Short-chain fatty acids (SCFAs), primarily acetate, propionate, and butyrate, are key microbial metabolites generated through the fermentation of indigestible carbohydrates by gut bacteria. Beyond their local actions in the intestinal environment, these metabolites exert far-reaching systemic effects, particularly in shaping neuroimmune communication along the gut-brain axis. Their interaction with free fatty acid receptor 2 (FFAR2), expressed on intestinal epithelial cells, peripheral immune populations, and microglia, has emerged as a central mechanism linking gut microbial activity to neuroinflammatory regulation. Disrupted FFAR2 signalling and altered SCFA production are now implicated in the pathogenesis of key neuroinflammatory and neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and multiple sclerosis. In this narrative review, we synthesize current evidence suggesting that SCFAs can mediate microglial development, cytokine cross-linking, and barrier stability, as well as neuronal-glial communication via FFAR2-mediated and receptor-independent mechanisms, including HDAC inhibition. Importantly, current evidence supports three partially overlapping mechanistic frameworks: (i) direct receptor-dependent signalling, including potential FFAR2-mediated effects on microglia, although such expression and functional relevance in adult microglia remain debated; (ii) receptor-independent intracellular mechanisms, particularly histone deacetylase (HDAC) inhibition and metabolic reprogramming; and (iii) indirect peripheral immune and gut-brain regulatory pathways, involving modulation of systemic cytokine milieus, barrier integrity, and immune cell trafficking, which appear to be more consistently supported in adult in vivo models. Experimental research shows that restoring SCFA supply or activating FFAR2 can suppress neuroinflammation, increase the clearance of pathological proteins by proteases, and promote neuronal survival. Available strategies to increase endogenous SCFA production include dietary fiber consumption, prebiotics, and customized SCFA formulations, and novel synthetic FFAR2 agonists offer a pharmacological approach to targeted therapy. Nonetheless, there remains a significant degree of variability in dosing, route of delivery, bioavailability, and interindividual microbiota profiles, which restricts clinical translation. Combined, the existing knowledge base places the SCFA-FFAR2 axis as an encouraging therapeutic agent regarding altering neuroimmune responses and creating new approaches to the control of neuroinflammatory and neurodegenerative diseases.
