A Systems Biology Approach Using Fecal Microbiota and Metabolomics to Identify Novel Subtypes in Irritable Bowel Syndrome.

项目摘要/摘要 候选人：艾伦·李博士，医学博士，胃肠病专家，曾接受过胃肠动力方面的高级培训， 研究重点是识别宿主-微生物相互作用的异常，以改善对肠易激的护理 综合征(IBS)。Lee博士的长期职业目标是识别新的IBS患者亚群，这些亚群有助于 对治疗的生物学反应和指导管理。拟议的K23指导职业发展 该奖项包括一个为期3年的培训、教学和研究活动计划，将为李博士提供 成为一名成功的独立调查员所需的技能和经验。 职业发展：李博士将在以下四个方面培养技能：1)与文化无关 研究IBS宿主-微生物相互作用的方法；2)先进的生物统计学方法研究纵向 数据集，包括混合模型或广义相加模型；3)基于实验室的翻译技术； 4)预测性分析，如机器学习算法。这些培训目标将直接有助于博士。 李的长期职业目标，并为他提交成功的R01申请做好准备。 研究背景：腹泻型肠易激综合征(IBS-D)的常用治疗方法对50%的≤患者有效。 此外，目前还没有方法来识别对不同治疗更有可能产生反应的患者。 目前管理IBS患者的范例围绕着识别和治疗主要的 症状复合体。然而，这是一个非常低效的模式，并导致患者和 医疗保健提供者。这项提议旨在确定系统生物学方法，即 结合微生物组和代谢组学数据以及详细的临床表型信息，可能 确定影响IBS-D治疗决策的新亚群。 研究计划：这个职业发展奖利用了一项正在进行的临床试验，比较了 不可吸收的抗生素利福昔明，饮食中可发酵的低聚糖，二糖， IBS-D患者的单糖和多元醇(FODMAP)以确定微生物群落的差异 治疗应答者与无应答者的结构和功能。特定目标1将识别粪便微生物 利福昔明或低FODMAP治疗反应的16S rRNA序列分析特征 节食。具体目标2将确定利福昔明或低FODMAP饮食治疗对粪便的影响 IBS-D患者的代谢组，包括短链脂肪酸和胆汁酸。将制定特定目标3 用于确定IBS-D患者对治疗反应的亚组的预测模型。我们还将确定风险因素 对利福昔明或低FODMAP饮食无反应。此提案的结果将通知两个未来的R01 建议验证这些发现并了解宿主-微生物 交互作用可能在IBS患者对不同疗法的反应中起中介作用。

PROJECT SUMMARY/ABSTRACT Candidate: Dr. Allen Lee, MD is a gastroenterologist with advanced training in gastrointestinal motility whose research focuses on identifying abnormalities in host-microbial interactions to improve care in irritable bowel syndrome (IBS). Dr. Lee’s long-term career goals are to identify novel subgroups of IBS patients which inform biological responses to therapies and guide management. The proposed K23 mentored career development award includes a 3-year plan for training, didactics, and research activities that will provide Dr. Lee with the necessary skills and experience to become a successful independent investigator. Career Development: Dr. Lee will develop skills in the following four areas: 1) culture-independent approaches to study host-microbial interactions in IBS; 2) advanced biostatistical methods to study longitudinal datasets, including mixed models or generalized additive models; 3) laboratory-based translational techniques; 4) predictive analytics, such as machine learning algorithms. These training goals will directly contribute to Dr. Lee’s long-term career goals and prepare him to submit a successful R01 application. Research Context: Common treatments in diarrhea-predominant IBS (IBS-D) are effective in ≤50% patients. Additionally, there are currently no methods to identify patients more likely to respond to different treatments. The current paradigm for managing IBS patients revolves around identifying and treating the predominant symptom complexes. However, this is a hugely inefficient model and leads to frustration for both patients and health care providers. This proposal seeks to determine whether a systems biology approach, which incorporates microbiome and metabolomics data along with detailed clinical phenotype information, may identify novel subgroups that inform treatment decisions in IBS-D. Research Plan: This career development award leverages an on-going clinical trial comparing the effects of a nonabsorbable antibiotic rifaximin with a diet low in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAP) in IBS-D patients to identify differences in microbial community structure and function in responders vs. non-responders to therapy. Specific Aim 1 will identify fecal microbial features by 16S rRNA sequence analysis characteristic of treatment response to rifaximin or a low FODMAP diet. Specific Aim 2 will determine how treatments with rifaximin or low FODMAP diet affect the fecal metabolome, including short chain fatty acids and bile acids, in IBS-D patients. Specific Aim 3 will develop predictive models to identify subsets of IBS-D patients responsive to treatment. We will also identify risk factors for non-response to either rifaximin or low FODMAP diet. Results from this proposal will inform two future R01 proposals to validate these findings as well as to understand the mechanisms by which host-microbial interactions may mediate response to different therapies in IBS.