The Hidden Relationship between Intestinal Microbiota and Immunological Modifications in Preeclampsia Pathogenesis

Abstract

Preeclampsia is a multifactorial gestational syndrome characterized by increased blood pressure during pregnancy associated with multiorgan involvement. The impact of this disease on maternal and neonatal health is significant, as it can lead to various fetal comorbidities and contribute to the development of maternal comorbidities later in life. Consistent evidence has shown that the microbiota acts as a regulator of the immune system, and it may, therefore, influence the development of preeclampsia by modulating immune factors. This narrative review aims to investigate the role of the immune system in the pathogenesis of preeclampsia and to summarize the most recent literature on the possible link between preeclampsia and alterations in the intestinal microbiota. To this end, we conducted a literature search, aiming to perform a narrative review, on PubMed and Embase from January 1990 to March 2024, focusing on the latest studies that highlight the main differences in microbial composition between patients with and without preeclampsia, as well as the effects of microbial metabolites on the immune system. From the review of 28 studies assessing the intestinal microbiota in preeclamptic women, preeclampsia could be associated with a state of dysbiosis. Moreover, these patients showed higher plasmatic levels of endotoxin, pro-inflammatory cytokines, and T helper 17 cells; however, the findings on specific microbes and metabolites that could cause immune imbalances in preeclampsia are still preliminary.

Keywords: gestational hypertension; gut metabolome; gut microbiota; hypertensive pregnancy disorder; preeclampsia.

Figure 1

Defective trophoblastic phenotype and related immunological dysfunctions in preeclampsia. On the left side, the physiological placentation processes are represented: the cytotrophoblast cells acquire an invasive phenotype to enhance efficient vascular anastomoses, and decidual T cells, NK cells, and M2 macrophages establish the maternal immune tolerance to the fetus. On the right side, there is a schematic representation of immunological changes in preeclampsia. The trophoblast without the invasive phenotype leads to the abnormal development of narrow vessels and endothelial damage (also due to higher levels of AT1-AAs) and increased ROS production. These changes cause an imbalance of angiogenic and anti-angiogenic factors (PIGF and sFlt-1) and a pro-inflammatory environment (Th1 shift, increasing levels of NK and M1 macrophages). Acronyms: Th1/Th2: T helper 1/2 cells; Treg: regulatory T cells; NK: natural killer cells; ROS: reactive oxygen species; AT1-AAs: antibodies against the angiotensin II type 1 receptor; PIGF: placental growth factor; sFlt-1: soluble FMS-like tyrosine kinase-1.