The study, published in the European Journal of Nutrition, found that daily synbiotic supplementation reduced post-exercise malaise and increased brain metabolites such as creatine and choline.
Sergej Ostojic of the University of Novi Sad, Serbia, who authored the research, said the findings suggest synbiotics may be a useful strategy for people with CFS, particularly those who have gut-related symptoms.
“Emerging research suggests that imbalances in the gut microbiota could play a role in CFS, and targeting this through synbiotics, probiotics or prebiotics may help reduce some clinical symptoms of CFS, metabolic features, and improve overall wellbeing,” he told NutraIngredients.
The study used a synbiotic mixture supplied by dsm-firmenich including four probiotics from the company’s Humiome portfolio—Lacticaseibacillus rhamnosus, Lactiplantibacillus plantarum, Bifidobacterium lactis, Bifidobacterium longum— combined with fructo-oligosaccharides and zinc. dsm-firmenich funded the sudy.
Chronic fatigue syndrome and the gut microbiome
Chronic fatigue syndrome (or Myalgic Encephalomyelitis) is characterized by extreme fatigue, post-exercise malaise (sometimes following even minor physical or mental exertion) and unrefreshing sleep.
Since the COVID-19 pandemic, cases of CFS have boomed, with research showing that the prevalence of CFS is 15 times higher than pre-pandemic levels.
While the underlying cause of the condition is not fully understood, it is hypothesized that CFS may be triggered by immune system changes following an infection. This is supported by a large-scale study which showed that, compared with non-COVID patients, those with COVID had a 62% higher risk of developing CFS during a one-year follow-up period.
The gut microbiome is also thought to play a role, with research showing that CFS patients have reduced α-diversity compared to healthy subjects. A significant number of CFS patients (ranging from 38% to 42%) also experience irritable bowel syndrome (IBS), and over 70% of this patient group report gastrointestinal disturbances.
This link has led researchers to hypothesize that synbiotic supplementation could improve symptoms related to CFS.
“A small number of previous clinical trials has examined the effects of various probiotic strains and blends in CFS, including a recent study in long COVID,” Robert E. Steinert, dsm-firmenich’s principal scientist told NutraIngredients. "This new study is the first to investigate the impact of a synbiotic blend, producing promising results."
Study details
The study recruited 26 post-COVID-19 CFS patients and randomly assigned them to either a synbiotic or maltodextrin placebo group.
Participants were assessed at baseline and at the end of the three-month follow-up period using the Multidimensional Fatigue Inventory (MFI-20) test, which evaluates key dimensions of fatigue including physical and mental fatigue, reduced motivation and reduced activity.
While synbiotic intake led to a significant reduction in general fatigue, physical fatigue and mental fatigue compared to baseline, similar results were identified in the placebo group, suggesting that the intervention may not have had a direct effect on these parameters.
“It is possible that the body’s own healing processes played a more significant role, and neither the placebo nor the synbiotic provided additional benefit beyond that,” Ostojic explained.
However, the synbiotic mixture significantly reduced scores for post-exercise malaise compared to baseline values, with the synbiotic superior to placebo. There was also a non-significant trend in the intervention arm, with this group reporting reduced concentration difficulties compared to the control group.
Synbiotic increased brain metabolites
The synbiotic significantly increased brain metabolites such as choline and creatine, with tissue creatine levels across the brain and skeletal muscle increasing by up to 15.3%.
“Since post-COVID-19 CFS is characterized by low tissue creatine concentrations, supplemental synbiotic plus zinc as used in the current study might be thus an effective dietary intervention to improve both muscle and brain energy metabolism,” the researchers wrote.
Choline and NAA (N-acetyl aspartate) were also elevated in the synbiotic group, suggesting additional neuroprotective effects.
Ostojic says that the observed improvements in concentration and post-exercise malaise may therefore be linked to enhanced energy metabolism in the brain and a reduction in inflammation and oxidative stress.
“These effects are likely driven by increased availability of gut-derived metabolites, such as short-chain fatty acids, promoted by the synbiotic formulation,” he said. “Additionally, synbiotics may help regulate neuroendocrine signaling and modulate neuroimmune interactions, contributing to improved overall physiological resilience in individuals experiencing prolonged fatigue following COVID-19 infection.”
A ‘complementary strategy’
While the results of the study are “extremely promising”, more research is needed to confirm the efficacy of synbiotics in CFS, according to Dr. Steinert.
“As this is the first study of its kind, further validation—including clarification of the specific mechanism of action—is required before endorsing the use of these synbiotics in clinical therapy,“ he said. ”However, the findings open new avenues for nutritional innovation to provide critical support and improve the quality of life for the millions of people around the world living with CFS."
Ostojic agrees, adding that the potential for synbiotics to modulate the gut-brain axis represents an “exciting area for future research.”
“At this stage, synbiotics should be seen as a potential complementary strategy rather than a proven treatment,” he said.
Source: European Journal of Nutrition. doi: 10.1007/s00394-025-03591-3. “The effects of 3-month supplementation with synbiotic on patient-reported outcomes, exercise tolerance, and brain and muscle metabolism in adult patients with post-COVID-19 chronic fatigue syndrome (STOP-FATIGUE): a randomized placebo-controlled clinical trial.” Authors: M. Ranisavljev, et al.