Effect of Lactobacillus GG on gut permeability and microbiome in VLBW neonates

描述(申请人提供)：坏死性小肠结肠炎(NEC)是一种危及生命的胃肠道急症，发生在7%至10%的极低出生体重(VLBW，&lt；1500 g)婴儿中。尽管新生儿重症监护有所改善，但新生儿出生体重相关发病率在过去20年中没有变化。然而，由于极不成熟婴儿的存活率增加，疾病的总负担正在增加。死亡率仍然很高，幸存者的发病率很高，包括手术后短肠综合征、生长不良、长期住院和长期神经发育障碍。早产、肠道生态失调和肠道屏障功能受损是NEC发病的三个关键因素。这三个因素的共存导致细菌易位穿过受损的肠粘膜屏障，强烈的局部和全身炎症反应，以及NEC典型的肠坏死。为了减轻NEC的风险，有人建议使用益生菌来纠正肠道屏障功能障碍，改善肠道生物失调。虽然在预防NEC的多个益生菌随机临床试验中，NEC的发病率降低了30%，但使用了不同的配方、剂量和疗程，但NEC发病率最高的婴儿和体重1000g的比例偏低，而且没有FDA批准的产品来确保良好的生产实践下的质量和安全。迫切需要在适当的监管监督下进行精心设计的试验，以解决特定益生菌产品在高危、特征良好的人群中的剂量问题。我们的长期目标是确定鼠李糖乳杆菌GG(LGG)预防极低出生体重儿NEC的安全性和有效性。目前提案的总体目标是进行LGG的开放标签、安全性和试点剂量递增研究，以收集在早产人群中设计LGG第三阶段安全性和有效性试验所需的信息。具体地说，这项拟议的研究将评估一种易于收集的新型生物标志物zonlin在监测肠道通透性方面的作用，并提供有关给极低出生体重婴儿服用3种不同剂量的LGG的安全性和可接受性、改善肠道屏障功能的最佳剂量以及LGG对GI微生物区系的影响的信息。具体目标将解决以下核心假设：1)生物标志物水平(血清zonrin、乳果糖/甘露醇尿比例和/或粪便a-1抗胰蛋白酶)水平的增加将识别肠道通透性增加的婴儿；以及2)口服LGG对肠道通透性生物标志物升高的极低出生体重儿将改善肠道屏障功能，有利于建立有益的肠道微生物区系。开发生物标记物来识别肠道通透性增加的婴儿谁是NEC的高风险，将促进潜在的预防治疗的临床试验。益生菌疗法是一种有前景的、低成本且可能安全的干预措施，可以降低高危婴儿的肠道通透性。拟议研究产生的数据将直接导致关于未来LGG预防早产人群NEC的随机安全性和有效性试验的决定。

DESCRIPTION (provided by applicant): Necrotizing enterocolitis (NEC) is a life-threatening, gastrointestinal emergency that occurs in 7 to 10% very low birth weight (VLBW, <1500 g) infants. Despite improvements in neonatal intensive care, the birth weight-specific incidence of NEC has not changed over the past 2 decades. However, the total burden of disease is increasing due to increased survival of very immature infants. Mortality remains high and survivors experience significant morbidity including post-surgical short bowel syndrome, poor growth, prolonged hospitalization, and long-term neurodevelopmental impairments. Prematurity, gut dysbiosis, and impaired intestinal barrier function are three key factors in NEC pathogenesis. The co-existence of these three factors leads to bacterial translocation across an impaired intestinal mucosal barrier, intense local and systemic inflammatory responses, and intestinal necrosis typical of NEC. To mitigate the risk of NEC, the use of probiotics has been proposed to correct the intestinal barrier dysfunction and improve gut dysbiosis. Although there was a 30% reduction in NEC incidence in multiple randomized clinical trials of probiotics to prevent NEC, various formulations, doses, and duration of therapy were used, infants <1000 g BW with the highest NEC incidence were underrepresented, and no FDA-approved products are available to assure quality and safety under good manufacturing practices. There is an urgent need for well-designed trials with proper regulatory oversight to address the dose of a specified probiotic product, in a high-risk, well characterized, population. Our long-term goal is to determine the safety and efficacy of Lactobacillus rhamnosus GG (LGG) to prevent NEC in VLBW infants. The overall objective of the current proposal is to conduct an open label, safety and pilot dose escalation study of LGG to collect information needed to design Phase III safety and efficacy trials of LGG in the preterm population. Specifically, the proposed study will assess the utility of an easily collected novel biomarker zonulin to monitor intestinal permeability, and provide information on the safety and acceptability of administering 3 different doses of LGG to VLBW infants, the optimal dose of LGG to improve intestinal barrier function, and the impact of LGG on GI microbiota. The specific aims will address the central hypotheses that 1) increased levels of biomarkers (serum zonulin, Lactulose/Mannitol urine ratio, and/or fecal a-1 anti-trypsin) will identify infants with increased intestinal permeability; and 2) oral administration of LGG in VLBW infants with elevated intestinal permeability biomarkers will improve gut barrier function and favor the establishment of a beneficial gut microbiota. Development of biomarkers to identify infants with increased intestinal permeability who are at high risk for NEC will facilitate clinical trials of potential preventive therapies. Probiotic therapy is a promising, low-cost, and likely safe intervention to reduce intestinal permeability in high-risk infants. The data generated from the proposed studies will directly lead to decisions concerning future randomized safety and efficacy trials of LGG to prevent NEC in the preterm population.