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) 是一种危及生命的胃肠道急症，发生于 7% 至 10% 的极低出生体重 (VLBW，<1500 g) 婴儿。尽管新生儿重症监护有所改善，但 NEC 的出生体重特定发病率在过去 20 年来并未发生变化。然而，由于非常不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，幸存者会经历显着的发病率，包括术后短肠综合征、生长不良、住院时间延长和长期神经发育障碍。早产、肠道菌群失调和肠道屏障功能受损是 NEC 发病机制的三个关键因素。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。为了降低 NEC 的风险，有人建议使用益生菌来纠正肠道屏障功能障碍并改善肠道菌群失调。尽管在益生菌预防 NEC 的多项随机临床试验中，NEC 发生率降低了 30%，但使用了不同的配方、剂量和治疗持续时间，但体重 <1000 g 且 NEC 发生率最高的婴儿的代表性不足，并且没有 FDA 批准的产品可以在良好生产规范下确保质量和安全。迫切需要精心设计的试验和适当的监管监督，以解决高风险、特征明确的人群中特定益生菌产品的剂量问题。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。当前提案的总体目标是开展 LGG 的开放标签、安全性和试验剂量递增研究，以收集设计 LGG 在早产人群中的 III 期安全性和有效性试验所需的信息。具体来说，拟议的研究将评估一种易于收集的新型生物标志物连蛋白（zonulin）在监测肠道通透性方面的效用，并提供有关对极低出生体重婴儿施用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（血清连蛋白、乳果糖/甘露醇尿比和/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； 2）肠道通透性生物标志物升高的极低出生体重儿口服LGG将改善肠道屏障功能，有利于建立有益的肠道微生物群。 开发生物标志物来识别肠道通透性增加且 NEC 高风险的婴儿将有助于潜在预防性疗法的临床试验。益生菌疗法是一种有前途、低成本且可能安全的干预措施，可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 LGG 未来预防早产人群 NEC 的随机安全性和有效性试验的决策。

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