Natural Compounds and Their Microbiota-Derived Metabolites as Modulators of the Microbiota-Gut-Brain Axis in Alzheimer Disease: Biochemical Mechanisms and Drug Discovery Insights-A Narrative Review.

The microbiota-gut-brain axis (MGBA) is a complex signaling network linking the gut microbiota with central nervous system function. Growing evidence suggests that gut microbial dysbiosis contributes to neurodegenerative diseases (NDs) through mechanisms involving oxidative stress, neuroinflammation, disruption of the epithelial barrier, and altered microbial metabolite production. Unfortunately, the currently available therapies for NDs remain predominantly focused on symptomatic relief and do not modify the underlying disease progression. Natural bioactive compounds, particularly polyphenols, have emerged as promising multi-target modulators of the MGBA due to their pleiotropic effects across microbial, epithelial, immune, and neural compartments. This narrative review summarizes the available evidence on natural compounds and their microbial metabolites that target the MGBA, as evaluated in both in vitro and in vivo models. With a focus on Alzheimer disease, the molecular and cellular mechanisms underlying their effects across microbial, epithelial, immune, and neural compartments, as well as their potential therapeutic value through MGBA modulation, are discussed.