Yuxiu Gu, Mingxiao Wang, Ying Mao
• HD exhibits consistent gut dysbiosis with loss of butyrate-producing taxa. • SCFAs modulate the MGB axis via HDAC inhibition and FFAR2/FFAR3/HCAR2 signaling. • Bile acids influence MGB-axis metabolic and inflammatory pathways through FXR and TGR5. • Tryptophan metabolism shapes MGB-axis 5-HT, indole–AhR and kynurenine signaling. • Targeting MGB-axis metabolites offers therapeutic opportunities in Huntington’s disease. 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.