Dietary Modulation of the Enteric Nervous System: From Molecular Mechanisms to Therapeutic Applications

The enteric nervous system (ENS), frequently referred to as the "second brain," is integral to maintaining gastrointestinal and systemic homeostasis. The structural and functional homeostasis of the ENS is crucial for both local intestinal processes (digestion, immunity) and systemic physiological equilibrium via the gut-brain axis, directly influencing overall health and disease. In recent years, dietary substances have attracted increasing scholarly attention for their potential to modulate the ENS, attributed to their safety and accessibility. This review commences with a systematic exploration of the anatomical structure of the ENS, including the myenteric and submucosal plexuses, its cellular constituents such as enteric neurons and enteric glial cells, and its core physiological functions, encompassing the regulation of gastrointestinal motility, the secretion-absorption balance, and the maintenance of immune homeostasis. Subsequently, it delineates the classification, distribution, and properties of essential dietary components, encompassing polyphenols, short-chain fatty acids, amino acids and their derivatives, as well as prebiotics and probiotics. Additionally, it examines the mechanisms through which these substances modulate the physiological functions of the ENS, including the regulation of intestinal motility, support for neuronal survival and network integrity, and the maintenance of neuro-immune homeostasis. The review concludes by highlighting current limitations-including reliance on rodent models, unclear human ENS mechanisms, and imprecise interventions-and proposes future directions focused on precision medicine, clinical translation, and advanced tools like single-cell sequencing and targeted delivery systems.