The Choline Metabolite TMAO Inhibits NETosis and Promotes Placental Development in GDM of Humans and Mice

Choline metabolite Trimethylamine N-oxide (TMAO) has been recognized as a risk factor of gestational diabetes mellitus (GDM), but its exact role in GDM has not been reported. In this study, we focused on the placenta development to reveal the role of TMAO in GDM. We found the TMAO levels in peripheral and cord plasma were increased in women with GDM, and TMAO levels were positively correlated with newborn weight and placental thickness. Neutrophil extracellular traps (NETs) in the peripheral and cord plasma and the myeloperoxidase expression in the placenta of women with GDM also increased. NETs could inhibit the proliferation, migration, invasion and angiogenesis of HTR-8/Svneo cells. However, TMAO could not only inhibit the formation of NETs, but also enhance the biological function of HTR-8/Svneo cells. By inducing GDM models in NETs deficient PAD4^-/- and wild-type mice, the placental weight of PAD4^-/- mice increased significantly. TMAO feeding also inhibited the formation of NETs and further increased the weight of the placenta and fetuses, and this increase did not affect the placental structure. Our data indicated that higher TMAO levels and the formation of abnormal NETs were associated with GDM. TMAO could not only promote the development of the placenta and fetuses, but also inhibit the formation of NETs.