Understanding Clostridium difficile Infection in Patients with inflammatory Bowel Disease

项目总结 在过去的十年中，艰难梭菌感染(CDI)的发病率和严重性有所增加，这些 感染对炎症性肠病(IBD)患者有特别有害的影响 引发疾病发作，增加结肠切除术的风险。众所周知，IBD患者有10%的终生风险 与非IBD患者相比，接受CDI的几率和复发率明显更高。 从机制上讲，复发性CDI被认为部分是由于提供胆汁的关键共生物种的丧失所致。 转化活动，将初级胆汁酸转化为艰难梭菌的促萌发信号，从而转化为 次级胆汁酸，已被证明对种子萌发和致病有抑制作用 有机体。此外，粪便微生物区系移植(FMT)是难治性疾病治疗的重大突破 CDI被认为部分是通过重建胆盐水解酶活性来发挥作用的。尚不清楚的是，为什么患者 IBD患者的CDI复发风险如此之高，因为CDI研究明显缺乏IBD患者 鉴于许多人患有基线腹泻，患者人数已被证明具有挑战性。有一个迫切的需要 在传统风险因素之外，利用机械性风险因素，更好地对IBD-CDI患者进行风险分层 流行病学暴露。通过个体化风险预测因素，高危患者将被更快地识别出来。 并及早给予适当治疗，从而预防IBD严重并发症，改善症状 负担和生活质量。我们的总体目标是在早期发现有复发CDI风险的IBD患者 病程和提供FMT治疗，不仅可以预防CDI的复发，而且还可以预防下游 与CDI相关的后果。我们的中心假设是(1)临床、微生物和 代谢危险因素，特别是胆汁酸谱，是IBD患者CDI复发的危险因素 经历了CDI的第一次发作将允许更早地识别高危患者和(2)FMT IBD患者在CDI首次发作后进行CDI是安全的，并能有效地重建胆汁。 盐水解酶活性。提出这项研究的理由是，与非IBD患者不同，许多IBD患者 患者有胆汁酸吸收不良的风险，要么是由于持续的肠炎和腹泻，要么是既往 切除手术。鉴于IBD-CDI患者通常被排除在试验之外，了解 胆汁酸成分的改变解释了CDI在该人群中的较高复发率是至关重要的 提供更有针对性的治疗。最近微生物组研究的扩展使这一点成为可能 以确定详细的肠道细菌图谱及其代谢物。

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.