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

Research output: Contribution to journalArticle

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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
JournalGastroenterology
Volume139
Issue number1
DOIs
Publication statusPublished - Jan 1 2010
Externally publishedYes

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Clostridium difficile
Caco-2 Cells
Wounds and Injuries
Intestinal Mucosa
Inflammation
Biopsy
Hypoxia-Inducible Factor 1
DNA-Binding Proteins
Colitis
Microbial Drug Resistance
Nitric Oxide Synthase
Glycine
Vascular Endothelial Growth Factor A
Virulence
Diarrhea
Down-Regulation
Tumor Necrosis Factor-alpha
Messenger RNA
Hypoxia
DNA

All Science Journal Classification (ASJC) codes

  • Hepatology
  • Gastroenterology

Cite this

Hypoxia-Inducible Factor Signaling Provides Protection in Clostridium difficile-Induced Intestinal Injury. / Hirota, Simon A.; Fines, Kyla; Ng, Jeffrey; Traboulsi, Danya; Lee, Josh; Ihara, Eikichi; Li, Yan; Willmore, William G.; Chung, Daniel; Scully, Melanie M.; Louie, Thomas; Medlicott, Shaun; Lejeune, Manigandan; Chadee, Kris; Armstrong, Glen; Colgan, Sean P.; Muruve, Daniel A.; MacDonald, Justin A.; Beck, Paul L.

In: Gastroenterology, Vol. 139, No. 1, 01.01.2010.

Research output: Contribution to journalArticle

Hirota, SA, Fines, K, Ng, J, Traboulsi, D, Lee, J, Ihara, E, Li, Y, Willmore, WG, Chung, D, Scully, MM, Louie, T, Medlicott, S, Lejeune, M, Chadee, K, Armstrong, G, Colgan, SP, Muruve, DA, MacDonald, JA & Beck, PL 2010, 'Hypoxia-Inducible Factor Signaling Provides Protection in Clostridium difficile-Induced Intestinal Injury', Gastroenterology, vol. 139, no. 1. https://doi.org/10.1053/j.gastro.2010.03.045
Hirota, Simon A. ; Fines, Kyla ; Ng, Jeffrey ; Traboulsi, Danya ; Lee, Josh ; Ihara, Eikichi ; Li, Yan ; Willmore, William G. ; Chung, Daniel ; Scully, Melanie M. ; Louie, Thomas ; Medlicott, Shaun ; Lejeune, Manigandan ; Chadee, Kris ; Armstrong, Glen ; Colgan, Sean P. ; Muruve, Daniel A. ; MacDonald, Justin A. ; Beck, Paul L. / Hypoxia-Inducible Factor Signaling Provides Protection in Clostridium difficile-Induced Intestinal Injury. In: Gastroenterology. 2010 ; Vol. 139, No. 1.
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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.",
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AU - Hirota, Simon A.

AU - Fines, Kyla

AU - Ng, Jeffrey

AU - Traboulsi, Danya

AU - Lee, Josh

AU - Ihara, Eikichi

AU - Li, Yan

AU - Willmore, William G.

AU - Chung, Daniel

AU - Scully, Melanie M.

AU - Louie, Thomas

AU - Medlicott, Shaun

AU - Lejeune, Manigandan

AU - Chadee, Kris

AU - Armstrong, Glen

AU - Colgan, Sean P.

AU - Muruve, Daniel A.

AU - MacDonald, Justin A.

AU - Beck, Paul L.

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N2 - 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.

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