Study of Pathway-Dependent Effects of Luminal Microbial Metabolites Including Short Chain Fatty Acids and Bile Acids in Irritable Bowel Syndrome Through Meta-omics Analysis of Fecal Specimens

通过粪便样本的元组学分析研究肠道微生物代谢物（包括短链脂肪酸和胆汁酸）对肠易激综合征的途径依赖性影响

基本信息

批准号：
10993051
负责人：
Andrea Shin
金额：
$ 11.66万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10993051
关键词：
Study Pathway Dependent Effects Luminal

项目摘要

PROJECT SUMMARY The gut microbiome and its metabolites including short chain fatty acids (SCFA) and bile acids (BA) regulate gastrointestinal (GI) physiology and carry immense potential as diagnostic and therapeutic tools for irritable bowel syndrome (IBS), a common and chronic disorder of gut-brain interaction (or functional GI disorder). However, the precise mechanisms by which the gut microbiome and its intermediaries contribute to IBS symptoms are unclear. A mechanistically-informed understanding of microbiome-metabolome-host interactions will be essential to developing novel and targeted strategies to enhance the care of individuals with IBS. This R03 application is submitted in response to PAR-19-365. In this application, the PI proposes a hypothesis-driven research strategy to (1) identify functional pathways (genes) associated with fecal SCFA and BA levels/profiles and physiological traits in IBS and control volunteers and (2) confirm functional pathway analysis through untargeted fecal metabolite profiling. This study will complement the objectives of the PI's K23 research study which are to (1) identify changes in fecal microbiota composition that are associated with SCFA and BA profiles in IBS through 16S rRNA gene sequencing and targeted metabolite analysis, (2) establish SCFA as actionable IBS biomarkers, and (3) investigate interactions between SCFA and BA in IBS. The specific aims of this R03 proposal are to (1) identify differentially abundant metabolic pathways (genes) of SCFA production and BA biotransformation in IBS (IBS with diarrhea [IBS-D], IBS with constipation [IBS-C]) and control volunteers through functional profiling of metagenomic sequencing data and (2) compare if/how the end-products of the genomically- encoded functions of key microbial taxa differ in IBS-D, IBS-C, and controls through untargeted metabolomics. To achieve these aims, the PI will leverage her existing K23 cohort of prospectively-recruited and well- phenotyped IBS and matched-control volunteers. As part of the K23-funded study, all participants have submitted 2-day stool samples using standardized collection procedures for assessment of the fecal microbiota, fecal SCFA, and fecal BA. Residual specimens are archived and available for further analysis as described in this R03 proposal. The strategies proposed in this application will complement the PI's current career development activities and benefit from the continued mentorship from a multidisciplinary K23 mentorship panel. Findings will guide the approach for a subsequent R01 by identifying which features of the fecal microbiota could be refined into practical microbiota-based tools (e.g. third generation, long-read technology) that could be tested in a larger IBS and control volunteer cohort. Alternatively, if the genomically-encoded metabolic potential cannot be confirmed by metabolomics, findings will inform the need measure gene expression (i.e. metatranscriptomics) or quantitative microbial profiles to investigate microbial effects on IBS pathophysiology in a subsequent R01. At the conclusion of the project, the PI will be ideally positioned to become an independent physician investigator studying novel microbial and metabolomics biomarkers and targeted strategies to restore health in IBS.

项目摘要肠道微生物组及其代谢产物，包括短链脂肪酸（SCFA）和胆汁酸（BA）调节胃肠道（GI）生理学，并具有巨大潜力作为诊断和治疗工具肠综合征（IBS），这是一种常见的肠脑相互作用（或功能性GI疾病）的常见和慢性疾病。但是，肠道微生物组及其中介对IBS的确切机制症状尚不清楚。对微生物组 - 代谢组主持人相互作用的机械信息理解对于制定新颖和有针对性的策略以增强IBS个人的护理至关重要。这 R03申请是根据Par-19-365提交的。在此应用中，PI提出了一个假设驱动的研究策略（1）识别与粪便SCFA和BA水平/轮廓相关的功能途径（基因） IBS和控制志愿者的生理特征以及（2）通过未靶向的粪便代谢物分析。这项研究将补充PI的K23研究的目标（1）确定与SCFA和BA剖面相关的粪便菌群组成的变化在IBS至16S rRNA基因测序和靶向代谢物分析中，（2）将SCFA建立为可起诉的 IBS生物标志物以及（3）研究IBS中SCFA和BA之间的相互作用。此R03的具体目的建议是（1）确定SCFA生产和BA的差异丰富的代谢途径（基因） IBS（具有腹泻[IBS-D]，具有便秘[IBS-C]的IBS）的生物转化和通过控制志愿者元基因组测序数据的功能分析和（2）比较是否/如何在基因组上的最终产物 IBS-D，IBS-C和控制通过未靶向的代谢组学在IBS-D，IBS-C中的编码功能不同。为了实现这些目标，PI将利用她现有的K23群体的前瞻性和良好的良好表型IBS和匹配控制的志愿者。作为K23资助的研究的一部分，所有参与者都提交了使用标准化收集程序评估粪便，粪便的2天粪便样品 SCFA和粪便ba。如本R03所述提议。本应用程序中提出的策略将补充PI当前的职业发展活动和受益于多学科K23指导小组的持续指导。调查结果会通过识别可以完善粪便菌群的哪些特征来指导随后的R01的方法进入基于微生物群的实用工具（例如第三代，长阅读技术），可以在较大的情况下进行测试 IBS和控制志愿者队列。另外，如果基因组编码的代谢潜力不能通过代谢组学确认，发现将为需求测量基因表达（即metatranscriptomics）提供信息或定量微生物谱，以研究随后的R01中对IBS病理生理学的微生物作用。在该项目的结论是，PI将成为理想的位置，成为一名独立的医师研究员研究新型的微生物和代谢组学生物标志物，并针对恢复IBS健康的策略。