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

肠道微生物组和肠道通透性在川崎病血管炎发生中的作用

• 批准号: 10310487
• 负责人: Magali Noval Rivas
• 金额: $ 43.75万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-01-01 至 2024-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10310487
• 关键词: 5 year old; Acute; Affect; Aneurysm; Antibiotics; Antifungal Agents; Aortic Aneurysm; Area; B-Lymphocytes; BLR1 gene; Bacteria; Blood Circulation; Blood Vessels; Cardiovascular Diseases; Cardiovascular system; Cell Compartmentation; Cell Wall; Cells; Cessation of life; Child; Childhood; Clinical Data; Communities; Complex; Coronary; Coronary Aneurysm; Coronary artery; Data; Deposition; Development; Disease; Distant; Etiology; Event; FOXP3 gene; Fever; Gastrointestinal tract structure; Germ-Free; Goals; Heart Diseases; Human; Illness Days; Immune; Immune System Diseases; Immune response; Immunoglobulin A; Immunoglobulin G; Immunologics; Interleukin-1; Intervention; Intestinal permeability; Intestines; Intravenous; Intravenous Immunoglobulins; Lactobacillus casei; Lead; Leaky Gut; Lesion; Link; Measures; Modeling; Molecular; Mucocutaneous Lymph Node Syndrome; Mucosal Immune Responses; Mucosal Immune System; Mucous Membrane; Mus; Myocardial Infarction; Myocardial Ischemia; Organism; Pathogenesis; Pathogenicity; Pathology; Patients; Physiology; Pilot Projects; Plasma Cells; Play; Prevention; Prevention approach; Preventive; Regulatory T-Lymphocyte; Research; Resistance; Risk; Role; Secretory Immunoglobulin A; Serum; Shapes; Site; Testing; Therapeutic; Tissues; Vasculitis; abdominal aorta; autoimmune vasculitis; base; beta-Glucans; commensal microbes; coronary arteritis; dectin 1; disease diagnosis; dysbiosis; effective therapy; fungus; gastrointestinal; gastrointestinal symptom; gut colonization; gut microbiome; gut microbiota; high risk; immunopathology; improved; microbial community; microbiome alteration; microbiota; microorganism; mouse model; mycobiome; new therapeutic target; novel strategies; novel therapeutic intervention; novel therapeutics; prevent; programmed cell death protein 1; receptor; response; translational potential; zonulin

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.

项目摘要 川崎病 (KD) 是一种病因不明的急性发热性疾病/系统性血管炎，主要表现为 影响幼儿，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 血管炎是获得性心脏病的主要原因 美国儿童中的疾病。 25% 未经治疗的川崎病儿童会出现 CAA，导致缺血 心脏病和心肌梗塞。虽然静脉注射免疫球蛋白 (IVIG) 治疗可降低以下风险： CAA 为 5%，高达 25% 的 KD 患者对 IVIG 具有耐药性，发生 CAA 的风险更大。因此，发现 寻找更有效的治疗方法来预防 KD 血管炎的心血管并发症是当前的当务之急 儿科和心血管研究。肠道微生物群是我们生理的一个组成部分， 肠道菌群失调影响许多免疫学和非免疫学的发展 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反应在 使用成熟的 KD 血管炎小鼠研究 KD 中冠状动脉炎的发展和动脉瘤形成 模型。根据我们的初步数据，我们假设肠道菌群失调和肠道通透性增加 在 KD 期间同时发生，并在显着调节免疫反应中发挥关键作用 导致与川崎病相关的心血管病变。这些事件将导致共生 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 IgA 进入血液循环，可能在调节和微调全身系统中发挥重要作用 局部免疫反应有助于推动免疫病理学并促进川崎病病变的发展。 破译肠道共生微生物和真菌组与肠道菌群增加的机制 通透性影响川崎病心血管病变的发展，可以为川崎病提供新的治疗靶点 干涉。为了检验这一假设，我们建议确定肠道的成分变化如何 共生体影响小鼠 KD 血管炎病理学（目标 1）。我们将研究增加的作用 肠道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。 （目的 2）。我们将描述从肠道泄漏的分泌型 IgA 在促进发育中的作用 KD 血管炎模型中的心血管病变（目标 3）。临床数据表明，患有 KD 的儿童经常 患有肠漏症，超过 80% 的人在川崎病诊断前一周接受了改变微生物群的抗生素。 因此，鉴于对 共生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影响心血管的分子机制 川崎病的并发症可能会带来新的治疗和预防方法。

项目成果

NLRP3 Inflammasome Mediates Immune-Stromal Interactions in Vasculitis.

NLRP3 炎症小体介导血管炎中的免疫基质相互作用。

• 发表时间: 2021
• 影响因子: 20.1
• 作者: Porritt, Rebecca A;Zemmour, David;Abe, Masanori;Lee, Youngho;Narayanan, Meena;Carvalho, Thacyana T;Gomez, Angela C;Martinon, Daisy;Santiskulvong, Chintda;Fishbein, Michael C;Chen, Shuang;Crother, Timothy R;Shimada, Kenichi;Arditi, Moshe;Nova
• 通讯作者: Nova

A Comprehensive Update on Kawasaki Disease Vasculitis and Myocarditis.

川崎病血管炎和心肌炎的全面更新。

• 发表时间: 2020
• 影响因子: 5
• 作者: Soni, Priya R;Noval Rivas, Magali;Arditi, Moshe
• 通讯作者: Arditi, Moshe

Notch1 signaling impairs regulatory T cells during multisystem inflammatory syndrome in children.

Notch1 信号传导会损害儿童多系统炎症综合征期间的调节性 T 细胞。

• 发表时间: 2023-01-03
• 作者: Noval Rivas, Magali;Arditi, Moshe
• 通讯作者: Arditi, Moshe

Kawasaki Disease and Multisystem Inflammatory Syndrome in Children: Common Inflammatory Pathways of Two Distinct Diseases.

川崎病和儿童多系统炎症综合征：两种不同疾病的常见炎症途径。

• 发表时间: 2023-08
• 作者: Noval Rivas, Magali;Arditi, Moshe
• 通讯作者: Arditi, Moshe

IL-1-dependent electrophysiological changes and cardiac neural remodeling in a mouse model of Kawasaki disease vasculitis.

川崎病血管炎小鼠模型中 IL-1 依赖性电生理变化和心脏神经重塑。

• 发表时间: 2020
• 影响因子: 4.6
• 作者: Abe, M;Rastelli, D D;Gomez, A C;Cingolani, E;Lee, Y;Soni, P R;Fishbein, M C;Lehman, T J A;Shimada, K;Crother, T R;Chen, S;Noval Rivas, M;Arditi, M
• 通讯作者: Arditi, M