Autophagy–Gut Microbiota–Epigenetic Interactions in Disease Pathogenesis: Focus on Neurodegenerative and Neuropsychiatric Disorders and Therapeutic Perspectives

Autophagy is a key cellular process that participates in numerous physiological functions, including maintaining epithelial barrier integrity, regulating intracellular degradation pathways, modulating immune responses, and enhancing antimicrobial defense. Impaired autophagy may contribute to the accumulation of misfolded proteins and insoluble aggregates in the neuronal cytoplasm, defective clearance of damaged organelles and proteins, and the buildup of toxic metabolites. In the gut, these alterations may disrupt the balance between beneficial and potentially harmful microorganisms, contributing to gut dysbiosis, chronic inflammation, and epigenetic alterations in intestinal cells that may indirectly affect the brain. Here, we review the current evidence on the interplay among autophagy, the gut microbiota, and the epigenome in the pathogenesis of diseases, particularly neuropsychiatric disorders (NPDs) and neurodegenerative diseases (NDs). First, we briefly discuss autophagy and its roles in health and disease. We then examine the association between impaired autophagy, inflammation, and epigenetic aberrations in the pathogenesis of NPDs and NDs. Next, we focus on the relationships among gut dysbiosis, defective autophagy, and epigenetic alterations in NPDs and NDs, and discuss microbiota-based therapeutic strategies that may influence epigenetic regulation and autophagic function. Finally, we highlight the current challenges and future directions for investigating the critical role of these interactions in the pathogenesis and treatment of NPDs and NDs.