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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），胃肠道（GI）生理学和携带作为诊断和治疗工具的巨大潜力，易激惹肠综合征（IBS），一种常见的慢性肠-脑相互作用障碍（或功能性GI障碍）。然而，肠道微生物组及其中介物对IBS的确切机制症状尚不清楚。对微生物组-代谢组-宿主相互作用的机械信息理解将是必不可少的发展新的和有针对性的战略，以加强个人与IBS的照顾。这 R 03申请应PAR-19-365提交。在本申请中，PI提出了一个假设驱动的研究策略：（1）确定与粪便SCFA和BA水平/特征相关的功能途径（基因）和生理特征，以及（2）通过以下方式确认功能途径分析：非靶向粪便代谢物分析。本研究将补充PI K23研究的目的其是（1）鉴定与SCFA和BA谱相关的粪便微生物群组成的变化通过16 S rRNA基因测序和靶向代谢物分析，（2）确定SCFA为可行 IBS生物标志物，和（3）研究IBS中SCFA和BA之间的相互作用。本R 03的具体目标建议是（1）鉴定SCFA产生和BA产生的差异丰富的代谢途径（基因 IBS（IBS伴腹泻[IBS-D]，IBS伴便秘[IBS-C]）和对照志愿者中的生物转化，宏基因组测序数据的功能概况分析和（2）比较基因组- 通过非靶向代谢组学，关键微生物分类群的编码功能在IBS-D、IBS-C和对照中不同。为了实现这些目标，PI将利用其现有的K23队列，这些队列是前瞻性招募的，表型IBS和匹配的对照志愿者。作为K23资助研究的一部分，所有参与者都提交了 2-使用标准化采集程序采集日粪便样本，以评估粪便微生物群、粪便 SCFA和粪便BA。剩余样本存档并可用于本R 03中所述的进一步分析提议本申请中提出的策略将补充PI当前的职业发展活动，并受益于多学科K23导师小组的持续指导。发现将通过确定粪便微生物群的哪些特征可以细化，为后续R 01提供指导转化为基于微生物的实用工具（例如第三代，长读技术），可以在更大的 IBS和对照志愿者队列。或者，如果基因组编码的代谢潜力不能被代谢组学证实，研究结果将告知需要测量基因表达（即元转录组学）或定量微生物谱，以在随后的R 01中研究微生物对IBS病理生理学的影响。在项目结束后，PI将理想地成为独立的医生研究者研究新的微生物和代谢组学生物标志物和有针对性的策略，以恢复IBS的健康。