Patients with long COVID can exhibit a reduction in circulating levels of the neurotransmitter serotonin, according to new research.

The study, led by researchers from the Perelman School of Medicine at the University of Pennsylvania and published in the journal Cell, sheds new light on the mechanisms of how persistent inflammation after contracting the SARS-CoV-2 virus can cause long-term neurological symptoms.

Long COVID has symptoms like brain fog, fatigue, or memory loss in the months or years following the infection. The mechanisms that cause long COVID have not been studied in depth.

"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,” said senior author, Maayan Levy, assistant professor of Microbiology at Penn Medicine.

The researchers determined that a subset of patients with long COVID had traces of the SARS-CoV-2 virus in their stool samples even months after acute COVID-19 infection, which suggests that components of the virus remain in the gut of some patients long after infection.

They found that this remaining virus, called a viral reservoir, triggers the immune system to release proteins that fight the virus, called interferons.

These interferons cause inflammation that reduces the 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 and carries messages between nerve cells in the brain and throughout the body.

It plays a key role in regulating memory, sleep, digestion, wound healing, and other functions that maintain homeostasis within the body.

Serotonin is also an important regulator of the vagus nerve, a system of neurons that mediate the communication between the body and the brain.

The researchers found that when tryptophan absorption is reduced by persistent viral inflammation, serotonin is depleted, leading to disrupted vagus nerve signalling, which in turn can cause several of the symptoms associated with long COVID, such as memory loss.

“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,” said co-senior author Sara Cherry.

The team demonstrated that serotonin levels could be restored, and memory impairment reversed, in small experimental models through treatment with serotonin precursors.

“Long COVID varies from patient to patient, and we don’t fully understand what causes the differences in symptoms,” said co-senior author, Christoph Thaiss.