Why Probiotics? The Gut-COVID-19 Link
Probiotics are live microorganisms that confer some health benefit to the host when administered in adequate amounts. They are generally bacteria, often hailing from the Lactobacillus and Bifidobacteria genera. Naturally found in fermented foods (yogurt, cheeses, kimchi), probiotics are also available in the form of dietary supplements.
But if COVID-19 is a respiratory disease, why would ingesting a probiotic (which is how most are taken) make any difference at all?
While SARS-CoV-2 is a respiratory virus, it can infect other body tissues, including the gut. Gastrointestinal symptoms are relatively common in individuals with COVID-19, though the percentage depends on the study and SARS-CoV-2 variant. For example, the JN.1 ("Pirola") variant, which is currently responsible for a majority of COVID-19 infections worldwide, may have a proclivity for triggering gut symptoms (diarrhea) relative to previous variants (though more data are needed to empirically determine this observation). Studies demonstrate that the gut microbiota of COVID-19 patients is also altered compared to healthy individuals, including a reduction in beneficial bacterial species and metabolites. These changes have implications for disease severity and immune responses.
In addition to direct gut-virus interactions, the gastrointestinal tract and its resident microbes engage in bidirectional communication with organs throughout the body-lungs included. Microbial metabolites, hormones and immune regulators can exit the gut and travel to the lungs (and vice versa). Scientists think that this "gut-lung axis" influences responses to respiratory pathogens. Research shows probiotics may reduce the risk and improve management of other respiratory infections, like those caused by respiratory syncytial virus (RSV) and influenza.
With all this in mind, it is reasonable to suspect that probiotics could be advantageous in the context of SARS-CoV-2 infection.
Probiotics and COVID-19: What We Know
But what do the data show? Broadly speaking, probiotics may improve symptoms of COVID-19 and show some benefit for infection prevention, reducing disease duration and improving long COVID symptoms, but clinical evidence is limited, especially as it pertains to the current infection landscape.
Prevention
In a recently published clinical trial, unvaccinated people exposed to COVID-19 (i.e., lived with someone diagnosed with COVID-19) who took the probiotic Lacticaseibacillus rhamnosus GG (LGG) for 28 days had fewer symptoms at day 28 compared to those taking a placebo (42.9% vs. 26.4%, respectively). Probiotic treatment also prolonged the time to laboratory confirmed COVID-19 infections-that is, people taking LGG still got sick, but it took longer for them to fall ill. Indeed, although the probiotic group had a lower incidence of COVID-19 diagnosis relative to the placebo group (8.8% vs. 15.4%, respectively) the difference was not significant. This may be due to study size (the trial enrolled 182 participants split between treatment and placebo groups). The trial ran from June 2020 to June 2021, when many people were still unvaccinated and the Delta SARS-CoV-2 variant had yet to become dominant.
The findings suggest that probiotics could be beneficial for post-exposure prophylaxis for COVID-19, which the scientists note might be useful when uptake of COVID-19 vaccines (a critical prevention measure) is low. How the results translate to vaccinated individuals, and in the context of current SARS-CoV-2 variants (e.g., JN.1), is unclear. Moreover, a recent systematic review and meta-analysis of 18 clinical studies concluded that probiotics were not effective at reducing COVID-19 incidence, underscoring the need for additional research.
Vaccine Responses
Probiotics might influence immune responses after COVID-19 vaccination. For instance, individuals who consumed Limosilactobacillus reuteri combined with vitamin D3 every day for 6 months, and were vaccinated with 2 doses of either a Pfizer or Moderna COVID-19 mRNA vaccine, had higher serum levels of antibodies (IgA) targeting the SARS-CoV-2 receptor binding domain compared to those who ingested a placebo product (vitamin D3 only). Additional studies gesture toward a link between probiotics and immune responses post-COVID-19 vaccination, though this link is purely associative, and how the observed immune differences between probiotic and placebo groups translate to COVID-19 vaccine efficacy is hazy.
Treatment for Acute COVID-19
For people with acute COVID-19, probiotics may improve digestive and respiratory symptoms (diarrhea, cough, shortness of breath). In a recent trial of 300 participants, individuals with COVID-19 who received a probiotic formula containing 3 strains of Lactiplantibacillus plantarum plus 1 strain of Pediococcus acidilactici for 30 days were more likely to achieve complete symptom and viral clearance compared to those receiving a placebo (53.1% vs. 28.1%, respectively). Probiotic supplementation also reduced nasopharyngeal viral load and boosted levels of antibodies (IgM and IgG) against SARS-CoV-2, pointing to a potential immunomodulatory mechanism. Some meta-analyses and systematic reviews of clinical investigations suggest probiotic administration can reduce mortality risk, COVID-19 symptom duration, time to recovery and length of hospital stay, though this varies from study to study.
Long COVID
Long COVID-defined as signs, symptoms and conditions that continue to develop after an acute COVID infection-affects ~65 million people across the world. Can probiotics help? Patients hospitalized for COVID-19 during March/April 2020 who received a probiotic formulation containing 6 different bacteria reported a lower prevalence of chronic fatigue (a symptom of Long COVID) 6 months after discharge compared to those who received standard care without probiotics. (The study authors highlight that their investigation lacked appropriate control, randomization and blinding, thus results should be interpreted accordingly).
In another trial (this one randomized, double-blind and placebo-controlled), 463 people with Long COVID were randomized to receive either a synbiotic (a mixture of probiotics and prebiotics, i.e., non-digestible fibers that help the bacteria grow) containing Bifidobacterium adolescentis, B. bifidum and B. longum or a placebo twice daily for 6 months.
Relative to those in the placebo group, patients taking synbiotics reported improvement in fatigue, memory loss, difficulty concentrating and gut upset, among other symptoms. These findings suggest synbiotics may alleviate some symptoms of Long COVID, though, as noted in a commentary about the trial, such alleviation "did not correspond with measurable improvements in quality of life or physical activity after 6 months, suggesting that the real benefits of the treatment on general health perception and functional capacity might be low."
What Do We Need to Learn?
So, should people take probiotics to prevent or treat COVID-19? The resounding message across studies is that we need more research. There are not enough data to draw definitive conclusions one way or the other-and certainly not enough to draft specific guidelines for if and how probiotics should be used for management of COVID-19. To reach that point, there are still questions to answer and actions to take.
Conduct More Trials
Many published trials assessing probiotics for COVID-19 largely took place in the early stages of the pandemic, either before or right as vaccines were being introduced. If and how the effects of probiotics change with varying vaccine status and SARS-CoV-2 variants may influence how they're used.
In addition, as for any prophylactic or therapeutic measure, the outcome depends on numerous confounding factors, from the age and immune status of study participant to the type and dose of probiotic administered. This, in turn, can make comparing studies-and crafting clinical recommendations-a challenge. Scientists note the need for more, large-scale studies on the COVID-19-probiotic link.
Though there is progress on that front-a quick search on clinicaltrials.gov for "COVID-19" and "Probiotics" yields various randomized controlled trials that have been conducted, are, or will be underway, with a particular emphasis on examining the relationship between probiotics and COVID-19 vaccination or Long COVID.
What Are the Mechanisms?
How probiotics work isn't entirely clear, though proposed mechanisms include stimulating/modulating the immune system, improving gut barrier function and inhibiting pathogens.
When it comes to COVID-19, probiotics may influence the microbiome and immune responses (and interactions between them) by way of the gut-lung axis. This includes producing health-promoting compounds like short chain fatty acids (SCFAs), which can help protect against lung infections. Notably, biosynthesis of SCFAs is impaired in COVID-19 patients and may correlate with immunity to the virus.
It is also possible probiotics produce bacteriocins (inhibitory antimicrobial compounds) that bind to SARS-CoV-2 and inhibit its ability to interact with host cells and replicate. Such compounds could also bind host cell receptors that are required for viral entry (e.g., ACE2). Likely, probiotics act via a mix of mechanisms, which are tied to the probiotic itself. A better understanding of their mechanisms could inform probiotic use and development.
Not All Probiotics Are the Same
With that, "probiotic" is an umbrella term for a slew of organisms whose effects depend on species and strain. The formulation of a probiotic product matters for its intended application and effect. But what are the most effective probiotics (i.e., species and strains) for COVID-19 patients? In which patient populations are they most efficacious? Are synbiotics better than just probiotics? Researchers don't really know-every trial uses something different.
There are also questions about how probiotics should be taken. For example, nasal-spraying probiotics are effective for treating respiratory symptoms caused by RSV and influenza infection in children-might something similar be beneficial for COVID-19? Preliminary research also indicates that dissolving probiotic tablets in the mouth reduced the probability of developing respiratory tract infections by ~65% in medical staff in contact with COVID-19 patients relative to a control group (i.e., staff who did not take any probiotic or placebo). This method of administration also improved markers of COVID-19 pathology in hospitalized patients. As such, populating the oral cavity/throat with probiotics may help fight SARS-CoV-2 and/or modulate the local immune response to combat it. Ultimately, how (and what) probiotics should be administered may depend on the person and infection symptoms.
The Bottom Line
Probiotics can benefit overall health. However, there is work to be done to determine what probiotics work, when they work, who they work for and how they work in the context of COVID-19. Still, there are enough encouraging data to make such exploration worthwhile.
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