Uterine Immunity and Microbiota: A Shifting Paradigm

Abstract

The female reproductive tract harbors distinct microbial communities, as in the vagina, cervical canal, uterus, and fallopian tubes. The nature of the vaginal microbiota is well-known; in contrast, the upper reproductive tract remains largely unexplored. Alteration in the uterine microbiota, which is dependent on the nutrients and hormones available to the uterus, is likely to play an important role in uterine-related diseases such as hysteromyoma, adenomyosis, and endometriosis. Uterine mucosa is an important tissue barrier whose main function is to offer protection against pathogens and other toxic factors, while maintaining a symbiotic relationship with commensal microbes. These characteristics are shared by all the mucosal tissues; however, the uterine mucosa is unique since it changes cyclically during the menstrual cycle as well as pregnancy. The immune system, besides its role in the defense process, plays crucial roles in reproduction as it ensures local immune tolerance to fetal/paternal antigens, trophoblast invasion, and vascular remodeling. The human endometrium contains a conspicuous number of immune cells, mainly Natural Killers (NK) cells, which are phenotypically distinct from peripheral cytotoxic NK, cells and macrophages. The endometrium also contains few lymphoid aggregates comprising B cell and CD8+ T cells. The number and the phenotype of these cells change during the menstrual cycle. It has become evident in recent years that the immune cell phenotype and function can be influenced by microbiota. Immune cells can sense the presence of microbes through their pattern recognition receptors, setting up host-microbe interaction. The microbiota exerts an appropriately controlled defense mechanism by competing for nutrients and mucosal space with pathogens. It has recently been considered that uterus is a non-sterile compartment since it seems to possess its own microbiota. There has been an increasing interest in characterizing the nature of microbial colonization within the uterus and its apparent impact on fertility and pregnancy. This review will examine the potential relationship between the uterine microbiota and the immune cells present in the local environment.

New Opportunities for Endometrial Health by Modifying Uterine Microbial Composition: Present or Future?

“…Endometrium seems to be an immunologically suited niche for microbiota with its possible function in modulating inflammatory and immune responses [30,37,97] (Figure 2). The mucosal layers of the female reproductive tract constitute a part of the mucosal immune system, which exhibits a broad repertoire of immune responses [98].…”

Ovarian hormones-autophagy-immunity axis in menstruation and endometriosis

“…In addition, autophagy promotes CCL2 transcription in epidermal keratinocytes through the AMPK-BRAF-MAPK1/3/ERK-activator protein 1 (AP1) pathway 75 , and upregulates CXCL8 to trigger mesenchymal stem cell-mediated CD4 + T cell migration and differentiation 76 . The presence of microbes in the uterine cavity has been widely demonstrated, which initiates immunologic reactions 77 . High levels of autophagy may participate in the regulation of endometrial infiltration of immune cells to play a protective role during the menstrual cycle, and the activation of COX-2/PGE 2 and up-regulation of chemokines may be involved in these processes ( Figure 2 ).…”

Hydrogen Gas: A Novel Type of Antioxidant in Modulating Sexual Organs Homeostasis

“…Kissing and saliva exchange can transmit oral microbiota [ 138 ], and oral sex can also transmit oral, respiratory, and genital infections from one site in body to the other [ 133 , 135 ]. Human lower reproductive tract (vagina, cervix, and penile urethra) is the direct place for sexual intercourse; the mucosal epithelia in these organs are exposed to sexually transmitted microbes [ 139 , 140 ]. As we have discussed above, the endogenous H 2 is mainly produced in the gastrointestinal tracts, mouth and pharynx, vagina, respiratory system, and skin by H 2 -producing fermentative bacteria [ 45 ].…”