Microbiome and Nutrition in Severe PARDS

严重 PARDS 中的微生物组和营养

基本信息

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
项目类别：
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

项目摘要

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。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。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，在 ARDS 动物模型中，丁酸盐预处理可减少肺部炎症和增加粪便丁酸盐。我们发现，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。 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该临床试验提供了一个研究潜力的独特机会。 EEN 的机制基础作为改善严重儿童预后的有针对性的方法我们将把我们的研究作为 PROSpect 研究的具体目标进行。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，粪便丁酸盐，并且患者结果因严重 PARDS 中 EEN 暴露而异。来自 180 名患者在机械通气第 0-7 天的样本，以评估 EEN 的效果和类型我们将通过 16S rRNA 基因测序评估 EEN（± 益生元）对肠道微生物组特征的影响。 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。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) 来识别目标 2：对 PARDS 患者重要的产生丁酸的共生细菌的种类和菌株。检验下呼吸道炎症、急性肺损伤和先天免疫细胞的假设我们将获得严重 PARDS 中粪便 SCFA 浓度不同的基因表达模式。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 的关键生物标志物我们将利用全气管抽吸单RNASeq（snRNA nucleiSeq）来比较基因。本研究将通过粪便丁酸盐检测患者气管吸出物免疫细胞群的表达模式。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方法，以改善 PARDS 儿童的预后。