Cervical cancer is one type of gynecological malignant tumors with a high incidence rate, which continues to increase year by year. Annually, over 200,000 patients die of cervical cancer worldwide, (1) and 85% of patients are from developing countries (1,2). Moreover, cervical cancer has predominated in China (3). Cervical cancer can threaten the lives and life quality of women and can impose a heavy burden on the social health system if not addressed promptly and adequately (4).

The female reproductive tract is a complex humid environment that harbors large numbers of microbial organisms that can cause genital disease. However, it remains largely unknown whether these organisms work together to contribute to disease pathogenesis or whether they work against each other. It is also not clear which organisms protect our health and which are detrimental. Among these microbial organisms, persistent high-risk human papilloma virus (HR-HPV) is the main cause of cervical cancer (5). However, cervical cancer does not occur in all patients with HPV; a minority of patients with weak immunity that cannot clear HR-HPV develop persistent infection (6).

A variety of sexually transmitted disease (STD) pathogens are associated with cervical cancer and account for a high proportion of cervical cancer cases, suggesting that STD pathogens play an important role in promoting HR-HPV carcinogenesis (7,8). Studies have shown that infection with certain STD microorganisms may reduce immunity, leading to immune evasion and increasing the risk and severity of HR-HPV infection (6,9). Other pathogens, such as Chlamydia trachomatis (CT), Ureaplasma urealyticum (Uu), and Mycoplasma hominis (Mh), which colonize in the genitourinary tract, can also cause damage, with people becoming infected through sexual contact. CT can cause tissue and organ damage, and often co-infects with other STDs (10). Mycoplasma are a genus of bacteria that mainly adhere to the host's susceptible cell receptors through their special surface structure, which damage host cells (11,12). Generally, Uu is divided into two clusters, or ‘biovars’: Biovar 1/parvo biovar, and biovar 2/T960 (13-15). Biovar 1 consists of four genotypes (1, 3, 6 and 14), while biovar 2 includes 10 serovars (15,16) It is widely accepted that biovar 1 shows fewer signs of danger, while biovar 2 tends to be much more aggressive (17).

Herpes simplex virus II (HSV II) can cause cervical cancer (18). Specifically, HSV-DNA integrates into the DNA of normal tissues, leading to cervical cell lesions (19). Some studies have shown that other STD pathogens, such as Neisseria gonorrhoeae (NG), Uu, Mh, and Mycoplasma genitalium (Mg), can cause repeated infections and change the environment of the genital tract to induce cervical cancer (20,21). The risk of cervical cancer increases with elevation of microbial species in the context of genital tract infection (22).

The complex micro-ecosystem of vagina poses a huge challenge to identifying the true role of each organism. In our study, we found that Ureaplasma urealyticum parvum (Uup6), Uup3, CT, and Mh may contribute to persistent HPV infection, and Uup3, Uup6, and Mg may accelerate cervical intraepithelial neoplasia (CIN) development and thus aggravate HR-HPV-mediated cervical cancer.

HPV infection is a common STD, with an infection rate of approximately 10% (3) According to data, there are approximately 70 million females with HPV infection in China, and the incidence of cervical cancer in China is approximately 130,000 per year (1,3). There is a certain correlation between infection with different pathogens in the genital tract and cervical cancer and CIN (23). Therefore, cervical cancer researchers are actively searching for synergistic factors of HPV carcinogenesis.

The warm and humid environment of the vagina makes it an ideal habitat for microorganisms. Pathogens, including viruses, bacteria, fungi, and mycoplasma, can easily breed. Many of these organisms can cause disease in the reproductive tract. Until now, little has been known about the distribution of pathogenic species in the vaginal and their exact role in cervical disease formation. In this study, HPV and 10 other pathogens were evaluated. The incidence of HPV was 61%. Approximately 19.16% of patients were affected by Uup3, 17.07% with Mh, 15.72% with Uup6, 11.83% with Uu, 9.88% with Uup1, and 9.43% with CT. In line with previous study, (24) Uu, Uup1, Uup3, Uup6, and Uup14 were most frequently observed.

Furthermore, CT, Mh, and Mg shared similar infection rates with HR-HPV (Table II; P<0.05). Possible synergistic effects also existed between CT, Uup3, Uup6, and Mh infections and HR-HPV infection (Table III). CT, Uup3, Uup6, and Mh likely contribute to HPV infection (25), which was different from the species that contributed to CIN progression. Combined with the results presented in Table IV, we note that it is not the exact same species of pathogen with that in Table III, that could promote CIN progression though mostly similar. CT, Uup3, Uup6, and Mg played an obvious role in CIN formation and progression. However, in patients infected with multiple pathogens and who harbored HR-HPV infection, it was not clear if it was the latter that was largely responsible for CIN formation and progression, especially in patients with HSILs.

Table V shows that a large proportion of patients with Uup3, Uup6, and Mh had HSILs and LSILs. Patients infected with Uup3, Uup6, and Mh with LSILs accounted for 18.75, 15.24 and 17.54% of total patients, respectively. Patients infected with Uup3, Uup6, and Mh with HSILs accounted for 7.03, 8.57 and 5.26% of total patients, respectively (Table V). Patients with HSILs were much more likely to develop cervical cancer. Thus, certain species of Uu are hazardous, including Uup3and Uup6. However, the role of HR-HPV in HSIL formation is still unknown, because not a small part of patients shares multi-pathogen coinfection (26). This could be because different HPV genotypes have synergistic effects on each other (7) or because different pathogens promote HPV persistence. More data will be required to differentiate and distinguish the role of each of these pathogens.

Our results show that HR-HPV infection increases the risk of CT infection, but there was no significant correlation between CT infection and CIN, possibly due to the small sample size, which may have failed to detect a sufficient number of positive patients. It was speculated that CT could increase the risk of CIN by synergistic action with HPV. No relationship was identified between Mh and CIN, but Mh did have a positive effect on HPV persistence.

It is believed that Uu is related to the persistence of HPV infection and early cervical cytological changes (27). The rate of Uu infection increases in HPV-positive patients and in patients with cervical cancer, and the increase in Uu infection is a significantly correlated with the occurrence of CIN caused by HPV infection (26,28); therefore, it should be highly valued when Uu infection is combined with HPV infection (28), which was frequently observed in our study.

HSV II infection increases the risk of cervical cancer and has a synergistic effect with HPV (29). It has also been confirmed that HSV DNA integrates into the DNA of normal cells to promote cancer cell development (30). However, HSV II infection is mostly asymptomatic. The results of this study show that HSV II infection is associated with HR-HPV infection, but not with the CIN development. This can be ascribed to regional differences and low positive infection rates.

In conclusion, the incidence of cervical cancer is complex and is determined by a variety of factors. Multiple STD pathogens are involved in the process of HR-HPV carcinogenesis. Varying conclusions have been drawn worldwide, which may be related to differences in the prevalence and methods used to detect STD pathogens between regions. Overall, we show that CT, Uup3, Uup6, and Mh could be risk factors for HR-HPV persistence and that Uup6, Uup4, and Mg significantly impact CIN progression.