In 2022, more than 660,000 women were diagnosed with cervical cancer and nearly 350,000 died from the disease, worldwide. In most cases, high-risk subtypes of the human papillomavirus (HPV) are the cause of the cancer. Evidence reveals that cervicovaginal microbiota may play a substantial role in the persistence or regression of the virus. This blog will look at the potential involvement of the vaginal microbiome in HPV evolution, mechanisms of action, and results from probiotic interventions.
HPV, in brief
Since groundbreaking research in the 1980s linked HPV to cervical cancer, considerable strides have been made in reducing cervical cancer rates through initiatives such as Pap smear screenings, early interventions, and the introduction of a prophylactic vaccine. However, this vaccine primarily targets HPV types 16 and 18 and is typically administered to populations lacking HPV infection. Moreover, its high cost and limited accessibility present significant challenges, particularly in developing countries. Despite being largely preventable, a staggering 94% of cervical cancer deaths occur in low-to-middle-income nations.
Over the course of her lifetime, a woman faces an 80% likelihood of contracting HPV. Fortunately, most cases are resolved spontaneously through an immune response that is not fully understood. However, a minority of women with persistent HPV infections may progress to develop the pre-invasive stages, referred to as high-grade cervical intraepithelial neoplasia (CIN2 & 3). At present, there exists no established drug protocol for managing HPV infection, particularly in individuals with low-grade cervical lesions.
Vaginal Microbiota and Infections
The vaginal microbiota in humans may serve as a critical factor in guarding against various urogenital diseases, including bacterial vaginosis, yeast infections, sexually transmitted infections, urinary tract infections, and HIV infection.
Contrary to most sites in the body where microbial diversity is indicative of good health, a healthy vaginal environment is typically characterized by dominance of specific species such as Lactobacillus crispatus, Lactobacillus gasseri, Lactobacillus iners, and Lactobacillus jensenii, with relatively low species diversity. Conversely, bacterial vaginosis (BV), a prevalent condition associated with HPV infection, is marked by reduced levels of lactobacilli and an overgrowth of pathogenic microorganisms.
Lactobacilli are vital for women’s cervicovaginal health, safeguarding against bacterial invasion by sustaining an acidic environment and enhancing the integrity of epithelial cell barriers and intercellular junctional proteins.
Lactobacilli maintain vaginal health by:
- Producing lactic acid, inhibiting pathogen growth, and inducing anti-inflammatory responses
- Releasing bacteriocins and H2O2, destroying pathogens, and preserving vaginal barrier integrity
- Competing for epithelial adhesion sites, modulating microbiota balance
- Enhancing local defense, reducing cervical lesion occurrence
- Regulating epithelial cell fucosylation, inhibiting cervical cancer cell proliferation
Researchers have created Community State Types (CSTs) to categorize various vaginal microbiota profiles impacting cervical disease development. CSTs I to III and V exhibit minimal diversity and are primarily composed of L.crispatus, L. gasseri, L.iners, and L. jensenii, respectively. Conversely, CST IV is distinguished by decreased levels of lactobacilli and increased diversity, featuring a substantial presence of anaerobic bacterial species including Gardnerella, Megasphaera, Sneathia, and Prevotella spp. The association between HPV infection status and cervicovaginal dysbiosis is evident with more than 40% of persistent HPV-positive women displaying the CST IV subgroup.
Gardnerella, a prevalent anaerobic pathogen found in CST IV, is a significant contributor to bacterial vaginosis and is frequently associated with HPV infection, particularly in women with Gardnerella vaginalis-dominated vaginal microbiota. Research indicates that the presence of Gardnerella, especially in combination with Prevotella, poses a heightened risk for HPV-positive women, potentially leading to cervical intraepithelial neoplasia (CIN2-CIN3) due to increased vaginal microbiota diversity. Moreover, Gardnerella produces sialidase, an enzyme implicated in the degradation of mucous secretions and mucosal cell surfaces, which may further contribute to its pathogenicity.
In addition, many other microorganisms have been associated with the onset of cervical cancer. Notably, a dominant vaginal microbe Lactobacillus iners, is detected at higher frequencies in infected women compared to those who are healthy. Various microorganisms are present at different stages of the disease.
Vaginal Microbiota: Influences
- Ethnicity: In a survey, Caucasian and Asian women were observed to have a higher prevalence of Lactobacillus spp.-dominant microbiota compared to Hispanic and Black women. The composition of vaginal communities may be influenced by genetic variations among hosts, affecting aspects such as immune systems, vaginal secretions, and epithelial cell surfaces.
- Female hormones: Estrogen and progesterone appear to be protective. Contraceptives (oral or IUD) with these hormones are linked with less BV.
- Smoking cigarettes is associated with less L. crispatus and more diversity. In one study, 50% of smokers had Lactobacillus-depleted microbiomes in comparison to just 15% of non-smokers.
- Recent intercourse is linked with reduced relative abundance of L. crispatus and increased species diversity.
- Vaginal douching increases BV and the risk of HPV. Douching may increase the risk of CIN and cervical cancer.
Vaginal Microbiota and HPV
Changes in vaginal microbiome composition, particularly decreased lactobacilli abundance and increased diversity, may contribute to HPV and cervical lesions, potentially fostering a pro-inflammatory environment and promoting malignant cell proliferation, as observed in several studies.
The interaction between HPV and the cervicovaginal microbiota is believed to create an imbalanced microenvironment, leading to dysbiosis, prolonged HPV presence, and ultimately promoting cervical carcinogenesis. In a prospective longitudinal study, researchers found that Lactobacillus depletion and the presence of specific anaerobic species at the time of CIN2 diagnosis was associated with a significantly lower chance of regression at 12- and 24-month follow-up.
Mechanisms
Dysbiosis may drive HPV infection by:
- Increased acquisition which implies epithelial cell damage and desquamation.
- Higher replication and shedding of viral particles
- Decreased mucus production causes reduced viral trapping and increased exposure of the cervical epithelium.
- Inflammation plays an important role. Vaginal proinflammatory cytokines can result in chronic inflammation, a risk factor for cervical carcinogenesis.
The rationale for using probiotic strains in HPV clearance is via three proposed mechanisms:
- By competing for space and nutrients, as well as producing inhibitory compounds like biosurfactants, hydrogen peroxide, lactic acid, bacteriocins, and aggregation molecules. This leads to competitive exclusion.
- Improved innate and adaptive immunity plays a critical role in defending against viral infections, including HPV. Early HPV clearance relies on innate responses, while adaptive responses are essential for identifying and eliminating HPV-induced lesions. A recent meta-analysis revealed reduced levels of helper and killer T cells in cervical lesions, suggesting potential immune evasion mechanisms in patients with persistent lesions.
- A direct antiviral effect via the secretion of specific metabolites. One study showed a strain of Bifidobacterium adolescentis had antiviral activity through suppression of E6 and E7 oncogene expression.
Thus, by replenishing the depleted pool of Lactobacillus spp., probiotics have been proposed as an interventional method to promote HPV clearance.
Can Probiotics Help Clear HPV?
Given the complex interactions between cervicovaginal microbiota, HPV, and cervical cancer, researchers have explored the impact of probiotics on outcomes. Table 2).
- In a randomized pilot study, women with HPV+low-grade squamous intraepithelial lesions who took oral Lacticaseibacillus casei for 6 months had twice as high clearance of their HPV-related cervical abnormality as a control group.
- In one trial of women affected by BV with HPV infections, researchers studied the effect of length of treatment. HPV clearance was higher in the treatment of metronidazole plus 6 months vaginal Lactobacillus implementation than that with 3 months of use.
- In a study of women with HPV infection (62 in the study group and 59 in the control group), the oral application of specific strains of Lacticaseibacillus rhamnosus and Limosilactobacillus reuteri did not influence HPV clearance but significantly reduced the rates of mildly abnormal and unsatisfactory cervical smears in the probiotic group.
- One study found that HPV-positive women who took L. crispatus orally for an extended period of time had reduced HPV-related cytological anomalies compared to the control group. However, HPV clearance was not significantly different between the probiotic group and the group without probiotics.
- However, other research reported an increase in HPV clearance after 90 days of consuming the same strain of L. crispatus. Furthermore, in some cases, the CVM shifted the CST status to CST I.
Takeaway
Screenings, treatments, and vaccines have proven revolutionary in reducing cervical cancer yet hundreds of thousands still die every year. The intricate interplay between vaginal microbiota and HPV progression underscores a critical aspect of cervical cancer prevention and treatment. Understanding how the vaginal microbiome influences HPV persistence and clearance opens avenues for innovative interventions, including the use of probiotics as potential primary or adjuvant therapies. Embracing further research and investment in probiotics could significantly enhance our arsenal against cervical cancer, offering new hope for reducing the global burden of this devastating disease and saving countless lives in the process.
Image by Lela Maffie from Pixabay
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