Embleton Nicholas D, Berrington Janet E, Dorling Jon, Ewer Andrew K, Juszczak Edmund, Kirby John A, Lamb Christopher A, Lanyon Clare V, McGuire William, Probert Christopher S, Rushton Stephen P, Shirley Mark D, Stewart Christopher J, Cummings Stephen P
Newcastle Neonatal Service, Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
Institute of Health and Society, Newcastle University, Newcastle upon Tyne, UK.
Front Nutr. 2017 May 8;4:14. doi: 10.3389/fnut.2017.00014. eCollection 2017.
Large randomized controlled trials (RCTs) in preterm infants offer unique opportunities for mechanistic evaluation of the risk factors leading to serious diseases, as well as the actions of interventions designed to prevent them. Necrotizing enterocolitis (NEC) a serious inflammatory gut condition and late-onset sepsis (LOS) are common feeding and nutrition-related problems that may cause death or serious long-term morbidity and are key outcomes in two current UK National Institutes for Health Research (NIHR) trials. Speed of increasing milk feeds trial (SIFT) randomized preterm infants to different rates of increases in milk feeds with a primary outcome of survival without disability at 2 years corrected age. Enteral lactoferrin in neonates (ELFIN) randomizes infants to supplemental enteral lactoferrin or placebo with a primary outcome of LOS. This is a protocol for the mechanisms affecting the gut of preterm infants in enteral feeding trials (MAGPIE) study and is funded by the UK NIHR Efficacy and Mechanistic Evaluation programme. MAGPIE will recruit ~480 preterm infants who were enrolled in SIFT or ELFIN. Participation in MAGPIE does not change the main trial protocols and uses non-invasive sampling of stool and urine, along with any residual resected gut tissue if infants required surgery. Trial interventions may involve effects on gut microbes, metabolites (e.g., short-chain fatty acids), and aspects of host immune function. Current hypotheses suggest that NEC and/or LOS are due to a dysregulated immune system in the context of gut dysbiosis, but mechanisms have not been systematically studied within large RCTs. Microbiomic analysis will use next-generation sequencing, and metabolites will be assessed by mass spectrometry to detect volatile organic and other compounds produced by microbes or the host. We will explore differences between disease cases and controls, as well as exploring the actions of trial interventions. Impacts of this research are multiple: translation of knowledge of mechanisms promoting gut health may explain outcomes or suggest alternate strategies to improve health. Results may identify new non-invasive diagnostic or monitoring techniques, preventative or treatment strategies for NEC or LOS, or provide data useful for risk stratification in future studies. Mechanistic evaluation might be especially informative where there are not clear effects on the primary outcome (ISRCTN 12554594).
针对早产儿的大型随机对照试验（RCT）为深入探究导致严重疾病的风险因素的作用机制，以及旨在预防这些疾病的干预措施的作用机制，提供了独特的契机。坏死性小肠结肠炎（NEC）是一种严重的肠道炎症性疾病，晚发性败血症（LOS）是常见的与喂养和营养相关的问题，它们可能导致死亡或严重的长期发病，是英国国立卫生研究院（NIHR）目前两项试验的关键结局指标。增加奶量速度试验（SIFT）将早产婴儿随机分为不同的奶量增加速度组，主要结局指标是校正年龄2岁时无残疾存活。新生儿肠内乳铁蛋白试验（ELFIN）将婴儿随机分为补充肠内乳铁蛋白组或安慰剂组，主要结局指标是晚发性败血症。这是一项关于肠内喂养试验中影响早产儿肠道机制的研究方案（MAGPIE），由英国NIHR疗效与机制评估项目资助。MAGPIE将招募约480名参加过SIFT或ELFIN的早产婴儿。参与MAGPIE研究不会改变主要试验方案，研究将采用粪便和尿液的非侵入性采样，以及如果婴儿需要手术则采集任何剩余的切除肠道组织。试验干预可能涉及对肠道微生物、代谢产物（如短链脂肪酸）以及宿主免疫功能方面的影响。目前的假说认为，NEC和/或LOS是由于肠道生态失调背景下免疫系统失调所致，但在大型随机对照试验中尚未对其机制进行系统研究。微生物组分析将采用新一代测序技术，代谢产物将通过质谱法进行评估，以检测微生物或宿主产生的挥发性有机化合物和其他化合物。我们将探究疾病病例与对照之间的差异，以及试验干预措施的作用。这项研究的影响是多方面的：促进肠道健康机制的知识转化可能解释试验结果，或为改善健康状况提供替代策略。研究结果可能会确定新的非侵入性诊断或监测技术、NEC或LOS的预防或治疗策略，或为未来研究中的风险分层提供有用数据。在对主要结局指标没有明确影响的情况下，机制评估可能会提供特别有价值的信息（国际标准随机对照试验编号：12554594）。
