Plasma Metabolome Changes Indicated Perturbed Oxidative Pathways of Cellular Energy Production
As baseline characteristics such as age, sex, and BMI were known to significantly influence plasma lipidomes and metabolomes, we constructed logistic regression models with these covariates to search for significant metabolites distinctly associated with different stages of COVID-19 (Figure S3). Several acylcarnitines, such as palmitoylcarnitine, stearoylcarnitine, and oleoylcarnitine, were reduced in COVID-19 (Figure S3, β-oxidation pathway). Reduced circulating levels of acylcarnitines may indicate attenuated entry of fatty acyls into the mitochondria for β-oxidation. Metabolites constituting the tricarboxylic acid (TCA) cycle were generally reduced in COVID-19 (Figure S3, TCA pathway). The reductions in polar metabolites participating in oxidative pathways of energy production (β-oxidation and TCA cycle), particularly in severe patients, may indicate metabolic response to declining lung functions and limiting blood oxygen to lower reliance on oxygen for cellular energy production. Lactate dehydrogenase was found to increase (p = 0.028) with increasing disease severity (Table S1), but plasma lactate was not significantly altered in COVID-19 compared to controls. The overall reductions in these polar metabolites might also reflect a response to change in nutrition, especially in severe patients. Although only 2 out of 13 severe patients were on mechanical ventilation at the point of blood collection (Table S3), a loss in appetite denotes a common general symptom of COVID-19 (Lechien et al., 2020). Interestingly, itaconic acid, a macrophage-specific metabolite derived from cis-aconitate, was progressively reduced with COVID-19 severity (Figure S3, TCA). Itaconate levels were previously reported to positively correlate with the expression of immune-responsive gene 1 (IRG1) in both human and mouse immune cells (Michelucci et al., 2013). Progressive reductions in sulfated steroids were also observed with increasing disease severity (Figure S3, steroid pathway). Numerous amino acids, including tryptophan, valine, proline, citrulline, and isoleucine, were significantly reduced in mild and moderate patients (Figure S3, amino acids). Decreases in specific amino acids were also previously observed in EVD fatalities (Eisfeld et al., 2017).