Metabolic rewiring and serotonin depletion in patients with postacute sequelae of COVID-19, 2022, Sadlier et al

Discussion in 'Long Covid research' started by Hutan, Oct 17, 2023.

  1. Hutan

    Hutan Moderator Staff Member

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    https://onlinelibrary.wiley.com/doi/10.1111/all.15253

    Letter, open access
    Cork study

    Serum was obtained from PASC patients (n = 20) at two time points (4–6 months following infection (T1) and 6–9 months following infection (T2)). All patients had been hospitalized for PCR-proven SARS-CoV-2 infection (median in-patient stay of 6.5 days, range 2 days to 25 days) during the first wave of the pandemic in Ireland (March–May 2020). The most common symptoms at follow-up clinics were fatigue and/or dyspnea. Demographic and clinical details for this cohort are summarized in Table S1. Sera from healthy controls (n = 20), collected prior to the pandemic, were assayed in parallel. There were no statistically significant differences in age, gender, or BMI between the PASC patients and healthy volunteers, while PASC patients were more likely to have pre-existing conditions such as hypertension or a respiratory disorder (i.e., asthma or COPD), compared to healthy volunteers (Table S1).
    ...
    Of the 1086 metabolites quantified, levels of 253 metabolites or 266 metabolites were significantly different between patients and controls at T1 or T2, respectively (Tables S2 and S3).
    ...
    Levels of multiple metabolites with immunomodulatory properties were elevated in PASC patients (examples include the sphingolipid sphingosine 1-phosphate (S1P) and the eicosanoid 12-HETE, Figure 2). In addition, significant disruption of central energy, fatty acid, and carbon metabolism was evident (examples include elevated mannose, glutamate, and succinate serum levels with reduced levels of the ketone body acetoacetate in PASC patients, Figure 2).

    Of particular interest was the dysregulated metabolism of tryptophan, characterized by a decrease in serotonin production coupled with the accumulation of quinolinate in PASC patients (Figure 2). We have previously shown that tryptophan metabolism was heavily disrupted in COVID-19 patients during the acute phase of the infection, especially in those with the poorest outcomes.4 Quinolinate is an excitotoxin that hinders neuronal function through multiple mechanisms including acting as an NMDA receptor agonist, and it indirectly drives accumulation of glutamate. In contrast, serotonin has essential modulatory effects on mood, anxiety, sleep, cognition, and memory. Recently, selective serotonin reuptake inhibitors (SSRIs) have been shown to have favorable results with respect to symptom resolution and hospitalizations in patients with COVID-19.5, 6 Perhaps in situations where available serotonin levels are decreased (e.g., during and following SARS-CoV-2 infection), SSRIs may exert beneficial effects by helping to maintain adequate levels of serotonin signaling. The use of SSRIs in PASC patients should be further explored.

    Our study contributes additional insights into underlying PASC mechanisms as we showed that infection-induced metabolic reprogramming and compensatory responses were long-lasting and did not substantially improve over the time course of the investigation (i.e., up to 9 months following the initial infection). These study findings identify novel mechanistic and diagnostic markers and potential therapeutic targets in PASC patients. These biomarkers should be included as integral components of future randomized controlled trials in order to better understand the pathobiology of SARS-CoV-2 infection and associated long-term sequelae.
     
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  2. Hutan

    Hutan Moderator Staff Member

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    Screen Shot 2023-10-17 at 11.58.33 am.png
    Here's the chart of serotonin. Controls on the left in blue, then PASC at T1 and T2.

    I find this less than convincing as evidence for a serotonin deficiency in PASC. I think the median values for controls and PASC probably aren't very different. There are some individuals with extremely low serotonin levels which is a bit odd, especially as it seems to have persisted across the two collection times, but, given the relatively small cohort size, I don't think this necessarily means that PASC is characterised by low serotonin.
     
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  3. SNT Gatchaman

    SNT Gatchaman Senior Member (Voting Rights)

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