IMPACT OF DIETARY SALT ON INFLAMMATION AND INFECTION: INSIGHTS INTO COLITIS

 描述(申请人提供)：炎症性肠病(IBD)是一组包括克罗恩病和溃疡性结肠炎的疾病。因此，IBD是美国最常见的胃肠道疾病之一，每年造成约17亿美元的损失。由于IBD是不治之症，患者被迫忍受反复的住院和手术。此外，由于IBD对社会经济地位较低的人的影响不成比例，IBD的成本负担最沉重地落在那些最容易受到经济困难影响的人身上。在过去的几十年里，对IBD遗传学的广泛研究导致了几种克罗恩病和溃疡性结肠炎的动物模型的发展。相比之下，对饮食等环境风险因素的研究只是在最近几年才加速到同等水平。事实上，尽管低纤维、高脂肪的西式饮食长期以来 与IBD的发展相关，直到最近才有研究表明，低膳食纤维会加重IBD。对包括盐在内的其他饮食因素的研究仍有待进行。我们特别建议研究高盐饮食(HSD)的作用。最近的研究表明，饮食中的盐会加剧自身免疫性脑炎，这表明HSD可能会导致其他自身免疫性疾病，如炎症性肠病(IBD)。事实上，在初步实验中，我们观察到HSD显示的动物在两种小鼠结肠炎模型中加剧炎症和增加炎症细胞因子的产生：IL10-/-炎症性结肠炎模型和鼠伤寒沙门氏菌感染性结肠炎模型。因此，我们的数据表明，HSD可以加剧小鼠的肠道炎症。基于这些数据，我们建议研究先天性免疫系统在HSD加重的结肠炎中的作用，以及血清和糖皮质激素激酶(SGK1)的参与，后者以前被描述为Th17细胞中的渗透感受器。我们特别假设，在这些结肠炎模型中，先天性免疫细胞对饮食盐做出反应，增加了它们的炎症输出。为了解决这一假设，我们将在两种模型中检查T细胞缺陷(RAG基因敲除)小鼠，并比较HSD和LSD的组织学、细胞因子表达和细胞募集。(目标1)。我们还将使用小分子抑制剂和基因敲除小鼠来具体研究SGK1在先天细胞中的作用。(目标2)。这项提议的影响是深远的。在确定饮食盐如何驱动IBD时，我们的研究可能会建议潜在的药物靶点(例如，负责增强免疫激活的信号通路)或预防性饮食指南(即，IBD患者的低盐饮食)。后一种公共卫生方法特别重要，因为饮食指南成本低廉，可以立即实施，为IBD患者提供缓解。

 DESCRIPTION (provided by applicant): Inflammatory Bowel Disease (IBD) is a group of disorders encompassing Crohn's disease and ulcerative colitis. As such, IBD represents one of the most prevalent gastrointestinal diseases in the US, costing approximately $1.7 billion annually. Because IBD is incurable, patients are forced to endure repeated hospitalizations and surgeries. Moreover, since IBD disproportionately impacts people of low socio-economic status, the cost burden of IBD falls most heavily on those most susceptible to financial hardship. Extensive research into the genetics of IBD over the last several decades led to the development of several animal models for Crohn's disease and ulcerative colitis. By comparison, the study of environmental risk factors like diet has accelerated to equivalent levels only in the last few years. Indeed, while a Western diet low in fiber and high in fat has long been correlated with development of IBD, it was only recently shown that low dietary fiber exacerbates IBD. Studies of other dietary factors, including salt, remain to be performed. We specifically propose to examine the role of a high-salt diet (HSD). Recent studies show that dietary salt can exacerbate autoimmune encephalitis, suggesting that a HSD could contribute to other auto-immune diseases like inflammatory bowel disease (IBD). Indeed, in preliminary experiments, we have observed that animals on a HSD display exacerbated inflammation and increased inflammatory cytokine production in two models of murine colitis: the Il10-/- model of inflammatory colitis, and the S. typhimurium model of infectious colitis. Our data thus indicates that a HSD can exacerbate intestinal inflammation in mice. Based on these data, we propose to examine the role of the innate immune system in HSD- exacerbated colitis, as well as the involvement of the serum and glucocorticoid kinase (SGK1) which has previously been described as an osmosensor in Th17 cells. We specifically hypothesize that innate immune cells respond to dietary salt, increasing their inflammatory output in these models of colitis. To address this hypothesis, we will examine T cell deficient (Rag knockout) mice in both models, and compare histology, cytokine expression and cellular recruitment on a HSD vs a LSD. (AIM 1). We will also specifically examine the role of SGK1 in innate cells using a small molecule inhibitor, and genetic knockout mice. (AIM 2). The implications of this proposal are far reaching. In determining how dietary salt drives IBD, our research may suggest potential drug targets (e.g. signaling pathways responsible for enhanced immune activation), or prophylactic dietary guidelines (i.e. low-salt diets for people with IBD). The latter public health approach is particularly important, as dietary guidelines are inexpensive and can be implemented immediately to provide relief to those suffering with IBD.