Mechanism of modulation of intestinal immune responses by dietary signals

项目摘要 肠道既是食物来源的营养物质的摄取管道，也是防止 微生物入侵宿主。这种屏障功能对维持肠道完整性很重要， 由免疫细胞促进，可以快速响应肠腔中的微生物存在， 保护功能。食物摄入时间和饮食组成的改变与 发生免疫介导的肠道功能障碍（例如肠易激综合征）。然而，尽管其 尽管存在着深刻的生物学和临床相关性，但在我们对肠道免疫如何产生的理解方面存在着重大差距。 肠道中存在的食物调节反应。该提案的长期目标是 确定如何，在喂养过程中，饮食来源的信号在肠道中被感知，并促进肠道的改变。 肠道免疫反应最近，我们发现了一个神经免疫回路，它协调肠道免疫- 介导的屏障功能响应于食物消耗。这种神经免疫回路是由 产生血管活性肠肽的肠神经元（VIPens）和3型先天淋巴样细胞的相互作用 （国际法委员会第3条）。VIPens被肠道中食物的存在激活，它们直接抑制ILC 3功能。 虽然VIPen介导的ILC 3抑制在进食过程中降低了肠屏障功能，但它也增加了肠屏障功能。 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 交互.我们建议研究饮食信号激活VIPens的机制，作为一个切入点， 了解进食如何促进肠道免疫力的改变。结合尖端技术 为了测量体内神经元活化（遗传编码的钙指示剂和活体成像）， 神经元活动（化学遗传学工具和基于AAV辅助的CRISPR/Cas9遗传操作），解剖 细胞回路的分子概况（单突触病毒追踪和单细胞基因组学），并控制摄入 具体的饮食信号（饮食工程），将使我们获得一个机械的理解，如何食物 食用可通过神经免疫回路影响肠道免疫。本提案的具体目标 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-营养平衡，以及2）剖析VIPens的细胞和分子途径 由食物衍生的信号激活。这些研究将为肠道如何 免疫反应受到食物消耗的调节，并提供了对肠道的新见解。 传感食物来源的信号和协调免疫营养权衡的机制。这些研究将 还推动基于饮食的疗法的发展，以增强免疫介导的屏障功能， 减轻肠道感染性和炎症性疾病。

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.