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

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要川崎疾病（KD）是一种急性发热疾病/全身性病因，主要是折磨幼儿，导致冠状动脉异常和动脉瘤（CAA），并可能导致在长期心血管后遗症中，甚至死亡。 KD血管炎是获得心脏的主要原因美国儿童的疾病。 CAA在25％的未经治疗的KD儿童中发展，导致缺血心脏病和心肌梗塞。静脉注射免疫球蛋白（IVIG）治疗降低了 CAA至5％，高达25％的KD患者具有IVIG耐药性，并且CAA风险更大。因此，发现更有效的治疗方法可防止KD血管炎的心血管并发症小儿和心血管研究。肠道微生物组是我们生理学不可或缺的一部分肠道营养不良会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菌群，肠道渗透性和失调的粘膜免疫反应在使用公认的KD血管炎小鼠在KD中形成冠状动脉炎和动脉瘤形成模型。根据我们的初步数据，我们假设肠道营养不良并增加肠道渗透性同时在KD期间发生，并在调节免疫反应中起着至关重要的作用导致与KD相关的心血管病变。这些事件将导致共同微生物群易位和/或细菌/真菌泵以及代谢物的肠道渗透性提高，和分泌的IgA进入血液循环，可能在调节和微调系统中起重要作用以及局部免疫反应，有助于推动免疫病理学并助长KD病变的发展。解解肠道微型和真菌组并增加肠道的机制渗透率影响KD的心血管病变的发展，可以为干涉。为了检验这一假设，我们建议确定肠道的组成改变如何共生影响鼠类KD血管炎病理学（AIM 1）。我们将调查增加的作用肠道通透性并确定其预防是否具有鼠KD血管炎期间的治疗价值。（目的 2）。我们将表征分泌的Iga从肠道泄漏在促进发展的发展中的作用 KD血管炎模型中的心血管病变（AIM 3）。临床数据表明KD的儿童经常在KD诊断前的一周，肠道漏水，超过80％的抗生素会改变抗生素。因此，鉴于对 Comensal Microbiota是一个具有高治疗诺言的研究领域。了解角色和肠道微生物组和肠道渗透性有助于心血管的分子机制 KD的并发症可能导致新颖的治疗方法和预防方法。

项目成果

期刊论文数量（13）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Platelets exacerbate cardiovascular inflammation in a murine model of Kawasaki disease vasculitis.

DOI：
10.1172/jci.insight.169855
发表时间：
2023-07-24
期刊：
JCI INSIGHT
影响因子：
8
作者：
Kocaturk, Begum;Lee, Youngho;Nosaka, Nobuyuki;Abe, Masanori;Martinon, Daisy;Lane, Malcolm E.;Moreira, Debbie;Chen, Shuang;Fishbein, Michael C.;Porritt, Rebecca A.;Franklin, Bernardo S.;Rivas, Magali Noval;Arditi, Moshe
通讯作者：
Arditi, Moshe

NLRP3 Inflammasome Mediates Immune-Stromal Interactions in Vasculitis.

DOI：
10.1161/circresaha.121.319153
发表时间：
2021-10-15
期刊：
Circulation research
影响因子：
20.1
作者：
Porritt RA;Zemmour D;Abe M;Lee Y;Narayanan M;Carvalho TT;Gomez AC;Martinon D;Santiskulvong C;Fishbein MC;Chen S;Crother TR;Shimada K;Arditi M;Noval Rivas M
通讯作者：
Noval Rivas M

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