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 (Siddell et al., 1983). 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-19 (K. Xu et al., 2020).
There are some mechanisms explaining the antiviral impacts of probiotics. A brief report (Hüseyin S Bozkurt, 2020) 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 patients (K. Bozkurt et al., 2019; Schiavi et al., 2016). Consequently,Bifidobacterium animalis theoretically 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 effect (Hüseyin Sancar Bozkurt & Quigley, 2019). 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 regard (Angeletti et al., 2020). 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) (Siegal et al., 1999; Trinchieri & Santoli, 1978) and mucosal T cell independent IgA production (Tezuka et al., 2011). pDC-derived type I IFNs can indirectly inhibit viral replication and spread (Theofilopoulos, Baccala, Beutler, & Kono, 2005), and activation of NK cells (Tezuka et al., 2011). Two distinct types of Toll-like receptors (TLR7 and TLR9) - expressed by pDCs - have some molecular role (Gilliet, Cao, & Liu, 2008); TLR7 recognizes the microbial RNA of virus (Lee, Lund, Ramanathan, Mizushima, & Iwasaki, 2007; Lund et al., 2004), and TLR9 senses the ssDNA containing CpG motifs (Bauer et al., 2001; Latz et al., 2007). 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 IFNs (Kawai et al., 2004). 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) (Fujii et al., 2017; Jounai, Sugimura, Ohshio, & Fujiwara, 2015; Shibata et al., 2016). Furthermore, some probiotic strains such as Enterococcus faecium HDRsEf1 could significantly downregulate the mRNA level of TLR4, TLR5, TLR7, and TLR8 (Tian et al., 2016).
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 (Liang et al., 2020) and human enterocytes (Feng, Wang, & Qi, 2020). in another study Lactobacillus acidophilus andBacillus clausii also failed to decrease the coronavirus receptors expression in the murine small intestine compared to control and post Salmonella infection (Pradhan et al., 2019).
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 (Askari & Moravejolahkami, 2019; Moravejolahkami & Chitsaz, 2019). 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.