AUTHOR=Amoroso Chiara , Marinoni Beatrice , Maragno Paola , Rimondi Alessandro , Bottaro Federico , Ciafardini Clorinda , Muià Martina , Honcharyuk Ivanna , Noviello Daniele , Caridi Bruna , Sommella Eduardo Maria , Bandera Alessandra , Gori Andrea , Mantero Marco , Blasi Francesco , Ferrucci Roberta , Priori Alberto , Strati Francesco , Vecchi Maurizio , Facciotti Federica , Caprioli Flavio 
  
TITLE=VSL#3® supplementation improves fatigue in long COVID: results from the DELong#3 randomized placebo-controlled trial
  
JOURNAL=British Journal of Biomedical Science
  
VOLUME=Volume 83 - 2026
  
YEAR=2026
  
URL=https://www.frontierspartnerships.org/journals/british-journal-of-biomedical-science/articles/10.3389/bjbs.2026.16993
  
DOI=10.3389/bjbs.2026.16993
  
ISSN=2474-0896
  
ABSTRACT=BackgroundLong COVID is frequently characterized by persistent fatigue and impaired quality of life. Increasing evidence suggests that gut microbiota dysbiosis and immune dysregulation may contribute to symptom persistence. We evaluated the effects of the probiotic formulation VSL#3® in patients with long COVID.MethodsIn this randomized, double-blind, placebo-controlled trial (ClinicalTrials.gov identifier: NCT05874089), patients with long COVID and clinically relevant fatigue received VSL#3® or placebo for 4 weeks. The primary endpoint was fatigue improvement assessed by the Chalder Fatigue Scale (CFS). Secondary and exploratory analyses included patient-reported outcomes, gut microbiota profiling, immune phenotyping, cytokine analyses, and targeted metabolomics.ResultsForty-eight patients completed the study (placebo n = 25; VSL#3® n = 23). VSL#3® supplementation significantly improved fatigue compared with placebo, with a greater reduction in CFS score (24.24% vs. 6.06%; p = 0.037) and a higher proportion of responders (68% vs. 35.7%; p = 0.019). Clinical benefit persisted after treatment discontinuation and was accompanied by improvements in selected quality-of-life and gastrointestinal symptom domains. VSL#3® supplementation was associated with selective enrichment of health-associated bacterial taxa, including Bifidobacterium, Lactobacillus, Ruminococcus, and Coprococcus, together with modulation of inflammatory and immune-related pathways. Exploratory multi-omic analyses identified coordinated associations among microbiota-derived metabolites, immune markers, and clinical outcomes.ConclusionVSL#3® supplementation improved fatigue and selected clinical outcomes in patients with long COVID and was associated with coordinated microbiota and immune changes. These findings support further investigation of microbiota-targeted interventions in long COVID.