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

项目摘要/摘要 肠道免疫反应与寄生在胃肠道的数万亿种微生物有关。 因此，肠道微生物群的个体间差异可能会导致免疫反应的改变，从而影响 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(Th17) 微生物区系可以促进自身免疫。此外，越来越多的证据表明，这种饮食对 免疫系统和微生物群。而饮食因素之间的成对互动，微生物区系， 和免疫力的广泛特征，该领域才刚刚开始研究机械的相互作用 饮食、微生物群和免疫之间的关系以及自身免疫的下游后果。这样做的目的是 工作是研究Th17细胞激活的微生物机制，它们对饮食的反应，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械性见解- 抑制特定致炎肠道细菌种类的依赖因子。两种流行的人类本能 与人类自身免疫性疾病有关的物种，兰氏埃格氏菌和青春型双歧杆菌， 以饮食依赖的方式在肠道中诱导Th17细胞。饮食精氨酸和生酮饮食(KDS)可预防 T17分别由E.lenta和B.adenescens诱导。此外，还发现了E.lenta中一个特异的细菌基因cgr2， 足以激活Th17细胞。我们的目标是确定由E。 Lenta代谢物和功能后果IBD和MS小鼠模型。通过结合免疫学和 微生物组技术与代谢组学和我们合作者的翻译研究专业知识，我们的目标是 确定由E.lenta代谢的负责Th17激活的小分子并评估疾病 饮食调节与这种新陈代谢的相关性。其次，我们的目标是研究其发病机制和疾病。 酮体与限制肠道细菌Th17诱导的相关性。KD相关的肠道微生物区系减少 通过酮体β-羟丁酸酯(βHB)选择性地抑制双歧杆菌的生长。 因此，我们假设酮体βHb选择性地抑制青春期Th17诱导。 导致多发性硬化症疾病模型的功能后果。为了解决这一假设并阐明 βHb影响青春型芽孢杆菌Th17诱导能力的机制，我们将利用细菌基因 操纵和疾病模型。拟议的目标将利用候选人在免疫学和 微生物组研究，新陈代谢组学、细菌遗传学和翻译研究方面的新培训。 加州大学旧金山分校专注于微生物组、代谢组学、免疫学和翻译研究 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。

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.