Microbial Metabolites and Neural Epigenetic Circuitry in Emotional Homeostasis and Depression

The objective of this study was to review current evidence on how dietary polyphenols alleviate mood disorders through gut microbiota-mediated metabolism and epigenetic regulation, with emphasis on the molecular mechanisms underlying the microbiota-gut-brain axis. Mood disorders are associated with gut microbiota dysbiosis, neuroinflammation, impaired neuroplasticity, and epigenetic alterations. Although dietary polyphenols have demonstrated therapeutic potential, most require microbial biotransformation to generate the neuroactive metabolites responsible for their biological effects. A comprehensive narrative review was conducted by synthesizing the evidence from experimental, mechanistic, and clinical studies on dietary polyphenols, the gut microbiota, microbial metabolites, epigenetic regulation, and mood disorders. The current evidence indicates that the gut microbial metabolism converts dietary polyphenols into bioactive metabolites, including urolithins, S-equol, phenyl-γ-valerolactones, and short-chain fatty acids, with greater bioavailability and neurobiological activity than their parent compounds. These metabolites modulate neuroinflammation, oxidative stress, neurotransmitter signaling, synaptic plasticity, and neuroendocrine function through epigenetic mechanisms, particularly histone deacetylase inhibition and DNA methylation regulation. Host genetic variation and gut microbial composition further influence microbial metabolism and contribute to interindividual differences in therapeutic responses. This review highlights the gut microbiota as a key mediator linking dietary polyphenols with brain function through microbial metabolism and epigenetic regulation. Understanding these interactions provides a mechanistic basis for precision nutrition and supports the development of microbiota-targeted dietary strategies for preventing and managing mood disorders.