Hypoxia-inducible factor signaling provides protection in Clostridium difficile-induced intestinal injury

SA Hirota, K Fines, J Ng, D Traboulsi, J Lee, E Ihara… - Gastroenterology, 2010 - Elsevier
SA Hirota, K Fines, J Ng, D Traboulsi, J Lee, E Ihara, Y Li, WG Willmore, D Chung…
Gastroenterology, 2010Elsevier
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 …
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.
Elsevier