Polyphenols and physical activity stimulate gut microbiota mediated Nrf2 signaling to combat neurodegeneration

Polyphenols and regular physical activity are increasingly recognized as complementary lifestyle interventions that influence the gut-brain axis and contribute to neuroprotection. Emerging evidence highlights the central role of the gut microbiota in mediating these effects by transforming dietary and host-derived substrates into bioactive metabolites. These metabolites can activate the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway, a key regulator of cellular antioxidant defenses, mitochondrial function, and anti-inflammatory responses processes that are critically impaired in neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. This review synthesizes current mechanistic insights into how polyphenol-derived metabolites and exercise-induced alterations in gut microbial composition converge to modulate Nrf2 signaling. We discuss the roles of key microbiota-derived metabolites, including short-chain fatty acids, urolithins, and indole derivatives, in regulating oxidative stress, neuroinflammation, and synaptic function. Furthermore, we examine evidence from preclinical models supporting the synergistic effects of dietary polyphenols and physical activity on gut microbiota-mediated neuroprotection. Finally, we address translational challenges and highlight the potential of integrating dietary and exercise-based strategies to harness microbiota-dependent Nrf2 activation. This integrative framework provides a basis for developing personalized, microbiome-informed interventions aimed at delaying or mitigating neurodegeneration.