Fecal microbiota, short chain fatty acids, bile acids, and colonic transit in Irritable Bowel Syndrome

项目总结 肠道微生物群与肠易激综合征(IBS)的确切机制 症状尚不清楚。然而，人们认识到，微生物代谢产物，如短链脂肪酸 单链脂肪酸(SCFA)和胆汁酸对胃肠生理有重要影响。因此，加强了对 肠道微生物组、单链脂肪酸和胆汁酸之间的关系对于开发新的 有效治疗IBS的策略。此职业发展申请是根据PA-18的答复提交的- 374其中候选人提出假设驱动的研究策略以(1)识别粪便中的变化 与IBS中SCFA和胆汁酸特征相关的微生物区系，(2)将SCFA确立为可操作的IBS 生物标志物；(3)探讨胆汁酸与胆汁酸在IBS中的相互作用。这项建议的基础是 在机构KL2的支持下获得的初步数据。这一研究战略的具体目标 目的是(1)确定与粪便有关的产生单链脂肪酸的细菌的相对丰度的变化。 SCFA水平，菊粉发酵生产SCFA的标志物(菊粉攻击后残留的粪便菊粉)， IBS伴便秘(IBS-C)、IBS伴腹泻(IBS-D)和对照组的结肠运输，以及(2)识别移位 与粪便胆汁酸和胆汁酸相关的胆汁酸脱羟基细菌的相对丰富 IBS-C、IBS-D和对照中SCFA产生的标志物以及胆汁酸特征是否与 SCFA生产的标志物。为了实现这些目标，候选人将发展一批预期的井- 表型IBS患者和匹配的对照组，他们将接受(1)粪便基线评估 微生物区系、粪便SCFAs、粪便胆汁酸和结肠运输，然后(2)重复评估粪便 标准膳食后的微生物区系、粪便单链脂肪酸、粪便胆汁酸以及粪便菊粉的测定 菊粉补充剂的干预。拟议的职业发展计划包括深入指导 由资深科学家组成的多学科团队，在生物信息学和微生物组方面的高级课程 通过开展拟议研究的分析、体验式学习和高度支持性的研究 环境。导师团队，其中包括具有临床和医疗专业知识的独立调查人员 微生物组科学(Nelson)和功能性胃肠紊乱(Camilleri)的翻译研究；数据 分析和生物统计学(徐)、生物信息学(董)和职业发展(查拉萨尼)将指导 应聘者的研究和职业发展。为青少年提供便利的一流机构基础设施 调查人员和大量的机构承诺大大加强了这一应用。在……结束时 在该计划中，候选人将处于有利地位，成为一名独立的医生研究人员 IBS中新的微生物和代谢组学生物标志物和新的干预措施。

PROJECT SUMMARY The precise mechanisms by which the gut microbiome and contributes to irritable bowel syndrome (IBS) symptoms are unclear. However , it is recognized that microbial metabolites such as short chain fatty acids (SCFA) and bile acids exert important effects on gastrointestinal physiology. Thus, an enhanced understanding of the relationships between the gut microbiome, SCFAs, and bile acids will be essential to developing novel strategies for effective IBS treatment. This career development application is submitted on response to PA-18- 374 in which the candidate proposes a hypothesis-driven research strategy to (1) identify changes in the fecal microbiota that are associated with SCFA and bile acid profiles in IBS, (2) establish SCFAs as an actionable IBS biomarker, and (3) interrogate interactions between SCFA and bile acids in IBS. This proposal builds on preliminary data acquired through the support of an institutional KL2. The specific aims of this research strategy are to (1) identify shifts in the relative abundance of SCFA-producing bacteria that are associated with fecal SCFA levels, markers of SCFA production through inulin fermentation (residual fecal inulin after inulin challenge), and colonic transit in IBS with constipation (IBS-C), IBS with diarrhea (IBS-D), and controls and (2) identify shifts in the relative abundance of bile acid dehydroxylating bacteria that are associated with fecal bile acids and markers of SCFA production in IBS-C, IBS-D, and controls and test if bile acid profiles are associated with markers of SCFA production. To achieve these aims, the candidate will develop a prospective cohort of well- phenotyped IBS patients and matched-controls who will undergo (1) baseline assessments of their fecal microbiota, fecal SCFAs, fecal bile acids, and colonic transit, followed by (2) repeat assessments of fecal microbiota, fecal SCFAs, fecal bile acids, as well as measurement of fecal inulin after standardized dietary intervention with inulin supplementation. The proposed career development plan integrates in-depth mentoring from a multidisciplinary team of senior scientists, advanced coursework in bioinformatics and microbiome analysis, experiential learning through the conduct of the proposed research, and a highly supportive research environment. The mentorship team, which includes independent investigators with expertise in clinical and translational research in microbiome science (Nelson) and functional gastrointestinal disorders (Camilleri); data analysis and biostatistics (Xu); bioinformatics (Dong); and career development (Chalasani) will guide the candidate's research and career development. The superb institutional infrastructure for facilitating junior investigators and substantial institutional commitment greatly strengthen this application. At the conclusion of the program, the candidate will be well positioned to become an independent physician investigator studying novel microbial and metabolomics biomarkers and novel interventions in IBS.