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

项目摘要 尽管现在有确凿证据表明，肠道微生物群落的变化先于并促进了 炎症性肠病(IBD)的发病机制，治疗策略的承诺有利 对这种生态的影响在很大程度上仍未实现。与人们普遍理解的良好- 具有从健康到疾病转变过程中发生的分类学变化的特征，相对较少的是 已知导致这种内环境平衡丧失的特定微生物介导的过程。这 差异在很大程度上是由于这样一个事实，即使在研究得很好的社区，如人类胃肠道(GI) 在文库中，只有一小部分样本的基因组内容，即元基因组组，可以被功能注释。 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 基因代谢功能的定量元基因组学和序列相似性网络分析。我们会 然后应用该方法更全面地评价硫代谢细菌在IBD中的作用。硫磺- 代谢细菌是一组在系统发育上不同的微生物，由它们处理食物的能力来定义 硫磺，通常会产生有害的副产品硫化氢(H2S)。胃肠道中的硫化氢会损害肠道 通过导致保护性粘液双层的破裂来保护屏障的完整性，粘液双层是肠道的必要前体 发炎。我们的中心假设是，硫代谢细菌的丰度较高与 更多的疾病活动，这一群体将被证明通过避免食物来选择性地耗尽。 我们的总体目标是全面鉴定参与硫磺的细菌种类和菌株 通过首先对它们中的哪一种编码已知或新的硫代谢酶来进行代谢。到时候我们会的 确定这些细菌、它们的转录活动和它们产生的代谢物如何影响疾病 一年中在24个时间点提供粪便的密集抽样IBD患者队列的严重程度 以及对饮食摄入量的短期和长期评估。最后，我们将开发并实现一个Rational 饮食避免策略，专门针对这些细菌，并使他们饥饿的食物，燃料 这一过程以一项在IBD患者中测试这种干预措施的随机对照试验结束。科学的 进行这一调查的理由得到了大量文献的严格支持，这些文献表明：1)两者都 饮食和精选的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 由候选人揭示，饮食可能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的方法来充分表征 整个生化途径--微生物的硫代谢--在人类体内。由此产生的预期结果 多学科的努力包括为假设开发一个开源的方法论框架-- 推动微生物组研究和创造一种基于饮食避免的患者友好的IBD治疗方法。

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.