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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.

Journal reference:

Wong, A. C., Devason, A. S., Umana, I. C., et al. (2023). Serotonin reduction in post-acute sequelae of viral infection. Cell. Doi:10.1016/j.Cell.2023.09.013

Your Guide To Nicotine Stomatitis, Or "Smoker's Palate"

This symptom of smoking is painless but can lead to discoloration and scar tissue on the top of your mouth.

Thanks to decades of research, we know that smoking and tobacco use can seriously affect our health.

While harm to your lung function may be the first risk that comes to mind, the reality is that nicotine and other chemicals released from smoking and tobacco use can affect virtually every major system in your body. Consistent tobacco use can also accelerate aging, leading to premature wrinkles, a loss of skin elasticity, and yellowing of your skin and teeth.

Nicotine stomatitis, also known as smoker's palate or smoker's mouth, is another possible side effect of regular smoking.

Nicotine stomatitis is a known side effect of chronic smoking that was first documented in 1926. Originally linked with cigars and pipe tobacco, the condition is now also linked with e-cigarettes, or vaping. Even though it's in the name of the condition, nicotine isn't to blame.

Instead, the intense heat of the smoke or vapor from cigarettes, cigars, and pipes causes lesions to form on the roof, or palate, of your mouth. Nicotine stomatitis is often considered a form of heat- or chemical-related keratosis, which is a thickening of the skin.

While nicotine stomatitis won't directly cause cancer, chronic tobacco use, in general, can increase your chance of developing cancer.

Smoker's palate is not a common side effect of smoking — but there is always a possibility that it will develop if you smoke heavily.

Nicotine stomatitis is usually a painless condition that doesn't cause irritation. Because of this, many people don't know they have it until it's discovered in a dental checkup or routine physical exam at the doctor's office.

In most cases, any symptoms related to smoker's palate are limited to physical changes. But if you wear dentures, the heat won't affect covered areas of your mouth.

What does nicotine stomatitis look like?

The primary symptom of nicotine stomatitis only involves visual changes. Repeated exposure to heated smoke or vapors from smoking will change the physical appearance of the palate so that it looks white or gray. These differences are only present in areas of your mouth with direct exposure to heat from tobacco products.

Share on PinterestNicotine stomatitis may appear as a reddened area with white fissures or dots.© Journal of Oral and Maxillofacial Pathology CC BY-NC-SA 3.0

Dental staining may be another symptom of nicotine stomatitis. But this also has close links with smoking in general, which can lead to dental problems if left unaddressed.

Typically, stopping smoking is the only treatment for nicotine stomatitis. Often, the lesions begin to heal once you stop smoking or using tobacco products.

This is even true for people who regularly use tobacco and may have had nicotine stomatitis for decades. Usually, sores will begin to heal within a few weeks of quitting smoking.

Trying to quit smoking alone can be difficult. Getting help is known to raise your chances of quitting for good. When you're ready, check out these organizations for more information:

Nicotine stomatitis is one of many ways tobacco use can affect your body. The heat from smoking or vaping can cause the roof of your mouth to turn white or gray with lesions and scar tissue.

Although smoker's palate is generally benign, the visual symptoms can resolve within weeks of quitting smoking.

Vitamins & Supplements Center

Considering taking a vitamin or supplement to treat Aphthous-Stomatitis? Below is a list of common natural remedies used to treat or reduce the symptoms of Aphthous-Stomatitis. Follow the links to read common uses, side effects, dosage details and read user reviews for the drugs listed below.

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