Gut-Brain Axis in Aging: Microbial Metabolites as Drivers of Blood-Brain Barrier Dysfunction and Neuroinflammation

Background: Aging is closely associated with a decline in gut microbial diversity, leading to reduced short-chain fatty acid (SCFA) levels and an increase in harmful metabolites. This process compromises blood-brain barrier (BBB) integrity by degrading endothelial tight junction proteins, allowing lipopolysaccharides (LPS) and pro-inflammatory mediators to enter the brain, driving chronic low-grade neuroinflammation and increasing vulnerability to neurodegenerative disorders like Alzheimer's and Parkinson's disease. Methods & Objective: This paper presents a comprehensive research proposal for a Phase II, randomized, double-blind, placebo-controlled, parallel-group clinical trial. The study is designed to investigate the therapeutic efficacy and synergistic potential of microencapsulated sodium butyrate (SCFA) and bioavailability-enhanced curcumin over a 24-week period. The primary focus is to evaluate their capacity to restore gut and BBB barrier integrity, attenuate microglial activation, and mitigate neuroinflammatory signaling in aging human populations at risk for cognitive decline. Significance: By mapping a strict methodological framework, this research aims to provide actionable clinical strategies for targeted dietary and supplement-based interventions to support healthy neurological aging and lower the risk of age-related neurodegeneration.