Vaginal microbiocenosis and factors affecting its condition
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1. Maternity Hospital at City Clinical Hospital No. 8, Moscow
2. Perinatal Center of City Clinical Hospital No. 29, Moscow
3. V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Moscow
Causes of Disturbances in the Vaginal Microbiocenosis
The study of the vaginal biocenosis is currently a focus of attention not only for clinical microbiologists but also for a wide range of clinical specialists. This is because the functioning and coordinated interaction of all parts of the microecosystem are ensured by the activity of the immune and endocrine systems, reflect their functional state, and depend on both internal and external environmental factors. A disruption in any of these parts invariably causes a disturbance in the vaginal microecology, which can subsequently lead to the development of inflammatory processes in the genital tract [1, 7, 20].
83% of patients suffering from disorders of the urogenital tract microbiocenosis have food, drug, or mixed allergic reactions, indicating a decrease in certain adaptive mechanisms and strain on the immune system.
50–55% of women suffering from bacterial vaginosis are found to have intestinal dysbiosis, indicating a unified dysbiotic process in the body with a dominant manifestation either in the genital or digestive system [2, 4, 8].
It has now been established that bacterial vaginosis is not only a cause of unpleasant discharge but also a risk factor, and sometimes one of the causes, of severe pathology of the female genital organs and complications of pregnancy and childbirth.
The vaginal biocenosis is a microecosystem, the features of which are determined not only by the vaginal microflora but also by the anatomical structure, histological structure of the mucous membrane, and the biological properties of the vaginal fluid [5, 10, 14]. It is known that the vaginal mucosa is covered by a non-keratinizing stratified squamous epithelium without glands, consisting of several cell layers: basal, parabasal, intermediate, and superficial. During cytolysis of the superficial cells, glycogen is released from the cytoplasm and becomes a nutrient substrate for providing energy and plastic processes for the normal vaginal microflora [6, 12, 18].
The normal vaginal microflora is subdivided into obligate, facultative, and transient.
Obligate microorganisms are mandatory components of it and prevent the development of pathogenic microbes that have entered the vagina.
Representatives of facultative microorganisms (non-pathogenic and opportunistic) are quite frequently, but not always, found in healthy women.
Transient microorganisms (non-pathogenic, opportunistic, pathogenic) are accidentally introduced into the genital tract from the environment. Under conditions of a normal biotope, they remain in the vagina for a short time and are quickly removed by the flow of mucus and through the activity of the mucociliary epithelium. If the protective mechanisms are impaired, pathogenic or opportunistic microorganisms from the transient or facultative flora attach to the cells of the vaginal epithelium (adhesion) with subsequent multiplication and tissue damage, resulting in the development of an inflammatory reaction [2, 5, 13, 18, 20].
The main representatives of the obligate microflora of the vagina in women of reproductive age are lactobacilli (Döderlein's bacilli). They play a major role in maintaining the normal vaginal biocenosis due to high competitiveness and antagonism towards most pathogenic and opportunistic bacteria [1, 3, 5, 19]. Lactobacilli metabolize glycogen to glucose and ultimately to lactic acid, which maintains the acidic reaction of the vaginal content (pH 3.8–4.4), necessary for the growth of the lactobacilli themselves [7, 9, 11, 19].
Materials and Methods of the Research
The species composition of lactobacilli varies among women [4, 10, 12, 18]. Species of lactic acid bacteria (Lactobacillus) obtained from vaginal samples of healthy women include: L. acidophilus, L. jensenii, L. casei, L. gasseri, L. crispatus, L. plantarum, L. fermentum, L. cellobiosus, L. brevis, and L. salivarius [5, 13, 20]. Most commonly found are microaerophilic, hydrogen peroxide-producing species, and less frequently, anaerobic species of lactobacilli [2, 7, 13, 16]. Lactobacilli that produce hydrogen peroxide are of particular importance in maintaining the normal vaginal microbiocenosis, with their detection frequency ranging from 46.5% to 100%. Their normal quantity in the vagina is 10⁵–10⁹ CFU/ml [5, 10, 13, 18]. It is the hydrogen peroxide produced by lactobacilli, together with peroxidase from cervical mucus and halide compounds, that suppresses the proliferation of many pathogenic microorganisms [7, 12]. For instance, according to data by V.N. Prilepskaya and G.R. Bayramova [6], hydrogen peroxide-producing lactobacilli are detected in 5% of women with bacterial vaginosis, 37% with an intermediate type of biocenosis, and 61% with normocenosis. Thus, the acidophilic microflora serves as a natural microecological barrier against the penetration of exogenous microorganisms into the vagina.
The protective properties of the endogenous vaginal microflora are realized through the following mechanisms [6]:
- Blocking adhesion receptors for foreign microorganisms;
- Competing with exogenous infection for nutritional substances;
- Producing short-chain fatty acids, peroxides, and bactericides;
- Stimulating the motility of the vaginal mucosal epithelium and the process of its renewal on the cell surface;
- Inducing an immune response against pathogenic microorganisms;
- Producing stimulators of immunogenesis and activators of phagocytic and enzymatic activity.
The concomitant microflora is mainly represented by aerobic, facultative anaerobic, and strict anaerobic microorganisms. Cultural studies can detect more than 30 species of microorganisms in the vagina of a healthy woman of reproductive age [3, 11, 13]. It should be noted that the application of modern molecular genetic identification methods allows for the detection of over 300 species of microorganisms in the vagina of a healthy woman. Research by domestic and foreign authors [7, 16] has shown that in some women, normal microflora is maintained even in the absence of lactobacilli. Bacteria such as Atopobium, Megasphaera, and Leptotrichia, which are also producers of lactic acid, can act as the dominant microorganisms in the microflora. This is possible when the proportion of lactobacilli in the vaginal microflora decreases for any reason; in this case, other lactate-producing bacteria occupy their niche in the vaginal microcenosis.
Research has shown that the normal vaginal microflora can also include staphylococci, mycoplasmas, corynebacteria, streptococci, peptostreptococci, Gardnerella, bacteroides, enterococci, enterobacteria, veillonella, and bifidobacteria, as well as yeast fungi of the genus Candida. The total proportion of these microorganisms should not exceed 5–8% [3, 12].
Many scientists have conducted several independent studies to characterize vaginal microbial communities in women of reproductive age [1, 12, 19]. The authors established that the concept of "norm" is relatively individual and depends on ethnic background and geographic location [13, 15].
Throughout a woman's life, changes occur in the epithelium due to fluctuations in ovarian hormone secretion, phases of the menstrual cycle, and pregnancy. Normally, the vagina of newborn girls is sterile in the first hours of life. Within the first 24 hours, it becomes colonized by lactobacilli and other aerobic and facultative anaerobic microorganisms from the intestines. Under the influence of maternal estrogens, vaginal epithelial cells accumulate glycogen, which is broken down to lactate, creating an acidic environment. During this period, the vaginal microflora of newborn girls resembles that of healthy adult women. After 3 weeks, maternal estrogens are completely metabolized, and the epithelium becomes thin. The overall colonization and number of lactobacilli in the vagina decrease, the acidic environment shifts to neutral, strict anaerobes begin to dominate the microflora, and the microbial count decreases. During puberty, with the activation of ovarian function and the appearance of endogenous estrogens, the thickness of the vaginal epithelium increases, and the number of receptor sites for lactobacilli adhesion rises. Lactobacilli become the dominant microorganisms in the vagina [3, 6, 19].
The greatest thickness of the vaginal epithelium is observed at the peak estrogen level – in women of reproductive age during the middle of the menstrual cycle. At this time, the cell cytoplasm contains a large amount of glycogen. As a woman enters menopause, estrogen and consequently glycogen levels in the genital tract significantly decrease. The overall bacterial level drops considerably, primarily lacto- and bifidobacteria. The qualitative composition of the microflora becomes scarce, with a predominance of obligate anaerobic bacteria. During this period, the pH of the vaginal environment becomes neutral [6, 13].
Some authors believe that the flora composition in the vagina of healthy women of reproductive age is quite stable and hardly changes even during menstruation [3, 6, 17]. However, according to other researchers, the qualitative and quantitative composition of the vaginal microflora is subject to various changes. For example, during the menstrual cycle, due to fluctuations in the secretion of sex hormones, days dominated by lactobacilli alternate with days dominated by Gardnerella and bacteroides [1, 3, 20].
To assess the state of the vaginal microflora, A.F. Heurlein proposed a bacteriological classification of four degrees of vaginal purity in 1910, taking into account the number of leukocytes, epithelial cells, and lactobacilli.
Considering modern achievements in clinical bacteriology and knowledge of infectious pathology of the female genital organs, E.F. Kira [3] developed a classification of vaginal biocenosis, which presents a microscopic characterization of 4 types of vaginal biocenosis corresponding to the main nosological forms:
- Normocenosis: Characterized by the dominance of lactobacilli, absence of Gram-negative microflora, spores, and mycelium of yeast-like fungi, presence of single leukocytes and "clean" epithelial cells. This picture reflects the typical state of the normal vaginal biotope.
- Intermediate Type: Moderate or reduced number of lactobacilli, presence of Gram-positive cocci, Gram-negative rods. Leukocytes, monocytes, macrophages, and epithelial cells are detected. It is a borderline type, often observed in healthy women, rarely accompanied by complaints and clinical manifestations.
- Vaginal Dysbiosis: Expressed as a small number or complete absence of lactobacilli, abundant polymorphic Gram-negative and Gram-positive rod and coccal microflora, presence of "clue cells." The number of leukocytes is variable, absence or incompleteness of phagocytosis is noted. Corresponds to the microbiological picture of bacterial vaginosis.
- Vaginitis (Inflammatory Type of Smear): Polymicrobial smear picture with a large number of leukocytes, macrophages, epithelial cells, marked phagocytosis is noted.
In 1991, R.P. Nugent et al. [16] proposed laboratory criteria for diagnosing bacterial vaginosis, which are still widely used in world medicine. They are based on a scoring system, where the combination of points assesses the degree of bacterial vaginosis based on three bacterial morphotypes in the vagina:
A – Lactobacilli – large Gram-positive rods (Lactobacillus acidophilus: large gram-positive rods);
B – Vaginal Gardnerella and Bacteroides – small Gram-variable and Gram-negative rods (Gardnerella vaginalis and Bacteroides species: small gram-variable or gram-negative rods);
C – Mobiluncus – curved Gram-variable rods (Mobiluncus species: curved gram-variable rods).
Vaginal smears are Gram-stained and evaluated on a 10-point scale based on the presence or absence of Lactobacillus morphological types under oil immersion (1000x magnification). A score of 0 to 3 indicates a predominance of normal Gram-positive microflora, 4–6 an intermediate state, and 7–10 a state corresponding to bacterial vaginosis, where the sample is dominated by small Gram-negative rods, straight and curved rods with variable Gram staining.
The problem associated with antibiotic use deserves special attention, as it in some cases leads to a vicious cycle. The necessity of using this type of drug to eliminate one infectious agent leads to the worsening of dysbiosis and the growth of other pathogens. The problem of vaginal dysbiosis is particularly acute during pregnancy, as it significantly affects the health and microflora of the newborn, as well as the course of the postpartum period in parturient women. A number of studies have established that as pregnancy progresses, the frequency of occurrence of opportunistic microorganisms increases. According to Russian authors, pathogenic and opportunistic flora account for up to 51.4% by the end of pregnancy [1, 5], and the frequency of disturbances in the microbiocenosis of the birth canal in women at risk of obstetric pathology during pregnancy averages 40–65% [7].
Based on available literature, it can be concluded that the vaginal microflora significantly influences the course of gestation. According to B. Anderson [9], bacterial vaginosis in combination with sexually transmitted infections (STIs) was detected in 84.6% of pregnant women with fetal growth restriction. There is evidence indicating that intrauterine infection (IUI) is one of the important mechanisms that can explain the genesis of 25–40% of preterm births [3, 9, 18]. Preterm birth is the leading cause of neonatal mortality worldwide [2, 5, 21], but the etiology of their occurrence remains largely unknown. A number of scientific works indicate a potential link between the spectrum of bacteria identified in amniotic fluid and the vaginal microbiota, with the latter being a constant reservoir and potential source of infection [13, 18, 20]. There is no doubt that the vaginal microflora affects both the course of pregnancy and the postpartum period, as well as the health of the newborn [2, 8, 12]. During childbirth, primary contamination of the child's body with the vaginal microflora occurs. The composition of the parturient woman's vaginal microflora determines the microflora of the conjunctiva, gastrointestinal tract, and skin of the newborn, which become identical to the microflora of the mother's birth canal [4, 7, 17].
Postpartum infectious-inflammatory diseases represent an important medical and social problem. Their frequency, according to various authors, ranges from 5% to 26%, and in the structure of causes of maternal mortality in the Russian Federation, they rank 2nd to 4th. Moreover, maternal mortality from septic complications accounts for 13–15% [2, 7].
Prevention of postpartum infection includes determining risk factors for purulent-inflammatory diseases, sanitizing foci of genital and extragenital infection, including vaginitis, rational management of labor, and should begin at the antenatal clinic and continue in the maternity hospital. The frequency of postpartum complications shows no clear tendency to decrease, which is associated with an increase in the number of women with concomitant extragenital pathology, induced pregnancy, hormonal treatment and surgical correction of isthmic-cervical insufficiency in cases of recurrent miscarriage, increased frequency of surgical delivery, widespread (sometimes irrational) use of antibiotics, etc. [1, 6, 8, 15].
The emergence of infectious-inflammatory diseases (IID) caused by autoflora is the most well-known, though not the only, consequence of the disruption of immunological and/or microbiological balance in the human body. Among the main reasons leading to the growth of opportunistic infections, most authors unanimously point to aggressive antibacterial therapy and the expansion of the contingent of immunodeficient individuals, including among pregnant women [18]. It is currently considered proven that the main reason for the development of diseases associated with the disruption of the normal microbial landscape of the mucous membranes lies in the disturbance of the immunobiological homeostasis of the macroorganism [7, 12, 21]. Thus, on one hand, the disruption of normocenosis causes suppression of local immune reactions, and on the other hand, against the background of reduced immunobiological defense, conditions arise for the realization of the pathogenic action of commensals, which, in turn, further exacerbates the immunological inadequacy of the organism [9, 16].
Successful Treatment of Bacterial Vaginosis
Successful treatment of bacterial vaginosis, like any disease, depends on correct and timely diagnosis and the implementation of pathogenetically justified therapy. Based on the understanding that vaginosis is a non-inflammatory but still infectious process, many practitioners primarily use antibacterial agents with various mechanisms of action.
The main directions for treating bacterial vaginosis are selective decontamination (selective elimination of disease pathogens) and the restoration of normal vaginal microflora. The goals are to relieve clinical symptoms, normalize laboratory parameters, and prevent the development of potential complications during pregnancy, in the postpartum period, and during invasive gynecological procedures.
Currently, many methods are proposed for correcting vaginal microflora. Despite numerous regimens and approaches, the search for an effective treatment method continues to this day.
Three groups of agents are used to restore microflora: probiotics, prebiotics, and synbiotics. Probiotics are food products, medications, or dietary supplements in the form of monocultures or combined cultures based on live representatives of the resident microflora (bifidobacteria, lactobacilli, enterococci) or non-pathogenic spore-forming microorganisms and Saccharomyces.
The study by L. Krauss-Silva et al. [13] proved the feasibility of using probiotics to correct disorders of the vaginal microbiocenosis. This randomized, double-blind, placebo-controlled study included 125 women aged 18 to 44 years diagnosed with bacterial vaginosis based on clinical signs, Nugent criteria, and the presence of the sialidase enzyme. All women received oral metronidazole (2 g) once daily from day 1 to day 7, and either probiotics – Lactobacillus rhamnosus GR-1 (2.5 x 10⁹) and L. reuteri RC-14 (2.5 x 10⁹) – or a placebo twice daily from day 1 to day 30 of treatment. By day 30 of the study, bacterial vaginosis persisted in 30% of women in the placebo group but was not detected in the probiotic group, while 30% in the placebo group and 12% in the probiotic group were classified into the intermediate category based on Nugent scores, sialidase test results, and clinical signs. An increase in the number of Lactobacillus sp. (>10⁵ CFU/ml) in the vagina was also found in 96% of women receiving the probiotic and in 53% in the control group. Thus, the efficacy of using lactobacilli in combination with an antibiotic for treating bacterial vaginosis was proven.
Prebiotics are natural or synthetic agents of non-microbial origin: medications, food products, and dietary supplements that selectively stimulate the growth and/or metabolic activity of one or several types of microflora [22–23]. Prebiotics are not absorbed in the small intestine and undergo bacterial fermentation in the large intestine. Lactulose – a synthetic disaccharide consisting of fructose and galactose – belongs to the group of oligosaccharide prebiotics and exerts its effect only in the large intestine. Since 1957, lactulose has been used in medical practice as a prebiotic. Its long history of use and semi-synthetic nature explain lactulose's solid status among medicinal products, unlike other prebiotics considered as food components or bioactive supplements.
Lactulose is the only prebiotic included in the European Pharmacopoeia 4.0 (2001).
Lactulose is hydrolyzed mainly by bifidobacteria and lactobacilli, for which it serves as a nutrient substrate, leading to their growth. The enhancement of bifidobacteria growth under the influence of lactulose was proven in a study conducted by Bouchnic Y. [24], who demonstrated that lactulose potentiates the positive effects of probiotic lacto- and bifidobacteria, normalizes the balance, and restores the functions of the microflora [25].
Based on this potentiating combination, biologically active additives and medicinal products classified as synbiotics are formed.
The prebiotic effects of lactulose can influence the immune system both directly and indirectly – as a result of intestinal fermentation and supporting the growth of specific members of the digestive tract biocenosis. By supporting intestinal microecology, lactulose stimulates innate immunity through the growth of normal intestinal microflora and helps maintain the macroorganism's anti-infective defense.
According to a study by S.I. Titova and N.G. Goncharova, the use of a lactulose preparation in combination with metronidazole for treating bacterial vaginosis had a more pronounced effect compared to metronidazole monotherapy. A comparative randomized study included 50 women diagnosed with bacterial vaginosis aged 18 to 45 years. It was shown that including lactulose in the therapy increases the number of lactobacilli in the vagina, more radically suppresses the growth of opportunistic flora, and avoids the clinical and microbiological changes in the gastrointestinal tract that develop while taking metronidazole [3]. A study by V.V. Kaminsky et al. on 68 women of reproductive age diagnosed with bacterial vaginosis showed that adding a lactulose preparation to standard therapy ensures a high level of clinical and microbiological recovery and reduces the percentage of recurrences based on microbiological indicators [4].
Conclusions
Lactulose in the innovative anhydro form contains 97–99% pure lactulose, with the total amount of impurities not exceeding 3%. Anhydro lactulose stimulates the growth and vital activity of the body's own beneficial microflora, serving as an ideal substrate and energy source for the bifidobacteria and lactobacilli that form its foundation. By supporting intestinal microecology, anhydro lactulose also stimulates the body's own immunity.
In terms of antimicrobial activity, eco-antibiotics are bioequivalent to traditional antibiotics, while significantly surpassing them in safety.
The inclusion of eco-antibiotics in the daily practice of gynecologists opens up new possibilities for antibacterial therapy of urogenital tract infections and correction of vaginal dysbiosis.
As obstetrician-gynecologists, we are interested in the prospect of studying eco-antibiotics for treating dysbiotic conditions in women of various ages and their inclusion in the complex of preconception preparation for patients at high infectious risk.
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