Metagenomics of the circulating blood microbiome and systemic inflammation in preterm infants

早产儿循环血液微生物组和全身炎症的宏基因组学

• 批准号: 9894147
• 负责人: Mohan Pammi
• 金额: $ 8万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-04 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9894147
• 关键词: 37 weeks gestation; Actinobacteria class; Adult; Anti-Inflammatory Agents; Antibiotics; Bacteria; Bacterial DNA; Bacteroidetes; Bioinformatics; Blood; Blood specimen; Brain Injuries; Bronchopulmonary Dysplasia; Characteristics; Clinical; Core Facility; DNA; Data; Disease; Donor Selection; Enrollment; Evaluation; Feces; Firmicutes; Functional disorder; Human; Human Volunteers; Infant; Infection; Inflammation; Inflammatory; Injury; Knowledge; Lead; Leukocytes; Literature; Liver diseases; Lung; Medical center; Medicine; Metadata; Metagenomics; Methods; Neonatal; Oral cavity; Organism; Outcome; Patient-Focused Outcomes; Patients; Phylogenetic Analysis; Plasma; Population; Premature Infant; Proteobacteria; Publishing; Recombinant DNA; Reporting; Research; Research Proposals; Retinopathy of Prematurity; Ribosomal RNA; Role; Route; Science; Sepsis; Serum; Shotgun Sequencing; Skin; Source; Sterility; Swab; Symptoms; Technical Expertise; Technology; Testing; Texas; Time; Tissues; Vagina; Viral; bacteriome; base; chemokine; clinically relevant; college; cytokine; gastrointestinal epithelium; gut microbiome; healthy volunteer; improved; innovation; insight; microbial; microbiome; microbiota; multiple omics; mycobiome; neonatal outcome; neonatal sepsis; neonate; novel; novel strategies; organ injury; preterm newborn; stool sample; tissue injury; tool; virome

PROJECT SUMMARY The sterility of circulating human blood has been questioned. A circulating blood microbiome in healthy and disease states have been reported in adults associated with systemic inflammation but no such data exists in preterm neonates. Our preliminary data shows that the blood of neonates whose blood cultures were negative and who were considered non-infected, contained microbial DNA that can be characterized into distinct phylogenetic groups. The hypothesis of the proposed research is that the microbial diversity and composition of the circulating blood microbiome in preterm neonates is altered in infective states such as sepsis, and the blood microbiome contributes to systemic inflammation. We will use a holistic, multi- omics approach to test our hypothesis using 2 specific aims. In specific aim 1, we will determine the microbial diversity and composition of the circulating blood microbiome (bacterial, fungal and viral) in healthy preterm neonates and compare it with infants with culture-positive and culture-negative sepsis. In our second specific aim, we propose to determine the association of the blood microbiome signatures with systemic inflammation and neonatal outcomes. Our study will enroll a total of 60 preterm neonates; 20 with culture-proven sepsis, 20 neonates who do not have sepsis but have blood cultures drawn for symptoms of sepsis and were negative and 20 asymptomatic preterm neonates. The bacterial microbiome will be evaluated by metagenomic whole shotgun sequencing, fungal microbiome (mycobiome) by targeting ITS2 region and virome by established methods. Stool and skin swabs will be evaluated by 16S rDNA sequencing and cytokines profiles in the serum will be evaluated. We will use multivariable analyses to correlate microbial load, diversity and composition and cytokine profiles to clinical outcomes. Our proposal is innovative in that the presence of the blood microbiome, it’s association with inflammation and outcomes in the neonatal population has not been reported and will challenge the current paradigm of sterile blood in healthy neonates. The significance of the proposed research is that we will underpin the pathophysiology of ‘culture-negative sepsis’ that is often associated with overuse of antibiotics. By utilizing our state-of-the-science technology, analysis tools and technical expertise available at the Texas Medical Center, we are poised to advance our knowledge on the blood microbiome and inflammatory injury, that may lead to innovative anti-inflammatory therapy in vulnerable preterm infants.

项目概要 健康和循环人类血液的无菌性受到质疑。 成人中已有与全身炎症相关的疾病状态报告，但在 我们的初步数据显示，血培养呈阴性的新生儿的血液。 那些被认为没有被感染的人，含有微生物 DNA，这些微生物 DNA 可以被表征为不同的特征 所提出的研究的假设是微生物多样性和 早产儿循环血液微生物组的组成在感染状态下发生改变，例如 作为脓毒症，血液微生物群会导致全身炎症，我们将使用整体的、多方面的方法。 使用 2 个具体目标的组学方法来检验我们的假设 在具体目标 1 中，我们将确定微生物。 健康早产儿循环血液微生物组（细菌、真菌和病毒）的多样性和组成 在我们的第二个具体例子中，将其与培养阳性和培养阴性败血症的婴儿进行比较。 目的，我们建议确定血液微生物组特征与全身炎症的关联 我们的研究将总共招募 60 名早产新生儿；其中 20 名患有脓毒症，20 名患有败血症。 没有败血症但针对败血症症状进行血培养且结果呈阴性的新生儿 将通过宏基因组全鸟枪法对 20 名无症状早产新生儿进行细菌微生物组评估。 通过既定方法针对 ITS2 区域和病毒组进行测序、真菌微生物组（真菌组）。 皮肤拭子将通过 16S rDNA 测序进行评估，并评估血清中的细胞因子谱。 我们将使用多变量分析将微生物负荷、多样性和组成以及细胞因子谱关联起来，以 我们的建议是创新的，因为血液微生物组的存在与临床结果有关。 新生儿群体中的炎症和结局尚未有报道，这将挑战当前的研究 健康新生儿无菌血液的范例。拟议研究的意义在于我们将支持这一研究。 “培养阴性败血症”的病理生理学通常与过度使用抗生素有关。 德克萨斯医学中心提供我们最先进的技术、分析工具和技术专业知识， 我们准备增进对血液微生物组和炎症损伤的了解，这可能会导致 针对脆弱早产儿的创新抗炎疗法。