{"doi":"10.1002/ctm2.1608","title":"From intestinal metabolites to the brain: Investigating the mysteries of Long COVID","abstract":"To date, more than 770 million individuals have been infected with SARS-CoV-2 worldwide.1 Postacute sequelae of COVID-19 (PASC), commonly called ‘Long COVID’, constitute a primary public health concern. Long COVID involves symptoms that emerge, persist, or relapse over more than 30 days after acute SARS-CoV-2 infection. The symptoms of PASC span a wide range of organs and are heterogeneous among patients. A recent study aimed at developing a comprehensive definition of PASC based on symptoms in a prospective cohort study involving 9764 patients.2 Given the intricacies of PASC, the underlying etiology remains poorly understood, posing an urgent global health challenge that necessitates resolution. We have recently conducted a study that may shed new light on one of the possible biological causes of PASC.3 This study began with exploring metabolite profiles that are distinct in Long COVID patients. Among the most significantly depleted metabolites observed in acute and postacute patients, compared to recovered patients, was serotonin (5-hydroxytryptamine, 5-HT). Mouse models of viral infection and an intestinal organoids model were employed to elucidate the molecular mechanisms underlying this phenotype. We found that viral RNA triggered type I interferon (IFN) signalling, which in turn suppressed serotonin levels by affecting serotonin production, storage and degradation. Beyond establishing a possible association between 5-HT and PASC and elucidating the potential molecular mechanisms underlying this connection, our study further suggests that the decrease of peripheral serotonin can lead to impaired hippocampal responses and memory by impeding the activity of the vagus nerve. The findings of this investigation may contribute to our understanding of the mechanisms involved in PASC and suggest new predictive biomarkers and potential therapeutic targets for intervention. The reduction of serotonin in plasma was identified through a plasma metabolomics analysis conducted on 58 PASC patients, compared to 30 individuals with symptom-free recovery and 60 individuals with acute COVID-19. Consistent with these findings in human cohorts, a reduction in plasma serotonin was observed in the SARS-CoV-2-infected K18-ACE2 mouse model, which expresses human ACE2. By using synthetic double-stranded RNA polyinosinic:polycytidylic acid (poly(I:C)) or viral infection, this study additionally revealed that the reduction in serotonin was mediated by the viral-induced type I interferon response in a TLR3- and STAT1-dependent manner. We next investigated the mechanisms through which viral-induced inflammation leads to a reduction in peripheral serotonin levels (Figure 1). Notably, tryptophan, the precursor of serotonin that is used as a substrate for serotonin synthesis by enterochromaffin cells in the gastrointestinal tract, was also diminished in PASC patients. Using a mouse model, organoids and intestinal epithelial cells, we uncovered that viral-driven inflammation inhibits tryptophan absorption by suppressing the epithelial expression of amino acid uptake genes, such as (Slc6a19), which encodes for the neutral amino acid transporter B0AT1, and its chaperone ACE2. In addition to suppression of serotonin production, we observed that viral inflammation also impaired serotonin storage and turnover. Following synthesis in enterochromaffin cells, platelets store and transport peripheral serotonin and MAO enzymes rapidly turn over free serotonin. Notably, platelet counts were decreased following viral infection or poly(I:C) treatment, suggesting that the carrying capacity for serotonin in the systemic circulation was diminished. This reduction could not be rescued by tryptophan supplementation, indicating that the impaired storage was independent of reduced amino acid uptake. Lastly, we found that the transcription levels of Maoa and 5-hydroxyindoleacetic acid (5-HIAA), a serotonin degradation product, increased in virally infected or poly (I:C)-treat","journal":"Clinical and Translational Medicine","year":2024,"id":483143,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9623,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1014313,"name":"Ashwarya S. Devason","orcid":"0009-0007-4444-3929","position":1,"is_corresponding":false},{"id":458332,"name":"Maayan Levy","orcid":"0000-0002-7149-9422","position":2,"is_corresponding":false},{"id":1324055,"name":"Shan Liu","orcid":"0000-0002-8159-2778","position":0,"is_corresponding":true}],"reference_count":11,"raw_metadata":null,"created_at":"2026-07-19T02:07:22.248464Z","pmid":"38468492","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}