Vascular Cognitive Impairment-The Molecular Basis and Potential Influence of the Gut Microbiota on the Pathological...

Cognitive impairment is a major healthcare challenge worldwide, with vascular cognitive impairment (VCI) being its second leading cause after Alzheimer's disease. VCI is a heterogeneous group of cognitive disorders resulting from various vascular pathologies. Therefore, it is particularly difficult to determine its underlying cause and exact molecular basis. Nevertheless, the current understanding of the pathophysiological processes underlying VCI has changed and evolved in the last decades. The aim of this narrative review is to summarize the current state of knowledge on VCI pathogenesis and to analyze the potential role of the gut microbiota in this process, considering the most recent scientific reports and in accordance with the current understanding of these processes. Chronic cerebral hypoperfusion, which results in impaired blood supply, i.e., oxygen and nutrient deficiency, is the main underlying mechanism of VCI. Furthermore, chronic cerebral hypoperfusion triggers a cascade of molecular changes, starting with an energy imbalance, leading to glutamate excitotoxicity, acidotoxicity, and oxidative stress. Also, all of the above provoke the activation of microglia and the release of pro-inflammatory cytokines that recruit systemic immune cells and lead to their infiltration into the central nervous system, resulting in neuroinflammation. Blood-brain barrier dysfunction may occur at various stages of chronic cerebral hypoperfusion, ultimately increasing its permeability and allowing potentially toxic substances to enter the brain parenchyma. Gut microbiota and their metabolites, which have been identified in numerous inflammatory conditions, may also influence the pathophysiological processes of VCI.