Introduction: The gut microbiota consists of millions of microorganisms that produce diverse metabolic products and can regulate gene expression through epigenetic pathways without altering DNA sequences, affecting immunity, metabolism, and brain function (gut–brain axis).
Clinical and experimental evidence indicates that alterations in the gut microbiota (gut microbiota dysbiosis), together with epigenetic dysregulation of genes, play a crucial role in the onset and progression of neurodegenerative diseases such as Alzheimer’s and Parkinson’s.
Animal and clinical studies have also shown that restoring microbial balance and enhancing SCFA-producing bacteria (Short-Chain Fatty Acids) can reduce disease symptoms and slow their progression.
By integrating these findings with multi-omics technologies and artificial intelligence, it is possible to identify each patient’s microbiota–metabolite signature and design personalized interventions, including dietary modifications, probiotics, or microbiota transplantation.
Methods: The gut microbiome produces diverse metabolic products such as butyrate, acetate, and propionate, SAM as the primary methyl group donor in DNA and histone methylation, and NAD⁺. These metabolites can modulate molecular pathways associated with pathological protein accumulation (e.g., amyloid-beta in AD or alpha-synuclein in PD) and inflammation.
The production of butyrate and other epigenetic metabolites depends on the composition of bacterial species and environmental conditions. Optimized anaerobic culture, the use of fermentable fibers, and symbiotic complementary species can enhance production efficiency.
Furthermore, some microorganisms produce metabolites with antibacterial or antifungal properties, demonstrating potential for multi-purpose industrial applications. This capacity could lead to the development of new supplements or drugs that directly target epigenetic pathways.
Results: The gut microbiota and epigenetic pathways influence each other, and external factors such as diet, antibiotics, stress, and environment can alter the composition and function of both systems. Among SCFAs, butyrate exhibits the strongest HDAC inhibition and neuroprotective effects and is discussed here as an example of microbial epigenetic metabolites.
In Alzheimer’s disease, gut microbiota changes include a reduction in Firmicutes and Bifidobacteria and an increase in Bacteroidetes and Proteobacteria. Epigenetic alterations include decreased methylation of genes related to inflammation and amyloid, increased expression of these genes, reduced histone acetylation, and silencing of beneficial neuronal genes, which may serve as predictors of disease progression.
In Parkinson’s disease, a decrease in SCFA-producing bacteria and an increase in pro-inflammatory bacteria result in reduced HDAC inhibition and silencing of neuroprotective genes. Consequently, epigenetic pathways are disrupted, neuroinflammation and α synuclein aggregation increase, and disease progression accelerates. These changes are regulated by microbial metabolites such as butyrate.
Butyrate, produced by fiber-fermenting bacteria, is a potent histone deacetylase inhibitor that increases histone acetylation and activates anti-inflammatory genes. In Alzheimer’s disease, butyrate enhances the expression of genes involved in learning and memory, such as BDNF, and reduces amyloid-beta deposition. In Parkinson’s disease, it prevents dopaminergic neuron degeneration by reducing oxidative stress and neuroinflammation and strengthens the blood–brain barrier, preventing the leakage of inflammatory and toxic factors into the brain. This is highly significant because increased BBB permeability is a key step in the pathogenesis of neurodegenerative diseases.
Therefore, SCFAs are key molecules that can regulate neuronal epigenetics, protect neurons from oxidative stress and inflammation, promote neurogenesis, and be utilized in the prevention and treatment of Alzheimer’s and Parkinson’s diseases. Considering the modifiable nature of both the gut microbiota and epigenetics, they can serve as therapeutic targets: probiotics and prebiotics to restore microbial balance, HDAC inhibitors or DNA demethylation agents to correct epigenetic alterations, gut biomarkers for early diagnosis, and dietary interventions (increasing fiber, reducing saturated fat, Mediterranean diet) to enhance the production of beneficial metabolites. These interventions can slow disease progression and potentially prevent disease onset in the early stages.
Conclusion: From restoring microbial balance to correcting epigenetic regulation and utilizing multi-omics technologies and machine learning, all evidence suggests that combating neurodegenerative diseases can benefit from a multidimensional, precise, and personalized approach.
Future research integrating these fields will enable the development of innovative strategies for prevention and treatment. However, individual differences in microbiome composition, lack of comprehensive databases on metabolomic and epigenetic patterns, limitations of long-term clinical trials, and safety considerations remain challenges. Additionally, non-invasive interventions such as nutrition, exercise, and stress management play an important role in designing preventive protocols.