SARS-CoV-2 persistence, low serotonin may cause long-COVID symptoms

Woman with memory loss

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In a study published yesterday in Cell, University of Pennsylvania researchers suggest that a reduction in the neurotransmitter serotonin caused by SARS-CoV-2 persistence in the gut leads to the neurocognitive symptoms of long COVID.

The authors, who conducted a large-scale study using blood and stool samples from clinical studies and mouse models, said their findings could apply to other postviral syndromes.

Restoring serotonin reversed memory loss in mice

A subset of long-COVID patients had components of SARS-CoV-2 in their stool samples months after infection. The remaining virus, or viral reservoir, provokes the immune system to release proteins that fight the virus (viral RNA-induced type 1 interferons). The interferons cause inflammation that reduces intestinal absorption of the amino acid tryptophan and leads to abnormal blood clotting.

Tryptophan is a building block of neurotransmitters such as serotonin, a chemical messenger between nerve cells in the brain and body mainly generated in the gastrointestinal tract. Serotonin helps regulate memory, sleep, digestion, wound healing, and the vagus nerve, a neuronal system that helps the body and the brain communicate.

When persistent inflammation impairs the absorption of tryptophan, circulating serotonin levels plummet. This, in turn, disrupts vagus nerve signaling, which may cause neurocognitive long-COVID symptoms such as memory loss.

Replenishing tryptophan or serotonin (through treatment with serotonin precursors or selective serotonin reuptake inhibitor [SSRI] antidepressants) in patients with neurocognitive long-COVID symptoms reversed memory loss in mice.

Serotonin may be long-COVID biomarker

Physicians treating patients who have long COVID have had to rely on self-reports to determine if their symptoms are improving, the authors noted.

"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," co-senior author Sara Cherry, PhD, said in University of Pennsylvania press release.

Co-senior author Benjamin Abramoff, MD, said that previous studies had suggested that SSRIs could be an effective way to prevent long COVID. "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," he said.

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.

Revealing how viral infection impairs the absorption of tryptophan represents the opportunity for future research into the other processes affected by tryptophan, a building block for other key metabolites such as niacin, which helps the body make energy from food, and the sleep hormone melatonin, the authors said.

They cautioned that their study was based on a small number of patients. "Similarly, we have not demonstrated a direct connection between intestinal viral persistence and chronically elevated levels of type I interferons in humans, which would require collecting a large number of intestinal biopsies from Long COVID patients," they concluded. "Our results thus call for the large-scale investigation of the causal connection between the presence of a viral reservoir in the gastrointestinal tract, sustained inflammatory responses, and manifestations of Long COVID."

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