Microbiome and Nutrition in Severe PARDS

严重 PARDS 中的微生物组和营养

• 批准号: 10178351
• 负责人: Katri Vanamo Typpo
• 金额: $ 51万
• 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/10178351
• 关键词: 16S ribosomal RNA sequencing; Acetates; Acute; Acute Lung Injury; Adult 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; Lung Inflammation; 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 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.

项目概要 严重小儿急性呼吸窘迫综合征 (PARDS) 是一种危及生命的疾病，其发病率很高。 死亡率（33%）。降低这种情况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）和 PARDS 儿童的死亡率降低，但这种关联的机制尚不清楚。相声 肺和肠道微生物组之间的相互作用是 EEN 可能降低 PARDS 死亡率的潜在机制。 饮食可以迅速改变有益的产生丁酸的共生肠道细菌的相对丰度， 增加粪便丁酸盐。在 ARDS 动物模型中，丁酸盐预处理可减少肺部炎症和 受伤。我们假设，在严重的 PARDS 中，EEN 会增加肠道产生丁酸的相对丰度 共生体，从而增加丁酸盐水平并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。 PROSpect 研究是一项由 NIH 资助的多中心研究 临床试验将随机抽取 1000 名患有严重 PARDS 的儿童来比较体位和通气策略 以改善患者的治疗效果。该临床试验提供了一个独特的机会来研究潜在的 EEN 的机制基础作为改善严重儿童预后的有针对性的方法 PARDS。我们将把我们的研究作为 PROSpect 研究的辅助研究来进行。我们的具体目标 研究目的： 目标 1：检验产生丁酸盐的粪便细菌的相对丰度的假设， 严重 PARDS 中粪便丁酸盐和患者结果因 EEN 暴露而异。我们将获得粪便 来自 180 名患者在机械通气第 0-7 天的样本，以评估 EEN 的效果和类型 EEN（±益生元）对肠道微生物组特征的 16S rRNA 基因测序。我们将评估 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。上一个 粪便样本的子集，我们将使用全基因组鸟枪法宏基因组测序 (WGS) 来识别 对 PARDS 患者很重要的产生丁酸的共生菌的种类和菌株。目标 2： 检验下呼吸道炎症、急性肺损伤和先天免疫细胞的假设 严重 PARDS 中粪便 SCFA 浓度的基因表达模式有所不同。我们将获得 在 PARDS 第 0 天和第 3 天从目标 1 中的患者身上采集气管内抽吸样本，以测试之间的关联 粪便 SCFA 和与 PARDS 肺病理生理学相关的关键细胞因子，以及 PARDS 的关键生物标志物 急性肺损伤。我们将利用全气管抽吸单核RNASeq（snRNASeq）来比较基因 粪便丁酸盐对患者气管吸出物免疫细胞群的表达模式。这项研究将 提高我们对 EEN 如何改善临床结果的机制基础的理解 PARDS。产生丁酸盐的共生细菌的损失可能被证明是风险的关键诊断读数 评估或确定潜在的基于微生物的治疗，以改善 PARDS 儿童的预后。