Gut Microbiota-Derived Short-Chain Fatty Acids Modulate Neuroinflammation via Microglial Regulation

The bidirectional communication between the gut microbiota and the central nervous system (CNS), known as the gut–brain axis, has become a key focus in neuroscience research. Short-chain fatty acids (SCFAs)—major metabolites produced by gut microbes through the fermentation of dietary fiber—can cross the blood–brain barrier (BBB) and directly modulate microglial function, thereby influencing neuroinflammatory processes. This review systematically examines the mechanisms by which SCFAs (primarily acetate, propionate and butyrate) regulate microglial activation states, cytokine secretion, phagocytic capacity, and metabolic phenotypes in the context of neurological and psychiatric disorders, including Alzheimer’s disease, Parkinson’s disease, stroke and depression. Current evidence suggests that SCFAs generally suppress excessive microglial activation and mitigate neuroinflammation, although their effects are context dependent and mediated through multiple pathways, such as histone deacetylase (HDAC) inhibition and G-protein-coupled receptor signaling. Overall, this review provides a theoretical foundation and new insights into targeting gut microbiota and their metabolites for the treatment of neuroinflammation-related disorders.