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

GG 乳杆菌对 VLBW 新生儿肠道通透性和微生物组的影响

• 批准号: 8536214
• 负责人: Alessio Fasano
• 金额: $ 22.11万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8536214
• 关键词: Address; Affect; Aftercare; Bacteria; Bacterial Translocation; Biological Markers; Birth Weight; Clinical Trials; Clinical Trials Design; Colony-forming units; Data; Development; Disease; Dose; Drug Formulations; Elements; Emergency Situation; Equilibrium; FDA approved; Functional disorder; Future; Goals; Growth; Incidence; Infant; Inflammatory Response; Intervention; Intestines; Lactobacillus; Lactobacillus casei rhamnosus; Lactulose; Lead; Life; Mannitol; Measurement; Measures; Modification; Monitor; Morbidity - disease rate; Necrosis; Necrotizing Enterocolitis; Neonatal Intensive Care; Neurodevelopmental Impairment; Operative Surgical Procedures; Oral Administration; Pathogenesis; Permeability; Phase; Play; Population; Predisposition; Preparation; Prevention; Preventive; Probiotics; Proteins; Randomized; Randomized Clinical Trials; Regimen; Reporting; Risk; Role; Safety; Serum; Short Bowel Syndrome; Specific qualifier value; Survivors; Tight Junctions; Time; Trypsin; Urine; Very Low Birth Weight Infant; burden of illness; cohort; cost; design; efficacy testing; efficacy trial; experience; gastrointestinal; gut microbiota; high risk; high risk infant; improved; in vivo; long term hospitalization; microbial; microbiome; microorganism; mortality; neonate; novel; open label; premature; prevent; pyrosequencing; rRNA Genes; therapy duration; zonulin

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.

描述（由申请人提供）：坏死性小肠结肠炎（NEC）是威胁生命的胃肠道紧急情况，发生在7％至10％的非常低的出生体重（VLBW，<1500 g）婴儿中。尽管新生儿重症监护病的改善，但在过去的20年中，NEC的出生体重特异性发病率并未发生变化。但是，由于非常未成熟的婴儿的存活率增加，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，不良的生长，长期住院和长期神经发育障碍。早产，肠道营养不良和肠屏障功能受损是NEC发病机理的三个关键因素。这三个因素的共存导致细菌易位在肠粘膜屏障，强烈的局部和全身性炎症反应以及NEC典型的肠道坏死。为了减轻NEC的风险，已经提出了使用益生菌来纠正肠道屏障功能障碍并改善肠道营养不良。尽管在多种益生菌的随机临床试验中，NEC发病率降低了30％，以预防NEC，使用了各种配方，剂量和治疗持续时间，但NEC发病率最高的婴儿<1000 g bw的婴儿含量不足，并且没有FDA批准的产品可用于良好的制造方法，以弥补质量和安全性。迫切需要进行精心设计的试验，并进行适当的监管监督，以应对高风险，表征良好的人口的特定益生菌产品的剂量。我们的长期目标是确定乳杆菌GG（LGG）的安全性和功效，以防止VLBW婴儿中的NEC。当前建议的总体目标是对LGG进行开放标签，安全性和试点剂量升级研究，以收集在早产中设计LGG的第三阶段安全性和有效性试验所需的信息。具体而言，拟议的研究将评估易于收集的新型生物标志物扎该蛋白的实用性，以监测肠道通透性，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的信息，VLBW婴儿（最佳的LGG剂量），LGG的最佳剂量以改善肠道屏障功能，以及LGG对GI Microbotobiota的影响。具体目的将解决中心假设，即1）生物标志物水平升高（血清Zonulin，乳lim/甘露醇尿比和/或粪便A-1抗tri蛋白）将确定肠道通透性增加的婴儿； 2）在肠道通透性生物标志物升高的VLBW婴儿中口服LGG将改善肠道屏障功能，并有利于建立有益的肠道微生物群。 生物标志物的开发以识别具有NEC高风险的肠道通透性增加的婴儿将促进潜在预防疗法的临床试验。益生菌治疗是一种有希望的，低成本且可能的安全干预措施，可降低高危婴儿的肠道渗透性。从拟议的研究中产生的数据将直接导致关于LGG的未来随机安全性和功效试验的决策，以防止早产中的NEC。

项目成果

Microbial Biomarkers of Intestinal Barrier Maturation in Preterm Infants.

• DOI: 10.3389/fmicb.2018.02755
• 发表时间: 2018
• 期刊: Frontiers in microbiology
• 影响因子: 5.2
• 作者: Ma B;McComb E;Gajer P;Yang H;Humphrys M;Okogbule-Wonodi AC;Fasano A;Ravel J;Viscardi RM
• 通讯作者: Viscardi RM

Intestinal Barrier Maturation in Very Low Birthweight Infants: Relationship to Feeding and Antibiotic Exposure.

• DOI: 10.1016/j.jpeds.2017.01.013
• 发表时间: 2017-04
• 期刊: The Journal of pediatrics
• 作者: Saleem B;Okogbule-Wonodi AC;Fasano A;Magder LS;Ravel J;Kapoor S;Viscardi RM
• 通讯作者: Viscardi RM

Impact of red blood cell transfusions on intestinal barrier function in preterm infants.

• DOI: 10.3233/npm-1828
• 发表时间: 2019
• 期刊: Journal of neonatal-perinatal medicine
• 作者: Ajayi OO;Davis NL;Saleem B;Kapoor S;Okogbule-Wonodi AC;Viscardi RM;Sundararajan S
• 通讯作者: Sundararajan S