Increased intestinal permeability and gut dysbiosis in the R6/2 mouse model of Huntington’s disease

Stan, Tiberiu Loredan; Soylu-Kucharz, Rana; Burleigh, Stephen; Prykhodko, Olena; Cao, Ling; Franke, Naomi; Sjögren, Marie; Haikal, Caroline; Hållenius, Frida Fåk; Björkqvist, Maria

doi:10.1038/s41598-020-75229-9

Cited by 72 publications

(43 citation statements)

References 47 publications

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“…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]. Very similar results were achieved independently in another mouse model of HD (R6/2) with the addition of proven increased intestinal permeability [148].…”

Section: Microbiomesupporting

confidence: 79%

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

Przybył

Woźna-Wysocka

Kozłowska

et al. 2021

IJMS

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Among the main challenges in further advancing therapeutic strategies for Huntington’s disease (HD) is the development of biomarkers which must be applied to assess the efficiency of the treatment. HD is a dreadful neurodegenerative disorder which has its source of pathogenesis in the central nervous system (CNS) but is reflected by symptoms in the periphery. Visible symptoms include motor deficits and slight changes in peripheral tissues, which can be used as hallmarks for prognosis of the course of HD, e.g., the onset of the disease symptoms. Knowing how the pathology develops in the context of whole organisms is crucial for the development of therapy which would be the most beneficial for patients, as well as for proposing appropriate biomarkers to monitor disease progression and/or efficiency of treatment. We focus here on molecular peripheral biomarkers which could be used as a measurable outcome of potential therapy. We present and discuss a list of wet biomarkers which have been proposed in recent years to measure pre- and postsymptomatic HD. Interestingly, investigation of peripheral biomarkers in HD can unravel new aspects of the disease pathogenesis. This especially refers to inflammatory proteins or specific immune cells which attract scientific attention in neurodegenerative disorders.

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Section: Microbiomesupporting

confidence: 79%

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

Przybył

Woźna-Wysocka

Kozłowska

et al. 2021

IJMS

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“…Consistent with this notion, recent studies showed gut barrier dysfunction and increased gut permeability in mouse models of AD and dementia patients [ 66 , 67 , 68 ]. Moreover, the integrity of the epithelial gut barrier is reduced with aging and neurodegenerative conditions [ 69 , 70 , 71 ]. Consistent with these findings, our RT-qPCR and immunohistochemistry data showed a significantly reduced expression of tight and adheren junction proteins in the colon tissues of 5xFAD mice compared to their age-matched control littermates, suggesting compromised gut barrier function in AD condition.…”

Section: Discussionmentioning

confidence: 99%

Alterations in the Gut-Microbial-Inflammasome-Brain Axis in a Mouse Model of Alzheimer’s Disease

Shukla

Delotterie

Xiao

et al. 2021

Cells

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Alzheimer’s disease (AD), a progressive neurodegenerative disorder characterized by memory loss and cognitive decline, is a major cause of death and disability among the older population. Despite decades of scientific research, the underlying etiological triggers are unknown. Recent studies suggested that gut microbiota can influence AD progression; however, potential mechanisms linking the gut microbiota with AD pathogenesis remain obscure. In the present study, we provided a potential mechanistic link between dysbiotic gut microbiota and neuroinflammation associated with AD progression. Using a mouse model of AD, we discovered that unfavorable gut microbiota are correlated with abnormally elevated expression of gut NLRP3 and lead to peripheral inflammasome activation, which in turn exacerbates AD-associated neuroinflammation. To this end, we observe significantly altered gut microbiota compositions in young and old 5xFAD mice compared to age-matched non-transgenic mice. Moreover, 5xFAD mice demonstrated compromised gut barrier function as evident from the loss of tight junction and adherens junction proteins compared to non-transgenic mice. Concurrently, we observed increased expression of NLRP3 inflammasome and IL-1β production in the 5xFAD gut. Consistent with our hypothesis, increased gut–microbial–inflammasome activation is positively correlated with enhanced astrogliosis and microglial activation, along with higher expression of NLRP3 inflammasome and IL-1β production in the brains of 5xFAD mice. These data indicate that the elevated expression of gut–microbial–inflammasome components may be an important trigger for subsequent downstream activation of inflammatory and potentially cytotoxic mediators, and gastrointestinal NLRP3 may promote NLRP3 inflammasome-mediated neuroinflammation. Thus, modulation of the gut microbiota may be a potential strategy for the treatment of AD-related neurological disorders in genetically susceptible hosts.

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“…Unintended weight loss is a hallmark of Huntington disease (HD), an autosomal dominant inherited neurodegenerative disorder caused by a CAG repeat expansion in the HTT gene, and occurs in both patients and premanifest mutation carriers, as well as many genetic animal models of the disease. 1,2 Recently, we found that body weight is a robust predictor of the rate of clinical progression in patients with HD. 3 Patients with a higher body mass index (BMI) at their first visit deteriorated more slowly in the motor, cognitive, and functional domains, independent of disease severity at baseline and mutant CAG repeat size.…”

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confidence: 99%

Effect of Body Weight on Age at Onset in Huntington Disease

et al. 2021

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ObjectiveWeight loss is associated with clinical progression in Huntington disease (HD), but whether body weight causally affects disease onset or progression is unknown. Therefore, we aimed to assess whether genetically determined variations in body weight are causally related to age at onset in HD.MethodsUsing data from different recent genome-wide association studies, we performed a 2-sample mendelian randomization (MR) analysis to assess whether genetic markers of body mass index (BMI) are causally related to residual age at onset in HD, i.e., the difference between observed and expected age at onset based on mutation size. Our study had a statistical power of 90% to detect a causal effect of ≥3.8 months per BMI unit change at a type I error rate of 0.05.ResultsInverse-variance weighted MR estimates showed that a higher genetically determined BMI was not causally related to residual age at onset in HD (β = −0.44 years per unit increase in BMI, confidence interval: −1.33 to 0.46, p = 0.34). All other complementary (nonparametric) MR regression methods yielded similar results.ConclusionsAlthough maintaining a healthy and stable body weight remains important in patients with HD, promoting weight gain with the aim of delaying disease onset or slowing down disease progression should be discouraged. Our findings point toward the existence of underlying pathologic processes that dictate both the rate of clinical progression and weight loss in HD, which need further elucidation as targeting these pathways, rather than body weight per se, could be of therapeutic value.

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Increased intestinal permeability and gut dysbiosis in the R6/2 mouse model of Huntington’s disease

Cited by 72 publications

References 47 publications

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

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

Alterations in the Gut-Microbial-Inflammasome-Brain Axis in a Mouse Model of Alzheimer’s Disease

Effect of Body Weight on Age at Onset in Huntington Disease

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