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

• 批准号: 10599335
• 负责人: Andrea Shin
• 金额: --
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10599335
• 关键词: 16S ribosomal RNA sequencing; Abdominal Pain; Acetates; Bacteria; Bacteroides; Bile Acids; Biological Markers; Butyrates; Carbohydrates; Caring; Chronic; Chronic Disease; Cohort Studies; Collection; Colon; Complement; Constipation; Consumption; Data; Diagnosis; Diagnostic; Diarrhea; Diet; Dietary Polysaccharide; Digestion; Disease; Enzymes; Esthesia; Evaluation; Fatty Acids; Feces; Fermentation; Frequencies; Functional Gastrointestinal Disorders; Functional disorder; Funding; Future; Gastrointestinal Diseases; Gastrointestinal Physiology; Gene Expression; Generations; Genes; Genetic; Genomics; Goals; Habits; Health; Health Promotion; Hydrolase; Individual; Intervention; Intestines; Irritable Bowel Syndrome; Link; Measurable; Measures; Mediating; Mentorship; Metabolic; Metabolic Biotransformation; Metabolic Pathway; Metagenomics; Modeling; Mucins; Mucous Membrane; Mucous body substance; Participant; Pathway Analysis; Pathway interactions; Patients; Peripheral; Phenotype; Physicians; Physiological; Physiology; Polysaccharides; Positioning Attribute; Predisposition; Procedures; Production; Propionates; Prospective cohort; Race; Recurrence; Reporting; Research; Research Personnel; Residual state; Role; Specimen; Standardization; Stress; Symptoms; Technology; Testing; Therapeutic; Time; United States; Volatile Fatty Acids; bile salts; biological specimen archives; career development; cell injury; cell motility; clinical phenotype; cohort; colon microbiota; dehydroxylation; dietary; disorders of gut-brain interaction; dysbiosis; fatty acid metabolism; fecal microbiota; gastrointestinal; gastrointestinal epithelium; gastrointestinal function; gut microbiome; gut microbiota; gut-brain axis; host microbiota; insight; laxative; metabolome; metabolomics; metagenomic sequencing; metatranscriptomics; microbial; microbial community; microbiome; microbiota; multidisciplinary; multiple omics; novel; novel marker; operational taxonomic units; point-of-care diagnostics; recruit; research study; response; stool sample; tool; trait; volunteer

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.

项目概要 肠道微生物组及其代谢物包括短链脂肪酸 (SCFA) 和胆汁酸 (BA) 调节 胃肠道 (GI) 生理学，作为烦躁症的诊断和治疗工具具有巨大的潜力 肠综合症（IBS），一种常见的慢性肠-脑相互作用疾病（或功能性胃肠道疾病）。 然而，肠道微生物组及其中间体导致 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理解 对于制定新颖且有针对性的策略来加强 IBS 患者的护理至关重要。这 R03 申请是为了响应 PAR-19-365 而提交的。在此应用中，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/概况相关的功能途径（基因） IBS 和对照志愿者的生理特征和（2）通过以下方式确认功能途径分析： 非目标粪便代谢物分析。这项研究将补充 PI K23 研究的目标 其目的是 (1) 识别与 SCFA 和 BA 谱相关的粪便微生物群组成的变化 通过 16S rRNA 基因测序和靶向代谢物分析来治疗 IBS，(2) 将 SCFA 确立为可操作的 IBS 生物标志物，(3) 研究 IBS 中 SCFA 和 BA 之间的相互作用。 R03的具体目标 建议 (1) 确定 SCFA 生产和 BA 的差异丰度代谢途径（基因） IBS（腹泻 IBS [IBS-D]、便秘 IBS [IBS-C]）和对照志愿者的生物转化 宏基因组测序数据的功能分析，以及（2）比较基因组的最终产物是否/如何 关键微生物类群的编码功能在 IBS-D、IBS-C 中有所不同，并且通过非靶向代谢组学进行控制。 为了实现这些目标，PI 将利用她现有的 K23 队列，由未来招募的优秀人才组成。 表型 IBS 和匹配对照志愿者。作为 K23 资助的研究的一部分，所有参与者都提交了 使用标准化采集程序采集 2 天粪便样本，以评估粪便微生物群、粪便 SCFA 和粪便 BA。剩余样本已存档并可用于本 R03 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 指导小组的持续指导。调查结果将 通过确定粪便微生物群的哪些特征可以改进来指导后续 R01 的方法 转化为实用的基于微生物群的工具（例如第三代长读技术），可以在更大的环境中进行测试 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 经代谢组学证实，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 R01 中研究微生物对 IBS 病理生理学的影响。在 项目结束后，PI 将成为一名独立的医师调查员 研究新型微生物和代谢组学生物标志物以及恢复 IBS 健康的针对性策略。