Involvement of trimethylamine N-oxide in major depressive disorder via astrocytic d-Serine dysregulation.

Trimethylamine N-oxide (TMAO), a co-metabolite of the gut microbiota and host, has been implicated in the pathogenesis of various neuropsychiatric disorders. However, its role in major depressive disorder (MDD) remains poorly understood. This study aims to verify the relationship between TMAO and MDD and elucidate the underlying mechanisms. Plasma TMAO concentrations were quantified by HPLC-MS/MS and compared between MDD patients and healthy controls. To explore the effects of TMAO on depressive-like behavior and cerebral d-serine metabolism, mice were administered TMAO via dietary supplementation. Finally, astrocytes were treated with TMAO to examine its impact on d-serine metabolism at the cellular level. Here, we found that plasma TMAO levels were significantly elevated in MDD patients and positively correlated with both HAMD-17 and HAMA-14 scores. Consistently, mice fed TMAO for seven weeks exhibited pronounced depressive-like behaviors. While TMAO exposure did not induce apparent astrocytic damage, it markedly promoted d-serine secretion and caused notable neuronal injury. Mechanistically, TMAO activated the AMPK/SIRT-1 signaling pathway in astrocytes, resulting in upregulated serine racemase expression. Furthermore, both exogenous d-serine and conditioned medium from TMAO-treated astrocytes triggered neuronal apoptosis. Collectively, these findings demonstrate that TMAO contributes to MDD pathogenesis by activating astrocytic AMPK/SIRT-1 signaling to enhance d-serine production, subsequently inducing neuronal apoptosis. TMAO may thus represent a promising therapeutic target for MDD.