Multi-Omics Characterization of Type 2 Diabetes Mellitus-Induced Cognitive Impairment in the db/db Mouse Model

Type 2 diabetes mellitus (T2DM) is a complex metabolic disorder frequently accompanied by cognitive impairment. Contributing factors such as modern lifestyle, genetic predisposition, and gene environmental interactions have been postulated, but the pathogenesis remains unclear. In this study, we attempt to investigate the potential mechanisms and interventions underlying T2DM-induced cognitive deficits from the brain–gut axis perspective. A combined analysis of the brain transcriptome, plasma metabolome, and gut microbiota in db/db mice with cognitive decline was conducted. Transcriptome analysis identified 222 upregulated gene sets and 85 downregulated gene sets, mainly related to mitochondrial respiratory, glycolytic, and inflammation. In metabolomic analysis, a total of 75 significantly altered metabolites were identified, correlated with disturbances of glucose, lipid, bile acid, and steroid metabolism under disease state. Gut microbiota analysis suggested that the species abundance and diversity of db/db mice were significantly increased, with 23 significantly altered genus detected. Using the multi-omics integration, significant correlations among key genes (n = 33), metabolites (n = 41), and bacterial genera (n = 21) were identified. Our findings suggest that disturbed circulation and brain energy metabolism, especially mitochondrial-related disturbances, may contribute to cognitive impairment in db/db mice. This study provides novel insights into the functional interactions among the brain, circulating metabolites, and gut microbiota.