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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 ( Il-1β ), chemokines (C-X-C motif chemokine ligand 10 ( Cxcl10 ), chemokine ligand 2 ( Ccl2 )), and immune system genes (S100 calcium binding protein 8 ( S100a8 ), lipocalin-2 ( Lcn2 )) were among the most significantly upregulated genes. Hypocretin neuropeptide precursor ( Hcrt ), a neuropeptide, and transcription factors such as neuronal PAS domain protein 4 ( Npas4 ), GATA binding protein 3 ( Gata3 ), and paired box 7 ( Pax7 ) 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.

Exploratory Transcriptomic Profiling Reveals the Role of Gut Microbiota in Vascular Dementia