Mild COVID causes increase in neurotoxic metabolites

In a recent study posted to the bioRxiv* pre-print server, researchers investigated the blood levels of neurotoxic metabolites in patients with mild coronavirus disease 2019 (COVID-19).

Study: Increased levels of circulating neurotoxic metabolites in patients with mild Covid19. Image Credit: DOERS / Shutterstock


Currently, there is a lack of understanding of the factors that drive the neuropsychiatric symptoms present during acute and long-term COVID-19. Studies have shown a correlation between the kynurenine pathway metabolites, such as quinolinic acid (QUIN) and 3-hydroxykynurenine (3-HK), and COVID-19 severity. Therefore, they could potentially serve as biomarkers of neuropsychiatric long COVID symptoms.

Some pathogenic infections, including COVID-19 and subsequent inflammatory conditions, can alter the activity of the enzymes of the kynurenine pathway. QUIN is glutamatergic N-methyl-D78 aspartate (NMDA) receptor antagonist, and its high concentrations induce excitotoxic neuronal death. Conversely, kynurenic acid (KYNA), an antagonist of NMDA-receptor, prevents excessive calcium influx in a cell. On the other hand, 3-HK is neurotoxic and pro-inflammatory, promotes the generation of reactive oxygen species (ROS), and accelerates endothelial cell apoptosis.

While a blood-brain barrier (BBB) partially prohibits the entry of QUIN and KYNA into the central nervous system (CNS), 3-HK and KYN, a metabolite produced from kynurenine pathway-mediated tryptophan (TRP) metabolism, can freely pass the BBB. The SARS-CoV-2 infection affects the KYN levels by inducing the production of the pro-inflammatory cytokine, interferon-gamma (IFN-ɣ) that stimulates the kynurenine pathway enzyme, indoleamine-2,3-dioxygenase (IDO). Moreover, SARS-CoV-2 infection can lead to an inflammatory response that affects the levels of some intracellular glycoproteins, such as the intercellular cell adhesion molecule-1 (ICAM-1) and the vascular cell adhesion protein-1 (VCAM-1). A decrease in IDO during pathogenic infections leads to an increase in VCAM-1 in endothelial cells of vessel walls.

About the study

In the present study, researchers collected and analyzed serum samples from 150 patients, 44 of whom tested positive for COVID-19 but exhibited mild disease. They determined whether the neurotoxic metabolites and glycoproteins involved in inflammation were altered in these patients.

A recent study showed that the inflammatory response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), driven by monocyte-derived macrophages, was detectable in convalescent COVID-19 patients following mild infection. ICAM-1 and VCAM-1 are also involved in the inflammatory response governing immune cell migration to the sites of T-cell-mediated immunity in tissues. Therefore, the authors also determined whether the ICAM-1 and VCAM-1 levels were altered in patients with mild COVID-19 and linked to kynurenine pathway activation.

They used reverse-phase ultra-high-performance liquid chromatography (UHPLC) coupled to a mass spectrometer to quantify all kynurenine pathway metabolites.

Study findings

The researchers found the ICAM-1 and VCAM-1 blood levels were significantly increased in patients with mild SARS-CoV-2, especially those with hypertension. This finding links the increase in endothelial cell adhesion molecules to kynurenine pathway metabolites, such as IDO.

Further, the authors observed a higher KYN/TRP ratio in SARS-CoV-2-positive patients compared to the healthy controls and those testing SARS-CoV-2-negative. Along with a higher KYN/TRP ratio, hypertensive COVID-19 patients had a higher cerebrospinal fluid (CSF) QUIN/TRP ratio. The KYN/TRP ratio is an indirect measure of the IDO activity, whereas the QUIN/TRP ratio is an early, predictive marker of a central nervous system (CNS) disease.

The authors did not observe any differences in serum IFN-ɣ levels in samples from COVID-19 patients with mild disease. In addition to IFN-ɣ, some non-canonical pathways might activate IDO. It explains the activation of the kynurenine pathway observed in the current study cohort. The kynurenine pathway activation leads to long-lasting inflammation; thus, kynurenine metabolites could be potent diagnostic markers for long COVID patients.

Cihan and colleagues analyzed kynurenine pathway metabolites and inflammatory cytokines to find a positive correlation between interleukin-6 (IL-6) and its various metabolites. The present study also found a positive correlation between IL-6 and 3-HK, as well as between IL-6 and QUIN. Furthermore, QUIN, 3-HK, and KYN increased in patients with mild COVID-19. Therefore, the inflammation observed in COVID-19 patients could be a major contributor to the neuronal damage caused by neurotoxic metabolites.

The kynurenine pathway is altered in patients with mild COVID-19, who present increased levels of neurotoxic metabolites. Significantly increased levels of kynurenine (data adjusted for age and sex, ANOVA test F: 11.195, p<0.001 ***), 3-hydroxykynurenine (data adjusted for age and sex, ANOVA test F: 3.390, p=0.009 **), anthranilic acid (data adjusted for age and sex, ANOVA test F: 4.024, p=0.009 **), and quinolinic acid (data adjusted for age and sex, ANOVA test F: 8.492, p<0.001 ***) were found in patients with mild COVID-19 when compared to controls. When the ratio of the metabolites was analyzed, significantly increased levels of KYN/TRP (data adjusted for age and sex, ANOVA test F: 6.377, p<0.001 ***) and QUIN/TRP (data adjusted for age and sex, ANOVA test F: 5.837, p<0.001 ***), as well as QUIN/KYNA (data adjusted for age and sex, ANOVA test F: 2.847, p= 0.040 *) were found in patients with COVID-19. Graphs show the median with 95% of CI. Abbreviations: IDO, Indoleamine 2,3-dioxygenase; TDO, Tryptophan 2,3-dioxygenase; KATs, Kynurenine aminotransferase; KYNA, kynurenic acid; KMO, Kynurenine 3-monooxygenase; AA, anthranilic acid; 3-HK, 3-hydroxykynurenine; KYNU, Kynureninase; 3-HAA, 3-hydroxyanthranilic acid; 3HAO, 3-hydroxyanthranilate oxidase; ACMSD, Aminocarboxymuconate-semialdehyde decarboxylase, and NAD, Nicotinamide adenine dinucleotide.


To summarize, the study results demonstrated an increase in blood levels of neurotoxic metabolites of the kynurenine pathway in patients with mild COVID-19. These neurotoxic metabolites correlated with inflammatory and vascular injury markers, such as VCAM-1, tumor necrosis factor (TNF)-α, IL-6,  and ICAM-1. Future studies should further evaluate their potential as biomarkers for long COVID and as potential contributors to the underlying mechanisms of long COVID.

*Important notice

bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Journal reference:
  • Increased levels of circulating neurotoxic metabolites in patients with mild Covid19, Estibaliz Santiago-Mujika, Kevin Heinrich, Sonia George, Colt D Capan, Cameron Forton, Zachary Madaj, Amanda R Burmeister, Matthew Sims, Andrew Pospisilik, Patrik Brundin, Stewart F Graham, Lena Brundin, bioRxiv pre-print 2022, DOI:,

Posted in: Medical Research News | Medical Condition News | Disease/Infection News

Tags: Adenine, Apoptosis, Blood, Brain, Calcium, Cell, Cell Adhesion, Cell Migration, Central Nervous System, Chromatography, Coronavirus, Coronavirus Disease COVID-19, covid-19, Cytokine, Cytokines, Diagnostic, Endothelial cell, Enzyme, immunity, Inflammation, Interferon, Interferon-gamma, Interleukin, Interleukin-6, Intracellular, Liquid Chromatography, Metabolism, Metabolite, Metabolites, Molecule, Monocyte, Necrosis, Nervous System, Oxygen, Protein, Receptor, Respiratory, SARS, SARS-CoV-2, Severe Acute Respiratory, Severe Acute Respiratory Syndrome, Spectrometer, Syndrome, T-Cell, Tryptophan, Tumor, Tumor Necrosis Factor, Vascular

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Neha Mathur

Neha is a digital marketing professional based in Gurugram, India. She has a Master’s degree from the University of Rajasthan with a specialization in Biotechnology in 2008. She has experience in pre-clinical research as part of her research project in The Department of Toxicology at the prestigious Central Drug Research Institute (CDRI), Lucknow, India. She also holds a certification in C++ programming.

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