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Cited by 101Gut microbiota and healthGastrointestinal motility and disordersBarrier Structure and Function Studies

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

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Stan, Tiberiu Loredan, Soylu-Kucharz, Rana, Burleigh, Stephen, Prykhodko, Olena, Cao, Ling, Franke, Naomi, Sjögren, Marie, Haikal, Caroline, Hållenius, Frida, Björkqvist, Maria·2020·Scientific Reports
DOI 10.1038/s41598-020-75229-9PMC PMC7589489
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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.

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Figure 1 Intestinal permeability is increased in R6/2 mice. Intestinal permeability measured by determining the concentration of FD4 in the serum of R6/2 mice vs. wild type (WT) littermates at 16 weeks of age 4 h after oral FD4 administration. Data represent mean ± SEM, N = 10 for WT; N = 10 for R6/2; unpaired t test; *p ≤ 0.05. FD4 = Fluorescein Isothiocyanate-dextran.
Figure 1 Intestinal permeability is increased in R6/2 mice. Intestinal permeability measured by determining the concentration of FD4 in the serum of R6/2 mice vs. wild type (WT) littermates at 16 weeks of age 4 h after oral FD4 administration. Data represent mean ± SEM, N = 10 for WT; N = 10 for R6/2; unpaired t test; *p ≤ 0.05. FD4 = Fluorescein Isothiocyanate-dextran.CC BY · PubMed Central
Figure 2 Tight junction protein expression is not altered in the colon and cortex of R6/2 mice. Quantitative western blot analysis showed no change in occludin (n = 5–7/genotype, p = 0.8763) (A) and ZO-1 (n = 5–7/genotype, p = 0.6389) (B) at 12 weeks and occludin (n = 6–7/genotype, p = 0.8357) (C) and ZO-1 (n = 5–8/genotype, p = 0.0653) (D) expression levels at 16 weeks in the proximal colon samples of R6/2 compared to WT mice. Western blot showing occludin and ZO-1 expression in the proximal colon samples of 12 and 16 weeks old R6/2 and WT mice (E). Qualitative analysis of occludin expression in the colon of WT and R6/2 mice at 18 weeks of age. The occludin immunohistochemistry with H&E shows the reduced expression of occludin in R6/2 mice compared to WT mice (red arrows show an intact epithelium in WT colon and black arrows show disrupted epithelia in R6/2 colon) (F). Assessment of occludin and ZO-1 protein expression levels showed no change in the cortex samples at 12 weeks (G and H) (occludin: n = 7/genotype, p = 0.1282, ZO-1: n = 7/genotype, p > 0.9999) and 16 weeks (occludin: n = 7/genotype, p = 0.62, ZO-1: n = 7/genotype, p0.0973) (I,J) in R6/2 compared with WT mice. (K) Western blot showing occludin and ZO-1 expression in the cortex of 12 and 16 weeks old R6/2 and WT mice. Data were normalized to β-actin protein expression and presented as a fold change in relation to WT animals. Non-parametric Mann–Whitney test was used for comparisons between the two groups. Data represent mean ± SEM. Scale bars represent 100 μm.
Figure 2 Tight junction protein expression is not altered in the colon and cortex of R6/2 mice. Quantitative western blot analysis showed no change in occludin (n = 5–7/genotype, p = 0.8763) (A) and ZO-1 (n = 5–7/genotype, p = 0.6389) (B) at 12 weeks and occludin (n = 6–7/genotype, p = 0.8357) (C) and ZO-1 (n = 5–8/genotype, p = 0.0653) (D) expression levels at 16 weeks in the proximal colon samples of R6/2 compared to WT mice. Western blot showing occludin and ZO-1 expression in the proximal colon samples of 12 and 16 weeks old R6/2 and WT mice (E). Qualitative analysis of occludin expression in the colon of WT and R6/2 mice at 18 weeks of age. The occludin immunohistochemistry with H&E shows the reduced expression of occludin in R6/2 mice compared to WT mice (red arrows show an intact epithelium in WT colon and black arrows show disrupted epithelia in R6/2 colon) (F). Assessment of occludin and ZO-1 protein expression levels showed no change in the cortex samples at 12 weeks (G and H) (occludin: n = 7/genotype, p = 0.1282, ZO-1: n = 7/genotype, p > 0.9999) and 16 weeks (occludin: n = 7/genotype, p = 0.62, ZO-1: n = 7/genotype, p0.0973) (I,J) in R6/2 compared with WT mice. (K) Western blot showing occludin and ZO-1 expression in the cortex of 12 and 16 weeks old R6/2 and WT mice. Data were normalized to β-actin protein expression and presented as a fold change in relation to WT animals. Non-parametric Mann–Whitney test was used for comparisons between the two groups. Data represent mean ± SEM. Scale bars represent 100 μm.CC BY · PubMed Central
Figure 3 R6/2 and WT mice gut microbiota analysis. Gut microbiota composition at phylum and genus level using16S rRNA analysis of faecal samples from 16 weeks of age mice (n = 9–10/genotype) (A). Partial least squares (PLS-X) loading and score scatter plots of different gut microbial taxa and biomarkers (blue) from R6/2 and WT mice (n = 4–6/genotype). Firmicutes taxa (purple) are associated with WT, while Bacteroidetes taxa (brown), FD4 permeability (Perm) and glucose levels (Gluc) are strongly associated with R6/2. R6/2 mice show an increased relative abundance of Bacteroidetes and a decreased relative abundance of Firmicutes (B).
Figure 3 R6/2 and WT mice gut microbiota analysis. Gut microbiota composition at phylum and genus level using16S rRNA analysis of faecal samples from 16 weeks of age mice (n = 9–10/genotype) (A). Partial least squares (PLS-X) loading and score scatter plots of different gut microbial taxa and biomarkers (blue) from R6/2 and WT mice (n = 4–6/genotype). Firmicutes taxa (purple) are associated with WT, while Bacteroidetes taxa (brown), FD4 permeability (Perm) and glucose levels (Gluc) are strongly associated with R6/2. R6/2 mice show an increased relative abundance of Bacteroidetes and a decreased relative abundance of Firmicutes (B).CC BY · PubMed Central

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Metadata

Authors
Stan, T. L., Soylu-Kucharz, R., Burleigh, S., Prykhodko, O., Cao, L., Franke, N., Sjögren, M., Haikal, C., Hållenius, F., & Björkqvist, M.
Affiliations
Lund University (SE)
Corresponding author
Soylu-Kucharz, Rana
ORCID
Venue
Scientific Reports
Publisher
Springer Science and Business Media LLC
Published
2020-10-26
Volume
10
Issue
1
Pages
18270-18270
ISSN
2045-2322 (ISSN-L)
DOI
10.1038/s41598-020-75229-9
PMC
PMC7589489
OpenAlex
W3094034464
Cited by
101
References
48
Citations by year
2026: 11 · 2025: 14 · 2024: 22 · 2023: 17 · 2022: 26 · 2021: 11
FWCI
4.38
Type
journal article
Language
en
Open access
Licence
Locations
  • Scientific Reports (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Lund University Publications (Lund University) (submittedVersion)
Funders
  • Royal Physiographic Society of Lund
  • Per Westlings funds
  • Knut och Alice Wallenbergs Stiftelse
  • Svenska Sällskapet för Medicinsk Forskning
  • The Direktör Albert Påhlsson Foundation, Sweden
  • Vetenskapsrådet (#2017-01080)
  • Lund University
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
  • Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
  • Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
Keywords
Huntington's disease, intestinal permeability, gut dysbiosis, R6/2 mouse model, tight junction proteins, occludin, zonula occludens, gut microbiota, Bacteroidetes, Firmicutes, leaky gut, weight loss, colon length
MeSH terms
Gastrointestinal Microbiome, Animals, Bacteria, Body Weight, Disease Models, Animal, DNA, Bacterial, DNA, Ribosomal, Female, Humans, Huntington Disease, Male, Phylogeny, RNA, Ribosomal, 16S, Sequence Analysis, DNA, Bacterial Physiological Phenomena, Bacterial Translocation, Mice, Tight Junction Proteins, Dysbiosis

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