Study Examines Probiotic Impact on Gut Microbiome in Long COVID Patients

A new study published in Microorganisms indicates that multi-strain probiotics can induce modest, targeted alterations in the gut microbiome of individuals experiencing long COVID.

However, any subsequent benefits, such as reduced inflammation or improvements in liver-related biomarkers, were limited and lacked statistical significance.

Background: Gut Dysbiosis and Probiotics

Gut dysbiosis, a disruption in the gut microbiome's balance, is hypothesized to contribute to persistent long COVID symptoms. Probiotics are being investigated as a potential therapeutic approach due to their known influence on the gut microbiome, immune responses, and metabolic processes.

The microbiome plays a central role in maintaining physiological balance, regulating immune responses, metabolic pathways, gut barrier integrity, and systemic inflammation. Probiotics are believed to help restore this balance by reshaping the microbial community and supporting the production of beneficial metabolites like short-chain fatty acids (SCFAs), which can regulate inflammatory responses and suppress pathogen growth.

SARS-CoV-2 infection, which causes COVID-19, has been linked to persistent inflammation and sustained gut dysbiosis. Long COVID, characterized by prolonged symptoms affecting multiple organs in up to 50% of COVID-19 patients, may result from interactions between secondary viral effects and gut dysbiosis.

Previous research on probiotics for long COVID primarily focused on Lactobacillus and Bifidobacterium species. This study considered a multi-strain approach, including Saccharomyces boulardii, a yeast known for anti-inflammatory and gut-protective effects, alongside Lacticaseibacillus rhamnosus GG and two Lactiplantibacillus plantarum strains, aiming for broader physiological impact.

Study Design and Methodology

The investigators conducted a double-blinded, prospective, non-randomized interventional study over 12 weeks. The study involved 23 participants with long COVID and 26 fully convalescent patients. Additionally, 25 healthy controls with no history of symptomatic COVID-19 served as reference. A total of 34 participants received the multi-strain probiotic intervention, while 40 participants were non-supplemented controls.

The probiotic formulation included:

• Saccharomyces boulardii
• Lacticaseibacillus rhamnosus GG
• Two Lactiplantibacillus plantarum strains

The gut microbiome was analyzed using 16S rRNA gene amplicon sequencing of fecal samples. Biochemical changes throughout the study period were also monitored.

Key Findings

The probiotic group exhibited selective changes in microbial community composition, though without altering overall microbial diversity. Long COVID patients showed more pronounced changes in specific genera compared to convalescent patients.

Five genera changed in abundance:

• Adlercreutzia, Ruminococcaceae, and Eubacterium increased, while Coprococcus showed a similar trend. These genera are involved in microbial metabolism and immune regulation and have been reported as depleted in acute COVID-19 and long COVID.
• Marvinbryantia showed the greatest increase in relative abundance.

The potentially pathogenic Prevotella_9 showed a decrease in abundance, with statistical significance varying by analytical approach. Lactobacillus abundance remained unchanged.

Functional prediction analysis suggested that probiotics in long COVID could enhance bacterial energy metabolism and reduce oxidative stress, reflecting predicted improvements in microbial respiration. A statistically insignificant trend toward reduced host inflammation and lower hepatic enzyme levels was also observed.

Spearman analysis identified 217 correlations between microbial shifts and host biochemical responses in long COVID patients, indicating associations rather than causation.

Discussion and Limitations

The authors observed that probiotics altered specific microbial taxa in long COVID patients, which exhibited greater responsiveness to microbial manipulation, possibly due to persistent baseline dysbiosis. Convalescent patients showed less change, suggesting greater microbiome stability post-recovery.

Several enriched genera are associated with anti-inflammatory processes, which could support recovery from long COVID. The decrease in Prevotella_9, a taxon often enriched in inflammation and dysbiosis, was noted. Biochemical tests indicated consistent, albeit modest and statistically insignificant, trends toward normalization with supplementation.

Limitations of the study include:

• A small sample size
• Non-randomized allocation
• The use of functional prediction analysis instead of direct metagenomic measurements

Methodological biases related to the technology used may also affect the results. Despite these limitations, different analyses consistently suggested a potential value for multi-probiotic supplementation in long COVID, although the findings did not reach statistical significance. The probiotic formulation received partial support from an industry source, which reportedly had no involvement in the study's design, analysis, or interpretation.