Title : The role of gut microbes in vascular dementia
Stroke is the second most common cause of cognitive impairment and dementia. Vascular dementia (VaD), a cognitive impairment following a stroke is common and substantially affects 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 cognitive outcomes. However, the molecular mechanisms that underly the role of the microbiome in VaD haven’t been explored in depth. To address this issue, we performed a comprehensive RNA-sequencing analysis to identify differentially expressed genes (DEGs), 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 DEGs were identified at pre, post-stoke day 1 and day 3, respectively. 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 (Il-1β), chemokines (Cxcl10, Ccl2), and immune system genes (S100a8, Lcn2) were among the most significantly upregulated genes. The top significantly downregulated genes were Hcrt, a neuropeptide, and transcription factors such as Npas4, Gata3 and Pax7. In conclusion, our results indicate that higher plasma TMAO levels induce differential mRNA expression profiles in the ischemic brain tissue in pre-clinical stroke model, and the predicted pathways provide the molecular basis for regulating the TMAO-enhanced neuroinflammatory response in the brain.
Audience Take away
- Higher TMAO concentrations cause altered mRNA expression patterns in an ischemic mice brain
- Comprehensive transcriptome analysis provides insights into the differentially expressed genes and molecular mechanisms of TMAO mediated VaD