Conventionally, the uterine cavity is assumed to be sterile, but in fact, microorganisms have been detected in the endometrial cavity of non-pregnant women [26,27,28,29].

It has been proposed that microorganisms ascending from the lower genital tract could colonize the uterine cavity; however, host mechanisms have been expected to restrict bacterial proliferation and invasion [26,27,28,29,30]. These mechanisms involve the cervical mucus plug [31,32,33,34], the endometrial epithelium and its immune cellular components (neutrophils, macrophages, and natural killer cells), and elements of the innate immune system, including natural antimicrobial peptides present in the EM [32,35,36,37]. An appropriate and balanced acute inflammatory process has been shown to play a major role in the eradication of microbial invasions [38].

Microorganisms form biofilms (i.e., matrices of polymeric compounds) as strategies against host immune mechanisms as well as against natural and synthetic antibiotics [39,40]. In fact, chronic infections such as valvular endocarditis, otitis media, chronic bacterial prostatitis, and periodontitis have been associated with the presence of bacterial biofilms, which contribute to subclinical colonization of the uterine cavity [41,42,43,44,45,46,47].

Interactions between infectious agents and the endometrial environment are a major concern in the treatment of infertility, miscarriage, and preterm labor [48]. In septic conditions, microorganisms are only a part of the problem; sepsis also involves problems in inflammatory control and/or the anti-inflammatory response of the host [49]. In a study of the mechanisms involved in preterm labor, the microorganisms present on the endometrial surface were not found to induce a pro-inflammatory response, and maintained peaceful coexistence with the host during the course of normal pregnancies [40,50,51,52,53,54]. However, if the host (mother, embryo/fetus, or both) became aware of the microorganisms via pattern-recognition receptors and initiated a pro-inflammatory response, peaceful co-existence was no longer possible. Changes in virulence patterns, such as planktonic bacteria released from biofilms, also caused a change in the balance between microorganisms and the host, resulting in inflammation-induced preterm parturition.

Inflammatory mediators in the EM, including leukocytes, immunoglobulins, and cytokines, have been found to play very important roles in regulating the immune response and trophoblast growth in implantation [7]. The EM was found to be physiologically colonized by a pleiotrophic population of immune-competent cells [55]. These immune-competent cells controlled local defenses and modulated the host reaction to the embryo, ultimately assisting in the implantation of the embryo and the maintenance of pregnancy. Successful implantation of the embryo and maintenance of the pregnancy were the result of a delicate balance between the embryo and the EM, reflecting the prevalence of a TH2 versus a TH1 cytokine profile in the EM. Therefore, any conditions that disturb this balance could damage endometrial receptivity.

Various immune-competent cells of the EM have been found to secrete chemokines, attracting natural killer (NK) cells and macrophages from the circulating peripheral blood toward the EM [56,57,58,59]. In addition, trophoblasts facilitated pro-inflammatory cytokine production from the recruited monocytes and macrophages, which had a significant role in implantation and placental formation [58].

An increase in the amount of NK cells in peripheral blood drove the cytokine balance to favor the TH1 pathway [55,60]. This is likely to have negative effects on trophoblast invasion and implantation, consequently increasing the possibility for early pregnancy loss.

In CE, endometrial receptivity decreases through mechanisms other than an increase in the percentage of NK cells. In fact, the secretory EM of patients with CE was found to show significantly lower percentages of CD56+ CD16− cells and CD56 bright CD16− cells than was observed in patients without CE (47.8% vs. 30.1% and 79.5% vs. 67.3%, p<0.01) [60]. The secretory EM of the CE group showed a significantly higher percentage of CD3+ cells than the secretory EM of patients without CE (25% vs. 10.5%, p<0.01). Additionally, in micropolypoid EM samples in patients with CE, the low endometrial NK cell density facilitated the survival of residual endometrial cells, possibly resulting in the development of mucosal polyps [61]. Kitaya and Yasuo [2] reported that lymphocyte B cell levels were elevated in the EM of patients with CE, as well as observing the abnormal expression of paracrine mediators such as adhesion molecules and chemokines. In fact, the menstrual effluent of women with CE showed elevated pro-inflammatory cytokine levels, including interleukin (IL)-6, IL-1β, and tumor necrosis factor α, in comparison to women without CE; these findings were argued to reflect a TH1/TH2 cytokine imbalance at the EM level [62].

Infection is the basis of CE. Cicinelli et al. [21] analyzed 438 cases of hysteroscopically diagnosed CE, and reported that 73.1% exhibited ≥1 positive pathogen finding. Most endometrial infections were common bacterial infections (58%), including Gram-negative bacteria, and Ureaplasma urealyticum was found in 10% of cases. Chlamydia was found in 2.7% of cases. Gram-negative bacterial colonization of the EM may lower the implantation rate of embryos while increasing the rate of miscarriage. The endotoxins of Gram-negative bacteria may induce a more predominant TH1 response at the decidua in order to stimulate pro-inflammatory cytokine production, thereby creating an endometrial paracrine milieu that could cause embryo damage, implantation failure, or spontaneous abortion [62,63]. Female genital tuberculosis can cause CE and infertility. It is uncommon in developed countries, and is associated with predisposing factors such as poverty, ill health, and immune suppression [64]. In addition, it is a secondary form of tuberculosis, mainly originating from pulmonary tuberculosis, so rare cases of solitary tuberculous endometritis may have occurred due to female genital tuberculosis spreading to the neighboring viscus [65]. We excluded tuberculous endometritis from the discussion of this article.

In EM with CE, the IGFBP1 gene was upregulated, whereas genes such as IGF1, IL-11, and CCL4 were downregulated [66]. IGF1 mediated the effect of estrogen on endometrial proliferation, while IGF2 mediated the effect of progesterone during the secretory phase by facilitating the implantation and invasion of embryos [59,67,68]. IGFBP1 was secreted from endometrial stromal cells during the process of decidualization, exerting negative effects on the implantation process of the embryo and counteracting the effect of IGF2. Increased IGFBP1 gene expression and reduction in IGF1 gene expression in EM with CE resulted in unfavorable conditions for implantation and embryo development.

IL-11 is a cytokine with anti-inflammatory properties. Its production was found to be greatest during decidualization [69,70]. Inappropriate IL-11 signaling resulted in dysregulation with respect to trophoblast invasion [56,71,72]; therefore, IL-11 downregulation in EM with CE at the implantation window was strongly associated with infertility.

During the early stage of pregnancy, trophoblasts were found to recruit NK cells and macrophages into the EM through chemokines such as CCL4 and to stimulate them to produce pro-inflammatory cytokines [56,57,58,59]. Downregulated CCL4 activity due to CE could result in the failure of implantation or abnormal placental formation.

In summary, chronic endometrial inflammation can alter endometrial cytokine production, damage endometrial function [73], result in the formation of abnormal patterns of lymphocyte subsets in the EM, and induce the altered secretion of paracrine factors, which ultimately may reduce the receptivity of embryos in the EM [60,66]. In fact, delayed differentiation of the EM in the mid-secretory phase (out-of-phase morphology) was observed in cases of CE [74]. The proliferative phenotype of the EM was found in cases of CE even during the secretory phase, due to an increase in estrogen receptors and cell proliferation-associated nuclear marker Ki-67 expression [75,76].