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: 10684245
• 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/10684245
• 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; Gene Expression; Gene Modified; Genes; Genetic; Goals; Growth; Health; Health Benefit; Homologous Gene; Human; Human Microbiome; Ingestion; 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; Proliferating; Proteins; RNA Interference; Regulation; Reproduction; Research; Rest; Role; Serine; Site; Specificity; Testing; Time; Tissues; Transferase; Work; assay development; candidate identification; 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.

项目摘要 肠道细菌与宿主组织结合，改变宿主生理，影响寿命和衰老。 一些类型的细菌，如乳杆菌，有益于健康，而另一些则会降低健康。存在的一个关键差距 我们的知识是宿主如何通过以下方式构建协调殖民的微环境 特定的细菌。特别是，哪些宿主细胞(目标1)、基因和分子(目标2)促进 特定细菌的定植？作为向前迈出的重要一步，这项提案旨在调查 新近分离的细菌在果蝇体内定植的寄主机制 从野生黑腹果蝇中分离到的植物乳杆菌和醋酸杆菌菌株， 被发现定居在苍蝇肠道中一个严格限定的物理空间。植物乳杆菌是一种益生菌。 人类，苍蝇为研究人类同源基因提供了独特而强大的遗传资源 疾病基因。这一建议利用了几种独特的分析方法来识别宿主 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。中心假设是特定的 果蝇前肠中的细胞类型产生了一个“共生生态位”：一种特殊的化学和物理 有利于特定细菌黏附和增殖的微环境 主持人。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 果蝇遗传学研究(II)探索细胞维持寄主组织的机制 特定细胞外基质的周转和局部分泌。作为对 假设，该提案将研究植物乳杆菌种群动力学，使其能够 与共生生态位相关联。通过研究共生生态位构建在 这项研究将建立一种新的范式，使审问 宿主及其共生体之间保守的分子和细胞相互作用，影响 寄主健康。该提案具有翻译潜力，可以开发工具来推动这些好处 互动。