Host mechanisms of gut colonization by commensal bacteria that affect lifespan

影响寿命的共生细菌肠道定植的宿主机制

• 批准号: 10522056
• 负责人: William Basil Ludington
• 金额: $ 40.38万
• 依托单位: CARNEGIE INSTITUTION OF WASHINGTON, D.C.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-15 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10522056
• 关键词: Acetobacter; Address; Adhesions; Affect; Aging; Bacteria; Bacterial Adhesion; Binding; Biological Assay; Biology; Candidate Disease Gene; Cells; Chemicals; Communities; Complement; Complementary DNA; Drosophila genus; Drosophila melanogaster; Duct (organ) structure; Engineering; Enhancers; Environment; Enzymes; Extracellular Matrix; Foundations; Gene Expression; Gene-Modified; Genes; Genetic; Goals; Health; Health Benefit; Homologous Gene; Human; Human Microbiome; Island; Kinetics; Knock-out; Knowledge; Lactobacillus; Lactobacillus plantarum; Link; Location; Longevity; Maintenance; Mediating; Microbe; Molecular; Mucins; Mucous body substance; Physiology; Polysaccharides; Population; Positioning Attribute; Primitive foregut structure; Probiotics; Proteins; RNA Interference; Regulation; Research; Rest; Role; Serine; Site; Specificity; Testing; Time; Tissues; Transferase; Work; assay development; cell type; commensal bacteria; cost; experimental study; fly; genetic resource; glycosylation; glycosyltransferase; gut bacteria; gut colonization; human disease; microbiome composition; microbiota; mutant; programs; recruit; single-cell RNA sequencing; stomach cardia; symbiont; tool; transcriptome sequencing; translational potential; uptake

Project Summary Gut bacteria associate with host tissues and alter host physiology, impacting lifespan and aging. Some types of bacteria, such as Lactobacilli, benefit health while others degrade it. A key gap in our knowledge is how the host constructs microenvironments that coordinate colonization by specific bacteria. In particular, which host cells (Aim 1), genes, and molecules (Aim 2) promote colonization by specific bacteria? As an important step forward, this proposal aims to investigate host mechanisms of bacterial colonization in Drosophila melanogaster using recently isolated bacterial strains of Lactobacillus plantarum and Acetobacter from a wild D. melanogaster, which are found to colonize a tightly-defined physical space in the fly gut. L. plantarum, is a probiotic in humans, and the fly provides unique and powerful genetic resources to study homologs of human disease genes. This proposal harnesses several unique assays developed to identify host mechanisms that mediate commensal strain specificity, including the host cell types, genes and molecules that recruit and maintain commensal bacteria. The central hypothesis is that specific cell types in the fly foregut produce a "commensal niche": a specialized chemical and physical microenvironment that facilitates adhesion and proliferation of specific bacteria that may benefit the host. The proposal aims to (i) use single cell RNA sequencing to identify the specific host cell types and genes that create this specialized microenvironment. This will enable the use of Drosophila genetics to (ii) probe the mechanisms of host tissue maintainance through cell turnover and localized secretion of a defined extracellular matrix. As a critical test of the hypothesis, the proposal will examine the L. plantarum population kinetics that enable its association with the commensal niche. By studying commensal niche construction in the Drosophila gut, this research will establish a new paradigm that enables interrogation of the conserved molecular and cellular interactions between hosts and their commensals that influence host health. The proposal holds translational potential for developing tools to drive these beneficial interactions.

项目概要 肠道细菌与宿主组织相关并改变宿主生理机能，影响寿命和衰老。 某些类型的细菌（例如乳酸杆菌）有益于健康，而另一些细菌则会损害健康。一个关键差距 我们的知识是宿主如何构建协调定殖的微环境 特定细菌。特别是，哪些宿主细胞（目标 1）、基因和分子（目标 2）促进 特定细菌定植？作为向前迈出的重要一步，该提案旨在调查 使用最近分离的果蝇细菌定植的宿主机制 来自野生黑腹果蝇的植物乳杆菌和醋杆菌菌株， 发现它们在果蝇肠道内的一个严格定义的物理空间中定居。 L. plantarum 是一种益生菌 人类，而苍蝇为研究人类同源物提供了独特而强大的遗传资源 疾病基因。该提案利用了几种独特的检测方法来识别宿主 介导共生菌株特异性的机制，包括宿主细胞类型、基因和 招募和维持共生细菌的分子。中心假设是具体的 果蝇前肠中的细胞类型产生“共生生态位”：一种专门的化学和物理环境 促进可能受益的特定细菌粘附和增殖的微环境 主人。该提案旨在 (i) 使用单细胞 RNA 测序来识别特定的宿主细胞 创造这种特殊微环境的类型和基因。这将允许使用 果蝇遗传学（ii）通过细胞探索宿主组织维持机制 特定细胞外基质的周转和局部分泌。作为对 假设，该提案将检查植物乳杆菌群体动力学，使其能够 与共生生态位的关联。通过研究共生生态位的构建 果蝇肠道，这项研究将建立一个新的范式，能够审问果蝇肠道 宿主及其共生体之间保守的分子和细胞相互作用，影响 宿主健康。该提案具有开发工具来推动这些有益的转化潜力 互动。