Introduction: The gut_brain axis is a bidirectional communication pathway between the gastrointestinal tract and the
central nervous system, operating through neural, hormonal, and immune pathways. The gut microbiome, comprising diverse bacteria, viruses, and fungi, plays a crucial role in regulating brain function and mental health. Recent studies have shown that metabolites produced by gut bacteria, including short-chain fatty acids, neurotransmitters, and signaling molecules, can influence neuronal activity and gene expression. One of the key pathways in this process involves epigenetic modifications, including DNA methylation, histone acetylation, and non-coding RNA activity. These modifications can influence the expression of genes associated with mood, memory, and stress responses.
Disruptions in gut microbiome composition, known as dysbiosis, are linked to numerous psychiatric and neurological disorders. Studies indicate that reduced microbial diversity and altered ratios of beneficial to harmful species can lead to systemic inflammation, HPA axis dysregulation, and changes in neuronal gene expression. These changes are observed not only in psychiatric disorders such as depression and anxiety but also in neurodegenerative diseases like Alzheimer’s and Parkinson’s.
Moreover, interactions between the microbiome and brain epigenetics offer new avenues for innovative therapies. Probiotics and prebiotics can improve microbiome composition and positively influence brain gene expression. Dietary modifications, stress reduction, and behavioral interventions can also enhance epigenetic pathways related to mental health. Given the importance of this topic, a comprehensive review of existing research and an analysis of molecular mechanisms of the gut–brain–epigenetic axis can play a key role in developing targeted treatments and improving patients’ quality of life.
Methods: A systematic review was conducted on published studies from reliable databases, including PubMed, Scopus, and Web of Science. Articles published between 2010 and 2025 using keywords such as “Gut Microbiome,” “Epigenetics,” “Neurobiology,” “Mental Health,” and “Brain Function” were identified. After removing unrelated and duplicate articles, 150 high-quality studies were selected for analysis.
Analysis included examination of molecular pathways, effective microbial metabolites, epigenetic modifications, and clinical outcomes related to brain function and mental health. Clinical studies and animal models were reviewed separately to compare laboratory and clinical findings. Extracted data included gene expression changes, behavioral outcomes, stress response, and effects of dietary or probiotic interventions.
All reviewed studies were evaluated for methodological quality, sample size, data reliability, and relevance to the gut_brain_epigenetic axis. The focus was on detailed molecular analysis and clinical implications to provide a comprehensive overview of current knowledge in this field.
Results: Recent studies have demonstrated that the gut microbiome exerts both direct and indirect regulation of brain epigenetics. Microbial metabolites such as butyrate, acetate, and propionate can inhibit histone deacetylase enzymes, leading to increased histone acetylation and altered expression of neuronal genes. These changes can affect cognitive function, memory, and stress responses.
In animal models, reduced microbial diversity was associated with increased DNA methylation of genes related to stress and anxiety responses. Mice suffering from gut dysbiosis exhibited social behavior deficits and heightened anxiety responses. Interventions such as microbiome restoration through probiotics or dietary changes reversed epigenetic alterations and improved behavior.
Human studies also indicate that imbalanced microbiome composition is linked to mental disorders such as depression, anxiety, and autism. An increase in harmful species and a reduction in beneficial species are associated with systemic inflammation and altered neuronal gene expression. Epigenetic modifications can exert long-term effects on brain function and are associated with a higher risk of neurodegenerative diseases such as Alzheimer’s and Parkinson’s.
Nutritional interventions, probiotics, and prebiotics have improved microbiome composition and induced positive epigenetic changes. Stress reduction and lifestyle modifications can reinforce brain epigenetic pathways and promote positive mental outcomes. These findings highlight that the gut–brain–epigenetic axis is a complex, multi-level pathway influenced by environmental, dietary, and microbial factors, and it represents a potential target for innovative treatments in mental and neurodegenerative disorders.
Conclusion: Recent studies indicate that the gut–brain–epigenetic axis plays a vital role in mental health and cognitive function. Alterations in gut microbiome composition can influence brain molecular pathways, inducing epigenetic changes in genes related to mood, memory, and stress response. Microbiome disturbances are associated with psychiatric and neurodegenerative disorders, while restoring microbial balance can provide significant therapeutic effects.
This article demonstrates that interventions such as probiotics, prebiotics, healthy diet, and stress reduction can induce positive epigenetic modifications and improve mental health. Future research should focus on precise molecular pathway identification, long-term impact of epigenetic changes, and development of targeted therapies. Understanding this complex relationship can lead to novel approaches for the prevention and treatment of psychiatric and neurodegenerative disorders.
Keywords: Gut Microbiome, Neuroepigenetics, Brain Function, Mental Health, Epigenetic Modifications