Luminal Factors Affecting Duodenal Protection and Chemosensing

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 有人认为部分原因是“肠漏”，这是一种小肠屏障功能的损害，有助于 腔内微生物衍生毒素进入体循环。具体地说，许多 与肥胖相关的疾病，肥胖影响着35%的美国人口，而且有相当大的比例 在退伍军人中，与“代谢性内毒素血症”有关，在这种情况下 循环中存在脂多糖(LPS)水平，归因于肠道旁细胞增多 渗透性。 循环内毒素的增加与炎症途径的激活有关，而炎症途径又反过来 与肥胖的许多代谢紊乱有关，包括胰岛素 抵抗力和过多的肝脏和脂肪储存，导致严重的临床发病率，如II型 糖尿病和肝硬变。进入门静脉的脂蛋白是肠肝轴的一个组成部分，参与了 发病机制与代谢性内毒素血症有关的上述疾病。 内毒素进入体循环的机制，尽管归因于细胞旁的增加 通透性，主要是基于小肠旁细胞通透性与 小溶质和内毒素血症。尽管这一假设看似合理，也很吸引人，但很少有直接研究 肠道对内毒素的吸收；现有的少数研究，包括我们实验室的研究，支持内毒素 通过三条跨细胞途径与管腔脂类共生，即吸收乳糜粒的途径 长链甘油三酯(LCT)进入淋巴管，以及两条跨细胞内吞途径吸收 内毒素通过依赖和非依赖机制进入门静脉(PV)。这些后一种途径 支持内毒素作为连接肠道的“肠道-肝脏轴”的一部分进入肝静脉的机制 伴有肝脏和全身炎症的微生物群。 某些膳食脂肪被认为既有抗炎作用，又有促炎作用。例如， 摄入长链饱和脂肪酸与慢性炎症有关，如 代谢综合征而多不饱和脂肪酸(PUFA)通常伴随着“地中海” 节食“被认为是抗炎的。高效表达的肠碱性胞外酶 一顿肥餐后，磷酸酶(IAP)被释放到循环中。由于IAP能解毒，我们 建议研究哪些脂类最大限度地将IAP释放到门静脉，从而解毒内毒素，以帮助 理解为什么某些饮食中的脂肪是抗炎的。 在我们先前研究的基础上，我们计划研究肠上皮细胞转运肠腔的机制。 通过使用内吞蛋白小窝蛋白已被删除的小鼠模型来研究脂类和内毒素。这 模型将用于研究脂质结构和跨细胞途径的关系，以检验 假设内毒素摄取途径是由共跨细胞脂质决定的，并且途径是 根据它们动员解毒IAP的能力，可以是促炎的，也可以是抗炎的。我们将检查吸收 在不同结构的脂类存在的情况下，将研究通过 某些脂类，最后研究饮食补充不同结构的脂类对小鼠的影响。 代谢综合征的诱发。通过这些研究，我们希望能够更深入地了解 我们希望可以用来发现削弱内毒素摄取的干预措施的内毒素摄取机制 慢性或急性地希望治疗和预防与“肠漏”相关的疾病。

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”.