Dietary Regulation of Intestinal Inflammation and Repair

项目摘要 炎症性肠病（IBD），包括溃疡性结肠炎和克罗恩病，估计 在美国，IBD影响了300万人，患有IBD的人数继续上升。 目前可用的药物价格昂贵，对某些患者无效，并伴有严重的风险 包括机会性感染、肝脏炎症、胰腺炎和癌症。因此，迫切需要 以提高我们对肠道炎症和修复调节剂的理解， 治疗和预防IBD的治疗靶点。微生物群是各种代谢物的来源， 它们在吸收部位（肠）和远端部位（例如通过血流的脑）的作用。在这方面，委员会注意到， 微生物群模仿内分泌器官，其输出才刚刚开始被理解。由于各种饮食 成分，如膳食纤维，影响微生物群衍生的代谢产物的水平， 饮食对免疫细胞的影响可以通过微生物群来介导。虽然膳食纤维具有一定的抗炎作用 为了减少炎症性肠病的影响，IBD患者通常被指导限制他们的纤维摄入量，以减少炎症性肠病的发生频率和严重程度。 疾病爆发。然而，膳食纤维诱导IBD相关症状加重的机制 是很难理解的。在新的初步研究中，我们发现富含纤维的饮食可以激活结肠中的ILC 2 并显著增加嗜酸性粒细胞（一种由ILC 2调节的2型炎性免疫细胞）的水平。的 膳食纤维对嗜酸性粒细胞反应的影响取决于微生物群， 微生物衍生代谢物的显著变化。此外，高纤维饮食增加了疾病 严重程度在肠道损伤和炎症的小鼠模型中。尽管有这些观察结果， 膳食纤维通过什么途径调节ILC 2-嗜酸性粒细胞轴和结肠炎症仍然未知。基于 根据我们新的初步数据，我们假设微生物代谢物调节结肠ILC 2， 高纤维饮食引起的这些代谢物的改变诱导ILC 2的病理性激活和严重的肠损伤。 炎症我们建议详细了解微生物代谢物如何影响 在小鼠肠道炎症模型中的炎症病理学，并在人类中检查这些途径 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，我们将采用一种新的基于CRISPR的微生物基因编辑技术来直接测试微生物。 高纤维饮食介导肠道炎症的代谢途径。在目标3中，我们将翻译 这些发现对人类疾病，并确定如何改变微生物代谢产物和ILC 2-嗜酸性粒细胞 轴与IBD疾病活动性的临床和内窥镜测量相关。除了发现新的 饮食和微生物群的免疫调节机制及其在IBD中的独特作用，这些研究将提供 开发靶向该途径的新疗法的临床前论证。

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.