Endometrial microbial dysbiosis and metabolic alteration promote the development of endometrial cancer

Abstract Objective Emerging evidence suggests that the endometrial microbiome plays important roles in the development of endometrial cancer (EC). Here, we evaluate stage‐specific roles of microbial dysbiosis and metabolic disorders in patients with EC, patients with endometrial hyperplasia (EH), and patients afflicted with benign uterine conditions (CK). Methods This prospective cohort study included 33 women with EC, 15 women with endometrial EH, and 15 women with benign uterine conditions (CK) from November 2022 to September 2023. Different typical endometrial samples were imaged with a scanning electron microscope and a transmission electron microscope. The endometrial microbiome was assessed by sequencing the V3–V4 region of the 16S rRNA gene and the ITS1 to fill the gap in relation to the study of the uterine fungal microbiome. Moreover, liquid chromatography‐mass spectrometry‐based metabolomics was used to identify and quantify metabolic changes among these groups. Results The endometrial microbiome revealed that there is a structural microbiome shift and an increase in the α‐diversity in the EC and EH cases, distinguishable from the benign cases, especially the fungal community structure. The fungal microbiome from patients with EC and EH was altered relative to controls and dominated by Penicillium sp. By contrast, Sarocladium was more abundant in controls. Significant differences were observed in the composition and content of compounds between benign cases and EC, especially estradiol‐like metabolism‐related substances. Altered microbiota was correlated with the concentrations of interleukin‐6 (IL‐6), IL‐11, transforming growth factor‐beta, and β‐glucuronidase activity especially the relative abundance increase of Penicillium sp. Conclusions This study suggested that the endometrial microbiome is complicit in modulating the development of EC such as estrogen activity and a pro‐inflammatory response. Our work provides a new insight into the endometrial microbiome from a perspective of stages, which opens up new avenues for EC prognosis and therapy.