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

项目摘要 尽管现在有确凿的证据表明，肠道微生物群落的改变先于并有助于 炎症性肠病（IBD）的发病机制，治疗策略的承诺， 这种生态的影响在很大程度上仍未实现。与广泛理解的良好的重要性形成鲜明对比- 在从健康到疾病的转变过程中发生的特征性分类变化， 已知特定的微生物介导的过程，有助于这种失去稳态。这 差异主要是由于这样一个事实，即使在充分研究的社区，如人类胃肠道（GI） tract中，只有一小部分的样品的基因组内容，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的计算框架来推断微生物 利用定量宏基因组学和序列相似性网络分析技术研究基因的代谢功能。我们将 应用该方法更全面地评价硫代谢细菌在IBD中的作用。硫磺- 代谢细菌是一组遗传多样性的微生物，由它们处理膳食的能力来定义。 硫，通常会产生硫化氢（H2S）作为有害的副产品。胃肠道中的H2S可损害肠道 屏障的完整性，造成破坏的保护性粘液双层，一个必要的前体，肠 炎症我们的中心假设是，高丰度的硫代谢细菌与 更大的疾病活动，这个社区将被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 通过首先分类它们中的哪些编码已知的或新的硫代谢酶来确定硫代谢。然后我们将 确定这些细菌，它们的转录活性和它们产生的代谢产物如何影响疾病 在一年内最多24个时间点提供粪便的密集采样IBD患者队列中的严重程度 沿着对饮食摄入的短期和长期评估。最后，我们将制定和实施一个合理的 饮食回避策略旨在专门针对这些细菌，并使它们挨饿， 这一过程，结束了随机对照试验测试这种干预IBD患者。科学 追求这一调查路线的基本原理得到了大量文献的严格支持，这些文献表明：1） 饮食和选择硫代谢细菌的存在影响IBD的严重程度和2）初步的努力导致 候选人的研究表明，饮食可以调节这些细菌的相对丰度和功能活性。 该方法需要创新的缩放解决方案，以应用基于同源性的方法来充分表征 整个生化途径-微生物硫代谢-在人类。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， 驱动的微生物组研究和创建基于饮食避免的患者友好型IBD治疗。

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.