The microbiota-gut-brain axis in Huntington's disease: pathogenic mechanisms and therapeutic targets

Abstract

Huntington's disease (HD) is a currently incurable neurogenerative disorder and is typically characterized by progressive movement disorder (including chorea), cognitive deficits (culminating in dementia), psychiatric abnormalities (the most common of which is depression), and peripheral symptoms (including gastrointestinal dysfunction). There are currently no approved disease-modifying therapies available for HD, with death usually occurring approximately 10-25 years after onset, but some therapies hold promising potential. HD subjects are often burdened by chronic diarrhea, constipation, esophageal and gastric inflammation, and a susceptibility to diabetes. Our understanding of the microbiota-gut-brain axis in HD is in its infancy and growing evidence from preclinical and clinical studies suggests a role of gut microbial population imbalance (gut dysbiosis) in HD pathophysiology. The gut and the brain can communicate through the enteric nervous system, immune system, vagus nerve, and microbiota-derived-metabolites including short-chain fatty acids, bile acids, and branched-chain amino acids. This review summarizes supporting evidence demonstrating the alterations in bacterial and fungal composition that may be associated with HD. We focus on mechanisms through which gut dysbiosis may compromise brain and gut health, thus triggering neuroinflammatory responses, and further highlight outcomes of attempts to modulate the gut microbiota as promising therapeutic strategies for HD. Ultimately, we discuss the dearth of data and the need for more longitudinal and translational studies in this nascent field. We suggest future directions to improve our understanding of the association between gut microbes and the pathogenesis of HD, and other 'brain and body disorders'.

Keywords: Huntington's disease; diet; gut dysbiosis; gut‐brain axis; microbiome; microbiota; mycobiome; neurodegeneration.

Fig. 1

Schematic illustration of the current known gut status and immune dysregulation in Huntington's disease subjects and animal models. Abnormalities in the gastrointestinal tract of Huntington's disease subjects and mice as well as the decreased expression of enteric neuropeptides. Immune dysregulation is also depicted, with differential levels of pro‐inflammatory and anti‐inflammatory cytokines in Huntington's disease subjects and mouse models. ↑: increase, ↓: decrease, ←: promotes. Green arrows represent clinical findings from human studies and purple arrows represent preclinical findings from animal studies. Created with BioRender.com.

Fig. 2

Schematic illustration of the current known gut microbial status in Huntington's disease subjects and animal models. Variations in gut microbial composition in Huntington's disease subjects and mice are known. The known connections between altered gut bacteria and their associations with neurological function in the context of Huntington's disease are shown. Additionally, bacterial‐fungal interactions and sex‐specific patterns within the gut microbiota are highlighted. ↑: increase, ↓: decrease, ←: promotes, +: positive correlation, −: negative correlation. Green arrows represent findings from human studies and purple arrows represent findings from animal studies. Created with BioRender.com.