Aorta- and liver-generated TMAO enhances trained immunity for increased inflammation via ER stress/mitochondrial ROS/glycolysis pathways

We determined whether gut microbiota-produced trimethylamine (TMA) is oxidized into trimethylamine N-oxide (TMAO) in nonliver tissues and whether TMAO promotes inflammation via trained immunity (TI). We found that endoplasmic reticulum (ER) stress genes were coupregulated with MitoCarta genes in chronic kidney diseases (CKD); TMAO upregulated 190 genes in human aortic endothelial cells (HAECs); TMAO synthesis enzyme flavin-containing monooxygenase 3 (FMO3) was expressed in human and mouse aortas; TMAO transdifferentiated HAECs into innate immune cells; TMAO phosphorylated 12 kinases in cytosol via its receptor PERK and CREB, and integrated with PERK pathways; and PERK inhibitors suppressed TMAO-induced ICAM-1. TMAO upregulated 3 mitochondrial genes, downregulated inflammation inhibitor DARS2, and induced mitoROS, and mitoTEMPO inhibited TMAO-induced ICAM-1. beta-Glucan priming, followed by TMAO restimulation, upregulated TNF-alpha by inducing metabolic reprogramming, and glycolysis inhibitor suppressed TMAO-induced ICAM-1. Our results have provided potentially novel insights regarding TMAO roles in inducing EC activation and innate immune transdifferentiation and inducing metabolic reprogramming and TI for enhanced vascular inflammation, and they have provided new therapeutic targets for treating cardiovascular diseases (CVD), CKD-promoted CVD, inflammation, transplantation, aging, and cancer.

Automated summary

This study investigated the production of TMAO by gut microbiota in nonliver tissues and its role in promoting inflammation through trained immunity. The researchers found that ER stress genes and MitoCarta genes were upregulated in CKD, TMAO upregulated genes in HAECs, and TMAO synthesis enzyme FMO3 was expressed in human and mouse aortas. TMAO transdifferentiated HAECs, phosphorylated kinases in cytosol, and integrated with PERK pathways. TMAO also induced mitoROS and upregulated TNF-alpha through metabolic reprogramming. These findings provide novel insights into the mechanisms of TMAO in EC activation, innate immune transdifferentiation, and metabolic reprogramming, and offer potential therapeutic targets for various diseases.