Deconstructing interactions between diet, microbiome, and immunity to gain mechanistic insight into health and disease

解构饮食、微生物组和免疫之间的相互作用，以获得对健康和疾病的机制洞察

• 批准号: 10673616
• 负责人: Margaret Rose Alexander
• 金额: $ 5.15万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2023-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10673616
• 关键词: Actinobacteria class; Address; Adhesions; Area; Arginine; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Bacteria; Bacterial Genes; Bacterial Infections; Bifidobacterium; Cells; Collaborations; Data; Development; Diet; Dietary Factors; Disease; Disease model; Environment; Enzymes; Fasting; Genetic Diseases; Genetic Research; Goals; Growth; Health; Human; Human Microbiome; Immune; Immune response; Immune system; Immunity; Immunologics; Immunology; Inflammatory; Inflammatory Bowel Diseases; Institution; Intervention; Intestines; Ketone Bodies; Link; Mediating; Metabolism; Microbe; Microbiology; Microscopy; Modeling; Multiple Sclerosis; Mus; Patients; Positioning Attribute; Postdoctoral Fellow; Production; Research; Role; Seminal; Severities; Severity of illness; Techniques; Terpenes; Training; Translational Research; Work; bacterial genetics; beta-Hydroxybutyrate; clinically relevant; dietary; dietary manipulation; empowerment; genetic manipulation; gut bacteria; gut colonization; gut microbiome; gut microbiota; human disease; immune activation; immunoregulation; inhibitor; insight; inter-individual variation; ketogenic diet; member; metabolomics; microbial; microbiome; microbiome alteration; microbiome composition; microbiome research; microbiota; microorganism; mouse model; multiple sclerosis patient; murine colitis; novel; prevent; programs; protective effect; protein intake; research study; skills; small molecule

Project Summary/Abstract Intestinal immune responses are linked to the trillions of microorganisms that colonize the gastrointestinal tract. Thus, inter-individual variations in the gut microbiome could contribute to altered immune responses that impact immune driven diseases such as autoimmunity. Activation of T helper 17 (Th17) cells by members of the gut microbiota can contribute to autoimmunity. Further, evidence is emerging that the diet influences both the immune system and the microbiome. While the pairwise interactions between dietary factors, the microbiota, and immunity have been broadly characterized, the field is just beginning to investigate the mechanistic interplay between diet, microbiome, and immunity and the downstream consequences on autoimmunity. The goals of this work are to investigate microbial mechanisms of Th17 cell activation, their diet-responsiveness, and the functional consequences of these interactions on autoimmune diseases such as inflammatory bowel disease (IBD) and multiple sclerosis (MS). Our preliminary studies reveal mechanistic insights into specific diet- dependent factors that counteract specific pro-inflammatory gut bacterial species. Two prevalent human gut species associated with human autoimmune diseases, Eggerthella lenta and Bifidobacterium adolescentis, induce Th17 cells in the intestine in a diet-dependent manner. Dietary arginine and ketogenic diets (KDs) prevent Th17 induction by E. lenta and B. adolescentis respectively. Further, a specific bacterial gene in E. lenta, cgr2, is sufficient to activate Th17 cells. We aim to determine diet-dependent mechanisms of Th17 activation by E. lenta metabolites and functional consequences IBD and MS mouse models. By combining immunological and microbiome techniques with metabolomics and translational research expertise of our collaborators we aim to identify a small molecule metabolized by E. lenta responsible for Th17 activation and assess the disease relevance of dietary modulation of this metabolism. Secondly, we aim to examine the mechanism and disease relevance of ketone bodies for limiting gut bacterial Th17 induction. A KD-associated gut microbiota reduces intestinal Th17 cells via selective inhibition of bifidobacterial growth by the ketone body β-hydroxybutyrate (βHB). Therefore, we hypothesize that the ketone body βHB selectively inhibits B. adolescentis-mediated Th17 induction resulting in functional consequences for MS disease models. To address this hypothesis and elucidate the mechanism by which βHB impacts the Th17 induction capacity of B. adolescentis, we will use bacterial genetic manipulation and disease models. The proposed aims will leverage the candidate’s expertise in immunology and microbiome studies with new training in metabolomics, bacterial genetics, and translational research studies. UCSF’s institutional focus on the microbiome, metabolomics, immunology and translational research and close collaboration with experts in these areas will provide an ideal environment for the proposed scientific and professional development leading to the creation of an independent research program.

项目概要/摘要 肠道免疫反应与胃肠道中数以万亿计的微生物有关。 因此，肠道微生物组的个体间差异可能有助于影响免疫反应 免疫驱动的疾病，例如肠道成员激活辅助性 T 17 (Th17) 细胞。 此外，越来越多的证据表明，饮食会影响自身免疫。 免疫系统和微生物群，而饮食因素、微生物群之间的成对相互作用。 和免疫已被广泛表征，该领域刚刚开始研究机械相互作用 饮食、微生物组和免疫之间的关系以及对自身免疫的下游影响。 工作是研究 Th17 细胞激活的微生物机制、它们的饮食反应性以及 这些相互作用对炎症性肠病等自身免疫性疾病的功能影响 （IBD）和多发性硬化症（MS）我们的初步研究揭示了对特定饮食的机制见解。 抵消特定促炎性肠道细菌种类的依赖因素。 与人类自身免疫性疾病相关的物种，迟缓艾格氏菌和青春双歧杆菌， 以饮食依赖的方式诱导肠道中的 Th17 细胞，膳食精氨酸和生酮饮食 (KD) 可以预防。 分别由慢肠杆菌和青春双歧杆菌诱导Th17。此外，慢肠杆菌中的特定细菌基因cgr2， 足以激活 Th17 细胞，我们的目标是确定大肠杆菌激活 Th17 的饮食依赖性机制。 通过结合免疫学和 MS 小鼠模型，迟缓代谢物和功能后果。 微生物组技术与我们合作者的代谢组学和转化研究专业知识相结合，我们的目标是 鉴定由 E. lenta 代谢的负责 Th17 激活的小分子并评估疾病 其次，我们的目的是研究其机制和疾病。 酮体与限制肠道细菌 Th17 诱导的相关性降低了与 KD 相关的肠道微生物群。 肠道 Th17 细胞通过酮体 β-羟基丁酸 (βHB) 选择性抑制双歧杆菌生长。 因此，我们认为酮体βHB选择性抑制青春双歧杆菌介导的Th17诱导 导致多发性硬化症疾病模型的功能后果。 βHB影响青春双歧杆菌Th17诱导能力的机制，我们将利用细菌遗传 拟议的目标将利用候选人在免疫学和疾病方面的专业知识。 通过代谢组学、细菌遗传学和转化研究方面的新培训进行微生物组研究。 加州大学旧金山分校的机构重点关注微生物组、代谢组学、免疫学和转化研究，并密切关注 与这些领域的专家合作将为拟议的科学和技术提供理想的环境。 专业发展导致独立研究项目的创建。