Gut dysbiosis induces lupus

 描述(由申请人提供)：越来越多的人接受肠道共生菌在调节健康和疾病的免疫系统中发挥重要作用。TH17和调节性T细胞能够改变肠道微生物区系的组成，包括节段性丝状细菌和转基因嗜酸乳杆菌，以塑造局部和系统免疫反应，这是一个重要的突破，随后对微生物区系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，生物失调与疾病进展有关，并确定了包括MyD88缺乏或雄激素暴露在内的通过微生物组导致疾病减轻的途径。因此，我们使用了狼疮的小鼠模型，B6.Sle1.Sle2.Sle3株，简称TC(三重同源基因)，它与B6共享其95%的基因组，以表明自身免疫与一个独特的肠道微生物区系有关，该微生物区系通过逆转疾病的治疗而正常化。重要的是，我们证明了自身免疫TC小鼠的微生物区系足以诱导抗dsDNA抗体的产生，并在无菌(GF)B6小鼠中引起强烈的免疫激活。就我们所知，这是第一次证明在自身免疫的小鼠模型中，微生物的失调可以诱导自身免疫的表型。根据这些新的初步数据和其他人关于微生物区系免疫调节作用的工作，我们假设肠道微生物区系失调直接或间接地通过产生关键代谢物(如丁酸盐)参与狼疮的发病。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区系的组成，独立于正在进行的自身免疫反应。在后一种情况下，随着狼疮的发展，炎症和自身免疫激活导致肠道生物失调，进而促进炎症，导致免疫平衡失调。为了验证这一假说并描述生物失调和自身反应性之间的关系，我们提出了两个具体的目标。1.阐明红斑狼疮易感TC小鼠微生物代谢紊乱诱导的自身免疫反应。我们将扩大我们的初步发现，即TC微生物群诱导更大数量的GF B6小鼠产生自身抗体和免疫激活，并在移植4周后描述供者和GF受体的粪便微生物群和微生物群。我们还将调查是否可以维持免疫表型，并通过多次粪便转移诱导自身免疫病理。最后，我们将测试Sle1基因座的表达是否足以赋予微生物区系免疫激活。2.探讨TC代谢失调与全身自身免疫发展的关系。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TC自身免疫的固有属性还是次要属性。对这一根本问题的回答是指导未来对系统性自身免疫和生物失调之间相互作用的任何机械论研究的需要。分析已经逆转疾病的TC小鼠的微生物区系也提供了识别可用作疾病生物标记物的微生物物种或产品的可能性。这一探索性提案将产生的知识体系将启动未来的研究，定义特定的细菌及其代谢物如何促进系统性自身免疫，以及评估微生物区系在产生疾病活动的生物标志物方面的潜在价值。

 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.