Characterization of Gastric Mucosa Biopsies Reveals Alterations in Huntington's Disease

McCourt, Andrew C; O'Donovan, Kirsty L; Ekblad, Eva; Sand, Elin; Craufurd, David; Rosser, Anne; Sanders, David D.; Stoy, Nicholas; Rickards, Hugh; Wierup, Nils; Bates, Gillian P.; Björkqvist, Maria; Quarrell, Oliver

doi:10.1371/10.1371/currents.hd.858b4cc7f235df068387e9c20c436a79

Cited by 3 publications

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“…Although HD also affects various gut functions (Table 1), the most prevalent non-neurological symptom in HD is weight loss (125). Since the gut expresses mutant HTT, and HD patients and a HD mouse model show the presence of HD pathology in the ENS (126,127), it can be postulated that the weight loss is due to intestinal dysfunction. Using an R6/2-transgenic mouse model, which expresses a transgene encoding the 5′ end of the human HTT gene with different lengths of CAG repeat expansions, van der Burg et al showed that the ENS in HD has significant neurodegeneration, a marked reduction in the expression of neuropeptides, and associated intestinal malabsorption that causes weight loss (125).…”

Section: Huntington's Diseasementioning

confidence: 99%

Neurodegenerative disorders and gut-brain interactions

Singh¹,

Dawson²,

Kulkarni³

2021

Journal of Clinical Investigation

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Neurodegenerative disorders (NDs) are chronic and progressive disorders that disproportionately affect the elderly and have been characterized by selective loss of neurons in the CNS (1). Their prevalence is increasing -partly owing to extensions in lifespan -and by 2030, individuals affected by NDs will account for more than 8 million patients in the United States (2). Various NDs can be characterized and differentiated by their primary clinical features, the anatomical location of the neurodegeneration, the various cell types they affect, and/or the principal molecular abnormality that causes them (3).Prior to the considerable progress made in recent years that will be discussed here, psychiatrists, neurologists, and gastroenterologists alike supported the idea of the existence of a disease called the "institutional colon." This term described the presence of an amotile and/or elongated and largely distended colon with resulting gut dysfunctions in psychiatric patients who lived in mental health institutions (4). That such a disease existed was often questioned by contemporary physicians, and the confluence of gut and behavioral dysfunction was ascribed to the side effects of medicines, incorrect or inadequate diets, or inattention. To prove that the "institutional colon" is a true disease, Sonnenberg et al. (4) combed through millions of medical records at the US Veterans Affairs to show that patients with presenile dementia, Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), or Huntington's disease (HD) had significantly higher odds of also experiencing colonic dysfunction. The authors pointed out that "not all neurons involved in control of intestinal motility are located within the enteric nervous system, but may originate, for instance, in the vagal nuclei at the medulla oblongata or in the sacral segments of the spinal cord" and that "any referral to the loss of neuronal control of colonic motility does not allude to a common pathway, and leaves a multitude of heterogeneous mechanisms possible" (4). This landmark study showing the involvement of both gut and brain dysfunction in NDs paved the way for the studies discussed in this Review.Here, we review the processes associated with ND etiology and how various gut-innervating and gut-brain connecting neurons are either affected in NDs or are involved in their etiology. We also review the role of microbiota in driving NDs and discuss some open questions in this field. This Review will focus on the classical NDs -PD, AD, HD, and ALS -given that these are not only the major NDs but are also the diseases for which substantial information is available about associated gut dysfunctions.Neurodegenerative disorders (NDs) affect essential functions not only in the CNS, but also cause persistent gut dysfunctions, suggesting that they have an impact on both CNS and gut-innervating neurons. Although the CNS biology of NDs continues to be well studied, how gut-innervating neurons, including those that connect the gut to the brain, ...

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Section: Huntington's Diseasementioning

confidence: 99%

Neurodegenerative disorders and gut-brain interactions

Singh¹,

Dawson²,

Kulkarni³

2021

Journal of Clinical Investigation

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“…Compared to the extensive evidence emerging in Parkinson’s disease, no gut microbiome studies have been reported in people with Huntington’s disease, despite intriguing findings from Huntington’s disease animal models ( Kong et al , 2018 ; Radulescu et al , 2019 ). For example, studies in Huntington’s disease mouse models show gut dysfunction, along with evidence of endocrine dysfunction, including hormonal abnormalities, decreased enteric neuropeptides, decreased mucosal thickness and villus length ( Ferrante et al , 2000 ; van der Burg et al , 2011 ; McCourt et al , 2015 ). Furthermore, deficient energy metabolism, as well as serum and cerebrospinal fluid metabolic differences, has been observed in presymptomatic transgenic Huntington’s disease rats ( Verwaest et al , 2011 ).…”

Section: Introductionmentioning

confidence: 99%

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

Wasser

Mercieca

Kong

et al. 2020

Brain Communications

128

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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.

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“…20 Although the most prominent symptoms of HD are related to the central nervous system, mHtt is ubiquitously expressed in human tissue, 2 prompting more attention to be paid to the possible involvement of non-CNS tissues and organs. [23][24][25] The vascular contribution to HD pathology is increasingly recognized 4,26 and thought to involve multiple pathogenic pathways. [27][28][29] Nevertheless, little is known about the prevalence and clinical effect of cardiovascular risk factors such as hypertension on patients with HD.…”

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confidence: 99%