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Alcohol and intestinal microvascular endothelium-immune axis and the role of gut derived immune nutrients

酒精与肠道微血管内皮-免疫轴以及肠道源性免疫营养素的作用

基本信息

批准号：
10675567
负责人：
Gail Ann Cresci
金额：
$ 50.98万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
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：
2020-09-01 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10675567
关键词：
Acetates Acute Adolescent Adult Affect Alcohol consumption Alcohol-Induced Disorders Alcohols Animal Model Autoimmune Diseases Biological Blood Vessels Brain Butyrates Cells Chronic Circulation Coculture Techniques Colon Consumption Development Diffuse Endothelium Endotoxins Epithelium Ethanol Fermentation Functional disorder Gene Expression Regulation Goals Healthcare Heart Heavy Drinking Hepatic Homeostasis Homing Human Immune Immune response Immune system Immunity Impairment Inflammation Inflammatory Inflammatory Response Intercellular Junctions Interleukin-10 Intestinal permeability Intestines Invaded Laboratories Lamina Propria Leukocytes Link Lipopolysaccharides Liver Lung Macrophage Malignant Neoplasms Mediating Microbe Microvascular Permeability Morbidity - disease rate Mucositis Mucous Membrane Mus Muscle Nutrient Oral Organ Oxidative Stress Pancreas Pathology Perfusion Play Population Portal vein structure Prevention Prodrugs Productivity Propionates Proteins Regulation Regulatory T-Lymphocyte Reporting Role STAT3 gene Splenocyte Supplementation System T cell response T-Cell Homing Receptors T-Lymphocyte TLR4 gene Testing Therapeutic Therapeutic Agents Tight Junctions Tretinoin United States Vascular Endothelial Cell Vascular Endothelium Virus Diseases Volatile Fatty Acids alcohol effect alcohol exposure alcohol testing alcohol use disorder cost cytokine driving force feeding gastrointestinal epithelium gut dysbiosis gut microbiome immune activation immune function improved in vivo insight intestinal epithelium intestinal homeostasis intestinal injury liver inflammation liver injury macromolecule microbial mortality mouse model novel novel therapeutics nutrient metabolism organ growth organ injury pathogenic bacteria preservation prevent preventable death protective effect recruit response transcription factor transcriptome sequencing tributyrin

项目摘要

ABSTRACT Chronic ethanol exposure is associated with gut dysbiosis, impaired immunity, and the development of organ dysfunction leading to a rising appreciation for inter-organ crosstalk for ethanol-induced pathologies. First hit by ethanol ingestion, the intestine and gut microbiome play a central role in immune system homeostasis. Chronic ethanol decreases gut bacterial abundance and diversity and destabilizes the intestinal epithelial barrier, which is associated with reduced luminal butyrate and intestinal all-trans retinoic acid (atRA) levels, systemic endotoxin, and inflammation. Intestinal microvascular endothelial cells (EC), located within the intestinal lamina propria, are critical for mucosal immune function by recruiting and activating leukocytes and regulating gut vascular perfusion. Following ethanol-induced epithelial barrier disruption and endotoxin translocation, proinflammatory molecules interact with intestinal microvascular EC and immune cells within the lamina propria. Endothelial and immune cell activation by bacterial endotoxins leads to their dysfunction. The intestinal microvascular endothelial barrier serves as second defensive barrier for a disrupted epithelium, providing additional protection against macromolecule and microbe translocation. Butyrate and atRA are intestinal-generated immune nutrients known to promote epithelial barrier function, and immune homeostasis via T-lymphocyte regulation. We have shown butyrate (tributyrin) supplementation mitigates ethanol-induced gut-liver injury by preventing disassembly of epithelial tight junction proteins, reducing oxidative stress, and promoting expression of intestinal microvascular endothelial associated junctional proteins and immune cells in mouse proximal colon. Here we propose the hypothesis that through ethanol’s disruption of the gut microbiome, depletion of butyrate and all-trans retinoic acid, and subsequent destabilization of the intestinal epithelial barrier and translocation of endotoxin, intestinal microvascular endothelium become functionally disrupted and activated which induces intestinal T-cell dysregulation and inflammation. We will test two specific aims. Aim 1: Test the hypothesis that ethanol-induced gut dysbiosis, resultant butyrate depletion and epithelial barrier destabilization disrupts intestinal microvascular endothelial junctional protein integrity. Using both in vivo and ex vivo approaches, we will study how butyrate mitigates the effects of ethanol on endothelium disassembly of barrier junctional proteins. Aim 2: Test the hypothesis that ethanol activates and induces alterations in T-cell homing and Treg expansion within the intestinal lamina propria which causes intestinal microvascular endothelial dysregulation in a butyrate and atRA dependent manner. We will utilize ex vivo co-culture system, and in vivo wild-type and Foxp3DTR mice to test for ethanol-induced activation of intestinal microvascular EC, T-cell homing receptors, and Treg expansion and cytokine responses in lamina propria and splenocytes. Importantly, intestinal microvascular EC has not been studied in the context of ethanol, butyrate and atRA, and therefore new mechanistic insights may bring novel therapeutics to protect against ethanol’s disruption in intestinal homeostasis.

抽象的慢性乙醇暴露与肠道菌群失调、免疫力受损和器官发育有关功能障碍导致人们对乙醇引起的病理的器官间串扰的认识不断提高。第一次被击中乙醇摄入后，肠道和肠道微生物组在免疫系统稳态中发挥着核心作用。慢性的乙醇会降低肠道细菌的丰度和多样性，并破坏肠上皮屏障的稳定性，从而与管腔丁酸盐和肠道全反式视黄酸 (atRA) 水平降低、全身内毒素、和炎症。肠微血管内皮细胞（EC）位于肠固有层内，是通过招募和激活白细胞以及调节肠道血管灌注，对粘膜免疫功能至关重要。乙醇诱导的上皮屏障破坏和内毒素易位后，促炎分子与肠道微血管 EC 和固有层内的免疫细胞相互作用。内皮和免疫细菌内毒素的细胞激活导致其功能障碍。肠道微血管内皮屏障作为受损上皮的第二道防御屏障，提供额外的保护大分子和微生物易位。丁酸盐和 atRA 是已知的肠道产生的免疫营养素通过 T 淋巴细胞调节促进上皮屏障功能和免疫稳态。我们已经展示了丁酸（三丁酸甘油酯）补充剂通过防止分解来减轻乙醇引起的肠肝损伤上皮紧密连接蛋白，减少氧化应激，促进肠道微血管表达小鼠近端结肠中的内皮相关连接蛋白和免疫细胞。在这里我们建议假设通过乙醇破坏肠道微生物组，消耗丁酸盐和全反式视黄酸酸，以及随后肠上皮屏障的不稳定和内毒素、肠的易位微血管内皮功能被破坏并被激活，从而诱导肠道 T 细胞失调和炎症。我们将测试两个具体目标。目标 1：检验乙醇诱导的假设肠道菌群失调、由此导致的丁酸盐消耗和上皮屏障不稳定会破坏肠道微血管内皮连接蛋白的完整性。使用体内和离体方法，我们将研究丁酸如何减轻乙醇对屏障连接蛋白内皮分解的影响。目标 2：测试假设乙醇激活并诱导 T 细胞归巢和 Treg 扩增的改变肠固有层，导致丁酸盐和 atRA 肠道微血管内皮失调依赖方式。我们将利用离体共培养系统以及体内野生型和 Foxp3DTR 小鼠来测试乙醇诱导的肠道微血管 EC、T 细胞归巢受体激活以及 Treg 扩张和固有层和脾细胞中的细胞因子反应。重要的是，肠道微血管 EC 尚未被研究在乙醇、丁酸盐和 atRA 的背景下进行研究，因此新的机制见解可能会带来新颖的结果防止乙醇破坏肠道稳态的治疗方法。