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Brain-gut interactions regulating stress-related gut inflammation and barrier permeability

脑肠相互作用调节应激相关肠道炎症和屏障通透性

基本信息

批准号：
10723593
负责人：
Kenny Chan
金额：
$ 9.15万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10723593
关键词：
Ablation Animals Anti-Inflammatory Agents Bacterial Toxins Behavior Behavioral Biological Brain Brain imaging Brain region Cells Central Nervous System Chronic Chronic stress Circulation Colon Colonic inflammation Communication Corticotropin-Releasing Hormone Disease Dopamine-beta-monooxygenase Emotional Endotoxemia Endotoxins Enteral Enteric Nervous System Environment Etiology Exhibits Female Fiber Flow Cytometry Functional Gastrointestinal Disorders Functional disorder Gastrointestinal Diseases Genes Genetic Human Hypothalamic structure Immunology Inflammation Inflammatory Intestinal permeability Intestines Irritable Bowel Syndrome Leaky Gut Leukocytes Link Major Depressive Disorder Maps Mediating Mental Depression Mental disorders Modeling Mus Neural Pathways Neuroimmune Neurons Neurosciences Pathway interactions Peripheral Permeability Phenotype Photometry Process Psychological Stress Psychosocial Stress Reporting Risk Factors Rodent Model Sensory Severities Signal Transduction Stress Surrogate Markers Symptoms T-Lymphocyte Techniques Tight Junctions Tissues Tracer Viral Wild Type Mouse afferent nerve avoidance behavior comorbidity depressive behavior detection platform experimental study genetic manipulation gut bacteria gut inflammation gut-brain axis intestinal barrier mad itch virus male migration paraventricular nucleus social social defeat stress related disorder systemic inflammatory response

项目摘要

Project Summary Chronic psychosocial stress is a major risk factor for functional gastrointestinal disorders, such as irritable bowel syndrome (IBS). Notably, there is high co-morbidity between IBS and stress-related psychiatric disorders such as major depressive disorder (MDD), with IBS and MDD representing two of the most prevalent and debilitating illnesses worldwide. Potentially underlying this co-morbidity is the recent finding that chronic stress elicits low-grade inflammation, which has been associated with both IBS and MDD. Moreover, increasing evidence suggests that the gut-brain axis, or connections between the central and enteric nervous systems, contributes to the etiology of IBS. However, the mechanisms through which an emotional state such as chronic stress influences gut pathophysiology, including inflammation, remain poorly understood. In preliminary experiments using the chronic social defeat stress (CSDS) model in mice, we find that intestinal inflammation and barrier permeability become elevated following CSDS in both male and female mice, and these phenomena correlate with depression-like behaviors such as social avoidance. In this project, I will investigate how psychosocial stress causes this gut pathophysiology. Using retrograde viral tracing strategies from the gut to the brain, and whole-brain imaging, I have generated a list of candidate stress-activated brain regions that directly innervate the gut. In the first aim of this proposal, I will use integrated neuroscience and immunology techniques, such as chemogenetics and flow cytometry, to determine if activation of these brain regions can trigger gut inflammation and barrier permeability. Moreover, I aim to identify subsets of enteric neurons in the intestine that receive signals from the brain during stress to propagate IBS-like symptoms. In the second aim, I will then assess how inflammatory signals in the gut are conveyed to the brain to influence stress-relevant behaviors. As the brain can detect the inflammatory state of peripheral tissues through sensory afferent nerves, I will first identify which stress-responsive brain regions receive input from gut. I will then use fiber photometry to evaluate how gut inflammation modulates neuronal activity in these brain regions and its consequences on behavior. In parallel, I will investigate if a compromised intestinal barrier allows bacterial toxin translocation from the gut lumen into circulation to promote systemic inflammation and depression-like behaviors. Collectively, this project aims to define bi-directional stress-activated gut-brain circuits that contribute to IBS- and MDD-related symptoms.

项目总结