Compromised hepatic bilirubin clearance drives depressive symptoms via regulating microglial engulfment of dendritic spines

Major depressive disorder (MDD) remains a debilitating global health issue with limited treatment efficacy. Liver qi stagnation (or called liver depression) has been associated with MDD, but the underlying mechanisms are poorly understood. This study investigates whether impaired hepatic function contributes to depressive symptomatology. Using retrospective clinical data, chronic unpredictable stress (CUMS) models, orthotopic liver transplantation, and microglia-specific genetic tools (including TRPM2 and SYK conditional knockouts), we combined behavioral assays, multi-omics, electrophysiology, and optogenetics to explore the liver-brain axis in depression. Compromised hepatic bilirubin clearance in depressive subjects drives depressive symptoms by enhancing microglial engulfment of dendritic spines in the anterior cingulate cortex (ACC). Clinical evidence highly reveals a correlation between hyperbilirubinemia and MDD severity, mirrored in chronic stress mouse models. Liver transplantation from stressed to non-stressed mice impaired bilirubin clearance and induced depressive behaviors, accompanied by ACC glutamatergic neuronal hypoactivity (ACC Glu ) and microglial overactivation. Conversely, transplanting healthy livers into stressed mice alleviated these symptoms. Mechanistically, hyperbilirubinemia activates the bilirubin-TRPM2-SYK axis in microglia, promoting excessive spine pruning and synaptic loss in ACC Glu by employing transcriptional pause-release mechanisms to prioritize protein synthesis of pro-phagocytosis machines. Pharmacological inhibition or genetic ablation of microglial TRPM2 rescues spine density and depressive behaviors. And the maladaptation of ACC Glu neurons in hyperbilirubinemic mice was reversible by TRPM2 blockade, either. Our results reveal a novel liver-brain pathway whereby impaired bilirubin clearance drives depression via microglial synaptic pruning. Targeting microglial TRPM2 offers a promising therapeutic strategy for MDD.