Molecular determinants of host-feeding manipulation and microbial colonization

宿主喂养操作和微生物定植的分子决定因素

• 批准号: 10686470
• 负责人: Michael Patrick ODonnell
• 金额: $ 133.88万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10686470
• 关键词: 3-Dimensional; Animals; Automobile Driving; Bacteria; Behavior; Behavioral; Behavioral Assay; Caenorhabditis elegans; Communication; Consumption; Coupled; Data; Decision Making; Development; Diet; Enteral; Environment; Eukaryota; Feeding behaviors; Genetic; Gnotobiotic; Health; Human; Hunger; Imaging Device; Ingestion; Invertebrates; Mammals; Metabolism; Microbe; Microfluidics; Modeling; Molecular; Nature; Nematoda; Nervous System; Nervous System Physiology; Neurobiology; Nutrient; Odors; Pattern; Physiology; Plants; Process; Proxy; Sensory; Signal Transduction; Structure; System; Technology; Time; Work; feeding; genetic manipulation; gut bacteria; gut colonization; gut microbes; gut microbiome; gut microbiota; host microbiota; host-microbe interactions; insight; microbial; microbial colonization; microbial community; microbiome; novel; preference; response; screening; tool; transmission process

Project Summary All animals live in environments surrounded by microbes, yet the impact of bacteria on nervous systems has been relatively under-studied. Recent data suggests that commensal gut bacteria may be capable of modulating host behavior. Gut bacteria benefit from nutrients consumed by their host and because these bacteria must be transmitted largely via diet, manipulation of host feeding behavior is a principal mode by which resident microbes can influence the gut microbial community. Due to the dynamic nature of such an interaction, studying feeding manipulation has been either challenging or impossible to date in most systems. First, we must identify systems in which both host and microbe are amenable to genetic manipulation, and which enable high-throughput behavioral screening in response to defined and naturalistic conditions. Here, we propose to comprehensively study this phenomenon for the first time in any experimental system, using the roundworm C. elegans — in combination with its natural associated bacteria — to gain mechanistic insights into inter-organismal signals driving host-microbe interactions and decision making. C. elegans is a bacterial- feeding nematode that is often found in rotting plant material and is commonly colonized by microbes. C. elegans has some of the most extensive molecular, neurobiological and genetic tools of any multicellular eukaryote, and, coupled with the ease of gnotobiotic culture in these worms, represents a highly attractive system in which to study microbial influence on host behavior. I have recently shown that in C. elegans, gut bacteria can influence chemosensory decisions — a proxy for feeding behavior in certain contexts — resulting in increased preference for odors produced by these enteric microbes. In parallel preliminary work, I have found that olfactory plasticity upon gut colonization by diverse microbes correlates with gut colonization patterns in naturalistic settings. Together, these findings suggest that the C. elegans native gut microbiota may be capable of impacting microbiome assembly by influencing feeding behavior. In this proposal, we aim to establish C. elegans as a system to study feeding manipulation by developing tools to identify the behavioral parameters which influence microbiome structure in naturalistic settings. We propose to experimentally isolate ingestion from locomotory behavior through the development of novel microfluidics imaging devices. We will develop new behavioral assays in 2- and 3- dimensional arenas to present microbial communities mimicking the worms’ natural environment. We will then identify the molecular basis of microbial-dependent changes in olfactory behaviors using naturalistic microbial communities. Together, we propose to develop a new field of feeding manipulation by gut microbes, with C. elegans centered as a preeminent model. We anticipate that the principles we identify in this proposal should generalize to multiple systems and the neuroactive compounds we identify have the potential to impact nervous system function in diverse hosts.

项目概要 所有动物都生活在被微生物包围的环境中，然而细菌对神经的影响 最近的数据表明，共生肠道细菌可能具有这种能力。 调节宿主行为的肠道细菌受益于宿主消耗的营养物质，因为这些 细菌必须主要通过饮食传播，操纵宿主摄食行为是主要方式 由于这种微生物的动态性质，哪些常驻微生物可以影响肠道微生物群落。 迄今为止，在大多数系统中，研究喂养操纵要么具有挑战性，要么不可能。 首先，我们必须确定宿主和微生物都适合基因操纵的系统，并且 在这里，我们能够根据定义的自然条件进行高通量行为筛选。 提议首次在任何实验系统中全面研究这种现象，使用 线虫线虫 - 与其天然相关细菌相结合 - 获得机制见解 转化为驱动宿主微生物相互作用和决策的生物体间信号。线虫是一种细菌。 经常在腐烂的植物材料中发现并且通常被微生物定殖的线虫 C. 线虫拥有所有多细胞动物中最广泛的分子、神经生物学和遗传工具 真核生物，再加上这些蠕虫中易于进行知生培养，代表了一种极具吸引力的 研究微生物对宿主行为影响的系统。 我最近证明，在线虫中，肠道细菌可以影响化学感应决策——一个代理 在某些情况下的进食行为 - 导致对这些产生的气味的偏好增加 在平行的初步工作中，我发现肠道微生物的嗅觉可塑性。 这些发现与自然环境中的肠道定植模式相关。 表明秀丽隐杆线虫天然肠道微生物群可能能够通过以下方式影响微生物组组装： 在这个影响摄食行为的提案中，我们的目标是建立秀丽隐杆线虫作为研究摄食的系统 通过开发工具来识别影响微生物组结构的行为参数来进行操作 我们建议通过实验将摄入与运动行为隔离。 新型微流体成像设备的开发我们将在 2- 和 3- 分析中开发新的行为分析。 然后我们将展示模仿蠕虫自然环境的微生物群落。 使用自然微生物识别微生物依赖性嗅觉行为变化的分子基础 我们建议共同开发肠道微生物喂养操纵的新领域，其中包括 C. 我们预计我们在该提案中确定的原则应该以线虫为中心。 推广到多个系统，我们发现的神经活性化合物有可能产生影响 不同宿主的神经系统功能。