Gut microbiota and endometrial cancer: research progress on the pathogenesis and application.

At present, the diagnosis and treatment of EC is being widely studied (as shown in Figure 3 ), and the gut microbiota and its associated metabolites can not only be used as a potential biomarker to assist in the diagnosis of EC but can also be affected by the active ingredients of traditional Chinese medicine to play an anti-inflammatory and antitumor role. In addition, gut microbiota and its associated metabolites can not only alleviate radiation-induced intestinal injury, but also promote the efficacy of immune checkpoint inhibitors. Application of the gut microbiota in the diagnosis and treatment of endometrial cancer. The gold standard for diagnosing EC is segmented curettage pathological biopsy. Transvaginal or transabdominal ultrasound may be used in patients with risk factors to monitor endometrial thickness and abnormalities. However, no specific, sensitive serum tumor markers have been identified, and there is no recommended routine screening method. Specific species in the gut microbiota provide a new possibility for the early prediction of EC. Porphyromonas somerae can be the most predictive microbial marker for EC, which has been proposed by 16S rRNA gene sequencing, and this has been confirmed using targeted qPCR. Further study has shown that the predictive value of EC is as high as 86% in postmenopausal and obese patients with the presence of Porphyromonas [ 63 , 64 ]. However, this is the result of a local sample of the endometrium, and there is currently no way to test the accuracy of this marker from a stool sample. Therefore, there are still shortcomings in practical application scenarios that cannot be used for large-scale screening, but it still has application value for patients with early detection of abnormal endometrial proliferation. Extrapelvic beam radiation is still the standard postoperative adjuvant therapy for patients with high-risk EC. Whether it is adjuvant radiotherapy, chemotherapy or radiotherapy combined with chemotherapy, radiotherapy using pelvic external radiation or vaginal brachytherapy, the chemotherapy regimen, and the number of courses, there is currently no unified answer, and therapy still needs to be selected according to the patient’s physical condition. However, radiotherapy and chemotherapy will undoubtedly adversely affect the gastrointestinal tract of the human body [ 65 , 66 ]. Since the rectum is irradiated more in patients after hysterectomy, it is highly susceptible to radiation bowel damage. A study of 5 postoperative patients with EC undergoing radiation therapy showed that fecal transplantation may improve symptoms of radiation bowel injury due to radiation therapy [ 67 ]. Because 3 of the patients received fecal transplantation from healthy women, their diarrhea, abdominal pain, rectal bleeding, fecal incontinence and other symptoms were significantly relieved. One study found that commensal bacteria and fungi differentially modulate how tumors respond to radiation therapy [ 68 ]. In addition, a series of studies have shown that probiotic preparations, especially the application of lactobacilli and bifidobacteria, can have a positive effect on radiation injury [ 69 , 70 ]. Although there are no studies on probiotic preparations to relieve radiation injury in patients after EC surgery, these preparations provide a new idea for future treatment and prevention. The gut microbiome has recently been recognized as a potential immune system modulator against cancer progression [ 71 ]. The gut microbiota may influence adaptive immune responses against tumor cells. It can affect cancer treatment by influencing the immune response during and after chemotherapy. As mentioned above, gut microbes and their metabolites may induce immune responses by producing proinflammatory cytokines, so it is easy to understand that specific bacteria may promote or inhibit the activity of immune checkpoint inhibitors (ICIs). Gut microbiota improves ICIs response by regulating innate immunity, adaptive immunity, and tumor cell immunogenicity [ 72 ]. Several studies have demonstrated that fecal microbiota transplantation (FMT) from patients who respond to ICIs into germ-free or antibiotic-treated mice can inhibit tumor growth and improve their response to ICIs [ 57 ]. Research has shown that Bifidobacteria activate tumor-specific T cells, increase the accumulation of CD8 T cells within melanoma and bladder tumors, and enhance IFN-γ production, which can slow the growth of cancer cells by downregulating the NF-kB signaling pathway [ 73 ]. In addition, microbiota-derived metabolites such as SCFAs can modulate the tumor microenvironment (TME) and potentially enhance antitumor immunity. Furthermore, traditional Chinese medicine ingredients also have good anti-inflammatory and antitumor effects. Baicalein is a steroid substance extracted from Scutellaria baicalensis that has anti-inflammatory effects and strongly inhibits cell proliferation in vitro , especially in CRC cell lines [ 74 ]. Curcumin has also been shown to be an anti-inflammatory, antioxidant and antiproliferative agent with potential anticancer properties by maintaining the diversity of the gut microbiota [ 75 ]. PHY906 can restore the intestinal epithelium by stimulating the regeneration of intestinal stem or progenitor cells after the transformation of bacterial β-glucuronidase in highly expressed gut microbiota [ 76 ]. Although there are no studies on the use of traditional Chinese medicine or the extraction of its active ingredients to inhibit the development of EC, the above studies still provide some reference significance in the treatment of EC. The development of high-throughput sequencing technology has not only made it possible to sequence gut microbiota, but also further deepened people’s understanding of the pathogenesis and molecular genetic characteristics of EC. Therefore, in this context, the traditional histological classification(Bokhman classification) of EC is not precise enough to stratify the risk of recurrence, and the help for the selection of subsequent individualized treatment regimens is limited. It has been more than 10 years since TCGA proposed the molecular classification of EC in 2013. In 2020, molecular classification was included in the United States National Comprehensive Cancer Network (NCCN) guidelines and the World Health Organization (WHO) Classification of Tumors of Female Reproductive Organs (5th Edition). The emergence of molecular classification has promoted the development of precision therapy, so that EC patients can receive individualized and comprehensive treatment plans. However, there are no studies focus on the association between gut microbiota and molecular classification of EC. This may be due to the fact that not all types of EC patients have immunohistochemistry and genetic testing analysis. And in some under-resourced settings, extensive immunohistochemistry and genetic testing analysis are not available. We look forward to seeing more research in this area in the future and providing some new adjuncts to individualized precision therapy for endometrial cancer.

There are 10 trillion bacteria parasitized in the human intestine, and the normal gut microbiota is mainly composed of gram-negative bacilli, gram-positive bacilli and actinomycetes. The gut microbiota not only participates in human food digestion and vitamin synthesis and maintains the integrity of the intestinal epithelial barrier but also removes harmful compounds and regulates inflammation and the immune response [ 4 , 5 ]. After metabolic substrates are activated by the gut microbiota, many beneficial or harmful substances are produced in the human body, such as short-chain fatty acids (SCFAs), lipopolysaccharides, trimethylamine, peptidoglycans, and secondary bile acids. Under physiological conditions, the abundance of intestinal bacteria is in dynamic equilibrium and can fluctuate due to changes in the characteristics of the host, for instance, race, age, sex, hormone levels, and environmental influences such as diet and drugs. When this fluctuation within the range of self-regulation is broken, homeostasis disappears, and the constitution and abundance of the gut microbiota change accordingly. In turn, the normal functions of the body, such as digestion and absorption, are destroyed. This dysbiosis may also cause changes in the local microenvironment, causing a state of systemic inflammation, which ultimately leads to the development of diseases [ 6 ]. Alterations in the intestinal flora and the pathological processes in which its metabolites participate, such as endothelial dysfunction, changes in the host immune system, bacterial translocations, chronic inflammation, and genomic instability, are characteristic of cancer [ 7 ]. At present, among the diseases of various systems, most of the research on the gut microbiota focuses on the digestive system. Many studies have confirmed that Helicobacter pylori plays a nonnegligible role in the occurrence and development of gastric cancer [ 8 ]. In addition, colorectal tumors are stimulated by the intestinal flora and its metabolites, resulting in increased colonization of conditional pathogenic bacteria and further enhancement of proinflammatory and protumor effects [ 9 ]. Furthermore, other systemic diseases are closely related to the intestinal flora, such as hypertension [ 10 ], diabetes [ 11 ], tuberculosis [ 12 ], and breast cancer [ 13 ]. In the female reproductive system, research on the gut microbiota and its metabolites is also in full swing. A study [ 14 ] of 18 EC patients and 18 normal subjects using 16S rRNA to sequence the gut microbiota showed no significant differences in bacterial α and β diversity between EC and control individuals. The abundance of Proteus in the EC group decreased, while that of pathogenic bacteria and conditional pathogenic bacteria increased, among which the abundances of Bacteroides and Verrucous were more obvious. The study further found that the abundance of Ruminococcus sp. N15. MGS-57 increased in EC patients, which was positively correlated with palmitoleic acid (C16:1) and arachidonic acid (C20:2) and negatively correlated with the synthesis of betaine and indole alkaloids. C16:1 and oleic acid (C18:1) were significantly enriched in tumor tissues, and C16:1 may promote EC cell invasion and metastasis through the mTOR signaling pathway. For some time, it has generally been accepted that a woman’s upper reproductive tract (uterus, fallopian tubes, and ovaries) is bioclean. However, recent studies suggest that the female upper genital tract is not sterile, and although the composition of the flora is not clear and contamination during sampling cannot be ruled out, Lactobacillus should still be the dominant bacteria [ 15 ]. The diseased upper genital tract usually contains many pathogenic bacteria, such as Chlamydia , Mycoplasma , Acinetobacter and Brucella , which may cause infertility. These germs are often infected retrogradely through the vagina and colonize the upper genital tract to adversely exert local or systemic effects [ 16 ]. In the study of Wanting Lu et al. [ 17 ], which included 25 EC patients and 25 women with benign uterine lesions, the endometrial microbiota profiles of the two groups were evaluated by 16S ribosomal RNA gene amplicon sequencing. The results showed that the abundance of M icrococci in the EC group increased, and its levels were positively correlated with the expression of IL-6 and IL-7 mRNA. These two inflammatory factors are involved in the proinflammatory response of EC. This finding suggests a link between the EC flora and the inflammatory response.

In summary, the gut microbiota and its metabolites play a nonnegligible role in EC. Since the mechanism of EC is still unclear, it is necessary to study the direct or indirect mechanisms of the gut microbiota and its metabolites in the pathogenesis and development of the disease in the future. It is necessary to discover more specific microflora and make full use of the characteristics of the applicable microflora, such as using them as tumor markers, using them in the early prediction of EC. Or using bacterial transplantation and other means to intervene and control the microflora in the body to alter the tumor microenvironment, thereby inhibiting the progression of tumors. In addition, microorganisms could be used to improve the sequelae after treatment of gynecological malignant tumors, and to promote the efficacy of immunoassay inhibitors.