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

基本信息

批准号：
9805532
负责人：
Andrea Shin
金额：
$ 18.2万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-13 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9805532
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 fecal microbiome fecal microbiota gastrointestinal gut microbiome gut microbiota improved innovation metabolome metabolomics microbial microbiome microbiome analysis microbiome composition microbiome research microbiota microbiota transplantation multidisciplinary novel novel strategies patient oriented research predictive signature programs reduce symptoms research and development response sex tool

项目摘要

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.

项目概要肠道微生物组导致肠易激综合征 (IBS) 的精确机制症状尚不清楚。然而，人们认识到微生物代谢产物如短链脂肪酸（短链脂肪酸 SCFA）和胆汁酸对胃肠道生理有重要影响。从而加深了理解肠道微生物群、短链脂肪酸 SCFA 和胆汁酸之间关系的研究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- 的回复提交的第374章候选人提出了一个假设驱动的研究策略，以（1）识别粪便的变化与 IBS 中的 SCFA 和胆汁酸谱相关的微生物群，(2) 将 SCFA 确立为可行的 IBS 生物标志物，(3) 研究 IBS 中 SCFA 和胆汁酸之间的相互作用。该提案建立在初步数据是通过机构 KL2 的支持获得的。本研究策略的具体目标 (1) 确定与粪便相关的产生 SCFA 的细菌相对丰度的变化 SCFA 水平，通过菊粉发酵产生 SCFA 的标记（菊粉挑战后残留的粪便菊粉），便秘 IBS (IBS-C)、腹泻 IBS (IBS-D) 和对照中的结肠传输和 (2) 识别变化与粪便胆汁酸相关的胆汁酸脱羟基细菌的相对丰度， IBS-C、IBS-D 和对照中 SCFA 产生的标记物，并测试胆汁酸谱是否与以下因素相关： SCFA 生产的标记。为了实现这些目标，候选人将培养一批优秀的人才表型 IBS 患者和匹配对照将接受 (1) 粪便基线评估微生物群、粪便 SCFA、粪便胆汁酸和结肠运输，然后 (2) 重复评估粪便微生物群、粪便短链脂肪酸、粪便胆汁酸以及标准化饮食后粪便菊粉的测量补充菊粉进行干预。拟议的职业发展计划整合了深入的指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、通过拟议研究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和临床专业知识的独立研究人员微生物组科学（Nelson）和功能性胃肠道疾病（Camilleri）的转化研究；数据分析与生物统计学（Xu）；生物信息学（董）；和职业发展（Chalasani）将指导候选人的研究和职业发展。完善的制度基础设施，为青少年提供便利研究人员和实质性的机构承诺极大地加强了这一应用。结束时该计划，候选人将有能力成为一名独立的医师调查员新型微生物和代谢组学生物标志物以及 IBS 的新型干预措施。