Metabolic Profiling at COVID-19 Onset Shows Disease Severity and Sex-Specific Dysregulation

Abstract

Backgroundmetabolic changes through SARS-CoV-2 infection has been reported but not fully comprehended. This metabolic dysregulation affects multiple organs during COVID-19 and its early detection can be used as a prognosis marker of severity. Therefore, we aimed to characterize metabolic and cytokine profile at COVID-19 onset and its relationship with disease severity to identify metabolic profiles predicting disease progression.Material and Methodswe performed a retrospective cross-sectional study in 123 COVID-19 patients which were stratified as asymptomatic/mild, moderate and severe according to the highest COVID-19 severity status, and a group of healthy controls. We performed an untargeted plasma metabolic profiling (gas chromatography and capillary electrophoresis-mass spectrometry (GC and CE-MS)) and cytokine evaluation.ResultsAfter data filtering and identification we observed 105 metabolites dysregulated (66 GC-MS and 40 CE-MS) which shown different expression patterns for each COVID-19 severity status. These metabolites belonged to different metabolic pathways including amino acid, energy, and nitrogen metabolism among others. Severity-specific metabolic dysregulation was observed, as an increased transformation of L-tryptophan into L-kynurenine. Thus, metabolic profiling at hospital admission differentiate between severe and moderate patients in the later phase of worse evolution. Several plasma pro-inflammatory biomarkers showed significant correlation with deregulated metabolites, specially with L-kynurenine and L-tryptophan. Finally, we describe a strong sex-related dysregulation of metabolites, cytokines and chemokines between severe and moderate patients. In conclusion, metabolic profiling of COVID-19 patients at disease onset is a powerful tool to unravel the SARS-CoV-2 molecular pathogenesis.ConclusionsThis technique makes it possible to identify metabolic phenoconversion that predicts disease progression and explains the pronounced pathogenesis differences between sexes.

Amino acid profiling of COVID-19 patients blood serum

“…According to the results obtained, kynurenine, phenylalanine and acetylcarnitine have strong association with the severity of COVID-19 infection. This is consistent with the findings of increased levels of kynurenine and phenylalanine for COVID-19 patients 3,8,15,16 and their negative correlation with the severity of infection 7,10 . Increased kynurenine levels in COVID-19 are associated with increased tryptophan degradation due to overactivation of the immune response through increased levels of interferon-gamma (increased inflammatory response) and strong T-cell activation 1,15 ; kynurenine pathway metabolites were shown to be associated with tricarboxylic acid cycle intermediates, inflammatory response, and cell death 4 .…”

“…Impaired synthesis and metabolism of arginine, threonine, ornithine, citrulline and alanine in COVID-19 patients, especially under hypoxic conditions, has been reported in many studies 9,11,16,19 . Decreased serum levels of glutamate, citrulline, ornithine, glutamine, urea, fumarate, ADMA and SDMA in COVID-19 patients were associated with liver dysfunction 14 .…”

Maintained imbalance of triglycerides, apolipoproteins, energy metabolites and cytokines in long-term COVID-19 syndrome (LTCS) patients

“…Several studies identified that inflammation, metabolism, and lipoprotein content act in unison to overall inform the status of specific disease state such as mild, moderate, or severe in COVID-19 patients and thus can help us to predict and stratify the disease severity [2; 3; 21; 36; 46; 50; 51; 52; 53]. Our cytokines and chemokine profiling showed that acute COVID-19 samples had a trend of highest levels of cytokines & chemokines compared with either HC, LTCS or Recov (Suppl.…”

“…Many scientific reports identified the important role of metabolites in the blood serum and plasma of mild, moderate, severe, and recovered COVID-19 patients. In fact, in COVID-19 disease or any other viral infection, immune cells require a lot of energy to fight off the infection, therefore, their metabolic demands drastically increase to produce cytokines and chemokines [2; 3]. A previous study described that peripheral blood mononuclear cells (PBMCs) have a dysregulated glycolysis and oxidative phosphorylation related metabolic profile, with specifically higher lactate and lower glucose levels in mild and moderate COVID-19 patients compared either with healthy controls (HC), convalescent (Co) COVID-19 individuals [4].…”

Maintained imbalance of triglycerides, apolipoproteins, energy metabolites and cytokines in long-term COVID-19 syndrome patients

“…In fact, in COVID-19 disease or any other viral infection, immune cells require a lot of energy to fight off the infection. Therefore, their metabolism demands a drastic increase to produce cytokines and chemokines ( 2 , 3 ). A previous study described that peripheral blood mononuclear cells (PBMCs) show a dysregulated glycolysis and oxidative phosphorylation related metabolic profile, with specifically higher lactate and lower glucose levels in mild and moderate COVID-19 patients compared with either healthy controls (HC) or convalescent (Co) COVID-19 individuals ( 4 ).…”