Gut microbiota-derived TMAO drives the kidney-bone-vascular axis in chronic kidney disease complications.

Chronic kidney disease (CKD) is often accompanied by comorbidities such as skeletal disorders and vascular calcification, which significantly elevate the mortality risk among affected patients. In recent years, dysbiosis of the gut microbiota has emerged as a key pathological factor in the progression of CKD, particularly through the accumulation of its metabolic product, trimethylamine-N-oxide (TMAO). TMAO is produced in the liver via the gut microbiota's metabolism of dietary precursors such as choline, betaine, and L-carnitine. It is primarily excreted via the kidneys, and its levels are markedly elevated in CKD patients due to impaired renal function. Studies have demonstrated that TMAO is not only closely associated with an increased risk of vascular calcification but may also exacerbate skeletal disorders in CKD patients by disrupting bone metabolism. This review aims to elucidate the mechanisms underlying TMAO's role in CKD, particularly focusing on its critical involvement in the kidney-bone-vascular axis. Based on existing evidence, we propose potential therapeutic strategies for modulating gut microbiota and TMAO levels, including dietary modifications, probiotic interventions, TMA cleavage enzyme inhibitors, FMO3 inhibitors, and pharmacological regulation, to improve skeletal and cardiovascular health in CKD patients.