Beyond the reproductive tract: gut microbiome and its influence on gynecological health.

PURPOSE OF REVIEW: The analysis of microbiome in association with female health is today a "hot topic" with the main focus on microbes in the female reproductive tract. Nevertheless, recent studies are providing novel information of the possible influence of the gut microbiome on gynecological health outcomes, especially as we start to understand that the gut microbiome is an extended endocrine organ influencing female hormonal levels. This review summarizes the current knowledge of the gut microbes in association with gynecological health. RECENT FINDINGS: The gut microbiome has been associated with endometriosis, polycystic ovary syndrome, gynecological cancers, and infertility, although there is a lack of consistency and consensus among studies due to different study designs and protocols used, and the studies in general are underpowered. SUMMARY: The interconnection between the gut microbiome and reproductive health is complex and further research is warranted. The current knowledge in the field emphasizes the link between the microbiome and gynecological health outcomes, with high potential for novel diagnostic and treatment tools via modulation of the microenvironment.

The Microbiome and Gynecologic Cancer: Current Evidence and Future Opportunities.

PURPOSE OF REVIEW: We review the emerging evidence regarding the relationship between the microbiota of the gastrointestinal and female reproductive tracts and gynecologic cancer. RECENT FINDINGS: The microbiome has essential roles in maintaining health. In recent years, the microbiota of the gastrointestinal and female reproductive tracts have been linked to many diseases, including gynecologic cancer. Alterations to the bacterial populations in a microbiota, or dysbiosis, have been shown to favor a pro-carcinogenic state through altered immune responses, dysregulated hormone metabolism, and modulation of the cell cycle. Pre-clinical and clinical studies have emerged, demonstrating that specific bacteria or microbial communities may be associated with increased risk for uterine, ovarian, and cervical cancers. Notably, numerous studies have linked a non-Lactobacillus-dominant vaginal microbiota, composed of anaerobic bacteria, with HPV infection, persistence, and development of invasive cervical cancer. Similarly, next-generation high-throughput sequencing techniques have enabled the characterization of unique microbiotas in patients with malignant and benign gynecologic conditions, shedding light on new associations between bacterial species and gynecologic cancers. Harnessing the power of the microbiome for early diagnosis, therapeutic intervention and modulation creates tremendous potential to optimize gynecologic cancer outcomes in the future.

Diet and gut microbiome interactions in gynecologic cancer.

Over the last decade, there has been a dramatic surge in research exploring the human gut microbiome and its role in health and disease. It is now widely accepted that commensal microorganisms coexist within the human gastrointestinal tract and other organs, including those of the reproductive tract. These microorganisms, which are collectively known as the "microbiome", contribute to maintaining host physiology and to the development of pathology. Next generation sequencing and multi-'omics' technology has enriched our understanding of the complex and interdependent relationship that exists between the host and microbiome. Global changes in the microbiome are known to be influenced by dietary, genetic, lifestyle, and environmental factors. Accumulating data have shown that alterations in the gut microbiome contribute to the development, prognosis and treatment of many disease states including cancer primarily through interactions with the immune system. However, there are large gaps in knowledge regarding the association between the gut microbiome and gynecologic cancers, and research characterizing the reproductive tract microbiome is insufficient. Herein, we explore the mechanisms by which alterations in the gut and reproductive tract microbiome contribute to carcinogenesis focusing on obesity, hyperestrogenism, inflammation and altered tumor metabolism. The impact of the gut microbiome on response to anti-cancer therapy is highlighted with an emphasis on immune checkpoint inhibitor efficacy in gynecologic cancers. We discuss dietary interventions that are likely to modulate the metabolic and immunologic milieu as well as tumor microenvironment through the gut microbiome including intermittent fasting/ketogenic diet, high fiber diet, use of probiotics and the metabolic management of obesity. We conclude that enhanced understanding of the microbiome in gynecologic cancers coupled with thorough evaluation of metabolic and metagenomic analyses would enable us to integrate novel preventative strategies and adjunctive interventions into the care of women with gynecologic cancers.

Comparison of vaginal microbiota in gynecologic cancer patients pre- and post-radiation therapy and healthy women.

BACKGROUND: While the importance of commensal microbes in vaginal health is well appreciated, little is known about the effects of gynecological cancer (GynCa) and radiation therapy (RT) on the vaginal microbiome (VM) of postmenopausal women. METHODS: We studied women with GynCa, pre- (N = 65) and post-RT (N = 25) and a group of healthy controls (N = 67) by sequencing the V4 region of the 16S rRNA gene from vaginal swabs and compared the diversity and composition of VMs between the three groups accounting for potential confounding factors in multivariate analysis of variance. RESULTS: Comparisons of cancer vs healthy groups revealed that Lactobacillus and Bifidobacterium have significantly higher relative abundance in the healthy group, while the cancer group was enriched in 16 phylogroups associated with bacterial vaginosis (BV) and inflammation, including Sneathia, Prevotella, Peptoniphilus, Fusobacterium, Anaerococcus, Dialister, Moryella, and Peptostreptococcus. In our sample, RT affected the α-diversity and correlated with higher abundance of typically rare VM species, including several members of the Lacnospiraceae family, a taxon previously linked to vaginal dysbiosis. In addition to cancer and treatment modalities, age and vaginal pH were identified as significant parameters that structure the VM. CONCLUSIONS: This is among the first reports identifying VM changes among postmenopausal women with cancer. RT alone seems to affect several phylogroups (12 bacterial genera), while gynecological cancer and its treatment modalities are associated with even greater significant shifts in the vaginal microbiota including the enrichment of opportunistic bacterial pathogens, which warrants further attention.

Bioinformatics approach to understand the mode of microbial pathogenesis of Chlamydia trachomatis and their implications in gynecologic malignancy.

Chlamydia trachomatis has a say on the target gene i.e., modulating the expression of target gene in the host so that it is given protection from the immune cells and so its survival and replication are not arrested by the host. The current study reports a wide range of C. trachomatis proteins that target the cellular as well as sub-cellular components of the host in gynecologic malignancy. Various bioinformatics tools was used to conduct an in-depth analysis on nuclear and eukaryotic sub cellular localization signal to find the sequences of the predicted proteins of C. trachomatis strain G. A total of 411 proteins was identified with 79.54% maximum expected accuracy and 51.02% least expected accuracy. There were uneven prediction of proteins along with redundancies between BaCeILo and HSLpred in the determination of sub-cellular localization of the CT proteins. The highest molecular weight proteins (>80 kDa) were observed to be the targeted proteins to nucleus of host cell. There was no constant patterns observed in the values of isoelectric point (pI) in case of mitochondrial targeting. The expression of eight proteins were significant with different fold changes. The in-silico study provided much detailed insights for further research in gynecological cancer. However, further experiments should be conducted to validate the specificity and confirmatory roles played by these predicted proteins in carcinogenesis.

The microbiome and gynaecological cancer development, prevention and therapy.

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.

Risk factors for bloodstream infections in gynecological cancer.

OBJECTIVE: Infections are a threat to frail patients as they have a higher risk of developing serious complications from bloodstream pathogens. The aim of this study was to determine which factors can predict or diagnose bloodstream infections in patients with an underlying gynecologic malignancy. MATERIALS AND METHODS: Between July 2016 and December 2017, 68 patients visiting the emergency room with an underlying gynecologic malignancy were evaluated. Variables concerning underlying disease, invasive procedures, and laboratory and clinical parameters were analyzed. Patients were divided into three groups based on their blood and urine specimens (positive blood specimens, positive urine specimens, and no positive specimens; patients who had both positive blood and urine specimens were included in the group of positive blood specimens). Risk factors for surgical site infections, recent (<30 days) surgery, and chemotherapy were studied separately. RESULTS: 68 patients were included in the analysis. Mean age was 55.6 years (standard deviation 14.1). 44% of patients had ovarian cancer, 35% cervical cancer, 12% endometrial cancer, and 9% had other cancer types. In total, 96% of all patients had undergone surgery. Patients who had been treated with chemotherapy were at a higher risk of developing bloodstream infection (P=0.04; odds ratio (OR)=7.9). C reactive protein, bilirubin, and oxygen saturation (SO2) were significantly different between patients with an underlying infection and those who had none. Only C reactive protein maintained its significance in a linear model, with a cut-off of 180 mg/L (linear regression, P=0.03; OR=4). CONCLUSIONS: Chemotherapy is a risk factor for the development of bloodstream infections in patients with an underlying gynecologic malignancy; C reactive protein could be a useful tool in making this diagnosis.

Pilot Study of Vaginal Microbiome Using QIIME 2™ in Women With Gynecologic Cancer Before and After Radiation Therapy.

OBJECTIVES: To characterize the vaginal microbiome using QIIME 2™ (Quantitative Insights Into Microbial Ecology 2) in women with gynecologic cancer. SAMPLE & SETTING: 19 women with gynecologic cancer before and after radiation therapy at a comprehensive cancer center in Atlanta, Georgia. METHODS & VARIABLES: This pilot study analyzed vaginal microbiome communities using a microbiome analysis pipeline, beginning with 16S rRNA gene sequencing and processing through use of a bioinformatics pipeline to downstream microbial statistical analysis. RESULTS: The findings showed the methods to be robust, and most women with gynecologic cancer showed depletion of Lactobacillus. Compared to those pre-radiation therapy, women post-radiation therapy showed higher abundances of Mobiluncus, Atopobium, and Prevotella but lower abundances of Lactobacillus, Gardnerella, and Peptostreptococcus, which are associated with bacterial vaginosis. IMPLICATIONS FOR NURSING: This study presents the fundamentals of human microbiome data collection and analysis methods to inform nursing science. Assessing the vaginal microbiome provides a potential pathway to develop interventions to ameliorate dysbiosis of the vaginal microbiome.

Uterine microbiome-low biomass and high expectations†.

The existence of different bacterial communities throughout the female reproductive tract has challenged the traditional view of human fetal development as a sterile event. There is still no consensus on what physiological microbiota exists in the upper reproductive tract of the vast majority of women who are not in periods of infection or pregnancy, and the role of bacteria that colonize the upper reproductive tract in uterine diseases or pregnancy outcomes is not well established. Despite published studies and advances in uterine microbiome sequencing, some study aspects-such as study design, sampling method, DNA extraction, sequencing methods, downstream analysis, and assignment of taxa-have not yet been improved and standardized. It is time to further investigate the uterine microbiome to increase our understanding of the female reproductive tract and to develop more personalized reproductive therapies, highlighting the potential importance of using microbiological assessment in infertile patients.

Uterine Microbiota: Residents, Tourists, or Invaders?

Uterine microbiota have been reported under various conditions and populations; however, it is uncertain the level to which these bacteria are residents that maintain homeostasis, tourists that are readily eliminated or invaders that contribute to human disease. This review provides a historical timeline and summarizes the current status of this topic with the aim of promoting research priorities and discussion on this controversial topic. Discrepancies exist in current reports of uterine microbiota and are critically reviewed and examined. Established and putative routes of bacterial seeding of the human uterus and interactions with distal mucosal sites are discussed. Based upon the current literature, we highlight the need for additional robust clinical and translational studies in this area. In addition, we discuss the necessity for investigating host-microbiota interactions and the physiologic and functional impact of these microbiota on the local endometrial microenvironment as these mechanisms may influence poor reproductive, obstetric, and gynecologic health outcomes and sequelae.

The role of the vaginal microbiome in gynaecological cancer.

Human microbiome research has shown commensal bacteria to be a major factor in both wellness and disease pathogenesis. Interest in the microbiome has recently expanded beyond the gut to include a multitude of other organ systems for which the microbiome may have health implications. Here, we review the role of the vaginal microbiome in health and disease, with a particular focus on gynaecologic malignancies. Further, we suggest that it may be possible to expand the use of probiotics in the treatment of gynaecological cancers. TWEETABLE ABSTRACT: A review of the research to date on the relation between the vaginal microbiome and gynaecological cancers.

Systematic Review: The Impact of Cancer Treatment on the Gut and Vaginal Microbiome in Women With a Gynecological Malignancy.

BACKGROUND AND AIM: Worldwide, 1,470,900 women are diagnosed yearly with a gynecological malignancy (21,000 in the UK). Some patients treated with pelvic radiotherapy develop chronic changes in their bowel function. This systematic review summarizes current research on the impact of cancer treatment on the gut and vaginal microbiome in women with a gynecological malignancy. METHODS: The Preferred reporting Items for Systematic Reviews and Meta-analyses guidelines for systematic reviews were used to ensure transparent and complete reporting. Quantitative studies exploring the gut or vaginal microbiome in this patient cohort were included. Animal studies were excluded. There were no language restrictions. RESULTS: No studies examined the possible effects of surgery or chemotherapy for gynecological cancers on the gut or vaginal microbiome.Three prospective cohort studies were identified using sequencing of changes in the gut microbiome reporting on a total of 23 women treated for gynecological cancer. All studies included patients treated with radiotherapy with a dosage ranging from 43.0 to 54.0 Gy. Two studies assessed gastrointestinal toxicity formally; 8 women (57%) developed grade 2 or 3 diarrhea during radiotherapy. The outcomes suggest a correlation between changes in the intestinal microbiome and receiving radiotherapy and showed a decrease in abundance and diversity of the intestinal bacterial species. Before radiotherapy, those who developed diarrhea had an increased abundance of Bacteroides, Dialister, and Veillonella (P < 0.01), and a decreased abundance of Clostridium XI and XVIII, Faecalibacterium, Oscillibacter, Parabacteroides, Prevotella, and unclassified bacteria (P < 0.05). CONCLUSION: The limited evidence to date implies that larger studies including both the vaginal and gut microbiome in women treated for a gynecological malignancy are warranted to explore the impact of cancer treatments on the microbiome and its relation to developing long-term gastrointestinal toxicity. This may lead to new avenues to stratify those at risk and explore personalized treatment options and prevention of gastrointestinal consequences of cancer treatments.

Primary lymphoma of the female genital tract: An analysis of 697 cases.

OBJECTIVE: Primary lymphoma of the female genital tract (PLFGT) is a rare entity. The aim of this population-based study was to elucidate the clinico-pathological, demographic characteristics and survival of women with PLFGT. MATERIALS AND METHODS: The Surveillance, Epidemiology, and End Results database was accessed and cases of PLFGT diagnosed between 1988 and 2012 were identified. Five-year overall (OS) and cancer-specific (CSS) survival rates were calculated with the Kaplan-Meier method. The influence of demographic and clinical parameters on survival was examined with the log-rank test. Factors independently associated with cancer-specific mortality were evaluated with a Cox proportional hazard model. RESULTS: A total of 697 women with PLFGT were identified with a median age of 54years. The most prevalent histological subtypes were diffuse large B-cell (59.8%) and follicular (11.9%) lymphoma. Tumors were most commonly located in the ovary (37%), cervix (21.4%), and uterus (16.5%). According to the Ann Arbor staging system, 42.6% and 17.9% of cases had stage I and stage II disease, respectively. Cancer-directed surgery (CDS) was performed in the majority of cases (62.8%). Five-year OS and CSS were 70.2% and 75.2% respectively. Localized disease, premenopausal age and follicular histology were associated with superior cancer-specific mortality while CDS did not confer any mortality benefit. CONCLUSIONS: This is the largest cohort of PLFGT presented in literature. While in our study surgical treatment was not associated with improved outcomes, larger multi-institutional studies should address the optimal management of women with PLFGT.

The vaginal and gastrointestinal microbiomes in gynecologic cancers: a review of applications in etiology, symptoms and treatment.

The human microbiome is the collection of microorganisms in the body that exist in a mutualistic relationship with the host. Recent studies indicate that perturbations in the microbiome may be implicated in a number of diseases, including cancer. More specifically, changes in the gut and vaginal microbiomes may be associated with a variety of gynecologic cancers, including cervical cancer, uterine cancer, and ovarian cancer. Current research and gaps in knowledge regarding the association between the gut and vaginal microbiomes and the development, progression, and treatment of gynecologic cancers are reviewed here. In addition, the potential use of probiotics to manage symptoms of these gynecologic cancers is discussed. A better understanding of how the microbiome composition is altered at these sites and its interaction with the host may aid in prevention, optimization of current therapies, development of new therapeutic agents and/or dosing regimens, and possibly limit the side effects associated with cancer treatment.

Impact of pelvic radiotherapy on gut microbiota of gynecological cancer patients revealed by massive pyrosequencing.

Although pelvic irradiation is effective for the treatment of various cancer types, many patients who receive radiotherapy experience serious complications. Gut microbial dysbiosis was hypothesized to be related to the occurrence of radiation-induced complications in cancer patients. Given the lack of clinical or experimental data on the impact of radiation on gut microbiota, a prospective observational study of gut microbiota was performed in gynecological cancer patients receiving pelvic radiotherapy. In the current study, the overall composition and alteration of gut microbiota in cancer patients receiving radiation were investigated by 454 pyrosequencing. Gut microbial composition showed significant differences (P < 0.001) between cancer patients and healthy individuals. The numbers of species-level taxa were severely reduced after radiotherapy (P < 0.045), and the abundance of each community largely changed. In particular, the phyla Firmicutes and Fusobacterium were significantly decreased by 10% and increased by 3% after radiation therapy, respectively. In addition, overall gut microbial composition was gradually remolded after the full treatment course of pelvic radiotherapy. In this set of cancer patients, dysbiosis of the gut microbiota was linked to health status, and the gut microbiota was influenced by pelvic radiotherapy. Although further studies are needed to elucidate the relationship between dysbiosis and complications induced by pelvic radiotherapy, the current study may offer insights into the treatment of cancer patients suffering from complications after radiation therapy.

Effect of a mixture of inulin and fructo-oligosaccharide on Lactobacillus and Bifidobacterium intestinal microbiota of patients receiving radiotherapy: a randomised, double-blind, placebo-controlled trial.

BACKGROUND & AIMS: The pathogenesis of enteritis after abdominal radiotherapy is unknown, although changes in faecal microbiota may be involved. In several studies, Lactobacillus and Bifidobacterium have proven beneficial for the host. Prebiotics stimulate the proliferation of Lactobacillus and Bifidobacterium, and this may have positive effects on the intestinal mucosa during abdominal radiotherapy. METHODS: We performed a randomised double-blind, placebo-controlled trial including 31 patients with gynaecological cancer who received radiotherapy (29 sessions, 52.2 Gy) after surgery. Patients were randomised to two groups: prebiotic and placebo. The first group received a mixture of fibre (50% inulin and 50% fructo-oligosaccharide) and the second received 6 g of maltodextrin twice daily from one week before to three weeks after radiotherapy. Lactobacillus and Bifidobacterium counts were determined in faeces samples (day -7 before radiotherapy, day 15 of radiotherapy, at the end of treatment, and three weeks after radiotherapy) by culture in selective media and fluorescent in situ hybridization (FISH) using genus-specific probes. Bacterial counts by FISH were significantly higher than by culture method. RESULTS: There were no differences in baseline microbiota between groups. At the end of radiotherapy, we observed a statistically significant decrease in Lactobacillus and Bifidobacterium counts in both groups. By cultural analysis, we observed higher numbers of Lactobacillus and Bifidobacterium three weeks after radiotherapy in the prebiotic group (5.6 vs. 6.3, p = 0.04 and 5.5 vs. 6 log cfu/g, p = 0.03). CONCLUSIONS: Abdominal radiotherapy negatively affects Lactobacillus and Bifidobacterium counts. The prebiotic mixture of inulin and fructoligosaccharide can improve the recovery of both genera after radiotherapy. Registered under ClinicalTrials.gov Identifier no. NCT01549782.

[Specifics of individual risks in a group of women with genital neoplasms]. / Particularitati privind riscurile individuale la un lot de femei cu neoplazii genitale.

UNLABELLED: Genital cancers represent an important issue regarding women health, as they produce a large number of cases, invalidities and deaths. AIM: The evaluation of individual risks for a group of women with genital neoplasia. MATERIAL AND METHODS: We conducted a pilot case-control study to validate the questionnaire for the evaluation of risk factors in genital cancers, in a number of 40 female subjects (20 cases and 20 controls). We have realized the data processing using the SPSS 16 and EpiInfo 3.5.1. soft wares. RESULTS: For questionnaire validation we have evaluated the reproducibility, the validity, the acceptability and the practicability of the questionnaire. In order to establish the test reproducibility, we have calculated k factors for inter-investigator (k = 0.34) and intra-investigator (k = 0.72) variation. To evaluate the questionnaire validity we calculated the sensitivity (cases = 94%; controls = 97%), specificity (cases = 67%, controls = 75%), positive predictive value (cases = 94%; controls = 94%), negative predictive value (cases = 67%; controls = 86%). The risk factors most frequently identified were genital infectious in clinical records (75% comparing to 52.5% - p = 0.036), and also the presence of other pathological records in genital area (65% comparing to 22.5% - p = 0.0001). CONCLUSIONS: For an accurate identification of individual risk at women with genital cancers subsequently studies on greater number of subjects is necessary.

Is chlamydial heat shock protein 60 a risk factor for oncogenesis?

Heat shock protein 60 (HSP60) plays an important role in the protein folding of prokaryotic and eukaryotic cells. Most of the papers published on chlamydial HSP60 concern its role in immune response during infection. In the last decade, exposure to Chlamydia trachomatis has been consistently associated with the development of cervical and ovarian cancer. Moreover, it has been suggested that chlamydial HSP60 may have an anti-apoptotic effect during persistent infection. We hypothesize that the accumulation of exogenous chlamydial HSP60 in the cytoplasm of actively replicating eukaryotic cells may interfere with the regulation of the apoptotic pathway. The concomitant expression of viral oncoproteins and/or the presence of mutations may lead to the ability to survive apoptotic stimuli, loss of replicative senescence, uncontrolled proliferation and, finally neoplastic transformation.