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

Mar 24, 2026Frontiers in neuroendocrinology

How gut bacteria may influence the brain in Huntington’s disease: Evidence, causes, and treatment possibilities

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Abstract

Huntington's disease is marked by reproducible β-diversity shifts in gut microbiota.

Loss of butyrate-producing bacteria and disruptions in bile-acid and tryptophan-derived metabolites are observed.
Dysbiosis may influence disease biology through pathways involving short-chain fatty acids that affect gene regulation and gut-brain signaling.
Bile acids are linked to neuroinflammation and mitochondrial vulnerability via specific receptor circuits.
Alterations in tryptophan metabolism are associated with changes in serotonin/melatonin rhythms and immune modulation.
Microbiota-targeted therapies are evaluated for their potential to impact these metabolic pathways in Huntington's disease.

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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.

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

Abstract

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