Hypoxia and gastrointestinal disease
Open accessAbstract
The gastrointestinal mucosa is a richly perfused vascular bed directly juxtaposed with the anaerobic and nonsterile lumen of the gut. As such, intestinal epithelial cells, which line the mucosa, experience a uniquely steep physiologic oxygen gradient in comparison with other cells of the body. Inflammation associated with a loss of epithelial barrier function and unregulated exposure of the mucosal immune system to luminal antigens leads to inflammatory bowel disease (IBD), a relatively common disorder with severe morbidity and a limited therapeutic repertoire. During IBD, increased tissue metabolism and vasculitis renders the chronically inflamed mucosa and particularly the epithelium hypoxic, giving rise to the activation of the hypoxia-responsive transcription factor hypoxia-inducible factor (HIF). Recent studies utilizing conditional intestinal epithelial hif1a-null mice have revealed a protective role for epithelial HIF-1alpha in murine models of IBD. Such protection occurs, at least in part, through HIF-dependent induction of barrier-protective genes in the epithelium. More recently, studies employing pharmacologic activation of HIF via inhibition of HIF prolyl hydroxylases revealed a profoundly protective effect of these agents in murine models of colitis. In this paper, we review this pathway in detail and examine the therapeutic potential for targeting HIF hydroxylases in intestinal mucosal inflammatory disease.
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Sites of mucosal inflammation are characterized by profound changes in tissue metabolism, including local depletion of nutrients, imbalances in tissue oxygen supply and demand, and generation of large quantities of reactive nitrogen and oxygen intermediates.
“Sites of mucosal inflammation are characterized by profound changes in tissue metabolism, including local depletion of nutrients, imbalances in tissue oxygen supply and demand, and the generation of large quantities of reactive nitrogen and oxygen intermediates3.”
From Hypoxia: an alarm signal during intestinal inflammation (2010) · cites this paper as [3]
During active inflammatory disease such as IBD, metabolic shifts toward hypoxia are severe.
“Furthermore, during active inflammatory disease such as IBD, metabolic shifts toward hypoxia are severe.”
From Hypoxia: an alarm signal during intestinal inflammation (2010) · cites this paper as [3]
Both the absorptive and barrier functions of the intestinal epithelium are regulated by the availability of O2.
“Both the absorptive and barrier functions of the intestinal epithelium are regulated by the availability of O23.”
From Hypoxia: an alarm signal during intestinal inflammation (2010) · cites this paper as [3]
The PMN oxidative burst is not hindered by even relatively low O2 (as low as 4.5% O2), so ROS can be generated in the relatively low O2 environments of inflamed intestinal mucosa.
“Notably, the PMN oxidative burst is not hindered by even relatively low O2 (as low as 4.5% O2)8, which is important, since it means that ROS can be generated in the relatively low O2 environments of inflamed intestinal mucosa3.”
From Hypoxia: an alarm signal during intestinal inflammation (2010) · cites this paper as [3]
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- Authors
- Taylor, C. T., & Colgan, S. P.
- Affiliations
- University College Dublin (IE)
- University of Colorado Health (US)
- Corresponding author
- Taylor, Cormac T.
- Venue
- Journal of Molecular Medicine
- Published
- 2007-11-20
- Volume
- 85
- Issue
- 12
- Pages
- 1295-1300
- ISSN
- 0946-2716 (ISSN-L)
- 1432-1440
- OpenAlex
- W2123891308
- Cited by
- 313
- References
- 39
- Citations by year
- 2026: 5 · 2025: 10 · 2024: 16 · 2023: 19 · 2022: 20 · 2021: 17 · 2020: 17 · 2019: 14 · 2018: 15 · 2017: 19 · 2016: 17 · 2015: 23 · 2014: 13 · 2013: 19 · 2012: 18
- FWCI
- 1.61
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Journal of Molecular Medicine (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK050189, R37DK050189)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Inflammatory Bowel Disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Keywords
- hypoxia, gastrointestinal mucosa, inflammatory bowel disease, hypoxia-inducible factor-1α, intestinal epithelial barrier function, colitis, mucosal inflammation
- MeSH terms
- Animals, Hypoxia, Enzyme Inhibitors, Gastrointestinal Agents, Humans, Intestinal Mucosa, Oxygen, Procollagen-Proline Dioxygenase, Inflammatory Bowel Diseases, Signal Transduction, Cell Hypoxia, NF-kappa B, Hypoxia-Inducible Factor 1, Mucositis
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