Review on Exploring the Role of Short-Chain Fatty Acids in Neuroinflammation: Mechanisms and Therapeutic Perspectives

Alzheimer's disease, Parkinson's disease, multiple sclerosis, and autism spectrum disorders are only a few of the neurodegenerative and neuropsychiatric conditions that are significantly influenced by neuroinflammation. The gut microbiota produces Short-Chain Fatty Acids (SCFAs), mainly acetate, propionate, and butyrate, by fermentation of dietary fibers. These are among the new modulators of neuroinflammation, have attracted significant scientific interest. This review critically examines the multifaceted mechanisms through which SCFAs influence neuroinflammatory processes. We explore how SCFAs modulate microglial activation and polarization, strengthen blood-brain barrier integrity, and regulate peripheral immune responses, often via G-protein-coupled receptor activation and histone deacetylase inhibition. While generally exhibiting neuroprotective and anti-inflammatory effects, SCFAs may also exert proinflammatory actions under specific pathological or concentration-dependent contexts, highlighting their dualistic role. Additionally, the efficacy of SCFAs is shaped by diet, gut microbiota composition, disease state, and interindividual variability. We discuss therapeutic strategies aimed at leveraging SCFA biology, including dietary interventions, prebiotics, probiotics, engineered microbial consortia, and novel delivery systems designed to enhance colonic and systemic SCFA availability. In order to maximize SCFA-based therapies, the review concludes by highlighting important research gaps, highlighting the necessity of extensive human clinical trials, the incorporation of multi-omics techniques, and the creation of precision medicine or tailored nutrition plans. Novel, microbiota-targeted treatments for neurodegenerative and neuroinflammatory diseases may be made possible by an understanding of the dynamic interactions between gut microbiota-derived SCFAs and neuroinflammation.