Linking diet, gut microbiota and autoimmune disease: Bacteria induced phytoestrogen metabolites impact immune function in Experimental Autoimmune Encephalitis

虽然免疫系统和肠道微生物群之间的联系越来越受到重视，但 微生物组与多发性硬化症等炎症性自身免疫性疾病之间的机制联系 (Ms)不清楚。因此，迫切需要确定肠道细菌维持免疫的机制。 动态平衡，从而影响神经炎症。我们最近报道了多发性硬化症患者的改变 肠道微生物区系与健康对照组相比，某些人类肠道细菌的丰度降低 (Parabacteroides、Adlercreutzia和Prevotea)具有代谢植物雌激素的能力。肠道细菌 将植物雌激素代谢成与雌激素结构相似的马醇，具有免疫调节作用。 通过雌激素受体和AMP激活的蛋白激酶(AMPK)进行反应。我们的初步数据 在含有植物雌激素(异黄酮类)的饮食中，小鼠的EAE明显低于 关于不含植物雌激素的饮食，表明植物雌激素在调节EAE中起着关键作用。另外， 普雷沃特拉菌是普氏菌属的一员，在实验性自身免疫中可以抑制疾病。 脑脊髓炎(EAE)，MS的临床前小鼠模型，然而，植物雌激素的重要性 猪链霉菌介导的疾病抑制中的代谢尚不清楚。建议中的中心假设 研究表明，人体肠道共生菌通过代谢调节其防病作用。 植物雌激素和随后免疫调节细胞的激活。我们将检验我们的中心假设 采用动物模型、转基因小鼠和细胞培养的方法有以下两个具体目的。在……里面 第一个目标，我们将利用P.histic ola作为一种具有代表性的植物雌激素代谢肠道共生菌来 确定植物雌激素的代谢是否对猪瘟病菌的抑病能力和 诱导Tregs和/或CD103+耐受树突状细胞(DC)。我们将确定AMPK的重要性 植物雌激素中的信号诱导树突状细胞和/或耐受性树突状细胞的激活。在第二个目标中，我们将 确定植物雌激素加细菌是否通过以下途径介导免疫调节细胞的诱导 肠道上皮细胞和/或免疫细胞中雌激素受体(ER)依赖的途径。我们的研究很适合 “高优先级免疫奖助金(R01)机制，因为我们建议确定 微生物对系统免疫的潜在影响机制可在设计中加以利用 潜在的单一疗法和联合疗法，因为药物具有不同的非重叠机制 可能为多发性硬化症患者提供最大益处。我们将确定植物雌激素代谢细菌 通过相互作用使Tregs从Th1/Th17平衡向Tregs倾斜，保持无病状态 与雌激素受体和AMPK途径有关。我们预计我们的研究结果将会有积极的 对肠道微生物菌群/饮食疗法治疗多发性硬化症和其他炎症性疾病的影响 自身免疫性疾病。

Although the link between the immune system and the gut microbiome is being increasingly appreciated, the mechanistic links between the microbiome and inflammatory autoimmune diseases such as multiple sclerosis (MS) are unclear. Thus, there is a critical need to define mechanisms by which gut bacteria maintain immune homeostasis and thereby affect neuroinflammation. We have recently reported that MS patients have altered gut microbiota compared to healthy controls, with a reduced abundance of certain human gut bacteria (Parabacteroides, Adlercreutzia, and Prevotella) with the ability to metabolize phytoestrogen. Gut bacteria metabolize phytoestrogen into equol which has structural similarity with estrogen, and can regulate immune responses through estrogen receptors and AMP-activated protein kinase (AMPK). Our preliminary data showing significantly milder EAE in mice on a phytoestrogen (Isoflavones) containing diet compared to those on a phytoestrogen free diet suggest a critical role of phytoestrogen in modulation of EAE. Additionally, Prevotella histicola, a member of the Prevotella genus, can suppress disease in experimental autoimmune encephalomyelitis (EAE), a preclinical murine model of MS. However, the importance of phyoestrogen metabolism in P. histicola–mediated disease suppression is unknown. The central hypothesis of the proposed studies is that the human gut commensal P. histicola mediate its disease-protective effect through metabolism of phytoestrogen and subsequent activation of immunoregulatory cells. We will test our central hypothesis using animal model, genetically modified mice, and a cell culture approach in the following two specific aims. In first aim, we will utilize P. histicola as a representative phytoestrogen-metabolizing gut commensal bacteria to determine whether metabolism of phytoestrogen is required for ability of P. histicola to suppress disease and induce Tregs and/or CD103+ Tolerogenic dendritic cells (DCs). We will determine the importance of AMPK signaling in the phytoestrogen induced activation of Tregs and/or tolerogenic DCs. In second aim, we will determine whether the phytoestrogen plus bacteria mediate the induction of immunoregulatory cells via estrogen receptor (ER)-dependent pathways in intestinal epithelial cells and/or immune cells. Our study is fit for the “High Priority Immunology Grant (R01) mechanism because we are proposing to determine the mechanisms underlying the microbial impact on systemic immunity which can be harnessed in designing potential mono as well as combination therapies because drugs with diverse non-overlapping mechanisms might provide maximal benefit to MS patients. We will determine whether phytoestrogen-metabolizing bacteria maintain a disease-free state by tilting the Tregs to Th1/Th17 balance towards Tregs through its interaction with estrogen receptors and the AMPK pathway. We expect the outcome of our study will have a positive impact on development of gut microbial-flora/diet-based therapies for MS as well as other inflammatory autoimmune diseases.