Inflammatory bowel disease

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

¹ School of Biomedical Sciences, University of Queensland, St Lucia, Australia
² Institute for Molecular Bioscience, University of Queensland, St Lucia, Australia
³ Mucosal Diseases Program, Mater Medical Research Institute, Mater Hospital, South Brisbane, Australia

Professor D Markovich, University of Queensland, St Lucia, QLD 4072, Australia; d.markovich{at}uq.edu.au

Objective: Sulfate (SO₄^2–) 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.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

Relevant Article

Digest

Robin Spiller and Severine Vermeire
Gut 2009 58: i. [Extract] [Full Text] [PDF]