• Posted October 18, 2023

Serotonin May Play Big Role in Long COVID

New research has uncovered evidence that remnants of the COVID-19 virus may remain in some patients' guts for months, contributing to the lingering symptoms known as long COVID.

The remnants appear to trigger a drop in levels of the chemical serotonin, which may explain such symptoms as fatigue, brain fog and memory loss.

About 20% of people who have had COVID-19 infections have symptoms that last for months or even years, a condition called long COVID.

“Many aspects of the basic biology underlying long COVID have remained unclear. As a result, we are lacking effective tools for the diagnosis and treatment of the disease,” senior author Maayan Levy, an assistant professor of microbiology at the University of Pennsylvania's Perelman School of Medicine, said in a Penn news release.

“Our findings may not only help to untangle some of the mechanisms that contribute to long COVID, but also provide us with biomarkers that can help clinicians diagnose patients and objectively measure their response to individual treatments,” Levy explained.

For the study, the researchers evaluated the effects of long COVID in blood and stool samples from various clinical studies and in small animal models.

The investigators found that some patients with long COVID had traces of the SARS-CoV-2 virus in their stools months after their infection.

This remaining virus triggers the immune system to release proteins called interferons that fight the virus, according to the study.

The interferons then cause inflammation that reduces absorption of the amino acid tryptophan in the gastrointestinal (GI) tract.

Tryptophan is a building block for several neurotransmitters, including serotonin, which is primarily produced in the GI tract. Serotonin carries messages between nerve cells in the brain and throughout the body, and is key in regulating memory, sleep, digestion and wound healing.

Serotonin is also an important regulator of the vagus nerve, which plays an important role in communication between the body and the brain.

When persistent inflammation reduces tryptophan absorption, serotonin gets depleted, the researchers found.

This disrupts vagus signaling, which can cause several symptoms linked to long COVID, such as memory loss, the study authors said.

“Clinicians treating patients with long COVID have been relying on personal reports from those patients to determine if their symptoms are improving," said co-senior author Sara Cherry. She is a professor of pathology and laboratory medicine at the Penn Center for Precision Medicine.

"Now, our research shows that there are biomarkers we may be able to use to match patients to treatments or clinical trials that address the specific causes of their long COVID symptoms, and more effectively assess their progress,” Cherry added.

The researchers also investigated whether replenishing tryptophan or serotonin would help these long COVID patients.

In small animal models, they were able to restore serotonin levels through treatment with serotonin precursors or selective serotonin reuptake inhibitors (SSRIs), a common form of antidepressant.

“There has been some evidence to suggest that SSRIs could be effective in preventing long COVID, and our research now presents an opportunity for future studies to select specific patients for a trial who exhibit depleted serotonin, and to be able to measure response to treatment,” said co-senior author Dr. Benjamin Abramoff, director of Penn's Post-COVID Assessment and Recovery Clinic.

The researchers noted that there are opportunities for further study, including research on other processes influenced by tryptophan, including niacin and melatonin levels. They help turn food into energy and regulate circadian rhythms and sleep, respectively.

“Long COVID varies from patient to patient, and we don't fully understand what causes the differences in symptoms,” according to co-senior author Christoph Thaiss, an assistant professor of microbiology.

“Our study provides a unique opportunity for further research to determine how many individuals with long COVID are affected by the pathway linking viral persistence, serotonin deficiency, and dysfunction of the vagus nerve and to uncover additional targets for treatments across the different symptoms patients experience,” Thaiss added.

The study findings were published online Oct. 16 in Cell.

More information

The U.S. Centers for Disease Control and Prevention has more on long COVID.

SOURCE: Perelman School of Medicine at the University of Pennsylvania, news release, Oct. 16, 2023