Crosstalk Between Gut Microbiota, Epigenome, and Neurotransmitters in Health and Disease

Beyond its established roles in digestion, immune regulation, and enteroendocrine signaling, the gut microbiota (GM) influences distant organs, particularly the brain, by producing or modulating the balance of neurotransmitters (NTs) and regulating their intestinal metabolism through epigenetic mechanisms, thereby shaping gut-brain communication. In this narrative review, first, we provide an overview of the major classes of NTs, such as serotonin, dopamine, GABA, glutamate, acetylcholine, epinephrine, and norepinephrine, and their functions in the body and brain. Second, we discuss the potential epigenetic mechanisms through which alterations in the levels and/or activity of NTs contribute to health and disease. Third, we explore the potential roles of the GM in the production of biologically active metabolites, such as short-chain fatty acids (SCFAs), and in the regulation of NT metabolism and function in health and disease through epigenetic mechanisms. We also highlight how GM-modulating therapies may improve disease outcomes by altering epigenetically mediated intestinal NT metabolism and availability, with downstream effects on NT activity in other organs. Finally, we discuss the current challenges and future directions for elucidating the interplay among the epigenome, the GM, and NTs.