Volume 167, 2022, Pages 141-184Author links open overlay panelAbstract

Huntington's disease (HD) is a fatal neurodegenerative disorder caused by an autosomal dominant trinucleotide (CAG) tandem repeat, resulting in complex motor, psychiatric and cognitive symptoms as well as gastrointestinal disturbances and other peripheral symptoms. There are currently no disease-modifying treatments, and the peripheral pathology of the disorder is not well understood. Emerging evidence suggests that the bi-directional communication pathways between the gut and the brain, including the microbiota-gut-brain axis, can affect motor, psychiatric and cognitive symptoms as well as weight loss and sexual dimorphism seen in HD. Furthermore, both HD and the microbiota-gut-brain axis can be influenced by environmental factors, opening potential new avenues to explore therapeutic options for this devastating disorder.

Section snippetsMicrobiota-gut-brain axis

The human body hosts a wide range of microorganisms that populate the oral and vaginal cavities, as well as the skin and gut, with distinct microbial communities within each area (Brown, Tanner, & Goldman, 2018). The term gut microbiota describes all commensal, symbiotic and pathogenic microorganisms that densely populate the gastrointestinal (GI) tract, consisting primarily of bacteria as well as fungi, archaea and viruses (Cryan et al., 2019).

Gut microbiota disruption

Gut microbiota are considered stable when they are resistant, resilient or display functional redundancy in response to change (Moya & Ferrer, 2016). If the gut microbiota do not change they are considered resistant, if they can restore the original composition they are considered resilient, and if they can restore original functional capacity they are functionally redundant (Moya & Ferrer, 2016). Microbial stability helps maintain host health and decreases in aging populations (Claesson et

HD history and prevalence

Huntington's disease (HD) is a devastating autosomal dominant neurodegenerative disorder that affects both males and females (Bates et al., 2015), resulting in motor, cognitive and psychiatric symptoms as well as disturbances in gut function (Bates et al., 2015, Ramos & Garrett, 2017, Wasser et al., 2020). The first patient record with what we now know as HD dates to 1842, but it was not until a lecture and description of the disease by George Huntington in 1872, that it became known as

The gut microbiota in HD

Dysfunction of the GI tract is frequently reported in people living with HD, including symptoms such as constipation and diarrhea, nutrient deficiencies, gastritis, and weight loss (Kobal, Matej, Koželj, & Podnar, 2018; Robbins, Ho, & Barker, 2006; van der Burg et al., 2017). Altered gut-derived metabolites and inflammatory plasma cytokines are found in people living with HD before the clinical onset (Andrich, Wobben, Klotz, Goetze, & Saft, 2009; Lin & Beal, 2006). Despite these presenting

Gut microbiota and HD motor symptoms

HD is characterized by severe movement disturbances consisting of bradykinesia, balance and gait disturbances as well as changes in eye movement, speech and hand movements (reviewed in McColgan & Tabrizi, 2018). An association between a lower abundance of Eubacterium hallii (E. hallii) correlated with more severe motor signs as measured on the UHDRS in symptomatic HDGECs, while in premanifest HDGECs, a significant negative relationship between the abundance of E. hallii and estimated proximity

Gut microbiota and HD-induced weight loss

Weight loss is a detrimental complication in HD and a hallmark characteristic of the disorder frequently leading to general weakness and a decline in quality of life for people living with HD (Djoussé et al., 2002). Surprisingly, the development of chorea is unlikely to affect weight loss, with body mass index (BMI) being significantly lower in people living with HD in comparison to control subjects, even at an early stage with a recent diagnosis and minimal involuntary movements (Djoussé et

Gut microbiota and cognition in HD

Cognitive impairments, culminating in dementia, can have onset in the pre-manifest (pre-motor symptomatic) stages of HD, with cognitive abilities declining over the course of the disease (reviewed in Bates et al., 2015). Investigating cognitive outcomes in HD research can provide insight into potential mechanisms and therapeutic targets (Paulsen, 2011). In their assessment of the relationship between the gut microbiota and HD symptomology, Wasser et al. (2020) found a significant negative

Gut microbiota and immune function in HD

Studies exploring the role of the immune system in HD have found altered gut-derived metabolites and inflammatory plasma cytokines in people living with HD before disease onset (Andrich et al., 2009; Lin & Beal, 2006). Diseases associated with disturbed gut microbiota often also feature immune dysfunction in their pathology, including IBD, obesity, ASD and neurodegenerative diseases including multiple sclerosis and AD (Bettcher, Tansey, Dorothée, & Heneka, 2021; Dorrestein et al., 2014).

Du et

Microbiota-gut-brain axis in HD

While we have previously discussed immune pathways of the microbiota-gut-brain axis in HD, this section will focus on the role of the mucous layer within the GI tract and its communication with the ENS, vagal nerve and HPA axis. Changes in the gut microbiota population in HD can result in the altered production of microbiota-derived metabolites such as neurotransmitters, SCFAs and BCFAs and other neuroactive compounds. Changes to these by-products can in turn affect the bi-directional

Gut microbiota and HD sexual dimorphism

Sexual dimorphism occurs when there are distinct features of a disorder between sexes and is a common feature of neurodegenerative diseases such as PD, AD and HD (Farhadi et al., 2017; Jiao et al., 2016; Roos et al., 1991). Clinical studies found that women with HD present more severe symptoms that progress faster (Zielonka, 2018; Zielonka et al., 2013), while in R6/1 mice, females showed exacerbated depressive-like behaviors due to impaired serotonin signaling (Renoir et al., 2011). On the

Environment

The gut lumen and its microbiota are a consistently changing environment, adapting to environmental factors such as diet, medication, stress, and exercise, all of which can result in individual variation in microbial diversity and species richness (Clarke et al., 2014; Cryan et al., 2019; Hawrelak et al., 2004) (Fig. 2). Despite environmental influences, overall greater microbial diversity has beneficial effects on human health and cognition (Coyte & Schluter, 2015; Le Chatelier et al., 2013).

Limitations

As with any animal research, the translatability of these predominantly preclinical findings to humans comes with its challenges. Each mouse model of HD is unique and can therefore only partially mimic the human HD phenotype, with differences in symptoms between transgenic mice and people living with HD to be expected. Furthermore, translatability challenges are also present in assessing GI structure and function, as well as microbiota profiling, metagenomics and metabolomics, due to anatomical

Conclusion

We are at the beginning of exciting research in the field of HD and the microbiota-gut-brain axis. Understanding the role of the gut microbiota in HD is a crucial step to improving our knowledge of this devastating disease. Collectively, these studies suggest that the microbiota could be involved in HD pathogenesis; however, whether this role is modulatory or comorbid, and whether microbiota dysfunction in the gut could influence brain dysfunction and associated symptoms, is yet to be

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