Vaginal dysbiosis-associated infections: Current and emerging treatment strategies

BV

BV is a polymicrobial infection of the vaginal tract that predominantly affects women of reproductive age and is linked to a range of adverse gynecological and obstetric outcomes. Epidemiological studies estimate that approximately 20– 50% of women in this age group experience BV at some point in their lives.^[19] Clinically, BV is characterized by a thin, greyish-white vaginal discharge with a distinctive fishy odor, often accompanied by a vaginal pH >4.5 and the presence of clue cells coated with bacteria on microscopic examination, through Nugent scoring.^[20] The hallmark of BV is the depletion of protective Lactobacillus species. This shift fosters the overgrowth of diverse anaerobic and facultative organisms, most notably Gardnerella vaginalis, along with Fannyhessea vaginae, Sneathia, Mobiluncus, and others.^[21,22]

While BV is a polymicrobial condition, G. vaginalis plays a key role in BV pathogenesis through biofilm formation on the vaginal epithelium, which in turn encourages the adhesion and proliferation of other anaerobic microbes.^[23] G. vaginalis causes pathogenesis with adhesins, cytolysins, and sialidases that degrade mucosal barriers, neutralizing their potential for defense.^[24] Recent reports highlight the role of G. vaginalis-derived extracellular vesicles (EVs) in BV-associated cellular pathogenesis. These bacterial extracellular vesicles (BEVs) deliver bacterial effectors directly into the vaginal epithelial cells. Literature documents that G. vaginalis-derived EVs contain vaginolysin and sialidases, which can degrade epithelial cell junctions, disrupt mucosal integrity, and promote cytolysis.^[25,26] In addition, the synergistic action of G. vaginalis and other pathogens not only destabilizes the vaginal ecosystem but also contributes to challenges and recurrence associated with BV management^,[27] underscoring the need for targeted therapeutic approaches beyond conventional antibiotics.

VVC

VVC is the most common fungal infection characterized by inflammation of the vulvovaginal region. Clinical manifestations include intense pruritus, erythema, edema, and a thick curdy white vaginal discharge. Epidemiological data indicate that approximately 75% of women experience at least one episode of VVC during their lifetime, and 40–50% of these women have a second episode. A subset of these women, estimated at 5–8% develop recurrent VVC, defined as three or more symptomatic episodes within 12 months.^[28-30]

Approximately 85–90% are caused by Candida albicans, whose virulence is linked to host cell adherence, biofilm formation, proteolytic enzymes, and yeast-to-hyphae morphogenesis features that enhance tissue invasion and immune evasion. The remaining 10–15% of infections are attributed to non-albicans species, primarily C. glabrata, C. krusei, C. tropicalis, and C. parapsilosis.^[30,31] While less frequent, non-albicans species are gaining clinical prominence due to their reduced susceptibility or intrinsic resistance to azole antifungals, complicating treatment and increasing recurrence rates.^[32,33]

In recent years, there has been a noticeable epidemiological shift toward a higher proportion of non-albicans infections, particularly in immunocompromised women and those with poorly controlled glycemic status. This is largely attributed to immune suppression, altered mucosal defense, and selective antifungal pressure that together create a permissive environment for opportunistic yeasts. The inflammatory pathology of VVC arises from the interplay between fungal virulence determinants and host immune responses, notably the activation of pattern recognition receptors (e.g., Dectin-1, TLRs) on epithelial and immune cells, which trigger pro-inflammatory cytokine release and neutrophil recruitment.^[34,35] While these immune mechanisms are essential for fungal clearance, they also amplify tissue inflammation, thereby intensifying clinical symptoms.^[36]

AV

AV is a distinct form of vaginal dysbiosis characterized by the predominance of aerobic microorganisms, most commonly Escherichia coli and Staphylococcus aureus, along with other facultative pathogens such as Enterococcus faecalis and group B Streptococcus.^[37,38] Unlike BV, which is typically associated with anaerobic overgrowth, AV presents with more severe local inflammation, epithelial atrophy, and a marked shift in the vaginal immune profile. Epidemiological studies report AV prevalence rates ranging from 4% to 12% in the general female population, with higher rates in women presenting with recurrent vaginal symptoms or during pregnancy.^[39] A significant proportion of AV cases are associated with concurrent or preceding urinary tract infections, as many causative organisms, particularly uropathogenic E. coli and S. aureus are capable of colonizing both the urogenital tract and vaginal mucosa.^[40,41]

The pathogenesis of AV reflects the virulence strategies of its causative agents. Uropathogenic E. coli employs adhesins such as type 1 and P fimbriae to bind vaginal epithelial cells, followed by biofilm formation and the release of toxins such as hemolysin, which contribute to epithelial damage and neutrophil recruitment.^[42] Similarly, S. aureus produces an array of virulence factors, including surface adhesins,^[43] hemolysins, and superantigen toxins, which can induce intense inflammatory responses and compromise epithelial barrier integrity. The heightened inflammation in AV not only drives symptom severity, manifesting as erythema, burning, and yellowish discharge, but may also predispose affected women to secondary infections and adverse reproductive outcomes.^[44] Given its distinct etiology and inflammatory profile, AV requires targeted diagnostic approaches and antimicrobials to avoid misclassification as BV and to decrease the risk of recurrence.^[45]

Mixed vaginitis

Mixed vaginitis refers to a polymicrobial infection of the vaginal ecosystem in which two or more pathogens coexist and contribute to disease pathology. It represents a complex interplay of bacterial, fungal, and sometimes aerobic organisms that simultaneously disrupt the mucosal barrier and alter local immunity. Clinically, the most frequently documented co-infection is BV-VVC ^[46], and a cooccurrence is approximated at 20–30% of women diagnosed with BV.^[47] This overlap likely reflects the antibiotic-induced depletion of protective Lactobacillus species during BV treatment, creating a niche that favors Candida overgrowth.^[48] Other reported combinations include BV with E. coli colonization ^[49], Candida with E. coli ^[50], and more complex microbial assemblages involving anaerobes such as G. vaginalis, Atopobium vaginae, and aerobic species like E. faecalis.^[51] These mixed infections often present with more severe symptoms, longer disease duration, and a higher likelihood of recurrence compared to single-pathogen infections, highlighting the clinical importance of accurate diagnosis and tailored, multi-targeted treatment strategies.

The overlapping clinical features of these infections present diagnostic and therapeutic complexities; the latter is further elaborated in the subsequent discussion on current treatment strategies.

Prebiotic interventions

Prebiotic interventions targeting the vaginal microbiome aim to selectively trigger the growth and metabolic activity of beneficial microbes, thereby promoting restoration of a healthy vaginal environment. Prebiotics typically contain non-digestible oligosaccharides, polysaccharides, or other bioactive substrates that serve as preferential fermentable carbon sources for Lactobacillus species, which suppress opportunistic and pathogenic microorganisms. Recently, topical gel-based prebiotic formulations have garnered interest as an adjunct or standalone therapy for vaginal dysbiosis. These formulations offer localized delivery, prolonged mucosal contact time, and targeted modulation of the vaginal microbiota while minimizing systemic absorption and off-target effects. Hakimi et al. reported that the cure rate was 86.2% in the group receiving the prebiotic vaginal gel plus oral metronidazole, compared to 62.1% in the metronidazole-only group.^[56] The recurrence rate after 3 months was significantly lower in the combination group (10.3% vs. 34.5%).^[56]

Nonetheless, further randomized controlled trials are required to determine optimal dosing regimens, formulation stability, synergistic potential with probiotics or vaginal microbiota transplantation (VMT), and long-term safety. In addition, a key limitation of prebiotic therapy is its strain specificity, as prebiotics stimulate only certain bacteria capable of metabolizing the substrate, leading to variable and sometimes inconsistent microbiota responses across individuals.^[57,58]

Probiotic therapy

Probiotics aid in symptom relief, recurrence prevention, and vaginal health by producing antimicrobials, regulating pH, and boosting immunity. Current research backs their usage as an alternate or complementary therapy, despite considerable drawbacks. While probiotics are widely regarded as a promising alternative to antibiotics, evidence on their sustained clinical effectiveness is still evolving.

The overuse of antibiotics has accelerated AMR among vaginal pathogens, further strengthening the case for developing safe, sustainable alternatives. In this context, probiotics offer significant advantages in terms of suitability, accessibility, and ease of administration. Clinical evidence suggests that oral supplementation with encapsulated strains such as Lactobacillus rhamnosus GR-1 and Lactobacillus fermentum RC-14, taken once or twice daily, can promote restoration of the vaginal microbiome toward a Lactobacillus-dominant state. These strains exhibit strong adhesion to vaginal and cervical epithelial cells, allowing them to compete with the pathogens. In addition, they release high amounts of lactic acid, hydrogen peroxide, and bacteriocin, inhibiting the growth of harmful vaginal pathogens.^[59] Lagenaur et al. conducted a phase 2b clinical trial in which the microbiome-based biologic drug, LACTIN-V (containing L. crispatus strain), was administered after metronidazole treatment.^[60] At 12 weeks post-treatment, the incidence of recurrent BV was significantly lower in the LACTIN-V group (30%) as compared to the placebo group (45%). This represents a relative risk reduction of approximately 34% indicating the adjunct probiotic therapy decreased the risk of BV recurrence.^[60]

However, not all studies have reported robust or durable effects. In a longitudinal metagenomic study, Hertz et al. investigated whether probiotic supplementation with Lactobacillus strains could effectively modulate the vaginal microbiome.^[61] Using shotgun metagenomics, they observed only minor shifts in microbial composition during the intervention, suggesting that probiotic efficacy may vary depending on host and microbial context.^[61,62]

AMPs and small-molecules

AMPs and small molecules represent promising alternatives for the treatment of vaginal dysbiosis, particularly in light of rising AMR and the limitations of conventional antibiotic therapies. The vaginal innate immune system naturally produces a repertoire of AMPs, including defensins, secretory leukocyte protease inhibitors, calprotectin, lysozyme, lactoferrin, and elafin, that play multifaceted roles in maintaining mucosal homeostasis. Beyond their direct antimicrobial activity, these peptides are integral to host defense against sexually transmitted infections, modulation of local immune responses, and even the exertion of anticancer effects. Harnessing or augmenting the activity of these endogenous AMPs could therefore offer a targeted strategy for restoring a healthy vaginal microenvironment.^[63]

In parallel, small molecules of microbial origin are emerging as novel therapeutic candidates. Of particular interest are nanoscale molecules and metabolites derived from Lactobacilli species, which have been shown to disrupt pathogenic biofilms, which happens to be a major barrier to successful treatment of vaginal dysbiosis [Figure 2]. For instance, Khan et al.^[45] evaluated EVs derived from L. gasseri and demonstrated their efficacy in disrupting pathogenic biofilms in vitro. These findings highlight the potential of probiotic-derived small molecules as biofilm-targeting agents that could complement or replace traditional antimicrobials.^[45]

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Figure 2:

Schematic depicting the contribution of current broad-spectrum treatments to recurrence and antimicrobial resistance through non-targeted or incomplete regimens, highlighting the need for targeted and sustainable therapeutic interventions. VMT: Vaginal microbiome transplantation

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While these early observations are promising, thorough in vivo studies and clinical trials are required to establish their safety, efficacy, and long-term impact on vaginal microbial ecology. Advancing this line of research holds significant potential not only for developing precision therapies for vaginal dysbiosis but also for contributing to global antimicrobial stewardship efforts.^[64,65]

VMT

VMT involves the transfer of a healthy donor’s vaginal microbial community to restore a balanced, Lactobacillus-dominated ecosystem in the recipient’s vaginal environment. The rationale behind this approach stems from the pivotal role of Lactobacillus spp., particularly L. crispatus, which provides colonization resistance against pathogenic microorganisms. Recent studies and clinical trials have reported encouraging outcomes, demonstrating the potential of VMT in managing recurrent BV and other gynecological disorders linked to persistent vaginal dysbiosis. A pilot study led by Lev-Sagie and group investigated the use of VMT from healthy donors as a therapeutic alternative for patients with intractable and recurrent BV, where 4 of 5 recruited BV individuals showed restoration of a healthy vaginal state.^[66] In 2023, a study by Wrønding et al. explored the use of VMT without antibiotics for a woman with a history of complicated pregnancy. After the administration of VMT, the woman successfully conceived a healthy child after a series of late pregnancy losses/ stillbirths.^[67] The study emphasizes the potential of VMT for vaginal dysbiosis-related pregnancy complications.^[67] Given the substantial heterogeneity in the etiology, microbial profiles, and host immune responses associated with vaginal dysbiosis, VMT offers a targeted, microbiome-based intervention that could surpass the limitations of conventional antimicrobial and probiotic therapies.^[68-70]

However, for the clinical translation of VMT, major challenges related to safety, standardization, and regulatory approval need to be addressed before it can be adopted as a mainstream therapeutic intervention. The development of robust donor screening protocols, optimal sample storage methods, microbiome composition evaluation standards, and clinical consistency cutoffs is the need of the hour.