Discussion:
This study showed that 3 participants in placebo group got SARS-COV2 infection in comparison to no participant in synbiotic group. Although there was a lower number of involved persons in synbiotic group, the difference was not statistically significant. This may be partly due to small sample size, however, as even a small reduction in COVID-19 involvement is still promising, larger studies are critically needed.
While vaccines will not be widely available in the near future for general population in many countries, additional preventive strategies are urgently needed especially in high risk groups including health care providers and hospital staffs.
There are many evidences that communications exist between gut and lung, which is called the gut-lung axis. To our knowledge, this is the first report of synbiotic application for prevention of COVID-19 and there is no other published trial using probiotic or prebiotic for prevention or treatment of this novel disease. There are some animal studies and very nice reviews that suggest specific strains of probiotics are effective against corona viruses and presumably, SARS-COV2. Julio Villena and Haruki Kitazawa have summarized the information regarding the effect of L. rhamnosus CRL1505 in the beneficial modulation of the mucosal antiviral immune response and suggest that this strain could be beneficial in the prevention and/or the reduction of the severity of infections caused by SARS-COV2[14]. They also concluded that immunobiotic interventions are mostly effective in the prevention of respiratory infections while they rarely influence the course of infection once the pathogen has started its replication in the host and immunobiotics should be considered as a strategy for prevention rather than as a therapeutic option.
Some patients with COVID-19 have intestinal microbial dysbiosis with low numbers of probiotic species such as Bifidobacterium and Lactobacillus which could be an indicator of their weak immunity, and therefore prebiotic, probiotic or synbiotic supplementation will help to re-normalize the intestinal flora balance and decrease the risk of infection[14].
Zuo and coworkers compared the fecal microbiota of fifteen patients infected with SARS-Cov2 to healthy controls and showed thatCoprobacillus spp. Clostridium ramosum andClostridium hatherwayi were associated with severity of COVID-19 symptoms[23]. Geva-Zatorsky demonstrated that Coprobacillusspp. can upregulate ACE2 (which is a receptor for virus entry) in the murine guts[24]. Beneficial effects include enhancement of the intestinal epithelial barrier, competition with pathogens for nutrients and adhesion, production of anti-microbial agents and modulation of the host immune system[25].
A recent systematic review and meta-analysis in 2020 concluded that synbiotic interventions reduced the incidence rate of respiratory tract infections (RTIs) by 16% and the proportion of participants experiencing RTIs by 16%[19]. Interestingly, Synbiotic intervention reduced the episodes of viral respiratory infections even in asthmatic children[14].
Our study showed that participants in synbiotic had less gastrointestinal symptoms. This era is another potential beneficial effect of the application of immunobiotics as diarrhea is a frequent symptom in 10 to 30% of patients infected with SARSCoV-2. Animal studies demonstrated that L. plantarum Probio-38 and L. salivarius Probio-37 were capable of reducing the replication of transmissible coronavirus. A mixture of probiotic strains was also capable of improving the immune system of pigs infected with coronavirus and improved their reproductive performance (Tsukahara et al., 2018). Interestingly, it was recently reported that a multi-strain probiotic mixture significantly reduced the fecal shedding of the feline coronavirus in cats infected with the pathogen[14].
Mak et al. reported that 58–71% of patients with COVID-19 in China were consumed antibiotics, and antibiotic-associated diarrhea occurred in 2–36% of patients. Probiotics intervention has been proposed to make these COVID-19 patients less prone to secondary infections[26].
In our study, one participant in placebo group versus no one in synbiotic group had anosmia. Dysgeusia and anosmia are common comorbidities in COVID-19 patients. Epidemiological studies have demonstrated that the incidence rate of olfactory problems in COVID-19 patients varies from 33.9-68% with female dominance [27]. There are some ongoing trials using intranasal probiotics for prevention and treatment of COVID-19. Their results will be interesting as to whether local use or probiotics produce inhibitory effects on olfactory problems (ClinicalTrials.gov Identifier: NCT04458519).
In COVID-19 patients, the main manifestations are fever and cough, lymphocytopenia and ground-glass changes on chest computed tomography [27]. In the current trial, fever and chill were seen in two cases in placebo group compared to one case in synbiotic group with no statistically significant difference.
Finally, although it seems that probiotics and synbiotic should be used mainly as a preventive strategy against COVID-19, there are some evidences that show they may also help patients after infection with SARS-COV2[28]. Interestingly, in an RCT of 65 critically ill, mechanically ventilated patients, a multi-strain synbiotic containing Pediococcus pentosaceus, Leuconostoc mesenteroides, L. paracasei ssp. Paracasei 19, L. plantarum plus inulin, oat bran, pectin, and resistant starch lowered the rate of infections, sepsis, days of admission in the intensive care unit, days under mechanical ventilation, and mortality[29].
Controversy still exists as some experts believe that blind use of probiotics for COVID-19 is not recommended until we have a better understanding of the pathogenesis of SARS-CoV-2 and its effect on gut microbiota [30].
The main limitation of this study was the small sample size. Many hospital staff were excluded from the study for their positive past clinical history or laboratory results of COVID-19. The strengths of this study were the novelty of application of synbiotic in COVID-19 and the study population, health care workers, which are in high risk group and any data regarding the prevention of COVID-19 in this population are highly needed.