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: 10688173
• 负责人: Jhimmy Talbot
• 金额: $ 52.08万
• 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/10688173
• 关键词: Advanced Development; Affect; Animals; Area; Autonomic nervous system; Behavior; Biochemical; Biological; Biological Assay; CRISPR/Cas technology; Calcium; Cell physiology; Cells; Central Nervous System; Communicable Diseases; 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; Functional disorder; Genetic; Genomics; Goals; Health; Homeostasis; Host Defense; Host resistance; Immune; Immune response; Immune system; Immunity; Infection; Inflammatory; Inflammatory Bowel Diseases; Ingestion; Intestinal Content; Intestines; Invaded; Irritable Bowel Syndrome; Knowledge; Lymphoid Cell; Maintenance; Measures; Mediating; Microbe; Molecular; Molecular Profiling; Nature; Neuroimmune; Neurons; Nutrient; Nutritional; Pathway interactions; Physiological; Positioning Attribute; Predisposition; Proteins; Regulation; Reporter; Resistance to infection; Sensory; Signal Transduction; Source; Technology; Therapeutic; Time; Vasoactive Intestinal Peptide; Viral; absorption; 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; transmission process; 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.

项目概要 肠道既是吸收食物中营养物质的管道，又是阻止食物摄入的屏障。 微生物入侵宿主。这种屏障功能对于维持肠道完整性很重要， 由免疫细胞促进，可以快速响应肠腔内的微生物协调 保护功能。食物摄入时间和饮食结构的改变与 免疫介导的肠道功能障碍（例如肠易激综合征）的发展。然而，尽管其 深刻的生物学和临床相关性，我们对肠道免疫如何理解存在重大差距 反应受到肠道中食物存在的调节。该提案的长期目标是 确定在喂养过程中如何在肠道中感知饮食来源的信号并促进肠道菌群的改变 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 响应食物消耗的介导屏障功能。该神经免疫回路是由 产生血管活性肠肽的肠神经元 (VIPens) 和 3 型先天淋巴细胞的相互作用 （ILC3）。 VIPen 会因肠道内食物的存在而被激活，它们直接抑制 ILC3 功能。 虽然进食过程中 VIPen 介导的 ILC3 抑制会降低肠道屏障功能，但也会增加 从饮食中吸收脂肪的效率（免疫-营养权衡）。重要的是，在实验小鼠中 模型中，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群的抵抗力 互动。我们建议研究饮食信号激活 VIPen 的机制，以此为切入点 了解喂养如何促进肠道免疫力的改变。尖端技术的结合 测量体内神经元激活（基因编码的钙指示剂和活体成像），操纵 神经元活动（化学遗传学工具和 AAV 辅助的基于 CRISPR/Cas9 的遗传操作），解剖 细胞回路的分子谱（单突触病毒追踪和单细胞基因组学）以及控制摄入 特定饮食信号（饮食工程）的研究将使我们能够从机械上理解食物如何 食用可以通过神经免疫回路影响肠道免疫力。本提案的具体目标 是：1）确定食物来源信号的性质，通过触发 VIPens 的激活，协调 肠道免疫-营养权衡，2) 剖析 VIPens 的细胞和分子途径 食物来源的信号激活。这些研究将为肠道如何发挥作用提供分子基础。 免疫反应受到食物消耗的调节，并提供了关于肠道的新见解 感知食物来源信号和协调免疫营养权衡的机制。这些研究将 还促进了基于饮食的疗法的开发，以增强免疫介导的屏障功能和 减轻肠道感染和炎症性疾病。

项目成果

Targeting adrenergic receptors to mitigate invariant natural killer T cells-induced acute liver injury.

• DOI: 10.1016/j.isci.2023.107947
• 发表时间: 2023-10-20
• 期刊: ISCIENCE
• 影响因子: 5.8
• 作者: Gonzatti, Michelangelo Bauwelz;Freire, Beatriz Marton;Antunes, Maisa Mota;de Menezes, Gustavo Batista;Talbot, Jhimmy;Peron, Jean Pierre Schatzmann;Basso, Alexandre Salgado;Keller, Alexandre Castro
• 通讯作者: Keller, Alexandre Castro