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.

项目总结/摘要 生物多样性的生态学概念看似简单：什么生物存在，它们是如何存在的 发放高通量测序的出现使十多年的观察人类 微生物组研究;然而，这些研究经常建立相关性，但不是因果关系， 微生物多样性和健康。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， 我们的大部分认识来自有限的模式生物，它们不能很好地代表大部分生物。 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， 机械研究。我的研究项目的使命是了解我们的微生物群落 塑造人类的健康和生理。我们通过利用计算生物学和大数据来实现这一点， 实验室实验，包括gnotobiotic动物模型，以平衡还原论和生物相关性。的 在这个提议中的研究主题提出了关于宿主和微生物的界面的离散问题，但是是统一的 在他们使用自然发生的菌株变异与比较基因组学作为基因分析工具的方法中， 这是在超过300个基因组测序的细菌分离物的参考小组中发现的。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性合成药物？ 社区？这些联合体将作为理解复杂系统的组装和功能的工具 社区，并将转化应用作为人类粪便移植治疗的替代品。主题 II将专注于解卷积共享的宿主和胆汁酸（BA）的微生物代谢，这是一个家族， 这些化合物与感染性和自身免疫性疾病、癌症和代谢健康具有广泛的相关性。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， 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的来源。了解这些跨物种途径 将解决一个重要的问题：我们能否预测一个社区的代谢输出的基础上，其总和 零件？主题三解决了医学上的一个紧迫问题：微生物菌株变异如何有助于 药物反应的人际差异？我们现在正在研究一种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 数据证明脱靶菌株可变的抗菌作用，我们将描述细菌相互作用如何 与抗疟药一起使用会影响治疗效率。这些主题有一个共同的和统一的目标： 资源和宿主-微生物相互作用的基本理解导致翻译应用。