Study traces long COVID symptoms to SARS-CoV-2 infection in gut
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Key takeaways:
- Viral persistence and low depleted serotonin levels may be the cause of some long COVID symptoms.
- SSRIs may effectively treat some patients with long COVID.
A new study links some neurocognitive symptoms of long COVID to persistent SARS-CoV-2 infection in the gut, which triggers a series of reactions that lowers serotonin levels.
The finding suggests that selective serotonin reuptake inhibitors (SSRIs) may reduce a patient’s risk for post-COVID-19 conditions.
According to the CDC, nearly one in five adults in the United States with a previous case of COVID-19 experience symptoms of long COVID.
The long COVID symptoms brain fog, fatigue and memory loss appear to be linked to reduced circulating levels of serotonin, Andrea C. Wong, PhD, and colleagues at the University of Pennsylvania Perelman School of Medicine, and colleagues wrote in the study, published this week in Cell.
“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,” Benjamin Abramoff, MD, MS, director of the Post-COVID Assessment and Recovery Clinic at Penn Medicine, said in a press release.
Wong, Abramoff and colleagues followed a cohort of 1,540 patients with long COVID at Penn Medicine and analyzed their symptoms using questionnaires and chart reviews. The review showed that in the post-acute state of infection, serotonin levels were predictive of either full recovery or long COVID.
They verified the finding in a comparison with patient cohorts treated as part of other published studies. The researchers concluded that serotonin levels are diminished during severe COVID-19 and remain low in severe cases of long COVID, according to the study.
To investigate the mechanisms of SARS-CoV-2 infection leading to reduced serotonin, the researchers infected mice with the original SARS-CoV-2 virus and observed a reduction in serotonin. Additionally, they found that serotonin levels returned to baseline after SARS-CoV-2 clearance, suggesting that long COVID may be a consequence of inflammation from persistent infection.
The researchers determined that some patients with long COVID still had traces of SARS-CoV-2 in their stool months after their acute infection, suggesting that some parts of the virus persist in the gut.
They investigated whether serotonin production in the gastrointestinal tract — “where it is synthesized from dietary tryptophan in enterochromaffin cells” — may be reduced during SARS-CoV-2 infection and found that patients with acute COVID-19 showed reduced plasma tryptophan levels. This was also seen in published data from other similar human cohorts.
Using mice, the researchers confirmed the effects of serotonin depletion on vagus nerve signaling and memory function common among patients with long COVID. They determined that although serotonin levels in the brain were not affected by viral inflammation, peripheral reduction of serotonin was behind cognitive symptoms of long COVID, according to the study.
In their conclusion, Wong and colleagues noted that although “no systemic exploration” of SSRIs for long COVID treatment have been conducted, the study’s findings suggest that SSRI drugs should be assessed as a method for regulating serotonin in patients long COVID.
“Many aspects of the basic biology underlying long COVID have remained unclear,” Maayan Levy, PhD, assistant professor of microbiology at Penn Medicine and an author of the study, said in the release. “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 actual treatments.”
The NIH in July announced its RECOVER initiative, which included the launch of four phase 2 trials testing treatments for long COVID, as well as plans to trial another seven treatments.
The initiative has already produced a symptom-based scoring system that experts said may help diagnose long COVID based on a set of 12 symptoms.
References:
- Wong AC, et al. Cell J 2023;doi:10.1016/j.cell.2023.09.013.
- CDC. National Center for Health Statistics: Nearly one in five American adults who have had COVID-19 still have long COVID. https://www.cdc.gov/nchs/pressroom/nchs_press_releases/2022/20220622.htm. Last reviewed June 22, 2022. Accessed Oct. 18, 2023.
- Viral persistence and serotonin reduction can cause long COVID symptoms, Penn Medicine research finds. https://www.pennmedicine.org/news/news-releases/2023/october/penn-study-finds-serotonin-reduction-causes-long-covid-symptoms. Published Oct. 16, 2023. Accessed Oct. 18, 2023.
Perspective
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This is as close as I have seen to a coherent and unifying framework of a mechanistic pathway that explains neurocognitive impairment in people with long COVID. The study links viral infection in the gut to impaired intestinal absorption of a serotonin precursor and hypercoagulation, leading to serotonin deficiency, which can then result in dysfunction of vagus nerve signaling and impaired cognition — a clear and compelling chain reaction.
Beyond mechanistic insights, the study also has potential therapeutic promise because we have several therapeutics that increase serotonin levels that are already on the market. These could be tested in randomized trials to assess efficacy in improving cognitive performance in people with long COVID.
It is important to also highlight that long COVID is a complex, nonmonolithic multisystemic disease that can affect nearly every organ system. There are likely many other mechanisms at play that are responsible for the wide-ranging phenotype of long COVID.
This paper, nevertheless, is meritorious and a welcome addition to the robust and rapidly growing literature documenting objective biologic abnormalities in people with long COVID vs. controls.
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