Probing enteric neuro-immune interactions mediated by intestinal microbes

项目摘要 胃肠道(GI)具有显著的多样性，使用多种独特的细胞类型执行 动态平衡功能以及观察和保护身体最大的表面。虽然微生物检测 在上皮和先天免疫系统中是不可或缺的，越来越多的证据表明，肠道 相关神经系统(EANS)在腔内成分检测中起着关键作用。形态和形态特征 肠内神经系统的神经化学编码(固有的)已被广泛使用 特性，这导致了对电路和功能的重要见解。来自周围神经的神经支配 系统(外部的)也被类似地询问过，但对电路的了解要少得多。总体而言，肠道 相关神经元(Eans)为小肠和大肠提供密集的神经支配，控制蠕动， 局部血流、跨粘膜液体交换和肠道炎症检测。最新研究 观察到本土和外来细菌会引起EAN的变化。特别令人感兴趣的是， 证明了一种减毒形式的鼠伤寒沙门氏菌，突变的SpiB，激活肠道- 相关的交感神经元释放去甲肾上腺素，进而改变巨噬肌细胞 (Mm)基因表达朝着组织保护性或抗炎性方向发展。目前尚未定义的 导致这些变化的细胞回路将被称为微生物神经免疫反射环(MNIRL)。而当 细菌对EAN的下游影响已经被阐明，但还没有确定细菌或他们的 代谢物可以激活或引起EAN的这些变化。为了正确剖析此电路，我们将设置 首先描述EAN的基本结构和基因图谱，结合EAN的影响 共生微生物组，利用新的成像和RNA图谱技术。在建立了这个eans之后 映射，特别注意感觉成分，我们将识别那些由 沙门氏菌减毒株和可能的EAN细胞伙伴。最后，利用细胞特有的 神经调节技术我们将研究MNIRL在稳态和 沙门氏菌感染。我们还将确定免疫细胞群体中的快速反应是否发生了变化 使用MNIRL操控。这项研究将加强对EANS的全面了解，并有可能 改变肠道感染或炎症模式，可能导致新的治疗路线。

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.