Systematical Comparison Reveals Distinct Brain Transcriptomic Characteristics in Depression Models Induced by Gut Microbiota Dysbiosis and Chronic Stress.

Major depressive disorder (MDD) is a devastating psychiatric illness with various etiologies. Both chronic stress and gut microbiome dysbiosis are implicated in the pathogenesis of MDD. However, limited research has been conducted to delineate the distinct effects of these two pathogenic factors on the brain transcriptome. We generated and compared transcriptomic features of the anterior cingulate cortex (ACC) from depressive-like mice induced by gut microbiome dysbiosis and canonical chronic stress paradigms, focusing on gene expression patterns and network characteristics. Data derived from MDD patients served as a reference standard to filter the molecular alterations associated with the disorder. Chronic stress induced a plethora of altered genes and biological functions associated with depression, prominently involving mitochondrial dysfunction. However, gut microbiota dysbiosis specifically regulated narrower range of genes and biological mechanisms, targeting aberrations in vesicular transport systems and perturbations of autophagy pathways. Network analysis revealed that hierarchical gene co-expression was specifically affected by gut microbiota dysbiosis rather than chronic stress. Further functional clustering analysis, along with the central distribution of inflammation-related differentially expressed genes, suggested an intricate interplay between disrupted autophagy processes, microglia-mediated inflammation, and synaptic dysfunctions in the network influenced by gut microbiota dysbiosis. Our findings reveal the distinctive transcriptomic alterations of brain shaped by gut microbiota and chronic stress in the development of MDD, contributing to a deeper understanding the heterogeneity of depression. Additionally, we provide a valuable data resource and bioinformatic analysis template for future studies.