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Role of alkaline phosphatase in colitis in man and rats
  1. A Tuin1,
  2. K Poelstra1,
  3. A de Jager-Krikken1,
  4. L Bok2,
  5. W Raaben3,
  6. M P Velders3,
  7. G Dijkstra2
  1. 1
    Department of Pharmacokinetics and Drug Delivery, University Centre for Pharmacy, University of Groningen, The Netherlands
  2. 2
    Department of Gastroenterology and Hepatology, University Medical Centre Groningen, The Netherlands
  3. 3
    AM-Pharma, Bunnik, The Netherlands
  1. Dr A Tuin, Department of Pharmacokinetics and Drug Delivery, University Centre for Pharmacy, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands; a.tuin{at}rug.nl

Abstract

Background and aims: Crohn’s disease (CD) and ulcerative colitis (UC) are chronic multifactorial inflammatory bowel diseases (IBDs) with unknown aetiology, but a deregulated mucosal immune response to gut-derived bacterial antigens is thought to be involved. Toll-like receptor ligands, especially lipopolysaccharide (LPS), contribute to the maintenance of the disease. It has previously been shown that the enzyme alkaline phosphatase (AP) is able to detoxify LPS, and the aim of this study was to examine a possible role in IBDs.

Methods: Intestinal AP (iAP) mRNA expression and LPS dephosphorylation in intestinal biopsies of control subjects and patients with IBD were examined, and the effect of orally administered iAP tablets on the progression of dextran sodium sulfate-induced colitis in rats was subsequently studied.

Results: In healthy persons, iAP mRNA and enzyme activity was high in the ileum relative to the colon. In patients with UC and CD, iAP mRNA expression was found to be markedly reduced when inflamed tissue was compared with non-inflamed tissue. Oral administration of iAP tablets to colitic rats resulted in a significant attenuation of colonic inflammation as reflected by reduced mRNA levels for tumour necrosis factor α, interleukin 1β, interleukin 6 and inducible nitric oxide synthase NOS (iNOS), a reduced iNOS staining and inflammatory cell influx, and a significantly improved morphology of the intestinal wall.

Conclusions: The present study shows that epithelial iAP mRNA expression is reduced in patients with UC and CD. The rat model demonstrates that oral administration of active iAP enzymes in the intestinal tract results in a significant reduction of inflammation. This provides new insight on IBD pathology and a novel treatment approach to this severe inflammatory disease.

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Footnotes

  • KP and GD contributed equally to this work.

  • Funding: This work was financially supported by the Dutch Organization for Scientific Research (NWO).

  • Competing interests: Declared (the declaration can be viewed on the Gut website at http://www.gut.bmj.com/supplemental).

  • Ethics approval: This study was approved by the Ethics Committee of the University Medical Centre Groningen.

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