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

• 批准号: 10545352
• 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
• 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/10545352
• 关键词: Ablation; Address; Affect; Afferent Neurons; Agonist; Anxiety; Award; Bacteriology; Behavior; Biological Models; Brain; Brain Diseases; Calcium; Catabolism; Cell Transplantation; Cell physiology; Cells; Chemicals; Communication; Development Plans; Diet; Disease; Edwardsiella tarda; Emotions; Enteral; Enterobacteriaceae; Enteroendocrine Cell; Epithelial; 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; K-Series Research Career Programs; Knowledge; Lead; Link; Measures; Mediating; Mentorship; Microbe; Microbiology; Mission; Molecular; Mus; Nerve Fibers; Nervous system structure; Neuraxis; Neurons; Neurotransmitters; Nociception; Nutrient; Nutritional; Outcome; Pain; Pathogenesis; Pathologic; Pathway interactions; Peptide Signal Sequences; Perception; Pharmacologic Substance; Pharmacology; Physiology; 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; 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; pituitary adenylate cyclase activating polypeptide; prevent; psychiatric symptom; receptor; response; single-cell RNA sequencing; skills; temporal measurement; therapeutic development

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.

项目摘要 肠腔中的微生物对脑功能和行为有重大影响。 微生物 - 脑通信的扰动被认为与知名的发病机理有关 肠脑疾病，例如肠易激综合征（IBS）和相关的功能性GI疾病。但是，那里 缺乏对精确的微生物机制和允许肠道微生物的细胞途径的了解 与大脑交流。为了解决这个关键的知识差距，申请人率先驱动了斑马鱼 研究微生物 - 脑通信的系统。使用体内实时测量细胞活性 在斑马鱼中，申请人的最新研究表明，特定的肠道细菌直接激活专业 通过受体瞬态受体的肠上皮上皮细胞（EEC）中的感觉细胞 潜在的Ankyrin A1（TRPA1）。 TRPA1+EEC的微生物，药物或光遗传学激活 激活肠神经元并刺激迷走神经神经节。初步研究确定了一个独特的子集 细菌的衍生成色氨酸分解代谢物是可能激活TRPA1的新型激动剂。目的 拟议的研究是确定启动子细菌激活EEC-的精确分子机制 迷走性感觉途径调节大脑活动。中心假设是细菌分泌的色氨酸 分解代谢物刺激EEC中的TRPA1通过新型EEC分泌信号激活迷走神经元 肽，型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gnotobiotic方法来定义微生物途径和机制 激活EEC TRPA1信号传导。其次，申请人将使用体内迷走钙成像，验光化学 和遗传操纵以识别EEC的特定亚型，这些EEC的特定亚型将细菌信息促进到 迷走神。最后，申请人将使用药物，遗传和细胞移植方法来定义 将细菌信息从肠道传输到迷走神经的EEC信号传导肽。提议 预计研究将对我们对分子机制的理解做出重大贡献 以及促进细菌与大脑通信的细胞途径。跨学科实验 与全面的职业发展计划一起，将把申请人的培训从 胃肠病学成迷走神经和脑生理以及分子微生物学。一个多元化的团队 在杜克大学和UNC Chapel Hill的研究人员成立的研究人员，具有主机薄饼的专业知识 与细菌与肠道生理的互动将监督申请人在 通过在智力上为她的研究培训，提供心态和提供职业的奖励期 建议。这个为期5年的职业发展奖将为申请人提供必要的专业人员和 成为独立且成功的微生物大脑科学家的科学技能。