Effects of cardiac ICU practice variation on intestinal epithelial barrier function and microbiome diversity

 描述(由申请人提供)：美国每年约有40,000名婴儿出生时患有先天性心脏病(CHD)，心脏缺陷是美国出生缺陷相关死亡的主要原因。虽然外科治疗和体外循环技术的进步提高了先天先天性心脏病儿童的存活率，但这些婴儿仍在遭受术后多器官功能障碍(MODS)的发病率2，26。患有左侧梗阻性冠心病的婴儿特别容易患多器官功能障碍综合征。术后MODS的可能机制是通过肠上皮屏障功能丧失(EBF)和低肠微生物群多样性[9，15，27]。在一项对20名先天性心脏病手术修复后的婴幼儿进行的单中心先导性研究中，我们发现延迟开始肠内营养(EN)与肠上皮完整性较差有关。我们还发现，术后持续较长时间的抗生素与紧密连接完整性的丧失和更差的肠道通透性有关， 也许是通过减少肠道微生物群多样性22、23、28。这些证据表明，术后抗生素预防的延迟和持续时间的延长可能会通过对宿主肠道EBF和微生物多样性的负面影响而增加左侧梗阻性冠心病手术后婴儿MODS的风险。这项建议的目的是让Typpo博士为独立的临床-转化性研究做好准备，通过教育计划和完成以下两个具体目标，调查肠道EBF和微生物群多样性对MODS发生率和严重性的作用：具体目标1：确定接受左侧梗阻性心脏缺陷手术矫正的婴儿术后7天内EN的时机和组成对肠道EBF恢复的影响。具体目标2：确定围术期抗生素暴露的时间和类型对接受左侧梗阻性心脏缺陷手术矫正的婴儿在术后7天内从基线微生物群多样性、肠道EBF和特定部位肠道通透性的变化的影响。我们将利用现有的实践差异，在三个心脏中心进行EN启动和抗菌预防的时机选择。这项建议意义重大，因为我们将解决在婴幼儿先天性心脏病手术矫正以维持肠道屏障功能后最佳肠内营养启动时机的知识空白。这一建议是创新的，因为我们将应用从动物模型中获得的知识来研究围手术期抗生素的持续时间以及EN时机和组成可能如何对人类儿童的肠道微生物群产生负面影响。在微生物组发育的关键窗口期间，旨在限制对肠道微生物组的负面影响的护理策略，除了对MODS 25、30-32、80、81的风险产生直接影响外，还可能对几种慢性病的发展产生长期影响。这项职业发展奖将为Typpo博士应用新兴的微创肠道EBF评估和微生物组分析的科学做好准备，以确定减少她的患者术后MODS的策略。

 DESCRIPTION (provided by applicant): Approximately 40,000 infants are born each year in the United States with congenital heart defects (CHD), and heart defects are the leading cause of birth defect-related deaths in the United States. While advances in surgical treatment and cardiopulmonary bypass have improved survival for children born with CHD, these infants continue to suffer morbidity from post-operative multiple organ dysfunction (MODS)2,26. Infants with left sided obstructive CHD are at particular risk of MODS. Putative mechanisms for post-operative MODS are via loss of intestinal epithelial barrier function (EBF) and low intestinal microbiome diversity9,15,27. In a single center pilot study of 20 infants and children after surgical repair of CHD, we found that delayed enteral nutrition (EN) initiation was associated with worse intestinal epithelial integrity. We also identified that longer duration of post- operatve antibiotics was associated with loss of tight junction integrity and worse intestinal permeability, perhaps through reduced intestinal microbiome diversity 22,23,28. These lines of evidence suggest that delayed EN initiation and longer duration of post-operative antibiotic prophylaxis may increase risk for MODS in infants after surgical correction of left sided obstructive CHD through negative effects on the host intestinal EBF and microbiome diversity. The goal of this proposal is to prepare Dr. Typpo for an independent career in clinical- translational research investigating the role intestinal EBF and microbiome diversity on MODS incidence and severity through an educational program and completion of the following 2 specific aims: Specific Aim 1: Determine the effect of timing and composition of EN on the recovery of intestinal EBF over the first 7 post- operative days for infants undergoing surgical correction of left sided obstructive cardiac defects. Specific Aim 2: Determine the effect of duration and type of perioperative antibiotic exposure on change from baseline microbiome diversity, intestinal EBF, and site-specific intestinal permeability over the first 7 post-operative days in infants undergoing surgica correction of left sided obstructive cardiac defects. We will leverage existing practice variation for timing of EN initiation and antimicrobial prophylaxis across three cardiac centers. This proposal is significant, because we will address gaps in knowledge regarding the optimal timing of EN initiation after surgical correction of infant CHD to maintain intestinal barrier functions. This proposal is innovative, because we will apply knowledge gained from animal models to investigate how duration of perioperative antibiotics and EN timing and composition might negatively alter the intestinal microbiome for human children. Care strategies with the intent to limit negative effects on the intestinal microbiome during a critical window of microbiome development may have long lasting effects on the development of several chronic illnesses, in addition to immediate effects on risk of MODS25,30-32,80,81. This career development award will prepare Dr. Typpo to apply the emerging science of minimally invasive intestinal EBF assessment and microbiome analysis to identify strategies to reduce post-operative MODS in her patients.