Cancer and Bugs: How much do we know about
the Relation between Vaginal Microbiome and
Fernandez-Aristi AR1,2 and Taco-Masias AA1,2
1School of medicine, Universidad Peruana de Ciencias Aplicadas, Peru
2Instituto de Investigacion de Enfermedades Infecciosas (IIEI), Peru
Submission: April 16, 2018; Published: July 11, 2018
*Corresponding author: School of medicine, Universidad Peruana de Ciencias Aplicadas, Instituto de Investigacion de Enfermedades Infecciosas (IIEI), Peru, Email: email@example.com
How to cite this article: Fernandez-Aristi A, Taco-Masias A . Cancer and Bugs: How much do we know about the Relation between Vaginal Microbiome
and Cervical Neoplasia?. J Gynecol Women’s Health. 2018: 10(3): 555789. DOI: 10.19080/JGWH.2018.10.555789
Cervical cancer is one of the most prevalent gynecologic cancers worldwide and has demonstrated a pathophysiology that involves various factors, but the infection of the Human Papillomavirus (HPV) remains the key stone in the pathogenesis and progression of this neoplasia. Although the colonization by the HPV is mainly driven by sexual transmission, this viral etiology needs to colonize the upper genital tract in order to perpetuate the infection. The Vaginal Microbiome, mainly composed by Lactobacillus Genus, has shown for many years since their discovery protective functions against various microbes which extends from local production of lactic acid, barrier effect, functions as an innate immune response, among others. Recent studies had linked dysbiosis of the Vaginal Microbiome, represented as fewer Lactobacillus strains, to increased risk of colonization of pathologic entities, which the HPV stands as the main etiology. The pro inflammatory state driven by this dysbiosis and the pathologic colonization of HPV, therefore; increase the overall risk of cervical neoplasia. Although this cascade is present in the dysbiotic state, some Lactobacillus strains promotes the HPV colonization and progression to cervical neoplasia.In this mini review we present the current knowledge of how the dysbiosis of the Vaginal Microbiome increased the risk of colonization of HPV and how some Lactobacillus strains and other bacteria in increase the overall risk of cervical cancer.
Keywords: Vaginal microbiome; Lactobacillus; Dysbiosis; Human papillomavirus; Inflammation; Cervical neoplasia
One of the current paradigms in microbiology that transcends to all human related science fields are a group of bacteria that colonizes mucosal surfaces, such as the female genital tract (FGT), among the body called the microbiome . A wide variety of bacterial groups that accounts this community has specific and beneficial functions such as a barrier exerting mucosal protection, maturation of immune function and production of soluble factors against microbial infection . In order to achieve this functions, the microbiota; in this case, the women genital microbiota, the balance of diversity and richness are crucial. Any alteration in its homeostasis causes an inflammatory state that promotes microorganism infection  and creates a positive loop, where the pathologic colonization creates an increased inflammatory response; further disrupting the vaginal microbiome (VM) . This state is called dysbiosis and it has been linked to pathologies such as Bacterial Vaginosis (VB) , increased risk of HIV infection  and two gynecologic cancer: Cervical and Endometrial Neoplasias [7,8] in where the
disbalanced state of the microbiota promotes etiological factor colonization and progression through the inflammatory state exerted by immune responses in this pathologies. On this matter, the main objective of this review is to compilate the current knowledge regarding the key role of the VM in the pathogenesis and the progression of tumorigenesis in cervical cancer.
Nearly 130 strains of Lactobacillus spp. are detected across the human body, but only 20 of them reside in the FGT  and most of the members in this genus are englobed in 4 particular strains: Lactobacillus Inners, Lactobacillus Crispatus, Lactobacillus Jenseii and Lactobacillus Gasseri . It is not completely unraveled why only these 4 strains are able to survive in the vaginal mucosa. To elucidate this issue, a previous study revealed that the genetic pool of those species are smaller and had fewer G+C in its genotype compared with other Lactobacillus. In addition, the genetic traits of higher mucous binding proteins and lack of
amino acids-generating enzymes are the most prevalent traits in
these strains , meaning that those species can´t survive for
themselves and need a larger enzyme machinery to metabolize
large polymers such as glycogen. A previous review by Nunn K,
et al. exposed this topic stating that the Lactobacillus can only
absorb this molecule if the vaginal mucous secretions presented
α-Amylase to break down the glycogen secreted by the caliciform
As stated before, these four Lactobacilli have characteristic
genetic traits that mostly explain its preference for the mucosa
present in the FGT. In exchange, these bacteria exert different
protective functions for the host, which functions as innate
immune system. Aside from the barrier-like protection in the
mucosal surface, these functions are the production of lactic
acid which acidifies the FGT maintaining the pH levels between
3.74±0.29 , secretion of soluble factors such as bacteriocins
and Hydrogen Peroxide  thus preventing the colonization
of pathogens such as Neisseria Gonorrhoeae, Staphylococcus
Aureus, Escherichia Coli, among others [3,15]. Other protective
function are the interactions of the Lactobacilli with epithelial
and mucous membrane receptors, inhibiting the adherence of
pathogenic bacteria and viruses and englobing those pathogens
reducing their ability to proliferate .
The execution of the defense mechanisms stated above
cannot be performed if the predominant Genus in the VM is not
the Lactobacillus. This state, evaluated with a Nugent score >3
which indicates decreased concentration of Lactobacillus strains
, is driven by the alteration in the vaginal environment
undergone by several factors such as a decreased concentration of
hormones during menopause and menstruation, age, pregnancy
and vaginal infections [10,12,14]. After the disbalanced state
settles in the VM, colonization of pathogenic Microbiome
such as Gardnerella, Mobilluncus, Prevotella, Corynebacterium,
Staphylococcus, among others [9,10] that predisposes a various
array of Sexual transmitted infections (STI’s), in which the Human
Papillomavirus (HPV) is included . The innate conformed
mainly by Neutrophils, Macrophages and Dendritic cells,
localized in the upper FGT , along with Pattern recognition
receptors (PPR) located in the mucosal epithelia [19,20]; exert
the first inflammatory response against the colonization of the
HPV. This first response against is followed by the interplay
between the dendritic cells and Th2 cells along with T memory
cells that initiate IgG secretion, the main soluble factor produced
in the vaginal fluid . Both responses helps perpetrate the
inflammatory state in vaginal dysbiosis and helps promote the
epithelial dysplasia by the HPV .
Although this pro inflammatory state is sufficient to promote
the colonization and progression of the HPV, other factor play an
important role in the variability of the risk of Cervical Neoplasia.
A previous study  performed in 70 healthy women with
both HPV-negative and HPV-positve showed that Lactobacillus
Gasseriwas related to increased HPV detection. In contrast,
other studies [24,25] showed that Lactobacilli supernants
were related with increased clearance of HPV and inhibitory
mechanisms through HPV proteins, E6 and E7. More studies
need to be performed to unravel the real interplay between the
Lactobacillus Gasseri and the HPV infection.
The VM is essential to maintain the balance of bacteria
in the female genital tract, any disruption of these bacterial
communities leads to greater risk of miscarriage, recurrent
abortion, HPV infection, and sexually transmitted infections
such HIV, CMV, Chlamydia Trachomatis, among other etiologies.
Currently, the association between the VM and the HPV infection
is poorly understood. On this
matter, many studies have tried to elucidate the role of VM in
the process of this precancerous infection.
Regarding HPV infection, a study done by Lee JE et al. found
that HPV-positive women had significantly higher microbial
diversity with a lower proportion of Lactobacillus spp. than
HPV-negative women. In addition, they found that Fusobacteria
is highly associated with HPV infection. Furthermore, they
conclude that there are many factors which can influence the VM
such as host physiology, genetic factors, and menopause status.
Finally, they also identified Sneathia spp.as a microbiological
marker of HPV infection . Another study done in Nigerian
women evaluated the composition of VM and prevalent high
risk of HPV infection. The authors found a moderate association
between prevalence of high risk of HPV and a low relative
abundance of Lactobacillus sp. Additionally, they found that
there was an increased proportion of women with composed of
a diverse array of facultative and strictly anaerobic bacteria such
as Atopobium and Gardnerella vaginalis, in those who had an
HPV infection compared to those without any HPV infection .
Likewise, a meta-analysis done by Guillet et al. has reported
an association between bacterial vaginosis and HPV infection.
The authors explain that loss of Lactobacillus facilitates survival
of other sexually transmitted agents such as HPV. This factor
along with others such as decreased pH, increased mucindegrading
enzymes play an important role in the degradation
of the gel layer coating the cervical epithelium, causing cervical
micro-abrasions and alterations of the cervical epithelial cells.
All of these increase the susceptibility to cervical HPV infection
by facilitation the invasion and adherence of HPV genes into the
genome of cells of the transformation zone .
These results are similar to that obtained in the previously
mentioned study. All of this results are according to the
literature, especially those bacteria which are decrease such as
Lactobacillus sp., since pathophysiologically, its decreasing leads to a vaginal dysbiosis, predisposing to get any infection such as
HPV. It is important to understand that despite the determinants
of the VM composition are not well known. The variations of
some factors such as ethnic groups may reflect a role for genetic
factors without rule out the non-genetic factors such as sociocultural
and health practices .
Regarding cervical cancer, according to the literature, VM
is important to maintain the stabilization in the female genital
tract, but when this VM can change if the body is under an
inflammatory process such as cervical cancer. On this matter, it
is known that its main predisposing factor is the HPV infection
(especially type 16 and 18). A review done by Chase et al.
concluded that Lactobacillus Gasseri and Gardnerella vaginalis
were found in significantly high frequencies in HPV positive
patients in contrast to those with HPV-negative infection .
Many studies have been done in high-risk populations in
which have found that there are many mechanisms implicated
in cervical cancer. One of these is the DNA oxidative damage
in which Piyathilake et al. state that this mediates the effect of
the microbiome on the natural history of HPV infection and the
severity of the high-risk cervical intraepithelial neoplasia (CIN
2). Despite they did not show a strong association between
microbiome diversity and CIN severity, they provide suggestive
evidence that the VM characterized by the predominance of
Lactobacillus is associated with CIN 2 in women infected with
high-risk HPV . However, another study done by Mitra et
al. found that advancing CIN disease severity is associated with
increasing vaginal microbiota diversity and may be involved in
regulating viral persistence and disease progression .
On this matter, both studies agree that unhealthy vaginal flora
is often characterized by high diversity bacterial populations
with an increased anaerobic bacteria and lower levels of
lactobacillus. All of these are related to pro-inflammatory
cytokine concentrations, especially IL-8 and TNF-alpha.
Moreover, other bacterial populations play a key role in the
development of cervical cancer. Some of these are Proteobacteria
and Fusobacteria which metabolize the B12 synthesis of
cobalamin, and Bacteroidetes which metabolizes the folate
biosynthesis. All of these micronutrients are important because
VM may influence the natural history of HPV infection and CIN
by altering the status of these in the cervical environment .
Despite all previously mentioned, the microbial communities
in the cervical mucosa have not been well studied, but we can
say that it is plausible that the VM modify the risk of developing
cervical cancer along other risk factors such as socio-economic,
health and genetic factors [30,31].
Foundational studies are increasing largely, as well as
emerging evidence is increasing to suggest that the vaginal
microbiota plays a substantial role in the persistence of the virus
and the presence of subsequent cervical pre-invasive disease.
Future studies should focus on elucidating the pathophysiology
and the main pathways in which the vaginal microbiota
are present and the way it can change the course of many
inflammatory processes such as cervical cancer. These studies
should aim to elucidate the complete understanding of the
relationship of vaginal microbiota and cervical cancer, especially
in risk populations.