ; Carcinogenesis ; Cervix Uteri/microbiology ; Dysbiosis/metabolism ; Dysbiosis/microbiology ; Estrogens/metabolism ; Fallopian Tubes/microbiology ; Female ; Gastrointestinal Microbiome ; Genital Neoplasms, Female/metabolism ; Genital Neoplasms, Female/microbiology ; Genital Neoplasms, Female/prevention & control ; Genital Neoplasms, Female/therapy ; Genitalia, Female/metabolism ; Genitalia, Female/microbiology ; Humans ; Lactobacillus ; Microbiota/physiology ; Ovary/microbiology ; Probiotics/therapeutic use ; Uterus/microbiology ; Vagina/microbiology
Chemical Substances	Anti-Infective Agents ; Estrogens
Language	English
Publishing date	2020-02-18
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2493737-X
ISSN	1759-4820 ; 1759-4812
ISSN (online)	1759-4820
ISSN	1759-4812
DOI	10.1038/s41585-020-0286-z
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Article ; Online: Novel Vaccine Strategies and Factors to Consider in Addressing Health Disparities of HPV Infection and Cervical Cancer Development among Native American Women.

Morales, Crystal G / Jimenez, Nicole R / Herbst-Kralovetz, Melissa M / Lee, Naomi R

Medical sciences (Basel, Switzerland)

2022 Volume 10, Issue 3

Abstract: Cervical cancer is the 4th most common type of cancer in women world-wide. Many factors play a role in cervical cancer development/progression that include genetics, social behaviors, social determinants of health, and even the microbiome. The prevalence ...

Abstract	Cervical cancer is the 4th most common type of cancer in women world-wide. Many factors play a role in cervical cancer development/progression that include genetics, social behaviors, social determinants of health, and even the microbiome. The prevalence of HPV infections and cervical cancer is high and often understudied among Native American communities. While effective HPV vaccines exist, less than 60% of 13- to 17-year-olds in the general population are up to date on their HPV vaccination as of 2020. Vaccination rates are higher among Native American adolescents, approximately 85% for females and 60% for males in the same age group. Unfortunately, the burden of cervical cancer remains high in many Native American populations. In this paper, we will discuss HPV infection, vaccination and the cervicovaginal microbiome with a Native American perspective. We will also provide insight into new strategies for developing novel methods and therapeutics to prevent HPV infections and limit HPV persistence and progression to cervical cancer in all populations.
MeSH term(s)	AIDS Vaccines ; Adolescent ; BCG Vaccine ; Diphtheria-Tetanus-Pertussis Vaccine ; Female ; Humans ; Influenza Vaccines ; Male ; Measles-Mumps-Rubella Vaccine ; Papillomavirus Infections/epidemiology ; Papillomavirus Infections/prevention & control ; Papillomavirus Vaccines/therapeutic use ; Respiratory Syncytial Virus Vaccines ; SAIDS Vaccines ; Uterine Cervical Neoplasms/epidemiology ; Uterine Cervical Neoplasms/prevention & control ; American Indian or Alaska Native
Chemical Substances	AIDS Vaccines ; BCG Vaccine ; Diphtheria-Tetanus-Pertussis Vaccine ; Influenza Vaccines ; Measles-Mumps-Rubella Vaccine ; Papillomavirus Vaccines ; Respiratory Syncytial Virus Vaccines ; SAIDS Vaccines
Language	English
Publishing date	2022-09-13
Publishing country	Switzerland
Document type	Journal Article ; Review ; Research Support, N.I.H., Extramural
ZDB-ID	2754473-4
ISSN	2076-3271 ; 2076-3271
ISSN (online)	2076-3271
ISSN	2076-3271
DOI	10.3390/medsci10030052
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Article ; Online: Cervicovaginal metabolome and tumor characteristics for endometrial cancer detection and risk stratification.

Lorentzen, Georgia M / Laniewski, Pawel / Cui, Haiyan / Mahnert, Nichole D / Mourad, Jamal / Borst, Matthew P / Willmott, Lyndsay / Chase, Dana M / Roe, Denise J / Herbst-Kralovetz, Melissa M

Clinical cancer research : an official journal of the American Association for Cancer Research

2024

Abstract: Purpose: Endometrial cancer is highly prevalent and lacking non-invasive diagnostic techniques. Diagnosis depends on histological investigation of biopsy samples. Serum biomarkers for endometrial cancer have lacked sensitivity and specificity. The ... ...

Abstract	Purpose: Endometrial cancer is highly prevalent and lacking non-invasive diagnostic techniques. Diagnosis depends on histological investigation of biopsy samples. Serum biomarkers for endometrial cancer have lacked sensitivity and specificity. The objective of this study was to investigate the cervicovaginal environment to improve understanding of metabolic reprogramming related to endometrial cancer and identify potential biomarker candidates for non-invasive diagnostic and prognostic tests. Experimental design: Cervicovaginal lavages were collected from 192 participants with endometrial cancer (n=66) and non-malignant conditions (n=108), and global untargeted metabolomics was performed. Using the metabolite data (n=920), we completed a multivariate biomarker discovery analysis. Results: We analyzed grade 1/2 endometrioid carcinoma (n=53) and other endometrial cancer subtypes (n=13) to identify shared and unique metabolic signatures between the subtypes. When compared to non-malignant conditions, downregulation of proline (p<0.0001), tryptophan (p<0.0001), and glutamate (p<0.0001) was found among both endometrial cancer groups, relating to key hallmarks of cancer including immune suppression and redox balance. Upregulation (q<0.05) of sphingolipids, fatty acids, and glycerophospholipids was observed in endometrial cancer in a type-specific manner. Furthermore, cervicovaginal metabolites related to tumor characteristics, including tumor size and myometrial invasion. Conclusions: Our findings provide insights into understanding the endometrial cancer metabolic landscape and improvement into diagnosis. The metabolic dysregulation described in this paper linked specific metabolites and pathophysiological mechanisms including cellular proliferation, energy supply, and invasion of neighbouring tissues. Furthermore, cervicovaginal metabolite levels related to tumor characteristics, which are used for risk stratification. Overall, development of non-invasive diagnostic can improve both the acceptability and accessibility of diagnosis.
Language	English
Publishing date	2024-04-30
Publishing country	United States
Document type	Journal Article
ZDB-ID	1225457-5
ISSN	1557-3265 ; 1078-0432
ISSN (online)	1557-3265
ISSN	1078-0432
DOI	10.1158/1078-0432.CCR-23-2934
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Article: Overcoming barriers in the mucosal delivery of virus-like particle-based vaccines.

Herbst-Kralovetz, Melissa M

Therapeutic delivery

2014 Volume 5, Issue 7, Page(s) 741–744

MeSH term(s)	Humans ; Immunity, Mucosal ; Vaccines, Virus-Like Particle/administration & dosage
Chemical Substances	Vaccines, Virus-Like Particle
Language	English
Publishing date	2014-07
Publishing country	England
Document type	Editorial
ISSN	2041-5990
ISSN	2041-5990
DOI	10.4155/tde.14.52
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Article ; Online: Analysis of Host Responses to Neisseria gonorrhoeae Using a Human Three-Dimensional Endometrial Epithelial Cell Model.

Łaniewski, Paweł / Herbst-Kralovetz, Melissa M

Methods in molecular biology (Clifton, N.J.)

2019 Volume 1997, Page(s) 347–361

Abstract: Neisseria gonorrhoeae infections have been associated with complications including chronic endometritis and pelvic inflammatory disease. Robust in vitro models of the female reproductive tract are urgently needed to better understand the biological ... ...

Abstract	Neisseria gonorrhoeae infections have been associated with complications including chronic endometritis and pelvic inflammatory disease. Robust in vitro models of the female reproductive tract are urgently needed to better understand the biological mechanisms leading to these pathophysiological changes. Our human three-dimensional (3D) endometrial epithelial cell (EEC) model, which is generated using the HEC-1A cell line and rotating wall vessel (RWV) bioreactor technology, replicates several hallmarks of endometrial tissue in vivo. Studying the interactions of N. gonorrhoeae with the host using this newly characterized human 3D EEC model allows for the investigation of unique mechanisms of gonococcal pathogenesis in the upper female reproductive tract. In this chapter, we describe methodologies that can be used to investigate the interactions of N. gonorrhoeae with the human 3D endometrial epithelium. Protocols for generating the human 3D EEC model using the RWV technology and assessing the host response (including morphological/ultrastructural changes to the epithelial cells; cytokine/chemokine secretion or gene expression changes) following infection with N. gonorrhoeae are presented.
MeSH term(s)	Bioreactors ; Cell Culture Techniques/methods ; Cell Line ; Cytokines/immunology ; Cytokines/metabolism ; Endometrium/cytology ; Endometrium/immunology ; Endometrium/microbiology ; Epithelial Cells/immunology ; Epithelial Cells/metabolism ; Epithelial Cells/microbiology ; Female ; Gene Expression Profiling ; Gonorrhea/immunology ; Gonorrhea/microbiology ; Host-Pathogen Interactions/immunology ; Humans ; Immunity, Innate ; Neisseria gonorrhoeae/immunology
Chemical Substances	Cytokines
Language	English
Publishing date	2019-05-23
Publishing country	United States
Document type	Journal Article
ISSN	1940-6029
ISSN (online)	1940-6029
DOI	10.1007/978-1-4939-9496-0_20
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