Tag: Bergquist

Central and peripheral kynurenine pathway metabolites in COVID-19: Implications for neurological and immunological responses

Abstract:

Long-term symptoms such as pain, fatigue, and cognitive impairments are commonly observed in individuals affected by coronavirus disease 2019 (COVID-19). Metabolites of the kynurenine pathway have been proposed to account for cognitive impairment in COVID-19 patients.

Here, cerebrospinal fluid (CSF) and plasma levels of kynurenine pathway metabolites in 53 COVID-19 patients and 12 non-inflammatory neurological disease controls in Sweden were measured with an ultra-performance liquid chromatography-tandem mass spectrometry system (UPLC-MS/MS) and correlated with immunological markers and neurological markers. Single cell transcriptomic data from a previous study of 130 COVID-19 patients was used to investigate the expression of key genes in the kynurenine pathway.

The present study reveals that the neuroactive kynurenine pathway metabolites quinolinic acid (QUIN) and kynurenic acid (KYNA) are increased in CSF in patients with acute COVID-19. In addition, CSF levels of kynurenine, ratio of kynurenine/tryptophan (rKT) and QUIN correlate with neurodegenerative markers.

Furthermore, tryptophan is significantly decreased in plasma but not in the CSF. In addition, the kynurenine pathway is strongly activated in the plasma and correlates with the peripheral immunological marker neopterin. Single-cell transcriptomics revealed upregulated gene expressions of the rate-limiting enzyme indoleamine 2,3- dioxygenase1 (IDO1) in CD14+ and CD16+ monocytes that correlated with type II-interferon response exclusively in COVID-19 patients.

In summary, our study confirms significant activation of the peripheral kynurenine pathway in patients with acute COVID-19 and, notably, this is the first study to identify elevated levels of kynurenine metabolites in the central nervous system associated with the disease. Our findings suggest that peripheral inflammation, potentially linked to overexpression of IDO1 in monocytes, activates the kynurenine pathway. Increased plasma kynurenine, crossing the blood-brain barrier, serves as a source for elevated brain KYNA and neurotoxic QUIN.

We conclude that blocking peripheral-to-central kynurenine transport could be a promising strategy to protect against neurotoxic effects of QUIN in COVID-19 patients.

Source: Li X, Edén A, Malwade S, Cunningham JL, Bergquist J, Weidenfors JA, Sellgren CM, Engberg G, Piehl F, Gisslen M, Kumlien E, Virhammar J, Orhan F, Rostami E, Schwieler L, Erhardt S. Central and peripheral kynurenine pathway metabolites in COVID-19: Implications for neurological and immunological responses. Brain Behav Immun. 2024 Nov 28:S0889-1591(24)00720-7. doi: 10.1016/j.bbi.2024.11.031. Epub ahead of print. PMID: 39615604. https://www.sciencedirect.com/science/article/abs/pii/S0889159124007207

Untargeted Metabolomics and Quantitative Analysis of Tryptophan Metabolites in Myalgic Encephalomyelitis Patients and Healthy Volunteers: A Comparative Study Using High-Resolution Mass Spectrometry

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic, complex illness characterized by severe and often disabling physical and mental fatigue. So far, scientists have not been able to fully pinpoint the biological cause of the illness and yet it affects millions of people worldwide.

To gain a better understanding of ME/CFS, we compared the metabolic networks in the plasma of 38 ME/CFS patients to those of 24 healthy control participants. This involved an untargeted metabolomics approach in addition to the measurement of targeted substances including tryptophan and its metabolites, as well as tyrosine, phenylalanine, B vitamins, and hypoxanthine using liquid chromatography coupled to mass spectrometry.

mass

Source: Abujrais S, Vallianatou T, Bergquist J. Untargeted Metabolomics and Quantitative Analysis of Tryptophan Metabolites in Myalgic Encephalomyelitis Patients and Healthy Volunteers: A Comparative Study Using High-Resolution Mass Spectrometry. ACS Chem Neurosci. 2024 Sep 20. doi: 10.1021/acschemneuro.4c00444. Epub ahead of print. PMID: 39302151. https://pubs.acs.org/doi/10.1021/acschemneuro.4c00444 (Full text)

Myalgic encephalomyelitis/chronic fatigue syndrome and fibromyalgia are indistinguishable by their cerebrospinal fluid proteomes

Abstract:

Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and fibromyalgia have overlapping neurologic symptoms particularly disabling fatigue. This has given rise to the question whether they are distinct central nervous system (CNS) entities or is one an extension of the other.

Material and methods: To investigate this, we used unbiased quantitative mass spectrometry-based proteomics to examine the most proximal fluid to the brain, cerebrospinal fluid (CSF). This was to ascertain if the proteome profile of one was the same or different from the other. We examined two separate groups of ME/CFS, one with (n = 15) and one without (n = 15) fibromyalgia.

Results: We quantified a total of 2083 proteins using immunoaffinity depletion, tandem mass tag isobaric labelling and offline two-dimensional liquid chromatography coupled to tandem mass spectrometry, including 1789 that were quantified in all the CSF samples. ANOVA analysis did not yield any proteins with an adjusted p value <.05.

Conclusion: This supports the notion that ME/CFS and fibromyalgia as currently defined are not distinct entities.

Key message: ME/CFS and fibromyalgia as currently defined are not distinct entities. Unbiased quantitative mass spectrometry-based proteomics can be used to discover cerebrospinal fluid proteins that are biomarkers for a condition such as we are studying.

Source: Schutzer SE, Liu T, Tsai CF, Petyuk VA, Schepmoes AA, Wang YT, Weitz KK, Bergquist J, Smith RD, Natelson BH. Myalgic encephalomyelitis/chronic fatigue syndrome and fibromyalgia are indistinguishable by their cerebrospinal fluid proteomes. Ann Med. 2023 Dec;55(1):2208372. doi: 10.1080/07853890.2023.2208372. Epub 2023 Sep 18. PMID: 37722890. https://www.tandfonline.com/doi/full/10.1080/07853890.2023.2208372 (Full text)