DIETARY FAT PROMOTES CHYLOMICRON-DEPENDENT INTESTINAL ABSORPTION OF GUT ANTIGENS

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目及 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 肥胖是动脉粥样硬化的一个重要危险因素。随着脂肪储存的扩大，它们变得越来越发炎，释放炎性细胞因子，然后对血管功能产生负面影响。然而，目前尚不清楚脂肪组织扩张期间炎症的根本原因。一个突出的事件是巨噬细胞的浸润，尽管目前还不清楚为什么会发生这种情况，以及这些巨噬细胞的作用。最近对小鼠的研究表明，在实验性肥胖期间，巨噬细胞浸润发生相对较晚，这表明在巨噬细胞浸润之前存在较早的炎症事件，并且可能导致巨噬细胞浸润。我们已经观察到，肠脂肪吸收与肠吸收来自肠道微生物菌群的抗原有关。吸收的抗原与新分泌的乳糜微粒相关，乳糜微粒是通过肠系膜淋巴将膳食脂肪转运到体内的大脂蛋白颗粒。由于乳糜微粒在脂肪组织中被显著清除，我们将在当前项目中测试肠道抗原以乳糜微粒依赖性方式沉积到脂肪组织中的假设。增加脂肪喂养将导致脂肪抗原富集增加，随后淋巴细胞浸润。我们的初步数据表明，乳糜微粒的形成促进肠道吸收和脂肪沉积的饮食卵清蛋白（OVA），一个原型的实验T细胞抗原。我们的初步数据还表明，脂肪富集与这种T细胞抗原是迅速其次是T细胞浸润，这可能是一个重要的初始事件在脂肪炎症，并可能随后招募巨噬细胞。 如果我们的假设是正确的，它不仅会使人们关注适应性免疫系统作为脂肪炎症的重要贡献者，而且还会关注肠道微生物菌群和饮食抗原作为脂肪组织和许多其他组织炎症的潜在来源。很可能是那些对细菌或饮食抗原耐受性降低的人，如果这些抗原进入人体，他们会对这些抗原产生反应，对肥胖相关的炎症特别敏感。此外，脂肪吸收和肠道抗原吸收之间的新联系可能会深刻影响我们对肠道微生物菌群影响我们身体的方式的思考。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Obesity is a strong risk factor for atherosclerosis. As fat stores expand, they become increasingly inflamed, releasing inflammatory cytokines, which then negatively affect blood vessel functioning. However, the underlying cause of inflammation during the expansion of adipose tissue is currently unknown. One prominent event is the infiltration of macrophages, though it is still unclear why this happens, and what these macrophages do. Recent studies with mice have suggested that macrophage infiltration occurs relatively late during experimental obesity, which suggests that there are earlier inflammatory events preceding, and perhaps causing macrophage infiltration. We have observed that intestinal fat absorption is associated with the intestinal absorption of antigens from gut microflora. The absorbed antigen was associated with newly secreted chylomicrons, which are the large lipoprotein particles that transport dietary fat via mesenteric lymph into the body proper. Since chylomicrons are prominently cleared in adipose tissue, we will test in the current project the hypothesis that gut antigens are deposited into adipose tissue in a chylomicron-dependent manner. Increased fat feeding would then lead to increased adipose antigen enrichment, followed by lymphocyte infiltration. Our preliminary data suggest that chylomicron formation promotes intestinal absorption and adipose deposition of dietary ovalbumin (OVA), a prototypical experimental T-cell antigen. Our preliminary data also show that adipose enrichment with such T-cell antigens is rapidly followed by T-cell infiltration, which may be an important initial event in adipose inflammation, and which may subsequently recruit macrophages. If our hypothesis is correct, it would not only put the spotlight on the adaptive immune system as an important contributor to adipose inflammation, but also on the intestinal microflora and dietary antigens as potential sources for inflammation in fat tissue, and in many other tissues. It may well be that individuals with reduced tolerance to bacterial or dietary antigens, and who thus would respond to these antigens if they make their way into the body proper, are especially sensitive to obesity-associated inflammation. Moreover, the novel link between fat absorption and gut antigen absorption may profoundly affect our thinking on the way the gut microflora affects our body.