Porphyromonas gingivalis outer membrane vesicles shape trophoblast cell metabolism impairing functions associated to adverse pregnancy outcome

Abstract

Periodontitis is proposed as a risk factor for preterm delivery, fetal growth restriction, and preeclampsia with severe consequences for maternal and neonatal health, but the biological mechanisms involved are elusive. Porphyromonas gingivalis gain access to the placental bed and impair trophoblast cell function, as assessed in murine and human pregnancy, suggesting a pathogenic role in adverse pregnancy and neonatal outcomes. P. gingivalis releases outer membrane vesicles (P. gingivalis OMV) during growth that spread to distant tissues and are internalized in host cells as described in metabolic, neurological, and vascular systemic diseases. Here we tested the hypothesis that P. gingivalis OMV internalized in trophoblast cells disrupt their metabolism leading to trophoblast and placenta dysfunction and adverse pregnancy outcomes. An in vitro design with human trophoblast cells incubated with P. gingivalis OMV was used together with ex vivo and in vivo approaches in pregnant mice treated with P. gingivalis OMV. P. gingivalis OMV modulated human trophoblast cell metabolism by reducing glycolytic pathways and decreasing total reactive oxygen species with sustained mitochondrial activity. Metabolic changes induced by P. gingivalis OMV did not compromise cell viability; instead, it turned trophoblast cells into a metabolic resting state where central functions such as migration and invasion were reduced. The effects of P. gingivalis OMV on human trophoblast cells were corroborated ex vivo in mouse whole placenta and in vivo in pregnant mice: P. gingivalis OMV reduced glycolytic pathways in the placenta and led to lower placental and fetal weight gain in vivo with reduced placental expression of the glucose transporter GLUT1. The present results point to OMV as a key component of P. gingivalis involved in adverse pregnancy outcomes, and even more, unveil a metabolic cue in the deleterious effect of P. gingivalis OMV on trophoblast cells and mouse pregnancy, providing new clues to understand pathogenic mechanisms in pregnancy complications and other systemic diseases.