Abstract
ABSTRACTThe cells of the intestinal epithelium provide a selectively permeable barrier between the external environment and internal tissues. The integrity of this barrier is maintained by tight junctions, specialised cell-cell contacts that permit the absorption of water and nutrients while excluding microbes, toxins and dietary antigens. Impairment of intestinal barrier function contributes to multiple gastrointestinal disorders, including food hypersensitivity, inflammatory bowel disease (IBD) and colitis-associated cancer (CAC). Glycoprotein A33 (GPA33) is an intestinal epithelium-specific cell surface marker and member of the CTX group of transmembrane proteins. Roles in cell-cell adhesion have been demonstrated for multiple CTX family members, suggesting a similar function for GPA33 within the gastrointestinal tract. To test a potential requirement for GPA33 in intestinal barrier function, we generated Gpa33−/− mice and subjected them to experimental regimens designed to produce food hypersensitivity, colitis and CAC. Gpa33−/− mice exhibited impaired intestinal barrier function. This was shown by elevated steady-state immunosurveillance in the colonic mucosa and leakiness to oral TRITC-labelled dextran after short-term exposure to dextran sodium sulphate (DSS) to injure the intestinal epithelium. Gpa33−/− mice also exhibited rapid onset and reduced resolution of DSS-induced colitis, and a striking increase in the number of colitis-associated tumours produced by treatment with the colon-specific mutagen azoxymethane (AOM) followed by two cycles of DSS. In contrast, Gpa33−/− mice treated with AOM alone showed no increase in sporadic tumour formation, indicating that their increased tumour susceptibility is dependent on inflammatory stimuli. Finally, Gpa33−/− mice displayed hypersensitivity to food allergens, a common co-morbidity in humans with IBD. We propose that Gpa33−/− mice provide a valuable model to study the mechanisms linking intestinal permeability and multiple inflammatory pathologies. Moreover, this model could facilitate preclinical studies aimed at identifying drugs that restore barrier function.
Highlights
Impaired intestinal epithelial barrier function is an emerging factor in the aetiology and pathology of a range of gastrointestinal disorders (Turner, 2009), including food hypersensitivity (Ventura et al, 2006), inflammatory bowel disease (IBD) (Heller et al, 2005; Zeissig et al, 2007) and colitis-associated cancer (CAC) (Kim and Kim, 2014)
The analysis of publicly available gene expression data revealed that glycoprotein A33 (GPA33) RNA expression is reduced in the inflamed bowel of individuals with either Crohn’s disease (CD) or ulcerative colitis (UC), suggesting that GPA33 deficiency might contribute to intestinal permeability in human disease
WT mice were unaffected by 2% dextran sodium sulphate (DSS) treatment, in accord with a published report in which effects on intestinal permeability were first observed in WT mice only after 3 days of 5% DSS treatment (Kitajima et al, 1999)
Summary
Impaired intestinal epithelial barrier function is an emerging factor in the aetiology and pathology of a range of gastrointestinal disorders (Turner, 2009), including food hypersensitivity (Ventura et al, 2006), inflammatory bowel disease (IBD) (Heller et al, 2005; Zeissig et al, 2007) and colitis-associated cancer (CAC) (Kim and Kim, 2014). The loss of JAM-A has been implicated in changes to intestinal permeability with subsequent inflammation, cytokine production and colitis in mice (Laukoetter et al, 2007) and IBD in humans (Vetrano and Danese, 2009; Vetrano et al, 2008)
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call