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Does long COVID brain fog start in the gut?

AYESHA RASCOE, HOST:

Brain fog, memory loss, fatigue - these are hallmarks of long COVID. What causes long COVID? NPR's Will Stone reports that scientists are now eyeing an intriguing explanation.

WILL STONE, BYLINE: The first clue emerged when researchers scoured the blood of long COVID patients. They saw having low levels of the chemical serotonin helped predict whether someone had persistent symptoms. Next, they had to figure out why. Maayan Levy, one of the study's authors at the University of Pennsylvania, says this brought them to the gut.

MAAYAN LEVY: What is interesting is that 90% of the serotonin in the body is actually made in the gut.

STONE: Their hunch was this lack of serotonin could be a consequence of what's known as viral persistence. It's a major line of research in long COVID. Multiple studies have found evidence of an ongoing viral infection. So, Levy says, they checked for genetic material in their own study participants.

LEVY: About 30% of the patients, we could find viral RNA in their gastrointestinal tract. We took this, and we tried to model it in mice.

STONE: There they focused on inflammation that was driven by Type I interferon. Christoph Thaiss, also on the Penn team, says this inflammatory response messed with the body's ability to absorb the amino acid tryptophan.

CHRISTOPH THAISS: And it's actually the direct precursor to the production of serotonin in the gut. So if there's less tryptophan, there's less serotonin production.

STONE: This immune response also led to clotting. Thaiss says that ends up reducing the amount of serotonin available in the bloodstream. And here the story moves to the vagus nerve, which connects to the gut and other organs.

THAISS: The vagus nerve is really interesting because it's essentially the brain's monitoring system of the body.

STONE: They found this depletion of serotonin affected the communication between the vagus nerve and the brain, leading to neurocognitive symptoms. One limitation of the study is that scientists don't have a good mouse model of long COVID. But Thaiss says what's promising is they could reverse these symptoms.

THAISS: We can make the animals remember perfectly again by just reactivating their vagus nerve or by restoring their serotonin signaling.

STONE: The next step, Levy says, is to pursue a clinical trial in humans. In their study, they gave the mice a generic form of Prozac, a class of medication known as an SSRI. The findings have caught the attention of other researchers, including Dr. Michelle Monje, a professor of neurology at Stanford.

MICHELLE MONJE: I thought it was a really elegant and very important paper.

STONE: She says it drives home a principle that probably underlies many aspects of long COVID.

MONJE: There are complex ways that immune challenges outside of the brain can profoundly affect nervous system function.

STONE: And she doesn't expect there's just one chain of events behind these symptoms.

MONJE: It's not the whole puzzle. It's, you know, not meant to be the whole puzzle.

STONE: The tricky thing with long COVID research in general is that it's not just one disorder. Dr. Saurabh Mehandru at Mount Sinai in New York says it remains to be seen which patients these findings may apply to.

SAURABH MEHANDRU: It's novel, exciting data. I would consider this as important but initial findings which have to be further studied.

STONE: Plus, he says, there are still big questions about what exactly is happening in the gut.

MEHANDRU: There appears to be viral RNA in some individuals. There appears to be viral protein in some individuals. But we've not been able to grow out virus from the intestine.

STONE: But he says this new research is the kind of careful work that needs to be done to understand long COVID.

Will Stone, NPR News. Transcript provided by NPR, Copyright NPR.

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