Post-natal nutrition, intestinal dysbiosis and pulmonary hypertension in premature infants: the role of the developing gut-lung axis

早产儿出生后营养、肠道生态失调和肺动脉高压： 肠肺轴发育 摘要 在出生后的最初几周和几个月内生长不良在极早产儿中非常常见， 在新生儿住院期间体重低于第10百分位数的极早产儿 重症监护室，一种被称为产后生长受限（PNGR）的并发症。作为重点， 在过去的几十年里，从生存转向改善结局，已经很清楚PNGR与 与包括肺动脉高压在内的早产相关的许多发病风险增加 (PH)，神经发育迟缓，坏死性小肠结肠炎，败血症，早产儿视网膜病变，和慢性肺 疾病（也称为支气管肺发育不良）。此外，早产儿的PNGR也 与许多成人疾病有关，这些疾病已被证明是由足月胎儿生长受限引起的。 婴儿包括代谢综合征、肥胖症和高血压。简单地在第一阶段最大限度地增加热量摄入 几个星期的生活已经有所帮助，但PNGR仍然非常普遍，由于令人难以置信的 与胃肠道不成熟相关的挑战。我们建议在动物身上进行新的研究， PNGR的模型，以发现PNGR触发PH的机制（最引人注目的临床 发展中的肠-肺轴改变的实例）。我们利用大鼠PNGR模型， 操纵一只母鼠照顾的幼崽数量。与PNGR相关的PH表型是 由于暴露于模拟常见临床情况的高氧而恶化（极早产儿， 严重的肺病和生长不良）。我们目前的初步数据支持两个开创性的 观察结果：首先，PNGR与肠道生态失调有关， 微生物可以防止PNGR相关的PH值，第二，增强营养可以防止 高氧的损害作用。在目标1中，我们提出了实验来定义发展窗口， 益生菌或增强营养预防PH。在目标2中，我们建议确定是否 TLR 4/MyD 88/NFκB通路在该模型中起重要作用。我们的新观察，肠杆菌科是 PNGR在小肠中的表达显著增加，表明TLR 4在PNGR的发展中的潜在作用。 肠-肺轴作为这些革兰氏阴性生物体的细胞壁含有丰富的脂多糖（ TLR 4识别的关键病原体相关分子模式）。机械地理解这些 过程对于预防婴儿和成人PNGR并发症至关重要。

Post-natal nutrition, intestinal dysbiosis and pulmonary hypertension in premature infants: the role of the developing gut-lung axis Abstract Poor growth in the first weeks and months of life is very common in very premature infants with up to 80% of extremely premature infants dropping below the 10th percentile for weight during hospitalization in the Neonatal Intensive Care Unit, a complication referred to as post-natal growth restriction (PNGR). As emphasis has shifted in the last decades from survival to improving outcomes, it has become clear that PNGR is associated with increased risk of much of the morbidity associated with prematurity including pulmonary hypertension (PH), neurodevelopmental delays, necrotizing enterocolitis, sepsis, retinopathy of prematurity, and chronic lung disease (also known as bronchopulmonary dysplasia). Furthermore PNGR in premature infants is also associated with many adult diseases that have been demonstrated to result from fetal growth restriction in term infants including metabolic syndrome, obesity, and hypertension. Simply maximizing caloric intake in the first weeks of life has been somewhat helpful, however PNGR remains very common due to the incredible challenges associated with immaturity of the gastrointestinal tract. We propose novel studies in an animal model of PNGR to discover the mechanisms by which PNGR triggers PH (the most compelling clinical example of alteration of the developing gut-lung axis). We utilize a rat model of PNGR based upon manipulation of the number of pups cared for by a single dam. The PH phenotype associated with PNGR is worsened by exposure to hyperoxia mimicking a common clinical situation (the extremely premature infant with severe lung disease and poor growth). We present preliminary data supporting two groundbreaking observations: first, that PNGR is associated with intestinal dysbiosis and that administration of probiotic microbes prevents PNGR-associated PH and second, that enhanced nutrition is protective against the damaging effect of hyperoxia. In aim 1 we propose experiments to define the developmental window in which probiotics or enhanced nutrition prevent PH. In aim 2 we propose to determine whether the TLR4/MyD88/NFκB pathway is essential in this model. Our novel observation that Enterobacteriaceae are significantly increased in the small intestine with PNGR suggests the potential role of TLR4 in the developing gut-lung axis as the cell wall of these Gram negative organisms contains abundant lipo-polysaccharide (one of the key pathogen associated molecular patterns recognized by TLR4). A mechanistic understanding of these processes is essential to prevention of both infant and adult complications of PNGR.