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Gut 58:910-919 doi:10.1136/gut.2007.147595
  • Inflammatory bowel disease

Reduced mucin sulfonation and impaired intestinal barrier function in the hyposulfataemic NaS1 null mouse

  1. P A Dawson1,
  2. S Huxley1,
  3. B Gardiner2,
  4. T Tran3,
  5. J L McAuley3,
  6. S Grimmond2,
  7. M A McGuckin3,
  8. D Markovich1
  1. 1
    School of Biomedical Sciences, University of Queensland, St Lucia, Australia
  2. 2
    Institute for Molecular Bioscience, University of Queensland, St Lucia, Australia
  3. 3
    Mucosal Diseases Program, Mater Medical Research Institute, Mater Hospital, South Brisbane, Australia
  1. Professor D Markovich, University of Queensland, St Lucia, QLD 4072, Australia; d.markovich{at}uq.edu.au
  • Revised 20 November 2008
  • Accepted 25 November 2008
  • Published Online First 6 February 2009

Abstract

Objective: Sulfate (SO42−) is an abundant component of intestinal mucins and its content is decreased in certain gastrointestinal diseases, including inflammatory bowel disease. In this study, the hyposulfataemic NaS1 sulfate transporter null (Nas1−/−) mice were used to investigate the physiological consequences of disturbed sulfate homeostasis on (1) intestinal sulfomucin content and mRNA expression; (2) intestinal permeability and proliferation; (3) dextran sulfate sodium (DSS)-induced colitis; and (4) intestinal barrier function against the bacterial pathogen, Campylobacter jejuni.

Methods: Intestinal sulfomucins and sialomucins were detected by high iron diamine staining, permeability was assessed by fluorescein isothiocyanate (FITC)–dextran uptake, and proliferation was assessed by 5-bromodeoxyuridine (BrdU) incorporation. Nas1−/− and wild-type (Nas1+/+) mice received DSS in drinking water, and intestinal damage was assessed by histological, clinical and haematological measurements. Mice were orally inoculated with C jejuni, and intestinal and systemic infection was assessed. Ileal mRNA expression profiles of Nas1−/− and Nas1+/+ mice were determined by cDNA microarrays and validated by quantitative real-time PCR.

Results: Nas1−/− mice exhibited reduced intestinal sulfomucin content, enhanced intestinal permeability and DSS-induced colitis, and developed systemic infections when challenged orally with C jejuni. The transcriptional profile of 41 genes was altered in Nas1−/− mice, with the most upregulated gene being pancreatic lipase-related protein 2 and the most downregulated gene being carbonic anhydrase 1 (Car1).

Conclusion: Sulfate homeostasis is essential for maintaining a normal intestinal metabolic state, and hyposulfataemia leads to reduced intestinal sulfomucin content, enhanced susceptibility to toxin-induced colitis and impaired intestinal barrier to bacterial infection.

Footnotes