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. 2023 Jul 24;13(7):879.
doi: 10.3390/metabo13070879.

Integrated NMR and MS Analysis of the Plasma Metabolome Reveals Major Changes in One-Carbon, Lipid, and Amino Acid Metabolism in Severe and Fatal Cases of COVID-19

Marcos C Gama-Almeida  1 , Gabriela D A Pinto  1 , Lívia Teixeira  2 , Eugenio D Hottz  3 , Paula Ivens  4 , Hygor Ribeiro  4   5 , Rafael Garrett  4 , Alexandre G Torres  1   5 , Talita I A Carneiro  1 , Bianca de O Barbalho  1 , Christian Ludwig  6 , Claudio J Struchiner  7   8 , Iranaia Assunção-Miranda  9 , Ana Paula C Valente  10 , Fernando A Bozza  11   12 , Patrícia T Bozza  2 , Gilson C Dos Santos Jr  13 , Tatiana El-Bacha  1   5
Affiliations

Integrated NMR and MS Analysis of the Plasma Metabolome Reveals Major Changes in One-Carbon, Lipid, and Amino Acid Metabolism in Severe and Fatal Cases of COVID-19

Marcos C Gama-Almeida et al. Metabolites. .

Abstract

Brazil has the second-highest COVID-19 death rate worldwide, and Rio de Janeiro is among the states with the highest rate in the country. Although vaccine coverage has been achieved, it is anticipated that COVID-19 will transition into an endemic disease. It is concerning that the molecular mechanisms underlying clinical evolution from mild to severe disease, as well as the mechanisms leading to long COVID-19, are not yet fully understood. NMR and MS-based metabolomics were used to identify metabolites associated with COVID-19 pathophysiology and disease outcome. Severe COVID-19 cases (n = 35) were enrolled in two reference centers in Rio de Janeiro within 72 h of ICU admission, alongside 12 non-infected control subjects. COVID-19 patients were grouped into survivors (n = 18) and non-survivors (n = 17). Choline-related metabolites, serine, glycine, and betaine, were reduced in severe COVID-19, indicating dysregulation in methyl donors. Non-survivors had higher levels of creatine/creatinine, 4-hydroxyproline, gluconic acid, and N-acetylserine, indicating liver and kidney dysfunction. Several changes were greater in women; thus, patients' sex should be considered in pandemic surveillance to achieve better disease stratification and improve outcomes. These metabolic alterations may be useful to monitor organ (dys) function and to understand the pathophysiology of acute and possibly post-acute COVID-19 syndromes.

Keywords: 1H-NMR; SARS-CoV-2; fatal COVID-19; high-resolution mass spectrometry; metabolic alterations; metabolomics; sex differences; virus-host interactions.

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Conflict of interest statement

The authors declare no competing interest. The funders were not involved in the study design, collection, analysis, or interpretation of data, nor in the writing of the report or the decision to submit it for publication.

Figures

Figure 1
Figure 1
1H NMR-based metabolomics shows different plasma metabolite profiling in severe COVID-19 patients compared to control subjects. 1H NMR representative spectra of control (red), COVID-19 survivors (green), and non-survivors (blue). Metabolites that differ significantly among groups are indicated as having higher (↑) or lower (↓) contents compared to controls; (A,B) aliphatic region (3× magnified); (C) amidic and aromatic regions (21× magnified); (D) Principal Component Analysis 3D score plot shows discriminating profiling among groups; control (red), COVID-19 survivors (green), and non-survivors (blue).
Figure 2
Figure 2
Metabolites that were significantly altered in severe COVID-19, according to 1H NMR-based metabolomics. Most discriminating metabolites according to PCA loading factors, presenting significant differences among groups. Control, n = 12 (red circles); survivors, n = 18 (green circles); non-survivors, n = 17 (blue circles). Metabolites related to one-carbon metabolism (A,B): (CH3)3 choline-related metabolites and glycine; metabolites related to glucose metabolism, insulin sensitivity, and inflammation (C–G): creatine/creatinine, N-Acetyl of glycoproteins, lactate, acetate, and formate; metabolites related to lipid metabolism (H–J): CH2 lipoproteins (mainly VLDL), lipids-TAG (CH=CH olefinic protons of triacylglycerols) and acetoacetate; metabolites related to amino acids and protein metabolism (K–P): glutamine, alanine, valine, isoleucine, leucine, and tyrosine; metabolites’ contents were determined according to their respective peak intensity. Data were presented as medians with an interquartile range, and only significant P values are shown, according to Kruskal-Wallis and Dunn’s post-hoc tests.
Figure 3
Figure 3
High-resolution mass spectrometry-based metabolomics shows an altered plasma metabolic profile in severe COVID-19. Assigned metabolites in the untargeted approach and confirmed in the targeted approach, presenting significant differences among groups. Control, n = 12 (red circles); survivors, n = 18 (green circles); non-survivors, n = 17 (blue circles). Metabolites related to one-carbon metabolism (A–D): glycerophosphocholine, serine, betaine, histidine, and nucleic acid metabolism (E,F): xanthine, hypoxanthine; metabolites related to glucose metabolism, insulin sensitivity, and inflammation (G–L): creatinine, 4-hydroxyproline, asymmetric dimethylarginine, gluconic acid, N-acetyl serine, and methylmalonic acid. Metabolite related to lipid metabolism (M): β-hydroxybutyrate; metabolite related to amino acid metabolism (N): tryptophan. Metabolites’ contents were determined according to their respective peak intensities. Data were presented as medians with an interquartile range, and only significant p values are shown, according to Kruskal-Wallis and Dunn’s post-hoc tests.
Figure 4
Figure 4
Lipoprotein dynamics changed significantly in severe COVID-19. (A) Total Cholesterol; (B) Low-Density Lipoprotein—LDL; (C) High-Density Lipoprotein—HDL; (D) Very Low-Density Protein—VLDL; (E) Triacylglycerol; (F) Non-HDL Cholesterol; (G) Cholesterol-to-HDL ratio; and (H) LDL-to-HDL ratio. Control, n = 12 (red circle); survivors, n = 18 (green circle); non-survivors, n = 17 (blue circle). Data were presented as medians with an interquartile range, and only significant p values are shown, according to Kruskal-Wallis and Dunn’s post-hoc tests.
Figure 5
Figure 5
Severe COVID-19-induced changes in lipoproteins and metabolites are greater in women than in men. (A) Total Cholesterol; (B) Low-Density Lipoprotein—LDL; (C) High-Density Lipoprotein—HDL; (D) Very Low-Density Protein—VLDL; (E) Triacylglycerol; (F) Non-HDL Cholesterol; (G) Cholesterol-to-HDL ratio; (H) LDL-to-HDL ratio; (I) (CH3)3 Choline; (J) Acetoacetate; (K) N-acetyl of glycoprotein; and (L) Creatine/creatinine. Female subjects: control, n = 7 (red triangles); survivors, n = 11 (green triangles); non-survivors, n = 7 (blue triangles). Male subjects: control, n = 5 (red squares); survivors, n = 7 (green squares); non-survivors, n = 10 (blue squares). Data were presented as medians with an interquartile range, and p values are shown according to a two-factor ANOVA and Tukey’s multiple comparison tests.
Figure 6
Figure 6
Metabolic alterations in severe COVID-19. Summary of changes in plasma metabolites in survivors and non-survivors. Metabolites that differ significantly among groups are indicated as having higher (↑) or lower (↓) contents compared to controls. Metabolites in bold were higher in the fatal cases of the disease compared to survivors and controls. * indicates metabolites with changes greater in women than in men. This figure was created with BioRender.com.
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