Probing enteric neuro-immune interactions mediated by intestinal microbes

探究肠道微生物介导的肠道神经免疫相互作用

• 批准号: 9328898
• 负责人: Paul Muller
• 金额: $ 4.4万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9328898
• 关键词: Acute; Address; Affect; Afferent Neurons; Anti-Inflammatory Agents; Anti-inflammatory; Architecture; Attention; Attenuated; Bacteria; Blood flow; Cells; Chronic; Code; Data; Detection; Enteral; Environment; Epithelium; Exposure to; Gastrointestinal tract structure; Gene Expression; Genes; Genetic; Genetic Transcription; Gnotobiotic; Image; Immune; Immune system; Indigenous; Infection; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Inflammatory disease of the intestine; Innate Immune System; Intestines; Large Intestine; Lead; Light; Liquid substance; Maps; Mediating; Microbe; Monitor; Morphology; Movement; Mus; Nervous system structure; Neuroimmune; Neurons; Norepinephrine; Pathogenicity; Peripheral Nervous System; Peristalsis; Population; Process; RNA; Reflex action; Role; Route; Salmonella; Salmonella infections; Salmonella typhimurium; Sensory; Small Intestines; Smooth Muscle; Surface; Surveys; Symbiosis; T-Lymphocyte; Techniques; Technology; Tissue imaging; Tissues; Translating; alternative treatment; arm; cell type; commensal microbes; design; gut microbiota; immunoregulation; insight; interest; macrophage; microbial; microbiome; microbiota; mutant; nerve supply; neurochemistry; neuroregulation; novel; novel therapeutics; pathogenic bacteria; response; tool

Project Summary The gastrointestinal (GI) tract has a remarkable diversity, using multiple unique cell types to perform homeostatic functions as well as survey and protect the largest surface in the body. While microbial detection is indispensible in the epithelium and innate immune system, there is mounting evidence that the enteric associated nervous system (EANS) is a pivotal player in detection of luminal composition. The morphology and neurochemical code for the nervous system contained within the intestine (intrinsic) has been extensively characterized, which has led to vital insights into circuitry and function. Innervation from the peripheral nervous system (extrinsic) has been similarly interrogated, but far less is understood regarding circuitry. In total, enteric associated neurons (EANs) provide dense innervation of the small and large intestine, controlling peristalsis, local blood flow, transmucosal fluid exchange, and detection of intestinal inflammation. Recent studies observed that indigenous and foreign bacteria induce changes in EANs. Of particular interest, it has been demonstrated that an attenuated form of Salmonella typhimurium, the mutant spiB, activates enteric- associated sympathetic neurons that release norepinephrine, which in turn alters muscularis macrophage (MM) gene expression towards a tissue-protective, or anti-inflammatory, profile. The presently undefined cellular circuit that results in these changes will be termed microbe neuro-immune reflex loop (MNIRL). While downstream effects of bacteria on EANs have been illustrated, it has yet to be determined how bacteria or their metabolites can activate or cause these changes in EANs. In order to properly dissect this circuit, we will set out to first characterize the basic architectural and genetic map of the EANS, incorporating the effects of the commensal microbiome, utilizing novel imaging and RNA profiling techniques. Upon establishing this EANS map with particular attention to sensory components, we will identify those EANs that are activated by an attenuated strain of Salmonella and possible EAN cellular partners. Finally, taking advantage of cell specific neuro-modulatory technology we will examine the necessity of the MNIRL in the steady-state and during Salmonella infection. We will also determine whether fast responses in immune cell populations are altered with MNIRL manipulation. This study will enhance overall understanding of the EANS and has the potential to change enteric infection or inflammation paradigms, possibly leading to new therapeutic routes.

项目摘要 胃肠道（GI）具有显着的多样性，使用多种独特的细胞类型来执行 自我平衡功能以及调查和保护身体最大的表面。微生物检测 是上皮和先天免疫系统中不可或缺的，越来越多的证据表明， 相关神经系统（EANS）在管腔组成的检测中起关键作用。形态和 神经化学代码的神经系统包含在肠（内在）已被广泛 特征，这导致了对电路和功能的重要见解。周围神经支配 系统（外部）已经被类似地询问，但关于电路的理解要少得多。总的来说，肠 相关神经元（EAN）为小肠和大肠提供密集的神经支配，控制肠梗阻， 局部血流、经粘膜液体交换和检测肠道炎症。最近的研究 观察到本土和外来细菌诱导EAN的变化。特别令人感兴趣的是， 证明了一种减毒的鼠伤寒沙门氏菌，突变体spiB，激活肠- 相关的交感神经元释放去甲肾上腺素，这反过来又改变肌层巨噬细胞 (MM)基因表达对组织保护或抗炎的作用。目前未定义的 导致这些变化的细胞回路将被称为微生物神经免疫反射回路（MNIRL）。而 尽管已经说明了细菌对EAN的下游作用，但还有待确定细菌或其 代谢物可以激活或引起EAN中的这些变化。为了正确地剖析这个回路，我们将设置 首先描述了EANS的基本结构和遗传图谱，结合了 肠道微生物组，利用新的成像和RNA分析技术。在建立EANS时， 特别注意感觉成分的地图，我们将识别那些被激活的EAN。 沙门氏菌的减毒株和可能的EAN细胞伴侣。最后，利用细胞特异性 神经调节技术，我们将研究的必要性，MNIRL在稳态和期间 沙门氏菌感染。我们还将确定免疫细胞群的快速反应是否被改变， MNIRL操作。这项研究将提高对EANS的全面理解，并有可能 改变肠道感染或炎症模式，可能导致新的治疗途径。