Microbiome and Nutrition in Severe PARDS

严重 PARDS 中的微生物组和营养

• 批准号: 10375539
• 负责人: Katri Vanamo Typpo
• 金额: $ 43.55万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10375539
• 关键词: 16S ribosomal RNA sequencing; Acetates; Acute; Acute Lung Injury; Acute Respiratory Distress Syndrome; Ancillary Study; Animal Model; Anti-Inflammatory Agents; Antiinflammatory Effect; Architecture; Aspirate substance; Bacteria; Biological Markers; Butyrates; Cell Nucleus; Cells; Child; Childhood; Clinical; Clinical Trials; Communities; Critical Illness; Data; Diagnostic; Diet; Disease; Enteral Nutrition; Functional disorder; Funding; Gene Expression Profile; Hospitals; Immune; Infrastructure; Intensive Care Units; Knowledge; Life; Lower Respiratory Tract Inflammation; Lung; Measures; Mechanical ventilation; Mediator of activation protein; Metalloproteases; Microbe; Nutrition Therapy; Oral; Organ; Outcome; Pathway interactions; Patient-Focused Outcomes; Patients; Pediatric Acute Respiratory Distress Syndrome; Population; Positioning Attribute; Process; Production; Pulmonary Inflammation; Pulmonary Surfactant-Associated Protein A; Randomized; Randomized Controlled Trials; Research; Retrospective Studies; Risk Assessment; Sampling; Secretory Cell; Severities; Shotguns; Signal Transduction; Small Nuclear RNA; Specimen; Structure; Testing; United States National Institutes of Health; Volatile Fatty Acids; base; beta diversity; biobank; commensal bacteria; cytokine; endotracheal; feeding; gut bacteria; gut dysbiosis; gut microbes; gut microbiome; gut microbiota; improved; improved outcome; innovation; lung injury; lung microbiome; metagenomic sequencing; microbial; microbiome; microbiome signature; mortality; mortality risk; novel; novel strategies; novel therapeutics; nutrition; prebiotics; preservation; programs; receptor for advanced glycation endproducts; secretory protein; targeted treatment; transcriptome sequencing; treatment as usual; ventilation; whole genome

PROJECT SUMMARY Severe Pediatric Acute Respiratory Distress Syndrome (PARDS) is a life-threatening condition with high mortality (33%). Novel therapies to improve mortality in this condition are critical. Multiple retrospective studies from our group and others have demonstrated an association between early enteral nutrition (EEN) and decreased mortality in children with PARDS, but mechanisms for this association are unclear. Crosstalk between the lung and gut microbiome is a potential mechanism by which EEN may reduce PARDS mortality. Diet can rapidly alter the relative abundance of beneficial butyrate-producing commensal gut bacteria to increase fecal butyrate. In animal models of ARDS, butyrate pre-treatment decreases lung inflammation and injury. We hypothesize, that in severe PARDS, EEN increases relative abundance of butyrate producing gut commensals, thereby increasing butyrate levels and reducing acute lung inflammation and injury. EEN is a novel pathway to improve outcomes in these children. The PROSpect study, a multi-center, NIH-funded clinical trial, will randomize 1000 children with severe PARDS to compare positioning and ventilation strategies to improve patient outcomes. This clinical trial presents a unique opportunity to investigate potential mechanistic underpinnings of EEN as a targeted approach to improve outcomes for children with severe PARDS. We will conduct our study as an ancillary study to the PROSpect study. The specific aims of our study are: Aim 1:To test the hypothesis that relative abundance of butyrate producing fecal bacteria, fecal butyrate, and patient outcomes differ by EEN exposure in severe PARDS. We will obtain fecal specimens from 180 patients on days 0-7 of mechanical ventilation to assess the effect of EEN and type of EEN ( ± prebiotics) on the gut microbiome signature with 16S rRNA gene sequencing. We will assess differences in measured fecal butyrate and other short chain fatty acids (SCFA) by EEN and type of EEN. On a subset of fecal samples, we will use whole genome shotgun metagenomics sequencing (WGS) to identify species and strains of butyrate-producing commensal bacteria important in patients with PARDS. Aim 2: To test the hypothesis that lower respiratory tract inflammation, acute lung injury, and innate immune cell gene expression patterns differ by fecal SCFA concentration in severe PARDS. We will obtain endotracheal aspirate specimens from patients in Aim 1 on PARDS days 0 and 3 to test associations between fecal SCFA and critical cytokines implicated in PARDS lung pathophysiology, and key biomarkers of PARDS acute lung injury. We will utilize whole tracheal aspirate single nuclei RNASeq (snRNASeq) to compare gene expression patterns for tracheal aspirate immune cell populations in patients by fecal butyrate. This study will improve our understanding of the mechanistic underpinnings for how EEN may improve clinical outcomes of PARDS. Loss of butyrate producing commensal bacteria may prove to be a critical diagnostic readout for risk assessment or to identify potential microbial-based treatment to improve outcomes for children with PARDS.

项目摘要 严重小儿急性呼吸窘迫综合征（PARDS）是一种危及生命的疾病， 死亡率（33%）。改善这种情况下死亡率的新疗法至关重要。多项回顾性研究 我们小组和其他人已经证明了早期肠内营养（EEN）与 降低了PARDS患儿的死亡率，但这种联系的机制尚不清楚。串扰 肺和肠道微生物之间的相互作用是EEN降低PARDS死亡率的潜在机制。 饮食可以迅速改变有益的丁酸生产肠道细菌的相对丰度， 增加粪便丁酸。在ARDS的动物模型中，丁酸盐预处理减少了肺部炎症， 损伤我们假设，在严重的PARDS中，EEN增加了丁酸产生肠道的相对丰度， 因此，增加丁酸水平，减少急性肺部炎症和损伤。EEN是一个 改善这些儿童的结果的新途径。前景研究是一项多中心、NIH资助的 临床试验，将随机选择1000名患有严重PARDS的儿童，比较体位和通气策略 来改善病人的治疗效果这项临床试验提供了一个独特的机会， EEN作为一种有针对性的方法，以改善严重营养不良儿童的结局的机制基础 帕兹。我们将作为前景研究的辅助研究开展本研究。我们的具体目标 目的1：检验产生丁酸盐的粪便细菌的相对丰度， 在重度PARDS中，EEN暴露对患者结局的影响不同。我们会从你的粪便中 180例患者在机械通气0-7天的标本，以评估EEN的效果和 EEN（±益生元）对肠道微生物组特征的影响，16 S rRNA基因测序。我们将评估 通过EEN和EEN类型测量的粪便丁酸盐和其他短链脂肪酸（SCFA）的差异。上 粪便样本的子集，我们将使用全基因组鸟枪宏基因组测序（WGS）来识别 PARDS患者中重要的产丁酸盐细菌的菌种和菌株。目标2： 检验下呼吸道炎症、急性肺损伤和先天性免疫细胞 在重度PARDS中，基因表达模式因粪便SCFA浓度不同而不同。我们将获得 在PARDS第0天和第3天，从目标1患者的气管内抽吸样本，以检测 与PARDS肺病理生理学有关的粪便SCFA和关键细胞因子，以及PARDS的关键生物标志物 急性肺损伤我们将利用全气管吸出物单核RNA测序（snRNA测序）比较基因表达谱。 通过粪便丁酸盐测定患者气管吸出物免疫细胞群体的表达模式。本研究将 提高我们对EEN如何改善临床结局的机制基础的理解， 帕兹。产丁酸盐细菌的损失可能被证明是风险的关键诊断读数 评估或确定潜在的微生物为基础的治疗，以改善与PARDS儿童的结果。