9 The Vaginal Microbiome

The Vaginal Microbiome

The vaginal microbiome is a reproductive organ-specific niche that harbors a unique collection of microorganisms that are important in a variety of aspects to human health. This microbial community has significance in maintaining vaginal homeostasis, protecting against urogenital infections, host immunity, and reproductive capacities.  In recent years, next generation sequencing (NGS) techniques have been employed to classify the vaginal microbiome into community state types (CSTs), or vaginotypes, based upon composition, which can enhance epidemiological studies to make better associations between the microbiome and host-vaginal health (France et al., 2020, Mancabelli et al., 2021).

Composition and Role

The vaginal microbiome is composed of over 200 different bacterial species, though it is primarily dominated by members from Lactobacillus genus (Ma et al., 2012, Auriemma et al., 2021). The Lactobacilli protect the vagina from potential pathogen invasion through their fermentation of vaginal epithelial cell-produced glycogen into lactic acid, which lowers vaginal pH, as well as their production of various antimicrobial compounds, and resource/space competitive inhibition (Boskey et al., 2001, Amabebe and Anumba, 2018, Chee et al., 2020, Jang et al., 2019). Though, the bacteriome is usually the emphasized feature of the vaginal microbiome, it also harbors protists, fungi, archaea and viruses, with each occupying their own niche in the normal healthy network (Belay et al., 1990, Bradford and Ravel, 2017, Happel et al., 2020, Chacra and Fenollar, 2021). The composition isn’t always fixed however, as factors like the menstrual cycle, hormone fluctuation, sexual partners, hygiene, genetics, age, the environment, drug use, and other aspects of lifestyle can affect the microbial makeup (Aagaard et al., 2012, Fettweis et al., 2014, Hyman et al., 2014, Zapata and Quagliarello, 2015, Martin and Marrazzo, 2016, Diop et al., 2019, Chacra and Fenollar, 2021).

As mentioned earlier, using 16S rRNA sequencing, the vaginal microbiome has been categorized into CSTs and allowed for deeper analysis, where comparisons of the consortia within these classifications can be used to make associations with host and vaginal health. There are 5 main CSTs each predominated by a particular species of Lactobacilli, except for group IV, which has been further dissected into additional subgroups: CST I—L. crispatus dominated, CST II—L. gasseri dominated, CST III—L. iners dominated, and CST V—L. jensenii dominated (Ravel et al., 2011, France et al., 2020, Chacra and Fenollar, 2021, Mancabelli et al., 2021). CST IV is not dominated by any particular species, and contains a mixture of both strict and facultative anaerobes including Gardnerella, Atopobium, Lactobacillus, Bifidobacterium, etc., where certain controversial subgroups (e.g. CST IV-A, CST IV-B, CST IV-C, CST IV-D, CST IV-G, etc.) have various combinations depending on the study (Gajer et al., 2012, Albert et al., 2015, France et al., 2020, Mancabelli et al., 2021). Each of the five groups has correlations with vaginal pH, microbial colonization and biodiversity, as well as host characteristics such as pregnancy, ethnicity, and age, though it is not always absolute (France et al., 2020, Mancabelli et al., 2021). With reproducible organization of the vaginal microbiome, connections can be made with medical conditions, which could benefit treatment and diagnosis of vaginal diseases and associated affairs.

Dysbiosis and Disease

As with other microbiomes associated with the human body, disturbance of the resident vaginal microbiome can result in complications of health. Many diseases of the urogenital tract such as bacterial vaginosis (BV), urinary tract infections (UTIs), yeast infections, and several sexually transmitted infections (STIs) are caused by pathogenic microbes associated with dysbiosis (Taha et al., 1998, Donders et al., 2000, Wiesenfeld et al., 2003; Lai et al., 2009, De Seta et al., 2019, Mancabelli et al., 2021). Normally, the local flora maintains homeostasis, however, changes in composition provide opportunistic pathogens a window to proliferate and invade.

Bacterial vaginosis, associated with CST IV, stems from a perturbance of the vaginal flora, specifically a decrease in Lactobacilli and an increase in other microbes like Gardnerlla vaginalis, Atopboium vaginae, Ureaplasma urealyticum, and others that are only usually found in low numbers (Gajer et al., 2012, Margolis and Fredricks, 2015, Onderdonk et al., 2016, Zozaya et al., 2016). This condition can be asymptomatic in up to half the women with BV, and in the others can be diagnosed by observed changes in vaginal discharge or by the Nugent scoring system which utilizes a Gram stain (Figure 1) (Nugent et al., 1991, Amsel et al., 1983, Schwebke, 2000). While not exactly considered a sexually transmitted disease, bacterial vaginosis is commonly associated with certain sexual practices, though other factors such as hygiene, nutrition, intrauterine devices, hormonal changes, and certain comorbidities can contribute to susceptibility (Avonts et al, 1990, Calzolari et al., 2000, Neggers et al., 2007, Verstraelen et al., 2010, Zabor et al, 2010, Margolis and Fredricks, 2015). Women with this disease also have a higher risk to contract sexually transmitted infections, and it can be linked to reproductive complications and poor infant health (Wiesenfeld et al., 2003, Prince et al., 2015, Chacra and Fenollar, 2021). Typically, antibiotics targeting anaerobic bacteria are administered to treat BV, however recurrence is common, likely due to the antimicrobial-resistant nature of biofilms formed by the pathogens and/or regular exposure to external reservoirs (Swidinski et al., 2008, Oduyebo et al., 2009, Marrazzo et al., 2012, Bradshaw and Sobel, 2016). Probiotics, specifically containing L. crispatus, may be the better option, and vaginal microbiota transplantation from a healthy donors is a promising treatment course of action (Hemmerling et al., 2010, Ma et al., 2019).

Urinary tract infections are a common problem, especially for females, which are disproportionately affected. This infection is most likely to occur in the urethra or bladder (though in severe cases the kidneys can be affected), which causes pain in the pelvic area and during urination, the frequent urge to urinate, and the presence of blood in urine (Lee and Neild, 2007, Sheerin, 2011, Hooton, 2012). The vaginal microbiome, or more specifically some normal residents, like Escherichia coli, can move to the urogenital tract and cause issues resulting in a UTI, which often occurs via sexual activity (Nicolle et al., 1982, Foxman, 2014, Stapleton, 2016, Lewis and Gilbert, 2020). Other fastidious microorganisms, like those abundant in women experiencing BV, contribute to a higher risk of contracting an infection in the urinary tract as compared with those not suffering from dysbiosis in the vagina (Hillebrand et al., 2002, Sumati and Saritha, 2009). In these cases, the vaginal opening may harbor potential uropathogens (Figure 2) and transient exposure to the urinary tract could prompt colonization or other reactions (e.g. immunomodulation) that results in a UTI (Lewis and Gilbert, 2020). Antibiotics are traditionally used to treat UTIs, however probiotics and estrogen administration could help to restore the Lactobacillus colonization and protect against complicated and recurrent infections (Raz and Stamm, 1993, Eriksen, 1999, Prais et al., 2003, Stapleton et al., 2011, Tan and Chlebicki, 2016, Lewis and Gilbert, 2020).

Yeast infection of the vaginal region caused by Candida species, also known as vulvovaginal candidiasis (VVC), is a common condition with severe symptoms and a high recurrence rate (Oerlemans et al., 2020). Those affected experience vaginal itchiness or soreness, dyspareunia (painful intercourse), abnormal vaginal discharge, redness, swelling, and thinning of the vaginal wall (Chew and Than, 2016, Oerlemans et al., 2020). While it is the second-most common infection of the vagina behind BV, this disease primarily affects premenopausal women with a low vaginal pH value under 4.5 (Kim and Park, 2017, Gupta et al., 2019). The exact cause of VVC isn’t exactly clear, though it is thought it can come as a result of microbiome dysbiosis induced by prolonged antibiotic usage, which allows various Candida species to overgrow and establish an infection (Goldacre et al., 1979, Mitchell, 2004, Peters et al., 2014, van de Wijgert and Verwijs, 2020). Traditionally, antifungal medication has been used to treat VVC, however administration of probiotic vaginal microbes may be more prudent as their mechanisms of pathogen colonization and biofilm formation inhibition are more effective to prevent disease recurrence (Petrova et al., 2016, Tachedjian et al., 2017, Allonsius et al., 2019, Oerlemans et al., 2020, van de Wijgert and Verwijs, 2020).

Individuals with vaginal microbiome dysbiosis characterized by a decrease in abundance of Lactobacilli species (i.e. BV) are at a higher risk of contracting sexually transmitted infections, such as those caused by Neisseria gonorrhoeae, Trichomonas vaginalis, Chlamydia trachomatis, and Mycoplasma genitalium (Martin et al., 1999, Cherpes et al., 2003, Peipert et al., 2008, Brotman et al., 2010, Molenaar et al., 2018, De Seta et al., 2022). Infections caused by these organisms usually result in symptoms similar to other genital infections such as vaginal itching, pain, unusual discharge, rash, etc. which like other conditions (e.g. vaginitis), result in decreased epithelial integrity and can exacerbate pathogen invasion (Miller and Shattock, 2003, Greenbaum et al., 2019). In those individuals with BV and non-inflamed tissue, the increased risk for STIs could be due to the negative effects dysbiosis-related bacteria have on the innate immune system (Murphy and Mitchell, 2016, Liebenberg et al., 2017). Similarly, contraction of sexually transmitted viral infections like human immunodeficiency virus (HIV), herpesviruses, and human papillomavirus (HPV) are frequently associated with vaginal dysbiosis, immunomodulation, and disruption of the epithelial barrier (Sewankambo et al., 1997, Borgdorff et al., 2016, Siqueira et al., 2019, Torcia, 2019, De Seta et al., 2022). While there is correlation between vaginal dysbiosis and STIs, the protective mechanisms of the resident vaginal microbiota are unknown and still need to be uncovered (De Seta et al., 2022).

Reproduction, Pregnancy, and Infant health

The vaginal microbiome has further implications in host immunity, fertility, pregnancy, spontaneous preterm birth, and infant health (Anahtar et al., 2015, Fettweis et al., 2019, Gupta et al., 2020, Xu et al., 2020). Indeed, there are a multitude of factors that affect reproduction like age, genetics, hormone levels, fallopian tube blockage, menstrual cycle, and vaginal pH, however only recently has the vaginal microbiome been studied for its association with various fertility factors (Xu et al., 2020, Fan et al., 2022).

Changes in the resident vaginal flora and infections by certain pathogens can cause complications for reproductive health and pregnancy. For example, infection by Group B Streptococcus (GBS) has been associated with a decline in ovarian function, pregnancy loss, preterm delivery, and is the leading cause of bacteremia and meningitis in newborns (Zaleznik et al., 2000, Phares et al., 2008, Kolter and Henneke, 2017, Tazi et al., 2019, Xu et al., 2020). The vaginal microbiome of pregnant women is less rich and diverse than non-pregnant individuals, likely caused by changes in sex hormone levels (Farage et al., 2010, Aagaard et al., 2012). These alterations can cause shifts in the vaginal microbiome that could then result in infection and a risk of preterm or spontaneous labor (Wylie et al., 2018, Fettweis et al., 2019, Feehily et al., 2020, Gupta et al., 2020).

Infants become introduced to the microbial world via their mother, and predominately right after birth where vaginal versus cesarean delivery has a great impact on composition (Chu et al., 2017). However, exposure may happen earlier in utero, as this environment may not be as sterile as once thought as some studies have shown the presence of microbes in the placenta and amniotic fluid (Aagaard et al., 2014, Collado et al., 2016, Kolter and Henneke, 2017). The establishment of a newborn’s microbiome has profound effects on the development of immunity and metabolism as well as the onset of diseases like atopic dermatitis and obesity in later life (Rautava et al., 2012, Collado et al., 2016, Ta et al., 2020).

Conclusion

The vaginal microbiome is a complex community which affects many facets of human health and disease including urogenital, reproductive, immune, and infant. Characterization of the vaginal flora has allowed categorization into community state types which can help to predict and diagnose disease states. Within so, these dynamic changes that occur under various conditions produce a unique fingerprint for the vaginal microbiome which can be analyzed and potentially treated in a specific manner (Ceccarani et al., 2019, Lagenaur et al., 2020, Abou Chacra and Fenollar, 2021). While antibiotic administration has its benefits, novel approaches using  targeted application of probiotic microbiomes (e.g. a gel containing specific Lactobacilli species) could help in treating diseases associated with vaginal dysbiosis by restoring those disrupted communities, as well as alleviating certain negative consequences of chemotherapy (Pino et al., 2019, Lagenaur et al., 2020 Oerlemans et al., 2020). More in-depth and continued research of the vaginal microbiome is necessary to illuminate the interactions and connections of it members to human health.

References