A possible probiotic (S. salivarius K12) approach to improve oral and lung microbiotas and raise defenses against SAR S-CoV-2

A possible probiotic (S. salivarius K12) approach to improve oral and lung microbiotas and raise defenses against SARS-CoV-2

The coronavirus disease 2019 (COVID-19), a pathology caused by a novel beta-coronavirus named SARS-CoV-2, is spreading rapidly and scientists are endeavoring worldwide to develop drugs for efficacious treatments and vaccines to protect human life. SARS-CoV-2 shares 79% sequence identity with SARS-CoV, the virus that caused a major outbreak in 2002-2003. In an identical manner to SARS-CoV, SARS-CoV-2 utilizes the ACE-2 receptor to bind to lung cells where it can cause severe, and possibly fatal, pneumonia. Most cases of transmission occur via person-to-person respiratory droplets and from environmental surfaces to the hands and then to the nose and mouth. Both pathways allow the virus to reach, as the first step, the upper respiratory tract from where it can spread to the lungs.1 The oral and the upper respiratory tract microbiotas contain large populations of the genus Streptococcus, with both commensal and pathogenic streptococci competing for several niches using a variety of strategies. For instance, streptococci have a remarkable ability to metabolize carbohydrates via fermentation, thereby generating acids as by-products. Excessive acidification of the oral environment by aciduric species such as Streptococcus mutans is directly associated with the development of dental caries. However, less acid-tolerant species such as Streptococcus salivarius can also produce large amounts of alkali, thereby playing an important role in the acid-base physiology of the oral cavity. Streptococcus salivarius is a numerically-prominent foundation member of the upper respiratory tract microbiota and some members of this species have been shown to exert a bacterial interference versus Streptococcus pyogenes, Streptococcus pneumoniae, Moraxella catarrhalis and Haemophilus influenzae, pathogens involved in recurrent pharyngitis, tonsillitis and in acute otitis media.2 A particular strain of Streptococcus salivarius, known as K12,3 has been clinically demonstrated to play a role in creating a stable upper respiratory tract microbiota capable of protecting the host from pathogenic bacteria, fungi and viruses, thereby reducing the incidence of streptococcal pharyngo-tonsillitis, acute and secretory otitis media, halitosis, oral thrush and viral infections (rhinitis, influenza, pharyngitis, laryngitis, tracheitis and enteritis). The antibacterial role of strain K12 has been attributed to the release of bacteriocins (Salivaricin A2 and Salivaricin B) that can create instability in the membranes of susceptible, pathogenic bacteria. In contrast, the anti-Candida action seems to be mainly due to the ability of strain K12 to compete with fungal hyphae in adhering to oral mucosa. The proposed antiviral capability of strain K12 has been attributed to the observed development of an adaptive immune response as revealed by detection of enhanced levels of IFN-γ in human saliva 10 hours after oral lozenge administration, with values at 24 hours between 22 and 139 pg/mL (Figure 1).4

Figure 1.—Detection of salivary IFN-γ after administration of Streptococcus salivarius K12. From: Chilcott et al.4

Intrinsic antiviral activities are mediated by interferon-induced proteins and can cause the induction of nitric oxide synthase, which can directly impacts upon virus viability, affecting RNA degradation in the cell and inducing cell apoptosis. IFN-γ release occurs without modifying either IL-1β or TNF-α levels, and substantially lowering IL-8 release, therefore occurring without evoking an inflammatory response. Moreover, Streptococcus salivarius K12 is capable of suppressing bronchial inflammatory responses by inhibiting NF-κB pathways and other important human immune cell functions. This last finding is important, because viruses have evolved the ability to modulate the NF-κB pathway, thereby enhancing their replication, reducing host cell survival and aiding evasion of host immune responses.

Anatomical and physiological considerations indicate that the oral cavity is the primary source of the lung microbiota community, acquired via microaspiration and inhalation.5 Indeed, the microbiota of healthy lungs overlaps with that found in the mouth. The prominent genera in bronchoalveolar lavage fluid samples from healthy subjects include Streptococcus, Prevotella and Veillonella, and these taxa are also detected in concurrently-collected oral samples. In contrast, in asthma or in chronic obstructive lung disease, oral cavity-derived pathogenic bacteria such as Haemophilus and Moraxella are particularly abundant within the lung microbiota and induce a higher production of inflammatory interleukins than in lung tissue where the bacteria consortium mainly consists of the oral commensal bacteria. In cystic fibrosis, the lung-dominant taxon, in at least 50% of all cases, is considered to be Pseudomonas aeruginosa. Its presence correlates with patient disease severity. Conversely, when commensal streptococci, especially Streptococcus salivarius, dominate the lung bacteria consortium, their presence correlates with patient stability.

Recent studies have shown that the microbiota in the lung contributes to immunological homeostasis and can potentially, when affected by dysbiosis, alter susceptibility to viral infection. With respect to COVID-19, a highly significant difference in the lung microbiota composition has been observed between patients with SARS-CoV-2 pneumonia and healthy subjects, implying a dysbiosis occurred in the lung microbiota of patients (Figure 2).6

Figure 2.—Principal Coordinates Analysis of lung microbiotas from healthy subjects or patients affected by pneumonia. From Shen et al.6

Unfortunately, only eight subjects with SARS-CoV-2 pneumonia have been assessed. Six of these had a pathogen-enriched microbiota, and the other two had a commensal-enriched microbiota. Just one lung microbiota among the COVID-19 patients showed the presence of the genus Streptococcus, with no analysis performed at the species level. Not only can lung microbiota dysbiosis create a more fertile ground for viral aggression, but it can also promote a worsening of the patient condition. It is well known that a common complication of viral infection, especially for respiratory viruses, is a secondary bacterial infection and these infections can contribute to a significant increase in morbidity and mortality. Therefore, the elevated levels of potentially pathogenic bacteria in the lungs of COVID-19 patients could increase the risk of secondary infection.

In conclusion, Streptococcus salivarius is a predominant commensal species in healthy oral and upper respiratory tract microbiotas, and some members of this species have been shown to actively interfere with the growth of potentially-pathogenic microbes. Along with other oral commensals, Streptococcus salivarius is a common member of the lung eubiotic microbiota, and its presence in the lung correlates with healthy or more stable conditions. COVID-19 patients have a significantly altered lung microbiota, particularly enriched by potentially pathogenic species of bacteria and markedly different to that of healthy subjects. Strain K12 is the most thoroughly studied strain of Streptococcus salivarius. Colonization of the upper respiratory tract with strain K12 leads to a significantly reduced occurrence of many viral upper respiratory tract infections, both in children and in adults, possibly due to its ability to stimulate IFN-γ release and to activate natural killer cells without triggering aggressive inflammatory responses.7 Although its efficacy has never been specifically evaluated with respect to SARS-CoV-2, the various observations of its clinical potential, together with its strong safety profile extending over more than 20 years of probiotic application, may prompt physicians to consider using it as an adjunct to help control viral lung infections and associated pneumonias and to improve host immune functions.

Francesco DI PIERRO *

Velleja Research, Milan, Italy

• Corresponding author: Francesco Di Pierro, Velleja Research, Milan, Italy. E-mail: f.dipierro@vellejaresearch.com

References

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3. Di Pierro F, Risso P, Poggi E, Timitilli A, Bolloli S, Bruno M, et al. Use of Streptococcus salivarius K12 to reduce the incidence of pharyngo-tonsillitis and acute otitis media in children: a retrospective analysis in not-recurrent pediatric subjects. Minerva Pediatr 2018;70:240–5. PubMed https://doi.org/10.23736/S0026-4946.18.05182-4

4. Chilcott CN, Crowley L, Kulkani V, Jack RW, McLellan AD, Tagg J. Elevated levels of interferon gamma in human saliva following ingestion of Streptococcus salivarius K12. Presented at: Joint New Zealand and Australian Microbiological Societies Annual Meeting. Dunedin, New Zealand, 22–25 November 2005.

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6. Shen Z, Xiao Y, Kang L, Ma W, Shi L, Zhang L, et al. Genomic diversity of SARS-CoV-2 in Coronavirus Disease 2019 patients. Clin Infect Dis 2020;ciaa203. PubMed https://doi.org/10.1093/cid/ciaa203

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Conflicts of interest.—The author works in the scientific department where a finished form of strain K12 has been developed.

Acknowledgements.—The author wishes to thank Ruth Dilleen for English language revision.

History.—Article first published online: April 7, 2020. - Manuscript accepted: April 2, 2020. - Manuscript received: March 31, 2020.

(Cite this article as: Di Pierro F, A possible probiotic (S. salivarius K12) approach to improve oral and lung microbiotas and raise defenses against SARS-CoV-2. Minerva Med 2020;111:281-3. DOI: 10.23736/S0026-4806.20.06570-2)