“Iron triangle” of regulating the uterine microecology: Endometrial microbiota, immunity and endometrium

Abstract

The uterus is the core place for breeding new life. The balance and imbalance of uterine microecology can directly affect or even dominate the female reproductive health. Emerging data demonstrate that endometrial microbiota, endometrium and immunity play an irreplaceable role in regulating uterine microecology, forming a dynamic iron triangle relationship. Up to nowadays, it remains unclear how the three factors affect and interact with each other, which is also a frontier topic in the emerging field of reproductive tract microecology. From this new perspective, we aim to clarify the relationship and mechanism of the interaction of these three factors, especially their pairwise interactions. Finally, the limitations and future perspectives of the current studies are summarized. In general, these three factors have a dynamic relationship of mutual dependence, promotion and restriction under the physiological or pathological conditions of uterus, among which the regulatory mechanism of microbiota and immunity plays a role of bridge. These findings can provide new insights and measures for the regulation of uterine microecology, the prevention and treatment of endometrial diseases, and the further multi-disciplinary integration between microbiology, immunology and reproductive medicine.

The endometrial microbiota and early pregnancy loss

“…Epithelial cells produce anti-microbial peptides (AMPs), chemokines and cytokines, helping to maintain epithelial integrity and repel potential pathogenic bacteria ( Yarbrough et al , 2015 ). Commensal bacteria and their metabolites interact with antigen-presenting cells (APCs) to modulate immune tolerance including the formation of specific T cells, such as regulatory T cells (Treg), and the transformation of Th1 to Th2 cells ( Tsuda et al , 2019 ; Zhu et al , 2022 ). Th2 cells secrete IL-4, IL-6, IL-10, and IL-13, which are important for cytokine haemostasis and pathogen resistance ( D'Ippolito et al , 2018 ; Tsuda et al , 2019 ) whereas uterine natural killer cells (uNK) interact with trophoblast HLA to modulate immune tolerance and secrete interferon (IFN)-γ and vascular endothelial growth factor (VEGF), which are involved in spiral artery remodelling for normal placentation( Brosens et al , 2022 ; Faas and de Vos, 2017 ; Papúchová et al , 2019 ).…”

Deciphering the role of female reproductive tract microbiome in reproductive health: a review

“…The uterus, a symbolic organ within the female reproductive tract, has thick-walled muscles and a hollow cavity shaped like a slightly flattened, inverted pear. Anatomically, the uterus is connected to the outside environment through the vagina and is adjacent to the rectum and bladder ( Zhu et al., 2022 ). The uterus comprises the endometrium, myometrium, and serosa, with the endometrium serving as the initial attachment site of the embryo ( Yang et al., 2019 ).…”

“…The endometrium distributes a large number of immune cells, primarily uterine natural killer (uNK) cells, along with a small proportion of B cells and CD8 + T cells, which can generate immune mediators ( Zhu et al., 2022 ). Immune mediators in the endometrial fluid and surface act as a barrier against direct contact between pathogens and epithelial cells while exhibiting bactericidal activity against gram-negative and gram-positive bacteria ( Gershon and Dekel, 2020 ; Jost et al., 2014 ; Romero et al., 2014 ).…”

“…Immune mediators in the endometrial fluid and surface act as a barrier against direct contact between pathogens and epithelial cells while exhibiting bactericidal activity against gram-negative and gram-positive bacteria ( Gershon and Dekel, 2020 ; Jost et al., 2014 ; Romero et al., 2014 ). It is worth noting that the number of immune cells is closely related to hormone levels, and during early pregnancy, immune cells may be as high as 30%~40% of the total number of cells in the endometrium ( Zhu et al., 2022 ). The most abundant decidual immune cells are uNK cells, which account for 70% of the total ( Yang et al., 2019 ).…”

“…These communities antagonize, promote, and coexist with the female reproductive tract mucosa, forming a complex reproductive tract microecosystem ( Chen et al., 2017 ). In the course of researching the female reproductive tract microecology, it was found that the microbiome, as a vital member of the reproductive tract microecology, interacted with the anatomy, histology, and immunity and had great potential in maintaining reproductive health ( Muzny et al., 2020 ; Wira et al., 2005 ; Zhu et al., 2022 ).…”