Serotonin reduction in post-acute sequelae of viral infection, 2023, Wong, Cherry et al

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The convoluted role of serotonin in infection-associated chronic illness

Janna Moen, a neuroscience PhD who's currently working in Dr Iwasaki's lab, has just published a substack on the recent Cell serotonin paper.

Her summary:

• A recent paper by Wong et al (2023) found decreased circulating serotonin levels were associated with long COVID, and used mouse models to show that viral inflammation can cause this effect by interfering with intestinal absorption and platelet destruction. In mouse models, viral infection had downstream effects on the vagus nerve and impacted novel object recognition.
  
  
• Serotonin is synthesized from the amino acid tryptophan, which must be sourced from diet. However, tryptophan supplementation did not restore serotonin levels in virus-treated mice due to insufficient intestinal uptake.
  
  
• Tryptophan is available over the counter as a nutritional supplement but has no evidence of therapeutic benefit for depression or sleep. People with myalgic encephalomyelitis (ME) should be particularly cautious with tryptophan supplementation, as side effects can exacerbate symptoms.
  
  
• A theory by leading ME expert Dr. Ron Davis hypothesizes that common mutations in one of the genes involved in tryptophan metabolism, IDO2, could predispose individuals to develop ME. Loss of IDO2 function prevents the conversion of tryptophan to kynurenine when tryptophan concentrations are high, which could result in ME symptoms.
  
  
• Selective Serotonin Reuptake Inhibitors (SSRIs) are commonly prescribed for depression and anxiety disorders. These drugs increase the concentration of serotonin within the synaptic cleft in the nervous system by blocking the serotonin transporter (SERT).
  
  
• The majority of serotonin in the body is absorbed into circulation and taken up by platelets for storage via SERT. It doesn’t actually cross the blood-brain barrier and instead participates in platelet activation and aggregation. By blocking SERT, SSRIs prevent platelets from storing serotonin, which instead is degraded by monoamine oxidase.
  
  
• Interestingly, the ability of SSRIs to reduce circulating serotonin levels may be implicated in their therapeutic effect, as people who respond well to SSRIs can be distinguished from non-responders by the magnitude of circulating serotonin suppression. People with depression are more likely to have cardiovascular health problems, and SSRIs might protect against this.
  
  
• Despite serotonin’s known role in promoting platelet activation, Wong et al (2023) found that reduced serotonin levels also promoted platelet aggregation, an interesting distinction between major depression and viral infection.

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Welcome @RaviHVJ.

 

I contacted one of the authors regarding their interesting findings with questions I had, many of which were also asked in this forum. As such I thought it might be interesting if I provided some of the answers, to be precise my own interpretation of the answers, that I received.

The stool analysis they performed was on a relatively small subset of patients from the Penn cohort. These patients had their last known infection months to more than a year before the stool was collected. Overall, it seems that they didn’t analyse the stool data in more depth because the sample size is too small to say something meaningful.

They believe that one of the reasons why the viral RNA findings sometimes come back positive and sometimes negative is that PCR tests aren’t sufficiently sensitive, especially when it comes to people who have low a RNA load in the gut.

That is why they are planing to do a larger trial where they will also measure IFN. Regarding inconsistent findings of IFN, which don’t support their paper, they believe that the standard ELISA tests for IFN are not sensitive enough in PASC and as such they are planning to use the Simoa assay. This was news to me and seems interesting, even though I can't say anything about IFN tests not being sensitive enough.

Finally the brain serotonin levels in mice were normal and only the peripheral serotonin levels were reduced, so they aren’t expecting any difference in brain serotonin levels based on their results.

I still can’t say that I properly understand the reasoning to trial an SSRI but they are apparently still in the process of deciding which one to use since some might work better than others. They are also considering Vagal stimulation as a possible study arm.

 

Jessica Maya commented on NIH #3: Metabolism that in their study Plasma metabolomics reveals disrupted response and recovery following maximal exercise in myalgic encephalomyelitis/chronic fatigue syndrome (2023, JCI Insight) they didn't find any difference in serotonin between ME and HCs. This was said to be in supplementary materials but I couldn't see the graphic she had on screen, although serotonin was listed in the Excel spreadsheets.

 

See commentary in Long COVID-19 and Peripheral Serotonin: A Commentary and Reconsideration (2024, Journal of Inflammation Research)

 

See also No reduced serum serotonin levels in patients with post-acute sequelae of COVID-19 (2024, Infection)