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Stroke is the second most common cause of cognitive impairment and dementia. Vascular dementia (VaD), a cognitive impairment following a stroke, is common and significantly impacts the quality of life. We recently demonstrated via gut microbe transplant studies that the gut microbe-dependent trimethylamine-N-oxide (TMAO) pathway impacts stroke severity, both infarct size and long-term cognitive outcomes. However, the molecular mechanisms that underly the role of the microbiome in VaD have not been explored in depth. To address this issue, we performed a comprehensive RNA-sequencing analysis to identify differentially expressed (DE) genes in the ischemic cerebral cortex of mouse brains at pre-stroke and post-stroke day 1 and day 3. A total of 4016, 3752 and 7861 DE genes were identified at pre-stroke and post-stroke day 1 and day 3, respectively. The Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis indicated pathways of neurodegeneration in multiple diseases, chemokine signaling, calcium signaling, and IL-17 signaling as the key enriched pathways. Inflammatory response genes interleukin-1 beta (<i>Il-1β</i>), chemokines (C–X–C motif chemokine ligand 10 (<i>Cxcl10</i>), chemokine ligand 2 (<i>Ccl2</i>)), and immune system genes (S100 calcium binding protein 8 (<i>S100a8</i>), lipocalin-2 (<i>Lcn2</i>)) were among the most significantly upregulated genes. Hypocretin neuropeptide precursor (<i>Hcrt</i>), a neuropeptide, and transcription factors such as neuronal PAS domain protein 4 (<i>Npas4</i>), GATA binding protein 3 (<i>Gata3</i>), and paired box 7 (<i>Pax7</i>) were among the most significantly downregulated genes. In conclusion, our results indicate that higher plasma TMAO levels induce differential mRNA expression profiles in the ischemic brain tissue in our pre-clinical stroke model, and the predicted pathways provide the molecular basis for regulating the TMAO-enhanced neuroinflammatory response in the brain.