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缺陷（CHD），心脏缺陷是美国出生缺陷相关死亡的主要原因。虽然手术治疗和心肺转流术的进步提高了先天性心脏病患儿的存活率，但这些婴儿仍存在术后多器官功能障碍（MODS）的发病率2，26。患有左侧阻塞性CHD的婴儿特别容易发生MODS。术后MODS的假定机制是通过肠上皮屏障功能（EBF）和低肠道微生物组多样性的丧失9，15，27。在一项对20名先天性心脏病手术修复后的婴儿和儿童进行的单中心初步研究中，我们发现延迟肠内营养（EN）启动与肠上皮完整性较差相关。我们还发现，术后抗生素的持续时间较长与紧密连接完整性的丧失和肠道通透性的降低有关， 可能是通过减少肠道微生物组多样性22，23，28。这些证据表明，延迟EN启动和术后抗生素预防的持续时间较长可能会增加婴儿在左侧梗阻性CHD手术矫正后发生MODS的风险，因为对宿主肠道EBF和微生物组多样性产生负面影响。该提案的目标是通过教育计划和完成以下2个具体目标，为Typpo博士在临床转化研究中的独立职业生涯做好准备，研究肠道EBF和微生物组多样性对MODS发生率和严重程度的作用：具体目标1：确定EN的时间和成分对术后前7个月肠道EBF恢复的影响。接受左侧梗阻性心脏缺陷手术矫正的婴儿的手术天数。具体目标二：确定围手术期抗生素暴露的持续时间和类型对接受左侧梗阻性心脏缺陷的婴儿术后前7天内微生物组多样性、肠道EBF和部位特异性肠道通透性较基线变化的影响。我们将在三个心脏病中心利用现有的实践差异来确定EN启动和抗菌预防的时间。这一建议是重要的，因为我们将解决知识的差距，关于最佳时机的EN开始手术纠正婴儿CHD，以维持肠道屏障功能。这项提议是创新的，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和EN时机和组成如何对人类儿童的肠道微生物组产生负面影响。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风险的直接影响外，还可能对几种慢性疾病的发展产生长期持久的影响25，30- 32，80，81。这项职业发展奖将帮助Typpo博士准备应用微创肠道EBF评估和微生物组分析的新兴科学，以确定减少患者术后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.