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

Raymond J. Langley, Marie E. Migaud, Lori Flores, J. Will Thompson, Elizabeth A. Kean, Murphy M. Mostellar, Matthew Mowry, Patrick Luckett, Lina D. Purcell, James Lovato, Sheetal Gandotra, Ryan Benton, D. Clark Files, Kevin S. Harrod, Mark N. Gillespie, Peter E. Morris

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

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.

Original languageEnglish
Article number10515
JournalScientific Reports
Volume11
Issue number1
DOIs
StatePublished - Dec 2021

Bibliographical note

Funding Information:
NR011186; Dr. Langley is partially funded by NIH (KL2TR003097 and UL1 TR001417). Dr. Migaud is partially funded by Elysium Health and NIH (NCCIH R21 Grant AT009908). Dr. Gillespie is partially supported by NIH (R01 HL113614, R01 GM127823, and UL1 TR001417).

Publisher Copyright:
© 2021, The Author(s).

ASJC Scopus subject areas

  • General

Fingerprint

Dive into the research topics of 'A metabolomic endotype of bioenergetic dysfunction predicts mortality in critically ill patients with acute respiratory failure'. Together they form a unique fingerprint.

Cite this