VSL#3® supplementation improves fatigue in long COVID: results from the DELong#3 randomized placebo-controlled trial

Background: Long 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.
Methods: In 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.
Results: Forty-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 healthassociated
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