Low serotonin levels observed in long COVID and other viral infections

In a recent study published in Cell, researchers identify a pathophysiological mechanism linking serotonin reduction to the multifaceted etiology of post-acute sequelae of the coronavirus disease 2019 (COVID-19) (PASC).

Study: Serotonin reduction in post-acute sequelae of viral infection. Image Credit: Vitalii Vodolazskyi / Shutterstock.com

Background 

Post-viral syndromes, including “long COVID” or PASC, persist long after the initial disease and are often associated with symptoms like fatigue, cognitive impairments, and serotonin deficiency. The exact molecular causes of these conditions remain elusive; however, some proposed theories include unresolved viral reservoirs, chronic inflammation, auto-antibodies, tissue damage from lingering antiviral reactions, platelet issues, and autonomic system dysfunction.

Further research is crucial to delineate whether the observed serotonin reduction mechanisms operate collectively or in specific patient subsets. This information would enhance the current understanding of post-viral syndromes, particularly long COVID, and guide targeted therapeutic approaches.

About the study 

Maintained under consistent conditions, sex-matched five to 12-week-old mice underwent several experiments, including behavioral tests and brain analyses.

One experiment was focused on tryptophan metabolism, during which fasting mice received labeled L-tryptophan. All samples obtained from these mice were analyzed through process and gas chromatography-mass spectrometry (GC-MS). Mice were also subjected to various treatments, including 5- Hydroxytryptophan (5-HTP) and fluoxetine. 

Plasma from acute and recovered COVID-19 and PASC patients were also analyzed. Tissue and stool samples were processed for ribonucleic acid (RNA) extraction and viral quantification.

Advanced techniques including fluorescence-activated cell sorting (FACS) and neural imaging were utilized alongside detailed immunofluorescence studies. Metabolomics approaches were also used to assess amino acid levels.

Study findings 

Upon the analysis of symptoms in 1,540 patients using advanced data analytics, eight PASC subtypes were identified. Targeted metabolomics revealed distinct metabolite profiles in long COVID patients as compared to those recovering without lingering symptoms.

Serotonin depletion was observed in acute and long COVID patients, which has the potential to be used as a biomarker of future long-term symptoms. Serotonin reduction was also observed after recovery from other viral infections.

In mice, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and other viruses led to reduced serotonin levels that were maintained with ongoing viral presence. In fact, these low serotonin levels persisted when mice were exposed to the synthetic viral replication compound polyinosinic:polycytidylic acid (poly(I:C)), thus indicating that persistent inflammation is likely a key factor contributing to these low serotonin levels.

Reduced serotonin levels were related to heightened type I interferon (IFN) signaling, which is often present during viral responses. Blocking this pathway or specific viral RNA sensing components prevented serotonin reduction, thus confirming the central role of this immune response.

Notably, reduced plasma tryptophan levels were observed in both COVID-19 patients and mice. Tryptophan derivative kynurenine was dismissed as a mediator due to its transient nature in acute phases.

This led the researchers to investigate intestinal amino acid uptake, with poly(I:C) significantly modifying intestinal gene expression related to nutrient metabolism and amino acid absorption, rather than serotonin synthesis. Thus, disrupted amino acid transport is likely a key factor in serotonin reduction during viral inflammation.

Further exploration in mice and intestinal organoids demonstrated that poly(I:C) influenced essential tryptophan absorption genes; however, this activity was inhibited by toll-like receptor 3 (TLR3) deletion. The nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) transcription factor, interferon receptor, and signal transducer and activator of transcription 1 (STAT1) were crucial in these transcriptional changes. Analysis of post-viral infection revealed consistent gene downregulation and SARS-CoV-2 RNA in the gastrointestinal tracts, which corroborates existing evidence linking viral remnants to prolonged symptoms.

Examining broader impacts of compromised amino acid uptake during viral inflammation, reduced plasma amino acid levels and altered tryptophan absorption were observed in poly(I:C)-treated mice, similar to angiotensin-converting enzyme 2 (ACE2)-deficient subjects. However, tryptophan supplements increased serotonin levels during viral inflammation, thus confirming that it disrupts intestinal tryptophan uptake and leads to reduced systemic serotonin levels.

Viral inflammation was also found to affect serotonin storage/function. More specifically, acute vesicular stomatitis virus (VSV), chronic lymphocytic choriomeningitis virus (LCMV), and poly(I:C) treatments reduced lowered platelet counts and circulating serotonin, both of which were attributed to TLR3-IFN-STAT1 signaling. Increased megakaryocytes, heightened platelet activation/aggregation, and intensified monoamine oxidase (MAO)-mediated serotonin turnover were also observed during viral inflammation, despite the use of serotonin degradation inhibitors.

The role of serotonin disruption in the cognitive deficits observed in PASC was also assessed, as peripheral serotonin has a crucial role in cognitive functions through sensory neurons, particularly the vagus nerve. Normalizing serotonin levels or stimulating sensory neurons restored cognitive functions, thus illustrating the intricate brain-body communication in the aftermath of viral illnesses.