Gut microbiome influences on autoimmune disease

肠道微生物组对自身免疫性疾病的影响

• 批准号: 8882581
• 负责人: CHRISTOPHE O. BENOIST
• 金额: $ 42.38万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-15 至 2015-07-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8882581
• 关键词: Address; Affect; Amplifiers; Amyloid; Amyloid Proteins; Anaerobic Bacteria; Animal Model; Antibiotics; Arthritis; Autoimmune Diseases; Autoimmunity; Bacteria; Biological Models; Cell Differentiation process; Cells; Coculture Techniques; Data; Dendritic Cells; Diabetes Mellitus; Diet; Dietary Factors; Distant; Elements; Epidemiology; Epithelial Cells; Event; Family; Gene Expression Profiling; Gene Transfer Techniques; Genes; Genetic; Genomics; Health; Heterogeneity; Human; Hygiene; Hypersensitivity; IL17 gene; IL6 gene; ITGAM gene; ITGAX gene; Immune; Immune system; Inbred NOD Mice; Incidence; Insulin-Dependent Diabetes Mellitus; Interleukin-1; Intestines; K/BxN model; Knockout Mice; Lamina Propria; Lead; Life Style; Link; Maps; Mediator of activation protein; Microbe; Multiple Sclerosis; Mus; Myelogenous; Myeloid Cells; Pathway interactions; Phenotype; Play; Process; Recombinants; Risk; Serum; Signal Pathway; Site; Small Intestines; System; T cell differentiation; T-Lymphocyte; Testing; Tissues; Transgenes; aryl hydrocarbon receptor ligand; cell type; cofactor; commensal microbes; cytokine; genetic profiling; gut microbiota; immune function; in vivo; insight; intestinal epithelium; macrophage; microbial; microbial community; microbiome; novel; resistin; response

DESCRIPTION (provided by applicant): The human species has co-evolved over hundreds of millennia with an array of commensal microbes, a symbiotic relationship now altered by profound changes in lifestyle, hygiene, or widespread antibiotic use, changes that may be linked to the increasing incidence of allergy or autoimmune diseases. Intestinal microbes strongly influence immune cell differentiation, as exemplified by Segmented Filamentous Bacteria (SFB), a gut- resident anaerobe which promotes the differentiation of IL17-producing "Th17" cells, which in turn unleash Th17-dependent autoimmune diseases. This project will analyze the mechanisms of the SFB>Th17 axis, a well-defined and tractable model system of the microbial influence on immune function. Gene expression profiling of changes induced by SFB in the small intestine brought forth several intriguing candidates, and we have obtained formal evidence that one of them, the serum amyloid protein SAA3, constitutes an essential relay in the cascade. We will build on these results to analyze the interplay between SFB and Th17 differentiation, and how the effects of SFB are influenced and integrated within other microbial or environmental influences. 1. Identify the sequence of cells and molecules through which SFB induces Th17 differentiation in vivo. We hypothesize that SFB elicits a response cascade, initiated in the epithelial cells with which SFB interacts, transmitted via macrophages of dendriti cells, which ultimately promotes the Th17 differentiation of CD4+ αβT cells. Genomic profiling show that SFB induces the expression of a number of genes whose products may function as intermediates in the cascade: the serum amyloid SAA3 whose importance we have begun to establish, and other candidates (SAA1, iNOS, Resistin-β). We will chart the sequence of events: (i) identify the cell-types in which these putative intermediates are induced; (ii) assess with inducible transgenesis and knockout mice which segment of the response maps downstream of each intermediate. 2. How SAA3 induces the Th17 in αβT cells. Recombinant SAA3 can induce Th17 differentiation but only in the presence of myeloid CD11b+ od CD11c+ cells. We will establish the mechanism at play by establishing which myeloid cell(s) can serve as the essential cofactor, analyzing which signaling pathways are triggered by SAA3, and testing which intermediate cytokines may be induced and required. 3. Are SFB effects modulated by, other microbes or environmental cofactors. It is likely that SFB's influence is modulated by other gut commensals, or by dietary factors. We will test this notion by correlating the micro- heterogeneity in SFB's effects with the abundance of other bacterial families, determined by microbial community genetic profiling, and by testing how SFB-induced Th17 cells and arthritis manifestations are influenced by dietary elements (Ahr ligands, NaCl). These studies should provide novel mechanistic insights into how the gut microbiota alters the host's immune system and modulate the risk of autoimmune diseases, mechanistic information which may suggest new strategies for addressing human autoimmune disease.

描述（由申请人提供）：人类与一系列共生微生物共同进化了数百年，这种共生关系现在因生活方式、卫生习惯或抗生素广泛使用的深刻变化而改变，这些变化可能与过敏或自身免疫性疾病发病率的增加有关。肠道微生物强烈影响免疫细胞分化，例如分段丝状细菌（SFB），它是一种肠道驻留厌氧菌，可促进产生 IL17 的“Th17”细胞的分化，进而引发 Th17 依赖性自身免疫性疾病。该项目将分析 SFB>Th17 轴的机制，这是一个定义明确且易于处理的微生物对免疫功能影响的模型系统。 SFB 在小肠中引起的变化的基因表达谱产生了几个有趣的候选者，我们已经获得了正式证据，证明其中之一，血清淀粉样蛋白 SAA3，构成了级联中的重要中继。我们将在这些结果的基础上分析 SFB 和 Th17 分化之间的相互作用，以及 SFB 的作用如何受到其他微生物或环境影响的影响和整合。 1. 鉴定SFB在体内诱导Th17分化的细胞和分子序列。我们假设 SFB 引发了一个反应级联，该反应在 SFB 相互作用的上皮细胞中启动，通过树突细胞的巨噬细胞传递，最终促进 CD4+ αβT 细胞的 Th17 分化。基因组分析表明，SFB 诱导许多基因的表达，这些基因的产物可能充当级联中的中间体：我们已经开始确定其重要性的血清淀粉样蛋白 SAA3，以及其他候选基因（SAA1、iNOS、Resistin-β）。我们将绘制事件的顺序：（i）识别诱导这些假定中间体的细胞类型； (ii) 用诱导转基因和基因敲除小鼠评估哪个反应片段映射到每个中间体的下游。 2. SAA3如何诱导αβT细胞中的Th17。重组 SAA3 可以诱导 Th17 分化，但仅在髓系 CD11b+ 和 CD11c+ 细胞存在的情况下。我们将通过确定哪些骨髓细胞可以作为必需的辅助因子、分析哪些信号通路由 SAA3 触发以及测试哪些中间细胞因子可能被诱导和需要来建立发挥作用的机制。 3. SFB 效应是否受其他微生物或环境辅助因子调节。 SFB 的影响很可能受到其他肠道共生菌或饮食因素的调节。我们将通过将 SFB 影响的微观异质性与其他细菌家族的丰度（由微生物群落遗传图谱确定）相关联，并测试 SFB 诱导的 Th17 细胞和关节炎表现如何受到饮食元素（Ahr 配体、氯化钠）的影响来测试这一概念。这些研究应该为肠道微生物群如何改变宿主的免疫系统并调节自身免疫性疾病的风险提供新的机制见解，这些机制信息可能会为解决人类自身免疫性疾病的新策略提供建议。