Intestinal Homeostasis Induced by Commensals

共生体诱导的肠道稳态

基本信息

批准号：
10029718
负责人：
Beth A McCormick
金额：
$ 56万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-15 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10029718
关键词：
ABCB1 gene Acute Address Anti-Inflammatory Agents Apical Bile Acids Biological Biological Models Cells Colitis Communication Communities Complex Computing Methodologies Cues Data Disease Elements Endocannabinoids Environment Epithelial Epithelial Cells Epithelium Equilibrium Ethanolamines Eubacterium Feces Foundations Functional disorder Gene Cluster Genes Genetic Genetic Transcription Goals Homeostasis Host Defense Human Immune system In Vitro Individual Inflammation Inflammatory Inflammatory Bowel Diseases Inflammatory Response Injury Intervention Intestinal Mucosa Intestines Invaded Knowledge Lactobacillus Link Lipids Machine Learning Maintenance Mediating Metabolic Modeling Modification Molecular Mucous Membrane Multi-Drug Resistance Mus Outcome Output P-Glycoprotein Pathway interactions Patients Pharmaceutical Preparations Phenotype Pilot Projects Play Process Public Health Pump Regulation Research Resolution Role Sentinel Severities Signal Transduction Structure Submucosa Surface System Testing Time Toxin Work Xenobiotic Metabolism arm bacterial community base commensal bacteria design efflux pump first responder healing host colonization host-microbe interactions in vivo inflammatory disease of the intestine innate immune mechanisms insight intestinal epithelium intestinal homeostasis mathematical model microbial microbiome microbiota microorganism migration mouse model neutrophil new therapeutic target normal microbiota novel novel therapeutic intervention nuclear factor 1 prevent recruit response theories transcriptomics

项目摘要

ABSTRACT While multidrug-resistance transporters including P-gp and MRP2 are generally studied for their role in exporting drugs and foreign compounds from the cell, our studies indicate that these efflux pumps expressed at the apical surface of intestinal epithelial cells provide a critical link in communication between sentinel functions of mucosal barriers and the immune system. Understanding how this P-gp/eCB anti-inflammatory arm is regulated will provide crucial insight into how dysfunction may promote intestinal inflammation and help identify potential new therapeutic targets. Because the resident microbiota is known to contribute to tolerance and homeostasis in the healthy intestine, the central hypothesis we aim to test is whether the normal microbiota actively drives the P-gp/eCB axis to prevent unnecessary inflammation. Our pilot studies indicate that the microbiota does influence P-gp expression and function, providing a unique foundation for further cause-effect studies. No data have previously demonstrated a link between the microbiota and eCBs or any other epithelial lipid signals, and may well provide great insight into a novel system. Bridging this gap could help explain how commensal bacteria can stabilize a state of tolerance and how genetic modification of specific pathway elements might predispose individuals to conditions of inflammatory bowel disease (IBD). To begin addressing these questions, in Aim 1 of this application will combine in vitro (including human colonoids) and in vivo murine model systems, as well as use healthy and UC patient stool, to more deeply understand the microbial consortia that collectively maximize P-gp expression and function. Aim 2 is designed to identify the microbial metabolites that drive activation of P-gp expression and eCB secretion to maintain an anti-inflammatory tone in the intestinal epithelium. Thus, transcriptomics and metabolite analyses will be performed to provide new information regarding microbial genes, gene clusters, and their metabolic products implicated in maintaining an anti- inflammatory tone in the intestinal epithelium through regulation of the P-gp/eCB axis. In Aim 3 we will employ novel computational methods will to uncover the inter-microbial network responses and the ecological structure of a stable community that is able to induce P-gp expression. Collectively, knowledge of the pathways that coordinate the maintenance of the P-gp/eCB axis will require a comprehensive understanding of distinct signals regulating intestinal homeostasis, how multiple signals are integrated in the complex intestinal environment, and pathways that modulate host-microbe interactions. Consequently, this proposal will directly advance novel biological principles with guidance of new therapeutic intervention strategies.

抽象的虽然包括 P-gp 和 MRP2 在内的多药耐药转运蛋白通常因其我们的研究表明，这些外流在从细胞中输出药物和外来化合物方面发挥着作用在肠上皮细胞顶端表面表达的泵提供了关键的联系粘膜屏障的前哨功能与免疫系统之间的沟通。了解 P-gp/eCB 抗炎臂的调节方式将提供重要的见解研究功能障碍如何促进肠道炎症并帮助识别潜在的新治疗目标。因为众所周知，常驻微生物群有助于耐受性和健康肠道的稳态，我们旨在测试的中心假设是正常肠道是否正常微生物群积极驱动 P-gp/eCB 轴以防止不必要的炎症。我们的飞行员研究表明微生物群确实影响 P-gp 的表达和功能，提供了为进一步的因果研究奠定了独特的基础。之前没有数据表明存在联系微生物群和 eCB 或任何其他上皮脂质信号之间的信号，很可能提供很好的洞察一个新颖的系统。弥合这一差距可能有助于解释共生细菌如何能够稳定耐受状态以及特定途径元件的基因修饰如何可能使个体易患炎症性肠病（IBD）。开始寻址这些问题，在本申请的目标 1 中将结合体外（包括人类结肠）和体内小鼠模型系统，以及使用健康和 UC 患者粪便，更深入地研究了解共同最大化 P-gp 表达和功能的微生物群落。目的 2 旨在鉴定驱动 P-gp 表达激活的微生物代谢物和 eCB 分泌以维持肠上皮的抗炎张力。因此，将进行转录组学和代谢物分析，以提供有关微生物基因、基因簇及其代谢产物与维持抗- 通过调节 P-gp/eCB 轴来调节肠上皮细胞的炎症张力。目标 3 我们将采用新颖的计算方法来揭示微生物间的网络反应以及能够诱导P-gp表达的稳定群落的生态结构。总的来说，协调维持 P-gp/eCB 轴的途径的知识需要全面了解调节肠道稳态的不同信号，多种信号如何在复杂的肠道环境中整合，以及这些信号的通路调节宿主-微生物相互作用。因此，该提案将直接推进新颖的生物学原理指导新的治疗干预策略。