Abstract

The acute phase of sepsis is characterized by a strong inflammatory reaction. At later stages in some patients, immunoparalysis may be encountered, which is associated with a poor outcome. By transcriptional and metabolic profiling of human patients with sepsis, we found that a shift from oxidative phosphorylation to aerobic glycolysis was an important component of initial activation of host defense. Blocking metabolic pathways with metformin diminished cytokine production and increased mortality in systemic fungal infection in mice. In contrast, in leukocytes rendered tolerant by exposure to lipopolysaccharide or after isolation from patients with sepsis and immunoparalysis, a generalized metabolic defect at the level of both glycolysis and oxidative metabolism was apparent, which was restored after recovery of the patients. Finally, the immunometabolic defects in humans were partially restored by therapy with recombinant interferon-γ, which suggested that metabolic processes might represent a therapeutic target in sepsis.

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Acknowledgements

Supported by the European Research Council (ERC-StG-310372 to M.G.N.) and the Center for Translational Molecular Medicine (Molecular Diagnosis and Risk Stratification of Sepsis project; 04I-201).

Author information

Author notes

    • Shih-Chin Cheng
    • , Brendon P Scicluna
    •  & Rob J W Arts

    These authors contributed equally to this work.

    • Tom van der Poll
    •  & Mihai G Netea

    These authors jointly directed this work.

Affiliations

  1. Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, the Netherlands.

    • Shih-Chin Cheng
    • , Rob J W Arts
    • , Mark S Gresnigt
    • , Ekta Lachmandas
    • , Jenneke Leentjens
    • , Frank L van de Veerdonk
    • , Leo A B Joosten
    •  & Mihai G Netea
  2. Center of Experimental & Molecular Medicine, Division of Infectious Diseases, Amsterdam Medical Center, University of Amsterdam, Amsterdam, the Netherlands.

    • Brendon P Scicluna
    • , Anne J van der Meer
    •  & Tom van der Poll
  3. 4th Department of Internal Medicine, University of Athens, Medical School, Athens, Greece.

    • Evangelos J Giamarellos-Bourboulis
  4. Department of Intensive Care and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, the Netherlands.

    • Matthijs Kox
    • , Jenneke Leentjens
    •  & Peter Pickkers
  5. Department of Biochemistry, Radboud Institute for Molecular Life Sciences, Nijmegen, the Netherlands.

    • Ganesh R Manjeri
    • , Jori A L Wagenaars
    •  & Peter H G M Willems
  6. Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, UK.

    • Ganesh R Manjeri
  7. Department of Intensive Care Medicine, University Medical Center Utrecht, Utrecht, the Netherlands.

    • Olaf L Cremer
  8. Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, the Netherlands.

    • Marc J Bonten
  9. Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands.

    • Marc J Bonten
  10. Department of Intensive Care Medicine Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.

    • Marcus J Schultz

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Contributions

S.-C.C., B.P.S., R.J.W.A., M.S.G., E.L., E.J.G.-B., M.K., G.R.M., J.A.L.W., J.L. and A.J.v.d.M. performed the experiments; B.P.S., R.J.W.A. and J.A.L.W. performed the analyses; E.J.G.-B., O.L.C., F.L.v.d.V., M.J.B., M.J.S. and P.P. were involved in the clinical studies; P.H.G.M.W., L.A.B.J., T.v.d.P. and M.G.N. designed the studies; and all authors were involved in writing and correcting the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Tom van der Poll or Mihai G Netea.

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https://doi.org/10.1038/ni.3398

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