Gut region-specific mechanisms that limit dissemination of microbial signals from the intestine

限制肠道微生物信号传播的肠道区域特异性机制

基本信息

批准号：
10283039
负责人：
Gwendalyn J Randolph
金额：
$ 44.1万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-08 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10283039
关键词：
Address Affect Antibody Therapy B-Lymphocytes Behavior Biological Biology Blood Blood Circulation Blood Vessels Cells Characteristics Colon Communities Crohn&apos s disease of the ileum Data Disease Distal Drainage procedure Endothelium Epithelial Epithelial Cells Evaluation Excision Experimental Models Extravasation Genes Gut Mucosa Hepatocyte High Density Lipoproteins Immune Immunology Infection Inflammation Inflammatory Inflammatory Bowel Diseases Intestinal Mucosa Intestines Knowledge Laboratories Leukocyte Rolling Leukocytes Lipids Lipoprotein (a)Lipoproteins Liver Liver diseases Location Lung Lymph Lymphatic Mediating Mesentery Microbe Molecular Mucous Membrane Mus Nature Nutrient Operative Surgical Procedures Outcome Phagocytes Phagocytosis Pharmaceutical Preparations Plasma Cells Portal vein structure Production Proteome Proteomics Regulation Resources Role Route Signal Transduction Site Small Intestines Sorting - Cell Movement Surface TLR4 gene TNF gene Thoracic Duct Tissues Vaccination Validation Veins Venous Villus White Blood Cell Count procedure Whole Blood absorption combat gut microbes ileum inhibitor/antagonist interest intestinal barrier intestinal epithelium intravital imaging lipidome lipidomics liver injury lymphatic vessel microbial microbiome monocyte mouse model multidisciplinary multiple omics neutralizing antibody neutrophil non-alcoholic novel nutrient absorption organ injury porcine model problem drinker programs response skills superior mesenteric vein

项目摘要

ABSTRACT A major concern of the intestinal mucosa is to execute its role in absorption of nutrients while minimizing inflammatory or adverse immune interactions with the microbiome. Managing absorption entails not only sorting of nutrients by intestinal epithelial cells but also delivery of those nutrients to specialized blood and lymphatic vessels present in each villus of the small intestine. In turn, the blood and lymphatic vessels that collectively manage outflow from the gut may need to rely on specialized mechanisms that operate to limit dissemination of microbial signals to distal sites like the lung or the liver to avoid downstream organ injury. It is now appreciated, for instance, that alcoholic and nonalcoholic liver damage is driven substantially by microbial transit from the gut to the liver via the portal vein. Likewise, pulmonary damage can ensue in response to injurious cargo in lymph that gains access to blood via the thoracic duct and quickly next flows to the lungs. Yet mechanisms protecting against dissemination of microbial signals from the intestinal mucosa remain incompletely understood, possibly making planned manipulations of the mucosal barrier, as in vaccination or disease therapy, riskier than needed or resulting in surprises. For instance, our preliminary data suggest that the documented and seemingly counterintuitive liver damage that can result from anti-TNF neutralizing antibody therapy to treat inflammatory disease of the bowel may be due, at least in part, to disruption of leukocyte-mediated surveillance of the draining venous vasculature that removes microbes that escape the intestinal mucosal before they arrive to the liver. To fill in these basic knowledge gaps, we propose herein to delineate how different regions of the intestine program leukocyte-dependent and leukocyte-independent strategies to protect downstream cells and tissues against dissemination of microbial signals. In aim 1, we focus on mechanisms operative in phagocytic removal from gut-draining venous blood of whole microbes that escape the intestinal mucosal barrier and otherwise deliver the microbes to deeper tissues or distal locations. In aim 2, we will compare how the small bowel and colon may differentially transport and neutralize soluble microbial signals, like LPS, that can inadvertently escape the epithelial barrier to promote inflammation. This effort will include comprehensive proteomic and lipidomic evaluation of lymph and blood draining different regions of the gut mucosa, working with expert collaborators and taking advantage of our laboratory’s expertise in lymphatic biology and recent studies in the transport of intestinal cargo into gut-draining venous blood.

抽象的肠粘膜的一个主要问题是执行其吸收营养物质的作用，同时最大限度地减少控制吸收不仅需要炎症或不良免疫相互作用。肠上皮细胞对营养物质进行分类，并将这些营养物质输送到专门的血液和淋巴管存在于小肠的每个绒毛中，反过来，血管和淋巴管也存在于小肠的每个绒毛中。集体管理肠道外流可能需要依赖专门的机制来限制将微生物信号传播到肺或肝脏等远端部位，以避免下游器官损伤。例如，现在人们认识到酒精性和非酒精性肝损伤主要是由微生物引起的同样，通过门静脉从肠道转移到肝脏，也会导致肺部损伤。淋巴液中的有害物质通过胸导管进入血液，然后迅速流向肺部。防止肠粘膜微生物信号传播的机制仍然存在不完全了解，可能对粘膜屏障进行有计划的操作，如疫苗接种或例如，我们的初步数据表明，疾病治疗的风险高于所需的水平或导致意外。抗 TNF 中和可能导致有记录的、看似违反直觉的肝损伤治疗肠道炎症性疾病的抗体疗法可能至少部分是由于破坏白细胞介导的对引流静脉脉管系统的监视，可清除逃逸的微生物为了填补这些基本知识空白，我们提出建议：描述肠道的不同区域如何进行白细胞依赖性和白细胞非依赖性编程保护下游细胞和组织免受微生物信号传播的策略在目标 1 中，我们。重点关注从肠道引流静脉血中吞噬去除完整微生物的机制逃离肠粘膜屏障，并将微生物输送到更深的组织或远端位置。在目标 2 中，我们将比较小肠和结肠如何差异运输和中和可溶性物质微生物信号，如脂多糖，可以无意中逃脱上皮屏障，促进炎症。工作将包括对淋巴和血液引流不同部位进行全面的蛋白质组学和脂质组学评估与专家合作者合作并利用我们实验室的专业知识来研究肠道粘膜区域淋巴生物学和最近将肠道货物运输到肠道引流静脉血的研究。