Understanding Clostridium difficile Infection in Patients with inflammatory Bowel Disease

了解炎症性肠病患者的艰难梭菌感染

• 批准号: 9892626
• 负责人: Jessica R. Allegretti
• 金额: $ 19.79万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9892626
• 关键词: Bile Acids; Bile fluid; Cholates; Clinical; Clinical Data; Clostridium difficile; Colectomy; Communicable Diseases; Data; Development; Diagnostic; Diarrhea; Disease; Early identification; Early treatment; Ecosystem; Epidemiology; Equilibrium; Evaluation; Excision; Feces; Flare; Foundations; Gastroenterology; Germination; Goals; Hydrolase; Incidence; Infection; Inflammation; Inflammatory Bowel Diseases; Intestines; Liquid Chromatography; Malabsorption Syndromes; Measures; Mentorship; Metabolic; Microbiology; Monitoring for Recurrence; Morbidity - disease rate; Nature; Organism; Pathogenesis; Patients; Pilot Projects; Population; Population Control; Quality of life; Recurrence; Recurrent disease; Refractory; Research; Risk; Risk Factors; Sampling; Secondary to; Severities; Signal Transduction; Symptoms; System; Training; Work; base; bile salts; commensal microbes; deoxycholate; enzyme activity; experience; fecal transplantation; gut bacteria; high risk; improved; insight; lifetime risk; metabolomics; microbial; microbiome research; patient population; predictive marker; prevent; profiles in patients; prospective; reconstitution; recurrent infection; safety and feasibility; symptomatic improvement; tandem mass spectrometry; targeted treatment; translational scientist

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.

项目概要 在过去的十年中，艰难梭菌感染 (CDI) 的发病率和严重程度有所增加，这些 感染对炎症性肠病（IBD）患者产生特别有害的影响 引起疾病发作并增加结肠切除术的风险。据了解，IBD 患者终生患病风险为 10% 与非 IBD 患者相比，患有 CDI 的患者的复发率明显更高。 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造成的。 转化活性，将初级胆汁酸（作为艰难梭菌的促发芽信号）转化为 次级胆汁酸已被证明可以抑制发芽和发病机制 生物。此外，粪便微生物群移植（FMT）是难治性肠道菌群治疗的重大突破 据信，CDI 的部分作用是通过重建胆汁盐水解酶活性来发挥作用。不知道的是为什么患者 鉴于 CDI 研究明显缺乏 IBD 患者，患有 IBD 的患者复发 CDI 的风险增加 事实证明，鉴于许多患者患有基线腹泻，患者群体具有挑战性。有一个迫切的需要 除传统方法外，还利用机械风险因素，更好地对 IBD-CDI 患者进行风险分层 流行病学暴露。通过个性化风险预测因素，可以更及时地识别高风险患者 及早给予适当的治疗，从而预防IBD的严重并发症，改善症状 负担和生活质量。我们的总体目标是尽早识别有复发性 CDI 风险的 IBD 患者 病程并提供 FMT 治疗，不仅可以预防 CDI 复发，还可以预防下游疾病 与 CDI 相关的后果。我们的中心假设是（1）临床、微生物和 患有以下疾病的 IBD 患者中 CDI 复发的代谢危险因素，特别是胆汁酸谱 经历第一次 CDI 发作将有助于更早识别高风险患者和 (2) FMT IBD 患者首次发生 CDI 后进行的治疗是安全的，并且可以有效地重建胆汁 盐水解酶活性。拟议研究的基本原理是，与非 IBD 患者不同，许多 IBD 患者 患者面临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之前 切除术。鉴于 IBD-CDI 患者经常被排除在试验之外，了解其程度 胆汁酸成分的改变解释了该人群中 CDI 复发率较高的关键 以提供更有针对性的治疗。最近微生物组研究的扩展使之成为可能 确定详细的肠道细菌特征及其代谢物。