Intestinal Homeostasis Induced by Commensals

共生体诱导的肠道稳态

• 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
• 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

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 通常，通常研究包括P-gp和MRP2在内的多药耐药转运蛋白 在从细胞中输出药物和外源化合物中的作用，我们的研究表明这些外排 在肠上皮细胞的顶部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通信。 了解该P-GP/ECB抗炎臂的调节如何提供至关重要的见解 功能障碍如何促进肠道炎症并帮助识别潜在的新 治疗靶标。因为已知居民微生物群有助于耐受性和 在健康肠道中稳态，我们旨在检验的中心假设是正常 微生物群积极驱动P-gp/欧洲央行轴，以防止不必要的炎症。我们的飞行员 研究表明，菌群确实会影响P-gp的表达和功能，从而提供了 进一步效应研究的独特基础。以前没有数据证明链接 在微生物群和ECB或任何其他上皮脂质信号之间，很可能提供很好的 深入了解新型系统。弥合此差距可以帮助解释共生细菌如何 稳定耐受状态以及特定途径元素的遗传修饰如何 倾向于炎症性肠病（IBD）的条件。开始解决 这些问题，在本应用的目标1中将结合体外（包括人类结肠）和 体内鼠模型系统以及使用健康和UC患者粪便更深入 了解共同最大化P-gp表达和功能的微生物伴侣。目的 2旨在识别驱动P-gp表达激活和的微生物代谢产物 欧洲央行分泌以保持肠上皮的抗炎张力。因此， 将进行转录组学和代谢物分析，以提供有关有关的新信息 微生物基因，基因簇及其代谢产物与维持抗 通过调节P-gp/欧洲央行轴的肠上皮炎症性张力。在目标3中 我们将采用新颖的计算方法来揭示微生物间网络响应 以及能够诱导P-gp表达的稳定社区的生态结构。 总体而言，了解协调P-gp/欧洲央行轴维护的途径 将需要对调节肠内稳态的不同信号有全面的理解， 如何将多个信号集成到复杂的肠道环境中，以及 调节宿主 - 微杆相互作用。因此，该提议将直接推动小说 新治疗干预策略的指导生物学原理。