The possible role of the endometrial microbiome as an immune modulator in the phase of implantation and during pregnancy

By Bhavana KunkalikarFeb 8 2023Reviewed by Danielle Ellis, B.Sc.

In a recent study published in the International Journal of Molecular Sciences, researchers reviewed the impact of endometrial microbiota on immune tolerance during pregnancy.

Background

Recent research has shown that the uterus houses its own microbiome. However, there is yet no consensus on the composition of endometrial microbiota. Therefore, its involvement in a healthy uterine environment remains a subject of investigation.

Endometrial receptivity is essential for embryo implantation; hence, immune tolerance in response to fetal antigens and carefully regulated production of inflammatory mediators is crucial. Studies have also suggested that the endometrial microbiome may interact with the immunological system in a very dynamic manner during periconception and later in pregnancy. Because of this, dysbiosis may result in unfavorable pregnancy outcomes.

Variation of endometrial microbiota across the lifespan

In the present study, researchers reviewed the data on the molecular pathways by which endometrial bacteria may interact with the immunological system.

Through transcervical sampling, research has discovered the presence of Gardnerella vaginalis, Lactobacillus (L.) spp., Mycoplasma hominis, and Enterobacter spp. Furthermore, studies have found a plethora of L. iners, L. crispatus, and Prevotella spp. In about 20% of patients, the vaginal and endometrial microbiomes differed with respect to the bacterial taxa detected or the comparative abundances represented in both sample types. Further research revealed that Lactobacillus was the most prevalent species in endometrial specimens, while Flavobacterium, Gardnerella, Bifidobacterium, Streptococcus, and  Prevotella were also often found.

Uterine cavity sampling of the microbiome

Acinetobacter, Sphingobium, Vagococcus, and Pseudomonas were the most prevalent bacteria in 80 endometrial specimens obtained from Chinese women undergoing surgery for non-infection-related cases. In the uterine cavity of 137 Chinese women, Moraxellaceae, Propionibacteriaceae, Streptococcaceae, and Pseudomonadaceae were identified as part of a separate investigation.

Acinetobacter, Comamonadaceae, Pseudomonas, and Cloacibacterium were also dominant in the endometrial microbiome of 25 Italian women undergoing hysterectomy due to fibroids. Furthermore, the researchers hypothesized that microbes including Acinetobacter, Cutibacterium, Corynebacterium, Escherichia, Streptococcus, and Staphylococcus might comprise the core of the endometrial microbiome, while Lactobacillus had an abundance rate of less than 16%.

Immunological agents in immune tolerance and endometrial receptivity in pregnancy

Essential immune agents such as uterine natural killer (uNK) cells, which represent 60% to 90% of decidual immune cells during initial gestational age, decline during middle and late gestational ages. Since peripheral NK cells are responsible for the cytolysis of cells that lacked a self-major histocompatibility complex (MHC)-I, these cells may play an important role in fetal rejection in the uterus.

However, cytolysis is prevented due to the distinct cell-surface receptors produced by uNKcells and the unusual MHC expression displayed by the fetal trophoblast. uNK cells are a part of the uterine spiral artery remodeling process during implantation, which is also aided by endometrial chemokines, like interleukin (IL)-11 and leukemia inhibitory factor (LIF), as well as by cytokines elicited by CD8+ T-cells like interferon-Ɣ and IL-8.

There are numerous strategies by which embryos can evade the immunological response to alloantigens. Most polymorphic MHC class Ia antigens are absent from the trophoblast cell surface. MHC class II antigens are also not expressed. In this scenario, most MHC class Ia and class II molecules are down-regulated just before implantation. Nonetheless, maternal immunological tolerance is also maintained when the paternal MHC is re-expressed artificially.

How does microbiota affect immune tolerance at the time of pregnancy?

Endometrial receptivity can be affected by uterine bacteria or bacterial fragments, resulting in an inflammatory, immunological response. Endometrial epithelial cells provide a physical barrier that prevents pathogen invasion and creates antimicrobial peptides (AMPs) related to crucial regulatory processes during implantation. Furthermore, studies have shown that commensal bacteria can promote membrane-associated mucin gene expression and sustain adherent and tight junctions.

The team also noted that polysaccharide A (PSA) release elicited an increase in the CD4+ population in germ-free mice infected with B. fragilis strain NCTC9343. In addition, PSA triggered a signaling link to toll-like receptor 2 (TLR2), which resulted in the Th1 cell differentiation and the generation of an optimal Th1/Th2 balance. Due to its immunomodulatory function, it is possible to hypothesize that PSA produced by Bacteroides has an important function in endometrial receptivity.

Also, in immature dendritic cell (DC) cultures obtained from healthy patients, Lactobacillus rhamnosus and Lactobacillus delbrueckii decreased human leukocyte antigen (HLA)-DR, CD80, CD83, CD86, and IL-12 expression while increasing IL-2, IL-10, and indoleamine-2,3-dioxygenase (IDO) expression. Altogether, Lactobacilli could display a tolerogenic impact on DC phenotypes throughout the maturation process.

Conclusion

The study findings highlighted that while plenty of research has addressed the composition of the uterine microbiota, a consensus has yet to be formed on the composition of the endometrial core and its relationship with the physiological processes that result in a healthy pregnancy. In addition, more research is required to determine the relationship between uterine microbiota, the immune response of the mother, and clinical obstetrical and reproductive outcomes.

Future studies could focus on analyzing microbiota across larger patient groups to lessen the vast amount of result variability and to comprehend the functions of microorganisms in diverse clinical illnesses.