Gut dysbiosis in Huntington’s disease: associations among gut microbiota, cognitive performance and clinical outcomes

Abstract

Huntington’s disease is characterised by a triad of motor, cognitive, and psychiatric impairments, as well as unintended weight loss. Although much of the research has focused on cognitive, motor and psychiatric symptoms, the extent of peripheral pathology and the relationship between these factors, and the core symptoms of Huntington’s disease, are relatively unknown. Gut microbiota are key modulators of communication between the brain and gut, and alterations in microbiota composition (dysbiosis) can negatively affect cognition, behaviour and affective function, and may be implicated in disease progression. Furthermore, gut dysbiosis was recently reported in Huntington’s disease transgenic mice. Our main objective was to characterise the gut microbiome in people with Huntington’s disease and determine whether the composition of gut microbiota are significantly related to clinical indicators of disease progression. We compared 42 Huntington’s disease gene expansion carriers (HDGECs), including 19 people who were diagnosed with Huntington’s disease (Total Functional Capacity > 6) and 23 in the premanifest stage, with 36 age and gender-matched healthy controls. Participants were characterised clinically using a battery of cognitive tests and using results from 16S V3-V4 rRNA sequencing of faecal samples to characterise the gut microbiome. For gut microbiome measures, we found significant differences in the microbial communities (beta diversity) based on unweighted UniFrac distance (p = 0.001), as well as significantly lower alpha diversity (species richness and evenness) between our combined HDGEC group and healthy controls (p = 0.001). We also found major shifts in the microbial community structure at Phylum and Family levels, and identified functional pathways and enzymes affected in our HDGEC group. Within the HDGEC group, we also discovered associations between gut bacteria, cognitive performance and clinical outcomes. Overall, our findings suggest an altered gut microbiome in HDGECs. These results highlight the importance of gut biomarkers and raise interesting questions regarding the role of the gut in Huntington’s disease, and whether it may be a potential target for future therapeutic intervention.

Gut–Brain Axis: Role of Gut Microbiota on Neurological Disorders and How Probiotics/Prebiotics Beneficially Modulate Microbial and Immune Pathways to Improve Brain Functions

“…Huntington's disease (HD) is a progressive neurodegenerative disorder that is characterized by a triad of clinical features, namely progressive motor, cognitive, and psychiatric impairments, as well as unintended weight loss [149]. It is mainly caused by the expansion and unstable trinucleotide (cytosine-adenine-guanine, CAG) repeat in the huntingtin (HTT) gene that is expressed in through the brain [150].…”

What, When and How to Measure—Peripheral Biomarkers in Therapy of Huntington’s Disease

“…Recent direct evidence that there are significant differences between healthy controls and HD patients with regard to microbiome diversity was proclaimed recently by Wasser et al [ 146 ]. They were able to pinpoint lowered abundances of Firmicutes , Lachnospiraceae and Akkermansiaceae in fecal samples from HD patients.…”

“…Interestingly, authors showed correlations between E. halli abundance and disease onset and progression. Still, authors are cautions about forming a strong conclusion given the small sample size (around 40 in each group), but the data they brought to light may have an impact on finding the peripheral biomarker in those bacterial species [ 146 ]. Correspondingly, in a mouse model of HD (R6/1), an increase in Bacteriodetes (Gram−), but a decrease in Firmicutes (Gram+), which corresponds to the abovementioned study on HD patients, was noticed [ 147 ].…”

Huntington’s disease: Pathophysiology and therapeutic intervention

“…Other than above factors gut microbiota impairment associated with the neurological disorders such as depression, Autism spectrum disorder, Alzheimer's, Parkinson's disease and Huntington disease (HD) [98,99].…”