Role of intestinal microbiome and gut permeability in the development of Kawasaki Disease vasculitis

项目摘要 川崎病(KD)是一种原因不明的急性发热性疾病/系统性脉管炎，主要 折磨幼儿，导致冠状动脉异常和动脉瘤(CAA)，并可能导致 长期的心血管后遗症，甚至死亡。KD脉管炎是获得性心脏的主要原因 美国儿童中的疾病。25%未经治疗的KD儿童发生CAA，导致缺血 心脏病和心肌梗塞。而静脉注射免疫球蛋白(IVIG)治疗则降低了 到5%，高达25%的KD患者对IVIG耐药，患CAA的风险更大。因此，发现 选择更有效的治疗方法来预防KD血管炎的心血管并发症是 儿科和心血管研究。肠道微生物群是我们生理和生理的组成部分 肠道生物失调影响许多免疫性和非免疫性疾病的发展 疾病，包括心血管疾病。在初步研究中，我们发现了惊人的新证据 肠道微生物区系、肠道通透性和失调的粘膜免疫反应在 利用一只公认的KD血管炎小鼠发展KD的冠脉炎和动脉瘤形成 模特。根据我们的初步数据，我们假设肠道生物失调和肠道通透性增加 同时发生在KD期间，并在显著调节免疫反应方面发挥关键作用 导致与KD相关的心血管损害。这些事件将导致共生 微生物区系易位和/或细菌/真菌PAMP以及代谢物的肠道通透性增加， 和分泌IgA进入血液循环，可能在调节和微调全身 局部免疫反应有助于推动免疫病理并推动KD皮损的发展。 破译肠道共生微生物群和真菌菌群与肠道增加的机制 通透性影响川崎病心血管病变的发展可能为川崎病提供新的治疗靶点 干预。为了验证这一假设，我们建议确定肠道的成分变化是如何 共病对小鼠KD血管炎病理的影响(目标1)。我们将调查增加的作用 并确定其在小鼠KD血管炎中的预防是否具有治疗价值。(目标 2)。我们将表征从肠道泄漏的分泌型IgA在促进糖尿病发展中的作用。 KD血管炎模型中的心血管损害(目标3)。临床数据表明，KD儿童经常 有肠漏，超过80%的人在KD诊断前一周接受了改变抗生素的微生物组治疗。 因此，该提案具有非常高的翻译潜力，因为对 共生微生物区系是一个具有很高治疗前景的研究领域。了解角色和 肠道微生物群和肠道通透性参与心血管疾病的分子机制 KD的并发症可能导致新的治疗和预防方法。

PROJECT ABSTRACT Kawasaki disease (KD) is an acute febrile illness/systemic vasculitis of unknown etiology that predominantly afflicts young children, causes coronary artery abnormalities and aneurysms (CAA), and could potentially result in long-term cardiovascular sequelae and even death. KD vasculitis is the leading cause of acquired heart disease among children in the US. CAA develop in 25% of untreated children with KD, leading to ischemic heart disease and myocardial infarction. While Intravenous immunoglobulin (IVIG) treatment lowers the risk of CAA to 5%, up to 25% of KD patients are IVIG-resistant and have a greater risk for CAA. Therefore, discovery of more effective treatments to prevent the cardiovascular complications of KD vasculitis is a high priority in pediatric and cardiovascular research. The intestinal microbiome is an integral part of our physiology and intestinal dysbiosis influences the development of a number of immunological and non-immunological diseases, including cardiovascular diseases. In preliminary studies, we discovered striking new evidence that intestinal microbiota, gut permeability, and dysregulated mucosal immune responses play a key role in the development of coronary arteritis and aneurysm formation in KD using a well-established KD vasculitis mouse model. Based on our preliminary data, we hypothesize that intestinal dysbiosis and increased gut permeability concomitantly occur during KD and play a crucial role in modulating immune responses significantly contributing to the cardiovascular lesions associated with KD. These events will result in commensal microbiota translocation and/or bacterial/fungal PAMPs as well as increased gut permeability of metabolites, and secretory IgA into blood circulation and may play an important role in modulating and fine-tuning systemic and local immune responses helping drive the immunopathology and fuel the development of KD lesions. Deciphering the mechanisms by which the intestinal commensal micro and mycobiome and increased gut permeability affect the development of cardiovascular lesions of KD could provide a novel therapeutic target for intervention. To test this hypothesis, we propose to determine how compositional alterations of the intestinal commensals influence murine KD vasculitis pathology (Aim 1). We will investigate the role of increased intestinal permeability and determine if its prevention has therapeutic value during murine KD vasculitis. (Aim 2). We will characterize the role of secretory IgA leaking from the gut in promoting the development of cardiovascular lesions in KD vasculitis model (Aim 3). Clinical data suggest that children with KD frequently have a leaky gut and more than 80% receive microbiome altering antibiotics in the week prior to KD diagnosis. Therefore, this proposal has a very high translational potential given that specific manipulation of the commensal microbiota is a research area with high therapeutic promises. Understanding the role and the molecular mechanism by which gut microbiome and gut permeability contribute to the cardiovascular complications of KD may lead novel therapeutic and preventive approaches.