Short-chain fatty acids in Huntington's disease: Mechanisms of action and their therapeutic implications

Abstract

Huntington's disease (HD) is a progressive neurodegenerative disorder characterized by motor dysfunction, cognitive decline, and emotional instability, primarily resulting from the abnormal accumulation of mutant huntingtin protein. Growing research highlights the role of intestinal microbiota and their metabolites, particularly short-chain fatty acids (SCFAs), in modulating HD progression. SCFAs, including acetate, propionate, and butyrate, are produced by gut bacteria through dietary fiber fermentation and are recognized for their neuroprotective properties. Evidence suggests that SCFAs regulate neuroinflammation, neuronal communication, and metabolic functions within the central nervous system (CNS). In HD, these compounds may support neuronal health, reduce oxidative stress, and enhance blood-brain barrier (BBB) integrity. Their mechanisms of action involve binding to G-protein-coupled receptors (GPCRs) and modulating gene expression through epigenetic pathways, underscoring their therapeutic potential. This analysis examines the significance of SCFAs in HD, emphasizing the gut-brain axis and the benefits of dietary interventions aimed at modifying gut microbiota composition and promoting SCFA production. Further research into these pathways may pave the way for novel HD management strategies and improved therapeutic outcomes.