The microbiota-gut-brain axis in Huntington’s disease: Evidence, mechanisms and therapeutic opportunities

Huntington's disease (HD) is increasingly recognized as a multisystem disorder in which perturbations of the gut microbiota may influence peripheral homeostasis and shape central neurodegeneration. Across human cohorts, HD is marked by reproducible β-diversity shifts, loss of butyrate-producing taxa, and disruptions in bile-acid and tryptophan-derived metabolites, indicating broad remodeling of microbiota-host metabolic interfaces. Integrating metabolomic evidence with mechanistic data from HD models, we delineate three convergent axes through which dysbiosis may modify disease biology: (i) short-chain fatty acids driven histone deacetylases and G-protein-coupled receptors pathways that impact transcriptional regulation and gut-brain endocrine signaling; (ii) bile acids dependent FXR/TGR5 circuits that couple metabolic stress to neuroinflammatory and mitochondrial vulnerability; and (iii) microbiota-regulated tryptophan metabolism, encompassing serotonin/melatonin rhythms, indole- aryl hydrocarbon receptor immunomodulation, and kynurenine-pathway neurotoxicity. Finally, we evaluate microbiota-targeted therapeutic strategies across these pathways and discuss their translational potential alongside central nervous system directed HTT-lowering approaches.