Introduction
Vulvovaginal candidiasis (VVC) is an exceedingly common infection of
female vulvovaginal inflammations[1]. The disease is estimated to
affect 75% of women at least once during their lives, and approximately
8% of women develop recurrent VVC (RVVC)[2, 3]. The most common
clinical symptoms of VVC are increased vaginal discharge that resembles
bean curd residue accompanied by vulval itching and burning, leading to
dyspareunia and dysuria in more severe cases[4]. While VVC is
non-lethal, the morbidity associated with VVC brings tremendous mental
distress, causing pain, low self-esteem, anxiety, and even impacting
affective relations and career[5]. Moreover, VVC has been reported
to cause adverse conditions such as cervicitis [6], pelvic
inflammatory disease[7], genital tract malignancy[8],
infertility[9], fetal intrauterine infection[10], HPV[11],
and preterm birth[12].
A variety of microorganisms are present in the vagina of healthy women,
which form a mutually regulated, coordinated, and dynamically balanced
vaginal microenvironment. The balance of the vaginal microenvironment
plays an important role in maintaining the self-cleaning function of the
vagina and the health of the host. Lactobacillus accounts for the
majority of the normal vaginal microbiota and helps defend against
pathogens by lowering the vaginal pH to maintain an acidic
environment[13]. Furthermore, cytokines and chemokines are regulated
to maintain an anti-inflammatory vaginal environment[14], competing
for adhesion sites to form a mechanical barrier[15], and secreting
bio-surface-active substances to regulate the host immune response[16,
17]. However, dysbiosis of the vaginal microbiota occurs due to a
variety of endogenous or exogenous factors that cause an imbalance in
the vaginal internal environment. The main pathogens causing vaginal
inflammatory diseases include Gardnerella vaginalis, Candida albicans,
and Trichomonas vaginalis, which are associated with bacterial
vaginitis, vulvovaginal candidiasis, and trichomoniasis, respectively.
Candida albicans is a serious opportunistic fungal pathogen[18] and
is the most common infectious yeast strain in women with VVC, showing a
prevalence of 90%[19]. It can colonize the mucosal surfaces of the
genitourinary and gastrointestinal tracts, as well as the asymptomatic
oral cavity and skin of healthy people[2]. Changes in microbial
community composition and systemic or local immunosuppression (e.g.,
pregnancy, diabetes, allergies, broad-spectrum antibiotics, oral
steroids, psychosocial stress, estrogen, and sexual activity) may result
in increased load and virulence of C. albicans, which may exceed the
tolerance threshold of epithelial cells, leading to the production and
release of pro-inflammatory factors and inducing an intense inflammatory
response[20]. However, C. albicans overload is not the only cause of
VVC, as it can invade host cells by inducing endocytosis and active
penetration[21]. Endocytosis is a passive process mediated by
epithelial cells in which C. albicans transforms from a yeast phase to a
more adherent mycelial phase, leading to loss of epithelial integrity
and barrier function through the interaction of the fungal invasin Als3
and host E- or N-cadherin on the surface of the mycelium[22].
Meanwhile, C. albicans secreted related enzymes (SAPs) can promote
tissue invasion by activating epithelial calpain1, mediating active
fungal penetration[23]. In addition, mycelial-phase C. albicans
produces a peptide toxin ”candida lysin” that activates the p38/cFos and
ERK/MKP1 signaling pathways by recruiting innate immune cells such as
neutrophils, macrophages, and innate type 17 cells, thereby leading to
cytokine and chemokine secretion[24]. Furthermore, candida lysin
promotes Candida invasion by affecting mitochondria and altering
immunomodulatory signaling in vaginal epithelial cells [25].
VVC is typically treated with short-term topical and single-dose oral
antimycotic agents to restore normal vaginal flora[26].
Nevertheless, due to the high level of resistance to commonly used
antifungal drugs, antibiotic efficacy is greatly reduced and a high
recurrence rate is observed despite standardized and multiple courses of
antifungal therapy[27]. Although VVC has been studied for more than
ten years[28], little is known about its pathogenesis. Therefore,
exploring the pathogenesis of VVC and identifying new targets for
alternative antibiotic therapy has great significance.
Metabolomics is an important part of modern omics research. Potential
biomarkers are identified by studying the upstream biological processes,
their metabolites, and metabolic pathways[29]. With the development
of metabolomics, a growing number of metabolites have been discovered
and studied as biomarkers, providing new insights for disease diagnosis,
pathogenesis, and drug intervention. Furthermore, the metabolic profile
of the cervicovaginal microenvironment can effectively be used to
distinguish between HPV infection, cervical dysplasia, and ICC[30].
Several metabolites are significantly associated with the clinical signs
and symptoms of bacterial vaginosis (BV), which has obvious metabolic
signatures across multiple metabolic pathways[31]. Moreover, the
composition of bacterial communities is affected during genital
infection due to the changes in vaginal metabolome composition;
significantly elevated metabolites such as TMA-NOx (TMAO), taurine, and
methanol have been observed in VVC vaginal discharge[32].
Nonetheless, the potential role of vaginal bioactive metabolites in the
development of VVC has not been reported.
In the present study, vaginal discharge profiling was performed with
non-targeted metabolomics methods, such as liquid chromatography-mass
spectrometry (LC–MS), to explore the difference in the metabolite
expression profiles between VVC patients and normal controls (CTL). In
addition to analyzing the global characteristics between VVC and CTL,
active substances affecting C. albicans infection could also be
identified, providing insights into the mechanism of VVC infection and
the corresponding defense mechanism of the body. The findings highlight
a new perspective on the treatment of C. albicans vaginal infection.