Influence of Vaginal Microbiota on Sexual and Reproductive Health: A Mini Review

INTRODUCTION

Human development and defenses as a whole are significantly influenced by microbiota. The macroscopic host and its commensal symbiotic bacteria are both multicellular beings that exist as meta-organisms [1]. Viruses, fungi, bacteria, protozoa, and other microbial species are present in these complex microbial communities [2, 3]. These symbionts are crucial in regulating the majority of host physiology due to their exceptional enzymatic capabilities and potential to express ten times as many different genes as their host's genome [4]. The human microbiota encompasses the communities of microorganisms that reside in the human body and the microbiome represents the genetic profile of all such microorganisms taken collectively [5-7]. The complex symbiotic, commensal, and pathogenic microbial association that lives in and colonizes the human body is essentially represented by a component of the cumulative genome of the human species [8]. The human microbiome, which is made up of about 10,000 different species of bacteria, lives inside the human body, similar to how the mouth and gut each have a variety of unique microbial populations. Additionally, trillions of tiny microorganisms, such as fungi, viruses, and bacteria, live in the female vagina [9]. This review's goal is to give a thorough explanation of the vaginal microbiome. The characteristics of bacterial vaginosis (BV) are reviewed about female health, and a strong correlation between BV and many illnesses is characterized by the need for thorough, accurate, and state-of-the-art treatment that lowers the negative effects on health (Figure 1).

Vaginal microbiota- introduction

In 1892, German obstetrician and gynecologist, Albert Doderlein discovered a long, thick, motile, rod-shaped, gram-positive, non-spore-producing microorganism in the vaginal fluid, which led to the discovery of vaginal microbiota [10]. When this bacterium was first identified, it was known as Doderlein's bacillus; however, because of its capacity to make lactic acid, it was later renamed Lactobacillus. Doderlein also found that the absence of Doderlein's bacillus in the vaginal fluid was linked to puerperal fever and that Doderlein's bacillus had an antagonistic effect on Staphylococcus growth [11, 12]. These key discoveries laid the groundwork that Lactobacillus is the most common bacterium in the vagina and is essential for women's health. It is now commonly acknowledged that the vaginal microbiome is more diverse and active than previously thought as a result of the advent and rapid development of high-throughput sequencing technologies [13]. A non-Lactobacillus dominant vaginal microbiome has also been linked to several diseases, including STIs, gynecologic cancer, infertility, and preterm birth, according to several observational studies [14].

Microbial communities of vaginal microbiota

The vaginal microbiome is a complex and dynamic micro-ecosystem that continuously changes throughout a woman's whole life and during her menstrual cycle. A stratified squamous non-keratinized epithelium and cervicovaginal secretion make up the vaginal mucosa [15]. Understanding the nature of the human body requires a study of the human microbiome, which will help researchers to establish whether the microbial communities in humans are uniform across the board or vary from person to person. Variations in the core microbiota have been suggested to be associated with changes in human health and the likelihood of contracting illnesses [16]. Bacteria are one of the many varieties of microbes that exist and are responsible for a major portion of all life on Earth. According to the thorough study of the human vaginal microbial community, the Lactobacillus bacterial species predominate in the vaginal composition in the majority of females. This particular group of bacteria acts as protective agents in the reproductive system, preventing the colonization of hazardous germs by releasing hydrogen peroxide and some other compounds, such as bacteriocins. Although they contain a diverse range of both strictly and facultative anaerobic bacteria, a sizable portion of asymptomatic and healthy women lack enough Lactobacillus sp. in their vaginal microbiota. As a consequence, it can be said that the human vagina contains many core microbiomes rather than just a single core microbiome [17, 18]. Moreover, one of the essential aspects influencing vaginal composition is ethnicity. Asian and Caucasian women have been shown to have much greater lactobacilli levels than Black and Hispanic women [19, 20]. However, it is yet unknown whether this variation in Lactobacilli levels is a result of genetic determinants or associated with various hygiene practices, particularly vaginal douching [21].

Researchers demonstrated that there exist five distinct classified microbial communities, or five different forms of Community State Types (CST), especially I, II, III, IV, and V as it is shown in Figure 2. Since no two females have the same vaginal environment, I assume it depends on which species of Lactobacillus plays a cent in these communities. Lactobacillus crispatus (L. crispatus) represents Community State Type I (CST I), L. gasseri leads Community State Type II (CST II), L. iners controls Community State Type III (CST III), and L. jensenli dominates Community State Type V (CST V). Although Community State Type IV (CST IV) lacks Lactobacillus sp., it is incredibly rich in BV-associated strictly anaerobic bacteria such as Megasphera, Prevotella, Gardenella, and Sneathia [22].

Throughout her lifetime, every woman appears to have the potential to transition from one CST state to another, with the transition from CST III to CST IV being the most common. Each species of Lactobacillus has distinct strengths and weaknesses [23, 24]. L. iners, for example, may be more effective across a larger pH range, but they are unable to inhibit the growth of strict anaerobes, such as those found in CST IV. The concentration of lactobacilli drops with time, which shifts the balance of power so that the strict anaerobes take control even if L. iners cannot combat these anaerobes [25]. According to recent studies comparing the makeup of the vaginal microbiome from three vaginal sites, namely the cervix, mid-vagina, and introitus, the female vagina encompasses more than 200 phylotypes, with the most prevalent belonging to the phylum level Firmicutes, Bacteroidetes, Actinobacteria, and Fusobacteria [26] (Figure 2).

Composition of vaginal microbiota

The term "microbiota" refers to the complete population of microorganisms in a specific niche, such as the human stomach, mouth cavity, and vaginal area. the composition of the vaginal microbiota in a state associated with health and what transpires when changes in microbes, particularly significant changes in bacterial populations, occur (dysbiosis). The vaginal microbiota of healthy women appears to be dominated by Lactobacillus spp. The more common species are Lactobacillus crispatus, Lactobacillus gasseri, Lactobacillus iners, and Lactobacillus jensenii. Other species, however, are also found, though in smaller numbers. These include Fusobacterium, Bacteroides, Actinomycetes, Veillonela, Peptococcus, Propionibacterium, Staphylococcus aureus, Staphylococcus epidermidis, Peptostreptococcus, Streptococcus viridian's, Bifidobacterium, Enterococcus faecalis, are (Table 1).

Table 1. The principal micro-organisms present in the vagina throughout the female life cycle.

Factors influencing the vaginal microbiota

Even though the vaginal microbiota in healthy women has a comparatively small level of variety, it needs to be taken into account that its characteristics might alter throughout a woman's life and the menstrual cycle. As shown in the Figure 3, age, ethnicity, and physiological elements including monthly hormone variations and the immune system all have an impact on the vaginal microbiota's extremely dynamic composition.

Immune system

The vaginal mucosa's immune system simultaneously interacts with and regulates the Vaginal microbiomes (VMB) content [32]. Pro/anti-inflammatory cytokines/chemokines, secretory antibodies, epithelial and immunological cells, as well as antimicrobial peptides, all play a role in the complex interplay between the immune system and the VMB [33]. Epithelial and immune cells (dendritic cells) of the cervicovaginal mucosa simultaneously check for infections and maintain homeostasis with the VMB. These cells recognize microbial structures (antigens) through pattern recognition receptors such as Toll-like receptors (TLRs), which cause the production of antimicrobial peptides and immunomodulatory cytokines/chemokines. Dendritic cells also act as a crucial link between the innate and adaptive immune systems by dispersing antigens to immune cells such as macrophages, NK cells, neutrophils, T, and B cells [29].

Urbanization

Urbanization may also impact the VMB composition by increasing variety, however, the available data only includes a small number of ethnic groups [34]. There is evidence that among the socioeconomic determinants, education level may be related to VMB composition.

Age

Women change vaginal microbiota composition as they grow, and these changes are closely correlated with estrogen levels. Children's vaginal environments have a pH that is slightly alkaline (or neutral), and the majority of the microbiota is made up of gram-negative anaerobic bacteria like Fusobacteria, Bacteroides, and Veillonella as well as gram-positive anaerobic bacteria like Peptococcus, Actinomyces, and Pepto streptococcus [35]. In addition, low levels of estrogen and glycogen are seen in prepubertal girls, which are associated with thin mucosa, as well as low frequencies of Prevotella bivia, Gardnerella vaginalis, and Mycoplasma hominis. During puberty, the vaginal epithelium builds up glycogen as a result of a process fueled by estrogen levels. Estrogen levels rise and glycogen deposits increase in the vaginal epithelium during puberty, which promotes the growth of lactic acid-producing bacteria. These bacteria create an unfavorable environment for pathogens by turning glycogen into glucose and then lactic acid, preventing infections and protecting the vaginal tract [36, 37]. Teenage girls' vaginal microbiome is similar to that of elderly women, with Lactobacillus spp. having a significant influence [38].

The plasma estrogen concentration is approximately 129 ng/L throughout the reproductive years, whereas the content is approximately 18 ng/L after menopause. On the other hand, estrogen levels in women decrease as they approach menopause [39]. As a result, the vaginal epithelium contains less glycogen, which in turn leads to a decrease in lactobacilli dominance. The pH of the vagina is raised because there are fewer lactobacilli than in prepubertal girls, which results in less lactic acid being produced. The alkalization of pH in the vaginal microbiota allows potential pathogens to enter or spread their colony there. Some accounts claim that the vagina is mostly occupied by Enterobacteriaceae and other fecal flora in an alkaline environment [40].

Ethnicity

In recent times, a variety of researchers have claimed that the ethnicity of the woman strongly influences the vaginal microbiota's composition, for instance, 396 North American women who appeared healthy and represented four ethnic groups had their vaginal microbiome evaluated by Ravel et al. (2011) for variances (White, Black, Hispanic, and Asian) [41]. These researchers found that Asian and White women (80.2% and 89.7%, respectively) had higher vaginal bacterial populations of Lactobacillus crispatus, Lactobacillus gasseri, Lactobacillus iners, and Lactobacillus jensenii than did Hispanic or Black women. Asian and White women showed lower pH levels than Black and Hispanic women (5.0± 0.59 and 4.7 ±1.04, respectively), suggesting that this trend may be related to pH fluctuations. Asymptomatic Japanese women, White and Black women from North America, and the researchers' findings all showed considerably varied bacterial type frequencies. These authors claim that lactobacilli communities are present in 24.7% of Japanese women, 40.5% of Black women, and 13.3% of White women. Additionally, Black women lacked the broad lactobacilli communities that were found in White and Japanese women [42].

Diet

Diet influences the vaginal tract as well as the gut microbiota, as is well documented. More precisely, studies show that a balanced diet high in nutrients, low in fat, and with a glycaemic index may lessen the incidence of BV. In addition, consuming more micronutrients, especially calcium, vitamin A, and folate, may reduce the incidence of bacterial vaginosis (BV). Additionally, higher vaginal Lactobacillus spp. abundance is linked to diets high in betaine [43]. Though the sample size was limited, a recent study by Song et al., (2020) found that vegetarian women had a higher total vaginal bacterial community than non-vegetarian women [44]. Obesity-related dysfunction/disturbances in the host metabolism, and hormonal, and immune system modulation, which may influence the vaginal environment, are potential underlying causes. Moreover, the dysbiotic gut microbiota composition that is linked to obesity can further influence the composition of the VMB by acting as an "extravaginal source" for vaginal bacteria. Larger research examining the impact of different diets and/or body mass index (BMI) on particular CSTs is limited, nevertheless.

Smoking

cigarette smoking has been linked to a vaginal microbiome that lacks the protective effects of Lactobacillus spp. In 2014, Brotman et al., (2010) assessed the vaginal microbiota of 20 women who smoked and 20 women who did not. According to these investigators, smokers' vaginal microbiome had lower concentrations of Lactobacillus spp [45]. than non-smokers did. Additionally, several studies have shown that smoking may increase the incidence of bacterial vaginosis in women. This increased susceptibility is probably due to smoking's anti-estrogenic effects and the presence of benzo[a]pyrene diol epoxide (BPDE), which has been found to encourage bacteriophage start in Lactobacillus spp [46].

Pregnancy

In addition to changes in the endocrine, metabolic, and immune systems, pregnancy results in considerable alterations in the microbiota, including a decrease in overall diversity and enrichment with Lactobacillus species. Freitas et al. carried out a comparison study between pregnant and non-pregnant women [47]. These researchers found that compared to non-pregnant women, healthy pregnant women had a higher bacterial load and a lower concentration of Mycoplasma and Ureaplasma in their vaginal microbiota. Additionally, the investigators discovered that pregnant women had a higher prevalence of Lactobacillus species than did non-pregnant women. David Pacha-Herrera et al., (2020) found a similar result when they used sequence-based methods to determine that Lactobacillus spp [48]. constituted the majority of the vaginal microbiota in pregnant women. Surprisingly, during pregnancy, the pH dropped, the amount of vaginal discharge increased, and the vaginal microbiota also changed. An increase in Lactobacillus species could act as a defense against pathogens during pregnancy since, as already mentioned, they have antibacterial properties [49].

Vaginal douching

Vaginal douching is the practice of cleaning or cleansing the intravaginal area, ideally with a liquid solution. The purposes of douche use include keeping oneself clean, preventing infections by washing the vagina with douche products, particularly after having sex or menstruating, treating various illnesses, preventing pregnancy, and other cosmetic reasons. Douching exposes females to infections by eliminating the healthy vaginal microbiome and permitting the growth of harmful germs. Most research indicates that frequent vaginal douching raises the risk of pelvic inflammatory diseases, ectopic pregnancy, preterm birth, decreased fecundity, Chlamydia trachomatis illnesses, Herpes simplex type 2 disorders, and bacterial vaginosis [50, 51].

Vaginal microbiota in different stages of life

Along with changes in a female's physiology and reproductive status, the vital functions and microorganisms in the reproductive tract also change. The composition of the microflora in the entire reproductive tract is crucial for both the ability to conceive and the maintenance of pregnancy, according to the accumulating facts. According to research on IVF (In-vitro Fertilization), the type of microorganisms present in the uterus interact at the time of embryo transfer, resulting in the formation of pregnancy. As a result of persistent behavioral and hormonal abnormalities, the vaginal microbiome significantly improves during a woman's life [52] (Figure 4).

In healthy women

In contrast to the vast majority of human body sites where elevated concentrations of bacterial diversity are typically hypothesized to be a characteristic of health, female reproductive tracts are assumed to be somehow healthy and active even in low microbial diversity situations where only one or a few Lactobacillus sp. reign supreme. A typical, healthy vaginal microbiome is primarily composed of Lactobacillus sp., which acts as a protective barrier by thwarting several uropathogens. The commonly recognized theory of vaginal health states that these beneficial bacteria produce hydrogen peroxide, which helps to maintain the low pH environment required for defense against harmful pathogens. In addition to an acidic pH, the mucous membrane contact has other immunological mechanisms available to it under normal conditions [53].

Reproductive age of women

As a consequence of the enhanced estrogen levels, substantial quantities of glycogen, the preferred food supply for lactobacilli, are deposited in the vaginal walls. The lactobacilli-colonized vagina of new-borns who are still affected by their mothers' high estrogen levels has an acidic pH, but as time passes and the estrogen begins to leave their bloodstream, the lactobacilli population decreases and the vaginal pH environment becomes neutral [54, 55]. Women of reproductive age are more likely to suffer urogenital disorders as a result of an unbalanced vaginal microbiome [56]. When the chance of reproduction is greatest, just before menopause and after adolescence, there are many lactobacilli in the vaginal microbiome. Increased estrogen levels help to restore the advantageous vaginal lactobacilli and acidic pH environment that decrease during and after adolescence because estrogen levels have an impact on the entire vaginal microbiome. During the premenopausal period, estrogen promotes the colonization of the vagina by lactobacilli, which metabolize glycogen, produce lactic acid, and preserve intravaginal health by lowering intravaginal pH values [57].

Women during the menopause stage

Postmenopausal women frequently experience hormonal, sexual, and genital issues in addition to climacteric disorders like insomnia, hot flashes, and melancholy [58]. The vaginal microbiota has a significant impact on the state of a postmenopausal woman's life, including her sexual health, vaginal dryness, vulvovaginal atrophy (VVA), etc. When a woman reaches menopause, the decline in estrogen levels that results in vulvovaginal atrophy has a substantial impact on her vaginal flora. Vulvovaginal atrophy (VVA), which causes symptoms like sexual dysfunction, bleeding after physical intimacy, burning when peeing, discomfort, irritation, and irregular vaginal discharges with foul odors, is thought to affect 25–50% of postmenopausal females [59]. Estrogen activity has an impact on the major link between menopause and vaginal microbiota. The natural microbial populations convert glycogen, and estrogen promotes the maturation of the vaginal epithelium by causing a buildup of glycogen, which produces organic acids (mostly lactate) to protect the reproductive tract. In postmenopausal women, decreased estrogen production results in a decrease in lactobacilli and an increase in intravaginal pH, both of which promote the colonization of the vagina by pathogenic bacteria. Controversial estrogen helps postmenopausal women manage the symptoms of vulvovaginal atrophy (VVA), but in some cases, particularly in people with a history of active liver disease, breast cancer, prior venous thromboembolic stroke, or coronary artery disorder, hormone therapy (HT) has been seen to make up the vast majority. Vaginal lubricants can help with some vulvovaginal problems; however, they are damaging to the vaginal microbiome, lamina propria, and vaginal epithelium. Estrogen therapy has also been related to serious adverse effects such vaginal bleeding, chest pain, and episiotomy pain [60].

Influence on sexual health and reproductive health

The female vagina has a naturally low pH because of the presence of hydrogen peroxide and lactic acid generated by Lactobacillus sp. The vaginal microbiome is disrupted by the regular disturbances of the vaginal environment, including the use of various lubricants, sexual activity, semen, menstruation, antibiotics, and hormonal contraception [61]. In the case of gut bacteria, antibiotics are also responsible for eliminating lactobacillus, which allowed dangerous pathogens to spread and grow [62]. Due to the reduction in Lactobacillus levels brought on by the use of conventional antibiotics, Pepto streptococcus anaerobic, Gardnerella vaginalis, Atopobium vaginae, Mobiluncus sp., Sneathia, Prevotella sp., Mycoplasma, Ureaplasma, and a variety of undeveloped or meticulous anaerobic organisms become much more energetic and can cause BV [63]. Therefore, a woman's reproductive health status can be inferred from the composition of her vaginal microbiome. Age also has an impact on the habitat of the vaginal microbiome [64]. As a result of the differences in microbial community composition among individuals, our understanding of the pathophysiology behind a wide range of illnesses, from atopic dermatitis to hepatocellular cancer, affecting certain areas of the body, is continually expanding [65, 66].

It has been demonstrated that the VM's structure affects IVF results, particularly diagnostic conception rate, implantation rates, and live birth rates, all of which are pertinent in uterine transplantation, where the live birth of a healthy infant is the main objective. Additionally linked to both premature and late miscarriage, and notably preterm birth is vaginal dysbiosis or lactobacillus depletion [47, 67, 68]. A healthful VM becomes much more lactobacillus dominant and much less diversified during pregnancy due to the impact of rising estrogen levels, but after delivery, when estrogen levels fall, many women acquire a lactobacillus-depleted or dysbiotic vaginal microbiome [35]. A lactobacillus-depleted or dysbiotic vaginal microbiome during pregnancy increases the risk of premature labor and, in particular, preterm prelabour barrier disruption. Contrarily, VM dominance of Lactobacillus crispatus is generally prophylactic towards premature birth. A higher incidence of neonatal early-onset sepsis has been linked to lactobacillus spp.-depleted or dysbiotic VMs [69, 70].

A healthy vaginal microbiota is essential for protecting against BV as well as other female reproductive illnesses like yeast infections, urinary tract infections (UTIs), sexually transmitted diseases (STDs), and more. Unbalanced vaginal microbiota frequently leads to vaginal infections, which can range from skin-related illnesses to potentially lethal disorders. For instance, a pregnancy-related streptococcus infection may result in circumstances that are lethal for the unborn child, and bacterial vaginosis may cause an early birth [71]. These infections necessitate prompt theragnostic, which entails a precise and expedient diagnosis followed by the appropriate course of therapy. If they are not promptly detected and treated, they might result in persistent vaginitis, pelvic inflammation, infertility, and endometriosis [72]. This section covers a variety of vaginal infections and ailments, including bacterial vaginosis, cytolytic vaginosis, vaginal candidiasis, and trichomoniasis.

Bacterial vaginosis disease (BV)

A disorder known as bacterial vaginosis (BV) affects the vaginal microbiome ecologically, upsetting the normal balance of the microbiota and causing an abundance of anaerobic bacteria. BV may manifest if some dangerous bacteria already present in the vagina—for example, Gardnerella vaginalis, Prevotella and Morbiluncus bacterial strains, Atopobium vaginae, etc.—have a chance to thrive. It is associated with preterm birth, poorer pregnancy outcomes, the emergence of STIs and STDs (including Chlamydia trachomatis, HIV, Neisseria gonorrhoeae, and HSV-2), as well as other vaginal conditions. Due to the lack of a foreign pathogen (such as HIV or syphilis bacteria) linked with BV, it is not considered an STI or STD [73].

As seen in Figure 5, common symptoms of BV include itching, a foul odor, soreness, and a burning sensation. Thin, white discharge from the vagina is another sign [74]. Women of reproductive age are more prone to have BV because of unsafe sex, douching, having several sexual partners, and other poor lifestyle choices. Additionally, BV rates vary across individuals from different ethnic groups with different vaginal flora. As a result, it is possible to conceptualize BV as a multifactorial illness that is influenced by a complex interplay between microbial, individual, and environmental factors.

Postmenopausal women are frequently reported to have BV due to huge colonies of anaerobic bacteria rather than lactobacilli in the vagina and higher vaginal pH (> 4.5) with more alkaline vaginal conditions. Both premenopausal and postmenopausal females have been reported to be affected negatively by this BV infection in terms of their gynecological and obstetric health. Although the recurrence rate is substantially greater and often occurs one year following therapy, antibiotics are typically used to treat it [75].

Cytolytic vaginosis

Other names for cytolytic vaginosis include Lactobacillus overgrowth syndrome and Doderlein's cytolysis. In typical circumstances, the female vagina has a significant amount of Lactobacillus, which aids in regulating the acidic pH microenvironment and releases lactic acid and hydrogen peroxide, an antibiotic. However, the overgrowth of these Lactobacilli results in a case of cytolytic vaginosis. Itching, vulval irritation (pruritus vulvae), burning or inflammation (vulvodynia and dysuria), and unpleasant sexual experience (dyspareunia) are all symptoms of lactobacilli overflow in the vagina. It is frequently misinterpreted as a fungal infection. Patients with diabetes mellitus (high blood sugar) are much more likely to contract this illness, and its symptoms are more pronounced when high levels of progesterone and estrogen occur in the luteal stage of the menstrual cycle [76].

Vulvovaginal candidiasis (VVC)

Candida sp. is the etiologic agent of vulvovaginal candidiasis (VVC), the second-most widespread and prevalent vaginal infection after BV. Premenopausal women with lower vaginal pH values (4.5) than BV are more susceptible to VVC than BV-positive women. Nearly 75% of fertile females get this illness just once throughout their lifetime. Uncomplicated VVC which is triggered by the Candida albicans (C. Albicans) species, typically affects non-pregnant women and results in mild to severe infections that can be cured with any antifungal medications [77]. Chronic and recurrent complex VVC is caused by non-C. albicans candidiasis. Complex VVC is more likely to develop in women of reproductive age, postmenopausal women who use exogenous estrogen, and women who have weakened immune systems [78]. Inflammation, edema, a cheese-like thick vaginal discharge, dysuria, and pruritus are typical signs of VVC [79]. Increased estrogen levels, diabetes mellitus, immunological state, and chronic antibiotic therapy are some of the potential causes for VVC formation, albeit the specific causes have not yet been determined (Table 2).

Table 2. Symptoms and causative agents of different vaginal infections