Decoding TMAO in the Gut-Organ Axis: From Biomarkers and Cell Death Mechanisms to Therapeutic Horizons

Jie Liu,1– 3,* Peng Ge,1– 3,* Yalan Luo,4,* Zhenxuan Sun,1– 3 Xinyu Luo,1– 3 Huijuan Li,5 Boliang Pei,1– 3 Lu Xun,1– 3 Xuetao Zhang,1– 3 Yunfei Jiang,1– 3 Haiyun Wen,1– 3 Jin Liu,1– 3 Qi Yang,6 Shurong Ma,1– 3 Hailong Chen1– 3 1Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, 116011, People’s Republic of China; 2Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, Liaoning, 116044, People’s Republic of China; 3Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, 116011, People’s Republic of China; 4Department of Gastroenterology, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, 116011, People’s Republic of China; 5Department of Cardiology, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, 116011, People’s Republic of China; 6Department of Traditional Chinese Medicine, The Second Affiliated Hospital of Dalian Medical University, Dalian, 116023, People’s Republic of China*These authors contributed equally to this workCorrespondence: Hailong Chen, Email [email protected]: The gut microbiota and its metabolites are bi-directionally associated with various human illnesses, which has received extensive attention. Trimethylamine N-oxide (TMAO) is a gut microbiota metabolite produced in the liver, which may serve the role of an “axis” connecting the gut and host organs. TMAO levels are significantly higher in the blood of individuals with cardiovascular, renal, neurological, and metabolic diseases. Endothelial cells are crucial for regulating microcirculation and maintaining tissue and organ barriers and are widely recognized as target cells for TMAO. TMAO not only induces endothelial dysfunction but also acts on various cell types, such as endothelial cells, epithelial cells, vascular smooth muscle cells, nerve cells, and pancreatic cells, triggering multiple cell death mechanisms, including necrosis and programmed cell death, thereby influencing host health. This paper thoroughly covers the origins, production, and metabolic pathways of TMAO, emphasizing its importance in the early detection and prognosis of human diseases in the “Gut-Organ” axis, as well as its mechanisms of influence on human diseases, particularly the cross-talk with cell death. Furthermore, we cover recent advances in treating human diseases by regulating gut microbiota structure and enzyme activity to influence TMAO metabolism and reduce TMAO levels, including the use of probiotics, prebiotics, antibiotics, anti-inflammatory drugs, antiplatelet drugs, hypoglycemic drugs, lipid-lowering drugs, and natural products.Keywords: trimethylamine N-oxide, gut-organ axis, cell death, biomarker, therapeutic strategies