Gut Dysbiosis and Cardiac Remodeling in IBD

IBD 中的肠道菌群失调和心脏重塑

基本信息

批准号：
10687085
负责人：
Ken Fujise
金额：
$ 63.5万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10687085
关键词：
Abdominal Pain Ablation Adult Affect American Anaerobic Bacteria Animals Attenuated BCL2 gene Bacteria Biological Markers Black race Brain Brain-Derived Neurotrophic Factor Butyrates Cardiac Cardiac Myocytes Cardiovascular Diseases Cardiovascular system Cell physiology Child Chronic Clinical Colitis Colon Coronary Crohn&apos s disease Data Diarrhea Disease Disease remission EFRAC Economic Burden Ensure Epigenetic Process Epithelial Cells Event Financial Hardship Gastrointestinal tract structure Gene Expression Profile Germ-Free Global Change Health Heart Heart Diseases Heart Hypertrophy Homeostasis Human Hypoxia Immunologics Impairment In Vitro Incidence Inflammation Inflammatory Bowel Diseases Interleukin-10 Intervention Intestines Knock-out Knockout Mice Knowledge Life Mediating Mediator Messenger RNA MicroRNAs Microcirculation Mission Molecular Morbidity - disease rate Mus Myocardial dysfunction Operative Surgical Procedures Organ Pathogenesis Pathogenicity Pathologic Patients Persons Pharmacotherapy Phenotype Plasma Play Preventive Probiotics Proliferating Proteins Proteobacteria Proteomics Public Health Quality of life Rattus Relapse Risk Reduction Role Signal Transduction Sodium Dextran Sulfate Spontaneous colitis Supplementation Symptoms System Tamoxifen Testing Therapeutic Transplantation Ulcerative Colitis United States National Institutes of Health Virulent dextran sulfate sodium induced colitis dysbiosis epidemiology study exosome fecal microbiota fecal transplantation gastrointestinal gastrointestinal symptom gut dysbiosis gut microbiome gut microbiota heart function human disease hypoperfusion improved in vivo inhibitor intestinal epithelium medical attention microbial microbiota mouse model multidisciplinary murine colitis novel

项目摘要

PROJECT SUMMARY/ABSTRACT Inflammatory bowel disease (IBD) is a debilitating and difficult to manage chronic inflammation in the digestive tract, causing gastrointestinal symptoms such as diarrhea. It is associated with lifelong morbidity, greater medical attention, and diminished quality of life. About 3 million Americans suffer from IBD and its huge financial burden. Extraintestinal manifestations (EIM) of IBD are common, especially in children, and even overshadow the intestinal symptoms. Accumulating evidence suggests that IBD is associated with an increased incidence of cardiovascular events. However, the molecular mechanisms by which IBD predisposes patients to cardiovascular diseases (CVD) remain elusive. In addition to chronic inflammation, a signature of IBD is dysbiosis of the gut microbiota marked by a significant reduction of obligate anaerobes and a sharp increase in facultative anaerobes. While inflammation could be well controlled by drug therapy or surgery, gut microbial dysbiosis persists and may play a key role in IBD-associated CVD. We confirmed this phenomenon in murine models of colitis, which recapitulate some common EIM of human IBD. Our preliminary findings suggest that dysbiotic gut microbiota contributes to cardiac dysfunction by up-regulating miR-155 and down-regulating brain- derived neurotrophic factor (BDNF), both identified as crucial players in cardiac system. We hypothesize that colitis-induced microbiota dysbiosis triggers molecular remodeling in the adult heart through epigenetic mechanisms. We will test the hypothesis by pursuing three specific aims. Aim 1 will establish dysbiosis as a key player in colitis-induced heart dysfunction by transplanting dysbiotic fecal microbiota from patients with IBD and mice with colitis to bacteria-depleted mice. We will also determine whether the disease signal can be ablated by transplantation of normal fecal microbiota and/or probiotics. Aim 2 will focus on characterizing exosomal miR- 155 as a key player in IBD-induced molecular remodeling. We foresee that exosomal miR-155 derived specifically from the intestinal epithelial cells (IEC) functions as a major mediator of the crosstalk between gut microbiota and the heart. Using novel IEC-specific miR-155-knockout (Mir155ΔIEC) and Mir155ΔIEC/IL10-/- mice, we aim to show that exosomal miR-155 of gut origin epigenetically down-regulates cardiac BDNF in the presence of chronic colitis. We will also determine if miR-155 inhibitors mitigate IBD-induced heart diseases. In Aim 3, epigenetic mechanisms of BDNF reduction in cardiomyocytes will be elucidated using in vivo, in vitro, and proteomics approaches. We will characterize the functional and phenotypic roles of BDNF in the adult heart using a novel tamoxifen-inducible, cardiac-specific BDNF knockout mouse model. We will also explore the preventive and therapeutic potential of BDNF for IBD-associated CVD. Our results should help establish a novel paradigm that colitis induces cardiac remodeling through microbiota dysbiosis→exosomal miR-155→BDNF signaling axis, resulting in heart dysfunction.

项目摘要/摘要炎症性肠病（IBD）是一种令人沮丧的，难以管理消化的慢性感染区域，导致胃肠道症状，例如腹泻。它与终生发病率，更大的医学有关注意，生活质量降低。大约300万美国人遭受了IBD及其巨大的金融伯恩（Burnen）的困扰。 IBD的肠外表现（EIM）很普遍，尤其是在儿童中，甚至掩盖了肠道症状。积累的证据表明，IBD与增加的事件有关心血管事件。但是，IBD易患患者的分子机制心血管疾病（CVD）仍然难以捉摸。除了慢性感染外，IBD的签名是肠道微生物群的营养不良，其明显减少的肌肉症和急剧增加兼性厌氧。虽然药物治疗或手术可以很好地控制炎症，但肠道微生物营养不良持续存在，可能在IBD相关的CVD中起关键作用。我们在鼠中确认了这种现象结肠炎的模型，概括了人类IBD的某些常见EIM。我们的初步发现表明不植物肠道菌群通过上调miR-155和下调大脑 - 衍生的神经营养因子（BDNF），均被确定为心脏系统中的关键参与者。我们假设这一点结肠炎诱导的微生物菌群营养不良会通过表观遗传触发成人心脏中的分子重塑机制。我们将通过追求三个具体目标来检验该假设。 AIM 1将确定营养不良作为关键通过从IBD患者和与细菌贫血小鼠结肠炎的小鼠。我们还将确定是否可以通过正常粪便菌群和/或益生菌的移植。 AIM 2将集中于表征外泌体mir- 155是IBD引起的分子重塑的关键参与者。我们预见了外泌体miR-155得出的特别是来自肠上皮细胞（IEC）的主要介体微生物群和心脏。使用新型IEC特异性miR-155-Knockout（miR155ΔIEC）和mir155Δiec/il10 - / - 小鼠，我们的目的是表明，肠道外的外泌体miR-155在存在下表观遗传性的心脏BDNF。我们还将确定miR-155抑制剂是否减轻IBD诱导的心脏病。在AIM 3中，使用体内，体外和蛋白质组学方法。我们将表征BDNF在成人心脏中的功能和表型作用使用一种新型的他莫昔芬诱导的心脏特异性BDNF敲除小鼠模型。我们还将探索 BDNF对IBD相关CVD的预防和治疗潜力。我们的结果应该有助于建立小说结肠炎诱导心脏重塑的范式通过微生物群疾病障碍→外泌体miR-155→BDNF 信号轴，导致心脏功能障碍。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Exosomal miR-29b of Gut Origin in Patients With Ulcerative Colitis Suppresses Heart Brain-Derived Neurotrophic Factor.

DOI：
10.3389/fmolb.2022.759689
发表时间：
2022
期刊：
Frontiers in molecular biosciences
影响因子：
5
作者：
Lian H;Zhong XS;Xiao Y;Sun Z;Shen Y;Zhao K;Ma X;Li Y;Niu Q;Liu M;Powell DW;Liu C;Li Q
通讯作者：
Li Q

Chronic colitis upregulates microRNAs suppressing brain-derived neurotrophic factor in the adult heart.