Understanding Clostridium difficile Infection in Patients with inflammatory Bowel Disease

项目摘要 在过去的十年中，艰难梭菌感染（CDI）的发病率和严重性增加，并且这些疾病的发病率和严重性增加。 感染对患有炎症性肠病（IBD）的患者具有特别有害的影响， 引发疾病发作并增加结肠切除术的风险。据了解，IBD患者有10%的终身风险 与非IBD患者相比，患有CDI的患者复发率明显更高。 从机制上讲，复发性CDI被认为部分是由于提供胆汁的关键生物物种的丧失 转化活性，转化初级胆汁酸，作为促萌发信号，以C。difficile，to 已经显示出抑制发芽和抑制病原体的继发胆汁酸， 有机体此外，粪便微生物群移植（FMT）是难治性 CDI被认为部分地通过重建胆盐水解酶活性而起作用。目前尚不清楚的是， IBD患者复发CDI的风险增加，因为CDI研究明显缺乏IBD患者， 由于许多患者患有基线腹泻，迫切需要 除了传统的危险因素外， 流行病学暴露。通过个体化的风险预测，高风险患者将被更迅速地识别 早期给予适当治疗，预防IBD严重并发症，改善症状， 生活负担和生活质量。我们的总体目标是在早期识别有复发CDI风险的IBD患者， 疾病过程，并提供FMT治疗，不仅可以预防复发性CDI， 与CDI相关的后果。我们的中心假设是（1）临床、微生物和 代谢风险因素，特别是胆汁酸谱，在IBD患者中CDI复发， 经历了他们的第一次发作的CDI将允许早期识别高风险患者和（2）FMT 在IBD患者中首次发生CDI后进行，将是安全的，并将有效地重建胆汁 盐水解酶活性。拟议研究的理由是，与非IBD患者不同，许多IBD患者 患者存在胆汁酸吸收不良的风险，无论是由于持续的肠道炎症和腹泻，还是先前的 切除术考虑到IBD-CDI患者经常被排除在试验之外， 胆汁酸组成的改变解释了在这一人群中观察到的较高的CDI复发率， 提供更有针对性的治疗。最近微生物组研究的扩展现在使其成为可能 以确定详细的肠道细菌谱以及它们的代谢物。

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.