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

Abstract

Huntington's disease is characterized 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 characterize 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, 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 characterized clinically using a battery of cognitive tests and using results from 16S V3 to V4 rRNA sequencing of faecal samples to characterize 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 Huntington's disease gene expansion carrier 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 Huntington's disease gene expansion carrier group. Within the Huntington's disease gene expansion carrier group, we also discovered associations among gut bacteria, cognitive performance and clinical outcomes. Overall, our findings suggest an altered gut microbiome in Huntington's disease gene expansion carriers. 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.

Keywords: Huntington’s disease; cognitive impairment; gut microbiome; gut–brain axis; neurodegenerative disease.

Graphical Abstract

Figure 1

Alpha and beta diversity differences in the gut microbiome in HDGEC and HC groups. (A) Alpha diversity analysis investigating richness (Observed) and evenness (Fisher) in HDGEC versus HC groups. (B) Beta diversity analysis showing variation in the composition of the samples based on their phylogenetic distance (unweighted UniFrac distance) in HDGEC versus HC groups.

Figure 2

Functional pathways differences in the gut microbiome between HDGEC and HC groups.

Figure 3

Enzyme differences in the gut microbiome between HDGEC and HC groups.

Figure 4

Relationship among E. hallii, clinical measures of disease progression in manifest HDGECs (TMS & TFC) and estimated disease onset (CAP_S) in premanifest HDGECs.

Figure 5

Overall performance between groups (HDGEC and HC) on cognitive outcomes (HD-CAB composite score).