942-P: The Choline Metabolite TMAO Inhibits NETosis and Promotes Placental Development in GDM of Humans and Mice

Abstract

Objective: Trimethylamine N-oxide (TMAO) is a choline metabolite and has been reported as a risk factor of gestational diabetes mellitus (GDM). Diabetes primes neutrophils to produce neutrophil extracellular traps (NETosis). We investigated the effect of TMAO and NETs on the placenta and revealed the role of TMAO and NETs in GDM. Methods: Peripheral plasma, cord plasma and placenta from normal pregnant and GDM women were collected. Plasma concentrations of TMAO, ds-DNA and myeloperoxidase (MPO) were compared and association analysis was performed. HTR-8/Svneo cells and GDM models of wild-type and PAD4-/- mice were used to observe the effect of TMAO and NETs on the placenta. Results: The peripheral and cord plasma TMAO levels of GDM women were significantly higher than those of control. BMI and glucose levels were positively correlated with the concentration of blood TMAO, especially the newborn weight and placental thickness were positively correlated with TMAO levels in cord blood. TMAO could promote proliferation, migration, invasion and angiogenesis of HTR-8/Svneo cells, and TMAO-treated neutrophils could resist NETosis stimulated by PMA or LPS. Plasma concentrations of ds-DNA and MPO in peripheral and cord blood were significantly higher in GDM women, and BMI and blood glucose levels were positively correlated with ds-DNA and MPO levels. MPO levels from GDM placenta were also higher than those in the control group. NETs inhibit the proliferation, migration, invasion and angiogenesis of HTR-8/Svneo cells. The placenta weight of PAD4-/- mice was significantly higher than that of wild-type mice. TMAO feeding also significantly increased the weight of the placenta and fetuses, and this increase did not affect the normal structure of the placenta. Conclusion: Higher TMAO levels and abnormal NETosis were associated with GDM. TMAO could not only promote the development of the placenta and fetus, but also inhibit NETosis to protect the placenta. Disclosure X. Lin: None. Y. Zhang: None. X. He: None. N. Chen: None. M. Wang: None. Y. Chen: None. X. Xiao: None. Funding National Natural Science Foundation of China (82071734, 81871222)