Understanding Clostridium difficile Infection in Patients with inflammatory Bowel Disease

项目总结

PROJECT SUMMARY Over the last decade the incidence and severity of Clostridium difficile infection (CDI) has increased, and these infections have had a particularly deleterious effect on patients with inflammatory bowel disease (IBD) by eliciting disease flares and increasing risk of colectomy. It is known that IBD patients have a 10% lifetime risk of getting CDI and experience significantly higher rates of recurrence compared to non-IBD patients. Mechanistically, recurrent CDI is thought in part to be due to a loss of key commensal species that provide bile transforming activities, which convert primary bile acids, that serve as pro-germination signals to C. difficile, to secondary bile acids which have been shown to be inhibitory to germination and to the pathogenesis of the organism. Additionally, Fecal Microbiota Transplantation (FMT), a major treatment breakthrough for refractory CDI, is believed to work in part by reconstituting bile salt hydrolase activity. What is not known is why patients with IBD are at such an increased risk for recurrent CDI given that CDI studies notably lack IBD patients as this patient population has proven challenging given many suffer from baseline diarrhea. There is an urgent need to better risk stratify those with IBD-CDI by utilizing mechanistic risk factors in addition to traditional epidemiologic exposures. By individualizing risk predictors, high risk patients will be identified more promptly and offered appropriate treatments earlier, thus preventing severe complications of IBD, improving symptom burden and quality of life. Our overall objective is to identify IBD patients at risk for recurrent CDI earlier in their disease course and provide therapy with FMT to not only prevent recurrent CDI but also the downstream consequences associated with CDI. Our central hypothesis is that (1) identification of clinical, microbial and metabolic risk factors, specifically bile acid profiles, for CDI recurrence among patients with IBD who have experienced their first episode of CDI will allow for earlier identification of high risk patients and (2) FMT performed after an initial episode of CDI in patients with IBD will be safe and will effectively reconstitute bile salt hydrolase activity. The rationale for the proposed research is that unlike non-IBD patients, many IBD patients are at risk for bile acid malabsorption, either from ongoing bowel inflammation and diarrhea or prior resections. Given that IBD-CDI patients are often excluded from trials, understanding the extent to which alterations in bile acid composition explain the higher rates of CDI recurrence seen in this population is critical to providing more targeted therapies. The recent expansion in microbiome research has now made it possible to ascertain detailed gut bacterial profiles as well as their metabolites.