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  • Review Article
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Hypoxia: an alarm signal during intestinal inflammation

Nature Reviews Gastroenterology & Hepatology volume 7, pages 281–287 (2010)Cite this article

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Abstract

Intestinal epithelial cells that line the mucosal surface of the gastrointestinal tract are positioned between an anaerobic lumen and a highly metabolic lamina propria. As a result of this unique anatomy, intestinal epithelial cells function within a steep physiologic oxygen gradient relative to other cell types. Furthermore, during active inflammatory disease such as IBD, metabolic shifts towards hypoxia are severe. Studies in vitro and in vivo have shown that the activation of hypoxia-inducible factor (HIF) serves as an alarm signal to promote the resolution of inflammation in various mouse models of disease. Amelioration of disease occurs, at least in part, through transcriptional upregulation of nonclassic epithelial barrier genes. There is much interest in harnessing hypoxia-inducible pathways, including stabilizing HIF directly or via inhibition of prolyl hydroxylase enzymes, for therapy of IBD. In this Review, we discuss the signaling pathways involved in the regulation of hypoxia and discuss how hypoxia may serve as an endogenous alarm signal for the presence of mucosal inflammatory disease. We also discuss the pros and cons of targeting these pathways to treat patients with IBD.

Key Points

  • A steep oxygen gradient exists from the anaerobic lumen of the intestine, across the intestinal epithelial barrier and into the highly vascular subepithelium

  • Loss of function of the intestinal epithelial barrier, together with hypoxia and inflammation, underlie the pathology of IBD

  • Expression of hypoxia-inducible factor 1 (HIF1) is induced in inflamed lesions, enabling HIF1 to trigger the transcription of many genes that allow the intestinal epithelial cells to act as an effective barrier, and, it is thought, to protect against inflammation and IBD

  • Prolyl hydroxylases (PHDs) and factor inhibiting HIF1 (FIH1) are expressed in the intestinal mucosal tissue and regulate the stability of HIF

  • Targeted therapies to stabilize HIF, for instance by inhibiting PHDs, are in development to treat IBD

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Figure 1: Potential sources of hypoxia in mucosal inflammation.
Figure 2: Detection of hypoxia in the mucosa.
Figure 3: Structural features of HIF and the mechanism of HIF stabilization.
Figure 4: Activation of HIF and NFκB in intestinal epithelial cells during inflammation.

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Acknowledgements

S. P. Colgan is supported by NIH grants DK50189, DE016191, HL60569 and by a grant from the Crohn's and Colitis Foundation of America. C. T. Taylor is supported by a grant from the Science Foundation of Ireland.

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Authors and Affiliations

  1. Division of Gastroenterology, Mucosal Inflammation Program, University of Colorado Denver, 12700 E. 19th Avenue MS B146, Aurora, 80045, CO, USA

    Sean P. Colgan

  2. UCD Conway Institute, School of Medicine and Medical Science, College of Life Sciences, University College Dublin, Belfield, 4, Dublin, Ireland

    Cormac T. Taylor

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Correspondence to Sean P. Colgan.

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S. P. Colgan declares no competing interests.

C. T. Taylor declares associations with Sigmoid Pharma and Johnson & Johnson. He is collaborating with Sigmoid Pharma to formulate drugs for better delivery to the gastrointestinal tract and with Johnson & Johnson to test new therapeutic approaches in models of IBD. These companies have provided some financial support for laboratory expenses only.

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Colgan, S., Taylor, C. Hypoxia: an alarm signal during intestinal inflammation. Nat Rev Gastroenterol Hepatol 7, 281–287 (2010). https://doi.org/10.1038/nrgastro.2010.39

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