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

描述（由申请人提供）：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, <1500 g）婴儿中。尽管新生儿重症监护有所改善，但在过去的20年里，新生儿体重特异性NEC发病率并没有改变。然而，由于非常不成熟的婴儿存活率增加，疾病的总负担正在增加。死亡率仍然很高，幸存者经历了包括术后短肠综合征、生长不良、长期住院和长期神经发育障碍在内的重大发病率。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。这三种因素的共存导致细菌在受损的肠粘膜屏障上易位，强烈的局部和全身炎症反应，以及NEC典型的肠道坏死。为了减轻NEC的风险，人们建议使用益生菌来纠正肠道屏障功能障碍和改善肠道生态失调。尽管在多个随机临床试验中，使用益生菌预防NEC的发病率降低了30%，但使用了各种配方、剂量和治疗时间，婴儿体重<1000 g时NEC发病率最高的比例不足，并且没有fda批准的产品可用于确保良好生产规范下的质量和安全性。迫切需要设计良好的试验，并有适当的监管监督，以解决特定益生菌产品在高风险、特征明确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VLBW婴儿NEC的安全性和有效性。目前提案的总体目标是开展一项LGG的开放标签、安全性和先导剂量递增研究，以收集设计LGG在早产儿人群中的III期安全性和有效性试验所需的信息。具体而言，该研究将评估一种易于收集的新型生物标志物zonulin在监测肠道通透性方面的实用性，并提供有关给VLBW婴儿使用3种不同剂量LGG的安全性和可接受性、LGG改善肠道屏障功能的最佳剂量以及LGG对胃肠道微生物群的影响的信息。具体目标将解决以下中心假设：1)生物标志物（血清zonulin、乳果糖/甘露醇尿比和/或粪便a-1抗胰蛋白酶）水平升高将识别肠道通透性增加的婴儿；2)肠道通透性生物标志物升高的VLBW婴儿口服LGG可改善肠道屏障功能，促进有益肠道菌群的建立。开发生物标志物来识别肠通透性增加的NEC高危婴儿，将促进潜在预防治疗的临床试验。益生菌治疗是一种有前景的、低成本的、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有关未来LGG预防早产儿NEC的随机安全性和有效性试验的决策。

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.