A metabolomic endotype of bioenergetic dysfunction predicts mortality in critically ill patients with acute respiratory failure
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 ab...
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Nature Portfolio
2021
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oai:doaj.org-article:ebfe182cebd342acb30834ed1318f6642021-12-02T16:51:04ZA metabolomic endotype of bioenergetic dysfunction predicts mortality in critically ill patients with acute respiratory failure10.1038/s41598-021-89716-02045-2322https://doaj.org/article/ebfe182cebd342acb30834ed1318f6642021-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-89716-0https://doaj.org/toc/2045-2322Abstract 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.Raymond J. LangleyMarie E. MigaudLori FloresJ. Will ThompsonElizabeth A. KeanMurphy M. MostellarMatthew MowryPatrick LuckettLina D. PurcellJames LovatoSheetal GandotraRyan BentonD. Clark FilesKevin S. HarrodMark N. GillespiePeter E. MorrisNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-12 (2021) |
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Medicine R Science Q |
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Medicine R Science Q 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 A metabolomic endotype of bioenergetic dysfunction predicts mortality in critically ill patients with acute respiratory failure |
| description |
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. |
| format |
article |
| author |
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 |
| author_facet |
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 |
| author_sort |
Raymond J. Langley |
| title |
A metabolomic endotype of bioenergetic dysfunction predicts mortality in critically ill patients with acute respiratory failure |
| title_short |
A metabolomic endotype of bioenergetic dysfunction predicts mortality in critically ill patients with acute respiratory failure |
| title_full |
A metabolomic endotype of bioenergetic dysfunction predicts mortality in critically ill patients with acute respiratory failure |
| title_fullStr |
A metabolomic endotype of bioenergetic dysfunction predicts mortality in critically ill patients with acute respiratory failure |
| title_full_unstemmed |
A metabolomic endotype of bioenergetic dysfunction predicts mortality in critically ill patients with acute respiratory failure |
| title_sort |
metabolomic endotype of bioenergetic dysfunction predicts mortality in critically ill patients with acute respiratory failure |
| publisher |
Nature Portfolio |
| publishDate |
2021 |
| url |
https://doaj.org/article/ebfe182cebd342acb30834ed1318f664 |
| work_keys_str_mv |
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