Effects of Probiotics on Neonatal Bacterial Meningitis

益生菌对新生儿细菌性脑膜炎的影响

基本信息

批准号：
7304529
负责人：
SHENG-HE HUANG
金额：
$ 19.69万
依托单位：
CHILDREN'S HOSPITAL OF LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-01 至 2009-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7304529
关键词：
Abbreviations Adhesions Adverse effects Ampicillin Resistance Animal Model Animals Antibiotic Resistance Antibiotics Appendix Applications Grants Bacteremia Bacteria Bacterial Meningitis Binding Binding Proteins Blood Blood - brain barrier anatomy Brain Caco-2 Cells Cell Culture System Cerebrospinal Fluid Child Colony-forming units Complementary and alternative medicine Cultured Cells Data Development Diarrhea Disadvantaged Disease Electrical Resistance Electronics Endothelial Cells Enterobacteriaceae Epithelial Cells Escherichia coli Escherichia coli Infections Ethylmaleimide Fimbria of hippocampus Frequencies Health Horseradish Peroxidase Host Defense Human In Vitro Incidence Infection Inflammatory Bowel Diseases Intestines Knowledge Lactobacillus Lactobacillus casei rhamnosus Life Lipopolysaccharides Low Birth Weight Infant Medical Meningitis Microbe Microbiology Microscopy Modeling Molecular Biology Techniques Morbidity - disease rate Neonatal Neonatal Mortality Neuraxis Newborn Infant Organism Pathogenesis Personal Satisfaction Pilot Projects Pilum Premature Infant Prevention Probiotics Prophylactic treatment Rate Rattus Streptococcal Infections Streptococcus Streptococcus Group B Symptoms System Testing Tissues Toll-like receptors Virulence Factors antimicrobial drug disorder prevention early onset in vitro Model in vivo in vivo Model intrapartum microbial monolayer mortality neonate pathogen postnatal prevent prophylactic protective effect response transcytosis transmission process type 1 fimbriae

项目摘要

DESCRIPTION (provided by applicant): This revised R21 project is being submitted in response to PA-06-316 for the development of probiotics as complementary and alternative medical (CAM) approaches that overcome the disadvantages of intrapartum antibiotic use (IAU) for the prevention of neonatal bacterial meningitis (NBM). Probiotics have been successfully used for reducing the duration of diarrhea in newborns and children, and for alleviating symptoms of inflammatory bowel diseases. However, it is unknown whether probiotics are beneficial to the prophylaxis of meningitis. Group B Streptococcus (GBS) and E. coli are the two most common bacterial pathogens causing NBM. Extensive studies demonstrated that intrapartum prophylaxis of GBS carriers and selective administration of antibiotics to neonates decrease newborn GBS infection by as much as 80 to 95%. However, widespread IAU, particularly with broad-spectrum antimicrobial agents, has resulted in an increasing incidence of early onset E. coli infections in low birth weight neonates and a rising frequency of ampicillin-resistant E. coli infections in preterm infants. Meningitis caused by enteric bacteria usually begins with intestinal adhesion and invasion. Bacteria enter the blood system and then cross the blood-brain barrier (BBB) to get access into the central nervous system. In order to dissect the pathogenesis of this disease, we have established both cell culture systems (endothelial and epithelial cells) and neonatal rat model of E. coli meningitis. Several host and pathogen virulence factors have been identified and characterized in these systems. Our preliminary data demonstrated that Lactobacillus GG (LGG) was able to suppress meningitic E. coli K1 invasion and transcytosis across human intestinal epithelial cell in vitro (Caco-2 cell culture model) and in vivo (neonatal rat model of E. coli meningitis). Our hypothesis is that probiotic and commensal bacterial organisms (microbiota) may have important influences on the pathogenesis and prophylaxis of neonatal meningitis. Probiotics suppresses meningitic pathogen adhesion to and invasion of host tissue barriers in vitro and in vivo, which are associated with probiotics-enhanced host tissue barrier functions. Our hypothesis will be tested with two Specific Aims. (1). To examine whether the maternal prophylaxis alone or combined with postnatal prophylaxis using probiotics LGG reduces the genesis of bacteremia and the incidence of neonatal E. coli meningitis in the rat model. (2). To determine how probiotic LGG suppresses meningitic E. coli K1 adhesion to and invasion of the host tissues using in vitro models of the gut barrier (Caco-2 & HT-29/cl.f8). The high morbidity and mortality of neonatal bacterial meningitis (NBM) is due to inadequate knowledge of the pathogenesis and prevention of this disease. This R21 grant application, however, should allow us to set up pilot studies to determine whether the maternal prophylaxis alone or combined with postnatal prophylaxis using probiotics Lactobacillus rhamnosus strain GG (LGG) reduces the rate of neonatal E. coli meningitis in the rat model. It should also allow us to determine how LGG suppresses meningitic E. coli K1 adhesion to and invasion of the host tissues using in vitro models of the gut barrier (Caco-2 & HT-29/cl.f8). The overall aims of this proposal are to examine whether NBM can be prevented by probiotics which have beneficial effects on human health and may overcome the crisis in antibiotic resistance due to widespread use of antibiotics.

描述（由申请人提供）：此修订版 R21 项目是为了响应 PA-06-316 的要求而提交的，目的是开发益生菌作为补充和替代医学 (CAM) 方法，克服产时使用抗生素 (IAU) 进行预防的缺点新生儿细菌性脑膜炎（NBM）。益生菌已成功用于缩短新生儿和儿童腹泻的持续时间，并减轻炎症性肠病的症状。然而，益生菌是否有益于预防脑膜炎尚不清楚。 B 族链球菌 (GBS) 和大肠杆菌是引起 NBM 的两种最常见的细菌病原体。广泛的研究表明，GBS 携带者的产时预防和对新生儿选择性施用抗生素可将新生儿 GBS 感染减少 80% 至 95%。然而，广泛的IAU，特别是广谱抗菌药物，导致低出生体重新生儿早发型大肠杆菌感染的发生率增加，以及早产儿耐氨苄青霉素大肠杆菌感染的频率增加。肠道细菌引起的脑膜炎通常始于肠道粘连和侵袭。细菌进入血液系统，然后穿过血脑屏障（BBB）进入中枢神经系统。为了剖析这种疾病的发病机制，我们建立了大肠杆菌脑膜炎的细胞培养系统（内皮细胞和上皮细胞）和新生大鼠模型。在这些系统中已经鉴定和表征了几种宿主和病原体毒力因子。我们的初步数据表明，乳杆菌 GG (LGG) 能够在体外（Caco-2 细胞培养模型）和体内（新生大鼠大肠杆菌脑膜炎模型）中抑制脑膜炎大肠杆菌 K1 入侵和跨人肠上皮细胞的转胞吞作用。我们的假设是，益生菌和共生细菌生物（微生物群）可能对新生儿脑膜炎的发病机制和预防具有重要影响。益生菌在体外和体内抑制脑膜炎病原体粘附和侵入宿主组织屏障，这与益生菌增强宿主组织屏障功能有关。我们的假设将通过两个具体目标进行检验。 (1).在大鼠模型中检查单独的母体预防或与益生菌 LGG 联合产后预防是否可以减少菌血症的发生和新生儿大肠杆菌脑膜炎的发生率。（2）。使用体外肠道屏障模型 (Caco-2 & HT-29/cl.f8) 确定益生菌 LGG 如何抑制脑膜炎大肠杆菌 K1 对宿主组织的粘附和侵袭。新生儿细菌性脑膜炎（NBM）的高发病率和死亡率是由于对该疾病的发病机制和预防认识不足造成的。然而，这项 R21 拨款申请应该允许我们开展试点研究，以确定单独使用孕产妇预防或与使用益生菌鼠李糖乳杆菌 GG (LGG) 菌株进行产后预防相结合是否可以降低大鼠模型中新生儿大肠杆菌脑膜炎的发生率。它还应该使我们能够使用体外肠道屏障模型（Caco-2＆HT-29/cl.f8）来确定LGG如何抑制脑膜炎大肠杆菌K1对宿主组织的粘附和侵袭。该提案的总体目标是研究益生菌是否可以预防 NBM，对人类健康产生有益影响，并可能克服因广泛使用抗生素而导致的抗生素耐药性危机。