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.

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Suicidal ideation and suicidal behavior according to the C-SSRS in a European cohort of Huntington's disease gene expansion carriers

Journal of Affective Disorders ◽

10.1016/j.jad.2017.11.074 ◽

2018 ◽

Vol 228 ◽

pp. 194-204 ◽

Cited By ~ 10

Author(s):

Erik van Duijn ◽

Eslie M. Vrijmoeth ◽

Erik J. Giltay ◽

G. Bernhard Landwehrmeyer

Keyword(s):

Suicidal Ideation ◽

Huntington's Disease ◽

Huntington’S Disease ◽

Suicidal Behavior ◽

Disease Gene ◽

Gene Expansion

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Assessing Impairment of Executive Function and Psychomotor Speed in Premanifest and Manifest Huntington’s Disease Gene-expansion Carriers

Journal of the International Neuropsychological Society ◽

10.1017/s1355617715000090 ◽

2015 ◽

Vol 21 (3) ◽

pp. 193-202 ◽

Cited By ~ 7

Author(s):

Ida Unmack Larsen ◽

Tua Vinther-Jensen ◽

Anders Gade ◽

Jørgen Erik Nielsen ◽

Asmus Vogel

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Neuropsychological Testing ◽

Distinct Group ◽

Healthy Controls ◽

Psychomotor Speed ◽

Gene Expansion ◽

Individual Scores ◽

Hd Gene ◽

Group Comparisons

AbstractExecutive functions (EF) and psychomotor speed (PMS) has been widely studied in Huntington’s disease (HD). Most studies have focused on finding markers of disease progression by comparing group means at different disease stages. Our aim was to investigate performances on nine measures of EF and PMS in a group of premanifest and manifest HD-gene expansion carriers and to investigate which measures were most sensitive for assessment of individual patients by analyzing frequencies of impaired performances relative to healthy controls. We recruited HD gene-expansion carriers, 48 manifest and 50 premanifest and as controls 39 healthy gene-expansion negative individuals. All participants underwent neurological examination and neuropsychological testing with nine cognitive measures. The frequency of impairment was investigated using cutoff scores. In group comparisons the manifest HD gene-expansion carriers scored significantly worse than controls on all tests and in classification of individual scores the majority of scores were classified as probably impaired (10th percentile) or impaired (5th percentile) with Symbol Digit Modalities Test (SDMT) being the most frequently impaired. Group comparisons of premanifest HD gene-expansion carriers and healthy controls showed significant differences on SDMT and Alternating fluency tests. Nevertheless the frequencies of probably impaired and impaired scores on individual tests were markedly higher for Alternating and Lexical fluency tests than for SDMT. We found distinct group differences in frequency of impairment on measures of EF and PMS in manifest and premanifest HD gene-expansion carriers. Our results indicate to what degree these measures can be expected to be clinically impaired. (JINS, 2015, 21, 1–10)

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Whole-Brain Connectivity in a Large Study of Huntington's Disease Gene Mutation Carriers and Healthy Controls

Brain Connectivity ◽

10.1089/brain.2017.0538 ◽

2018 ◽

Vol 8 (3) ◽

pp. 166-178 ◽

Cited By ~ 19

Author(s):

Flor A. Espinoza ◽

Jessica A. Turner ◽

Victor M. Vergara ◽

Robyn L. Miller ◽

Eva Mennigen ◽

...

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Gene Mutation ◽

Large Study ◽

Disease Gene ◽

Brain Connectivity ◽

Healthy Controls ◽

Whole Brain ◽

Mutation Carriers

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Alterations of Gut Microbiome in Untreated Chronic Lymphocytic Leukemia (CLL); Future Therapeutic Potentials

Blood ◽

10.1182/blood-2019-121643 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5455-5455

Author(s):

Mohammed Kawari ◽

Mahmood Akhtar ◽

Mohamed Sager ◽

Zakaria Basbous ◽

Ibrahim Baydoun ◽

...

Keyword(s):

Gut Microbiota ◽

Chronic Inflammation ◽

Systemic Inflammation ◽

Gut Microbiome ◽

Healthy Subjects ◽

The Body ◽

Healthy Controls ◽

Bacterial Phyla ◽

Gut Dysbiosis

Introduction: Gut dysbiosis is an imbalance of the gut microbiome. The presence of dysbiosis can be a cause of systemic inflammation in the body or can be a contributing factor to it. Chronic systemic inflammation is a common feature of CLL, creating an environment in which CLL cells have a survival advantage. NF-κB and STAT3, master transcriptional regulators of pro-inflammatory markers, like IL-1 and IL-6, are reported to be involved in this process as are the Toll-like receptors (TLRs), key innate immunity receptors that are implicated in CLL pathophysiology. With increasing evidence for the role of dysbiosis in chronic inflammation, as well as the role of systemic inflammation in CLL, it seems relevant to prove the presence and the possible role of microbiome in the pathophysiology of CLL, to unravel the complex interaction between microbiome, nutrition and the host in patients with CLL. Our research investigate the hypothesis that dysbiosis i.e. the loss of "health-promoting" commensal gut microbes and/or the overgrowth of pathogenic bacteria distinguishes untreated patients with CLL versus aged-matched unaffected individuals. Methodology: Eight untreated CLL patients were with no history of gastrointestinal disorders, other malignancies and have not been on antibiotics for 4 weeks prior to samples collection. Two of them were not followed for logistical reasons. Six healthy volunteers matched for sex and age were also enrolled in the study. Stool samples from six patients and additional six matched healthy controls were collected and stored in a -40 freezer immediately until they were used for DNA isolation. Total genomic DNA was extracted using the Qiamp DNA stool mini kit and sequenced using Next Generation Sequencing and then analysis were done as per the manufacturer recommendations. Results: Our data indicates a reduced diversity and variability in bacterial phyla of gut microbiota in CLL patients as compare to healthy controls. Lower diversity with increase in certain bacterial types is a well-accepted sign of gut dysbiosis, which have been shown in many disorders such as; type-2 diabetes, obesity, and various autoimmune and neurological diseases. An increase in Proteobacteria numbers has been recognized as the signature of gut dysbiosis which we confirmed in our cohort of patients. Proteobacteria, Firmicutes and Bacteriodetes were also the most abundant bacterial phyla in CLL patients of our study which were reported previously in breast cancer patients. An elevated Firmicutes to Bacteroidetes ratio with altered gut microbiota in CLL patients compared with healthy subjects was also suggested in clinical studies involving obese individuals with insulin resistance. We have observed in CLL patients of this study relative increase in the numbers of Firmicutes and reduction in Bacteriodetes which is considered to be an inverted ratio as compared to healthy individuals which were also reported in ulcerative colitis, colonic and ileal crohn's disease as compared to healthy subjects. . Our finding of gut dysbiosis in this study is linked the association between CLL, inflammatory processes and dysbiosis. The microbiota may play a role in promoting malignancy through chronic inflammation, by disturbing the balance of cell proliferation, death and by initiating unwanted innate and adaptive immune responses. Conclusion: Restoring gut microbiota might open a new avenue for future researches as potential therapeutic intervention in CLL patients. Figure Disclosures No relevant conflicts of interest to declare.

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