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’.

Cannabinoids’ Role in Modulating Central and Peripheral Immunity in Neurodegenerative Diseases

“…Changes in the composition of the microbiome are reported when neurodegeneration is present. Akkermansia muciniphila , a bacterium, was reported to be increased in the microbiome of MS patients and animal models, with a correlation between exacerbations and the severity of the disease [ 213 ]. In contrast, the protective effects of A. muciniphila were reported on cognitive deficits and amyloid pathology in a mouse model of AD [ 214 ].…”

Heavy Metals Interactions with Neuroglia and Gut Microbiota: Implications for Huntington’s Disease

“…The intricate relationship between the GM and HD pathophysiology is a burgeoning area of research with significant therapeutic potential. Recent studies suggest a multifaceted interplay between gut bacteria, the immune system, and the CNS that may contribute to HD progression [77,[139][140][141]. One key mechanism in this scenario involves SCFAs produced by beneficial bacteria like Bifidobacterium and Faecalibacterium prausnitzii that exert neuroprotective effects [55,142,143].…”

Gut Microbiota as a Modifier of Huntington’s Disease Pathogenesis

“…These studies herald new research directions to better understand the impact of gene-environment interactions in disease progression. Recent reviews of this literature have elaborated the importance of gut dysbiosis and microbial metabolites on the pathogenesis of HD and have speculated on how the gut-brain pathways could help to better understand the role of gene-environment interactions in disease onset and severity, as well as the development of gut-based therapeutics [31][32][33][34]. I refer the readers to these excellent reviews.…”