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What causes long Covid? Penn Medicine study solves the mystery

A study from the Perelman School of Medicine at the University of Pennsylvania has brought to light new information regarding long COVID, a condition that leaves patients with lingering symptoms such as brain fog, fatigue, and memory loss after recovering from a COVID-19 infection. 

This research, published in the journal Cell, reveals that a decrease in circulating levels of the neurotransmitter serotonin might be a key factor contributing to these prolonged symptoms.

According to the CDC, almost 20% of American adults who were infected with COVID-19 report symptoms consistent with long COVID. 

Focus of the study 

Symptoms commonly reported include brain fog, difficulty focusing, memory lapses, general fatigue, and headaches. The exact mechanisms behind long COVID remain largely unknown, and effective treatments are yet to be identified.

“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,” said study senior author Dr. Maayan Levy. 

“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.”

In collaboration with various departments, the research team studied the impact of long COVID on blood and stool samples from clinical studies and small animal models.

Key findings 

A subset of long COVID patients still had traces of the SARS-CoV-2 virus in their stool samples months after the acute phase of the infection.

The lingering virus, known as a “viral reservoir,” prompts the immune system to produce interferons, proteins that combat the virus. This results in inflammation that diminishes the absorption of the amino acid tryptophan in the GI tract.

Tryptophan plays a crucial role as it’s a precursor for neurotransmitters, including serotonin. This neurotransmitter is mainly produced in the GI tract and mediates various functions like memory, sleep, digestion, and wound healing. 

Furthermore, serotonin regulates the vagus nerve, which bridges the communication between the body and the brain. The study found that the depletion of serotonin due to diminished tryptophan absorption can lead to disrupted vagus nerve signaling, resulting in symptoms consistent with long COVID.

Potential treatments 

The research further examined the potential treatment avenues for long COVID. “Clinicians treating patients with long COVID have been relying on personal reports from those patients to determine if their symptoms are improving,” explained co-senior author Dr. Sara Cherry.

“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.”

The team tested if replenishing tryptophan or serotonin could alleviate long COVID symptoms. In small animal models, they found that treatment with serotonin precursors or selective serotonin reuptake inhibitors (SSRIs) restored serotonin levels and reversed memory impairment.

“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.

Study implications 

The research suggests that further exploration into how viral infections influence tryptophan absorption could unlock more answers, especially since tryptophan is integral to other processes, such as the production of niacin and melatonin.

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

“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.”

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