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Review
. 2024 Apr 3;39(4):638-646.
doi: 10.1093/humrep/dead274.

The endometrial microbiota and early pregnancy loss

Joshua Odendaal  1   2 , Naomi Black  1   2 , Phillip R Bennett  3   4   5 , Jan Brosens  1   2 , Siobhan Quenby  1   2 , David A MacIntyre  3   4   5
Affiliations
Review

The endometrial microbiota and early pregnancy loss

Joshua Odendaal et al. Hum Reprod. .

Abstract

The human endometrium is a dynamic entity that plays a pivotal role in mediating the complex interplay between the mother and developing embryo. Endometrial disruption can lead to pregnancy loss, impacting both maternal physical and psychological health. Recent research suggests that the endometrial microbiota may play a role in this, although the exact mechanisms are still being explored, aided by recent technological advancements and our growing understanding of host immune responses. Suboptimal or dysbiotic vaginal microbiota, characterized by increased microbial diversity and reduced Lactobacillus dominance, has been associated with various adverse reproductive events, including miscarriage. However, the mechanisms linking the lower reproductive tract microbiota with pregnancy loss remain unclear. Recent observational studies implicate a potential microbial continuum between the vaginal and endometrial niche in patients with pregnancy loss; however, transcervical sampling of the low biomass endometrium is highly prone to cross-contamination, which is often not controlled for. In this review, we explore emerging evidence supporting the theory that a dysbiotic endometrial microbiota may modulate key inflammatory pathways required for successful embryo implantation and pregnancy development. We also highlight that a greater understanding of the endometrial microbiota, its relationship with the local endometrial microenvironment, and potential interventions remain a focus for future research.

Keywords: endometrial microbiota; immune microenvironment; inflammation; microbiome; miscarriage; recurrent pregnancy loss.

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Conflict of interest statement

P.R.B. and D.A.M. have a patent for the use of Lactobacillus crispatus CTV-05 in the prevention of preterm birth (US63/151474).

Figures

Graphical Abstract
Graphical Abstract
Does dysbiosis cause early pregnancy loss? A review of recent findings, causality, and potential mechanisms. Created with BioRender.com
Figure 1.
Figure 1.
Endometrial microbiota and contamination sources. Accurately sampling the endometrial microbiota can be challenging owing to the high risk of cross-contamination. Sampling through the cervicovaginal route is the most practical but risks contamination from bacteria resident in the vagina, many of which are likely also present in the endometrium. Bacterial DNA may exist on protective equipment present in both the clinical and laboratory environments, as well as in laboratory reagents. Owing to the low biomass of the endometrial microbiota, the PCR amplification and sequencing strategies may lead to significantly confounded results. Created with BioRender.com.
Figure 2.
Figure 2.
Overview of potential mechanisms linking endometrial microbiota to early pregnancy loss. In an optimal state, low levels of commensal bacteria promote host immune and inflammatory response supportive of endometrial function. 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). A shift towards a dysbiotic endometrial microbiota and increased pathogen colonisation could reduce AMP, chemokine, and cytokine production resulting in loss of epithelial integrity, increased permeability, and bacterial translocation (Benner et al., 2018). Abnormally activated APCs drive aberrant immune pathway activation, including changes to T cell production leading to an increased ratio of Th17 and the transformation of Th2 to Th1 cells, leading to increased tumour necrosis factor (TNF)-α production, which has been implicated in abnormal pregnancy development (D'Ippolito et al., 2018). Altered stimulation of uNK may affect angiogenesis and foetal–maternal immune tolerance (Brosens et al., 2022) and plasma cells in the endometrial stroma may reflect an immune response to pathogens and impair endometrial receptivity (Buzzaccarini et al., 2020; Teng et al., 2012). Created with BioRender.com.
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