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.