Certain commensal bacteria that reside in the human intestine produce compounds that inhibit SARS-CoV-2

Researchers from Yonsei University in South Korea have found that certain commensal bacteria that reside in the human intestine produce compounds that inhibit SARS-CoV-2.

The research will be presented on June 20 at World Microbe Forum, an online meeting of the American Society for Microbiology (ASM), the Federation of European Microbiological Societies (FEMS), and several other societies that will take place online June 20-24.

Previous clinical findings have shown that some patients with moderate to severe COVID-19 have gastro-intestinal symptoms, while others showed signs of infection solely in the lungs.

“We wondered whether gut resident bacteria could protect the intestine from invasion of the virus,” said Mohammed Ali, a Ph.D. student in Medicine at Yonsei University, Seoul, South Korea.

To investigate this hypothesis, the researchers screened dominant bacteria inhabiting the gut for activity against SARS-CoV-2. Their search revealed that Bifidobacteria, which have previously been shown to suppress other bacteria such as H. pylori and have proven active against irritable bowel syndrome, had such activity, said Ali.

The investigators also used machine learning to search for potential illness-fighting compounds in databases containing microbially produced molecules, discovering some that might also prove useful against SARS-CoV-2. “To train our model we leveraged previous coronavirus datasets in which several compounds were tested against targets from coronaviruses,” said Mr. Ali. “This approach seems to be significant as those targets share features in common with SARS-CoV-2.”

Ali emphasized the ecological nature of his approach to this work, observing that many existing antibiotics and cancer therapies are compounds that bacteria use to compete with each other within the gastrointestinal tract, and that these were initially purified from microbial secretions.

“Finding microbes that secrete anti-coronavirus molecules will be a promising method to develop natural or engineered probiotics to expand our therapeutics prevention techniques, to provide a more sustainable way to combat the viral infection,” said Ali.

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Acute respiratory tract infections (pneumonia, influenza, enterovirus, adenovirus, and respiratory syncytial virus infections) accounts for one of the major causes of death and debility worldwide (Soriano et al. 2020). A majority of these infections are caused by DNA/RNA viruses. Infections associated with RNA viruses are notable than those caused by DNA viruses (Zolnikova et al. 2018).

Coronaviruses, in particular, represent a highly important emerging RNA virus family causing respiratory infections (Su et al. 2016). The recent ‘Coronavirus disease 2019’ (COVID-19) pandemic causes Severe Acute Respiratory Syndrome (SARS). Some patients with COVID-19 showed a striking dysbiosis in the probiotic group of intestinal microbes such as Lactobacillus and Bifidobacterium (Xu et al. 2020).

In addition, some reports have confirmed a relationship between gut microbiota, secondary gut infection, and COVID-19 disease (Gu et al. 2020; Yeo et al. 2020; Gao et al. 2020). Furthermore, some reports have shown the presence of RNA of SARS-CoV-2 in fecal samples of some infected patients that tested negative for the presence of SARS-CoV-2 RNA in their respiratory samples (Wu et al. 2020; Xiao et al. 2020; Kopel et al. 2020).

These shreds of evidence suggest crosstalk between the gut-lung axis, which to some extent may be modulated by probiotics, by favorably altering the gastrointestinal symptoms and shielding the respiratory system (Gu et al. 2020; Bottari et al. 2020). Therefore, this review article emphasizes to provide insights into the possible role of probiotics in COVID-19 prevention, in so doing, providing a starting point for future studies on it.

Using keywords like COVID-19; SARS-CoV-2; probiotics in the respiratory tract infection; probiotics and antiviral activity; gut-lung axis; probiotics and coronavirus, we have derived the articles and reviewed for this review article.

Cross-talk between gut and lungs microbiome: an important aspect of respiratory diseases

The term microbiome encompasses the entire microbial community such as bacteria, archaea, fungi, and viruses. Advances in research have led to the understanding that there is a dynamic cross-talk between the microbes of the gut-lung axis.

This breakthrough quivered the ancient dogma of the sterile lung environment (Marsland et al. 2015). Linking of the gut and the lung niche is mediated through this axis as it is a route for the passage of hormones, microbial metabolites, cytokines, and endotoxins into the bloodstream.

A balanced gut community is of vital importance in pulmonary immunity. Several studies suggest that dysbiosis in gut microbiota influence pulmonary dysfunction by modulating the immune responses of neutrophils (Enaud et al. 2020), T cell subsets (Ohnmacht 2016; Luu et al. 2017), inflammatory cytokines (Scales et al. 2016)

Toll-like receptors (Wang et al. 2018) and many more. The local or distal immune modulation of the commensal microbes in the lungs and gut affects the onset of the infection process. However, the indigenous gut commensals confer colonization resistance from the microbial pathogens by the concept of ‘barrier effect’ and thus, aid in protecting the gut niche from being altered (George Kerry et al. 2018). The role of the gut microbiome and its effect on respiratory disease is summarized in Table ​Table22.

Table 2 – Microbial and immune alteration of the gut-lung axis in pulmonary infection

Sr no.	Disease/medical condition	Altered gut microbes	Immuno-modulatory factors	References
1	Tuberculosis	↑Haemophilus parainfluenzae, Roseburia inulinivorans, Roseburia hominis, Roseburia, Faecalibacterium, Phascolarctobacterium, and Eubacterium↓Prevotella and Lachnospira and commensal genera of Bacteroidetes	↓CD4, regulatory and memory T cells	Saitou et al. (2018), Zhang et al. (2020a)
2	Bacterial pneumonia	Altered gut microbiota	Down-regulation of CD47, impaired TLR4 function, ↑production of GM-CSF, Th17 cytokine, IL-22 and neutrophils, ↓surfactant protein D	Brown et al. (2017), Felix et al. (2018), Enaud et al. (2020)
3	Fungal pneumonia	Reduction in the commensal gut microbiome	↑Anti-TNFα facilitates migration of dendritic cells from gut to lungs resulting in ↑Tregs	Tweedle and Deepe (2018)
4	Influenza and RSV flu	↑Bacteroidetes↓Firmicutes	↑IFN-γ, IL-6 and CCL2 in lungs and ↓Tregs in lung and gut	Grayson et al. (2018), Rangelova et al. (2019), Li et al. (2019)
5	Asthma	↑Haemophilus, Pseudomonas, Rickettsia, Moraxella, Lactobacillus and Malassezia↓Akkermansia muciniphila, and Faecalibacterium prausnitzii	↑CRP, TNF-α, IL-6	Zhang et al. (2018), Demirci et al. (2019)
6	Cystic fibrosis	In children: ↓Bacteroides, Firmicutes, Faecalibacterium prausnitzii, Bifidobacterium adolescentis and Eubacterium rectale, Candida albicans and Aspergillus fumigatus along with ↑Streptococcus, Staphylococcus, Veillonella dispar, Clostridium difficile, Pseudomonas aeruginosa, and Escherichia coliIn adults: ↓Faecalibacterium prausnitzii and ↑Ruminococcus gnavus, Enterobacteriaceae, and Clostridia species	Not known	Enaud et al. (2020)Fouhy et al. (2017)
7	Chronic obstructive pulmonary disease (COPD)	Presence of Enterobacter cloacae, Citrobacter, Eggerthella, Pseudomonas, Anaerococcus, Proteus, Clostridium difficile, and Salmonella	↑ CRP, IL-6, gut, microflora-dependent metabolite trimethylamine-N-oxide (TMAO)	Charlson et al. (2011); Young et al. (2016), Schaible et al. (2012); Enaud et al. (2020)
8	Lung cancer	Enterococcus sp, Veillonella, Bacteroides, and FusobacteriumBifidobacterium sp., Dialister, Enterobacter, Escherichia–Shigella, Fecalibacterium, and Kluyvera	Alteration of PLR, NLR and LMR	Zhang et al. (2018), Zhuang et al. (2019)

During infection of the respiratory tract, the commensal organisms of our body stimulate the local (from lungs) and the adjacent distal immune response (at the sites of the gut) (Chang and Kao 2019). The gut-lung axis is assumed to be bidirectional, meaning infection by SARS-CoV-2 at the lungs trigger an immune response in the GI tract.

The infection of the lungs with SARS-CoV-2 causes an epithelial disruption in the gas exchange areas and the associated airways (Fanos et al. 2020). Epithelial cells of the alveoli with angiotensin-converting enzyme 2 (ACE2) receptor serve as the binding site for SARS and SARS-CoV-2.

The concentration of pro-inflammatory cytokines [Interferon gamma-induced protein 10 (IP-10); monocyte chemoattractant protein 1 (MCP1) and Interleukin 8 (IL-8)] (Sinha et al. 2020). Overproduction of cytokines and chemokines, activation of T helper cell-mediated immunity, and host inflammatory response was observed during the acute phase of SARS and SARS-CoV-2 infection (Qian et al. 2013).

Recent studies suggest that the involvement of the gut in COVID-19 is even greater and more prolonged compared with the lung (Xu et al. 2020). Strikingly, it has been reported that probiotics show significant microbial inhibitory properties through alveolar macrophage, neutrophils, natural killer cells, and increased levels of pro-inflammatory cytokines like TNF-α and IL-6 in the lung (Dumas et al. 2018). In addition, probiotic bacteria can bind the invading virus and inhibit the pathogen-host cell receptor interaction. Therefore, the use of probiotics as medication restricts respiratory viral infections by fortifying the mucosal immunity (Marsland et al. 2015).

Immunomodulatory activities of probiotics

Given the fundamental importance of gut microbiota in influencing lung diseases, the targeted manipulation of gut bacteria using certain dietary supplements, propose a promising therapeutic approach. Emerging studies suggest the use of probiotic bacteria in the treatment or prevention of a wide range of human diseases, medical conditions, and syndromes.

Probiotics are live microorganisms that, when administered in adequate amounts, confer a health benefit to the host (FAO and WHO, UN). Probiotic mechanisms in preventive and therapeutic approaches consist of amending the intestinal microbial communities, immunomodulation, clamping down the pathogens, and protection of the intestinal barrier. They have already been used in the treatment of antibiotic-associated diarrhea, inflammatory bowel disease, and different chronic inflammatory diseases (Mortaz et al. 2013).

Immune system modulation is a key factor in the prevention of infectious diseases. Probiotic microbes have demonstrated their ability to stimulate and modulate the immune system and also to reduce inflammation (Hardy et al. 2013). Probiotics are known to decrease the severity of infections in the GI tract and the upper respiratory tract by acting on both the innate and the adaptive immune systems.

Currently, the use of probiotic microorganisms and their metabolic products represents a promising approach for the treatment of viral diseases (Ryan et al. 2015). Colonization of intestinal epithelium by the probiotic bacteria has been shown to reduce the incidences and symptoms of viral respiratory infections.

This is achieved by the upsurge of IgA expressing B cells in the colon and lymph nodes in conjunction with the increasing population of the T follicular helper cells and IL-23–expressing dendritic cells. Furthermore, probiotics also comprise of immunostimulatory constituents such as peptidoglycan, lipoteichoic acid, Toll-like receptor (TLR) ligands, and muramyl dipeptide, which accentuates their immunomodulatory potency (Kanauchi et al. 2018).

The recent study of Ji et al., demonstrated that the supplementation of probiotics to RSV-infected mice has significantly elevated the abundance of short-chain fatty acid (SCFA) producing gut microbiota which in turn up-regulate the production of interferon β. Besides, they have also reported the upsurge of Corynebacterium and Lactobacillus species in the lung due to higher SCFA production, consequently leading to the activation of interferon β production in alveolar macrophages (Ji et al. 2020).

A randomized, double-blind and placebo-controlled human study of 109 adults demonstrated the enhanced level of anti-inflammatory cytokines IL-4 and IL-10 and reduced plasma peroxidation and oxidative stress upon administration of L. plantarum DR7.

The COVID-19 infection affects the lung tissues and gut, thus activating the inflammatory response. It increases the proinflammatory cytokines (IFN-γ, TNF-α) which lead to the emergence of the cytokine storm. This response is probably because of the activation of T helper cells (Th1) cell response in the lung tissue (Lehtoranta et al. 2014).

In the case of the human gut environment, dysbiosis in the gut microbiota results in the imbalance of Th1 and Th2 which further results in the activation of proinflammatory cytokine and eventually the cytokine storm in the lungs as well (Qian et al. 2017). Upon administration of probiotics, there is colonization of so-called “good bacteria” in the gut which leads to a shift in the balance between Th1/ Th2 cells that reduces the cytokine storm and reduces the severity of diseases (Qian et al. 2017).

Recently it has been found that medication with probiotic bacteria using Bifidobacteria and Lactobacillus provides a significant chance of recovery against COVID-19 (Fanos et al. 2020). Previously, these probiotic bacteria Probiotics were reported to have beneficial effects against respiratory infection by the influenza virus (Zelaya et al. 2016).

Administration and consumption of probiotics advance the immune system by enhancing the level of type I interferons, antigen-presenting cells (APC), Natural Killer cells (NK cells), and B and T cells of the lungs (Dhar and Mohanty 2020). Probiotic administration can also improve the pro- and anti-inflammatory cytokines, helping to clear the viral infection by minimizing the cell damage in the lungs (Baud et al. 2020).

Role of probiotics in respiratory virus infections

By maintaining the gut homeostasis probiotics are beneficial in preventing antibiotic-associated diarrhea, also prevent the adhesion and colonization of pathogenic microbes (Guo et al. 2019). Hence, protect from infections in the gastrointestinal tract and various other body sites.

The respiratory tract is one of them. Several animal model studies have reported the beneficial effects of L. plantarum species that, reduce the symptoms of influenza viral infection and increases the body weight and survival rate of mice (Maeda et al. 2009; Kawashima et al. 2011; Park et al. 2013). Similarly, the anti-viral activity of L. casei was reported by Hori et al. (2001) against the H1N1 virus, they observed a reduction in viral titer (Hori et al. 2001). L. rhamnosus is reported for its ability to stimulate the host immune system and anti-influenza viral activity.

With Lactobacillus species, Bifidobacterium species are also commensal bacterium of the human gut and reported for their beneficial effects to host. It promotes good digestion, boosts the immune system, and inhibits intestinal pathogens (Mayo and Sinderen 2010).

In many studies, bifidobacterial strains were used in combination with lactic acid bacteria to assess their anti-vital potential. A double-blind, placebo-controlled, randomized trial of 201 healthy infants aged between 4 and 10 months was administered with a combination of L. reuteri DSM 1793 and B. animalis spp. Lactis BB12. The combination reduced the RTI symptoms, fever, and antibiotic consumption (Weizman et al. 2005), while a similar effect was also observed with only B. animalis spp. and Lactis BB12 strain (Taipale et al. 2011).

The use of L. plantarum, L. salivarius, L. rhamnosus GG, and L. casei Shirota is well reported for their antiviral activity against rotavirus, transmissible gastroenteritis coronavirus (Maragkoudakis et al. 2010; Rejish Kumar et al. 2010). Furthermore, the in vitro antiviral activity of probiotic strain Enterococcus faecium NCIMB 10,415 demonstrated the 3-log reduction in the viral titer.

The authors also reported that the E. faecium alters the expression of interleukins, IL-6, and IL-8 and induces the production of Nitric oxide which might be the reason for its antiviral activity (Chai et al. 2012). The study of Wang et al. (2019) also reported the antiviral activity of Lactobacillus plantarum against transmissible gastroenteritis virus, which in turn activates the antiviral proteins via JAK-STAT signalling pathway and up-regulate the expression of interferon genes, resulting in anti-transmissible gastroenteritis virus activity (Wang et al. 2019). These reports further indicate the efficacy of probiotic strains to treat the infection of coronavirus.

Besides the oral intake of probiotics, the nasopharynx sprays have also shown promising results in terms of reduced viral infections (Lehtoranta et al. 2014). The topical application of probiotics has been proved effective against Chronic Rhinosinusitis (CRS) and asthma, redefining the futuristic research (Cervin 2018). The ability of probiotics to combat viral infections can be a solution to the lack of antiviral agents (Kassaa et al. 2015). Lactobacillus and Bifidobacterium genus are the most studied genus concerning anti-respiratory virus activity specifically against H1N1, Influenza, and RSV viruses (Table ​(Table33).

Table 3 – Use of probiotics as antiviral supplements

Sr. No	Probiotic strains	Origin	Anti-viral activity	Mechanisms of immune modulation	References
1	Lactobacillus plantarum L-137	Fermented food	Influenza virus A—H1N1	Proinflammatory activity	Murosaki et al. (1998)
Th1 immune response	Maeda et al. (2009)
2	L. plantarum DK 119	Fermented food	Influenza virus A	Increase of IFNγ and IL-2	Park et al. (2013)
3	L. rhamnosus CRL 1505	–	RSV	Innate immunity stimulation and induction of IFN-α production via TLR3/RIG-I-triggered antiviral respiratory immune response	Tomosada et al. (2013)
4	L. gasseri TMC0356	Human gut	H1N1	Decrease in the severity of symptoms and viral titer. Stimulation of IL-12, IL-6, IFNγ, and IgA production	Kawase et al. (2010)
5	Bifidobacterium longum BB536	Healthy Infant	H1N1	Increase in IFNγ and IL-6	Iwabuchi et al. (2011)
6	B. animalis ssp. Lactis BB12	–	RTIs	Reduction in the viral titer	Taipale et al. (2011)

All these studies found that the administration of probiotics shortens the duration of infections, reduces the severity, (de Vrese et al. 2006; Boge et al. 2009) improves immunity and gut health (Akatsu et al. 2013). Hence, we believe that these probiotics can be good neutraceutical and promising immunobiotic agents to treat the infection of COVID-19.

Probiotic metabolites and antiviral activity

Lactic acid bacteria (LAB) are known to produce a variety of antimicrobial substances such as acids, peptides or proteins, non-ribosomal peptides (NRP), hydrogen peroxide, and other metabolites. Hydrogen peroxide is toxic to many non-catalase microorganisms; however, their anti-respiratory tract viral activity is not known but their activity against human immunodeficiency virus HIV-1 and Herpes simplex virus HSV-2 were reported earlier (Klebanoff and Coombs 1991; Conti et al. 2009).

Lactic acid, the product of carbohydrate metabolism is an important microbicidal compound, it kills acid-sensitive microbes. It helps the host cells in preventing viral replication (Conti et al. 2009). Furthermore, the study of Verma et al. 2019, demonstrated the expression and secretion of Human (Angiotensin-Converting Enzyme) ACE-2 (a receptor required by COVID-19 virus for its binding) in Lactobacillus paracasei (Verma et al. 2019). Binding of this secreted ACE-2 with COVID-19 binding protein can prevent its entry into the cell and thus reduced the chances of infection (Rizzo et al. 2020).

Antimicrobial peptides are produced by probiotics organisms are the molecules most characterized for their antimicrobial activity and anti-viral activity. Bacteriocins are the antimicrobial peptides produced by genera Lactobacillus and Enterococcus spp. having broad-spectrum activity against various Gram-positive and Gram-negative bacteria.

It can be used as alternatives to antibiotics or in combination with antibiotics. Bacteriocin compounds such as staphylococcin 188, enterocin AAR-74, erwiniocin NA4 have been evaluated for antiviral activity. Their activity is reported against HIV, HSV, Coliphage, influenza virus, and particularly H1N1 virus (Klebanoff and Coombs 1991; Quereshi et al. 2006; Conti et al. 2009; Lange-Starke et al. 2014).

Similarly, the nonribosomal peptides (NRPs) are also the secondary metabolites produced by probiotic microbes that have very broad clinical applications. Their uses are reported as antibiotics (daptomycin), anti-tumor drugs (bleomycin), antifungal drugs, and immunosuppressants (cyclosporin) (Walsh 2008).

reference link : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7690945/

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