Frontiers in Aging Neuroscience · Oct 23, 2026
Reprogramming the gut–brain axis in neurodegeneration: comparative microbiome, metabolite, immunometabolic, polyphenol, probiotic, and epigenetic mechanisms in Alzheimer’s and Parkinson’s diseases
By Cheng YJ, Tao MP, Qian K et al.
The gut–brain axis has emerged as a central mechanistic framework linking dietary bioactives, microbial ecology, and neurodegenerative disease progression. Similar microbiome-related mechanisms have also been implicated in colorectal cancer, suggesting potential shared links between microbial dysbiosis, inflammation, and disease progression. This study synthesizes preclinical evidence examining how polyphenols, polyphenol-derived compounds, and advanced delivery systems, including nanoparticles and synbiotics, modulate Alzheimer’s disease (AD) and Parkinson’s disease (PD) through microbiome-dependent mechanisms. Evidence from transgenic mice, toxin-induced rodent models, and Drosophila systems was compared across microbiome alterations, microbial metabolites, signaling pathways, epigenetic regulation, and functional outcomes. Across AD and PD models, dietary bioactives consistently promoted restoration of gut microbial homeostasis, characterized by enrichment of beneficial taxa and reduction of dysbiosis-associated microorganisms. These changes were accompanied by alterations in microbial metabolites, particularly short-chain fatty acids (SCFAs), tryptophan-derived metabolites, and lipid-associated signaling molecules. These metabolites provide functional links between microbial ecology and CNS physiology and may regulate epigenetic processes, including histone acetylation, DNA methylation, chromatin remodeling, and non-coding RNA activity. Despite substantial upstream convergence, downstream effects showed disease-specific patterns. In AD models, microbiome modulation predominantly influenced metabolic, amyloidogenic, and neurotrophic pathways, including AKT/GSK3β, NRF2, NF-κB, and BDNF-associated signaling, contributing to reduced amyloid-β deposition, attenuated tau pathology, and improved cognitive outcomes. In PD models, greater emphasis was placed on inflammatory, oxidative, and mitochondrial pathways involving SIRT1/NRF2, TLR4/MyD88/NF-κB, inflammasome signaling, and neuronal survival mechanisms, resulting in reduced neuroinflammation and preservation of dopaminergic neurons and motor function. Epigenetic regulation represents an additional convergence layer through which microbial metabolites and polyphenols may influence inflammatory, metabolic, mitochondrial, and neuronal gene programs in both disorders. Nanoparticle-based delivery systems enhanced bioavailability, tissue targeting, and microbiome-related effects, whereas synbiotic strategies reinforced microbial and metabolic homeostasis. Collectively, these findings support a microbiome–metabolite–epigenome–brain framework in which dietary bioactives modulate neurodegeneration through interconnected microbial, metabolic, immune, redox, mitochondrial, and epigenetic pathways. This framework provides a mechanistic basis for developing disease-tailored and precision-oriented gut–brain interventions for AD and PD.