Grant: Operating Grant

Clostridium difficile (Cdf) is a serious concern in hospitals throughout Canada and around the world. The majority of Cdf cases occur in hospitalized elederly patients on antibiotic medications. Antibiotic treatment disrupts the colonic flora, allows Cdf to over-populate the colon, and results in Cdf-associated colitis. This condition is characterized by severe diarrhea and abdominal pain, affects ~25% of hospitalized patients who undergo antibiotic treatment, and if left untreated, can develop into acute toxic megacolon. Colonic tissue from Cdf colitis displays marked pathological similarities with tissue from patients with ischaemic colitis. One hallmark of ischaemic colitis is hypoxia (i.e. a lack of oxygen), and a key regulator of the cellular response to hypoxia and other stresses is the hypoxia inducible factor (HIF). HIF has been found to play a protective role in intestinal tissue from patients with Inflammatory Bowel Diseases. We have recently found increased HIF protein in colonic tissue removed from patients with Cdf colitis. Furthermore, we have identified that purified Cdf toxins are novel activators of HIF. These preliminary studies suggest that HIF is an important regulator of the intestinal inflammation and damage that occurs in response to Cdf. This proposal will employ biochemical and physiological methods to define the link between Cdf and HIF in the development of Cdf-colitis and toxic megacolon. Model systems (i.e. genetically modified mice) will be used to examine the contributions of HIF to the development of inflammation following exposure to Cdf. In summary, this proposal will assess whether HIF plays a protective role in Cdf disease progression to acute toxic megacolon. We need to understand the specific molecular mechanism(s) by which Cdf induces colonic inflammation and tissue damage so that more effective therapeutic interventions for the Cdf-infected patient population can be developed.