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.

项目总结/摘要 肠道免疫反应与在胃肠道定植的数万亿微生物有关。 因此，肠道微生物组的个体间差异可能有助于改变免疫反应， 免疫驱动的疾病，如自身免疫。肠道成员激活辅助性T细胞17（Th 17） 微生物群可以促进自身免疫。此外，有证据表明，饮食既影响 免疫系统和微生物组。虽然饮食因素，微生物群， 和免疫已经被广泛地描述，该领域才刚刚开始研究机制的相互作用， 饮食，微生物组和免疫力之间的关系以及对自身免疫的下游后果。这个的目标 研究Th 17细胞活化的微生物机制，它们的饮食反应性， 这些相互作用对自身免疫性疾病如炎症性肠病 (IBD)多发性硬化症（MS）我们的初步研究揭示了对特定饮食的机械见解- 抵抗特定促炎肠道细菌种类的依赖因子。两种常见的人类肠道 与人类自身免疫性疾病相关的菌种，缓慢埃格特菌和双歧杆菌， 以饮食依赖性方式诱导肠道中的Th 17细胞。精氨酸和生酮饮食（KD）可预防 E. lenta和B。分别为。此外，还在E. lenta，CGR2， 足以激活Th 17细胞。我们的目标是确定大肠杆菌激活Th 17的饮食依赖性机制。 慢代谢产物和功能后果IBD和MS小鼠模型。通过结合免疫学和 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，我们的目标是 鉴定由E. Lenta负责Th 17激活和评估疾病 这种代谢的饮食调节的相关性。其次，我们的目标是研究机制和疾病 酮体与限制肠道细菌Th 17诱导的相关性。KD相关的肠道微生物群减少 通过酮体β-羟基丁酸酯（βHB）选择性抑制双歧杆菌的生长来抑制肠道Th 17细胞。 因此，我们假设酮体βHB选择性抑制B。细胞介导的Th 17诱导 导致MS疾病模型的功能后果。为了解决这一假设并阐明 βHB影响B的Th 17诱导能力的机制。首先，我们将使用细菌遗传 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， 微生物组学研究与代谢组学，细菌遗传学和转化研究的新培训。 UCSF的机构重点是微生物组学，代谢组学，免疫学和转化研究， 与这些领域的专家合作将为拟议的科学和 专业发展导致创建一个独立的研究计划。