Decoding Microbial Diversity in the Human Gut Microbiome

解码人类肠道微生物组中的微生物多样性

• 批准号: 10713170
• 负责人: Jordan Adam Bisanz
• 金额: $ 38.3万
• 依托单位: PENNSYLVANIA STATE UNIVERSITY, THE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10713170
• 关键词: Address; Affect; Animal Model; Anti-Bacterial Agents; Antimalarials; Autoimmune Diseases; Big Data; Bile Acids; Biological; Communicable Diseases; Communities; Complex; Computational Biology; Coupled; Data; Equilibrium; Family; Gastrointestinal tract structure; Genetic Variation; Genome; Genotype; Gnotobiotic; Goals; Health; High-Throughput Nucleotide Sequencing; Human; Human Microbiome; Libraries; Malignant Neoplasms; Medicine; Metabolic; Metabolic Pathway; Microbe; Mission; Oral Administration; Organism; Output; Pathway interactions; Pharmaceutical Preparations; Phenotype; Phylogenetic Analysis; Physiology; Research; Resources; Shapes; Sum; Therapeutic; Variant; bile acid metabolism; comparative genomics; fecal transplantation; gene discovery; gut microbiome; host microbiome; host-microbe interactions; laboratory experiment; microbial; microbial community; microbiome research; model organism; programs; rational design; response; tool; translational applications; transplantation therapy

PROJECT SUMMARY / ABSTRACT The ecological concept of diversity is deceptively simple: what organisms are present and how are they distributed. The advent of high-throughput sequencing enabled more than a decade of observational human microbiome studies; however, these studies frequently established correlation, but not causation, between microbial diversity and health. Through mechanistic research, I and others have shown the significance of strain variation, i.e. phenotypic and genotypic variation within a species, in host-microbiome interactions; however, most of our understanding comes from a limited range of model organisms which poorly represent the large diversity observed in the human gastrointestinal tract. Rather than view strain diversity as a limitation and caveat in microbiome research, my group takes a fundamentally different approach: we exploit it as a tool for mechanistic research. The mission of my research program is to understand how our microbial communities shape human health and physiology. We do this through leveraging computational biology and big data with wet lab experiments including gnotobiotic animal models to balance reductionism and biological relevance. The research themes in this proposal ask discrete questions about the interface of host and microbe but are unified in their approach of using naturally occurring strain variation coupled to comparative genomics as a tool for gene discovery in a reference panel of >300 genome sequenced bacterial isolates. Theme I will ask a fundamental question: can we leverage 10 years of publicly available data to rationally design functional synthetic communities? These consortia will act as both tools for understanding the assembly and function of complex communities, and will have translational applications as alternatives to human fecal transplant therapy. Theme II will focus on deconvoluting the shared host and microbial metabolism of bile acids (BAs), a family of compounds with broad relevance to infectious and autoimmune diseases, cancer, and metabolic health. Despite their importance, the microbial metabolic pathways of BA metabolism and their phylogenetic distribution are poorly characterized. Through comprehensive analysis of our strain library and synthetic communities derived thereof, we will determine the origins of biologically significant BAs. Understanding these trans-species pathways will address an important question: can we predict the metabolic output of a community based on the sum of its parts? Theme III addresses an urgent question in medicine: how does microbial strain-variation contribute to interpersonal variation in drug response? We are now working on a new class of important orally administered drugs which were not previously known to interact with the gut microbiome: antimalarials. Building on preliminary data demonstrating off-target strain-variable antibacterial effects, we will characterize how bacterial interactions with antimalarials affect therapeutic efficiency. These themes have a shared and unified goal: to generate both resources and fundamental understanding of host-microbe interactions leading to translational applications.

项目概要/摘要 多样性的生态概念看似简单：存在哪些生物体以及它们如何存在 分布式。高通量测序的出现使十多年来的人类观察 微生物组研究；然而，这些研究经常建立相关性，而不是因果关系 微生物多样性与健康。通过机理研究，我和其他人已经证明了应变的重要性 宿主-微生物组相互作用中的变异，即物种内的表型和基因型变异；然而， 我们的大部分理解来自于有限范围的模式生物，它们不能代表大量的生物体。 在人类胃肠道中观察到的多样性。而不是将菌株多样性视为限制和警告 在微生物组研究中，我的团队采取了一种根本不同的方法：我们将其作为一种工具 机理研究。我的研究计划的任务是了解我们的微生物群落如何 塑造人类健康和生理。我们通过利用计算生物学和大数据来做到这一点 实验室实验包括知生动物模型，以平衡还原论和生物学相关性。这 该提案中的研究主题提出了有关宿主和微生物界面的离散问题，但又是统一的 他们使用自然发生的菌株变异与比较基因组学作为基因工具 在超过 300 个基因组测序细菌分离株的参考小组中发现。主题我会问一个基本的 问题：我们能否利用10年的公开数据来合理设计功能合成 社区？这些联盟将充当理解复杂组件的组装和功能的工具。 社区，并将具有转化应用作为人类粪便移植疗法的替代方案。主题 II 将重点关注胆汁酸 (BA) 的共享宿主和微生物代谢，胆汁酸是一个家族 与传染病和自身免疫性疾病、癌症和代谢健康具有广泛相关性的化合物。尽管 它们的重要性、BA代谢的微生物代谢途径及其系统发育分布是 特征不佳。通过综合分析我们的菌株库和合成群落得出 因此，我们将确定具有生物学意义的 BA 的起源。了解这些跨物种途径 将解决一个重要问题：我们能否根据一个群落的代谢产物的总和来预测其代谢输出？ 部分？主题 III 解决了医学中的一个紧迫问题：微生物菌株变异如何促进 药物反应的人际差异？我们现在正在研究一类新的重要的口服药物 以前不知道与肠道微生物组相互作用的药物：抗疟药。在初步基础上 数据证明了脱靶菌株变异的抗菌作用，我们将描述细菌如何相互作用 与抗疟药一起使用会影响治疗效果。这些主题有一个共同且统一的目标： 对宿主-微生物相互作用的资源和基本理解导致转化应用。