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.

Keywords: cellular immunity; immune cells; menstruation; microbiota; pregnancy; uterus.

Figure 1

(A) Endometrium of human uterus. Immunohistochemical analysis of human endometrium on frozen section stained with CK7 monoclonal antibody (Dako) of uterus in proliferative phase. Bound antibody was revealed using the LSAB+ HRP kit and 3,3′-diaminobenzidine tetrahydrochloride (DAB) as chromogen. The sections were counterstained with hematoxylin. Monostratified columnar epithelium and the basal layer, which remains intact during menstruation, is occupied by the base of the uterine glands. Original magnifications 200×. (B) Immunological components of uterine mucosa. The endometrium is populated by a range of immune cells, such as mast cells, Macrophages (MΦ), Neutrophils (Neu), Dendritic cells (DC), T and B cells. The presence of lymphoid aggregates in the endometrial tissue suggests that this is an active site for cell-mediated immunity. Lymphoid aggregates found beneath the endometrium are composed of B cells in the inner core, surrounded by CD8⁺ CD4⁻ T cells and an outer layer of macrophages. Scattered CD56⁺ natural killer (NK) cells and CD4⁺ T cells can also be found in between lymphoid aggregates.

Figure 2

The immune cells (Left) and microbiota (Right) within the female genital tract and semen. On the left side are the percentage with (respect to total CD45 positive cells) of T Lymphocytes (T), NK cells (NKs), Granulocytes (G), Macrophages (M), and B Lymphocytes (B) in Endometrium, Endocervix, Ectocervix, Vagina and semen. On the right side, is shown the median relative abundance of microbial genera. + + ++/+ represent the relative abundance amount of microorganisms and immune cells in different areas.

Figure 3

Uterine immune stages during menstruation cycle. During the normal menstrual cycle, the human endometrium is exposed to cyclical fluctuations of sex hormones. The repetitive cycles of proliferation, differentiation, decidualization, and shedding of this tissue during mensuration and the steroid hormones per se cause profound changes in the immune cells' population. The estrogen-dominant proliferative phase is characterized by the regeneration of the functional layer of the endometrium. In the progesterone driven secretory phase, the endometrium undergoes a number of changes in preparation for implantation of the embryo. The immune cells that undergo greater number variations in the secretory phase are the NKs and macrophages. The microbiota, on the other hand, does not undergo large variations during different phases of the menstrual cycle. Sphingobium sp., Propionibacterium acnes, and Pseudomonas sp. are differentially enriched during the proliferative and secretory phases; P. acnes is more abundant in the secretory phase and has previously been identified in the placenta and cultured from follicular fluid. Functionally, the proliferative phase, compared to the secretory phase, appears associated with increased bacterial proliferation. + + ++/+ represent the relative abundance amount of microorganisms.