Dietary Regulation of Intestinal Inflammation and Repair

肠道炎症和修复的饮食调节

基本信息

批准号：
10592429
负责人：
David Artis
金额：
$ 68.19万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-03-15 至 2026-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10592429
关键词：
Address Adoptive Cell Transfers Affect Antiinflammatory Effect Bacteria Bacteroidetes Bile Acids Biological Blood Circulation Brain CRISPR/Cas technology Cells Cholic Acids Chronic Disease Clinical Clustered Regularly Interspaced Short Palindromic Repeats Colon Colonic inflammation Complex Consumption Crohn&apos s disease Data Development Diet Dietary Component Dietary Fiber Disease Distant Economic Burden Endocrine Glands Environmental Risk Factor Eosinophilia Etiology Fermentation Fiber Flare Food Frequencies Gene Deletion Gene Expression Gene Expression Profiling Genes Genetic Genetic Engineering Germ-Free Human Immune Immune response Immunologic Factors Immunologics In Vitro Individual Indoles Inflammation Inflammatory Inflammatory Bowel Diseases Interleukin-5 Intestines Inulin Libraries Lymphoid Cell Malignant Neoplasms Mammalian Cell Measures Mediating Metabolic Metabolic Pathway Mus Opportunistic Infections Outcome Output Pancreatitis Pathologic Pathology Pathway interactions Patients Persons Pharmaceutical Preparations Production Propionic Acids Public Health Recommendation Regulation Risk Role Sampling Serum Severity of illness Site Source Stromal Cells Symptoms Techniques Testing Tissues Translating Ulcerative Colitis United States Volatile Fatty Acids absorption associated symptom comparative cost cytokine dietary eosinophil genetic manipulation gut inflammation human disease immunoregulation improved in vivo liver inflammation metabolomics microbial microbiota microbiota metabolites mouse model mutant new therapeutic target novel novel therapeutics pre-clinical prevent receptor receptor expression repaired response transcriptional reprogramming transcriptomics

项目摘要

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.

项目概要据估计，炎症性肠病（IBD）包括溃疡性结肠炎和克罗恩病影响美国 300 万人，并且 IBD 患者人数持续增加。目前可用的药物价格昂贵，对某些患者无效，并且存在严重风险包括机会性感染、肝脏炎症、胰腺炎和癌症。因此，迫切需要提高我们对肠道炎症和修复调节剂的了解，以便识别新的治疗和预防 IBD 的治疗目标。微生物群是各种代谢物的来源，这些代谢物可以发挥作用它们在吸收部位（肠道）以及通过血流在大脑等远处部位产生影响。对此，微生物群模仿内分泌器官，其输出才刚刚开始被了解。由于各种饮食膳食纤维等成分会影响微生物群衍生的代谢物的水平，其中许多影响对免疫细胞的饮食可以通过微生物群介导。膳食纤维虽然有一定的抗炎作用影响，IBD 患者经常被指示限制纤维消耗，以减少炎症的频率和严重程度疾病发作。然而，膳食纤维引起 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 并显着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 型炎症免疫细胞。这膳食纤维对嗜酸性粒细胞反应的影响取决于微生物群，并与微生物群衍生的代谢物发生显着变化。此外，高纤维饮食会增加疾病的发生小鼠肠道损伤和炎症模型的严重程度。尽管有这些观察结果，但机制膳食纤维通过何种途径调节 ILC2-嗜酸性粒细胞轴和结肠炎症仍不清楚。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 ILC2，并且高纤维饮食对这些代谢物的改变会导致 ILC2 的病理性激活，并严重影响肠道功能。炎。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研究炎症病理学，并在人类中检查这些途径 IBD 患者样本。在目标 1 中，我们将确定什么是微生物代谢物和宿主代谢物受体参与高纤维饮食诱发的 2 型炎症及其在肠道损伤和炎症中的作用。在目标2中，我们将采用一种新型的基于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有影响，并确定微生物代谢物和 ILC2-嗜酸性粒细胞的变化如何轴与 IBD 疾病活动的临床和内窥镜测量相关。除了揭开小说的面纱饮食和微生物群的免疫调节机制及其在 IBD 中的独特作用，这些研究将提供针对该途径开发新疗法的临床前理由。