Gut Microbial-Related Alanine, Aspartate, and Glutamate Metabolism is Disordered in Peripheral and Central Tissues of Depressed Mice

Introduction: Depression is a complex and common mental disease, but the pathogenesis of depression is still unclear. This study was conducted to explore its pathogenesis via metabolic analysis in peripheral and central tissues. Materials and Methods: The Chronic restraint stress (CRS) model of depression was established, and gut microbiota in feces and metabolites in the microbiota-gut-brain (MGB) axis (feces, colon, blood, and prefrontal cortex) were detected. At baseline, control group and CRS group were matched on age, body wight and sucrose preference to avoid the possible effects of confounding factors on metabolite levels in various tissues. Results: There were six differential species in CRS mice, and the alanine, aspartate, and glutamate metabolism in which these species were involved was significantly suppressed in CRS mice. Metabolic analyses showed that there were 277, 155, 219, and 113 differential metabolites in feces, colon, blood, and prefrontal cortex, respectively. Pathway analyses showed that alanine, aspartate, and glutamate metabolism was found to be significantly affected in the MGB axis. The built metabolite interaction network using differential metabolites in this pathway showed that ammonia-related pathways occupied the main role in this network. NH4Cl (the chemical donor of ammonia) could improve the CRS-induced depressive-like behavior (immobility time) in mice after intraperitoneal administration for 12 hours, but not after 24 hours. Discussion: Evidence showed that the disturbances of gut microbiota were closely related to the pathogenesis of depression, and gut microbiota-related metabolites played an important role in this process. Here, using the CRS-induced depression model, we found that the disturbances of gut microbial- related alanine, aspartate and glutamate metabolism in the MGB axis might be involved in the onset of CRS-induced depression. Our findings would be helpful for further exploring the pathogenesis of depression. Conclusion: These results indicated that alanine, aspartate, and glutamate metabolism might be a mediator in the crosstalk of gut and brain in depression, and future studies should further explore whether ammonia could be a potentially therapeutic target for depression.