Gut Dysbiosis and Cardiac Remodeling in IBD

IBD 中的肠道菌群失调和心脏重塑

• 批准号: 10469626
• 负责人: Ken Fujise
• 金额: $ 64.35万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 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/10469626
• 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; Congestive; Coronary; Crohn' 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 of activation protein; 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; Role; Signal Transduction; Sodium Dextran Sulfate; Spontaneous colitis; Supplementation; Symptoms; System; Tamoxifen; Testing; Therapeutic; Transplantation; Ulcerative Colitis; United States National Institutes of Health; Virulent; base; 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

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.

项目概要/摘要 炎症性肠病 (IBD) 是一种使人衰弱且难以控制的消化道慢性炎症 道，引起胃肠道症状，如腹泻，它与终生发病有关，更严重的医疗。 约 300 万美国人患有 IBD 及其巨大的经济负担。 IBD 的肠外表现 (EIM) 很常见，尤其是在儿童中，甚至掩盖了 IBD 的症状。 越来越多的证据表明 IBD 与肠道症状的发生率增加有关。 然而，IBD 使患者易发生心血管事件的分子机制。 心血管疾病 (CVD) 仍然难以捉摸 除了慢性炎症之外，炎症性肠病 (IBD) 的一个特征是。 肠道微生物群失调，其特征是专性厌氧菌显着减少和厌氧菌急剧增加 虽然炎症可以通过药物治疗或手术得到很好的控制，但肠道微生物。 菌群失调持续存在，可能在 IBD 相关 CVD 中发挥关键作用，我们在小鼠身上证实了这种现象。 结肠炎模型，概括了人类 IBD 的一些常见 EIM。 失调的肠道微生物群通过上调 miR-155 和下调脑功能导致心脏功能障碍 衍生神经营养因子（BDNF），两者都被认为是心脏系统的关键参与者。 结肠炎引起的微生物群失调通过表观遗传触发成人心脏的分子重塑 我们将通过实现三个具体目标来检验这一假设，目标 1 将生态失调作为一个关键。 通过移植 IBD 患者的失调粪便微生物群，在结肠炎引起的心脏功能障碍中扮演重要角色 我们还将确定是否可以通过以下方法消除疾病信号：患有结肠炎的小鼠和细菌耗尽的小鼠。 正常粪便微生物群和/或益生菌的移植将重点关注外泌体 miR- 的特征。 155 作为 IBD 诱导的分子重塑的关键参与者，我们预见外泌体 miR-155 衍生。 特别是来自肠上皮细胞 (IEC) 的功能是肠道之间串扰的主要介质 使用新型 IEC 特异性 miR-155 敲除 (Mir155ΔIEC) 和 Mir155ΔIEC/IL10-/- 小鼠， 我们的目的是证明，肠道来源的外泌体 miR-155 在表观遗传上下调心脏 BDNF 在目标 3 中，我们还将确定 miR-155 抑制剂是否可以减轻 IBD 引起的心脏病。 心肌细胞中 BDNF 减少的表观遗传机制将通过体内、体外和 我们将描述 BDNF 在成人心脏中的功能和表型作用。 我们还将探索一种新型他莫昔芬诱导型、心脏特异性 BDNF 敲除小鼠模型。 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一种新的方法。 结肠炎通过微生物群失调→外泌体 miR-155→BDNF 诱导心脏重塑的范例 信号轴，导致心脏功能障碍。