Role of dietary fiber-microbiota Interactions in the development and function of small intestinal T cells

膳食纤维-微生物群相互作用在小肠 T 细胞发育和功能中的作用

• 批准号: 10280531
• 负责人: Luisa Cervantes Barragan
• 金额: $ 47.83万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10280531
• 关键词: Address; Affect; American; Bacteria; Behavior; Body Weight decreased; C57BL/6 Mouse; CD4 Positive T Lymphocytes; Carbon; Cell Communication; Cell physiology; Cells; Chronic; Citrobacter rodentium; Colitis; Colon; Complex; Consumption; Crohn' s disease; Development; Diet; Diet therapy; Dietary Fiber; Dietary Intervention; Disease; Disease Progression; Energy-Generating Resources; Environment; Environmental Risk Factor; Europe; Fiber; Flow Cytometry; Food; Genetic; Germ-Free; Goals; Gut Mucosa; Health; Histologic; Human; Ileitis; Immune; Immune response; Immune system; Individual; Infiltration; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Intake; Interleukin-17; Intervention; Intestinal Mucosa; Intestines; LCN2 gene; Lamina Propria; Large Intestine; Lead; Macronutrients Nutrition; Measures; Mediating; Metabolic; Metabolic Pathway; Metagenomics; Microbe; Modeling; Mucositis; Mucous Membrane; Mus; Pathogenesis; Pathology; Pathway interactions; Population; Process; Regulation; Regulatory T-Lymphocyte; Research; Rest; Risk; Role; Sampling; Series; Severities; Severity of illness; Small Intestines; Structure; Supplementation; T-Cell Development; T-Lymphocyte; Toxoplasma gondii; Ulcerative Colitis; Volatile Fatty Acids; cytokine; design; dietary; dietary constituent; epidemiology study; experimental study; feeding; gain of function; gut microbiota; human microbiota; immunoregulation; inflammatory disease of the intestine; interest; intraepithelial; member; microbial; microbiome; microbiome composition; microbiota; mouse model; nutrition; nutritional approach; prevent; programs; response

Summary Crohn’s disease and Ulcerative colitis collectively referred as inflammatory bowel disease (IBD) are diseases in which an aberrant intestinal immune response leads to chronic inflammation. IBD affects an estimated 1.5 million Americans, 2.2 million people in Europe and hundreds of thousands in the rest of the world. The pathogenesis of IBD, while not completely elucidated, is thought to be multifactorial and caused by the interplay of genetics, the microbiome and the environment. One of the major environmental factors associated with increasing the risk for IBD is the diet that an individual consumes. Therefore, the ability to harness nutrition to treat disease is a unique opportunity for profound intervention in IBD progression. The major challenge for implementing dietary therapy for IBD is the lack of understanding of detailed mechanistic pathways to explain the impact of dietary interventions on IBD severity or progression. Epidemiological studies of IBD have shown dietary fiber as the most consistent macronutrient associated with changing risk of IBD. Fiber affects several aspects of the digestive process. Notably, it is also a main energy source for several bacterial species of the microbiome, and differences in fiber consumption strongly affect the microbiome composition and metabolic behavior. However, very few studies have systematically addressed the role of fiber consumption in fluctuations of the microbiome that lead to specific changes in the intestinal immune response. The overall goal of this project is to discover relevant dietary fiber-microbe-immune cell interactions that prevent, induce or alter the course of gut inflammation. We will analyze the changes in microbiota composition and intestinal cell populations caused by the lack of fermentable fiber intake using a model in which mice are fed a complex diet that contains fermentable and non-fermentable fiber or semi-purified ingredients diet lacking fermentable fiber. Moreover, we will select purified fibers representing different fiber types and supplement them in the non-fermentable diet to identify those whose consumption modulate intestinal responses in a healthy state and during inflammation. Finally, to assess the impact of consuming a diet lacking fermentable fiber on the immune system in the context of human microbiota, we will colonize germ free mice with healthy human donor fecal samples and feed them either a mixed fiber, a non- fermentable fiber or a non-fermentable fiber diet supplemented with specific fibers to identify specific fiber supplementations that result in the modulation of immune responses by human microbiota, as well as the bacterial members mediating this interaction.

总结 克罗恩病和溃疡性结肠炎统称为炎症性肠病（IBD） 是异常肠道免疫反应导致慢性炎症的疾病。IBD 据估计，150万美国人、220万欧洲人和数百名 在世界其他地方的成千上万。IBD的发病机制，虽然没有完全阐明， 被认为是多因素的，由遗传学、微生物组和 环境与IBD风险增加相关的主要环境因素之一 是一个人的饮食。因此，利用营养治疗疾病的能力 这是一个深刻干预IBD进展的独特机会。的主要挑战 实施IBD的饮食治疗是缺乏对详细机制的理解， 解释饮食干预对IBD严重程度或进展的影响的途径。 IBD的流行病学研究表明，膳食纤维是最一致的常量营养素 与IBD风险变化相关。纤维影响消化过程的几个方面。 值得注意的是，它也是微生物组的几种细菌物种的主要能量来源， 纤维消耗的差异强烈影响微生物组的组成和代谢 行为然而，很少有研究系统地阐述了纤维消耗的作用， 微生物组的波动导致肠道免疫反应的特定变化。 本项目的总体目标是发现相关的膳食纤维-微生物-免疫细胞 预防、诱导或改变肠道炎症过程的相互作用。我们将分析 由于缺乏维生素C而引起的微生物群组成和肠道细胞群的变化 可发酵纤维的摄入量，使用一种模型，在该模型中，小鼠被喂食一种复杂的饮食， 可发酵和不可发酵纤维或缺乏可发酵纤维的半纯化成分饮食。 此外，我们将选择代表不同纤维类型的纯化纤维，并将其补充到 非发酵饮食，以确定那些消费调节肠道反应， 健康状态和炎症期间。最后，为了评估饮食缺乏的影响， 可发酵纤维对免疫系统在人类微生物群的背景下，我们将殖民细菌 用健康的人类捐赠者粪便样本释放小鼠，并给它们喂食混合纤维，非- 可发酵纤维或非发酵纤维饮食补充特定的纤维，以确定 导致人免疫应答调节的特异性纤维表达 微生物群，以及介导这种相互作用的细菌成员。