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

肠易激综合症中的粪便微生物群、短链脂肪酸、胆汁酸和结肠运输

• 批准号: 10408145
• 负责人: Andrea Shin
• 金额: $ 18.07万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-13 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10408145
• 关键词: Abdomen; Abdominal Pain; Acetates; Active Learning; Affect; Antibiotics; Bacteria; Bicarbonates; Bile Acids; Bioinformatics; Biological Markers; Biometry; Body mass index; Brain; Butyrates; Carbohydrates; Characteristics; Clinical Research; Clostridium; Complex; Constipation; Data; Data Analyses; Development; Development Plans; Diagnostic; Diarrhea; Diet; Dietary Intervention; Duodenum; Economic Burden; Environment; Epithelial; Etiology; Feces; Fermentation; Functional Gastrointestinal Disorders; Functional disorder; Future; Gastrointestinal Diseases; Gastrointestinal Physiology; Goals; Habits; Heterogeneity; Immune; Infrastructure; Intervention; Intestines; Inulin; Ions; Irritable Bowel Syndrome; Knowledge; Lead; Liquid substance; Malabsorption Syndromes; Measurement; Measures; Mentors; Mentorship; Morbidity - disease rate; Patients; Pattern; Pharmaceutical Preparations; Phenotype; Physicians; Positioning Attribute; Prevalence; Production; Propionates; Prospective cohort; Recurrence; Research; Research Personnel; Residual state; Role; Senior Scientist; Serotonin Receptors 5-HT-3; Standardization; Supplementation; Symptoms; Testing; Therapeutic; Time; Translational Research; Visceral; Volatile Fatty Acids; base; career; career development; clinical biomarkers; dietary; fecal microbiome; fecal microbiota; gastrointestinal; gut microbiome; gut microbiota; improved; innovation; metabolome; metabolomics; microbial; microbiome; microbiome analysis; microbiome composition; microbiome research; microbiome signature; microbiota; microbiota transplantation; multidisciplinary; novel; novel strategies; patient oriented research; predictive signature; programs; reduce symptoms; research and development; response; sex; tool

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.

项目摘要 肠道微生物组并导致肠易激综合征（IBS）的确切机制 症状尚不清楚。但是，人们认识到微生物代谢物，例如短链脂肪酸 （SCFA）和胆汁酸对胃肠道生理产生重要影响。因此，增强的理解 肠道微生物组，SCFA和胆汁酸之间的关系对于发展新颖 有效IBS治疗的策略。该职业发展应用程序是对PA-18-的回应提交的 374候选人提出了一种假设驱动的研究策略以（1）确定粪便的变化 与IBS中的SCFA和胆汁酸轮廓相关的微生物群，（2）将SCFA建立为可行的IBS 生物标志物和（3）IBS中SCFA和胆汁酸之间的相互作用。该提议建立在 通过机构KL2的支持获得了初步数据。该研究策略的具体目的 要（1）识别与粪便相关的产生SCFA的相对丰度的变化 SCFA水平，通过菊粉发酵产生SCFA的标志物（杀菌蛋白挑战后残留的粪便）， 具有便秘（IBS-C），具有腹泻（IBS-D）的IBS的IBS中的结肠传输和对照组，以及（2）识别偏移 在相对丰富的胆汁酸脱羟基化细菌中，与粪便胆汁酸和 IBS-C，IBS-D和对照组中SCFA产生的标志物，并测试胆汁酸轮廓是否与 SCFA生产的标记。为了实现这些目标，候选人将建立一个预期的人群 表型IBS患者和匹配的控制者将接受（1）基线评估其粪便 微生物群，粪便SCFA，粪便胆汁酸和结肠传输，然后（2）重复评估粪便 菌群，粪便SCFA，粪便胆汁酸以及标准化饮食后的粪便中的测量 补充尿素的干预。拟议的职业发展计划集成了深入的指导 来自高级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，通过拟议研究的进行体验式学习以及高度支持性的研究 环境。指导团队，包括具有临床专业知识的独立调查员 微生物组科学（Nelson）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。促进初级的精湛机构基础设施 调查人员和实质性的机构承诺极大地增强了这一应用。结束 该计划，候选人将有能力成为一名独立医师研究人员 新型微生物和代谢组学生物标志物以及IBS中的新干预措施。