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

项目摘要 川崎是一种病因不明的急性发热性疾病/全身性血管炎， 折磨幼儿，导致冠状动脉异常和动脉瘤（CAA），并可能导致 长期心血管后遗症甚至死亡。川崎病血管炎是后天性心脏病的主要原因 美国儿童的疾病。25%未经治疗的KD儿童发生CAA，导致缺血性 心脏病和心肌梗塞。虽然静脉注射免疫球蛋白（IVIG）治疗降低了 CAA至5%，高达25%的KD患者是IVIG耐药的，CAA的风险更大。因此，发现 更有效的治疗，以防止心血管并发症的KD血管炎是一个高度优先， 儿科和心血管研究。肠道微生物组是我们生理学的组成部分， 肠道生态失调影响许多免疫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， 肠道微生物群、肠道通透性和失调的粘膜免疫应答在肠道免疫反应中起关键作用。 使用明确的KD血管炎小鼠在KD中发生冠状动脉炎和动脉瘤形成 模型根据我们的初步数据，我们假设肠道生态失调和肠道通透性增加 在KD期间伴随发生，并且在显著调节免疫应答中起关键作用 导致与KD相关的心血管病变。这些事件将导致 微生物群易位和/或细菌/真菌PAMP以及代谢物的肠道通透性增加， 和分泌型伊加进入血液循环，并可能在调节和微调系统性 和局部免疫应答帮助驱动免疫病理学并促进KD病变的发展。 解读肠道微生物和真菌群落以及肠道菌群增加的机制 血管通透性影响KD心血管病变的发展，可为KD的治疗提供新的靶点。 干预为了验证这一假设，我们建议确定肠道的组成变化是如何发生的。 药物影响小鼠KD血管炎病理学（目的1）。我们将研究增加的作用 肠通透性，并确定其预防在小鼠KD血管炎期间是否具有治疗价值。（目标 2）。我们将描述从肠道泄漏的分泌型伊加在促进胃肠道疾病发展中的作用。 KD血管炎模型中的心血管病变（目的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微生物组的抗生素。 因此，考虑到对蛋白质的特定操作，该提议具有非常高的翻译潜力。 肠道微生物群是一个具有很高治疗前景的研究领域。了解角色和 肠道微生物组和肠道通透性有助于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.