Hypoxia-Inducible Factor Signaling Provides Protection in Clostridium difficile-Induced Intestinal Injury

Simon A. Hirota, Kyla Fines, Jeffrey Ng, Danya Traboulsi, Josh Lee, Eikichi Ihara, Yan Li, William G. Willmore, Daniel Chung, Melanie M. Scully, Thomas Louie, Shaun Medlicott, Manigandan Lejeune, Kris Chadee, Glen Armstrong, Sean P. Colgan, Daniel A. Muruve, Justin A. MacDonald, Paul L. Beck

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Abstract

Background & Aims: Clostridium difficile is the leading cause of nosocomial infectious diarrhea. Antibiotic resistance and increased virulence of strains have increased the number of C difficile-related deaths worldwide. The innate host response mechanisms to C difficile are not resolved; we propose that hypoxia-inducible factor (HIF-1) has an innate, protective role in C difficile colitis. We studied the impact of C difficile toxins on the regulation of HIF-1 and evaluated the role of HIF-1α in C difficile-mediated injury/inflammation. Methods: We assessed HIF-1α mRNA and protein levels and DNA binding in human mucosal biopsy samples and Caco-2 cells following exposure to C difficile toxins. We used the mouse ileal loop model of C difficile toxin-induced intestinal injury. Mice with targeted deletion of HIF-1α in the intestinal epithelium were used to assess the effects of HIF-1α signaling in response to C difficile toxin. Results: Mucosal biopsy specimens and Caco-2 cells exposed to C difficile toxin had a significant increase in HIF-1α transcription and protein levels. Toxin-induced DNA binding was also observed in Caco-2 cells. Toxin-induced HIF-1α accumulation was attenuated by nitric oxide synthase inhibitors. In vivo deletion of intestinal epithelial HIF-1α resulted in more severe, toxin-induced intestinal injury and inflammation. In contrast, stabilization of HIF-1α with dimethyloxallyl glycine attenuated toxin-induced injury and inflammation. This was associated with induction of HIF-1-regulated protective factors (such as vascular endothelial growth factor-α, CD73, and intestinal trefoil factor) and down-regulation of proinflammatory molecules such as tumor necrosis factor and Cxcl1. Conclusions: HIF-1α protects the intestinal mucosa from C difficile toxins. The innate protective actions of HIF-1α in response to C difficile toxins be developed as therapeutics for C difficile-associated disease.

Original languageEnglish
Pages (from-to)259-269.e3
JournalGastroenterology
Volume139
Issue number1
DOIs
Publication statusPublished - Jul 2010

All Science Journal Classification (ASJC) codes

  • Hepatology
  • Gastroenterology

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    Hirota, S. A., Fines, K., Ng, J., Traboulsi, D., Lee, J., Ihara, E., Li, Y., Willmore, W. G., Chung, D., Scully, M. M., Louie, T., Medlicott, S., Lejeune, M., Chadee, K., Armstrong, G., Colgan, S. P., Muruve, D. A., MacDonald, J. A., & Beck, P. L. (2010). Hypoxia-Inducible Factor Signaling Provides Protection in Clostridium difficile-Induced Intestinal Injury. Gastroenterology, 139(1), 259-269.e3. https://doi.org/10.1053/j.gastro.2010.03.045