The gut-brain-vascular axis: converging neuroinflammatory and hypertension-mediated pathways from gut dysbiosis to cognitive decline

Abstract

Hypertension and cognitive decline are major public health burdens, and both have been associated with gut microbiome dysbiosis. We propose the gut-brain-vascular axis as a testable synthesis in which dysbiosis may contribute to cognitive decline through two converging routes: direct neuroinflammatory signaling and hypertension-mediated cerebrovascular injury. In the proposed direct route, intestinal barrier dysfunction, lipopolysaccharide translocation, altered microbial metabolites, microglial activation, and vagal signaling may promote neuroinflammation. In the indirect route, dysbiosis-associated metabolites, immune activation, autonomic imbalance, and endothelial injury may contribute to hypertension, which is linked to cerebral small vessel disease, impaired cerebral autoregulation, neurovascular uncoupling, and blood-brain barrier dysfunction. The component relationships are supported to different degrees, but the complete temporal pathway and an interaction between the two routes have not been established in humans. This narrative review synthesizes gut-hypertension, gut-cognitive, cerebrovascular, shared-mechanism, and therapeutic evidence and identifies the study designs needed to test the framework. Longitudinal cohorts and trials that measure microbiome, blood pressure, cerebrovascular, and cognitive outcomes together are required to determine whether the proposed routes occur independently, sequentially, or interactively.