Metabolic responses in neonatal sepsis—A systematic review of human metabolomic studies

Bjerkhaug, Aline Uhirwa; Granslo, Hildegunn Norbakken; Klingenberg, Claus

doi:10.1111/apa.15874

Cited by 12 publications

(7 citation statements)

References 58 publications

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“…These regulations likely inhibit vast ATP production, which is necessary for strong immune responses, and instead support the maintenance of organ functions. Similar observations were shown previously in septic patients, demonstrating transcriptomic profiles with highly up-regulated glycolysis and HIF-1α signaling (36). When conducting plasma metabolomics, we found metabolic pathways related to the TCA cycle and mitochondrial activities were significantly enhanced in sepsis survivors.…”

Section: Discussionsupporting

confidence: 90%

Regulation of host metabolism and defense strategies to survive neonatal infection

Wu,

Tien,

Bæk

et al. 2024

Preprint

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Upon infection, mammals utilize either disease resistance, which seeks to eliminate pathogens at the cost of potential tissue damage, or disease tolerance, which reduces physiological damage without killing the pathogen. Newborns, constrained by limited energy reserves, predominantly rely on disease tolerance strategies to cope with infection. However, this approach may fail as pathogen levels surpass a critical threshold, prompting a shift to dysregulated immune responses that can lead to excessive inflammation and, consequently, neonatal sepsis, a condition with significant mortality risk. The mechanisms governing the interplay between disease tolerance and resistance in newborns remain poorly understood. Here, we compare infection defense strategies of sepsis survivors and non-survivors in aStaphylococcus epidermidis-infected preterm piglet model, mimicking sepsis in preterm infants. Our findings show that compared to non-survivors, sepsis survivors showed elevated disease resistance during early infection, with a stronger disease tolerance in later stages. In contrast, animals succumbing to sepsis showed limited disease resistance after infection and weaker tolerance phenotype with dysregulated immune responses at later time points, including clear signs of respiratory and metabolic acidosis, together with exaggerated inflammation and organ dysfunctions. Hepatic transcriptomics at euthanasia revealed a strong association of tolerance phenotype in survivors with enhanced oxidative phosphorylation, dampened glycolysis and innate and adaptive immune signaling. Plasma metabolomics confirmed our transcriptomic results, highlighting a tolerance phenotype in neonatal infection survivors. This was characterized by rewired metabolic regulations that emphasize mitochondrial activities, including upregulation of the tricarboxylic acid (TCA) cycle and vital interconnected pathways. Our findings suggest potential mechanisms of host metabolism to control a delicate balance of defense strategies to survive newborn infection. Further, metabolic regulations related to disease tolerance can be exploited to discover novel therapeutics for neonatal infection.

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Section: Discussionsupporting

confidence: 90%

Regulation of host metabolism and defense strategies to survive neonatal infection

Wu,

Tien,

Bæk

et al. 2024

Preprint

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“…Our ndings shed light on new ways in which platelet activation and mineral absorption may in uence heart metabolism. Many diseases can be better detected and treated early with metabolomic investigations, which provide a precise assessment of individual metabolic reactions to pathophysiological stimuli (Bjerkhaug et al, 2021). When activated in abnormal circumstances, they can induce blood clots in the circulatory system, a leading cause of death in the elderly.…”

Section: Discussionmentioning

confidence: 99%

Integrated proteomics and metabolomics analysis of cardiac-tissue in mice with sepsis

Xiao

Li³

et al. 2022

Preprint

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Introduction: Sepsis remains a devastating disease with a high fatality rate in most nations. Heart failure accounts for around half of all deaths in sepsis patients. Because of the peculiarities of cardiac tissue, the specific mechanism of sepsis-induced cardiac dysfunction remains largely unknown. Objectives: The goal of this study was to develop a more complete understanding of the molecular pathways of septic cardiomyopathy by doing an integrated proteome and metabolomics analysis on a sepsis-infected mouse model. Methods: The CLP mice were utilized as a model in this study to investigate the impact of septic cardiomyopathy on the molecular changes in heart tissues through combining metabolomics and proteomics studies. Results: The present findings suggest that 118 proteins (75-upregulated and 43-downregulated) and 138 metabolites (124-upregulated and 14-downregulated) were significantly altered. Additionally, these compounds play a significant role in biological processes, such as platelet activation, mineral absorption, drug metabolism, terpenoid backbone biosynthesis, and butanoate metabolism. The comprehensive analysis discovered that prostaglandin H2, prostaglandin I2, thromboxane A2, and L-Glutamine might play essential roles in combating sepsis-induced heart dysfunction. Conclusions: Overall, this work adds to our understanding of the implications of sepsis-induced cardiac dysfunction and may lead to identifying novel potential biomarkers and a better understanding of sepsis pathophysiology.

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“…As in any other field of science, Omics technologies and machine learning may be very useful in the advance of the methods used to diagnose NS, including LOS. Transcriptomics [ 247 , 248 , 249 , 250 ], proteomics [ 251 , 252 , 253 , 254 , 255 ] and metabolomics [ 252 , 256 , 257 , 258 ] have been used to characterize the response of preterm neonates to NS [ 259 , 260 ] and, together with machine learning approaches, can help to identify promising biomarkers, to determine NS risk, treatment response and prognosis [ 261 , 262 ]. Some steps were already made in that direction and Pediatric Sepsis Biomarker Risk Model, PERSEVERE, was developed and validated as a prognostic enrichment tool for pediatric septic shock [ 260 , 263 ].…”

Section: Los Diagnosis and Treatmentmentioning

confidence: 99%

The Role of Coagulase-Negative Staphylococci Biofilms on Late-Onset Sepsis: Current Challenges and Emerging Diagnostics and Therapies

França

2023

Antibiotics

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Infections are one of the most significant complications of neonates, especially those born preterm, with sepsis as one of the principal causes of mortality. Coagulase-negative staphylococci (CoNS), a group of staphylococcal species that naturally inhabit healthy human skin and mucosa, are the most common cause of late-onset sepsis, especially in preterms. One of the risk factors for the development of CoNS infections is the presence of implanted biomedical devices, which are frequently used for medications and/or nutrient delivery, as they serve as a scaffold for biofilm formation. The major concerns related to CoNS infections have to do with the increasing resistance to multiple antibiotics observed among this bacterial group and biofilm cells’ increased tolerance to antibiotics. As such, the treatment of CoNS biofilm-associated infections with antibiotics is increasingly challenging and considering that antibiotics remain the primary form of treatment, this issue will likely persist in upcoming years. For that reason, the development of innovative and efficient therapeutic measures is of utmost importance. This narrative review assesses the current challenges and emerging diagnostic tools and therapies for the treatment of CoNS biofilm-associated infections, with a special focus on late-onset sepsis.

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Metabolic responses in neonatal sepsis—A systematic review of human metabolomic studies

Abstract: This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Cited by 12 publications

References 58 publications

Regulation of host metabolism and defense strategies to survive neonatal infection

Regulation of host metabolism and defense strategies to survive neonatal infection

Integrated proteomics and metabolomics analysis of cardiac-tissue in mice with sepsis

The Role of Coagulase-Negative Staphylococci Biofilms on Late-Onset Sepsis: Current Challenges and Emerging Diagnostics and Therapies

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