Targeting the Intestinal Mucosa and Microbiome to Prevent Neonatal Late-onset Sepsis

针对肠粘膜和微生物组预防新生儿迟发性脓毒症

基本信息

批准号：
10458103
负责人：
Michael Jeffrey Gray
金额：
$ 70.52万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10458103
关键词：
Adult Alabama Anaerobic Bacteria Anaerobiosis Animal Model Antibiotics Automobile Driving Biology Cell Maturation Cells Child Clinical Collaborations Development Disease Dose Enterobacteriaceae Epithelial Epithelial Cells Family Foundations Future Genes Genetic Genetic Transcription Goals Immune Immunity Incidence Infant Infection Inflammation Intervention Intestinal Mucosa Intestines Klebsiella pneumoniae Lactobacillus Link Mediating Metagenomics Microbial Genetics Molecular Morbidity - disease rate Neonatal Neonatology Outcome Oxidants Oxidation-Reduction Oxygen Pathway interactions Patients Predisposition Premature Infant Prevention Probiotics Research Research Personnel Respiration Sampling Science Sepsis Signal Transduction Staphylococcaceae Testing Therapeutic Intervention Translating Variant Work age related base clinically relevant commensal bacteria commensal microbes design dysbiosis electron donor enteric infection gut dysbiosis gut inflammation gut microbes gut microbiome high risk infant host microbiome human disease insight interdisciplinary approach intestinal epithelium lactic acid bacteria late onset sepsis microbial microbial genomics microbiome microbiota mortality mouse model neonate novel pathobiont prebiotics prevent programs rational design respiratory

项目摘要

PROJECT SUMMARY Targeting the Intestinal Mucosa and Microbiome to Prevent Neonatal Late-onset Sepsis. Late-onset sepsis (LOS) is a leading cause of morbidity and mortality in premature infants and is thought to be caused by the systemic spread of commensal microbes. Perturbation in the developing intestinal microbiome (dysbiosis) is far more common in premature infants than in full-term infants and is thought to underlie their heightened susceptibility to LOS, although the mechanisms that predispose to this are not well understood. We recently developed a new murine model of neonatal LOS, which has confirmed the long-held clinical suspicion of a direct link between dysbiosis and LOS. We discovered that, by altering the developing microbiome to prevent dysbiosis, we were able to prevent LOS. This protection correlated with the abundance of endogenous Ligilactobacillus (formerly Lactobacuillus) murinus, some isolates of which proved to be effective in preventing LOS when administered as probiotics. Remarkably, however, even closely-related L. murinus isolates differed considerably in their probiotic efficacy, as did other strains of Lactobacilli—including a number of strains that are components of commercial probiotics. Moreover, we have found that probiotic strains of L. murinus that prevented dysbiosis and LOS altered the oxygen status of the intestinal epithelium, suggesting that these strains may modulate intestinal redox status to prevent the outgrowth of facultative anaerobes that can respire oxygen or other respiratory terminal electron acceptors. Although a major mechanism driving dysbiosis in adults is increased availability of substrates of bacterial respiration that allows facultative anaerobes to outcompete the obligate anaerobes that predominate in a healthy microbiome, our preliminary studies indicate that mechanisms that predispose the adult intestine to dysbiosis under conditions of inflammation or infection are at least partially disparate with those in the immature neonatal intestine. We therefore posit that the neonatal intestine is susceptible to dysbiosis via mechanisms distinct from those previously characterized in adults, reflecting developmental immaturity of the intestines and early instability of the developing intestinal microbiome. Here, we will take a team science approach to elucidate both host and microbial determinants of neonatal dysbiosis that predispose to LOS, marrying the efforts of two labs with complementary expertise in intestinal biology and immunity (Weaver), and microbial genetics and bacterial respiration (Gray) with collaborators who are leaders in microbial genomics (Julie Segre), inflammation-associated gut dysbiosis (Sebastian Winter) and neonatology (Namasivayan Ambalavanan). Through the identification of mechanisms of dysbiosis unique to the developing intestines and microbiome we will provide a foundation for more rational design of probiotics and prebiotics for therapeutic interventions that prevent LOS in premature infants.

项目摘要靶向肠粘膜和微生物组，以防止新生儿发作败血症。晚发败血症（LOS）是早产儿发病和死亡率的主要原因，被认为是由共生微生物的全身传播。发育中的肠道微生物组（营养不良）的扰动远远不足在早产儿中比在完整婴儿中更常见，被认为是其增强尽管对此易感性的机制对LOS的敏感性尚不清楚。我们最近开发了一种新的新生儿Los的新鼠模型，该模型已证实了长期以来的临床怀疑营养不良与LOS之间的联系。我们发现，通过改变发展的微生物组以防止营养不良，我们能够预防LOS。这种保护与内源性核杆菌的抽象相关（以前为乳酸菌）murinus，一些分离物被证明有效预防LOS 用作益生菌。然而，值得注意的是，即使是密切相关的Murinus L. r. l. l. selyates 在其益生菌效率上，其他乳杆菌菌株也是如此 - 包括许多成分的菌株商业益生菌。此外，我们发现了预防营养不良的Murinus的益生菌菌株 LOS改变了肠上皮的氧状况，表明这些菌株可能会调节肠道氧化还原状态，以防止可以呼吸氧或其他的兼性厌氧菌的生长呼吸末端电子受体。尽管增加了成人营养不良的主要机制增加了可获得细菌呼吸的底物，允许兼性厌食症胜任义务我们的初步研究在健康的微生物组中占主导地位的厌氧菌表明，这种机制是在感染或感染条件下，易于诱发成年肠对营养不良的人至少部分部分与未成熟的新生儿肠道中的那些不同。因此，我们肯定新生儿肠是通过与以前在成年人中表征的机制不同的机制易受营养不良，反映肠道的发育不成熟和发育中的肠道微生物组的早期不稳定。在这里，我们将采用团队科学方法来阐明新生儿营养不良的宿主和微生物决定剂，易于使用Los，嫁给了两个实验室的努力，并具有肠道生物学的完整专业知识和与领导者合作者在微生物基因组学（Julie Segre）中，炎症相关肠癌（Sebastian Winter）和新生儿学（Namasivayan Ambalavanan）。通过鉴定发育不良的营养不良机制肠道和微生物组我们将为更合理的益生菌和益生元设计提供基础治疗性干预措施，可防止早产儿的LO。