Dietary strategies for rational manipulation of the gut microbiome in inflammatory bowel disease

合理调控炎症性肠病肠道微生物组的饮食策略

• 批准号: 10041384
• 负责人: Long H Nguyen
• 金额: $ 20.13万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10041384
• 关键词: Address; Affect; Area; Bacteria; Biochemical Pathway; Calories; Cataloging; Catalogs; Chemicals; Chronic; Clinical Trials Design; Collection; Communities; Complex; Control Groups; Crohn' s disease; Data; Development; Diet; Diet Modification; Dietary Assessment; Dietary Intervention; Dietary Sulfur; Dietary intake; Disease; Disease remission; Disulfides; Eating; Ecology; Enzymes; Epithelial; Epithelium; Equipment and supply inventories; Expert Opinion; Feces; Food; Funding; Gastrointestinal Diseases; Gastrointestinal tract structure; General Hospitals; Genes; Genetic Transcription; Genomics; Glare; Goals; Health Transition; Homeostasis; Human; Human Microbiome; Hydrogen Sulfide; Immune; Immune response; Individual; Inflammatory Bowel Diseases; Inflammatory Response; Informatics; Intervention; Lead; Leukocyte L1 Antigen Complex; Link; Literature; Manuals; Massachusetts; Measures; Mediating; Mentors; Metabolic; Metagenomics; Methodology; Methods; Microbe; Mucous body substance; Nutritional; Outcome; Pathogenesis; Pathway Analysis; Patients; Phylogenetic Analysis; Physicians; Population; Process; Processed Meats; Proteins; Randomized Controlled Trials; Recommendation; Relapse; Reporting; Research; Research Personnel; Research Project Grants; Resolution; Role; Sampling; Severity of illness; Sulfoxide; Sulfur; Sulfur Metabolism Pathway; Sulfur-Reducing Bacteria; Taxonomy; Testing; Therapeutic; Time; Training; Ulcerative Colitis; base; cohort; colorectal cancer risk; comparative; computer framework; design; distilled alcoholic beverage; disulfide bond; dysbiosis; food avoidance; genetic variant; gut bacteria; gut microbiome; gut microbiota; improved; indexing; inflammatory disease of the intestine; innovation; insight; large bowel Crohn' s disease; member; metabolomics; metagenome; metatranscriptomics; microbial; microbiome; microbiome research; multidisciplinary; novel; open source; treatment guidelines; treatment strategy

PROJECT ABSTRACT Despite now conclusive evidence that alterations in gut microbial communities precede and contribute to the etiopathogenesis of inflammatory bowel disease (IBD), the promise of therapeutic strategies to favorably influence this ecology is still largely unrealized. In sharp contrast to the widely understood importance of well- characterized taxonomic changes that occur during transitions from health to disease, comparatively little is known about the specific microbially-mediated processes that contribute to this loss of homeostasis. This disparity is largely due to the fact that even in well-studied communities, such as the human gastrointestinal (GI) tract, only a small fraction of the genomic content of a sample, the metagenome, can be functionally annotated. To address this glaring deficiency, we propose to develop a novel computational framework to infer a microbial gene’s metabolic function using quantitative metagenomics and sequence similarity network analysis. We will then apply this method to more comprehensively evaluate the role of sulfur-metabolizing bacteria in IBD. Sulfur- metabolizing bacteria are a phylogenetically diverse group of microbes defined by their ability to process dietary sulfur, often generating hydrogen sulfide (H2S) as a harmful byproduct. H2S in the GI tract can compromise gut barrier integrity by causing a breach in the protective mucus bilayer, a necessary precursor to intestinal inflammation. Our central hypothesis is that higher abundance of sulfur-metabolizing bacteria is associated with greater disease activity, and this community will prove amenable to selective depletion through food avoidance. Our overall objective is to comprehensively identify the bacterial species and strains participating in sulfur metabolism by first cataloging which of them encode known or novel sulfur metabolizing enzymes. We will then determine how these bacteria, their transcriptional activities, and the metabolites they generate influence disease severity in a cohort of densely sampled IBD patients who provided stool at up to 24 timepoints over one year along with short- and long-term assessments of dietary intake. Finally, we will develop and implement a rational dietary avoidance strategy designed to specifically target these bacteria and starve them of the foods that fuel this process, concluding with a randomized controlled trial testing this intervention in IBD patients. The scientific rationale to pursue this line of inquiry is rigorously supported by a body of literature demonstrating that: 1) both diet and the presence of select sulfur-metabolizing bacteria influence IBD severity and 2) preliminary efforts led by the candidate reveal that diet may modulate the relative abundance and functional activities of these bacteria. The approach requires innovative scaling solutions to apply homology-based methods to fully characterize an entire biochemical pathway—microbial sulfur metabolism—in humans. Anticipated outcomes from this multidisciplinary effort include the development of an open-sourced methodological framework for hypothesis- driven microbiome research and the creation of a patient-friendly IBD treatment based on dietary avoidance.

项目摘要 尽管现在有确凿的证据表明肠道微生物群落的变化先于并促成了 炎症性肠病（IBD）的发病机制，治疗策略的前景 与人们广泛理解的良好生态的重要性形成鲜明对比。 从健康到疾病的转变过程中发生的分类学变化的特征，相对较少 了解导致这种体内平衡丧失的特定微生物介导的过程。 差异很大程度上是由于即使在经过充分研究的群体中，例如人类胃肠道（GI） 在大范围内，只有样本基因组内容的一小部分（宏基因组）可以进行功能注释。 为了解决这一明显的缺陷，我们建议开发一种新颖的计算框架来推断微生物 我们将使用定量宏基因组学和序列相似性网络分析来分析基因的代谢功能。 然后应用该方法更全面地评价硫代谢菌在IBD中的作用。 代谢细菌是一组系统发育多样的微生物，其定义为它们处理饮食的能力 硫，通常会在胃肠道中产生有害副产品硫化氢 (H2S)，从而损害肠道。 通过引起保护性粘液双层的破裂来保持屏障的完整性，这是肠道的必要前体 我们的中心假设是，较高丰度的硫代谢细菌与炎症有关。 更大的疾病活动，并且这个社区将证明可以通过避免食物来选择性消耗。 我们的总体目标是全面鉴定参与硫的细菌种类和菌株 我们将首先对编码已知或新型硫代谢酶的酶进行分类。 确定这些细菌、它们的转录活性以及它们产生的代谢物如何影响疾病 一组密集采样的 IBD 患者在一年内多达 24 个时间点提供粪便的严重程度 最后，我们将制定并实施合理的饮食摄入量评估。 饮食避免策略旨在专门针对这些细菌并让它们缺乏提供能量的食物 这一过程的最后一项随机对照试验在 IBD 患者中测试了这种干预措施。 进行这一研究的基本原理得到了大量文献的严格支持，这些文献表明：1） 饮食和特定硫代谢细菌的存在会影响 IBD 的严重程度，2) 初步努力导致 候选人揭示饮食可以调节这些细菌的相对丰度和功能活动。 该方法需要创新的缩放解决方案来应用基于同源性的方法来充分表征 人类的整个生化途径——微生物硫代谢——的预期结果。 多学科的努力包括开发一个开源的假设方法框架 推动微生物组研究并创建基于饮食避免的患者友好型 IBD 治疗方法。