Research on the role and mechanism of stress liver regulation of negative emotions

Post-stress hepatic metabolic dysfunction is a critical factor in the development of negative emotional states after liver transplantation (NEALT), severely impairing postoperative patient recovery. However, its pathological mechanisms remain unclear. Microglia (Mg), as central immune cells, express numerous sensory receptors on their membranes and serve as a key link between peripheral organ stress and brain nucleus regulation. By constructing microglia-specific gene knockout mice, liver transplantation, and restraint stress models, combined with behavioral tests and multi-omics analysis, we found that transplanting a stressed donor liver into a non-stressed recipient mouse could mimic clinical NEALT symptoms. The anterior cingulate cortex (ACC) is a key brain region regulating emotional responses and sensory perception. Mechanistic studies revealed that stress-induced liver detoxification dysfunction leads to elevated bilirubin levels, which acts as a ligand to activate the TRPM2 receptor in ACC microglia, enhancing their impact on glutamatergic synapses and ultimately leading to decreased neuronal activity and NEALT development. We propose a hypothesis: stressed livers drive microglia to excessively engulf glutamatergic synapses via the liver-brain-Mg TRPM2 signaling axis. Evaluating interventions targeting this axis holds significant potential for NEALT prevention and treatment, providing significant insights into its mechanisms and therapeutic strategies. Freshly dissociated single-cell suspensions were loaded to 10X Genome GenCode Single-cell instrument to generate GEMs (Gel Bead-In-EMlusion). ScRNA-seq libraries were subsequently prepared following the manufacturer’s protocol of Chromium Next GEM Single Cell 3’ Regent Kits v3.1. Libraries were then sequenced using the Novaseq 6000 platform with paired-end sequencing (PE150) mode.