Reduced mucin sulfonation and impaired intestinal barrier function in the hyposulfataemic NaS1 null mouse
- P A Dawson1,
- S Huxley1,
- B Gardiner2,
- T Tran3,
- J L McAuley3,
- S Grimmond2,
- M A McGuckin3,
- D Markovich1
- 1School of Biomedical Sciences, University of Queensland, St Lucia, Australia
- 2Institute for Molecular Bioscience, University of Queensland, St Lucia, Australia
- 3Mucosal Diseases Program, Mater Medical Research Institute, Mater Hospital, South Brisbane, Australia
- Professor D Markovich, University of Queensland, St Lucia, QLD 4072, Australia;
- Revised 20 November 2008
- Accepted 25 November 2008
- Published Online First 6 February 2009
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.
▸ An additional table and figure are published online only at http://gut.bmj.com/content/vol58/issue7
Competing interests: None.