Metabolomic analyses reveal new stage-specific features of COVID-19, 2022, Hongling Jia et al

Abstract

The current pandemic of coronavirus disease 2019 (COVID-19) has affected >160 million individuals to date, and has caused millions of deaths worldwide, at least in part due to the unclarified pathophysiology of this disease. Identifying the underlying molecular mechanisms of COVID-19 is critical to overcome this pandemic.

Metabolites mirror the disease progression of an individual and can provide extensive insights into their pathophysiological significance at each stage of disease. We provide a comprehensive view of metabolic characterisation of serum from COVID-19 patients at all stages using untargeted and targeted metabolomic analysis. As compared with the healthy controls, we observed different alteration patterns of circulating metabolites from the mild, severe and recovery stages, in both the discovery cohort and the validation cohort, which suggests that metabolic reprogramming of glucose metabolism and the urea cycle are potential pathological mechanisms for COVID-19 progression.

Our findings suggest that targeting glucose metabolism and the urea cycle may be a viable approach to fight COVID-19 at various stages along the disease course

We first analysed the metabolic variations using an untargeted approach, and then confirmed our findings using a targeted approach. Further analysis showed that these altered metabolites are mainly involved in the tricarboxylic acid (TCA) cycle and the urea cycle pathway. More importantly, recovery groups were included in our investigation. We obtained more valuable information about metabolic variations by comparing the recovery group with other groups.

We identified circulating metabolites, including malate, 2-oxoglutaratek and asparate, which were increased compared to normal levels, suggesting that the dysregulated glucose metabolism and TCA cycle could be crucial in susceptibility, severity and recovery during the COVID-19 disease course. Glucose either goes through aerobic metabolism and provides energy for diverse biological processes or is oxidised through the pentose phosphate pathway to yield NADPH to maintain redox homeostasis, which involves in host immune responses against pathogenic micro-organisms under aerobic conditions. While under anaerobic conditions, which is most common in COVID-19 patients, glucose goes through glycolysis and is fermented to lactate with a limited amount of ATP production, and causes the elevated blood lactate and lactate dehydrogenase levels [22, 23].

Our findings indicate that, in addition to anaerobic glycolysis, which usually occurs in most COVID-19 patients, the TCA cycle was also enhanced during all stages of the disease. We proposed that SARS-CoV-2 viruses hijack the host machinery, including glucose metabolism, to promote pathogenesis of COVID-19.

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