A metabolomic endotype of bioenergetic dysfunction predicts mortality in critically ill patients with acute respiratory failure

Acute respiratory failure (ARF) requiring mechanical ventilation, a complicating factor in sepsis and other disorders, is associated with high morbidity and mortality. Despite its severity and prevalence, treatment options are limited. In light of accumulating evidence that mitochondrial abnormaliti...

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Bibliographic Details
Published in:	Scientific reports Vol. 11; no. 1; p. 10515
Main Authors:	Langley, Raymond J., Migaud, Marie E., Flores, Lori, Thompson, J. Will, Kean, Elizabeth A., Mostellar, Murphy M., Mowry, Matthew, Luckett, Patrick, Purcell, Lina D., Lovato, James, Gandotra, Sheetal, Benton, Ryan, Files, D. Clark, Harrod, Kevin S., Gillespie, Mark N., Morris, Peter E.
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 18-05-2021 Nature Publishing Group Nature Portfolio
Subjects:	631/45 631/553 692/308 692/53 Acetaminophen Acute Disease Adenine Adult Bile acids Bioavailability Bioenergetics Chromatography, High Pressure Liquid - methods Cofactors Critical Illness Drug metabolism Energy Metabolism Female Glutathione Humanities and Social Sciences Humans Intermediates Male Mass Spectrometry - methods Mechanical ventilation Metabolites Metabolomics Middle Aged Mitochondria Morbidity Mortality multidisciplinary NAD - metabolism NADP NADP - metabolism NADPH Patients Pyridoxine Respiratory failure Respiratory Insufficiency - metabolism Respiratory Insufficiency - mortality Retrospective Studies Riboflavin Science Science (multidisciplinary) Sepsis Thiamine Variance analysis Vitamins
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Summary:	Acute respiratory failure (ARF) requiring mechanical ventilation, a complicating factor in sepsis and other disorders, is associated with high morbidity and mortality. Despite its severity and prevalence, treatment options are limited. In light of accumulating evidence that mitochondrial abnormalities are common in ARF, here we applied broad spectrum quantitative and semiquantitative metabolomic analyses of serum from ARF patients to detect bioenergetic dysfunction and determine its association with survival. Plasma samples from surviving and non-surviving patients (N = 15/group) were taken at day 1 and day 3 after admission to the medical intensive care unit and, in survivors, at hospital discharge. Significant differences between survivors and non-survivors (ANOVA, 5% FDR) include bioenergetically relevant intermediates of redox cofactors nicotinamide adenine dinucleotide (NAD) and NAD phosphate (NADP), increased acyl-carnitines, bile acids, and decreased acyl-glycerophosphocholines. Many metabolites associated with poor outcomes are substrates of NAD(P)-dependent enzymatic processes, while alterations in NAD cofactors rely on bioavailability of dietary B-vitamins thiamine, riboflavin and pyridoxine. Changes in the efficiency of the nicotinamide-derived cofactors’ biosynthetic pathways also associate with alterations in glutathione-dependent drug metabolism characterized by substantial differences observed in the acetaminophen metabolome. Based on these findings, a four-feature model developed with semi-quantitative and quantitative metabolomic results predicted patient outcomes with high accuracy (AUROC = 0.91). Collectively, this metabolomic endotype points to a close association between mitochondrial and bioenergetic dysfunction and mortality in human ARF, thus pointing to new pharmacologic targets to reduce mortality in this condition.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2045-2322 2045-2322
DOI:	10.1038/s41598-021-89716-0