4. Discussion:
Here, we reviewed the literature regarding several probiotics based on the papers which described single probiotics in clinical trial to avoid the crosstalk or mutual interference between probiotics. To the best of our knowledge, this is the first systematic review reporting probiotics-related findings in COVID-19 pandemic. Probiotic strains likeLactobacillus plantarum, Lactobacillus casei,Bifidobacterium animalis, Bacillus coagulans, Streptococcus salivarius, and Enterococcus faecium  had inhibitory effects on proinflammatory interleukins. Moreover, several conventional probiotics (Lactobacillus gasseri, Lactobacillus rhamnosus, Bifidobacterium longum ) potentially increased the level of antibodies.
Coronaviruses (CoVs) involve a large family of surrounded, positive-stranded RNA viruses that infect a wide range of animal hosts as well as humans. The most common representatives are porcine respiratory CoV, porcine transmissible gastroenteritis virus, porcine epidemic diarrhoea virus, canine CoV, human CoVs, severe acute respiratory syndrome-associated CoV, murine hepatitis virus (MHV), avian CoV infectious bronchitis virus (IBV) and turkey CoV (TCoV). The most recognized coronavirus, the Middle East respiratory syndrome virus, was found in Africa and Asia 38. At the present, antivirals have been developed for management of the CoV-induced infections, however, the treatment process is affected by other determinants. For example, some data are available on the association of COVID-19 and intestinal microbiota. Lactobacilli andBifidobacteria are two conventional probiotics that can really tip the balance of a diverse gut ecosystem in combating COVID-199.
There are some mechanisms explaining the antiviral impacts of probiotics. A brief report 39 claimed that high-single dose endoscopic administration of appropriate and reliableBifidobacterium Infantis (BB-12 ), as potential probiotic, or use of these strains’ lipopolysaccharide membranes in vaccine development especially in patients with gastrointestinal symptoms (diarrhea, abdomen pain, vomiting) can result in more therapeutic and preventive effects in Coronavirus-infected patients40,41. Consequently, Bifidobacterium animalistheoretically can inhibit the replication of coronaviruses by reducing ER stress-related autophagy, especially the inositol-requiring enzyme 1 (IRE1) pathway, over its anti interleukin-17 effect19. Apparently, the main pathogenic mechanism that makes viral infection-induced pneumonia seems to be a “cytokine storm”; IL-6 is the main proinflammatory marker in this regard42. Anyway, the state of knowledge regarding the immunomodulatory effects of probiotics has recently advanced.
Some probiotics have potency to induce the interferon (IFN) production pathways. Lactococcus lactis JCM5805 can activate human Plasmacytoid dendritic cells (pDCs) in vitro; pDCs play a crucial role in antiviral immunity as proficient type I IFN producing cells (IPCs)43,44 and mucosal T cell independent IgA production45. pDC-derived type I IFNs can indirectly inhibit viral replication and spread 46, and activation of NK cells 45. Two distinct types of Toll-like receptors (TLR7 and TLR9) - expressed by pDCs - have some molecular role47; TLR7 recognizes the microbial RNA of virus48,49, and TLR9 senses the ssDNA containing CpG motifs50,51. Upon sensing the viral nucleic acid, interferon regulatory factor 7 (IRF7) is activated, phosphorylated, and translocated into the nucleus to begin the transcription of type I IFNs52. In conclusion, this strain had many important roles in both innate immunity and adaptive immunity; as well, several human-based trials confirmed this observation (influenza virus as main target) 53-55. Furthermore, some probiotic strains such as Enterococcus faecium HDRsEf1 could significantly downregulate the mRNA level of TLR4, TLR5, TLR7, and TLR824.
As discussed earlier, there have also been negative reports against probiotics. According to scRNA-Seq analysis, Feng et al. found that the SARS-Cov-2 receptor, ACE2, could be elevated in the presence of both invasive bacteria Salmonella Enterica and its counterpart,Segmented Filamentous Bacteria as probiotics in the mouse small intestine 56 and human enterocytes57. in another study Lactobacillus acidophilusand Bacillus clausii also failed to decrease the coronavirus receptors expression in the murine small intestine compared to control and post Salmonella infection 58.
In total, the US Food and Drug Administration classifies these as GRAS (Generally Recognized As Safe) organisms, so the risks of probiotics administration seem to be low, although the amount and type of strains are also considerable 59,60. Notably, unconfirmed prescription of conventional probiotics for COVID-19 is not recommended until further investigations regarding the pathogenesis of SARS-CoV-2 and its effect on gut microbiota were published.
A few limitations of this review shall be highlighted; systematic review table was not designed due to inconsistent data of relevant studies; COVID-19 papers did not report the required detail. Moreover, meta-analysis has not been performed due to heterogeneity of studies, especially in relation to published data for SARS-CoV-2. Secondly, we excluded a large number of research on supplementation of different nutrients, which were related to immune function. However, the main strength of the current study was that we performed an exclusive investigation for diseases of the same origin i.e. virus disease, especially COVID-19 for first time.