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

项目摘要 肠道微生物组导致肠易激综合征（IBS）的确切机制 症状尚不清楚。然而，认识到微生物代谢物如短链脂肪酸 （SCFA）和胆汁酸对胃肠道生理发挥重要作用。因此， 肠道微生物组，SCFAs和胆汁酸之间的关系对于开发新的 有效的IBS治疗策略。此职业发展申请是根据PA-18提交的- 374其中候选人提出假设驱动的研究策略，以（1）确定粪便中的变化 微生物群与SCFA和IBS中的胆汁酸谱相关，（2）将SCFA建立为可操作的IBS 生物标志物，和（3）询问IBS中SCFA和胆汁酸之间的相互作用。该提案基于 通过机构KL 2的支持获得的初步数据。本研究战略的具体目标 是（1）确定与粪便相关的SCFA产生细菌的相对丰度的变化， SCFA水平，通过菊粉发酵产生SCFA的标志物（菊粉激发后残留的粪便菊粉）， IBS伴便秘（IBS-C）、IBS伴腹泻（IBS-D）和对照组的结肠转运和（2）确定变化 与粪便胆汁酸相关的胆汁酸脱羟细菌的相对丰度， IBS-C、IBS-D和对照中SCFA产生的标志物，并检测胆汁酸谱是否与 SCFA生产的标志物。为了实现这些目标，候选人将发展一个良好的前瞻性队列- 表型IBS患者和匹配的对照者将进行（1）基线评估其粪便 （2）重复评估粪便中的微生物、粪便SCFA、粪便胆汁酸和结肠转运， 在标准化饮食后，测量微生物群、粪便SCFA、粪便胆汁酸以及粪便菊粉。 菊粉补充干预。拟议的职业发展计划纳入了深入的辅导 来自资深科学家的多学科团队，生物信息学和微生物组的高级课程 分析，通过建议的研究进行经验学习，并高度支持研究 环境导师团队，其中包括独立的研究人员与专业知识，在临床和 微生物组科学（纳尔逊）和功能性胃肠道疾病（Camilleri）的转化研究;数据 分析和生物统计学（Xu）;生物信息学（Dong）;和职业发展（Chalasani）将指导 候选人的研究和职业发展。一流的机构基础设施，以促进初级 调查人员和大量机构承诺大大加强了这一应用。结束时 该计划，候选人将很好地定位，成为一个独立的医生研究员学习 新的微生物和代谢组学生物标志物以及新的IBS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.