Dietary Regulation of Intestinal Inflammation and Repair

项目总结 炎症性肠病(IBD)，包括溃疡性结肠炎和克罗恩病，估计 在美国有300万人受到影响，感染IBD的人数还在继续上升。 目前可用的药物价格昂贵，对一些患者无效，并与严重的风险相关 包括机会性感染、肝脏炎症、胰腺炎和癌症。因此，迫切需要 提高我们对肠道炎症和修复调节因子的了解，以识别新的 治疗和预防IBD的治疗靶点。微生物区系是各种代谢物的来源，这些代谢物可以 它们在吸收部位(肠道)和远端部位(如通过血液的大脑)起作用。在这方面， 微生物区系模仿一个内分泌器官，它的输出才刚刚开始被理解。因为不同的饮食 成分，如膳食纤维，影响微生物区系衍生的代谢物的水平，许多影响 免疫细胞上的饮食可以通过微生物区系来调节。虽然膳食纤维有一定的抗炎作用 为了减少IBD的影响，经常指导患者限制纤维摄入量，以降低IBD的频率和严重性 疾病爆发。然而，膳食纤维导致IBD相关症状恶化的机制 人们对此知之甚少。在新的初步研究中，我们发现富含纤维的饮食会激活结肠中的ILC2 并显著增加嗜酸性粒细胞的水平，嗜酸性粒细胞是一种受ILC2调节的2型炎性免疫细胞。这个 膳食纤维对嗜酸性粒细胞反应的影响依赖于微生物区系，并与 微生物区系衍生代谢物的显著变化。此外，高纤维饮食增加了疾病的发病率。 肠道损伤和炎症的小鼠模型中的严重程度。尽管有这些观察，但这些机制 膳食纤维通过什么来调节ILC2-嗜酸性粒细胞轴和结肠炎仍不清楚。基座 根据我们新的初步数据，我们假设微生物代谢产物调节结肠ILC2s，并且 高纤维饮食改变这些代谢物可导致ILC2s和严重肠道的病理性激活 发炎。我们建议对微生物代谢物如何影响 小鼠肠炎模型的炎性病理变化及其在人类中的研究 IBD患者样本。在目标1中，我们将确定微生物代谢物和宿主代谢物受体是什么 参与高纤维饮食诱导的2型炎症及其在肠道损伤和炎症中的作用。 在目标2中，我们将使用一种新的基于CRISPR的微生物基因编辑技术来直接测试微生物 高纤维饮食调节肠道炎症的代谢途径。在《目标3》中，我们将翻译 这些发现与人类疾病有关，并确定了微生物代谢产物和ILC2-嗜酸性粒细胞的变化 AXIS与IBD疾病活动性的临床和内窥镜检查结果相关。除了揭开小说 饮食和微生物区系的免疫调节机制及其在IBD中的独特作用，这些研究将提供 针对这一途径开发新的治疗药物的临床前理由。

PROJECT SUMMARY Inflammatory bowel diseases (IBD), which include both ulcerative colitis and Crohn's disease, are estimated to affect three million individuals in the United States, and the number of people living with IBD continues to rise. Currently available medications are costly, ineffective for some patients, and associated with serious risks including opportunistic infections, hepatic inflammation, pancreatitis, and cancer. Thus, there is an urgent need to improve our understanding of the modulators of intestinal inflammation and repair in order to identify novel therapeutic targets to treat and prevent IBD. The microbiota is the source of various metabolites which can exert their effects at the site of absorption (intestine), and at distant sites such as brain via bloodstream. In this regard, the microbiota mimics an endocrine organ, and its output has only begun to be understood. Since various dietary components, such as dietary fiber, influence the levels of microbiota-derived metabolites, many of the effects of diets on immune cells could be mediated via the microbiota. Although dietary fiber has some anti-inflammatory effects, IBD patients are often instructed to limit their fiber consumption to reduce the frequency and severity of disease flares. However, the mechanism behind dietary fiber-induced exacerbation of IBD-associated symptoms is poorly understood. In new preliminary studies, we identified that a fiber-rich diet activates ILC2s in the colon and significantly increases the levels of eosinophils, a type 2 inflammatory immune cell regulated by ILC2s. The effects of dietary fiber on the eosinophil responses are dependent on the microbiota and are associated with remarkable changes in microbiota-derived metabolites. Furthermore, the high fiber diet increased disease severity in a murine model of intestinal damage and inflammation. Despite these observations, the mechanisms through which dietary fiber regulates the ILC2-eosinophil axis and colonic inflammation remain unknown. Based on our new preliminary data, we hypothesize that microbial metabolites regulate colonic ILC2s and that alterations of these metabolites by a high fiber diet induce pathologic activation of ILC2s and severe intestinal inflammation. We propose to generate a detailed understanding of how microbial metabolites influence inflammatory pathologies in murine models of intestinal inflammation and examine these pathways in human IBD patient samples. In Aim 1, we will determine what microbial metabolites and host metabolite receptors are involved in the high fiber diet-induced type 2 inflammation and their role in intestinal damage and inflammation. In Aim 2, we will employ a novel CRISPR-based microbial gene-editing technique to directly test the microbial metabolic pathways through which a high fiber diet mediates intestinal inflammation. In Aim 3, we will translate these findings to human disease and determine how alterations in microbial metabolites and the ILC2-eosinphil axis correlate with clinical and endoscopic measures of IBD disease activity. In addition to uncovering novel immunoregulatory mechanisms of diet and microbiota and their unique roles in IBD, these studies will provide preclinical justification for development of novel therapeutics to target this pathway.