From cells to communities: The multi-scale impacts of bacteriophages in the gut microbiome

从细胞到群落：噬菌体对肠道微生物组的多尺度影响

• 批准号: 10714109
• 负责人: Andrew John Hryckowian
• 金额: $ 38.88万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10714109
• 关键词: Affect; Antibiotic Resistance; Antibiotics; Bacteria; Bacteriophages; Bacteroides thetaiotaomicron; Biological Models; Biology; Cells; Collection; Communities; Data; Development; Disease; Family; Feces; Foundations; Future; Gastrointestinal tract structure; Generations; Gnotobiotic; Goals; Health; Heterogeneity; Human; Human Microbiome; In Vitro; Infection; Knowledge; Methods; Mus; Phenotype; Play; Productivity; Recovery; Reproducibility; Research; Resistance; Role; Scientist; Systems Biology; Therapeutic; Work; bacterial genetics; gastrointestinal function; gut microbiome; host microbiome; human model; human pathogen; in vivo Model; insight; member; microbial community; microbiome; microbiome components; microbiome research; neglect; programs; tool

PROJECT SUMMARY/ABSTRACT Bacteriophages (phages) are the most abundant but least understood constituents of microbial communities. This is especially evident in the mammalian gastrointestinal tract, where a diverse community of up to 1012 phages are present per gram of stool. Though mounting evidence suggests the importance of phages in human microbiomes, methods of data generation and analysis routinely used in microbiome science neglect important aspects of phage biology. Furthermore, there is a lack of foundational knowledge and experimental tools for understanding phages and the roles they play in microbiomes. This lack of understanding is especially salient when the burgeoning antibiotic resistance crisis is considered: many important human pathogens are becoming increasingly resistant to our antibiotic arsenal. While a growing number of clinicians and scientists believe that “phage therapy” (the therapeutic application of phages to remove specific bacteria from host- associated microbiomes) will be important in our recovery from the antibiotic resistance crisis, phage therapy is inconsistently effective. This is largely due to an incomplete understanding of how phages impact their target bacteria, their off-target effects on other microbiome members, and their interactions with the mammalian host. Without such knowledge, important facets of phage-centric microbiome community dynamics will remain obscure and hinder robust and reproducible phage therapy applications. The goal of the proposed research program is to build a deep understanding of the roles that phages play in host-associated microbiomes and to eventually exploit this understanding to inform phage-based therapeutic strategies. We will work towards this goal using phage isolates, bacterial culture, bacterial genetics, gnotobiotic mice, and systems biology approaches. Using these tools, the proposed research program will build on my previous work with Bacteroides thetaiotaomicron-infecting phages and will focus on an isolate of the prominent crAss-like phage family, DAC15. We will determine how phenotypic heterogeneity in B. thetaiotaomicron influences resistance to DAC15, the specific interactions between DAC15 and B. thetaiotaomicron that lead to productive infection, and how DAC15 influences microbiome-host interactions. We will additionally build a collection of phages that infect other members of a model human gut microbiome to facilitate similar work with diverse bacteria and phages. Together, this work will be a much-needed foundation to understand the roles and identities of gut- resident phages, will build tools for sustained and powerful phage-centric study of the gut microbiome, and will inform the development of robust and reproducible phage therapy.

项目摘要/摘要 噬菌体（噬菌体）是微生物群落的最丰富但最不知情的构成。 这是哺乳动物胃肠道的尤其证据 每克粪便存在噬菌体。尽管越来越多的证据表明噬菌体的重要性 人类微生物组，数据生成和分析方法通常用于微生物组科学 噬菌体生物学的重要方面。此外，缺乏基础知识和实验性 了解噬菌体及其在微生物中扮演的角色的工具。缺乏理解尤其是 当考虑了堤抗生素抗性危机时，显着的是：许多重要的人类病原体是 越来越对我们的抗生素武库具有耐药性。而越来越多的临床医生和科学家 相信“噬菌体疗法”（噬菌体的治疗应用以从宿主中去除特定细菌 - 相关的微生物组）对于我们从抗生素耐药性危机中恢复至关重要，噬菌体治疗是 不一致的有效。这在很大程度上是由于对噬菌体如何影响其目标的不完全理解 细菌，它们对其他微生物组成员的脱靶影响及其与哺乳动物宿主的相互作用。 没有这样的知识，以噬菌体为中心的微生物组社区动态的重要方面仍然存在 模糊而阻碍了强大而可重复的噬菌体疗法。拟议研究的目标 程序是对噬菌体在宿主相关的微生物中的作用以及对 最终利用这种理解来告知基于噬菌体的理论策略。我们将努力 使用噬菌体分离株，细菌培养，细菌遗传学，gnotobiotic小鼠和系统生物学的目标 方法。使用这些工具，拟议的研究计划将基于我以前的工作 细菌性疫苗感染噬菌体，并将集中于突出的Crass样噬菌体的分离物 家庭，DAC15。我们将确定B. thetaiotaomicron中的表型异质性如何影响对 DAC15，DAC15与B. thetaiotaomicron之间的特定相互作用，导致生产性感染，以及 DAC15如何影响微生物组宿主相互作用。我们还将建立一个噬菌体的集合 感染模型人类肠道微生物组的其他成员，以促进与潜水细菌和 噬菌体。总之，这项工作将是一个急需的基础，以了解肠道的角色和身份 居民噬菌体将建立以持续且强大的以噬菌体为中心的肠道微生物组的工具，并将 告知鲁棒和可再现的噬菌体疗法的发展。