Gut Dysbiosis and Cardiac Remodeling in IBD

项目摘要/摘要 炎症性肠病(IBD)是一种使人虚弱且难以控制的消化系统慢性炎症。 肠道，引起腹泻等胃肠道症状。它与终生发病率有关，更多的医学 注意力，以及生活质量的下降。大约有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，甚至使 肠道症状。越来越多的证据表明，IBD与糖尿病发病率的增加有关 心血管事件。然而，IBD使患者易感的分子机制 心血管疾病(CVD)仍然难以捉摸。除了慢性炎症，IBD的一个特征是 肠道微生物区系失调，其特征是专性厌氧菌显著减少和肠道微生物区系急剧增加 兼性厌氧菌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 微生态失调持续存在，并可能在IBD相关的CVD中发挥关键作用。我们在小鼠身上证实了这一现象 结肠炎模型，它概括了一些常见的人类IBD的EIM。我们的初步调查结果表明 肠道微生物区系通过上调miR-155和下调脑-155而导致心功能不全 衍生神经营养因子(BDNF)，两者都被认为是心脏系统中的关键角色。我们假设 结肠炎诱导的微生物区系失调通过表观遗传学触发成人心脏的分子重塑 机械装置。我们将通过追求三个具体目标来检验这一假设。目标1将把生态失调确立为关键 通过移植IBD和IBD患者粪便微生物群在结肠炎所致心功能障碍中的作用 从患有结肠炎的小鼠到细菌耗尽的小鼠。我们还将确定疾病信号是否可以通过 移植正常粪便微生物区系和/或益生菌。目标2将重点描述外体miR- 155在IBD诱导的分子重塑中起关键作用。我们预测外体miR-155来源于 具体地说，来自肠道上皮细胞(IEC)的功能是肠道之间串扰的主要中介 微生物区系和心脏。使用新的IEC特异性miR-155基因敲除(Mir155ΔIEC)和Mir155ΔIEC/IL10-/-小鼠， 我们的目的是证明肠道来源的外体miR-155在存在的情况下从表观上下调心脏BDNF的表达 慢性结肠炎。我们还将确定miR-155抑制剂是否可以减轻IBD引起的心脏病。在《目标3》中， 心肌细胞BDNF减少的表观遗传学机制将通过体内、体外和 蛋白质组学的方法。我们将描述BDNF在成人心脏中的功能和表型作用 使用一种新的他莫昔芬诱导的心脏特异性BDNF基因敲除小鼠模型。我们还将探索 脑源性神经营养因子对IBD相关性脑血管病的预防和治疗作用我们的结果应该有助于建立一部小说 结肠炎通过微生物区系失调→外体miR-155bdnf诱导心脏重构的范式 信号轴，导致心脏功能障碍。

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.