Placental Microbial Colonization and Its Association With Pre-eclampsia

Abstract

The existence and role of the microbiome in regulating physiological and pathophysiological conditions including metabolism, energy homeostasis, immune tolerance, behavior, obesity, diabetes, and cardiovascular-related diseases is of immense interest. It is now clear that the human placenta is not sterile, but rather colonized with microbes. The placental and vaginal microbiomes are distinct however, the placental microbiome is comparable with the oral microbiome, with a limited variation when compared with the gut microbiome. Pre-eclampsia (PE), a pregnancy-specific hypertensive disorder, remains the leading cause of maternal-fetal morbidity and mortality. This is largely due to the lack of a clear etiology of PE and consequently, diagnostic strategies, and treatment are sub-optimal. The present review focuses on the current understanding of the placental microbiome and its implication in the etiology of PE. It provides a perspective on the alteration of placental microbiome as a possible therapeutic approach in the prevention and management of PE.

Keywords: immune tolerance; metabolism; microbe; placental microbiome; pre-eclampsia; pregnancy.

Figure 1

Seeding of placental microbiome; microbes ascend from the vagina, gut, and oral cavity which are internalized and translocated by hematogenous spread to the placenta.

Figure 2

Interaction between commensal bacteria and toll like receptors of the trophoblast in the formation of regulatory cytokines. Commensal bacteria present at the epithelium of the uterus promote the induction of regulatory cytokines by trophoblast and macrophages. Macrophages secrete antimicrobial products that mitigate commensal overgrowth and prevent invasion of pathogenic bacteria. Recognition of bacterial products such as LPS or LPP by trophoblast potentiates the expression of anti-inflammatory factors, increasing T regulatory cells (Tregs), and promoting tolerance. TLR, toll-like receptor; DC, decidual cell; LPS, lipopolysaccharide; MAC, lipoprotein macrophage.

Figure 3

Interaction between pathogenic bacteria and toll-like receptors of the trophoblast in the formation of inflammatory cascades. Pathogenic bacteria, including the Gram-positive and Gram-negative present at the epithelium of the uterus promote the induction of inflammatory cascades by the interactions between the bacterial products LPP/LPS and toll-like receptors, TLR2/TLR4 expressed by trophoblast. Dysbiosis of placental microbiome increases the growth of pathogenic bacteria disrupting symbiosis among microbiota, trophoblast, and immune cells in the uterus, leading to inflammatory cascades that have been recognized in the pathogenesis of PE. Tregs, T regulatory cells; TLR, toll-like receptor; DC, decidual cell; LPS, lipopolysaccharide; LPP, lipoproteins; MAC, macrophage.

Figure 4

Implication of the placental microbiome in pre-eclampsia. Alteration of placental structures could result from the direct action of pathogenic bacteria through the release of lipopolysaccharide (LPS) or lipoproteins (LPP), which activates inflammatory cytokines via interactions with toll-like receptors (TLRs especially TLR4/TLR2). This invokes the pathogenic process of pre-eclampsia. Whereas, under physiological condition commensal bacteria release bacterial products such as LPS/LPP from gram-negative and positive bacteria, respectively, which is ligated by toll-like receptors (TLR4) and activated by TLR2 located on the surface of trophoblast. This in turns activates regulatory cytokines to promote tolerogenic microenvironment (maternal-fetal immune tolerance) and maintains energy homeostasis in normal pregnancy. SA, spiral artery.