Dietary regulation of type 2 immunity and inflammation in the gut

肠道 2 型免疫和炎症的饮食调节

基本信息

批准号：
10740269
负责人：
Mohammad Arifuzzaman
金额：
$ 9.88万
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：
2023
资助国家：
美国
起止时间：
2023-07-10 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10740269
关键词：
Abdominal Pain Address Affect Anemia Antiinflammatory Effect Bacteria Bile Acids Biology Cholic Acids Chronic Clinical Colon Colon Carcinoma Colorectal Cancer Communication Complex Data Diarrhea Diet Dietary Fiber Dietary Intervention Disease Disease Outcome Economic Burden Environment Environmental Risk Factor Eosinophilia Epithelium Etiology Fermentation Fiber Flow Cytometry Food Gastrointestinal Diseases Genes Genetic Genetic Engineering Germ-Free Gnotobiotic Goals Hemorrhage Hydrolase Immune response Immunity Immunology Individual Inflammation Inflammatory Inflammatory Arthritis Inflammatory Bowel Diseases Inflammatory Response Institution Interleukin-4 Interleukin-5 Intervention Intestines Inulin Laboratories Lamina Propria Lymphoid Cell Malnutrition Mediating Mentors Metabolic Pathway Microscopy Modeling Molecular Mucous Membrane Mus Outcome Pathogenesis Pathologic Pathology Patients Pattern Phase Phenotype Postdoctoral Fellow Production Public Health Quality of life Rectum Regulation Research Research Personnel Risk Role Severity of illness Signal Transduction Stromal Cells Symptoms Testing Therapeutic Therapeutic Intervention Tissues Training Programs Transgenic Mice Ulcerative Colitis United States Up-Regulation Volatile Fatty Acids Work Writing animal facility bacterial genetics bile acid metabolism bile salts career cytokine dietary eosinophil eosinophil peroxidase experimental study gut inflammation host microbiota immunoregulation improved infection risk inhibitor instrument mesenchymal stromal cell metabolomics microbial microbiota microbiota metabolites migration mouse model mutant novel preventive intervention rational design receptor rectal response skills

项目摘要

PROJECT SUMMARY Understanding the role of environmental factors including signals derived from the diet and microbiota is key to improving therapeutic and intervention strategies for gastrointestinal disorders including inflammatory bowel diseases (IBD) and inflammation-associated colorectal cancer (CRC). Dietary fiber can exert immunoregulatory effects through microbial fermentation products including short chain fatty acids (SCFAs). However, the influence of dietary fiber on most microbiota-derived metabolites and their role in immunoregulation remain unclear. In new preliminary studies, I identified that an inulin-rich high fiber diet triggers colonic eosinophilia in a microbiota- dependent manner which exacerbates disease outcomes in murine models of intestinal damage and inflammation-associated CRC. These diet-induced type 2 inflammatory responses are associated with upregulation of microbiota-derived bile acids and activation of mesenchymal stromal cells (MSCs) and group 2 innate lymphoid cells (ILC2s). However, the cellular and molecular components in the host and the metabolic pathways in the microbiota that mediate the dietary effects on intestinal inflammation remain unclear. In Aim 1, I will determine how bile acids regulate type 2 cytokines and eosinophilia during high fiber diet-induced intestinal inflammation. In Aim 2, I will investigate how dietary fiber-induced eosinophils contribute to intestinal damage. In Aim 3, I will employ bacterial genetics and gnotobiotic approaches to identify the microbial metabolic pathways required for high fiber diet-induced intestinal inflammation. Upon successful completion of the proposed aims, I expect to contribute to a fundamentally new understanding of the biology of dietary fiber, microbiota-derived metabolites, and stromal cells in regulating type 2 inflammation which could contribute to rational design of diet- and microbiota-based therapeutic approaches. My overarching career goals are to become an independent investigator and an inspirational mentor at a leading academic institution and to study the mechanisms by which environmental factors regulate intestinal inflammation and gastrointestinal diseases. Completion of my research aims in this proposal will allow me to develop various scientific, professional, and personal skills critical to become a successful independent investigator. These will include acquiring expertise in various fields including metabolomic analyses and genetic engineering with help of my collaborators, as well as developing skills in writing, mentoring, communicating and laboratory management. I will perform the K99 phase in the laboratory of Dr. David Artis, a world leader in the fields of mucosal immunology and host-microbiota interactions. The laboratory has access to all instruments and facilities necessary to complete the proposed aims including a gnotobiotic animal facility and provides an outstanding environment and training program to support postdoctoral researchers. In addition to my mentor and co-mentor, I have support from several distinguished investigators with extensive expertise as advisors and collaborators that will greatly facilitate the completion of my experiments during the K99 phase as I progress to become an independent investigator.

项目概要了解环境因素（包括来自饮食和微生物群的信号）的作用是关键改善胃肠道疾病（包括炎症性肠病）的治疗和干预策略疾病（IBD）和炎症相关结直肠癌（CRC）。膳食纤维可发挥免疫调节作用通过微生物发酵产物（包括短链脂肪酸（SCFA））产生的影响。然而，影响膳食纤维对大多数微生物群衍生代谢物的影响及其在免疫调节中的作用仍不清楚。在在新的初步研究中，我发现富含菊粉的高纤维饮食会引发结肠微生物群中的嗜酸性粒细胞增多—— 依赖的方式加剧了小鼠肠道损伤模型中的疾病结果炎症相关的结直肠癌。这些饮食引起的 2 型炎症反应与微生物群衍生胆汁酸的上调以及间充质基质细胞 (MSC) 和第 2 组细胞的激活先天淋巴细胞（ILC2）。然而，宿主中的细胞和分子成分以及代谢微生物群中介导饮食对肠道炎症影响的途径仍不清楚。在目标 1 中，我将确定胆汁酸在高纤维饮食诱导的肠道过程中如何调节 2 型细胞因子和嗜酸性粒细胞增多炎。在目标 2 中，我将研究膳食纤维诱导的嗜酸性粒细胞如何导致肠道损伤。在目标 3 中，我将采用细菌遗传学和无菌方法来识别微生物代谢途径高纤维饮食引起的肠道炎症所需。在成功完成拟议目标后，我期望有助于对膳食纤维的生物学、微生物群衍生的全新认识做出贡献代谢物和基质细胞调节 2 型炎症，这可能有助于合理设计饮食- 和基于微生物群的治疗方法。我的首要职业目标是成为一名独立的人领先学术机构的研究员和励志导师，并研究其机制环境因素调节肠道炎症和胃肠道疾病。完成我的研究该提案中的目标将使我能够发展各种科学、专业和个人技能，这些技能对于成为一名成功的独立调查员。这些将包括获得各个领域的专业知识，包括在我的合作者的帮助下进行代谢组学分析和基因工程，以及发展以下方面的技能写作、指导、沟通和实验室管理。我将在实验室进行K99阶段 David Artis 博士是粘膜免疫学和宿主微生物相互作用领域的世界领先者。这实验室拥有完成拟议目标所需的所有仪器和设施，包括限生动物设施，并提供出色的环境和培训计划来支持博士后研究人员。除了我的导师和共同导师之外，我还得到了几位杰出研究人员的支持作为顾问和合作者拥有丰富的专业知识，这将极大地促进我的实验的完成在 K99 阶段，我逐渐成为一名独立调查员。