Circulating N-formylmethionine and metabolic shift in critical illness: a multicohort metabolomics study

  • Crit Care. 2022 Oct 19;26(1):321. doi: 10.1186/s13054-022-04174-y.
Martin Ingi Sigurdsson  1  2 ,  Hirotada Kobayashi  3 ,  Karin Amrein  4 ,  Kiichi Nakahira  5  6 ,  Angela J Rogers  7 ,  Mayra Pinilla-Vera  8 ,  Rebecca M Baron  8 ,  Laura E Fredenburgh  8 ,  Jessica A Lasky-Su  9 ,  Kenneth B Christopher  10  11
Affiliations
  • 1. Anesthesiology and Critical Care Medicine, Landspitali University Hospital, University of Iceland, Hringbraut 101, 101, Reykjavík, Iceland.
  • 2. Faculty of Medicine, University of Iceland, Vatnsmyrarvegur 16, 101, Reykjavik, Iceland.
  • 3. Division of Renal Medicine, Brigham and Women's Hospital, 75 Francis Street, Boston, 02115, USA.
  • 4. Division of Endocrinology and Diabetology, Medical University of Graz, Auenbruggerplatz 15, 8036, Graz, Austria.
  • 5. Nara Medical University, 840 Shijocho, Kashihara, Nara, 634-8521, Japan.
  • 6. Weill Cornell Medicine, 1300 York Avenue, New York, 10065, USA.
  • 7. Stanford University Medical Center, 300 Pasteur Dr. H3143, Stanford, 94305, USA.
  • 8. Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, 75 Francis Street, Boston, 02115, USA.
  • 9. Channing Division of Network Medicine, Brigham and Women's Hospital, 181 Longwood Avenue, Boston, 02115, USA.
  • 10. Division of Renal Medicine, Brigham and Women's Hospital, 75 Francis Street, Boston, 02115, USA. [email protected].
  • 11. Channing Division of Network Medicine, Brigham and Women's Hospital, 181 Longwood Avenue, Boston, 02115, USA. [email protected].
PMID: 36261854 DOI: 10.1186/s13054-022-04174-y
Abstract

Background: Cell stress promotes degradation of mitochondria which release danger-associated molecular patterns that are catabolized to N-formylmethionine. We hypothesized that in critically ill adults, the response to N-formylmethionine is associated with increases in metabolomic shift-related metabolites and increases in 28-day mortality.

Methods: We performed metabolomics analyses on plasma from the 428-subject Correction of Vitamin D Deficiency in Critically Ill Patients trial (VITdAL-ICU) cohort and the 90-subject Brigham and Women's Hospital Registry of Critical Illness (RoCI) cohort. In the VITdAL-ICU cohort, we analyzed 983 metabolites at Intensive Care Unit (ICU) admission, day 3, and 7. In the RoCI cohort, we analyzed 411 metabolites at ICU admission. The association between N-formylmethionine and mortality was determined by adjusted logistic regression. The relationship between individual metabolites and N-formylmethionine abundance was assessed with false discovery rate correction via linear regression, linear mixed-effects, and Gaussian graphical models.

Results: Patients with the top quartile of N-formylmethionine abundance at ICU admission had a significantly higher adjusted odds of 28-day mortality in the VITdAL-ICU (OR, 2.4; 95%CI 1.5-4.0; P = 0.001) and RoCI cohorts (OR, 5.1; 95%CI 1.4-18.7; P = 0.015). Adjusted linear regression shows that with increases in N-formylmethionine abundance at ICU admission, 55 metabolites have significant differences common to both the VITdAL-ICU and RoCI cohorts. With increased N-formylmethionine abundance, both cohorts had elevations in individual short-chain acylcarnitine, branched chain amino acid, kynurenine pathway, and pentose phosphate pathway metabolites.

Conclusions: The results indicate that circulating N-formylmethionine promotes a metabolic shift with heightened mortality that involves incomplete mitochondrial fatty acid oxidation, increased branched chain amino acid metabolism, and activation of the pentose phosphate pathway.

Keywords
Acylcarnitine; Branched chain amino acids; Critical illness; Metabolic shift; Metabolomics; N-formylmethionine; Pentose phosphate pathway.
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