Patient Stratification in Sepsis: Using Metabolomics to Detect Clinical Phenotypes, Sub-Phenotypes and Therapeutic Response

Hussain, Humma; Vutipongsatorn, Kritchai; Jiménez, Beatriz; Antcliffe, David

doi:10.3390/metabo12050376

Cited by 19 publications

(19 citation statements)

References 166 publications

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“…HCC utilizing the top 25 altered metabolites revealed two main branches, one containing the control and CLP/DCS Day 28 samples and the second containing the CLP/DCS Days 4 and 8 samples ( Figure ). Interestingly, numerous metabolites (including amino acids) that are found increased in septic patient serum/plasma or in septic non‐survivors compared with survivors 36 are also increased in CLP/DCS muscle ( Figure ).…”

Section: Resultsmentioning

confidence: 99%

Muscle stem cells contribute to long‐term tissue repletion following surgical sepsis

Schmitt

Dasgupta

Arneson‐Wissink

et al. 2023

J cachexia sarcopenia muscle

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Background Over the past decade, advances in sepsis identification and management have resulted in decreased sepsis mortality. This increase in survivorship has highlighted a new clinical obstacle: chronic critical illness (CCI), for which there are no effective treatment options. Up to half of sepsis survivors suffer from CCI, which can include multi-organ dysfunction, chronic inflammation, muscle wasting, physical and mental disabilities, and enhanced frailty. These symptoms prevent survivors from returning to regular day-to-day activities and are directly associated with poor quality of life. Methods Mice were subjected to cecal ligation and puncture (CLP) with daily chronic stress (DCS) as an in vivo model to study sepsis late-effects/sequelae on skeletal muscle components. Longitudinal monitoring was performed via magnetic resonance imaging, skeletal muscle and/or muscle stem cell (MuSCs) assays (e.g., post-necropsy wet muscle weights, minimum Feret diameter measurements, in vitro MuSC proliferation and differentiation, number of regenerating myofibres and numbers of Pax7-positive nuclei per myofibre), post-sepsis whole muscle metabolomics and MuSC isolation and high-content transcriptional profiling. Results We report several findings supporting the hypothesis that MuSCs/muscle regeneration are critically involved in post-sepsis muscle recovery. First, we show that genetic ablation of muscle stem cells (MuSCs) impairs post-sepsis muscle recovery (maintenance of 5-8% average lean mass loss compared with controls). Second, we observe impaired MuSCs expansion capacity and morphological defects at 26 days post-sepsis compared with control MuSCs (P < 0.001). Third, when subjected to an experimental muscle injury, sepsis-recovered mice exhibited evidence of impaired muscle regeneration compared with non-septic mice receiving the same muscle injury (CLP/DCS injured mean minimum Feret is 92.1% of control injured, P < 0.01). Fourth, we performed a longitudinal RNA sequencing study on MuSCs isolated from post-sepsis mice and found clear transcriptional differences in all post-sepsis samples compared with controls. At Day 28, CLP/DCS mice satellite cells have multiple altered metabolic pathways, such as oxidative phosphorylation, mitochondrial dysfunction, sirtuin signalling and oestrogen receptor signalling, compared with controls (P < 0.001). Conclusions Our data show that MuSCs and muscle regeneration are required for effective post-sepsis muscle recovery and that sepsis triggers morphological, functional, and transcriptional changes in MuSCs. Moving forward, we strive to leverage a more complete understanding of post-sepsis MuSC/regenerative defects to identify and test novel therapies that promote muscle recovery and improve quality of life in sepsis survivors.

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Section: Resultsmentioning

confidence: 99%

Muscle stem cells contribute to long‐term tissue repletion following surgical sepsis

Schmitt

Dasgupta

Arneson‐Wissink

et al. 2023

J cachexia sarcopenia muscle

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“…Metabolic perturbations are a well-established aspect of sepsis pathophysiology and have reliably been linked to acute illness severity and patient mortality ( 3 ). Described disruptions include a hypermetabolic state that results in catabolism of protein and fat, a glycolytic shift with a subsequent upregulation of the TCA cycle, and mitochondrial dysfunction ( 42 – 44 ). Our work contributes toward the Surviving Sepsis Campaign’s goal to better understand sepsis-induced metabolic disruptions ( 6 ) by providing a more comprehensive mapping of the dynamic metabolic changes in sepsis and its relationship to the host-immune response.…”

Section: Discussionmentioning

confidence: 99%

“…perturbations are a well-established aspect of sepsis pathophysiology and have reliably been linked to acute illness severity and patient mortality (3). Described disruptions include a hypermetabolic state that results in catabolism of protein and fat, a glycolytic shift with a subsequent upregulation of the TCA cycle, and mitochondrial dysfunction (42)(43)(44).…”

Section: Discussionmentioning

confidence: 99%

Sustained Perturbation of Metabolism and Metabolic Subphenotypes Are Associated With Mortality and Protein Markers of the Host Response

Jennaro

Puskarich

Evans

et al. 2023

Critical Care Explorations

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Perturbed host metabolism is increasingly recognized as a pillar of sepsis pathogenesis, yet the dynamic alterations in metabolism and its relationship to other components of the host response remain incompletely understood. We sought to identify the early host-metabolic response in patients with septic shock and to explore biophysiological phenotyping and differences in clinical outcomes among metabolic subgroups. DESIGN:We measured serum metabolites and proteins reflective of the hostimmune and endothelial response in patients with septic shock. SETTING:We considered patients from the placebo arm of a completed phase II, randomized controlled trial conducted at 16 U.S. medical centers. Serum was collected at baseline (within 24 hr of the identification of septic shock), 24-hour, and 48-hour postenrollment. Linear mixed models were built to assess the early trajectory of protein analytes and metabolites stratified by 28-day mortality status. Unsupervised clustering of baseline metabolomics data was conducted to identify subgroups of patients. PATIENTS:Patients with vasopressor-dependent septic shock and moderate organ dysfunction that were enrolled in the placebo arm of a clinical trial. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS:Fifty-one metabolites and 10 protein analytes were measured longitudinally in 72 patients with septic shock. In the 30 patients (41.7%) who died prior to 28 days, systemic concentrations of acylcarnitines and interleukin (IL)-8 were elevated at baseline and persisted at T24 and T48 throughout early resuscitation. Concentrations of pyruvate, IL-6, tumor necrosis factor-α, and angiopoietin-2 decreased at a slower rate in patients who died. Two groups emerged from clustering of baseline metabolites. Group 1 was characterized by higher levels of acylcarnitines, greater organ dysfunction at baseline and postresuscitation (p < 0.05), and greater mortality over 1 year (p < 0.001).CONCLUSIONS: Among patients with septic shock, nonsurvivors exhibited a more profound and persistent dysregulation in protein analytes attributable to neutrophil activation and disruption of mitochondrial-related metabolism than survivors.

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“…In recent years, metabolomics has been widely applied in infectious and immune diseases, and some metabolic changes have been found. [31][32][33][34][35][36] However, there is a lack of metabolomic information on Pneumocystis infection.…”

Section: Discussionmentioning

confidence: 99%

Metabolomic Profiling of Lungs from Mice Reveals the Variability of Metabolites in Pneumocystis Infection and the Metabolic Abnormalities in BAFF-R-Deficient Mice

Rong¹,

Kang²,

Tong³

2023

JIR

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The incidence of Pneumocystis pneumonia (PCP) in patients without human immunodeficiency virus (HIV) has been increasing. In this study, we aimed to investigate the metabolic changes in Pneumocystis infection and the metabolic abnormalities in B-cell-activating factor receptor (BAFF-R)-deficient mice with Pneumocystis infection. Methods: The important function of B cells during Pneumocystis infection is increasingly recognized. In this study, a Pneumocystisinfected mouse model was constructed in BAFF-R -/mice and wild-type (WT) mice. Lungs of uninfected WT C57BL/6, WT Pneumocystis-infected, and BAFF-R -/-Pneumocystis-infected mice were used for metabolomic analyses to compare the metabolomic profiles among the groups, with the aim of exploring the metabolic influence of Pneumocystis infection and the influence of mature B-cell deficiency during infection. Results:The results indicated that many metabolites, mainly lipids and lipid-like molecules, were dysregulated in Pneumocystis-infected WT mice compared with uninfected WT C57BL/6 mice. The data also demonstrated significant changes in tryptophan metabolism, and the expression levels of key enzymes of tryptophan metabolism, such as indoleamine 2,3-dioxygenase 1 (IDO1), were significantly upregulated. In addition, B-cell development and function might be associated with lipid metabolism. We found a lower level of alitretinoin and the abnormalities of fatty acid metabolism in BAFF-R -/-Pneumocystis-infected mice. The mRNA levels of enzymes associated with fatty acid metabolism in the lung were upregulated in BAFF-R -/-Pneumocystis-infected mice and positively correlated with the level of IL17A, thus suggesting that the abnormalities of fatty acid metabolism may be associated with greater inflammatory cell infiltration in the lung tissue of BAFF-R -/-Pneumocystis-infected mice compared with the WT Pneumocystis-infected mice. Conclusion: Our data revealed the variability of metabolites in Pneumocystis-infected mice, suggesting that the metabolism plays a vital role in the immune response to Pneumocystis infection.

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Patient Stratification in Sepsis: Using Metabolomics to Detect Clinical Phenotypes, Sub-Phenotypes and Therapeutic Response

Cited by 19 publications

References 166 publications

Muscle stem cells contribute to long‐term tissue repletion following surgical sepsis

Muscle stem cells contribute to long‐term tissue repletion following surgical sepsis

Sustained Perturbation of Metabolism and Metabolic Subphenotypes Are Associated With Mortality and Protein Markers of the Host Response

Metabolomic Profiling of Lungs from Mice Reveals the Variability of Metabolites in Pneumocystis Infection and the Metabolic Abnormalities in BAFF-R-Deficient Mice

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