The critical relationship between vaginal microecology and Ureaplasma urealyticum: a retrospective study

Introduction

Ureaplasma urealyticum (UU) is a bacterium included in the genus Ureaplasma. UU is a commonly found microorganism in the human reproductive tract and is generally associated with reproductive tract infections. Infection with UU manifests itself clinically as an extensive range of symptoms, particularly in women, and may lead to diseases such as vaginitis and pelvic inflammatory disease (Bender & Gundogdu, 2022; Liu et al., 2023). The proportion of UU infections varies in the bacterial vaginosis (BV) and aerobic vaginitis (AV) groups compared to healthy women (Rumyantseva et al., 2018). Thus, vaginal dysbiosis and different flora status reflect different vaginosis in women (Abou Chacra, Fenollar & Diop, 2022). Detection of interleukin-1beta (IL-1beta) and IL-1 receptor antagonist (IL-1ra) levels in vaginal specimens from pregnant women in early pregnancy has been associated with UU infection (Doh et al., 2004). However, UU positivity in the female vagina is not associated with abnormal vaginal secretions or pH (Plummer et al., 2021). The female vaginal microecology is a complex and dynamic microecosystem composed of vaginal microorganisms, the endocrine system, and the local immune system, and normal vaginal microbiota is essential for maintaining microecosystem homeostasis. Therefore, the relationship between patients with UU infections and vaginal microecological health status remains to be determined. In the future, to prevent and treat vaginal diseases more effectively, it will be necessary to explore and the impact of UU on the microecology of the female vagina.

The female vagina is a complex microbial ecosystem. The female reproductive tract’s microbiome reflects the woman’s health, and a healthy microbiome consists mainly of Lactobacillus (Moreno & Simon, 2018). Hernández-Rodríguez et al. (2011) tested vaginal secretions from healthy pregnant women and identified 21 different microorganisms, with the highest positive detection rate of 21% for the UU, which is associated with bacterial vaginosis (Fig. 1). The women’s vaginal microecology changes continuously before, during, and after childbirth during puberty, menstruation, pregnancy, and menopause (Shen et al., 2022). Human vaginal microecology imbalances can lead to inappropriate inflammatory responses and abnormal immune responses, leading to a wide range of female reproductive health challenges (Shen et al., 2022). The levels of vaginal hydrogen peroxide (H₂O₂) are associated with the presence of a wide range of microorganisms (Hillier et al., 1993). Several studies have indicated that six indicators such as pH, H₂O₂, leukocyte esterase (LEU), sialidase (SNA), β-glucuronidase (GUS), and acetylglucosidase assist in understanding vaginal microecology and diagnosing vaginitis and cervical cancer (Feng et al., 2024; Li et al., 2020). Additionally, Wang, Wan & Zhang (2024) found that Systemic Immune Inflammation Index (SII) is associated with Mycoplasma pneumonia, and can be used as a valid indicator for predicting its severity in children. Patients with UU infection are associated with abnormalities in inflammatory markers such as tumor necrosis factor (TNF)-alpha, interleukin-6, and toll-like receptor 2 (Jacobsson et al., 2009; Hassanein et al., 2012; Noh et al., 2019). Therefore, vaginal microecology may assist in better understanding, studying, and treating UU. Studies have indicated that vaginal microecology may be associated with human papillomavirus, vaginitis, and other female reproductive tract disease infections (Ilhan et al., 2019; Fan et al., 2024; Wei et al., 2022). Always although both vaginal microecology and UU positivity are associated with female diseases, the relationship between them has not been clarified.

The monitoring of vaginal microecology-related and inflammation indicators can assist in the diagnosis and adjuvant treatment of vagina-related diseases in women. Therefore, this study aimed to explore the association between vaginal microecological factors and UU infection to provide new ideas for further research and clinical treatment of UU.

Materials & Methods

Results

Discussion

UU, as a common reproductive tract pathogen, has become a critical threat to women’s health (Noh et al., 2019; Cicinelli et al., 2008). The factors contributing to UU infection in women were explored. The proportion of UU-positive participants who were cleanliness-positive, H₂O₂-positive, LEU-positive, SNA-positive, NAG-positive, or GUS-positive populations was higher than that of UU-negative populations. Cleanliness and H₂O₂ were found to be risk factors for UU infection in women. Consequently, to reduce vaginal microecological abnormalities and the incidence of UU infection and other diseases in women, more education should be imparted on healthy living for women.

UUs are pathogenic microorganisms that attach to various types of cells, such as epithelial and germ cells, and primarily colonize the mucosal surfaces of the genitourinary tract in adults. UU infections not only lead to reproductive tract inflammation but also to infertility and adverse outcomes of pregnancy, such as preterm premature rupture of the membrane (Li et al., 2010). This study found that a higher percentage of UU-positive participants had lower vaginal cleanliness than the UU-negative participants. No study has directly demonstrated the association between UU and vaginal cleanliness. However, cervical cancer and bacterial vaginosis are associated with abnormal vaginal cleanliness in patients (Zhang et al., 2023; Shen et al., 2024). Differences in the degree of vaginal cleanliness lead to differences in the abundance of vaginal microbial composition. Moreover, abnormalities in vaginal microbiota can cause diseases such as vaginitis (Liao et al., 2022). Thus, the vaginal microbiome plays a critical role in women’s health. UU-positive participants had a higher percentage of vaginal H₂O₂ positivity compared to the UU-negative participants. Although H₂O₂ is produced by probiotics such as lactobacilli, it can be used to assess vaginal health status, and abnormally normal levels of H₂O₂ may be associated with immune cytokines in vaginal secretions (Jacobsson et al., 2009; Hassanein et al., 2012; Noh et al., 2019; Mei & Li, 2022; Cai et al., 2022). Vaginal microecology, a complex system, is mediated by multiple factors, including normal anatomy, microflora, endocrine changes, and local immune responses (Ye & Qi, 2023). This is in accordance with the findings of our study that found a higher percentage of UU-positive participants with positive vaginal LEU, SNA, NAG, and GUS. Autoimmune status and viral infections were significantly associated with vaginal microbiota involved in the regulation of the immune system of the female lower genital tract, suggesting that the vaginal microflora dysbiosis may be a risk factor affecting persistent infections in the female genital tract (Pino et al., 2021). Therefore, vaginal cleanliness must be maintained, and vaginal microecology must be stable for women’s health.

An interdependence and mutual constraint exist between vaginal microecological-related factors, forming a dynamic balance system (Buggio et al., 2019). An imbalance in the vaginal microecosystem can be recognized when there is an alteration in indicators such as the number, species, dominant bacteria, pathogenic microorganisms, pH, and Lactobacillus function in the vagina (Wang et al., 2022; Ge et al., 2023). The analysis was performed between vaginal microecology and UU susceptibility. This study found that cleanliness was an independent risk factor for UU infection in patients. Similar to this study’s findings, several studies have identified the association of vaginal cleanliness with female reproductive diseases, including polycystic ovary syndrome and postpartum pelvic floor dysfunction (Hong et al., 2020; Cheng et al., 2022). The route of UU infection in the female genital tract is primarily through the vagina; therefore, extensive vaginal cleansing is critical. A low vaginal cleanliness grade indicates that a woman has a large number of Lactobacillus and epithelial cells in her vagina. Still, fewer leukocytes, and the vaginal microecology is in a healthy state. In a healthy female vagina, Lactobacillus produces H₂O₂, which protects the vagina. Garza et al.’s study found that the percentage of patients with UU infection who were positive for Lactobacillus in the vagina was lower than the percentage of Lactobacillus positivity in the healthy control population. Combined with our findings that high vaginal cleanliness is a risk factor for UU infection in patients, we hypothesize that Lactobacillus in the vagina and the Lactobacillus product, H₂O₂, may be essential factors in reducing UU infection in women. In the future, this study will further explore the mechanisms by which vaginal cleanliness level affects UU infection in women. In this study, H₂O₂ (OR = 7.24, 95% CI [4.19–12.51], P <  0.001), another indicator of vaginal microecology, was found to be an independent risk factor for UU infection in patients. Consistent with the above results, Li et al. found that abnormal levels of H₂O₂ could lead to cervical intraepithelial neoplasia and cervical squamous cell carcinoma (Zheng et al., 2019a; Zheng et al., 2019b). Stoyancheva found that H₂O₂-producing Lactobacillus has a vital role in protecting the vaginal microecological balance (Stoyancheva, Danova & Boudakov, 2006). Women who were negative for Lactobacillus vaginalis were more likely to be infected with Mycoplasma hominis, UU et al. than those who were positive for Lactobacillus in the vagina (Hillier et al., 1993). Vaginal H₂O₂ is mainly derived from Lactobacillus, so we hypothesized that H₂O₂ may be detrimental to UU infection in female patients. In the future, we will also explore the mechanism by which vaginal H₂O₂ reduces UU infection in women. Therefore, maintenance of vaginal microecological stability is critical to improve women’s health.

In addition, LEU, SNA, NAG, and GUS were found to be risk factors for UU infection in women in the univariate logistic analysis of this study. still, multivariate logistic analysis found that LEU, SNA, NAG, and GUS had no significant effect on UU infection in women. First, the results of univariate analysis are affected by other confounding factors, while multifactorial analysis corrects for the effects of other confounding factors, making the results more plausible. second, it is possible that whether LEU, SNA, NAG, or GUS is positive or not is indirectly related to UU infection in women. Finally, it may be that the sample size of this study is insufficient, and we will continue to collect samples for validation afterward. This study conducted a correlation analysis between SII and UU infection in women, but the results showed no significant correlation between SII and UU infection in women. However, it has been shown that there is an increase in polymorphonuclear leukocytes (PMNL) in the vagina of women with UU infection (Bender & Gundogdu, 2022). Afterward, we will test to examine further the relationship between other inflammatory markers and UU infection and analyze the role of inflammation in UU infection.

This study systematically investigated the association between vaginal microecology and UU infection. However, it has several limitations. First, the study population is primarily concentrated in northern China. Genetic differences, environmental factors, and cultural factors are all critical factors that may influence the results of the study, so in the future, we may also improve the generalizability of our findings through multicenter collaboration and cross-population comparisons for different populations to enhance the accuracy of our findings. Second, the exploration of potential mechanisms is insufficient. Vaginal cleanliness and H₂O₂ content are both associated with Lactobacillus in the vagina, so we hypothesized that Lactobacillus and Lactobacillus products such as H₂O₂ may be detrimental to UU infection in female patients. In the future, we will explore the mechanism of vaginal cleanliness and H₂O₂ content on UU infection in women for this speculation to further validate and improve our findings.

In conclusion, we found that UU-positive patients exhibited higher rates of cleanliness, H₂O₂, and other studied factors compared to UU negative patients. In addition, cleanliness and H₂O₂ were identified as independent risk factors for UU infection in women. Therefore, vaginal microecological examination should be strengthened in women to prevent UU infection caused by the abnormalities of the vaginal microecology.

Supplemental Information