Research progress on the relationship between trimethylamine N-oxide (TMAO) and depression

Over the past decade, gut microbiota has emerged as a major research focus in depression, greatly promoting the understanding of its novel pathological mechanisms and clinical management. Trimethylamine N-oxide (TMAO), a key co-metabolite of gut microbiota and host, has also garnered increasing attention from researchers in recent years. TMAO exerts critical effects on the nervous system, especially in modulating neuroinflammation, oxidative stress, and blood-brain barrier integrity. Mechanistically, TMAO activates the nucleotide-binding domain leucine-rich repeat and pyrin domain-containing receptor 3 (NLRP3) inflammasome pathway, induces the release of inflammatory cytokines such as interleukin-1β (IL-1β), and stimulates microglial activation, thereby triggering inflammatory cascades. TMAO also promotes mitochondrial dysfunction and excessive reactive oxygen species production, leading to oxidative damage. In addition, TMAO disrupts blood-brain barrier integrity by downregulating tight junction proteins. These effects are closely linked to the pathophysiology of depression, indicating that TMAO may contribute to the onset and development of depression. A systematic review of the association between TMAO and depression and recent advances will provide a theoretical basis and new directions for the diagnosis and treatment of depression, and facilitate further progress in this field.