Enteroendocrine cells sense gut bacteria and activate a gut-brain pathway

肠内分泌细胞感知肠道细菌并激活肠脑通路

基本信息

批准号：
10640981
负责人：
Lihua Ye
金额：
$ 15.05万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-20 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10640981
关键词：
Ablation Address Affect Afferent Neurons Agonist Anxiety Award Bacteriology Behavior Biological Models Brain Brain Diseases Calcium Catabolism Cell Transplantation Cell physiology Cell secretion Cells Central Nervous System Chemicals Communication Development Plans Diet Disease Edwardsiella tarda Emotions Enteral Enterobacteriaceae Enteroendocrine Cell Epithelial Cells Fishes Functional Gastrointestinal Disorders Gastroenterology Gastrointestinal Diseases Gastrointestinal tract structure Genetic Gnotobiotic Goals Gram-Negative Bacteria Health Homeostasis Hormonal Human Image Immunologics Infection Intestinal Diseases Intestines Irritable Bowel Syndrome Irritants K-Series Research Career Programs Knowledge Link Measures Mediating Mentorship Microbe Microbiology Mission Molecular Mus Nerve Fibers Nervous System Neurons Neurotransmitters Nociception Nutrient Nutritional Outcome Pain Pathogenesis Pathologic Pathway interactions Penetration Peptide Signal Sequences Perception Pharmacologic Substance Physiology Postdoctoral Fellow Production Public Health Research Research Personnel Research Training Scientist Sensory Sensory Ganglia Signal Transduction Signaling Molecule Spinal Stress System TRPA channel Testing Training Tryptophan United States National Institutes of Health Universities Vagus nerve structure Vertebral column Visceral Zebrafish bacterial genetics brain pathway burden of illness career career development detection of nutrient genetic manipulation gut bacteria gut microbes gut microbiota gut-brain axis host-microbe interactions in vivo intestinal epithelium microbial microorganism nervous system disorder neuronal circuitry novel novel therapeutics optogenetics pathogen peripheral pain pharmacologic pituitary adenylate cyclase activating polypeptide polypeptide prevent psychiatric symptom receptor response single-cell RNA sequencing skills temporal measurement therapeutic development transmission process

项目摘要

PROJECT SUMMARY Microorganisms residing in the intestinal lumen have a significant impact on brain function and behavior. Perturbation of microbe-gut-brain communication is believed to be involved in the pathogenesis of well-known gut-brain disorders such as irritable bowel syndrome (IBS) and related functional GI disorders. However, there is lack of understanding of the precise microbial mechanisms and the cellular pathways that allow gut microbes to communicate with the brain. To address this critical knowledge gap, the applicant has pioneered the zebrafish system for the study of microbe-gut-brain communication. Using in vivo real-time measurements of cell activity in zebrafish, the applicant’s recent research revealed that specific gut bacteria directly activate specialized sensory cells in the intestine epithelium, enteroendocrine cells (EECs), through the receptor transient receptor potential ankyrin A1 (Trpa1). Microbial, pharmacological, or optogenetic activation of Trpa1+EECs directly activates enteric neurons and stimulates vagal sensory ganglia. Preliminary studies identified a distinct subset of bacterial derived tryptophan catabolites as novel agonists that potently activate Trpa1. The objective of the proposed research is to determine the precise molecular mechanism by which enteric bacteria activate the EEC- vagal sensory pathway to modulate brain activity. The central hypothesis is that bacterial secreted tryptophan catabolites stimulate Trpa1 in EECs to activate vagal sensory neurons through a novel EEC secreted signal peptide, pituitary adenylate cyclase activating polypeptide (Pacap). To test this, the applicant will first use molecular microbiology and zebrafish gnotobiotic approaches to define the microbial pathway and mechanism that activates EEC Trpa1 signaling. Second, the applicant will use in vivo vagal calcium imaging, optochemical and genetic manipulation to identify the specific subtype of EECs that transmit enteric bacterial information to the vagus. Finally, the applicant will use pharmaceutical, genetic and cell transplantation approaches to define the EEC signaling peptide that transmits bacterial information from the gut lumen to the vagus. The proposed research is expected to make a significant new contribution to our understanding of the molecular mechanisms and cellular pathways by which enteric bacteria communicate with the brain. The interdisciplinary experimental approach together with the comprehensive career development plan will extend the applicant’s training from gastroenterology into vagal and brain physiology as well as molecular microbiology. A diverse team of established investigators at Duke University and UNC Chapel Hill, with expertise ranging from host-microbe interaction to gut-brain physiology to bacteriology, will oversee the applicant’s career development during the award period by contributing intellectually to her research training, providing mentorship, and offering career advice. This 5-year career development award will provide the applicant with the necessary professional and scientific skills to be an independent and successful microbiota-gut-brain scientist.

项目概要肠腔中的微生物对大脑功能和行为有重大影响。微生物-肠-脑通讯的扰动被认为与众所周知的发病机制有关然而，肠脑疾病，如肠易激综合症（IBS）和相关的功能性胃肠道疾病。缺乏对肠道微生物的精确微生物机制和细胞途径的了解为了解决这一关键的知识差距，申请人开创了斑马鱼的研究。使用体内实时测量细胞活动来研究微生物-肠-脑通讯的系统。在斑马鱼中，申请人最近的研究表明，特定的肠道细菌直接激活专门的肠上皮的感觉细胞，肠内分泌细胞（EEC），通过受体瞬时受体 Trpa1+EEC 的潜在锚蛋白 A1 (Trpa1) 的微生物、药理学或光遗传学激活。激活肠神经元并刺激迷走神经感觉神经节。初步研究确定了一个独特的子集。细菌衍生的色氨酸分解代谢物作为有效激活Trpa1的新型激动剂。拟议的研究旨在确定肠道细菌激活 EEC 的精确分子机制迷走神经感觉通路调节大脑活动的中心假设是细菌分泌色氨酸。分解代谢物刺激 EEC 中的 Trpa1，通过新的 EEC 分泌信号激活迷走神经感觉神经元肽，垂体腺苷酸环化酶激活多肽（Pacap）为了测试这一点，申请人将首先使用。分子微生物学和斑马鱼生殖方法来定义微生物途径和机制其次，申请人将使用体内迷走神经钙成像、光化学。和基因操作来识别将肠道细菌信息传递给的 EEC 的特定亚型最后，申请人将使用药物、遗传和细胞移植方法来定义迷走神经。 EEC 信号肽，将细菌信息从肠腔传递到迷走神经。研究预计将为我们理解分子机制做出重大的新贡献以及肠道细菌与大脑通讯的细胞途径。方法与全面的职业发展计划相结合，将使申请人的培训范围从胃肠病学、迷走神经和大脑生理学以及分子微生物学。在杜克大学和北卡罗来纳大学教堂山分校建立了研究人员，其专业知识涵盖宿主微生物肠脑生理学和细菌学的相互作用，将监督申请人在此期间的职业发展奖励期通过为她的研究培训做出智力贡献、提供指导和提供职业生涯这个为期 5 年的职业发展奖将为申请人提供必要的专业和建议。成为一名独立且成功的微生物-肠-脑科学家的科学技能。