Metabolomics analysis identifies glutamic acid and cystine imbalances in COVID-19 patients without comorbid conditions. Implications on redox homeostasis and COVID-19 pathophysiology

Abstract

It is well known that the presence of comorbidities and age-related health issues may hide biochemical and metabolic features triggered by SARS-CoV-2 infection and other diseases associated to hypoxia, as they are by themselves chronic inflammatory conditions that may potentially disturb metabolic homeostasis and thereby negatively impact on COVID-19 progression. To unveil the metabolic abnormalities inherent to hypoxemia caused by COVID-19, we here applied gas chromatography coupled to mass spectrometry to analyze the main metabolic changes exhibited by a population of male patients less than 50 years of age with mild/moderate and severe COVID-19 without pre-existing comorbidities known to predispose to life-threatening complications from this infection. Several differences in serum levels of particular metabolites between normal controls and patients with COVID-19 as well as between mild/moderate and severe COVID-19 were identified. These included increased glutamic acid and reduced glutamine, cystine, threonic acid, and proline levels. In particular, using the entire metabolomic fingerprint obtained, we observed that glutamine/glutamate metabolism was associated with disease severity as patients in the severe COVID-19 group presented the lowest and higher serum levels of these amino acids, respectively. These data highlight the hypoxia-derived metabolic alterations provoked by SARS-CoV-2 infection in the absence of pre-existing co-morbidities as well as the value of amino acid metabolism in determining reactive oxygen species recycling pathways, which when impaired may lead to increased oxidation of proteins and cell damage. They also provide insights on new supportive therapies for COVID-19 and other disorders that involve altered redox homeostasis and lower oxygen levels that may lead to better outcomes of disease severity.

Metabolomics as a powerful tool for diagnostic, pronostic and drug intervention analysis in COVID-19

“…Tryptophan is an essential amino acid and a neurotransmitter, and with phenylalanine also involved in the modulation of the immune response ( Fernstrom and Wurtman, 1971 ) and inflammatory processes in lung and kidney diseases, or other infections like HIV or sepsis ( Darcy et al, 2011 ; Kimhofer et al, 2020 ). SARS-CoV-2 infection also alters many other metabolic pathways ( Albóniga et al, 2022 ), with changes in the serum amino acid signature (for instance, elevated glutamine/glutamate and Fischer’s ratios) ( Doğan et al, 2021 ; Páez-Franco et al, 2022 ). Glutamate alteration in COVID-19 is in part mediated by the α-glutathione S-transferase, associated with certain processes such as liver failure, skeletal muscle metabolism, cancer or immunodeficiency ( Kinscherf et al, 1996 ; Cruzat et al, 2018 ).…”

Diagnostic, Prognostic and Mechanistic Biomarkers of COVID-19 Identified by Mass Spectrometric Metabolomics

“…Multivariate statistical methods are a critical part of the metabolomics workflow for the extraction of reliable information from complex data sets and the elimination of spurious correlations [ 60 ]. Standard tools for data analysis include principal component analysis (PCA), partial least square discriminant analysis (PLS-DA), and orthogonal partial least squares (OPLS), and all these tools have been used to distinguish the overall profile of uninfected and SARS-CoV-2-infected patients [ 43 , 44 , 61 , 62 ]. Functional analysis software is evolving to identify alterations in metabolic pathways informing on the severity of COVID-19 [ 42 , 43 , 63 ].…”

“…It is interesting to note that elevations of kynurenate accompany clinical deterioration in male (but not female) COVID-19 patients [ 66 ]. α-hydroxylated amino acid increased with disease severity and was related to reduced oxygen saturation and clinical markers of lung damage [ 18 , 61 , 64 , 69 ]. In addition to these amino acid-focused studies, alterations in carbohydrate and energy metabolism, tricarboxylic acid cycle (TCA), purine metabolism (adenine, GMP, cysteine, urea), polyamines, and nicotinamide metabolites have been reported.…”

“…Many amino acids and their derivatives are modified by COVID-19 and are associated with the severity of the disease, as reported for valine, L-citrulline, L-isoleucine, asparagine, aspartate, arginine, proline, and glycine [ 43 , 61 , 67 ]. Glutamine plays biosynthetic and bioenergetic roles in several pathways, including the TCA cycle, nucleotide, and fatty acid biosynthesis.…”

SARS-CoV-2 infection induces the production of autoantibodies in severe COVID-19 patients in an age-dependent manner

“…We here hypothesize that both possibilities are reasonable and may be complementary. The severe COVID-19 infection promotes a body environment, i.e., the SARS-CoV-2 induced immune dysregulation, which is favorable for the production of autoantibodies, which could act synergistically with multiple metabolites 91 , cytokines, and chemokines, which are naturally dysregulated in elderly patients as part of immunosenescence [35][36][37] , worsening the COVID-19 outcomes through several well-known mechanisms of autoantibody-induced pathology 92 . In this context, autoantibodies -in concert with other immune molecules (e.g., cytokines and chemokines) -could interact in a highly complex network underlying immunopathological processes 93 in severe COVID-19 patients, potentiated by aging-associated health conditions and lead to the development of severe disease.…”