Gut dysbiosis induces lupus

肠道菌群失调诱发狼疮

• 批准号: 9199844
• 负责人: Laurence Morel
• 金额: $ 18.64万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-04 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9199844
• 关键词: Age; Androgens; Antinuclear Antibodies; Autoimmune Diseases; Autoimmune Process; Autoimmune Responses; Autoimmunity; Bacteria; Biological Markers; Butyrates; Collaborations; Congenic Mice; DNA; Data; Development; Disease; Disease Progression; Experimental Models; Feces; Future; Genes; Genome; Germ-Free; Health; Homeostasis; Immune; Immune response; Immune system; Immunoglobulin G; Immunology; Immunophenotyping; Inflammation; Institution; Intestines; Knowledge; Lactobacillus acidophilus; Lupus; Lymphocyte; Lymphocyte Activation; Maps; Microbe; Modeling; Mus; Pathogenesis; Pathology; Pathway interactions; Phenotype; Play; Production; Property; Rag1 Mouse; Regulatory T-Lymphocyte; Research Personnel; Role; SLEB1 gene; SLEB2 gene; SLEB3 gene; Secondary to; Shapes; System; Testing; Therapeutic; Time; Transplantation; Variant; Work; attenuation; autoreactivity; base; cohort; commensal microbes; congenic; design; ds-DNA; follow-up; gut microbiota; immune activation; immunoregulation; metabolomics; microbial; microbiome; microbiota; mouse model; novel; public health relevance

 DESCRIPTION (provided by applicant): It is increasingly accepted that gut commensal bacteria play a major role in regulating the immune system in health and disease. An important break-through was achieved with the discovery of the ability of TH17 and regulatory T cells to modify the composition of the gut microbiota, including segmented filamentous bacteria and genetically modified L. acidophilus to shape the local and systemic immune responses, which have been followed up with studies of the role of the microbiota in all major autoimmune diseases. These studies have shown that dysbiosis is associated with disease progression, as well as identify pathways, including MyD88- deficiency or androgen exposure resulting in disease attenuation through the microbiome. Accordingly, we have used a mouse model of lupus, the B6.Sle1.Sle2.Sle3 strain, called TC (triple congenic) for short, which shares >95% of its genome with B6, to show that autoimmunity was associated with a distinct intestinal microbiota that is normalized by a treatment that reversed the disease. Importantly, we demonstrated that microbiota for autoimmune TC mice was sufficient for inducing the production of anti-dsDNA IgG and also caused a strong immune activation in germ free (GF) B6 mice. To the best of our knowledge, this is the first demonstration that the autoimmune phenotype can be induced by microbial dysbiosis in an autoimmune mouse model. Based on these novel preliminary data and on the work of others on the immunoregulatory role of microbiota, we hypothesize that a dysregulated gut microbiota contributes to lupus pathogenesis either directly or indirectly, through the production of critical metabolites (e.g., butyrate). In the former case, variations in immune related genes or others intrinsically change the composition of the microbiota, independently from the ongoing autoimmune response. In the latter case, the inflammation and autoimmune activation that develops with lupus leads to gut dysbiosis, which in turn, promotes inflammation resulting in dysfunctional immune homeostasis. To test this hypothesis and to delineate the relationship between dysbiosis and autoreactivity, we propose two specific aims. 1. To elucidate the autoimmune responses induced by microbial dysbiosis from lupus-prone TC mice. We will expand our initial findings that TC microbiota induces autoAb production and immune activation in a larger cohort of GF B6 mice, with a characterization of the fecal microbiota and microbiome of the donors and the GF recipients 4 wks post transfer. We will also investigate whether we can sustain the immunophenotypes and induce autoimmune pathology with multiple fecal transfers. Finally, we will test whether the expression of the Sle1 locus is sufficient to confer immune activation to the microbiota. 2. To Test the mechanisms of TC dysbiosis relative to the development of systemic autoimmunity. Based on the experimental setting developed in Aim 1, determine whether the autoimmune-inducing properties of TC microbiota are intrinsic or secondary to TC autoimmunity. An answer to this fundamental question is required to direct any future mechanistic studies of the interplay between systemic autoimmunity and dysbiosis. Analyzing the microbiota of TC mice that have already reverted disease also offers the possibility of identifying microbial species or products that can be used as disease biomarkers. The body of knowledge that will be generated from this exploratory proposal will launch future studies that define how specific bacteria and their metabolites promote systemic autoimmunity, as well as to assess the potential value of the microbiota in generating biomarkers of disease activity.

 描述（由申请人提供）：人们越来越认识到肠道共生细菌在调节健康和疾病中的免疫系统中发挥着重要作用。发现 TH17 和调节性 T 细胞能够改变肠道微生物群的组成，包括分段丝状细菌和转基因嗜酸乳杆菌，以塑造局部和全身免疫反应，这是一项重要的突破，随后对微生物群在所有主要自身免疫性疾病中的作用进行了研究。这些研究表明，生态失调与疾病进展相关，并确定了一些途径，包括 MyD88 缺乏或雄激素暴露，通过微生物组导致疾病减弱。因此，我们使用了狼疮小鼠模型，即 B6.Sle1.Sle2.Sle3 菌株，简称 TC（三重同源），其基因组与 B6 共享超过 95%，以表明自身免疫与独特的肠道微生物群相关，而通过逆转疾病的治疗可使该微生物群正常化。重要的是，我们证明自身免疫 TC 小鼠的微生物群足以诱导抗 dsDNA IgG 的产生，并且还在无菌 (GF) B6 小鼠中引起强烈的免疫激活。据我们所知，这是首次证明自身免疫小鼠模型中的微生物失调可以诱导自身免疫表型。基于这些新的初步数据以及其他人关于微生物群免疫调节作用的工作，我们假设肠道微生物群失调通过产生关键代谢物（例如丁酸盐）直接或间接导致狼疮发病。在前一种情况下， 免疫相关基因或其他基因的变异本质上改变了微生物群的组成，独立于正在进行的自身免疫反应。在后一种情况下，狼疮引起的炎症和自身免疫激活会导致肠道菌群失调，进而促进炎症，导致免疫稳态功能失调。为了检验这一假设并描述生态失调与自身反应性之间的关系，我们提出了两个具体目标。 1. 阐明易患狼疮的 TC 小鼠微生物失调诱导的自身免疫反应。我们将扩展我们的初步发现，即 TC 微生物群在更大的 GF B6 小鼠群体中诱导自身抗体产生和免疫激活，并在移植后 4 周对供体和 GF 受体的粪便微生物群和微生物组进行表征。我们还将研究是否可以通过多次粪便转移来维持免疫表型并诱导自身免疫病理。最后，我们将测试 Sle1 基因座的表达是否足以赋予微生物群免疫激活作用。 2. 测试TC生态失调与全身自身免疫发展相关的机制。根据目标 1 中开发的实验设置，确定 TC 微生物群的自身免疫诱导特性是固有的还是继发于 TC 自身免疫的。需要回答这个基本问题，才能指导未来系统性自身免疫和生态失调之间相互作用的机制研究。分析已经恢复疾病的 TC 小鼠的微生物群还提供了鉴定可用作疾病生物标志物的微生物物种或产品的可能性。该探索性提案将产生的知识体系将启动未来的研究，定义特定细菌及其代谢物如何促进系统性自身免疫，并评估微生物群在产生疾病活动生物标志物方面的潜在价值。