Introduction
Despite strategies based on social distancing, hygiene, and screening, COVID-19 is
progressing rapidly throughout the world, with healthcare systems at risk of being
overwhelmed. While identification of effective drug therapies is ongoing, vaccines
will not be available in the near future. Therefore, additional preventive strategies
are urgently needed.
COVID-19 presents with a spectrum of disease severity, ranging from mild and non-specific
flu-like symptoms, to pneumonia, and life-threatening complications such as acute
respiratory distress syndrome (ARDS) and multiple organ failure. While transmission
of SARS-CoV-2 is thought to occur mainly via respiratory droplets, the gut may also
contribute toward the pathogenesis of COVID-19 (1). SARS-CoV-2 RNA has been detected
in the gastrointestinal tract and stool samples from patients (2–4), and in sewage
systems (5). Coronaviruses, including SARS-Cov-2 can invade enterocytes, thereby acting
as a reservoir for the virus (4). Indeed, large clinical studies from China indicate
that gastrointestinal symptoms are common in COVID-19, and are associated with disease
severity (3, 4).
Probiotics are live microorganisms that when administered in adequate amounts confer
a health benefit on the host (6). Clinical evidence shows that certain probiotic strains
help to prevent bacterial and viral infections, including gastroenteritis, sepsis,
and respiratory tract infections (RTIs). The reason for adding probiotic strains to
the overall prevention and care strategy is founded in science and clinical studies,
albeit hitherto none directly on the etiological agent of this pandemic.
Clinical Data Supporting the Use of Probiotics to Prevent Covid-19
Probiotics can prevent antibiotic-associated diarrhea, and infections in the gastrointestinal
tract, but also infections at other sites, including sepsis, and RTIs (7–13). Meta-analyses
are the gold standard for evidence-based medicine. In one analysis of more than 8,000
preterm infants included in randomized control trials (RCTs), patients receiving enteral
supplementation with probiotics showed a reduction in necrotizing enterocolitis, nosocomial
sepsis, and all-cause mortality (14). A well-conducted RCT including >4,000 newborns
in India found a reduction in sepsis and lower RTIs in infants treated with a strain
of Lactobacillus plantarum combined with prebiotics (which are growth substrates specific
for beneficial microorganisms) (15).
Viruses are etiologic agents of over 90% of upper RTIs. The positive impact of probiotics
on prevention of upper RTIs is documented in a number of studies. A meta-analysis
of 12 RCTs including 3,720 adults and children reported a 2-fold lower risk of developing
upper RTI in subjects taking probiotics, and a small but significant reduction in
disease severity in those infected. A randomized, double-blind, placebo-controlled
intervention study of 479 adults showed that Lactobacillus gasseri PA 16/8, Bifidobacterium
longum SP 07/3, and Bifidobacterium bifidum MF 20/5 with vitamins and minerals lowered
not only the duration of common cold episodes but also days with fever (16). The impact
of probiotics on prevention of upper RTIs caused by specific viruses has also been
documented. An RCT including 94 preterm infants showed that galacto-oligosaccharide
and polydextrose prebiotic mixture (1:1), or probiotic Lactobacillus rhamnosus GG
given between 3 and 60 days of life lowered the incidence of clinically defined virus-associated
RTI by 2- to 3-fold compared to placebo (17). The incidence of rhinovirus-associated
episodes, which comprised 80% of all RTIs in this study, was also strongly reduced
with probiotics or prebiotics. The incidence of influenza RTI was reduced following
consumption of Lactobacillus brevis in an open label study of 1,783 school children
(18). Pertinent to the pandemic affecting adults more than children, these positive
findings were confirmed in an RCT that included 27 elderly subjects receiving Bifidobacterium
longum or placebo (19). Furthermore, lactic acid bacteria, from which many probiotics
are selected, are part of the upper respiratory tract microbiota in healthy people,
and some strains are being considered for prevention of recurrent otitis media (20,
21). This makes their use for contributing to slow down progression of the coronavirus
pandemic worthy of consideration.
Probiotics have also been used to prevent bacterial lower RTIs in critically ill adults.
Meta-analyses of RCTs including close to 2,000 patients found that probiotic strains
reduce the incidence of ventilator-associated pneumonia (22, 23). But low quality
of evidence and conflicting results among different studies calls for additional well-conducted
RCTs.
It should be noted that not all probiotics, even those with gastrointestinal benefits,
necessarily contribute in every way to reducing the risk of respiratory infection.
For example, Lactobacillus rhamnosus GG and Bifidobacterium animalis ssp. lactis may
contribute to intestinal benefits, but do not reduce the number of viruses in the
nasopharynx (24). Examples of products that could be considered, depending on availability
in a given country, are provided in Table 1.
Table 1
The following are examples (not exclusive) of probiotic products, or web sites listing
products, with documentation in human studies that may have relevance to reducing
the burden of the coronavirus pandemic.
Products
Basis for inclusion
When to administer
References
Lactobacillus casei DN-114 001; DanActive/Actimel Fermented drink, Danone
Reduced incidence and duration of RTIs
Once daily for duration of the pandemic
(12, 13)
Lactobacillus gasseri PA 16/8, Bifidobacterium longum SP 07/3, and B. bifidum MF 20/5;
Tribion harmonis, Merck
Lowering duration and severity of flu-like illness
Once daily for duration of the pandemic
(16)
Lactobacillus rhamnosus GG; Culturelle or other brand names
For digestive health and gut barrier integrity, and prevention of viral RTIs
One capsule daily for duration of the pandemic
(17)
Lactobacillus plantarum DR7; Malaysia
Prevention of upper RTIs, immune modulation
2 g sachet per day for duration of pandemic
(25)
Bifidobacterium breve Yakult, and Lactobacillus casei Shirota; available as fermented
drinks
Lower incidence of ventilator-associated pneumonia
One of each day for duration of the pandemic
(26)
Bifidobacterium longum BB536; Morinaga, and sold in many formulations
Enhances innate immunity, prevents influenza infection
One each day for duration of the pandemic
(19)
Pediococcus pentosaceus 5-33:3, Leuconostoc mesenteroides 32-77:1, L. paracasei ssp.
paracasei 19, L. plantarum 2,362 plus inulin, oat bran, pectin, and resistant starch;
Medipharm, Sweden
To reduce rate of SIRS, infections, sepsis, days of stay in the intensive care unit,
days under mechanical ventilation, and mortality
For COVID-19 patients
(27)
A list of probiotics available in Canada for various health issues; www.probioticchart.ca
A list of probiotics available in the USA for various health issues; www.usprobioticguide.com
We must emphasize that none have been tested or proven to have an effect against SARS-CoV2,
the virus causing COVID-19, nor are they proven treatments or cures for this condition.
Mechanistic Basis for the Action of Probiotics to Prevent Infections and Relevance
to Covid-19
Mechanisms that might explain clinical success of probiotics include enhancement of
the intestinal epithelial barrier, competition with pathogens for nutrients and adhesion
to the intestinal epithelium, production of anti-microbial substances and modulation
of the host immune system (28). An RCT of 55 infants showed that enteral supplementation
with a combination of Bifidobacterium bifidum and Streptococcus thermophilus reduced
the incidence of diarrhea and shedding of rotaviruses (29), an effect that has been
confirmed in subsequent studies (30). This would indicate interference with viral
entry into cells and/or inhibition of viral replication in the intestine. While this
mechanism may have a role in reducing dissemination of coronavirus via the gut, the
probiotic strains were not administered to the respiratory tract. So, direct inhibition
may appear impossible at this site. Having said that, lungs have their own microbiota
and a gut-lung connection has been described whereby host-microbe, microbe-microbe
and immune interactions can influence the course of respiratory diseases (31). RTIs
such as influenza are associated with an imbalance in the microbial communities of
the respiratory and gastrointestinal tracts (32, 33). This dysbiosis may alter subsequent
immune function and predispose to secondary bacterial infection. As reports from China
indicate that COVID-19 might be associated with intestinal dysbiosis causing inflammation
and poorer response to pathogens (34, 35), the case exists for probiotic strains that
restore gut homeostasis (36). It is feasible that orally administered probiotic strains
could further influence this gut-lung axis, as some can migrate from the gut to distant
sites, such as the breast to treat mastitis (37).
The gut microbiome has a critical impact on systemic immune responses, and immune
responses at distant mucosal sites, including the lungs (38, 39). Administration of
certain bifidobacteria or lactobacilli has beneficial impact on influenza virus clearance
from the respiratory tract (39, 40). Probiotic strains improve levels of type I interferons,
increase the number and activity of antigen presenting cells, NK cells, T cells, as
well as the levels of systemic and mucosal specific antibodies in the lungs (16, 19,
39). There is also evidence that probiotic strains modify the dynamic balance between
proinflammatory and immunoregulatory cytokines that allow viral clearance while minimizing
immune response-mediated damage to the lungs. This might be particularly relevant
to prevent ARDS, a major complication of COVID-19. An RCT with Lactobacillus plantarum
DR7 showed suppression of plasma pro-inflammatory cytokines (IFN-γ, TNF-α) in middle-aged
adults, and enhancement of anti-inflammatory cytokines (IL-4, IL-10) in young adults,
along with reduced plasma peroxidation and oxidative stress levels (25). Given the
cytokine storm that appears to occur in many COVID-19 patients, this type of modulation
may prove to be very important. The manner in which orally administered probiotic
strains contributes to this appears to involve the immune response emanating from
the intestine, a focal point of the body's defenses. Therefore, probiotic strains
documented to enhance the integrity of tight junctions, for example through increasing
butyrate, a fuel for colonocytes could theoretically reduce SARS-Cov-2 invasion.
Evidence for antiviral activity of probiotic strains against common respiratory viruses,
including influenza, rhinovirus, and respiratory syncytial virus comes from clinical
and experimental studies (17–19, 41). While none of these effects or mechanisms have
been tested on the new SARS-CoV-2 virus, this should not negate considering this approach,
especially when effects of probiotics against other coronavirus strains have been
reported (42–45). Furthermore, patients are dying from secondary bacterial infections.
A recent study in mice has shown that oral administration of Lactobacillus acidophilus
CMCC878, started 24 h after pulmonary inoculation of Pseudomonas aeruginosa and Staphylococcus
aureus reduced bacterial load in the lungs, and decreased lung damage and systemic
inflammation (46).
Safety of Probiotics
Probiotics are generally safe, even in the most vulnerable populations and in intensive
care settings (14, 47). Cases of probiotic-associated bacteremia and fungaemia have
occurred on extremely rare occasions, mainly in premature and immunocompromised patients
treated with preparations lacking adequate quality control (48, 49). Rather than consider
intensive care patients too ill to receive probiotic and prebiotic therapy, RCTs of
probiotics for the prevention of ventilator-associated pneumonia provide a reason
to consider them (22, 23, 26). Moreover, in an RCT of 65 critically ill, mechanically
ventilated, multiple trauma patients, the synbiotic Pediococcus pentosaceus 5-33:3,
Leuconostoc mesenteroides 32-77:1, L. paracasei ssp. paracasei 19, L. plantarum 2,362
plus inulin, oat bran, pectin, and resistant starch resulted in reduced rate of infections,
systemic inflammatory response syndrome, sepsis, days of stay in the intensive care
unit, days under mechanical ventilation, and mortality (27).
Summary
In summary, orally administered probiotic strains can reduce the incidence and severity
of viral RTIs. At a time when doctors are using drugs with little anti- COVID-19 data,
probiotic strains documented for anti-viral and respiratory activities (not low-quality
undocumented imitations) should become part of the armamentarium to reduce the burden
and severity of this pandemic. Government funding is being used to test numerous drugs
but just as important, they should fund probiotic trials. In addition, use of recognized
prebiotics (e.g., fructans, galactans) to enhance propagation of probiotic strains
and indigenous beneficial microbes should be recommended as part of the overall strategy
to flatten the curve (11, 50).
Author Contributions
EG, DB, and VD contributed conception of the manuscript. EG and VD wrote the first
draft. DB, GG, and GR wrote sections of the manuscript. All authors contributed to
manuscript revision, read, and approved the submitted version.
Conflict of Interest
GG and GR provide advice to probiotic and prebiotic companies. The remaining authors
declare that the research was conducted in the absence of any commercial or financial
relationships that could be construed as a potential conflict of interest.