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Bacterioph00ages for gut health

Bacteriaph00ages 有益于肠道健康

基本信息

批准号：
BB/W015706/1
负责人：
Evelien Adriaenssens
金额：
$ 78.3万
依托单位：
Quadram Institute
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2022
资助国家：
英国
起止时间：
2022 至无数据
项目状态：
未结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FW015706%2F1
关键词：
Bacterioph00ages gut health

项目摘要

Bacteriophages (phages), viruses that specifically target and infect bacteria, are a major component of the gut microbiome, but they are not as well-studied as their bacterial hosts. Recent high-throughput sequencing approaches have revealed tens of thousands of different phage species in the healthy gut. These phages continuously interact with each other and their bacterial hosts, but we have very limited information on how they interact with the cells of the human gut. Previous studies on individual bacteriophages raised the possibility that the gut epithelium can act as a sink for bacteriophages, while other studies showed a range of gut epithelial responses differing from phage to phage. What we currently have no information on, is how phage communities as a whole interact with the human gut epithelial environment. In this project, we will take advantage of the availability of gut microbiome studies and human biopsy-derived intestinal organoid-based cell models at our Institute to investigate phage-gut interactions with the epithelium. The gut microbiome studies currently running at the Quadram Institute Bioscience (QIB), the PEARL study (investigating the role of the gut microbiome in pregnancy and early life) and the MOTION study (investigating the role of the gut microbiome in older adults), will allow us to use microbiome sequencing information and the associated faecal samples to generate natural human gut phage communities. These communities will then be tested on biopsy-derived culture models of human gut cells, called organoids, that mimic the gut environment. More specifically, we will combine the phage communities with the human gut organoids and monitor the changes over time for both the phage communities and the human gut cells. Using high-throughput sequencing and qPCR, we will quantify the changes in phage community composition and structural protein content, and track phages across the cell monolayer. We will investigate the cellular response by looking at markers of gut barrier function. In parallel, we will develop a phage biobank of cultured isolates that can be used in the future for the biocontrol of gut-associated bacterial pathogens or for the modulation of the gut microbiome. Informed by the data on the phage-gut interactions, we will assemble cocktails of different phages that are most suited for use in the human gut, and test these on our gut organoid system. This study will increase our functional understanding of bacteriophages as part of a healthy gut microbiome. Through the identification of the phage types that are most adapted to the gut environment and the response of the gut epithelium, we will be able to form a more comprehensive picture of phage-gut interactions. In addition, the findings will allow us to make better informed decisions on the appropriateness of specific phage types for potential application as therapeutics.

噬菌体（Bacteriophage，简称BPV）是一种专门针对和感染细菌的病毒，是肠道微生物组的主要组成部分，但它们的研究不如细菌宿主。最近的高通量测序方法已经揭示了健康肠道中成千上万种不同的噬菌体种类。这些细菌不断相互作用，并与它们的细菌宿主相互作用，但我们对它们如何与人类肠道细胞相互作用的信息非常有限。先前对单个噬菌体的研究提出了肠道上皮可以作为噬菌体的水槽的可能性，而其他研究显示了一系列噬菌体与噬菌体不同的肠道上皮反应。我们目前没有关于噬菌体群落作为一个整体如何与人类肠道上皮环境相互作用的信息。在这个项目中，我们将利用我们研究所的肠道微生物组研究和人类活检衍生的肠道类器官细胞模型的可用性来研究噬菌体-肠道与上皮的相互作用。目前在Quadram Institute Bioscience（QIB）进行的肠道微生物组研究，PEARL研究（调查肠道微生物组在妊娠和早期生活中的作用）和MOTION研究（调查肠道微生物组在老年人中的作用），将使我们能够使用微生物组测序信息和相关的粪便样本来生成天然的人类肠道噬菌体群落。然后，这些社区将在模拟肠道环境的人类肠道细胞（称为类器官）的活检衍生培养模型上进行测试。更具体地说，我们将联合收割机结合噬菌体群落与人类肠道类器官，并监测噬菌体群落和人类肠道细胞随时间的变化。使用高通量测序和qPCR，我们将量化噬菌体群落组成和结构蛋白含量的变化，并跟踪整个细胞单层的噬菌体。我们将通过观察肠道屏障功能的标志物来研究细胞反应。同时，我们将开发一个培养分离株的噬菌体生物库，将来可用于肠道相关细菌病原体的生物防治或肠道微生物组的调节。根据噬菌体-肠道相互作用的数据，我们将组装最适合在人类肠道中使用的不同微生物的鸡尾酒，并在我们的肠道类器官系统上测试这些。这项研究将增加我们对噬菌体作为健康肠道微生物组一部分的功能性理解。通过鉴定最适应肠道环境的噬菌体类型和肠道上皮的反应，我们将能够形成更全面的噬菌体-肠道相互作用的图景。此外，这些发现将使我们能够对特定噬菌体类型作为治疗剂的潜在应用的适当性做出更明智的决定。