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Metabolites
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Metabolic Alterations in Sepsis and Major Trauma
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Metabolic Alterations in Sepsis and Major Trauma

A special issue of Metabolites (ISSN 2218-1989). This special issue belongs to the section "Endocrinology and Clinical Metabolic Research".

Deadline for manuscript submissions: closed (7 February 2022) | Viewed by 10695

Special Issue Editor

Dr. Masao Kaneki

E-Mail Website
Guest Editor
Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA
Interests: sepsis; burn injury; diabetes; metabolism; inflammatory response; immune dysfunction; signal transduction

Special Issue Information

Dear Colleagues,

Metabolic derangements are a major complication of critical illness, including sepsis and major trauma, and negatively affect the short- and long-term clinical outcomes of critically ill patients. Critical illness induces a wide range of metabolic alterations that include hypermetabolism, catabolism, hyperglycemia, hyperlactatemia, insulin resistance, muscle wasting, the Warburg effect, and mitochondrial dysfunction. Metabolic aberrations in sepsis and major trauma have recently attracted more scientific attention than previously, although their impact on pathophysiology is still relatively underappreciated. In addition, the role of metabolic reprogramming (aka the Warburg effect) in the activation of immune cells (e.g., monocytes/macrophages, T-cells) has been established. However, despite intensive investigation for many years, fundamental questions remain to be clarified, which include: (1) the molecular mechanisms by which critical illness causes metabolic alterations; and (2) whether metabolic dysfunction plays a pathogenic role in critical illness and/or some metabolic changes are protective. Metabolites function as signaling molecules and modulate post-translational modifications (e.g., acetylation, methylation), epigenetics, activities of many enzymes, and redox signaling in health and diseases. Metabolic inflammatory complex, in which metabolic derangements and inflammatory response enhance each other via positive feed-forward mechanisms, has been proposed to be a contributor to the pathophysiology of critical illness. Recently, metabolomics has been employed to identify metabolites that predict the morbidity and mortality of critically ill patients. Moreover, alterations in microbiota-derived metabolites are proposed to play a role in the disease development of critical illness.

This Special Issue aims to highlight various aspects of metabolic alterations in sepsis and major trauma. Authors are invited to submit basic, translational and clinical studies, and review articles on this topic.

Dr. Masao Kaneki
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Metabolites is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • sepsis
  • trauma
  • metabolism
  • metabolomics
  • microbiota
  • inflammation
  • the Warburg effect

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Published Papers (4 papers)

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Research

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18 pages, 3880 KiB  
Communication
Farnesysltransferase Inhibitor Prevents Burn Injury-Induced Metabolome Changes in Muscle
by Harumasa Nakazawa, Lai Ping Wong, Laura Shelton, Ruslan Sadreyev and Masao Kaneki
Metabolites 2022, 12(9), 800; https://doi.org/10.3390/metabo12090800 - 27 Aug 2022
Cited by 5 | Viewed by 1751
Abstract
Burn injury remains a significant public health issue worldwide. Metabolic derangements are a major complication of burn injury and negatively affect the clinical outcomes of severely burned patients. These metabolic aberrations include muscle wasting, hypermetabolism, hyperglycemia, hyperlactatemia, insulin resistance, and mitochondrial dysfunction. However, [...] Read more.
Burn injury remains a significant public health issue worldwide. Metabolic derangements are a major complication of burn injury and negatively affect the clinical outcomes of severely burned patients. These metabolic aberrations include muscle wasting, hypermetabolism, hyperglycemia, hyperlactatemia, insulin resistance, and mitochondrial dysfunction. However, little is known about the impact of burn injury on the metabolome profile in skeletal muscle. We have previously shown that farnesyltransferase inhibitor (FTI) reverses burn injury-induced insulin resistance, mitochondrial dysfunction, and the Warburg effect in mouse skeletal muscle. To evaluate metabolome composition, targeted quantitative analysis was performed using capillary electrophoresis mass spectrometry in mouse skeletal muscle. Principal component analysis (PCA), partial least squares discriminant analysis (PLS-DA), and hierarchical cluster analysis demonstrated that burn injury induced a global change in metabolome composition. FTI treatment almost completely prevented burn injury-induced alterations in metabolite levels. Pathway analysis revealed that the pathways most affected by burn injury were purine, glutathione, β-alanine, glycine, serine, and threonine metabolism. Burn injury induced a suppressed oxidized to reduced nicotinamide adenine dinucleotide (NAD+/NADH) ratio as well as oxidative stress and adenosine triphosphate (ATP) depletion, all of which were reversed by FTI. Moreover, our data raise the possibility that burn injury may lead to increased glutaminolysis and reductive carboxylation in mouse skeletal muscle. Full article
(This article belongs to the Special Issue Metabolic Alterations in Sepsis and Major Trauma)
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17 pages, 2177 KiB  
Article
Bioavailability of Reduced Coenzyme Q10 (Ubiquinol-10) in Burn Patients
by Naohide Kuriyama, Tomoyuki Nakamura, Harumasa Nakazawa, Tyler Wen, Lorenzo Berra, Edward A. Bittner, Jeremy Goverman and Masao Kaneki
Metabolites 2022, 12(7), 613; https://doi.org/10.3390/metabo12070613 - 1 Jul 2022
Cited by 4 | Viewed by 2245
Abstract
Mitochondrial dysfunction has been implicated in the pathogenesis of inflammation and multi-organ dysfunction in major trauma, including burn injury. Coenzyme Q10 (CoQ10) is a metabolite of the mevalonate pathway and an essential cofactor for the electron transport in the mitochondria. In addition, its [...] Read more.
Mitochondrial dysfunction has been implicated in the pathogenesis of inflammation and multi-organ dysfunction in major trauma, including burn injury. Coenzyme Q10 (CoQ10) is a metabolite of the mevalonate pathway and an essential cofactor for the electron transport in the mitochondria. In addition, its reduced form (ubiquinol) functions as an antioxidant. Little is known as to whether oral CoQ10 supplementation effectively increases intracellular CoQ10 levels in humans. To study the bioavailability of CoQ10 supplementation, we conducted a randomized, double-blind, placebo-controlled study of reduced CoQ10 (ubiquinol-10) (1800 mg/day, t.i.d.) in burn patients at a single, tertiary-care hospital. Baseline plasma CoQ10 levels were significantly lower in burn patients than in healthy volunteers, although plasma CoQ10/cholesterol ratio did not differ between the groups. CoQ10 supplementation increased plasma concentrations of total and reduced CoQ10 and total CoQ10 content in peripheral blood mononuclear cells (PBMCs) in burn patients compared with the placebo group. CoQ10 supplementation did not significantly change circulating levels of mitochondrial DNA, inflammatory markers (e.g., interleukins, TNF-α, IFN-γ), or Sequential Organ Failure Assessment (SOFA) scores compared with the placebo group. This study showed that a relatively high dose of reduced CoQ10 supplementation increased the intracellular CoQ10 content in PBMCs as well as plasma concentrations in burn patients. Full article
(This article belongs to the Special Issue Metabolic Alterations in Sepsis and Major Trauma)
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17 pages, 2009 KiB  
Article
Integration of Metabolomic and Clinical Data Improves the Prediction of Intensive Care Unit Length of Stay Following Major Traumatic Injury
by Animesh Acharjee, Jon Hazeldine, Alina Bazarova, Lavanya Deenadayalu, Jinkang Zhang, Conor Bentley, Dominic Russ, Janet M. Lord, Georgios V. Gkoutos, Stephen P. Young and Mark A. Foster
Metabolites 2022, 12(1), 29; https://doi.org/10.3390/metabo12010029 - 31 Dec 2021
Cited by 6 | Viewed by 2404
Abstract
Recent advances in emergency medicine and the co-ordinated delivery of trauma care mean more critically-injured patients now reach the hospital alive and survive life-saving operations. Indeed, between 2008 and 2017, the odds of surviving a major traumatic injury in the UK increased by [...] Read more.
Recent advances in emergency medicine and the co-ordinated delivery of trauma care mean more critically-injured patients now reach the hospital alive and survive life-saving operations. Indeed, between 2008 and 2017, the odds of surviving a major traumatic injury in the UK increased by nineteen percent. However, the improved survival rates of severely-injured patients have placed an increased burden on the healthcare system, with major trauma a common cause of intensive care unit (ICU) admissions that last ≥10 days. Improved understanding of the factors influencing patient outcomes is now urgently needed. We investigated the serum metabolomic profile of fifty-five major trauma patients across three post-injury phases: acute (days 0–4), intermediate (days 5–14) and late (days 15–112). Using ICU length of stay (LOS) as a clinical outcome, we aimed to determine whether the serum metabolome measured at days 0–4 post-injury for patients with an extended (≥10 days) ICU LOS differed from that of patients with a short (<10 days) ICU LOS. In addition, we investigated whether combining metabolomic profiles with clinical scoring systems would generate a variable that would identify patients with an extended ICU LOS with a greater degree of accuracy than models built on either variable alone. The number of metabolites unique to and shared across each time segment varied across acute, intermediate and late segments. A one-way ANOVA revealed the most variation in metabolite levels across the different time-points was for the metabolites lactate, glucose, anserine and 3-hydroxybutyrate. A total of eleven features were selected to differentiate between <10 days ICU LOS vs. >10 days ICU LOS. New Injury Severity Score (NISS), testosterone, and the metabolites cadaverine, urea, isoleucine, acetoacetate, dimethyl sulfone, syringate, creatinine, xylitol, and acetone form the integrated biomarker set. Using metabolic enrichment analysis, we found valine, leucine and isoleucine biosynthesis, glutathione metabolism, and glycine, serine and threonine metabolism were the top three pathways differentiating ICU LOS with a p < 0.05. A combined model of NISS and testosterone and all nine selected metabolites achieved an AUROC of 0.824. Differences exist in the serum metabolome of major trauma patients who subsequently experience a short or prolonged ICU LOS in the acute post-injury setting. Combining metabolomic data with anatomical scoring systems allowed us to discriminate between these two groups with a greater degree of accuracy than that of either variable alone. Full article
(This article belongs to the Special Issue Metabolic Alterations in Sepsis and Major Trauma)
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Review

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32 pages, 1677 KiB  
Review
Past Experiences for Future Applications of Metabolomics in Critically Ill Patients with Sepsis and Septic Shocks
by Konlawij Trongtrakul, Chanisa Thonusin, Chaicharn Pothirat, Siriporn C. Chattipakorn and Nipon Chattipakorn
Metabolites 2022, 12(1), 1; https://doi.org/10.3390/metabo12010001 - 21 Dec 2021
Cited by 5 | Viewed by 3684
Abstract
A disruption of several metabolic pathways in critically ill patients with sepsis indicates that metabolomics might be used as a more precise tool for sepsis and septic shock when compared with the conventional biomarkers. This article provides information regarding metabolomics studies in sepsis [...] Read more.
A disruption of several metabolic pathways in critically ill patients with sepsis indicates that metabolomics might be used as a more precise tool for sepsis and septic shock when compared with the conventional biomarkers. This article provides information regarding metabolomics studies in sepsis and septic shock patients. It has been shown that a variety of metabolomic pathways are altered in sepsis and septic shock, including amino acid metabolism, fatty acid oxidation, phospholipid metabolism, glycolysis, and tricarboxylic acid cycle. Based upon this comprehensive review, here, we demonstrate that metabolomics is about to change the world of sepsis biomarkers, not only for its utilization in sepsis diagnosis, but also for prognosticating and monitoring the therapeutic response. Additionally, the future direction regarding the establishment of studies integrating metabolomics with other molecular modalities and studies identifying the relationships between metabolomic profiles and clinical characteristics to address clinical application are discussed in this article. All of the information from this review indicates the important impact of metabolomics as a tool for diagnosis, monitoring therapeutic response, and prognostic assessment of sepsis and septic shock. These findings also encourage further clinical investigations to warrant its use in routine clinical settings. Full article
(This article belongs to the Special Issue Metabolic Alterations in Sepsis and Major Trauma)
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