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: 10371420
• 负责人: Margaret Rose Alexander
• 金额: $ 12.5万
• 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 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10371420
• 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; Intervention; Intestines; Ketone Bodies; Link; Mediating; Metabolism; Microbe; Microbiology; Microscopy; Modeling; Multiple Sclerosis; Mus; Patients; Positioning Attribute; Production; Research; Role; Seminal; Severities; Severity of illness; Techniques; Training; Translational Research; Work; bacterial genetics; beta-Hydroxybutyrate; clinically relevant; dietary; dietary manipulation; empowered; 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.

项目摘要/摘要 肠道免疫调查与胃肠道的几万亿微生物有关。 这就是肠道微生物组的个体间变化可能导致影响的免疫复杂的改变 免疫驱动的疾病，例如自身免疫性。肠道成员激活T辅助17（Th17）细胞 微生物群可以导致自身免疫性。此外，有证据表明饮食都会影响 而饮食因素之间的成对相互作用，微生物群， 并且免疫力已广泛表征，该领域才刚刚开始研究机械相互作用 在饮食，微生物组和免疫学之间以及对自身免疫性的下游后果。目标的目标 工作是研究Th17细胞激活的微生物机制，其饮食反应性和 这些相互作用对自身免疫性疾病（例如炎症性肠病）的功能后果 （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理见解 - 抵消特定促炎性肠道细菌种类的因素。两个普遍的人类肠道 与人类自身免疫性疾病有关的物种，eggerthella lenta和Bifidobacterium Adementis， 以饮食依赖的方式以肠道诱导Th17细胞。饮食精氨酸和生酮饮食（KDS）预防 E. lenta和B. decelectis的Th17诱导。此外，在E. lenta，CGR2， 足以激活Th17细胞。我们旨在确定E. Th17激活的饮食依赖性机制。 Lenta代谢产物和功能后果IBD和MS小鼠模型。通过结合免疫学和 具有代谢组学的微生物组技术，并翻译了我们的合作者的研究专业知识，我们旨在 确定由E. lenta代谢的小分子，负责Th17激活和评估该疾病 这种新陈代谢的饮食调节的相关性。其次，我们旨在检查机制和疾病 酮体与限制肠道细菌Th17诱导的相关性。 KD相关的肠道菌群减少 肠道Th17细胞通过选择性抑制酮体β-羟基丁酸（βHB）对双歧杆菌生长的选择性抑制。 因此，我们假设酮体βHb有选择地抑制B. th17诱导的B.b。 导致MS疾病模型的功能后果。解决这一假设并阐明 βHb影响青少年芽孢杆菌的Th17诱导能力的机制，我们将使用细菌通用细菌 操纵和疾病模型。拟议的目标将利用候选人在免疫学方面的专业知识和 微生物组研究对代谢组学，细菌遗传学和翻译研究的新培训。 UCSF的机构专注于微生物组，代谢组学，免疫学和翻译研究以及关闭 与这些领域的专家合作将为拟议的科学和 专业发展导致创建独立研究计划。