Evaluation of the Safety and Efficacy of SALI-10 Probiotic Lozenges

Официальное название

Evaluation of the Safety and Efficacy of SALI-10 Probiotic Lozenges: A Prospective, Randomized, Double-Blind, Placebo-Controlled Trial

Обзор

Gingivitis is among the most common oral conditions, affecting 50-90% of adults globally. It is a reversible inflammatory disease triggered primarily by the accumulation of microbial plaque on teeth and gingival tissues. Standard treatment involves plaque reduction and maintenance of oral hygiene, often supplemented with antimicrobial therapeutics to prevent disease progression. While plaque control remains the cornerstone of prevention, emerging research points to certain beneficial microbes that may protect gingival health. Notably, Streptococcus species have been associated with both antimicrobial and anti-inflammatory activities, suggesting their potential as oral probiotics. Recent investigations have focused on a novel strain, Streptococcus salivarius SALI-10, which produces a lantibiotic called Salivaricin 10. This peptide exhibits unique immunomodulatory properties. In murine models, Salivaricin 10 was shown to enhance neutrophil recruitment and activity while directing monocytes toward the M2 pro-resolution macrophage phenotype, a cell population integral to tissue repair and late-stage wound healing. Such effects highlight the potential of SALI-10 to reduce gingival inflammation while fostering microbial balance. The concept of employing S. salivarius strains in oral health is not entirely new. Other variants isolated from the oral cavities of healthy individuals produce lantibiotics with lanthionine or β-methyllanthionine residues that demonstrate antimicrobial effects against pathogens. Clinical investigations have explored these probiotic strains for halitosis, plaque control, and gingivitis, reporting safety and efficacy. Moreover, salivaricin-producing strains are considered valuable in the ongoing search for alternatives to conventional antibiotics in light of increasing resistance. Understanding the microbial ecology of gingivitis helps contextualize this therapeutic potential. In health, gram-positive bacteria, particularly Streptococcus species, dominate the oral microbiome. Gingivitis involves a shift toward gram-negative periopathogens such as Porphyromonas, Tannerella, Treponema, and Prevotella. This dysbiosis provokes an inflammatory cascade characterized by neutrophil infiltration, tissue damage, and, if unresolved, progression to periodontitis. A recent human experimental gingivitis study revealed distinct host response phenotypes. Participants retaining beneficial Streptococcus species, such as S. sanguinis and S. oralis, experienced reduced periopathogen emergence and milder inflammation. By contrast, participants who lost these protective bacteria demonstrated greater inflammatory severity, underscoring the critical role of Streptococcus persistence in oral homeostasis. Neutrophils, the most abundant immune cells in periodontal tissues, are central to this dynamic. Their numbers increase proportionally with gingivitis severity. Importantly, Health Canada has recently recognized salivary neutrophil activity as a valid biomarker for assessing inflammatory burden and risk of gingivitis or periodontal disease. This regulatory approval highlights the growing emphasis on immune function as both a diagnostic measure and therapeutic target in oral health. Against this backdrop, S. salivarius SALI-10 presents a compelling intervention strategy. Its hypothesized benefits include reducing inflammation via promotion of the M2 macrophage phenotype, suppressing periopathogen growth through competitive exclusion and Salivaricin 10 production, and mitigating halitosis by blocking volatile sulfur compound-producing bacteria. To evaluate these benefits, a proposed study design involves administering a twice-daily lozenge , one in the morning and one in the evening, after brushing a tongue scraping each containing 3 billion CFU of SALI-10 over a four-week period. In summary, gingivitis remains highly prevalent but reversible. Beyond traditional hygiene approaches, microbial therapeutics such as S. salivarius SALI-10 may offer a dual antimicrobial and anti-inflammatory benefit. By promoting immune resolution and reshaping the microbial community, SALI-10 could emerge as a novel probiotic strategy in maintaining oral health and addressing the limitations of conventional antimicrobial therapies.

Подробное описание

Gingivitis is an oral disease condition affecting 50% to 90% of adults globally. The gingivitis pathology can be reversed by reduction or removal of microbial plaque that accumulates on hard and soft tissues and is considered standard of care in the industry. Regular oral hygiene in combination with therapeutics that deliver an anti-microbial benefit is thought to mitigate the onset of gingivitis. However, some oral microbes, specifically Streptococcal species, have been identified with both antimicrobial and anti-inflammatory attributes that are speculated to play a role in protecting and potentiating healthy gingival tissues and are currently being investigated as probiotic opportunities in oral health support.

Recently, a new strain of Streptococcus salivarius SALI-10 has been identified with unique lantibiotic (Salivaracin 10) production that highlights a possible anti-inflammatory benefit. Using a mouse model, S. salivarius SALI-10 isolated Salivaracin 10 was shown to increase neutrophil recruitment and activation while also driving monocyte differentiation toward an M2 pro-resolution macrophage phenotype, widely found to participate in the oral cavity and late stages of the wound healing response. Other studies have shown certain Streptococcus salivarius strains, found in the oral cavity of healthy patients, produce similar lantibiotic salivaricins containing lanthionine and/or β-methyllanthionine residues. These molecules have been found to promote antimicrobial activity towards relevant oral pathogens and have been applied through the development of salivaricin-producing probiotic strains. Indeed, several groups have investigated the efficacy of different Streptococcus salivarius probiotic strains with success in halitosis, safety, plaque and gingivitis clinical trials. These salivaricins may also prove to be of great value in the development of new and novel antibacterial therapies in this era of emerging antibiotic resistance.

Gingivitis is a reversible inflammatory condition caused by the accumulation of dental plaque and the associated disruption of the host-microbial homeostasis. During gingivitis, the microbial community transitions from being dominated by gram-positive health-associated bacteria, such as Streptococcus species, to gram-negative periopathogens, including species of the genera Porphyromonas, Tannerella, Treponema and Prevotella. This dysbiotic shift triggers inflammatory responses, subsequent increase in neutrophils, leading to tissue damage and, in some cases, progression to periodontitis.

A recent study on human experimental gingivitis identified three distinct host response phenotypes.The microbial analysis revealed that the persistence of beneficial Streptococcus species, such as S. sanguinis and S. oralis, in slow and low responders correlated with a protective effect against the emergence of periopathogens and the associated inflammatory cascade. Conversely, the loss of these beneficial bacteria in high responders was linked to more severe inflammation, highlighting the critical role of the oral microbiome in modulating gingivitis severity.

Alterations in the oral microbiome alter host immune functions and stimulate immune cells to dominate the gingival tissues. Neutrophils, a type of white blood cell (leukocyte), represent a key component of the innate defence system that protects periodontal tissue from both gingivitis and periodontitis. Not only are they the first line of cellular defence, but they are among the most abundant leukocytes within the periodontal tissues. During gingivitis a significant increase in the number of neutrophils is seen to correspond to disease severity. In accordance, there was a recent approval by Health Canada for the use of salivary neutrophil activity as a measure of inflammatory load that corresponds with risk for gingivitis and/or periodontal disease.

Investigators propose using a novel strain, Streptococcus salivarius SALI-10, as a targeted microbial intervention to reduce oral inflammation. S. salivarius SALI-10 is hypothesized to:

* Reduce inflammation by driving M2 Resolution Phenotype. * Inhibit the growth of periopathogens such as Porphyromonas, Tannerella and Prevotella through competition and production of Salivaricin 10. * Reduce halitosis by inhibiting periopathogens that produce volatile sulfur compounds.

A twice-daily lozenge, one in the morning and one in the evening, after brushing and tongue scraping, will be issued containing S. salivarius SALI-10 (3 billion CFU/lozenge) for 4 weeks.

Вмешательства

• Пищевая добавка 3B SALI-10 Lozenge
  A lozenge containing 3B CFUs of the probiotic . S. salivarius SALI-10
• Другое Placebo
  It is a placebo lozenge with no active ingredient.

Первичные конечные точки

• Reduction of gingival inflammation between the probiotic and placebo groups determined by bleeding on probing (BOP) [Срок оценки: 81 days]
• Reduction of gingival inflammation between the probiotic and placebo groups determined by oral inflammatory load [Срок оценки: 81 days]
• Number of patients with treatment-related adverse events of twice-daily SALI-10 lozenge using an end of study questionnaire [Срок оценки: 81 days]

Вторичные конечные точки (2)

• Determine the probiotics impacts on halitosis through patient-reported outcomes using the HALT questionnaire [Срок оценки: 81 days]
• Determine the probiotics' impacts on halitosis through volatile sulfur compounds (VSC) in pbb [Срок оценки: 81 days]

Критерии участия

Критерии включения

• Male or female volunteers aged 18-70 years
• In good general health, ASA I
• Non-smokers
• Fluent in English
• For sexually active volunteers of childbearing potential, one of the following methods must be used to prevent pregnancy during the study by participants.

• Post-menopausal
• hormonal birth control (oral, injectable, transdermal, intra-vaginal) or intrauterine device must be in use at least 30 days prior to first study drug administration;
• barrier methods must be in use at least 14 days prior to study drug administration;
• that vasectomy on the male partner must be completed 3 months prior to first study drug administration;
• or in the alternative that a 0 sperm count for the male partner will suffice

Критерии исключения

• Presence of orthodontic bands.
• Presence of partial removal dentures.
• Dental pain at time of screening.
• History of allergy to a consumer or personal care products or dentifrice ingredients as determined by the dental profession monitoring the study, or to any of the following: sorbitol, isomalt, dibasic calcium phosphate, potato or potato starch, mint or mint flavour, glyceryl dibehenate, steviol glycosides.
• Participation in any other clinical study or test panel within one month before entering the study.
• Current use of anti-inflammatory, antibiotics, or antimicrobial drugs or within the last 30 days of enrolment.
• Those taking anticoagulant medications and have blood and bleeding disorders
• Those who have recently experienced (past 30 days) or will be experiencing (next 90 days) dental, oral, or any type of surgery
• History of systemic inflammatory or immune conditions or immunocompromised conditions
• Pregnant or nursing women or those planning on getting pregnant.
• Use of tobacco products.
• Long-term antibiotic or anti-inflammatory therapy.
• Medical condition or any current usage of medication that the investigator considers may compromise the subject's safety as well as the quality of the study results (note, only Advil and Tylenol are allowed during the study for analgesia)
• Medication or Natural Health Products (NHPs) that could affect the gingiva like calcium channel blockers, anti-epileptic therapy etc.
• Participants who are experiencing nausea, fever, vomiting, bloody diarrhoea or severe abdominal pain.
• Presence of active infections
• Use of any probiotic
• Use of anti-plaque/anti-gingivitis products
• Subjects who must receive dental treatment during the study elates
• Concurrent orthodontic treatment
• Untreated carious lesions and/or inadequate restorations on maxillary posterior teeth
• Periodontal disease (periodontal pockets, probing depth (PD) < 3.0 mm on at least one tooth/site, presence of Clinical Attachment Loss (CAL) = 0 mm, or periodontal disease history)

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Четверное слепое

Основная цель

Лечение

Центры проведения

Канада · 1 центр

• OMGPerio — Hamilton

Публикации

• Yin L, Li X, Hou J. Macrophages in periodontitis: A dynamic shift between tissue destruction and repair. Jpn Dent Sci Rev. 2022 Nov;58:336-347. doi: 10.1016/j.jdsr.2022.10.002. Epub 2022 Oct 28. PMID 36340583
• Tarasenko VD, Kozin IaB. [Work standards for the medical personnel of radiodiagnostic laboratories]. Med Radiol (Mosk). 1975 Feb;20(2):43-7. No abstract available. Russian. PMID 1134231
• LOE H, SILNESS J. PERIODONTAL DISEASE IN PREGNANCY. I. PREVALENCE AND SEVERITY. Acta Odontol Scand. 1963 Dec;21:533-51. doi: 10.3109/00016356309011240. No abstract available. PMID 14121956
• Loe H. The Gingival Index, the Plaque Index and the Retention Index Systems. J Periodontol. 1967 Nov-Dec;38(6):Suppl:610-6. doi: 10.1902/jop.1967.38.6.610. No abstract available. PMID 5237684
• Li X, Fields FR, Ho M, Marshall-Hudson A, Gross R, Casser ME, Naito M. Safety assessment of Streptococcus salivarius DB-B5 as a probiotic candidate for oral health. Food Chem Toxicol. 2021 Jul;153:112277. doi: 10.1016/j.fct.2021.112277. Epub 2021 May 15. PMID 34004226
• Lee YH, Shin SI, Hong JY. Investigation of volatile sulfur compound level and halitosis in patients with gingivitis and periodontitis. Sci Rep. 2023 Aug 14;13(1):13175. doi: 10.1038/s41598-023-40391-3. PMID 37580412
• Landzberg M, Doering H, Aboodi GM, Tenenbaum HC, Glogauer M. Quantifying oral inflammatory load: oral neutrophil counts in periodontal health and disease. J Periodontal Res. 2015 Jun;50(3):330-6. doi: 10.1111/jre.12211. Epub 2014 Jul 14. PMID 25040400
• Kuninaka Y, Ishida Y, Ishigami A, Nosaka M, Matsuki J, Yasuda H, Kofuna A, Kimura A, Furukawa F, Kondo T. Macrophage polarity and wound age determination. Sci Rep. 2022 Nov 25;12(1):20327. doi: 10.1038/s41598-022-24577-9. PMID 36434083

Идентификаторы

NCT: NCT07508839 · OstiaOralHealth

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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