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In this study, we investigated whether fatigue severity in individuals previously infected with SARS-CoV-2 is associated with immune and metabolic alterations in serum and whether these peripheral changes can influence hippocampal cell function in vitro. Serum cytokines, kynurenine pathway, and tryptophan-derived and monoamine-related metabolites were measured in a total of 38 individuals with past COVID-19 infection. Human hippocampal progenitor cells were exposed to 1% patient serum during proliferation and differentiation, with readouts including cytokine release, metabolite production, and markers of neurogenesis (doublecortin, DCX) and astrocytic reactivity (glial fibrillary acidic protein, GFAP; aquaporin-4, AQP4). Results show that fatigue severity correlates with lower serum levels of interleukin-8 (IL-8) and with lower levels of metabolites of the kynurenine pathway and tryptophan-derived and monoamine-related metabolites, including kynurenine (KYN) and quinolinic acid (QUIN), and 5-hydroxyindoleacetic acid (5HIAA). Exposure of hippocampal cells to serum from individuals with higher fatigue was associated with increased endogenous production of interleukin-13 (IL-13) and the kynurenine metabolite anthranilic acid (ANA) in the cell supernatant, as well as with increased neurogenesis (increased DCX expression) and enhanced astrocytic reactivity (increased GFAP expression). Notably, serum IL-8 level was inversely correlated with both cellular outcomes. Likewise, serum 5-HIAA levels were negatively correlated with IL-13 release, with mediation analysis indicating that 5-HIAA significantly mediated the association between fatigue severity and IL-13 production (71% explained). Overall, our results suggest that fatigue after COVID-19 infection is associated with neuroimmune and metabolic changes in hippocampal cells, involving peripheral serotonin metabolism (5-HIAA) and cytokine signalling (IL-13).<\/jats:p>","DOI":"10.1038\/s41398-026-04250-9","type":"journal-article","created":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T10:26:27Z","timestamp":1784111187000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Fatigue after COVID-19 infection is associated with peripheral immunometabolic alterations affecting neuroimmune responses in the hippocampus"],"prefix":"10.1038","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7918-3492","authenticated-orcid":false,"given":"Nicole","family":"Mariani","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0239-8206","authenticated-orcid":false,"given":"Daniel","family":"Martins","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federico","family":"Imbeni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madeline","family":"Kirkpatrick","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nuriza","family":"Tukiran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Alboni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9132-5091","authenticated-orcid":false,"given":"Carmine","family":"Pariante","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4410-7865","authenticated-orcid":false,"given":"Alessandra","family":"Borsini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,15]]},"reference":[{"key":"4250_CR1","doi-asserted-by":"publisher","first-page":"101019","DOI":"10.1016\/j.eclinm.2021.101019","volume":"38","author":"HE Davis","year":"2021","unstructured":"Davis HE, Assaf GS, McCorkell L, Wei H, Low RJ, Re'em Y, et al. 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