Gut microbiota as a modulator of HDAC: insights into Alzheimer's disease treatment

The human gut microbiota (GMB) has a significant impact on physiological function, including gastrointestinal health, immune regulation, and redox homeostasis. It consists of diverse microorganisms that support digestion, nutrient absorption, and intestinal barrier function. Emerging evidence suggests that gut microbiota-derived metabolites may influence the gut-brain axis and regulate epigenetic mechanisms through modulation of histone deacetylases (HDAC). HDAC are key enzymes involved in gene expression, neuronal survival, neuroinflammation, and the pathogenesis of Alzheimer's disease (AD). Gut microbiota-derived metabolites have been reported to modulate HDAC activity and may contribute to neuroprotective and anti-inflammatory effects. Through these mechanisms, the GMB may influence cognitive function and the progression of AD. However, the precise molecular mechanisms involved in these interactions are not yet fully understood and continue to be extensively investigated. Therefore, this review focuses on the correlation between HDAC and the restoration of a healthy GMB as a therapeutic approach for the treatment and prevention of AD. It emphasizes the role of gut-derived metabolites, peptides, and dietary bioactive compounds in regulating HDAC-mediated epigenetic pathways. These interactions may influence gene expression, neurotransmitter biosynthesis, neuroinflammation, and neuroprotective signalling associated with cognitive function. Furthermore, the review delineates the bidirectional interplay among neurotransmitter signalling, GMB composition, and HDAC-mediated epigenetic regulation, along with their potential roles in the pathophysiology of neurodegenerative disorders.