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.

项目摘要了解环境因素的作用，包括饮食和菌群衍生的信号是至关重要的改善胃肠道疾病（包括炎症性肠）的治疗和干预策略疾病（IBD）和炎症相关结直肠癌（CRC）。饮食纤维可以发挥免疫调节性通过微生物发酵产物（包括短链脂肪酸（SCFA））的影响。但是，影响大多数微生物群的饮食纤维及其在免疫调节中的作用尚不清楚。在我确定了新的初步研究，发现一种富含浓度蛋白的高纤维饮食会触发微生物群中的结肠嗜酸性粒细胞。在肠道损伤和炎症相关的CRC。这些饮食引起的2型炎症反应与微生物源衍生的胆汁酸的上调以及间质基质细胞（MSC）和2组的激活先天淋巴样细胞（ILC2S）。但是，宿主和代谢中的细胞和分子成分介导饮食对肠道炎症影响的微生物群中的途径尚不清楚。在AIM 1中，我将确定在高纤维饮食诱导的肠道期间如何调节2型细胞因子和嗜酸性粒细胞炎。在AIM 2中，我将研究饮食纤维诱导的嗜酸性粒细胞如何造成肠道损伤。在AIM 3中，我将采用细菌遗传学和gnotobiotic方法来识别微生物代谢途径高纤维饮食引起的肠炎所必需的。成功完成拟议的目标后，我期望有助于对饮食纤维的生物学产生新的理解代谢物和基质细胞调节2型炎症，这可能有助于饮食的合理设计和基于微生物群的治疗方法。我的总体职业目标是成为一个独立的目标领先的学术机构的研究者和鼓舞人心的导师，并研究了该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的目标将使我能够发展出至关重要的各种科学，专业和个人技能成为成功的独立调查员。这些将包括在包括代谢组分析和基因工程在我的合作者的帮助下以及发展技能写作，指导，沟通和实验室管理。我将在实验室执行K99阶段戴维·阿蒂斯（David Artis）博士，粘膜免疫学领域的世界领导者和宿主 - 微生物互动。这实验室可以使用所有必要的工具和设施来完成拟议的目标，包括 gnotobiotic动物设施，并提供了一个出色的环境和培训计划，以支持博士后研究人员。除了我的导师和联合学者外，我还得到了几位杰出调查员的支持作为顾问和合作者的广泛专业知识，将极大地促进我的实验完成在K99阶段，随着我的发展成为独立研究者。