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Composition of vaginal flora and its role in the pathogenesis of bacterial vaginosis

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  • Save American Journal of Medicine and Medical Sciences 2021, 11(2): 154-159 DOI: 10.5923/j.ajmms.20211102.19 Composition of the Vaginal Flora Community and Its Pathogenetic Role in Bacterial Vaginosis Rakhmatullaeva Makhfuza Mubinovna, Nurxanova Nilufar Odilovna Bukhara State Medical Institute, Bukhara, Uzbekistan Abstract The review article presents an analysis of the literature data characterizing the vaginal microbiota in bacterial vaginosis. A modern view of the pathogenetic properties of Gardnerella vaginalis isolated in women with and without BV is presented. Issues related to the mechanisms of maintaining the vaginal ecosystem with the participation of Lactobacillus iners were discussed. Pathogenetic bases of bacterial vaginosis development associated with biofilm formation and release of lipopolysaccharides of gram-negative bacteria are considered. Keywords Vaginal microbiota, Bacterial vaginosis, Gardnerella vaginalis, Bacterial biofilm 1. Introduction Bacterial vaginosis (BV) is characterized by significant changes in the composition of the vaginal microbiota from communities with dominance of lactobacilli to a polymicrobial community [1], pushing the total extent of colonization of the vagina by a variety of microorganisms (up to 109–1011 CFU/ml), mostly anaerobic microflora (the proportion of Gardnerella vaginalis, Mycoplasma hominis, Mobiluncus spp.), increase in vaginal discharge pH (over 4.5) [2]. The change in acidity characteristic of BV contributes to the formation of "key cells" – epithelial cells, on the surface of which a significant number of opportunistic microorganisms adhere, using energy and substrate reserves. The maximum density of bacterial cells on the surface of the epithelium was recorded at a pH of 5.0 to 6.0 [2]. A large variety of the detected microflora in bacterial vaginosis was revealed [3]. The presence of certain members of the vaginal community has been associated with specific clinical characteristics of BV [4], but it has not yet been proven that any particular microorganism or group of microorganisms plays a role in the development of the disease. Many of these bacterial vaginosis-associated bacteria (BVAB) are common representatives of the normal vaginal microbiota [5], but to date little has been studied about the synergistic or antagonistic effects between them [1]. 2. Properties and Types of Bacteria Representing BV Received: Feb. 6, 2021; Accepted: Feb. 26, 2021; Published: Feb. 28, 2021 Published online at Since Gardnerella vaginalis is the most common bacterial species in BV [6], most studies have focused on it. A number of studies are related to the special ability of Gardnerella vaginalis to form biofilms, which is an important link in the pathogenesis of BV [7]. Alves P. et al. [8] 30 species of BVAB were isolated, and their virulence was characterized in model experiments, including such parameters as high adhesion, cytotoxicity, and a predisposition to form biofilms. It was shown that most of them tended to grow as biofilms, but Gardnerella vaginalis had the highest virulence. The main virulence factors of Gardnerella vaginalis are cytotoxicity, the ability to produce the enzyme sialidase, adhesion to epithelial cells, and the ability to form bacterial films [8]. Gardnerella vaginalis produces a protein toxin – vaginolysin, which leads to the lysis of red blood cells. Some strains of Gardnerella vaginalis can produce the enzyme sialidase, which releases sialic acids. Sialic acids are used by pathogens as a mechanism of adhesion to cellular and inert surfaces, increasing the ability to produce biofilms, as a food source, as well as to change the physiological mucosal barrier and to protect against the host's immune response [6]. It should be mentioned that the species Gardnerella vaginalis is a very diverse taxon, both phenotypically and genotypically. Two forms of existence of Gardnerella vaginalis that do not pass into each other were found: dispersed – which is part of the normal microflora, and does not occur in BV, the other in the form of biofilms, was found in women with BV and their sexual partners [9]. It was also found that Gardnerella vaginalis isolates isolated from BV-positive women have significant differences in the content of the genome and the order of genes with variable metabolic and virulent ability [3]. A recent analysis of the entire genome sequence showed that there are 13 species within the genus Gardnerella [10]. American Journal of Medicine and Medical Sciences 2021, 11(2): 154-159 155 Complete genome sequencing of various strains of Gardnerella vaginalis in combination with the study of their phenotypic characteristics revealed significant differences in the level of pathogenicity between different strains of Gardnerella vaginalis [11,12]. Misha K. et al [13] in their study showed the relationship between biotypes and virulence factors of Gardnerella vaginalis. Most Gardnerella vaginalis isolates isolated from BV-positive women show a greater number of virulence factors than isolates found in healthy women. According to the authors, isolates associated with BV showed better adhesion, biofilm formation, hemagglutination, phospholipase and protease production compared to isolates not related to BV. Similarly, in another study, the presence of a gene encoding sialidase was found in BV-positive vaginal samples of women, whereas strains isolated from BV-negative women were characterized by the absence of a gene encoding sialidase [14]. Recent studies show that Gardnerella vaginalis may be a necessary but insufficient stimulus for the development of BV [15], since the presence of this bacterium does not always lead to BV [16]. Studies by Janulaitiene M. et al. [14] showed that Gardnerella vaginalis is present in the vagina in women who do not have signs of BV, and the incidence of BV is significantly higher, which suggests that each member of the polymicrobial community of this ecosystem can play a role in the pathogenesis of the disease. The second frequency of occurrence after Gardnerella vaginalis were identified bacteria of the genus Prevotella. The proportion of gram-negative microorganisms Prevotella spp. among all anaerobes isolated from BV-positive women is about 44-78% [17]. A positive correlation was observed between the detection of Prevotella DNA and the species diversity of opportunistic flora [17]. A number of studies have also noted the manifestation of synergy between Gardnerella vaginalis and Prevotella spp. and other bacterial vaginosis-associated microorganisms [15]. Machado A. et al [18] also noted the symbiotic relationship between Gardnerella vaginalis and Prevotella bivia, demonstrating that the presence of the Gardnerella vaginalis biofilm stimulates the growth of Prevotella bivia in vitro. It is known that for gram-negative bacteria, including Prevotella spp., the most pathogenetically significant, of course, is the exopolysaccharide of the cell wall. By using surface polysaccharides to mimic the host's glycan structure, pathogenic bacteria can evade the host's immune system during colonization [19]. Perhaps this feature does not exclude the successful colonization of both Prevotella spp. and Gardnerella vaginalis and creates conditions for the realization of pathogenic properties of bacteria. Currently, a number of BVAB have been identified using molecular biological diagnostic methods, such as Atopobium vaginae, Megasphaera spp., Eggertella spp., Leptotrichia spp., Dialister spp., Slackia spp., BVAB-1, BVAB-2, BVAB-3, Sneathia spp., etc. [4,5,20]. Like Gardnerella vaginalis, Atopobium vaginae is also an almost universal marker of BV [14]. According to Shipitsina EV. et al. [21] the DNA of Gardnerella vaginalis and Atopobium vaginae was detected in 93 and 83% of women with BV, respectively. Both microorganisms were also found in many women with vaginal eubiosis (in 52 and 38% of cases, respectively), but the concentration of these bacteria in vaginal samples in women with normoflora was significantly lower than the concentration in samples in women with BV. It should be noted that the synergy between these microorganisms is confirmed by the fact that Atopobium vaginae is extremely rare in the absence of Gardnerella vaginalis [22]. Atopobium vaginae produces a large amount of lactic acid compared to acetic and formic acids and is a strict anaerobe [23]. In an in vitro model, it was demonstrated that Atopobium vaginae stimulates the innate immune response of epithelial cells by interacting with TLR2, leading to the launch of the production of IL-6, IL-8 and the antimicrobial peptide β-defensin, and this may contribute to the pathogenesis of BV [24]. The bacterium rarely exists in the form of single planktonic forms, as it quickly loses its viability [25], it is more characteristic of its existence in complex polymicrobial communities surrounded by extracellular matrices – biofilms [9]. Eubacterium, gram – positive bacteria of the Eubacteriacea family, has a significant association with BV. In a study by Nazarova VV. et al. [20] this microorganism was identified in almost all BV-positive women, and its content in some samples was quite high (up to 60% of the total bacterial mass). Mobiluncus spp./Corynebacterium spp. (95.2%) and Megasphaera spp./Veillonella spp./Dialister spp. (92.9%) are also present in significant amounts in BV. Ureaplasma spp. it is detected more often than Mycoplasma hominis in BV. According to the authors, the frequency of detection of Ureaplasma spp. is 69-71.2%, and Mycoplasma hominis – 28-34.2% [20]. The role of Corynebacterium spp. is considered in the literature of recent years as a causative agent of infectious and inflammatory pathology of the vagina. The ability of Corynebacterium spp. the ability to produce organic acids, thus reducing pH, the ability to stimulate the production of anti-inflammatory cytokines, increase the antagonistic activity of acid-producing lactobacilli against opportunistic microorganisms, as well as the ability to destroy biofilms of pathogenic microorganisms indicates an important role of these microorganisms in the formation of eubiosis and, probably, in protecting the vaginal biotope from infection in those women who do not have lactobacilli [26]. Regarding Candida spp. we can say that they (Candida albicans) are one of the most common representatives of the vaginal microflora, although there are enough studies that argue that Candida spp. infections are reflected in a significant change in the ecology of the vagina [1,29]. It is known that Candida albicans fungi can transform from yeast to hyphae under favorable conditions [27]. Due to the morphological plasticity that promotes the formation of yeast in hyphae in Candida albicans, they can easily invade 156 Rakhmatullaeva Makhfuza Mubinovna and Nurxanova Nilufar Odilovna: Composition of the Vaginal Flora Community and Its Pathogenetic Role in Bacterial Vaginosis the epithelial cells of the vagina with the development of symptomatic vulvovaginal candidiasis [28]. When the vaginal microbiota is disturbed (the presence of BVAB, a reduction in the population of lactobacilli), the invasive ability of Candida albicans increases [29]. As you can see, BV is associated with a huge range of bacteria. Five species of bacteria, namely Atopobium vaginae, Gardnerella vaginalis, Eggerthella-like, Megasphaera ph. and Leptotrichia / Sneathia were found in most BV-positive women and can be considered as bacterial indicators of this disease [14]. BV-associated microorganisms are quite often found in the vagina of women without clinical manifestations of this condition [5]. It should be noted that the normal functioning of the vaginal microbiocenosis, which is represented by BVAB, was maintained even with a deficiency of Lactobacillus spp. due to the ability of bacteria of the genus Atopobium vaginae, Megasphaera spp., Leptotrichia spp. and Corynebacterium spp. to produce lactic acid. Although the structure of microbial communities may vary from population to population, the stability of the vaginal ecosystem can be maintained if the protective function of these communities, i.e. the production of lactic acid, is maintained. Therefore, the absence of lactobacilli or the presence of certain microorganisms, such as Gardnerella vaginalis, Peptostreptococcus spp., Prevotella spp., Pseudomonas spp., Streptococcus spp. and/or Corynebacterium spp., is not a pathological condition [5,26]. In this case, it is likely that the composition of the community is controlled by the efforts of these microorganisms. Despite the fact that B B has been studied for several decades, there are many gaps in understanding the etiology and pathogenesis of this disease. Given the polymicrobial nature of the disease and the complexity of its pathogenesis to date, the only root cause of vaginal dysbiosis has yet to be determined. 3. The Role of Lactobacillus iners in the Development of Vaginal Dysbiosis A healthy vaginal environment created by lactobacilli through the production of lactic acid, hydrogen peroxide, and bacteriocins prevents the reproduction of BVAB [30]. Lactic acid increases the activity of both bacteriocins and hydrogen peroxide. In addition, lactobacilli compete for binding to the receptors of vaginal epithelial cells, which actually prevents the adhesion of pathological microorganisms to these cells. The main, but not the only link in the pathogenesis of this polymicrobial clinical syndrome is a decrease in the population of acid-producing and an increase in the pH of the vaginal fluid. According to Campisciano G. et al. [31] in women with BV, a decrease in the number of dominant species of acid-producing lactobacilli was revealed, with a massive increase in the number of rare Lactobacillus species, while at the same time a low presence of Gardnerella vaginalis was observed. Most researchers have now concluded that the presence of Lactobacillus iners is associated with a high risk of replacing the normal vaginal microflora with a pathological one [3, 20]. This is due to the fact that this type of lactobacilli does not produce hydrogen peroxide and has the ability to adapt to increased pH values of the vaginal environment. Due to the structure of its genome, Lactobacillus iners has the ability to quickly adapt to changing environmental conditions [3], switching its metabolism and using as a nutrient substrate not glycogen, but glycerin of phospholipids of the destroyed cell membranes. Lactobacillus iners produces toxin-cholesterol-dependent cytolysin, similar in properties to Gardnerella vaginalis vagolysin, and under conditions of insufficient acidity (at pH 4.5-6.0), its production is 6 times more active than at pH less than 4.5 [32]. At the same time, other types of lactobacilli die, the concentration of lactic acid decreases, and the pH of the vaginal environment increases. As a result of changing the pH of the vaginal fluid, the tissue potential difference decreases, which leads to a decrease in the negative charge of the surface of epithelial cells, as a result of which the adhesive ability of conditionally pathogenic anaerobic microflora increases [33]. It is noteworthy that the decrease in the acidity of the vaginal ecosystem favors the growth of anaerobes, which increase not only in number, but also in diversity in BV [4]. However, as with other changes associated with BV, studies have not been able to conclude whether the decrease in vaginal fluid acidity was a cause or consequence of dysbiosis. 4. Views on the Process of Biofilm Formation of BVAB The second important link in the pathogenesis of B C is the increased growth of opportunistic flora with the gradual formation of biofilms. In a study by Hardy L. et al. [22] biofilms were found in half of the women with BV included in the study. When analyzing biofilms obtained from patients with BV by fluorescence in situ hybridization (FISH) using probes to bacterial rRNA, it was shown that the biofilm contained Atopobium vaginae in 54.1% and Gardnerella vaginalis in 82.0% of the samples. At the same time, Gardnerella vaginalis was also detected in almost all cases of detection of Atopobium vaginae. Atopobium vaginae accompanied Gardnerella vaginalis in 99.5% of the samples. It is obvious that the symbiosis of these two microorganisms plays an important role in the formation of bacterial biofilms, and as the authors suggest, the formation of biofilms is more likely when Atopobium vaginae is present in this community [22]. Moreover, given that Atopobium vaginae almost always accompanies Gardnerella vaginalis in BV biofilms, Castro J. et al. [25] put forward the hypothesis that Atopobium vaginae may use Gardnerella vaginalis to survive in the ecosystem American Journal of Medicine and Medical Sciences 2021, 11(2): 154-159 157 of the vagina. In an in vitro model using the FISH method, the authors confirmed that Atopobium vaginae is able to maintain viability when co-cultured with Gardnerella vaginalis and can be incorporated into a biofilm preformed by Gardnerella vaginalis taking into account up to 20% of the total number of biofilm cells. An equally important link in the pathogenesis is an increase in the activity of proteolytic enzymes-sialidase and mucinase [34], which disrupt the function of mucin formation. As a result, the availability of epithelial cells for the adhesion of anaerobic microorganisms increases. In polymicrobial infection, different types of microorganisms can play different roles in the initiation and development of BV [15]. The ability of BVAB bacteria to attach to the surface of epithelial cells plays an essential role in understanding the pathogenesis of BV. Since initial adhesion is the first step in biofilm formation [8], it was determined which species are most common in the early stages of BV development. Interestingly, only Gardnerella vaginalis and Mycoplasma hominis had the property of adhering in the in vitro model to HeLa cells (uterine endothelial cells). This suggested that these two species may play an important role as early colonizers in BV [15]. It is noteworthy that the first species associated with BV may be Prevotella bivia. Muzny CA. et al. [35] examining daily smear samples, it was found that the content of this species tends to increase relative to its initial level before the occurrence of BV. In an in vivo model, Gilbert NM. et al. [36] after studying the synergistic relationship between Gardnerella vaginalis and Prevotella bivia, it was concluded that in the case of a single presence, both bacteria do not show their pathogenic potential, and only when they are co-colonized through the production of sialidase, induction of epithelial exfoliation, and promotion of Prevotella bivia into the uterus, Gardnerella vaginalis directly contributes to the pathogenesis of BV and its associated symptoms and outcomes. Muzny CA. et al. [15] proposed a conceptual model for the pathogenesis of BV, where Gardnerella vaginalis and Prevotella bivia were considered early colonizers, and Atopobium vaginae and other BVAB as secondary colonizers of BV. It has been suggested that Gardnerella vaginalis competes with vaginal Lactobacillus spp. and allows other BV-associated bacteria to interact and grow in biofilms, vaginal sialidase and other enzymes produced by Gardnerella vaginalis and Prevotella bivia contribute to the destruction of the mucous layer of the vaginal epithelium and the loss of the protective mucosal layer leads to increased adhesion of secondary colonizers, including Atopobium vaginae, to the mature polymicrobial biofilm BV [35]. Primary colonizers of Gardnerella vaginalis and Prevotella bivia can evade the immune system of the macroorganism and do not cause a strong inflammatory response from the vaginal epithelial cells [36]. Atopobium vaginae and other BVABs stimulate a vivid manifestation of the body's inflammatory response to the resulting imbalance of the vaginal microflora and contribute to the development of adverse outcomes and difficulties in treatment [34]. Microbial biofilms consist of single bacteria and their aggregates surrounded by an organic matrix. They can cover the surface of the cells of the macroorganism, or they can also be located in the mucous layer secreted by the cells [7]. Macroorganism components such as fibrin, immunoglobulins, or platelets can be integrated into the biofilm matrix [37]. Biofilms can consist of one type of microbes or be polymicrobial, as well as contain fungi [38]. It is known that more than 90% of bacterial species have the ability to form biofilms. It should be noted that an increase in the probability of biofilm formation is associated with an increase in the number of opportunistic microorganisms in the medium up to 106 CFU/ml [38]. Biofilm formation in BV is a mechanism of virulence, and this increases pathogenicity [35]. According to a number of authors, bacterial biofilms cause a prolonged course of the process and a tendency to its chronization, lead to the ineffectiveness of traditional antimicrobial therapy methods [34,38]. Biofilms on the mucous membranes can block the inflammatory response, and the bacteria in the biofilm do not respond to the immune system of the macroorganism. In addition, they preserve the viability of microorganisms at concentrations of hydrogen peroxide and lactic acid 4-8 times higher than required for the suppression of individual bacteria outside the films. It is assumed that when exposed to an antibiotic within the biofilm, the number of resistant microorganisms may initially be insignificant, but with repeated use of drugs of the same group, due to the exchange of resistance plasmids (transmission of resistance from species to species), the number of resistant bacteria increases, which as a result leads to rapid colonization of the biofilm with resistant forms [34]. The presence of a permanent and adhesive bacterial biofilm of Atopobium vaginae together with Gardnerella vaginalis was confirmed, which may be the reason for the lack of effect from the treatment of BV when using metronidazole [34]. In the literature of recent years shows that active work on the study of pathogenetic aspects of BV with the inclusion of factors such as the interaction of the host organism by microorganisms, especially immune status, and genetic characteristics of macro- and microorganisms [31,39]. 5. Conclusions Thus, the indication of Lactobacillus iners and rare species of lactobacilli may indicate a predisposition to the development of BV. The formation of the Gardnerella vaginalis biofilm in association with Prevotella bivia and further attachment of Atopobium vaginae to this biofilm plays an important role in the pathogenesis of BV. However, an analysis of the literature data shows that the mechanisms of maintaining the vaginal ecosystem and the development of bacterial vaginosis remain not fully understood. The degree of protection provided by different 158 Rakhmatullaeva Makhfuza Mubinovna and Nurxanova Nilufar Odilovna: Composition of the Vaginal Flora Community and Its Pathogenetic Role in Bacterial Vaginosis communities of the vaginal ecosystem is to be formulated by studying the intraspecific metabolomic characteristics of bacteria and the influence of their metabolites on inter-microbial relations in the community. 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