ISTRY has been covering the advancements in knowledge around tryptophan metabolism and COVID-19 since our newsletter in 2021. We have provided ongoing updates in our Featured Article series (from August 2022 and June/July 2023) which have highlighted the duality of tryptophan catabolites; quinolinic acid (QA) has been implicated in long-covid, and picolinic acid (PA) has broad-spectrum antiviral properties in in-vivo models. There is now new evidence from Wong et al. 2023, from the University of Pennsylvania, Philadelphia, that implicates peripheral serotonin deficiency in the post-viral sequelae of “long COVID”. Metabolomic analysis in long COVID patients, acute COVID patients, and fully recovered COVID patients revealed evidence of serotonin depletion in both acute and post-acute phases of COVID-19, with the latter being predictive of the development of long COVID symptoms. These results were further corroborated in separate long COVID cohort samples and experimental animal models.
Wong et al. also used mice models of viral infection to elucidate the mechanisms of serotonin depletion, which was protracted in long COVID patients, and primarily driven by type 1 interferon-mediated inflammation. The researchers clarified that the presence of the virus persists in the gastrointestinal tract of long COVID patients, and their mice model demonstrated that this reduced gut gene expression for the absorption of serotonin precursor, tryptophan. Interestingly, both serotonin and tryptophan levels could be normalised via supplementation in mice diets.
Other mechanisms of serotonin depletion in the context of interferon-mediated viral inflammation included reduced peripheral serotonin storage in platelets due to thrombocytopenia and increased serotonin metabolism. This manifested clinically in mice, as hippocampal-dependent memory impairment, and was linked to reduced vagus nerve sensory neuronal activity.
This study highlights (i) aberrant tryptophan catabolism in the context of type 1 interferon inflammation; (ii) the role of dietary supplementation (i.e., tryptophan and serotonin) in remediating symptoms of long COVID, and (iii) the need for further exploration of the relationship between gut microbiome changes in the context of viral-driven inflammation, peripheral tryptophan catabolites, and brain function.