Mechanism of modulation of intestinal immune responses by dietary signals

饮食信号调节肠道免疫反应的机制

• 批准号: 10508375
• 负责人: Jhimmy Talbot
• 金额: $ 52.8万
• 依托单位: FRED HUTCHINSON CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-22 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10508375
• 关键词: Advanced Development; Affect; Animals; Area; Autonomic nervous system; Behavior; Biochemical; Biological; Biological Assay; CRISPR/Cas technology; Calcium; Cell physiology; Cells; Complex; Computer Analysis; Detection; Development; Diet; Diet Modification; Dietary Component; Dietary Fats; Dietary intake; Disease; Diurnal Rhythm; Eating; Engineering; Enteral; Enteric Nervous System; Fatty acid glycerol esters; Food; Foundations; Functional disorder; Genomics; Goals; Health; Homeostasis; Host Defense; Host resistance; Immune; Immune response; Immune system; Immunity; Infection; Inflammatory; Inflammatory Bowel Diseases; Ingestion; Intestinal Content; Intestines; Irritable Bowel Syndrome; Knowledge; Lymphoid Cell; Maintenance; Measures; Mediating; Microbe; Molecular; Molecular Profiling; Nature; Neuraxis; Neuroimmune; Neurons; Nutrient; Nutritional; Pathway interactions; Periodicity; Physiological; Positioning Attribute; Predisposition; Proteins; Regulation; Reporter; Resistance to infection; Sensory; Signal Transduction; Source; Technology; Therapeutic; Time; Vasoactive Intestinal Peptide; Viral; absorption; base; calcium indicator; circadian; clinically relevant; commensal microbes; dietary; dietary control; enteric infection; enteric pathogen; feeding; food consumption; gastrointestinal; genetic manipulation; host microbiota; improved; in vivo; innovation; insight; interest; intestinal barrier; intravital imaging; microbial; microorganism; mouse model; neuroimmunology; neuronal circuitry; prevent; response; success; therapeutic target; tool; uptake

Project Summary The intestine serves both as a conduit for the uptake of food-derived nutrients and as a barrier that prevents host invasion by microorganisms. This barrier function is important to maintain intestinal integrity and it is promoted by immune cells, which can quickly respond to microbial presence in intestinal lumen coordinating protective functions. Alterations in timing of food intake and diet composition have been associated with the development of immune-mediated intestinal dysfunctions (e.g. irritable bowel syndrome). However, despite its profound biological and clinical relevance, there is a major gap in our understanding of how intestinal immune responses are modulated by food presence in the intestinal tract. The long-term goal of this proposal is to determine how, during feeding, dietary-derived signals are sensed in the intestine and promote alterations in intestinal immune responses. Recently, we uncovered a neuroimmune circuit that coordinates intestinal immune- mediated barrier functions in response to food consumption. This neuroimmune circuit is formed by the interaction of vasoactive intestinal peptide-producing enteric neurons (VIPens) and type 3 innate lymphoid cells (ILC3s). VIPens are activated by the presence of food in the intestinal tract, they directly inhibit ILC3 functions. Although VIPen-mediated inhibition of ILC3 during feeding reduces intestinal barrier functions, it also increases efficiency of fat absorption from the diet (immune-nutritional trade-off). Importantly, in experimental mouse models, perturbations in this neuroimmune circuit alters host resistance to enteropathogens and host-microbiota interactions. We propose to study the mechanism of activation of VIPens by dietary signals as an entry point to understand how feeding promotes alterations in intestinal immunity. A combination of cutting-edge technologies to measure neuronal activation in vivo (genetically encoded calcium indicators and intravital imaging), manipulate neuronal activity (chemogenetic tools and AAV-assisted CRISPR/Cas9-based genetic manipulation), dissect molecular profiles of cellular circuits (monosynaptic viral tracing and single cell genomics), and control ingestion of specific dietary signals (diet engineering), will allow us to acquire a mechanistic understanding of how food consumption can affect intestinal immunity through neuroimmune circuits. The Specific Aims of this proposal are: 1) to determine the nature of food-derived signals that, by triggering activation of VIPens, coordinate intestinal immune-nutritional trade-offs, and 2) to dissect the cellular and molecular pathways of VIPens activation by food-derived signals. These studies will provide the molecular underpinnings of how intestinal immune responses are being modulated by food consumption, as well as provide new insights of the intestinal mechanisms for sensing food-derived signals and orchestrating immune-nutritional trade-offs. These studies will also advance the development of dietary-based therapies to boost immune-mediated barrier functions and the mitigation of intestinal infectious and inflammatory diseases.

项目摘要 肠道既是吸收食物中营养物质的管道，又是防止 微生物入侵宿主。这种屏障功能对保持肠道完整性很重要，而且 由免疫细胞促进，可对肠腔内微生物的存在做出快速反应 具有保护功能。食物摄取时间和饮食结构的改变与 免疫介导的肠道功能障碍的发展(例如肠易激综合征)。然而，尽管它的 深刻的生物学和临床相关性，在我们对肠道免疫如何 反应由肠道中食物的存在来调节。这项提议的长期目标是 确定在喂养过程中，肠道中如何感知饮食衍生的信号，并促进 肠道免疫反应。最近，我们发现了一个协调肠道免疫的神经免疫回路- 调节屏障功能，以回应食物的消耗。这种神经免疫回路是由 血管活性肠肽产生的肠神经元(VIPens)与3型固有淋巴样细胞的相互作用 (ILC3s)。VIPens是由肠道中食物的存在而激活的，它们直接抑制ILC3功能。 虽然VIPen介导的在喂养过程中抑制ILC3会降低肠道屏障功能，但它也会增加 饮食中脂肪吸收的效率(免疫-营养权衡)。重要的是，在实验小鼠中 模型，这种神经免疫回路的扰动改变了宿主对肠道病原体和宿主微生物区系的抵抗力 互动。我们建议研究饮食信号激活VIPens的机制作为切入点 了解喂养如何促进肠道免疫力的变化。尖端技术的结合 为了测量活体神经元的激活(遗传编码的钙指示器和活体成像)，操纵 神经元活动(化学遗传学工具和基于AAV的CRISPR/Cas9遗传操作)，解剖 细胞回路的分子图谱(单突触病毒示踪和单细胞基因组学)和控制摄取 特定的饮食信号(饮食工程学)，将使我们能够机械地理解食物是如何 消费会通过神经免疫回路影响肠道免疫。这项建议的具体目的 是：1)确定食物来源的信号的性质，通过触发VIPens的激活，协调 肠道免疫-营养权衡，以及2)剖析VIPens的细胞和分子途径 由食物产生的信号激活。这些研究将为肠道如何 免疫反应正受到食物消费的调节，并提供了对肠道的新见解 感知来自食物的信号和协调免疫-营养权衡的机制。这些研究将 也促进了以饮食为基础的疗法的发展，以增强免疫介导性屏障功能和 减轻肠道传染病和炎症性疾病。