Aberrant Mucin Assembly in Mice Causes Endoplasmic Reticulum Stress and Spontaneous Inflammation Resembling Ulcerative Colitis
Open accessAbstract
BACKGROUND: MUC2 mucin produced by intestinal goblet cells is the major component of the intestinal mucus barrier. The inflammatory bowel disease ulcerative colitis is characterized by depleted goblet cells and a reduced mucus layer, but the aetiology remains obscure. In this study we used random mutagenesis to produce two murine models of inflammatory bowel disease, characterised the basis and nature of the inflammation in these mice, and compared the pathology with human ulcerative colitis. METHODS AND FINDINGS: By murine N-ethyl-N-nitrosourea mutagenesis we identified two distinct noncomplementing missense mutations in Muc2 causing an ulcerative colitis-like phenotype. 100% of mice of both strains developed mild spontaneous distal intestinal inflammation by 6 wk (histological colitis scores versus wild-type mice, p < 0.01) and chronic diarrhoea. Monitoring over 300 mice of each strain demonstrated that 25% and 40% of each strain, respectively, developed severe clinical signs of colitis by age 1 y. Mutant mice showed aberrant Muc2 biosynthesis, less stored mucin in goblet cells, a diminished mucus barrier, and increased susceptibility to colitis induced by a luminal toxin. Enhanced local production of IL-1beta, TNF-alpha, and IFN-gamma was seen in the distal colon, and intestinal permeability increased 2-fold. The number of leukocytes within mesenteric lymph nodes increased 5-fold and leukocytes cultured in vitro produced more Th1 and Th2 cytokines (IFN-gamma, TNF-alpha, and IL-13). This pathology was accompanied by accumulation of the Muc2 precursor and ultrastructural and biochemical evidence of endoplasmic reticulum (ER) stress in goblet cells, activation of the unfolded protein response, and altered intestinal expression of genes involved in ER stress, inflammation, apoptosis, and wound repair. Expression of mutated Muc2 oligomerisation domains in vitro demonstrated that aberrant Muc2 oligomerisation underlies the ER stress. In human ulcerative colitis we demonstrate similar accumulation of nonglycosylated MUC2 precursor in goblet cells together with ultrastructural and biochemical evidence of ER stress even in noninflamed intestinal tissue. Although our study demonstrates that mucin misfolding and ER stress initiate colitis in mice, it does not ascertain the genetic or environmental drivers of ER stress in human colitis. CONCLUSIONS: Characterisation of the mouse models we created and comparison with human disease suggest that ER stress-related mucin depletion could be a fundamental component of the pathogenesis of human colitis and that clinical studies combining genetics, ER stress-related pathology and relevant environmental epidemiology are warranted.
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Mice with Muc2 mutations spontaneously develop inflammation.
“Mice with mutations in the Muc2 gene also spontaneously develop inflammation 18.”
From The composition of the gut microbiota shapes the colon mucus barrier (2015) · cites this paper as [18]
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Loss of intestinal core 1–derived O-glycans causes spontaneous colitis in mice
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Interactions between Intestinal Microbiota and Host Immune Response in Inflammatory Bowel Disease
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Depletion of luminal iron alters the gut microbiota and prevents Crohn's disease-like ileitis
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- Authors
- Heazlewood, C. K., Cook, M. C., Eri, R., Price, G. R., Tauro, S. B., Taupin, D., Thornton, D. J., Png, C. W., Crockford, T. L., Cornall, R. J., Adams, R., Kato, M., Nelms, K. A., Hong, N. A., Florin, T. H. J., Goodnow, C. C., & McGuckin, M. A.
- Affiliations
- Mater Health Services (AU)
- Canberra Hospital (AU)
- Wellcome Centre for Cell-Matrix Research (GB)
- John Radcliffe Hospital (GB)
- Australian National University (AU)
- Corresponding author
- McGuckin, Michael A
- ORCID
- Venue
- PLoS Medicine
- Publisher
- Public Library of Science (PLoS)
- Published
- 2008-03-04
- Volume
- 5
- Issue
- 3
- Pages
- e54
- ISSN
- 1549-1277 (ISSN-L)
- 1549-1676
- PMC
- PMC2270292
- OpenAlex
- W2031558979
- Cited by
- 701
- References
- 78
- Citations by year
- 2026: 20 · 2025: 25 · 2024: 29 · 2023: 31 · 2022: 56 · 2021: 44 · 2020: 37 · 2019: 36 · 2018: 44 · 2017: 40 · 2016: 44 · 2015: 35 · 2014: 41 · 2013: 43 · 2012: 45
- FWCI
- 24.89
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS Medicine (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Minerva Access (University of Melbourne) (submittedVersion, cc-by)
- eCite Digital Repository (University of Tasmania) (submittedVersion)
- National University of Singapore (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- ANU Open Research (Australian National University) (submittedVersion, cc-by)
- Research Explorer (The University of Manchester) (submittedVersion)
- Funders
- National Health and Medical Research Council (235608)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Inflammatory Bowel Disease
- Health Sciences › Medicine › Ophthalmology › Ocular Diseases and Behçet’s Syndrome
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glycosylation and Glycoproteins Research
- Keywords
- ulcerative colitis, MUC2, endoplasmic reticulum stress, unfolded protein response, goblet cells, intestinal mucus barrier, N-ethyl-N-nitrosourea mutagenesis, Th1/Th2 cytokines, intestinal permeability
- MeSH terms
- Adult, Animals, Colitis, Ulcerative, Endoplasmic Reticulum, Gene Expression Regulation, Humans, Inflammation, Intestinal Mucosa, Male, Mice, Inbred C57BL, Middle Aged, Mucins, Mutation, Protein Precursors, Apoptosis, Protein Folding, Genetic Predisposition to Disease, Goblet Cells, Protein Structure, Quaternary, Cell Proliferation, Mice, Mucin-2
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