Profiling metabolites and lipoproteins in COMETA, an Italian cohort of COVID-19 patients

Abstract

Metabolomics and lipidomics have been used in several studies to define the biochemical alterations induced by COVID-19 in comparison with healthy controls. Those studies highlighted the presence of a strong signature, attributable to both metabolites and lipoproteins/lipids. Here, 1H NMR spectra were acquired on EDTA-plasma from three groups of subjects: i) hospitalized COVID-19 positive patients (≤21 days from the first positive nasopharyngeal swab); ii) hospitalized COVID-19 positive patients (>21 days from the first positive nasopharyngeal swab); iii) subjects after 2–6 months from SARS-CoV-2 eradication. A Random Forest model built using the EDTA-plasma spectra of COVID-19 patients ≤21 days and Post COVID-19 subjects, provided a high discrimination accuracy (93.6%), indicating both the presence of a strong fingerprint of the acute infection and the substantial metabolic healing of Post COVID-19 subjects. The differences originate from significant alterations in the concentrations of 16 metabolites and 74 lipoprotein components. The model was then used to predict the spectra of COVID-19>21 days subjects. In this group, the metabolite levels are closer to those of the Post COVID-19 subjects than to those of the COVID-19≤21 days; the opposite occurs for the lipoproteins. Within the acute phase patients, characteristic trends in metabolite levels are observed as a function of the disease severity. The metabolites found altered in COVID-19≤21 days patients with respect to Post COVID-19 individuals overlap with acute infection biomarkers identified previously in comparison with healthy subjects. Along the trajectory towards healing, the metabolome reverts back to the “healthy” state faster than the lipoproteome.

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

“…Frequently associated COVID-19 co-morbidities including obesity, diabetes mellitus and cardiovascular diseases, all comprise ~80% of the patients attended in our third level health center, which made quite difficult to recruit for the present metabolomics study patients free of co-morbidities. In this vein, our findings are comparable with other studies including larger numbers of patients and presence of comorbidities in which altered levels of branched-chain amino acids, glutamine, glutamate, and proline also were identified, suggesting that neither differences in patient number or abscence of comorbidities influenced on the general metabolic reshaping provoked by SARS-CoV2 infection [ 1 , 79 , 81 , 90 – 93 ]. Another limitation is that we did not include additional controls with other viral pneumonias in which hypoxia and respiratory failure may lead to altered metabolomics, particularly when associated to hypoxic liver injury [ 94 , 95 ].…”

Quantitative NMR-Based Lipoprotein Analysis Identifies Elevated HDL-4 and Triglycerides in the Serum of Alzheimer’s Disease Patients

“…We would like to stress that even though many of the solely gender-based comparisons showed strong FDR values, these findings are prone to multiple confounding factors, such as smoking [ 57 ]. Other comorbidities, such as diabetes type 2, cardiovascular disease, imbalances in dietary supplementation, obesity, and various other health conditions, including the emerging coronavirus pandemic, can further alternate the lipoprotein profile on a long-term basis [ 58 , 59 , 60 ]. Therefore, we may once more address the rather insignificant main findings of the dementia-driven changes where we estimate that larger cohorts with much higher n numbers and consideration of clinical metadata that were not available within this study would have resulted in stronger statistical findings.…”

Reduced circulating FABP2 in patients with moderate to severe COVID-19 may indicate enterocyte functional change rather than cell death

“…Accordingly, low HDL cholesterol and high triglycerides prior to infection are risk factors for progression to severe COVID-19 46 . Nonetheless, the most commonly reported lipid changes in COVID-19 patients at all stages of disease are reduced circulating cholesterol (LDL and HDL) and elevated triglycerides 21 , 47 – 50 , 52 . Reported metabolite changes includes increased levels of acetoacetic acid, 3-hyroxybutyric acid, acetone and 2-hdroxybutyic acid; changes have also been reported in porphyrin levels, branched chain amino acids and tryptophan pathways 21 , 45 , 49 , 53 .…”

“…Nonetheless, the most commonly reported lipid changes in COVID-19 patients at all stages of disease are reduced circulating cholesterol (LDL and HDL) and elevated triglycerides 21 , 47 – 50 , 52 . Reported metabolite changes includes increased levels of acetoacetic acid, 3-hyroxybutyric acid, acetone and 2-hdroxybutyic acid; changes have also been reported in porphyrin levels, branched chain amino acids and tryptophan pathways 21 , 45 , 49 , 53 . The most severely affected patients have a further reduction of HDL compared to patients with moderate disease 46 , 47 , with increases of cholesterol and triglycerides upon recovery in survivors 52 .…”

“…We investigated the role of the gut in affected COVID-19 patients, grouped according to mild and moderately severe disease, who were admitted to Fondazione Ca’ Grande Ospedale Maggiore Policlinico (Lombardy, Italy) 20 . For this pilot study we assayed commonly used plasma biomarkers of gut permeability (zonulin) and enterocyte cell death (Intestinal Fatty Acid Binding Protein / Fatty Acid Binding Protein 2, I-FABP/FABP2) as well as a range of plasma metabolites with nuclear magnetic resonance (NMR) spectroscopy 21 . The earliest available timepoint plasma sample (closest to date of admission) was analysed and compared to patient clinical data recorded within 3 days of the experimental sample collection.…”