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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.

项目总结