Long Covid
Thaiss and colleagues found that ongoing inflammation in the gut, which they link to a persistent reservoir of the virus, sabotages circulating levels of the neurotransmitter in multiple ways, including through blood clotting abnormalities. Picture used for illustrative purposes only. Image Credit: AP

Covid may trigger complex biological reactions from the bowel to the brain, leading to persistent neurological symptoms in some people, according to a study that points the way toward a treatment.

Viral vestiges in the gastrointestinal tracts of a subset of long-Covid patients may drive chronic inflammation that interferes with a key chemical messenger involved in nerve activity, brain function and memory, researchers at the University of Pennsylvania reported Monday in the journal Cell.

The findings provide an explanation for poor concentration, memory problems and other neurocognitive symptoms in long Covid, they said. Importantly, their experiments identified Prozac and other drugs that boost levels of the chemical messenger - serotonin - as promising targets for future study.

More than 200 symptoms have been associated with long Covid, an umbrella term applied to the often debilitating health problems estimated to afflict 10% or more of people who have had COVID-19. The new research suggests some hallmark symptoms "may converge on common pathways," said co-author Christoph Thaiss, an assistant professor of microbiology at the Penn Institute for Immunology in Philadelphia.

Further research may determine how many long Covid sufferers are affected by this cascade of reactions and uncover additional potential therapies, he said. The implications of the study may also extend to other post-viral syndromes.

While serotonin is most widely associated with mood and mental health, the researchers had a different focus as they sought to unravel drivers of long Covid. Thaiss and colleagues found that ongoing inflammation in the gut, which they link to a persistent reservoir of the virus, sabotages circulating levels of the neurotransmitter in multiple ways, including through blood clotting abnormalities.

'Unifying framework'

"This is as close as I have seen to a unifying framework for long Covid," said Ziyad Al-Aly, director of the clinical epidemiology center at the Veterans Affairs St. Louis Health Care System in Missouri, whose research has led to important long Covid findings. "This is a very important advance in the field."

Cohort studies and lab experiments were used to interpret the cause of serotonin depletion and its downstream effects. The researchers focused on the molecule's activity on the vagus nerve, which innervates internal organs and is thought to stimulate neurons in the hippocampus, a brain region involved in learning, memory and cognition.

"The fact that we see serotonin being dysregulated in some individuals with long Covid can potentially explain why there's such a broad spectrum of symptoms," spanning brain fog and mood to problems sleeping and gastric upset, Thaiss said.

Low serotonin has been observed across several long-Covid studies, including patients with different but over-lapping symptoms, he said.

"The sicker the person is in terms of the number of symptoms they present with, the lower their serotonin," Thaiss said.

No silver bullet

A single biological pathway isn't likely to explain all long Covid cases, said Akiko Iwasaki, a professor of immunobiology at the Yale School of Medicine in New Haven, who also studies the condition. Other proposed drivers of neurologic symptoms include persistent neuroinflammation, possibly from a deficient immune response that allows the virus to linger in the brain.

"But still, it's a very important mechanism that deserves a lot of attention," Iwasaki said in an interview. Serotonin might help gauge the effects of treatments in studies, including a trial of Pfizer Inc.'s antiviral Paxlovid that she is working on.

"If serotonin is really the key marker, we definitely should be including that," Iwasaki said.

Not all scientists are convinced that low serotonin is playing a key role or acting in isolation in long Covid. Also many sufferers have taken the medicines without benefit.

Avindra Nath, clinical director of the National Institute of Neurological Disorders and Stroke in Bethesda, Maryland, praised the study for its extensive body of research, but said that except in some rare disorders or micronutrient and vitamin deficiencies, it's unlikely alterations in levels of a single molecule can be blamed for starting a disease process, especially one triggered by an infection.

Targeted studies

Strategies aimed at increasing serotonin levels or targeting its signaling should be examined in randomized, controlled trials of patients most likely to benefit from the approach, said Liam O'Mahony, a professor of immunology at University College Cork, whose own research found serotonin depletion in long Covid patients.

Prozac, Luvox and other antidepressants that work by increasing serotonin in the brain have been studied during the pandemic to both prevent and treat Covid due to their potential to disrupt the biological processes of infection, but results have been mixed. People taking them when they caught Covid had about a 25% lower risk of developing long Covid, scientists at the National Institutes of Health found in a retrospective study released in November before peer-review and publication.

"It may be a combination of therapies that ends up being the most effective for patients and not one drug in isolation," said study co-author Benjamin Abramoff, director of Penn Medicine's Post-Covid Assessment and Recovery Clinic.