Microbiome and Nutrition in Severe PARDS

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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.