Microbiome and Nutrition in Severe PARDS

严重 PARDS 中的微生物组和营养

• 批准号: 10630085
• 负责人: Katri Vanamo Typpo
• 金额: $ 45.46万
• 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/10630085
• 关键词: 16S ribosomal RNA sequencing; Acetates; Acute; Acute Lung Injury; Acute Respiratory Distress Syndrome; Admission activity; Ancillary Study; Animal Model; Anti-Inflammatory Agents; Antiinflammatory Effect; Architecture; Bacteria; Biological Markers; Butyrates; Cell Nucleus; Cells; Child; Childhood; Clinical; Clinical Trials; Communities; Critical Illness; Data; Diagnostic; Diet; Disease; Dryness; 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; 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; Specimen; Structure; Testing; Trachea; United States National Institutes of Health; Volatile Fatty Acids; aspirate; 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; microbial based therapy; microbiome; microbiome signature; mortality; mortality risk; novel; novel strategies; novel therapeutics; nutrition; prebiotics; preservation; programs; receptor for advanced glycation endproducts; secretory protein; single nucleus RNA-sequencing; 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 严重的小儿急性呼吸窘迫综合征（PARS）是一种威胁生命的疾病 死亡率（33％）。在这种情况下提高死亡率的新疗法至关重要。多个回顾性研究 来自我们的小组和其他人已经证明了早期肠内营养（EEN）与 儿童的死亡率降低，但这种关联的机制尚不清楚。相声 在肺和肠道微生物组之间是一种潜在的机制，通过它可以降低PARD的死亡率。 饮食可以快速改变有益的丁酸酯产生共生肠道细菌的相对丰度 增加粪便丁酸酯。在ARDS动物模型中，丁酸预处理可减少肺注射和 受伤。我们假设在严重的帕克中，EEN增加了丁酸酯的相对丰度 共生，从而增加丁酸水平并减少急性肺部感染和损伤。 Een是一个 改善这些孩子的结果的新途径。 Prospect研究，一项多中心的NIH资助 临床试验将使1000名患有严重pard的儿童随机比较定位和通风策略 改善患者的预后。这项临床试验为调查潜力提供了独特的机会 EEN的机械基础是改善严重儿童预后的目标方法 帕克。我们将作为前景研究的辅助研究进行研究。我们的具体目的 研究是：目标1：检验以下假设：丁酸酯产生粪便细菌的相对抽象， 粪便丁酸酯和患者的预后因严重的pard暴露而不同。我们将获得粪便 在机械通气的0-7天，来自180例患者的标本，以评估EEN的影响和类型 具有16S rRNA基因测序的肠道微生物组特征上的EEN（±益生元）。我们将评估 通过EEN和EEN类型，测得的粪便丁酸酯和其他短链脂肪酸（SCFA）的差异。在 粪便样品的子集，我们将使用整个基因组shot弹枪宏基因组学测序（WGS）识别 丁酸酯产生的共生细菌的物种和菌株对PARS患者很重要。目标2：到 测试下呼吸道注射，急性肺损伤和先天免疫细胞的假设 严重pard中的粪便SCFA浓度不同。我们将获得 在PARDS第0天和第3天，来自AIM 1的患者的气管气管吸气标本测试关联 PARDS肺病理生理学实施的粪便SCFA和关键细胞因子以及PARS的关键生物标志物 急性肺损伤。我们将利用整个气管抽吸单核RNASEQ（SNRNASEQ）比较基因 粪便丁酸酯患者的气管抽吸物群体的表达模式。这项研究会 提高我们对EEN机械基础的理解如何改善 帕克。丁酸酯产生共生细菌可能被证明是对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，以改善帕德儿童的预后。