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

Abstract

Huntington’s disease (HD) is a progressive, multifaceted neurodegenerative disease associated with weight loss and gut problems. Under healthy conditions, tight junction (TJ) proteins maintain the intestinal barrier integrity preventing bacterial translocation from the intestinal lumen to the systemic circulation. Reduction of TJs expression in Parkinson’s disease patients has been linked with increased intestinal permeability—leaky gut syndrome. The intestine contains microbiota, most dominant phyla being Bacteroidetes and Firmicutes; in pathogenic or disease conditions the balance between these bacteria might be disrupted. The present study investigated whether there is evidence for an increased intestinal permeability and dysbiosis in the R6/2 mouse model of HD. Our data demonstrate that decreased body weight and body length in R6/2 mice is accompanied by a significant decrease in colon length and increased gut permeability compared to wild type littermates, without any significant changes in the protein levels of the tight junction proteins (occludin, zonula occludens). Moreover, we found an altered gut microbiota in R6/2 mice with increased relative abundance of Bacteroidetes and decreased of Firmicutes. Our results indicate an increased intestinal permeability and dysbiosis in R6/2 mice and further studies investigating the clinical relevance of these findings are warranted.

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

“…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].…”

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

“…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.…”

Gut microbial imbalance and neurodegenerative proteinopathies: from molecular mechanisms to prospects of clinical applications

“…Moreover, this gut dysbiosis seemed to be related with loss in body weight and motor deficits in HD mice at 12 weeks of age. These results, alongside to an impaired intestinal permeability, were subsequently confirmed in transgenic R6/2 HD mice in early and early/mid stages of disease [171]. Furthermore, the BACHD mouse model of HD placed in a GF conditions exhibited defects in myelin plasticity [172].…”