Phytosterols as modulators of gut-brain axis and neuroinflammation in Alzheimer’s disease: A novel therapeutic avenue in aging research

Abstract

Alzheimer’s disease (AD) is characterized by amyloid-β deposition and neuroinflammation. Emerging evidence implicates gut microbiota dysbiosis and gut–brain axis dysfunction in AD pathogenesis, while phytosterols—plant sterols similar to cholesterol—modulate microbiota composition, lipid metabolism, and inflammatory pathways. To review evidence of phytosterols as modulators of the gut–brain axis and neuroinflammation in AD, outlining mechanisms, therapeutic potential, and delivery approaches. A literature search of PubMed, Scopus, and Web of Science identified studies on phytosterols, gut microbiota modulation, neuroinflammation, and AD. Mechanistic data on sterol structure–activity relationships, microbiota-derived metabolites, and in vivo AD outcomes were extracted and synthesized. Phytosterols lower systemic cholesterol, cross the blood–brain barrier, and accumulate in neural tissue. They enrich short-chain fatty acid–producing gut microbes, suppress pathogens, and increase secondary bile acids that activate FXR and TGR5 signaling, attenuating neuroinflammation. Preclinical AD models show reduced amyloid-β, decreased microglial activation, and improved cognition. Nanoencapsulation and esterification strategies enhance CNS bioavailability. Phytosterols modulate cholesterol, gut microbiota, and neuroinflammatory pathways through FXR- and TGR5-mediated signaling. Advanced delivery systems and microbiome-informed dosing strategies may enhance their therapeutic precision and uptake. Future studies should focus on stratified human trials to validate efficacy and enable personalized interventions in Alzheimer’s disease.