Streptococcus salivarius

Streptococcus salivarius: A Comprehensive Reference

1. Identity, Taxonomy, and Natural Source

1.1 Taxonomic Classification

Streptococcus salivarius is a spherical, Gram-positive, facultative anaerobic commensal bacterium that is both catalase and oxidase negative. It belongs to the Domain Bacteria, Phylum Firmicutes, Class Bacilli, Order Lactobacillales, Family Streptococcaceae, Genus Streptococcus. The salivarius group of streptococci consists of three genetically similar species: Streptococcus salivarius and Streptococcus vestibularis, two commensal bacteria, and Streptococcus thermophilus, a nonpathogenic dairy species — all belonging to the viridans group of streptococci.

1.2 Natural Habitat and Ecological Role

Streptococcus salivarius is a predominant member of the oral microbiome that persists throughout the human life; it is not known to initiate infections in healthy or immunocompetent individuals. S. salivarius colonizes the buccal epithelium and is a resident of the tongue dorsum. Streptococcus species make up 5–20% of a healthy adult's oral microbiota, of which S. salivarius represents 10–30% of the total streptococcal taxa. S. salivarius has been detected in saliva samples of children and adults at levels in the ranges of 10⁷–10⁸ CFU/mL; thus, exposure to S. salivarius occurs on a continual daily basis.

S. salivarius is also commonly detected as an inhabitant of the gastrointestinal tracts of healthy humans and has been described as a typical small intestine commensal species. S. salivarius is an early colonizer species that colonizes the human oral cavity from newborn infants and persists as a predominant member of the commensal microbiota throughout life.

1.3 Clinically Relevant Strains Used as Supplements

Three strains of S. salivarius — M18, K-12, and 24SMB — have been the focus of probiotic research, and all have demonstrated positive benefits in clinical studies. These strains differ in their bacteriocin profiles and primary applications:

• K12 (BLIS K12^®): A probiotic strain producing the bacteriocins salivaricin A2 and salivaricin B, both of which strongly antagonize the growth of Streptococcus pyogenes, the most important bacterial cause of pharyngeal infections in humans. Strain K12 was originally isolated from the oral cavity of a healthy child.
• M18: Strain M18 offers the potential to confer oral health benefits as it produces bacteriocins targeting the important cariogenic species Streptococcus mutans, as well as the enzymes dextranase and urease, which could help reduce dental plaque accumulation and acidification, respectively.
• 24SMB: Genome analysis of the S. salivarius 24SMBc strain has revealed biosynthetic gene clusters involved in antimicrobial effects on Streptococcus pneumoniae and Streptococcus pyogenes.

1.4 Common Commercial Forms and Preparations

Oral administration of S. salivarius supplements is available as a chewable tablet or powder. Lozenges are another commonly employed form in clinical trials and commercial products. Streptococcus salivarius K12 is registered as a food supplement in the majority of countries in Europe, Australia, Asia, and the Americas, and holds Generally Recognized As Safe (GRAS) status in the United States, reflecting its safety history in both children and adults.

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2. Traditional and Historical Use

S. salivarius is not a botanical ingredient with a documented ethnobotanical or herbal medicine history. Rather, its therapeutic application emerged exclusively from scientific investigation into the human oral microbiome during the latter decades of the twentieth century. The organism's role as a pioneer colonizer of the infant oral cavity and its naturally antagonistic relationship with pathogenic streptococci were recognized by researchers, particularly at the University of Otago in New Zealand, as a basis for developing what is now called bacterial replacement therapy.

S. salivarius plays a positive role in oral and digestive tract ecology. It may exert its positive impact through effects on the stability of the microbiome, bacterial interference, and/or host interaction. The recognition of this naturally protective role led to deliberate isolation of bacteriocin-producing strains and their development as commercial probiotic products — a process formalized in academic publications from the early 2000s onward. There is no pre-modern traditional use documented in indigenous or historical medical systems for this specific organism as an isolated therapeutic agent.

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3. Key Constituents and Active Compounds

3.1 Salivaricins (Bacteriocins)

Some strains of S. salivarius secrete bacteriocins with antimicrobial activity against other species; these compounds are called salivaricins. Salivaricins are ribosomally synthesized and posttranslationally modified peptides (RiPPs), mostly belonging to the lantibiotic class II of lanthipeptides.

The oral probiotic strain K12 is known to produce the megaplasmid-encoded class I lantibiotics, salivaricin A2 and salivaricin B. Expression of these two salivaricins enables BLIS K12 to counteract the growth of Streptococcus pyogenes and, to a lesser extent, Haemophilus influenzae, Streptococcus pneumoniae, and Moraxella catarrhalis, all of which are involved in the etiopathogenesis of acute otitis media.

Specific salivaricins include salivaricins A2, B, and 9, which are active against a broad range of competing bacteria, including common respiratory pathogens like Streptococcus pyogenes.

More recently, a novel phospho-modification was identified in the lantibiotic bacteriocin salivaricin 10. Synthesized by the sal10 strain of S. salivarius, salivaricin 10 is a class II lantibiotic that was found to have a phosphothreonine at position 4 along its N-terminus — the first of any lantibiotic known to possess such a post-translational modification. While possessing a similar bioactivity spectrum to other reported lantibiotics, it was also found to have unique immunomodulatory capabilities partly due to the presence of the phosphate moiety.

3.2 Enzymes (Strain M18)

Strain M18 produces, in addition to bacteriocins, the enzymes dextranase and urease, which could help reduce dental plaque accumulation and acidification, respectively. Dextranase degrades dextran-based polymers in the biofilm matrix, while urease hydrolizes urea to raise local pH — both mechanisms that inhibit the cariogenic activity of Streptococcus mutans.

3.3 Lipoteichoic Acid (LTA) and Cell-Surface Components

The surface molecules of S. salivarius G7 do not induce the expression of inflammatory cytokines, and S. salivarius G7 LTA inhibits the inflammatory cytokines induced by LPS and LTA of periodontopathogens. S. salivarius G7 LTA also inhibits the binding of pathogen-derived LPS and LTA to cells, and blocks the binding of these molecules to CD14 and LPS-binding protein (LBP).

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4. Established Mechanisms of Action

4.1 Bacteriocin-Mediated Pathogen Inhibition (Competitive Exclusion)

S. salivarius K-12 was selected for its ability to produce bacteriocin-like inhibitory substances (BLISs), which actively inhibit Streptococcus pyogenes, a key agent of streptococcal pharyngitis. This is a significant part of its mode of action. S. salivarius K-12 and S. salivarius M18 have the ability to colonize the upper respiratory tract and outcompete pathogens through niche competition and immune modulation.

4.2 Inhibition of the NF-κB Inflammatory Pathway

S. salivarius is a pioneer colonizer of the oral cavity and gastrointestinal tract in humans and is known to promote the establishment of immune homeostasis and management of host inflammatory responses by inhibiting the activation of the nuclear factor kappa B (NF-κB) pathway. Studies have shown that an oral probiotic commensal strain of S. salivarius is able to inhibit inflammatory responses in human bronchial epithelial cells by downregulating the NF-κB pathway.

This suppression decreases the secretion of inflammatory cytokines, such as Interleukin-8 (IL-8) and Groα, even when the cells are challenged with known pathogens.

4.3 Inhibition of Pro-Inflammatory Cytokine Production

In addition to bacteriocin production, the K12 strain has immunomodulatory properties and contributes actively to the host defense process: downregulating inflammatory responses by inhibiting the NF-κB pathway, interfering with IL-8 synthesis, and suppressing IL-8 secretion.

4.4 Colonization and Persistence

BLIS K12 colonizes the oral cavity and, to a lesser extent, the nasopharynx and adenoids, remaining present in the tissues for up to 1 month after the last administration. K12 can be detected at the mucosa surface for as long as 3 weeks following its entry to the oral cavity. The amount of S. salivarius K12 decreases steadily from the 8th day after stopping use.

4.5 Immunomodulation via Salivaricins

Salivaricin 10 was shown to directly augment host immunity through activation of neutrophils, downregulation of pro-inflammatory macrophages, and upregulation of anti-inflammatory macrophages. Additionally, the compound demonstrated highly selective activity, antagonizing species associated with cariogenicity and malodorousness.

4.6 Biofilm Inhibition

S. salivarius strains have been reported to inhibit biofilm formation by Streptococcus pyogenes and Streptococcus mutans as well as adherence by Candida albicans.

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5. Scientific Evidence by Area of Clinical Application

5.1 Streptococcal Pharyngitis and Tonsillitis (Upper Respiratory Tract)

Evidence strength: Moderate — multiple RCTs exist but most assessed as methodologically limited.

Sore throat resulting from pharyngotonsillitis is one of the commonest reasons for primary care consultation and inappropriate antibiotic prescription; researchers have sought to evaluate the evidence for using the probiotic S. salivarius K12 (SsK12) for the prevention or treatment of pharyngotonsillitis.

A systematic review identified four articles (1,846 participants). All were deemed to be of poor quality using the Cochrane risk-of-bias assessment. Two trials studied SsK12 prophylaxis for streptococcal pharyngitis in children without a history of recurrence.

A clinically notable pilot investigation enrolled children with a documented recent history of recurrent pharyngeal streptococcal disease. In total, 48 children with a recent history of recurrent pharyngeal streptococcal disease were enrolled in the treated group. The daily use of BLIS K12 was associated with a concurrent and persisting reduction in the occurrence of pharyngeal, recurrent, streptococcal disease. Moreover, the benefits to children may also extend to a reduction of nonstreptococcal diseases, including tracheitis, viral pharyngitis, rhinitis, flu, laryngitis, acute otitis media, and enteritis. However, this was a pilot study without a parallel control group, limiting the strength of conclusions.

5.2 Acute Otitis Media (AOM)

Evidence strength: Mixed — small supportive trials exist, but the largest high-quality RCT found no effect.

Early pilot data: Twenty-two children with a diagnosis of secretory otitis media (SOM) were treated daily for 90 days with an oral formulation containing the oral probiotic S. salivarius K12. After treatment, children were evaluated for AOM episodes and subjected to tone audiometry, tympanometry, endonasal endoscopy, otoscopy, and tonsillar examination. Subject compliance and probiotic tolerability and side effects were also evaluated. Results indicated a good safety profile, a substantial reduction of AOM episodes, and positive outcomes for all clinical outcomes tested. The researchers concluded that strain K12 may have a role in reducing the occurrence and/or severity of SOM in children. This was, however, an uncontrolled pilot study.

The largest controlled trial to date yielded a negative result: In a randomized clinical trial of 827 children aged 1 to 6 years, the daily use of a S. salivarius K12 oral probiotic product for 6 months did not reduce the occurrence of AOM. These findings suggest that oral S. salivarius K12 should not be recommended for prevention of AOM in children. This double-blind, randomized placebo-controlled clinical trial was conducted from August 1, 2020, to May 31, 2021, at 50 day care centers in the Oulu region of Finland. Eligible participants were randomly allocated to receive 1 daily dose of a S. salivarius K12 product or placebo every evening for 6 months.

5.3 Dental Caries and Oral Health (Strain M18)

Evidence strength: Preliminary to moderate — multiple small RCTs showing plaque and S. mutans reductions; longer-term caries-incidence data are limited.

The oral probiotic S. salivarius M18 offers the potential to confer oral health benefits as it produces bacteriocins which target Streptococcus mutans. The purpose of one clinical trial was to assess the effect of SM18 probiotics on salivary S. mutans and to identify the correlation between dental caries and salivary S. mutans count. This clinical trial was conducted in 40 children between the age group of 3–6 years, subjects were randomly selected, and the decay extracted filled (DEF) score was recorded.

A pivotal randomized double-blind, placebo-controlled study: In a study of 100 dental caries-active children, treatment with M18 was administered for 3 months and the participants were assessed for changes to their plaque score and gingival and soft-tissue health. At treatment end, the plaque scores were significantly (P = 0.05) lower for children in the M18-treated group, especially in subjects having high initial plaque scores. Cell-culture analyses of sequential saliva samples showed no differences between the probiotic and placebo groups in counts of the specifically enumerated oral micro-organisms, with the exception of the subgroup of M18-treated children who appeared to have been colonized most effectively with M18. This subgroup exhibited reduced S. mutans counts, indicating that the anti-caries activity of M18 probiotic treatments may be enhanced if the efficiency of colonization is increased. It was concluded that S. salivarius M18 can provide oral health benefits when taken regularly.

Regarding anti-gingivitis effects: A double-blind, randomized, placebo-controlled, two-arm parallel-group trial evaluated the effect of oral probiotic containing S. salivarius M18 strain on gingival inflammation, bleeding on probing, and oral biofilm. In that study, 87.5% of M18 salivary bacteria users who had a large amount of plaque at the beginning of the intervention showed a significant decrease in plaque formation, while those with large plaque in the placebo group showed a 44% decrease in plaque formation.

5.4 Halitosis (Bad Breath)

Evidence strength: Preliminary — a small number of controlled trials show reductions in oral malodor.

A randomized, controlled clinical trial was conducted by Jamali et al. (Faculty of Dentistry, Tabriz University of Medical Sciences) on 208 male and female children between the ages of 6 and 9 years exhibiting mild-to-strong oral malodor, as recorded by experienced examiners. The investigators found that add-on supplementation with BLIS K12^® significantly reduced oral malodor, to varying degrees, in virtually every child.

Researchers concluded that the reduction of malodor may be due to the prolonged survival of S. salivarius K12 and the selective suppression of malodor-related microbes by competitive growth on the tongue surface; probiotics used as an adjunctive method to relieve tongue coating–related malodor and maintain the effect persistently have more utility for preventive than therapeutic aims.

5.5 Oral Mucositis in Cancer Radiotherapy

Evidence strength: Emerging — one prospective RCT and animal model data show promise; evidence is limited to head and neck cancer populations.

Oral mucositis (OM) is a common debilitating toxicity associated with radiotherapy for malignant head and neck tumors. Recent evidence suggests the involvement of oral microbiota in radiation-induced OM, and modulation of oral microbiota is promising for the management of OM. Streptococcus salivarius K12 is a commercially available oral probiotic with strong oral colonization ability, BLIS-producing capability, and immunomodulatory properties and has been used to treat oral candidiasis, pharyngitis, tonsillitis, halitosis, and otitis media.

In a prospective, randomized, double-blind clinical trial, head and neck cancer severe acute radiotherapy-associated oral mucositis was delayed in onset and decreased in incidence and duration by the use of a SsK12 probiotic.

An earlier preclinical study provided the mechanistic basis: Radiotherapy is one of the most commonly used treatment modalities for head and neck cancers, but with frequent complications including oral mucositis. Limited evidence has suggested the involvement of oral microbes in the development of oral mucositis in this context. S. salivarius K12 may represent a promising adjuvant treatment to improve the quality of life of cancer patients receiving radiotherapy.

5.6 COVID-19 and Viral Upper Respiratory Infections

Evidence strength: Very preliminary — a single small randomized controlled trial; results are exploratory and should not be interpreted as definitive.

To verify if the modulation of the oral microbiota could have an impact on the current coronavirus disease, researchers administered for 14 days a well-recognized and oral-colonizing probiotic (S. salivarius K12) to hospitalized COVID-19 patients. The preliminary results of their randomized and controlled trial appeared to demonstrate the potential role of this oral strain in improving the course of the main markers of pathology, as well as its ability to apparently reduce the death rate from COVID-19. Although in a preliminary and only circumstantial way, the results appeared to confirm the hypothesis of a direct involvement of the oral microbiota in the construction of a lung microbiota whose taxonomic structure could modulate the inflammatory processes generated at the pulmonary and systemic level by a viral infection. These results must be interpreted with significant caution given the small sample size and preliminary nature of the study.

A broader review confirms: Originally developed for its bacteriocin-mediated inhibition of the important bacterial pathogen Streptococcus pyogenes, BLIS K12 has more recently also demonstrated potential in the modulation and prevention of viral infections, including COVID-19. Emerging evidence also suggests a broader role for BLIS K12 in immune regulation, with implications for controlling hyperinflammatory responses and enhancing mucosal immunity.

5.7 Periodontal Disease

Evidence strength: Early/preliminary — in vitro and small clinical data show anti-inflammatory effects against periodontal pathogens; no large-scale RCTs yet published.

One study determined the ability of S. salivarius to inhibit IL-6 and IL-8 production by gingival fibroblasts when activated by periodontal pathogens, and assessed its effect on the salivary microbiome. S. salivarius G7 has an inhibitory effect on inflammation induced by LPS or LTA of periodontopathogens, and may be a candidate probiotic for prevention of periodontitis.

In a pilot clinical study on post-radiotherapy patients: A four-week intervention with oral probiotic lozenges containing Streptococcus salivarius M18 was trialled in seven patients. Xerostomia detrimentally affects the oral health of many head and neck cancer patients who undergo radiotherapy. The data presented in this pilot study, based on only seven patients, mean that any long-term benefit should be investigated in additional trials with larger cohorts and longer intervention periods.

5.8 Pediatric Prophylaxis (General)

A 2024 systematic review using the Cochrane Collaboration methodology offers the most comprehensive pediatric overview: The review synthesized existing evidence on the use of S. salivarius probiotics as prophylactic or therapeutic tools for pediatric oral, dental, and respiratory diseases. The systematic literature search identified 613 publications; ultimately, 15 suitable citations were included. Three strains of S. salivarius — M18, K-12, and 24SMB — were used, and all demonstrated positive benefits in pediatric pathology. The review concluded that administration of S. salivarius has benefits, is effective, and is convenient (cost-effective) in pediatric prophylaxis.

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6. Body Systems and Health Areas of Association

• Oral cavity: Dental plaque, dental caries, gingivitis, periodontal disease, halitosis, oral candidiasis, oral mucositis.
• Upper respiratory tract: Streptococcal pharyngitis, tonsillitis, nasopharyngeal colonization resistance.
• Ears: Acute otitis media, secretory otitis media (prevention studies — results mixed).
• Mucosal immune system: Immune regulation, including control of hyperinflammatory responses and enhancement of mucosal immunity.
• Gastrointestinal tract: S. salivarius is commonly detected as an inhabitant of the gastrointestinal tracts of healthy humans and has been described as a typical small intestine commensal species.
• Pulmonary immune interface: Anatomical and physiological considerations indicate that the oral cavity is the primary source of the lung microbiota community, acquired via aspiration and inhalation. The microbiota of the lungs overlaps in large extent with that found in the mouth — providing the theoretical basis for potential lung health implications.

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7. Dosage Forms and Dosages Reported in Studies

Dosing in published clinical studies and trials has varied. Only doses specifically cited in sources are listed here:

• In a safety study in healthy adults (18–60 years), participants consumed one orally dissolving tablet twice daily delivering 10 billion CFU/day for 1 month, followed by 3 months of observation.
• Twenty-two children with secretory otitis media were treated daily for 90 days with an oral formulation containing the oral probiotic S. salivarius K12.
• In the 827-child Finnish RCT, eligible participants were randomly allocated to receive 1 daily dose of an S. salivarius K12 product or placebo every evening for 6 months.
• In the 100-child dental caries study, treatment with M18 was administered for 3 months.
• In a radiotherapy-associated oral mucositis trial, participants were instructed to suck a S. salivarius K12 or placebo lozenge three times daily from the beginning to the end of radiotherapy. After using the lozenges, patients were advised to avoid eating, drinking, and conducting any oral hygiene activities for at least 1 hour.
• In an extended safety study, one dose corresponded to approximately 10 times the level typically used in commercial probiotic formulations.

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8. Safety Considerations

8.1 Regulatory Status

Streptococcus salivarius K12 is registered as a food supplement in the majority of countries in Europe, Australia, Asia, and the Americas and holds GRAS status in the United States, reflecting its safety history in both children and adults. BLIS Technologies Ltd. notified the U.S. Food and Drug Administration that S. salivarius M18, as manufactured by BLIS, is Generally Recognized as Safe (GRAS) under the conditions of its intended use.

8.2 Safety Data from Clinical Studies

Studies of strain K12 showed no evidence of genotoxicity and no acute or subacute toxicity effects. To determine the occurrence and concentrations in human saliva of S. salivarius having the same bacteriocin phenotype as strain K12, saliva samples from 780 children were evaluated. The level of dosing with strain K12 required to achieve oral cavity colonization levels similar to those occurring naturally for this type of bacteriocin-producing S. salivarius was established using 100 human subjects. Following the oral instillation of lyophilized S. salivarius K12 cells in these subjects, its persistence was not at levels higher than those found naturally. The various sets of data showed no evidence of genotoxicity and no acute or subacute toxicity effects associated with strain K12. Based on this information, it is concluded that S. salivarius K12 is safe for human consumption.

In a recent randomized, double-blind, placebo-controlled safety study, all participants completed the study and S. salivarius eK12 was well-tolerated, with no serious adverse events or discontinuations.

8.3 Antibiotic Susceptibility and Resistance

Strains are sensitive to various antibiotics, including ciprofloxacin, levofloxacin, metronidazole, penicillin, amoxicillin, ceftriaxone, clindamycin, rifampicin, gentamicin, cefuroxime, moxifloxacin, and vancomycin. However, certain strains of S. salivarius have shown partial resistance to penicillin, ceftriaxone, erythromycin, and meropenem.

A concerning trend is the high prevalence of resistance to certain antibiotic classes, particularly macrolides like erythromycin and tetracyclines. Studies have reported that macrolide resistance can be found in more than 75% of commensal isolates and over 50% of clinical isolates. This resistance is mediated by specific genes, such as erm(B) and mef(A/E), which encode for different mechanisms that modify the drug target or pump the drug out of the cell.

The safety assessment of probiotic strains specifically requires strain-by-strain evaluation: Although S. salivarius is a predominant member of the commensal oral microbiota and generally regarded as a safe species, it is recognized that each strain needs to be comprehensively assessed for safety. Assessment involves in silico, in vitro, and clinical testing.

8.4 Opportunistic Infections in Vulnerable Populations

Some strains of S. salivarius have been associated with opportunistic infections: a growing number of meningitis cases, several cases of endocarditis, bacteremia in immunocompromised patients, and invasion of the gut in patients with liver cirrhosis. These events are associated primarily with non-probiotic commensal strains and typically occur in the context of significant underlying illness or immune compromise, not in healthy individuals using probiotic formulations of characterized strains such as K12 or M18. Nonetheless, this biological context is relevant when considering use in severely immunocompromised individuals.

8.5 Antibiotic Interactions

Because S. salivarius K12 and M18 are live bacterial organisms, antibiotic use concurrent with probiotic administration may reduce or eliminate the live bacteria before mucosal colonization can occur. Strain K12 is characterized by excellent antibiotic sensitivity profiles. This antibiotic sensitivity means that concurrent antibiotic therapy would be expected to inhibit or eliminate probiotic colonization, potentially reducing efficacy; timing of administration relative to antibiotic courses is therefore a practical consideration noted in clinical research protocols.

8.6 Megaplasmid Considerations

Bacteriocin production in strains K12 and M18 is encoded on large megaplasmids. The persistence of the oral probiotic S. salivarius M18 is dose-dependent, and megaplasmid transfer can augment their bacteriocin production and adhesion characteristics. The transferability of megaplasmids has been studied in the context of safety assessments; current evidence from approved strains does not indicate an associated safety concern under normal conditions of use, but this remains an area of ongoing scientific scrutiny.

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