Bacterial vaginosis (BV) is an imbalance of the vaginal microbiome that can lead to adverse health outcomes, including increased likelihood of potential pathogens colonizing the vagina, yet the mechanisms underlying these processes are poorly understood.
A study published in PLOS Biology by Amanda Lewis at University of California, San Diego, and colleagues suggests that mutually beneficial relationships between different species of vaginal bacteria may encourage growth of potentially harmful pathogens, such as the common oral bacterium Fusobacterium nucleatum.
The work challenges the belief that a suitable living environment supporting pathogen colonization is created solely by the absence of healthy bacteria, and may explain prior clinical links between oral sex and BV.
Approximately 29% of women in the United States are affected by BV, putting them at risk for adverse health outcomes such as preterm labor and amniotic fluid infections during pregnancy.
To analyze interaction between bacterial communities and the ability of different bacteria to access required nutrients in an already-occupied microbiome, Lewis and colleagues conducted experiments in human vaginal specimens and in mice.
The authors inoculated mice or mouse vaginal communities with F. nucleatum and found evidence of increased biochemical activities previously linked with BV, such as the enzyme sialidase.
After performing models in mice, the authors conducted similar experiments in which Fusobacterium nucleatum, a bacterium found in the mouth and linked with gum disease, intrauterine infection and preterm birth, was inoculated into human vaginal microbial communities cultivated from vaginal swabs of twenty-one women.
Samples incubated with Fusobacterium displayed higher levels of multiple key indicators of BV compared to the identical women’s microbiomes incubated without Fusobacterium.
The experiments led to the discovery that Fusobacterium nucleatum does not act in a simple one-way relationship with other bacteria, but may engage in a mutually beneficial relationship, potentially encouraging dysbiosis (microbial imbalance) in susceptible vaginal communities.
Fusobacterium was helped by bacteria in BV-like communities that produce an enzyme called sialidase, enabling Fusobacterium to consume sialic acids from mucus produced by the host.
Fusobacterium also acted by unknown mechanisms to greatly benefit the growth of Gardnerella vaginalis, a sialidase producer believed to be a key player in BV.
The researchers demonstrated that mutual benefit between bacteria species may promote pathogen colonization of the vagina and encourage features of vaginal dysbiosis.
However, additional studies are needed to develop modes of prevention or treatment of BV in women.
Fusobacterium is widespread in human mouths and overgrows in dental plaque; the authors speculate that it may be introduced during oral sex, which has been identified in some clinical studies as a risk factor for BV.
Vaginitis has a broad differential diagnosis, and successful treatment frequently rests on an accurate diagnosis. The most common causes of vaginitis include vulvovaginal candidiasis, bacterial vaginosis, and trichomoniasis.
Among patients with vaginal symptoms, vaginal candidiasis is diagnosed in 17–39% of cases, bacterial vaginosis in 22–50% of cases, and trichomoniasis in 4–35% of cases; however, vaginitis may remain undiagnosed in 7–72% of patients (1, 4).
Although vulvovaginal candidiasis, bacterial vaginosis, and trichomoniasis are the most common causes of vaginitis symptoms, other etiologies include vulvar skin diseases, desquamative inflammatory vaginitis, and genitourinary syndrome of menopause (5–9).
Estrogen and the Vaginal Environment
Estrogen status plays a crucial role in determining the normal state of the vagina. During the reproductive years, the presence of estrogen increases glycogen content in vaginal epithelial cells, which in turn encourages colonization of the vagina by lactobacilli.
This increased level of colonization leads to lactic acid production and a resulting decrease in the vaginal pH to less than 4.5. This acidic environment protects against the growth of pathogenic organisms and is key to maintaining a balanced vaginal ecosystem.
The normal vaginal flora remains heterogeneous, and Gardnerella vaginalis, Escherichia coli, group B streptococci, genital Mycoplasma species, and Candida albicans are commonly found.
In prepubertal girls and postmenopausal women, the lack of estrogen inhibits normal growth of the vaginal bacterial ecosystem; therefore, microscopy typically shows a paucity of epithelial cells and background bacteria.
In addition, the vaginal epithelium is thin and the pH of the vagina is elevated (higher than 4.5) because lactic acid-producing lactobacilli are sparse. Growth of bacteria associated with bacterial vaginosis and yeast forms are less common in an estrogen-depleted environment, thus prepubertal girls and postmenopausal women (not using estrogen) uncommonly have bacterial vaginosis or vaginal candidiasis (10, 11).
Bacterial vaginosis is not a true infectious or inflammatory state. It represents a change in the normal microbiome of the vagina with an overgrowth of facultative anaerobic organisms (eg, G vaginalis, Bacteroides species, Peptostreptococcus species, Fusobacterium species, Prevotella species, and Atopobium vaginae) and a lack of hydrogen peroxide-producing lactobacilli (12, 13).
Bacterial vaginosis is the most common cause of abnormal vaginal discharge in patients of reproductive age and has a higher prevalence in black, Hispanic, and Mexican American women compared with white non-Hispanic women (14, 15).
In addition to race and ethnicity, age, douching, and sexual activity are associated with increased risk of bacterial vaginosis (4, 15). Although the occurrence of bacterial vaginosis is associated with sexual activity for both heterosexual (16, 17) and lesbian couples (17, 18), and rarely occurs in patients who have never been sexually active (19), it is not directly caused by the sexual transmission of a single pathogen (17, 20).
Nonpregnant patients with bacterial vaginosis are at an increased risk of various infections of the female reproductive tract, including pelvic inflammatory disease (PID) and postprocedural gynecologic infections, and have increased susceptibility to sexually transmitted infections (STIs) such as HIV and herpes simplex virus type 2 (21–24).
Many patients with bacterial vaginosis are asymptomatic (4). However, those who do have symptoms commonly report having an abnormal vaginal discharge and a fishy odor, particularly after vaginal intercourse and menses (4, 12).
Vaginal trichomoniasis, which is caused by infection with the protozoan parasite Trichomonas vaginalis, is the most common nonviral STI in the United States, with approximately 3–5 million cases annually (25, 26).
Like bacterial vaginosis, there are prevalence disparities with this vaginal condition. African American women are ten times more commonly affected compared with non-Hispanic white women (26).
Other risk factors identified include increased number of sex partners, low socioeconomic status, and douching (26). Trichomoniasis has been found to be associated with PID, posthysterectomy cuff cellulitis, HIV, and other STIs (20, 27).
More than 50% of patients with trichomoniasis are asymptomatic or have minimal symptoms; however, symptomatic patients with trichomoniasis may report an abnormal vaginal discharge, itching, burning, or postcoital bleeding (26, 28).
Although trichomoniasis is an STI, because asymptomatic carriage can occur for prolonged periods in men and women, a recent diagnosis of trichomoniasis does not necessarily establish recent acquisition unless the patient has had documented negative Trichomonas testing results in the recent past.
Vulvovaginal candidiasis represents inflammation and infection of the vagina with Candida species. It is the second most common cause of vaginitis behind bacterial vaginosis (20), and 29–49% of females report at least one lifetime episode (29).
Physical manifestations of vulvovaginal candidiasis range from asymptomatic colonization to severe vulvovaginal symptoms such as burning, itching, edema, dysuria, dyspareunia, and an abnormal discharge (20).
In one study of the vaginal and endocervical environment in nonpregnant patients, 12% of asymptomatic patients were culture positive for Candida species (10, 30). Vulvovaginal candidiasis is uncommon in prepubescent girls and postmenopausal women (not using estrogen) and is often over-diagnosed in these populations (30).
Symptomatic patients with bacterial vaginosis should receive treatment, which works by reducing the overgrowth of the patient’s endogenous facultative and anaerobic bacteria and enabling the lactobacilli to become dominant.
Treatment of bacterial vaginosis also may decrease a patient’s risk of transmission and acquisition of other STIs, including chlamydial infection, gonorrhea, trichomoniasis, HIV, and herpes simplex virus type 2 (24, 44, 45). Currently, the CDC recommends that patients with bacterial vaginosis also be tested for HIV and other STIs (20).
Oral or intravaginal metronidazole or intravaginal clindamycin is recommended for the treatment of bacterial vaginosis.
Alternative treatments include oral secnidazole, oral tinidazole, or oral clindamycin (Table 2).
Because these treatments have comparable safety and efficacy profiles, the choice of therapy should be individualized based on factors such as patient preference, cost, convenience, adherence, ease of use, and history of response or adverse reactions to previous treatments (20, 46–49).
Patients who are unable to tolerate oral metronidazole because of gastrointestinal adverse effects may find that the intravaginal metronidazole gel is tolerable.
Secnidazole is a newer FDA-approved agent for the treatment of bacterial vaginosis that in randomized clinical trials has been found to be superior to placebo and comparable to metronidazole in treating bacterial vaginosis (50, 51).
Abstaining from alcohol use during treatment with oral nitroimidazoles and for 24 hours after completion of metronidazole treatment or 72 hours after treatment with tinidazole is currently recommended by the drug manufacturers because of a theoretical concern of a disulfiram-like reaction that may occur with the use of nitroimidazoles (52, 53).
Patients also should refrain from sexual activity during bacterial vaginosis treatment unless condoms are used. Experts advise that patients who are using an intravaginal product to treat a vaginal infection may want to avoid use of tampons during treatment to ensure adequate dispersion of the medication.
More information: Agarwal K, Robinson LS, Aggarwal S, Foster LR, Hernandez-Leyva A, Lin H, et al. (2020) Glycan cross-feeding supports mutualism between Fusobacterium and the vaginal microbiota. PLoS Biol 18(8): e3000788. doi.org/10.1371/journal.pbio.3000788