Trial Report VSL#3® supplementation improves fatigue in long COVID: results from the DELong#3 randomized placebo-controlled trial, 2026, Amoroso et al

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

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

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 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.

Conclusion
VSL#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.

Web | DOI | PDF | British Journal of Biomedical Science | Open Access
 
My first instinct on seeing the ® in the title was to check the funding statement:

Funding​

The author(s) declared that financial support was received for this work and/or its publication.
This study was partially funded by the Italian Ministry of Health through Ricerca Corrente and by the 5 × 1000 research award from Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico (to FC).
The study also received a non-conditioning financial grant from Actial Farmaceutica S.r.l., which provided the probiotic formulation used in the trial.
The funder was not involved in the study design, analysis, interpretation of data, the writing of this article or the decision to submit it for publication.

Conflict of interest​

The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
 
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I remember correctly when I was big into probiotic research there's some controversy around VSL3:

"In 2016, De Simone severed his relationship with VSL Pharmaceuticals. After June 2016 the VSL#3®* formulation was changed. However, the distributors continued to sell their new product under the name VSL#3®*, attempting to pass it off as the same as the original formula, while neglecting to tell customers or physicians about the change. In June 2019, a federal court issued a permanent injunction against the distributors of VSL#3®*, preventing them from linking their new formulation to the De Simone Formulation in certain ways and stopping any marketing claims that state or suggest a false continuity between the new VSL#3®*"

www.visbiome.com

Visbiome vs VSL#3 | Visbiome High Potency | Visbiome®

A federal jury unanimously found that Alfasigma has made false statements to patients and healthcare professionals. Learn more about Visbiome vs VSL#3.
www.visbiome.com www.visbiome.com
 
I took VSL-3 for a long period 8-9 years ago. Took me quite a while to work up to a full sachet as it seemed to increase fatigue. (All probiotics have had this effect on me.) I was on a downward trajectory at the time and stayed on that trajectory while on it. No obvious benefit for me.

I did, however, tolerate it a lot better than the heavily marketed Symprove, which a relative without ME loved, but in me, acted like paintstripper.

Ultimately I gave up on probiotics because they were expensive and had side effects. If there are true responders, that's great. I'd want to see this replicated in a bigger sample, though.
 
Perhaps this is one of my usual tangents, but … … …

Even if having the ‘wrong’ balance of gut flora is contributing to ME/CFS it seems there are a range of potential contributory factors in somehow creating a better balance:
  • Everyone seems to focus on supplementing with ‘good’ bacteria, but is this alone sufficient to realise the supposed target balance?
  • Getting rid of the ‘bad’ bacteria theoretically could be a necessary first step. In the 1990s, when I was in the trying any and everything I saw a nutritionalist who pushed the idea of clearing the bad bacteria before supplementing with the ‘good’ ones. I have no idea if this is necessary or not, but it does seem a logical idea.
  • Creating the right environment for the desired balance would also seem necessary. The said nutritionalist also insisted that it is only possible to establish and maintain the right balance with the right diet. He had very strong views on what constitutes a right diet, though this is an area where lots of different people have lots of very different views with not a lot of good evidence one way or the other.
  • There seems to be an association between ME/CFS and ‘imbalanced’ gut flora and fauna, but that is a long way from demonstrating a causal relationship or the direction of any causality. The gut flora may impact on ME, but it has not been demonstrated to be causal, it could be that the ME causes the gut issues and the only way to sustain better gut health would be to first cure the ME. Alternatively both issues could arise from a third cause.
It strikes me that given this range of potential contributing issues you might expect very varied responses to just giving probiotics. Personally I have at times felt probiotics seemed to help and at others they seemed to have little or no effect. (I can not now remember what I tried.
 
I think in the year after ME/CFS onset in my family, a family friend arranged for my one of my children with ME/CFS to be referred to a pediatric gastroenterologist. The gastroenterologist seemed very disappointed to find out that my child had been born normally (not cesarean section) and had been breast fed for a good length of time. She obviously had some theories about both those things setting up someone with a good microbiome.

Anyway, she prescribed VSL#3. This was back before 2016, and from @ChronicallyOverIt's post above, it seems that the formulation may have changed. I can't remember much about it, other than it was pretty expensive and didn't seem to do anything for the three of us with ME/CFS.
 
Hutan said:
The gastroenterologist seemed very disappointed to find out that my child had been born normally (not cesarean section) and had been breast fed for a good length of time. She obviously had some theories about both those things setting up someone with a good microbiome.
Click to expand...
Haha I had this same experience with a naturopath. I was born c-section, which does have a different microbiome introduction than normal birth. However I’m an identical twin. She ranted about this for about 15min before I dropped that I am sick and my identical twin is not. That put a damper on that “theory”. It’s also so unverifiable and easy to point to, it’s an easy cop out for these practitioners.
 
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