The DELong#3 trial randomized 48 patients with long COVID and clinically significant fatigue at Fondazione IRCCS Ca' Granda in Milan to either high-dose VSL#3 probiotic or placebo for four weeks. The primary endpoint was fatigue measured by the Chalder Fatigue Scale.
The probiotic group showed a greater reduction in fatigue score (24.24 percent versus 6.06 percent, p = 0.037) and a higher proportion of treatment responders (68 percent versus 35.7 percent, p = 0.019). Improvements persisted four weeks after participants stopped taking it, and secondary outcomes showed gains in physical functioning, emotional wellbeing, and gastrointestinal symptoms.
Responders also showed measurable shifts in gut bacteria, including enrichment of Bifidobacterium and Lactobacillus, alongside changes in immune signaling. This is a small single-center trial and the authors frame it as support for further investigation of microbiota-targeted approaches, not as established treatment.