Gut Microbiota Disorder, Gut Epithelial and Blood–Brain Barrier Dysfunctions in Etiopathogenesis of Dementia: Molecular Mechanisms and Signaling Pathways

Emerging evidences indicate a critical role of the gut microbiota in etiopathogenesis of dementia, a debilitating multifactorial disorder characterized by progressive deterioration of cognition and behavior that interferes with the social and professional functions of the sufferer. Available data suggest that gut microbiota disorder that triggers development of dementia is characterized by substantial reduction in specific species belonging to the Firmicutes and Bacteroidetes phyla and presence of pathogenic species, predominantly, pro-inflammatory bacteria of the Proteobacteria phylum. These changes in gut microbiota microecology promote the production of toxic metabolites and pro-inflammatory cytokines, and reduction in beneficial substances such as short chain fatty acids and other anti-inflammatory factors, thereby, enhancing destruction of the gut epithelial barrier with concomitant activation of local and distant immune cells as well as dysregulation of enteric neurons and glia. This subsequently leads to blood–brain barrier dysfunctions that trigger neuroinflammatory reactions and predisposes to apoptotic neuronal and glial cell death, particularly in the hippocampus and cerebral cortex, which underlie the development of dementia. However, the molecular switches that control these processes in the histo-hematic barriers of the gut and brain are not exactly known. This review integrates very recent data on the molecular mechanisms that link gut microbiota disorder to gut epithelial and blood–brain barrier dysfunctions, underlying the development of dementia. The signaling pathways that link gut microbiota disorder with impairment in cognition and behavior are also discussed. The review also highlights potential therapeutic options for dementia.