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Luminal Factors Affecting Duodenal Protection and Chemosensing

影响十二指肠保护和化学传感的管腔因素

基本信息

批准号：
10700480
负责人：
Jonathan D. Kaunitz
金额：
--
依托单位：
VA GREATER LOS ANGELES HEALTHCARE SYSTEM
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-01 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10700480
关键词：
Acute Adipose tissue Affect Alkaline Phosphatase Anti-Inflammatory Agents Applications Grants Arthritis Asthma Bacterial Toxins Caveolins Cell Line Characteristics Chronic Chronic Fatigue Syndrome Chylomicrons Circulation Cirrhosis Clathrin Clinical Diabetes Mellitus Dietary Fats Dietary Supplementation Disease Drug Metabolic Detoxication Duodenum Endotoxemia Enterocytes Fatty acid glycerol esters Fibromyalgia Functional disorder Hepatic Impairment Inflammatory Ingestion Insulin Resistance Intervention Intestines Laboratories Leaky Gut Link Lipids Lipopolysaccharides Lymphatic Mediterranean Diet Metabolic Metabolic syndrome Modeling Morbidity - disease rate Multiple Sclerosis Mus Non-Insulin-Dependent Diabetes Mellitus Obesity Pathogenesis Pathway interactions Permeability Poison Polyunsaturated Fatty Acids Population Portal vein structure Saturated Fatty Acids Small Intestines Structure Syndrome Testing Toxin Translating Triglycerides Veterans absorption glucose transport gut microbiome gut-liver axis intestinal barrier lipid structure liver inflammation metabolic endotoxemia microbial military veteran mouse model prevent solute systemic inflammatory response uptake

项目摘要

The pathophysiology of many diseases that are common in the Veteran population such as diabetes, multiple sclerosis, chronic fatigue syndrome, fibromyalgia, arthritis, asthma, and the metabolic syndrome is thought to be due in part to a “leaky gut”, an impairment of small intestinal barrier function that facilitates the entrance of luminal microbial-derived toxins into the systemic circulation. Specifically, many of the morbidities associated with obesity, which affects 35% of the US population and a much great percentage of the Veteran population, are related to “metabolic endotoxemia”, a condition in which elevated lipopolysaccharide (LPS) levels are present in the circulation, attributed to increased intestinal paracellular permeability. Increased circulating LPS has been implicated in the activation of inflammatory pathways, which in turn have been associated with many of the metabolic derangements characteristic of obesity, including insulin resistance and excess hepatic and adipose lipid storage, leading to serious clinical morbidity such as type II diabetes and cirrhosis. LPS entering the portal vein is a component of the “gut liver axis” implicated in the pathogenesis the aforementioned diseases associated with metabolic endotoxemia. The mechanism by which LPS enters the systemic circulation, though attributed to increased paracellular permeability, is primarily based on the association between small intestinal paracellular permeability to small solutes and endotoxemia. As plausible and attractive as is this hypothesis, there are few direct studies of intestinal LPS absorption; the few studies available, including those from our laboratory, support that LPS is cotrancytosed with luminal lipids via three transcellular pathways, the chylomicron pathway that absorbs long-chain triglycerides (LCT) into the lymphatics, and two transcellular endocytic pathways that absorbs LPS into the portal vein (PV) by clathrin-dependent and -independent mechanisms. These latter pathways support the mechanism whereby LPS enters the PV as part of the “gut-liver axis”, that links the gut microbiome with hepatic and systemic inflammation. Certain dietary lipids are considered to be either anti-inflammatory and pro-inflammatory. For example, the ingestion of long-chain saturated fatty acids are associated with chronic inflammatory conditions such as the metabolic syndrome whereas polyunsaturated fatty acids (PUFA) that often accompany the “Mediterranean diet” are believed to be anti-inflammatory. The highly expressed ecto-enzyme intestinal alkaline phosphatase (IAP) is released into the circulation following a fat meal. Since IAP detoxifies LPS, we propose to study which lipids maximally release IAP into the portal vein, detoxifying LPS, in order to help understand why certain dietary lipids are anti-inflammatory. Building on our prior studies, we plan to study the mechanisms by which enterocytes cotrancytose luminal lipids and LPS by using mouse models in which the endocytic protein caveolin has been deleted. This model will be used to study the relation between lipid structure and transcytotic pathway to test the hypothesis that the LPS uptake pathways is determined by the co-transcytosed lipid and that pathways are either pro or anti-inflammatory based on their ability to mobilize detoxifying IAP. We will examine the uptake in the presence of lipids of varying structure, will study the inhibition of intestinal active glucose transport by certain lipids, and finally study the effect of dietary supplementation with lipids of varying structure on the induction of the metabolic syndrome. Through these studies we hope to gain a deeper understanding of LPS uptake mechanisms that we hope can be used to discover interventions that impair LPS uptake chronically or acutely with the hope of treating and preventing diseases associated with the “leaky gut”.

退伍军人中常见的许多疾病的病理生理学，如糖尿病，多发性硬化症、慢性疲劳综合征、纤维肌痛、关节炎、哮喘和代谢综合征，这被认为部分是由于“肠漏”，即小肠屏障功能受损，腔微生物来源的毒素进入体循环。具体来说，许多与肥胖相关的疾病，影响了35%的美国人口，与“代谢性内毒素血症”有关，脂多糖（LPS）水平存在于循环中，这归因于肠旁细胞磁导率循环LPS的增加与炎症通路的激活有关，而炎症通路反过来又与炎症反应有关。与肥胖症的代谢紊乱有关，包括胰岛素抵抗和过量的肝脏和脂肪脂质储存，导致严重的临床发病率，如II型糖尿病和肝硬化进入门静脉的LPS是参与门静脉高压的“肠肝轴”的组成部分。发病机制与代谢性内毒素血症相关的上述疾病。 LPS进入体循环的机制，虽然归因于细胞旁的增加，渗透性，主要是基于小肠细胞旁渗透性与小溶质和内毒素血症。尽管这一假设看似合理，也很有吸引力，但几乎没有直接的研究肠内脂多糖吸收;少数研究，包括我们实验室的研究，支持LPS 通过三种跨细胞途径与管腔脂质共转运，即乳糜微粒途径，长链甘油三酯（LCT）进入细胞内吞，以及两个跨细胞内吞途径， LPS通过网格蛋白依赖性和非依赖性机制进入门静脉（PV）。后一种途径支持LPS作为“肠-肝轴”的一部分进入PV的机制，微生物组与肝脏和全身炎症的关系。某些膳食脂质被认为具有抗炎和促炎作用。比如说长链饱和脂肪酸的摄入与慢性炎性疾病有关，代谢综合征，而多不饱和脂肪酸（PUFA），往往伴随着“地中海” 饮食”被认为是抗炎的。高表达的胞外酶肠碱性脂肪餐后，磷酸酶（IAP）被释放到循环中。由于IAP解毒LPS，我们我建议研究哪些脂质最大限度地释放IAP到门静脉，解毒LPS，以帮助了解为什么某些膳食脂质具有抗炎作用。在我们先前研究的基础上，我们计划研究肠上皮细胞共转运管腔的机制，脂质和脂多糖通过使用小鼠模型，其中内吞蛋白小窝蛋白已被删除。这模型将被用来研究脂质结构和胞吞途径之间的关系，以测试假设LPS摄取途径是由共转胞吞脂质决定的，根据其动员解毒IAP的能力，可以是促炎或抗炎的。我们将检查吸收情况在存在不同结构的脂质的情况下，将研究通过以下途径抑制肠主动葡萄糖转运：某些脂质，最后研究膳食补充不同结构的脂质对诱发代谢综合征。通过这些研究，我们希望能够更深入地了解 LPS摄取机制，我们希望可以用来发现干预，损害LPS摄取慢性或急性的，希望治疗和预防与“肠漏”相关的疾病。