Review of Probiotics: Adjunctive Treatment of Periodontitis

Review of Probiotics: Adjunctive Treatment of Periodontitis

Probiotics are defined by the World Health Organization as ‘live microorganisms that when administered in adequate amounts confer a health benefit on the host”.1Food and Agricultural Organization of the United Nations and World Health Organization. Health and nutritional properties of probiotics in food including powder milk with live lactic acid bacteria. World Health Organization [online], (2001). While frequently used in the prevention and treatment of gastrointestinal diseases,2Ritchie ML, Romanuk TN. A meta-analysis of probiotic efficacy for gastrointestinal diseases. PLoS One 2012;7(4):e34938. doi:10.1371/journal.pone.0034938. probiotics are now also being researched and used for other purposes, including the prevention and treatment of oral disease.3Bonifait L, Chandad F, Grenier D. Probiotics for Oral Health: Myth or Reality? www.cda-adc.ca/jcda 2009;75(8):585-90.^,4Mahasneh SA, Mahasneh AM. Probiotics: A Promising Role in Dental Health. Dent J (Basel) 2017;5(4):26. doi:10.3390/dj5040026.^,5Lee DS, Kim M, Nam SH et al. Effects of Oral Probiotics on Subjective Halitosis, Oral Health, and Psychosocial Health of College Students: A Randomized, Double-Blind, Placebo-Controlled Study. Int J Environ Res Public Health 2021;18(3):1143. doi:10.3390/ijerph18031143.^,6Cheng B, Zeng X, Liu S et al. The efficacy of probiotics in management of recurrent aphthous stomatitis: a systematic review and meta-analysis. Sci Rep 2020;10(1):21181. doi:10.1038/s41598-020-78281-7. Based on the research, mechanisms of action for probiotics include the inhibition of biofilm formation, restoration of a healthy biofilm, protection of epithelial barriers and modulation of the host response.3Bonifait L, Chandad F, Grenier D. Probiotics for Oral Health: Myth or Reality? www.cda-adc.ca/jcda 2009;75(8):585-90.^,4Mahasneh SA, Mahasneh AM. Probiotics: A Promising Role in Dental Health. Dent J (Basel) 2017;5(4):26. doi:10.3390/dj5040026.^,7MacDonald KW, Chanyi RM, Macklaim JM et al. Streptococcus salivarius inhibits immune activation by periodontal disease pathogens. BMC Oral Health 2021;21(1):245. doi: 10.1186/s12903-021-01606-z.^,8Karczewski J, Troost FJ, Konings I et al. Regulation of human epithelial tight junction proteins by Lactobacillus plantarum in vivo and protective effects on the epithelial barrier. Am J Physiol Gastrointest Liver Physiol 2010;298(6):G851-9. doi: 10.1152/ajpgi.00327.2009. In this article, we will review probiotics in the context of adjunctive treatment for patients with chronic periodontitis (CP) and potential pathways for these probiotics.

Characteristics and Development of CP

CP is a multifactorial, polymicrobial inflammatory disease. During biofilm development, early colonization by Streptococcus mutans (SM) and other Gram-positive microorganisms occurs, after which Gram-negative microorganisms colonize the biofilm and the subgingival biofilm develops and matures. In research in the 1990s, the most virulent periodontal pathogens were found to be Tannerella forsythia (Tf), Porphyromonas gingivalis (Pg) and Treponema denticola (Td).9Socransky SS, Haffajee AD, Cugini MA et al. Microbial complexes in subgingival plaque. J Clin Periodontol 1998;25(2):134-44. More recently, research determined that the biofilm as a whole is involved, including Gram-positive microorganisms. For example, Filifactor alocis (Fa) is Gram-positive, associated with CP, prevalent in periodontal pockets and, together with Aggregatibacter actinomycetemcomitans (Aa), is associated with localized aggressive periodontitis.10Kumar PS, Leys EJ, Bryk JM et al. Changes in periodontal health status are associated with bacterial community shifts as assessed by quantitative 16S cloning and sequencing. J Clin Microbiol 2006;44:3665-73.^,11Abusleme L, Dupuy AK, Dutzan N et al. The Subgingival Microbiome in Health and Periodontitis and Its Relationship With Community Biomass and Inflammation. ISMEJ 2013;7:1016-25. doi: 10.1038/ismej.2012.174.^,12Wang J, Qi J, Zhao H et al. Metagenomic Sequencing Reveals Microbiota and Its Functional Potential Associated With Periodontal Disease. Sci Rep 2013;3:1843. doi: 10.1038/srep01843. Furthermore, based on the keystone pathogen hypothesis, even a small amount of a specific pathogen (keystone) can influence the microbial content of dental biofilm, and initiate an inflammatory response.13Hajishengallis G, Darveau RP, Curtis MA. The keystone-pathogen hypothesis. Nat Rev Microbiol 2012;10:717-25. Keystone pathogens are noted to be a key component of CP progression.14Sedghi LM, Bacino M, Kapila YL. Periodontal Disease: The Good, The Bad, and The Unknown. Front Cell Infect Microbiol 2021;11:766944. doi: 10.3389/fcimb.2021.766944.

The initial phase of periodontal disease (gingivitis) involves an inflammatory response to biofilm, and changes in the local environment encourage a shift in microorganisms (dysbiosis). If gingivitis develops and is not reversed, the inflammatory process may progress and involve destruction of both the soft and hard tissues (alveolar bone) of the periodontium, i.e., CP.15Lang NP, Schätzle MA, Löe H. Gingivitis as a risk factor in periodontal disease. J Clin Periodontol 2009;36(Suppl 10):3-8. Additionally, the dental biofilm is inflammophilic and, as inflammation progresses, further shifts in the microbial community occur, favoring an increased inflammatory response.16Hajishengallis G. The inflammophilic character of the periodontitis associated microbiota. Mol Oral Microbiol 2014;29:248-57.^,17Hajishengallis G, Chavakis T, Lambris JD. Current understanding of periodontal disease pathogenesis and targets for host-modulation therapy. Periodontol 2000 2020;84(1):14-34. doi: 10.1111/prd.12331. The inflammatory response is host-dependent, and involves both pro- and anti-inflammatory mediators.

Periodontal Therapy and Probiotics

Goals of periodontal therapy include halting disease progression, maintaining/ gaining clinical attachment, and preventing active disease recurrence. Standard initial therapy consists of nonsurgical scaling and root planing (SRP), with the outcome related to the host response, removal and reduction of modifiable risk factors, robust home care, and long-term regular periodontal maintenance (and further therapy as indicated). Adjunctive treatment modalities have historically included the use of systemic and locally-applied antibiotics, and anti-inflammatory agents. The use of adjunctive probiotics is one of several other potential approaches. Probiotic species researched as adjuncts for the treatment of periodontal disease include numerous species of Lactobacillus, Streptococcus salivarius K12 and M18, S. boulardi, and Bifidobacterium such as B. lactis.18Stašková A, Sondorová M, Nemcová R et al. Antimicrobial and Antibiofilm Activity of the Probiotic Strain Streptococcus salivarius K12 against Oral Potential Pathogens. Antibiotics (Basel) 2021;10(7):793. doi: 10.3390/antibiotics10070793.^,19Ausenda F, Barbera E, Cotti E et al. Clinical, microbiological and immunological short, medium and long-term effects of different strains of probiotics as an adjunct to non-surgical periodontal therapy in patients with periodontitis. Systematic review with meta-analysis. Jpn Dent Sci Rev 2023;59:62-103. doi: 10.1016/j.jdsr.2023.02.001. ^,20Ochôa C, Castro F, Bulhosa JF et al. Influence of the Probiotic L. reuteri on Periodontal Clinical Parameters after Nonsurgical Treatment: A Systematic Review. Microorganisms 2023;11(6):1449. doi: 10.3390/microorganisms11061449. The most frequently researched probiotic as an adjunct for treating periodontal disease is Lactobacillus reuteri (L. reuteri).

Reviews and Recent Studies on Adjunctive Probiotics in Periodontal Therapy

In a systematic review of 25 studies, the use adjunctive probiotics in patients receiving SRP was evaluated.19Ausenda F, Barbera E, Cotti E et al. Clinical, microbiological and immunological short, medium and long-term effects of different strains of probiotics as an adjunct to non-surgical periodontal therapy in patients with periodontitis. Systematic review with meta-analysis. Jpn Dent Sci Rev 2023;59:62-103. doi: 10.1016/j.jdsr.2023.02.001. A majority of studies utilized L. reuteri as the probiotic (16 of 25), including 3 studies in which it was combined with other probiotics. For 5 of 10 studies solely on L. reuteri, significantly greater reductions in pocket probing depth (PD) were found for the test group than for the control group. Among the studies in which no significant differences were found, three used delivery vehicles other than lozenges and one study compared probiotics with antibiotics. Conflicting outcomes were found for clinical attachment levels (CAL). For the three studies investigating combinations of L. reuteri and other probiotics, two reported significant differences for PD reductions and CAL gains. However, results were mixed across the studies using other probiotics. As noted in the systematic review, the studies were heterogeneous with differences in patient selection (severity of CP, systemic health status, smoker/non-smoker), delivery vehicle, dosing, duration of probiotic use, and study length.

In a second systematic review, 9 studies were included and in all studies patients were receiving SRP, systemically healthy and non-smokers, and L. reuteri was given to the test group.20Ochôa C, Castro F, Bulhosa JF et al. Influence of the Probiotic L. reuteri on Periodontal Clinical Parameters after Nonsurgical Treatment: A Systematic Review. Microorganisms 2023;11(6):1449. doi: 10.3390/microorganisms11061449. In 6 of 9 studies, improvements in measured clinical parameters were significantly greater for the test groups compared to the control groups. It was again noted that the studies were heterogeneous. These findings are corroborated by a systematic review published in 2021 with 10 studies from the prior 10-year period,21Canut-Delgado N, Giovannoni ML, Chimenos-Küstner E. Are probiotics a possible treatment of periodontitis? Probiotics against periodontal disease: a systematic review. Br Dent J 2021;Nov 23. doi: 10.1038/s41415-021-3624-5. and conflicting results were also reported in earlier systematic reviews.22Ikram S, Hassan N, Raffat MA et al. Systematic review and meta-analysis of double-blind, placebo-controlled, randomized clinical trials using probiotics in chronic periodontitis. J Investig Clin Dent 2018;9(3):e12338. doi: 10.1111/jicd.12338.^,23Gatej S, Gully N, Gibson R, Bartold PM. Probiotics and Periodontitis – A Literature Review. J Int Acad Periodontol 2017;19(2):42-50.

Recent Clinical Studies
In one RCT, the effect of adjunctive treatment with lozenges containing L. reuteri was investigated in patients with advanced CP who had received SRP.24Hadžić Z, Pašić E, Gojkov-Vukelić M, Hadžić S. Effects of Lactobacillus reuteri lozenges (Prodentis) as adjunctive therapeutic agent in non-surgical therapy of periodontitis. Balk J Dent Med 2021;25:41-5. At the end of 40 days, significantly greater reductions were found for the plaque index (PI), gingival bleeding index (GBI) and bleeding on probing (BOP), and greater gains in CAL, in the test group compared to the control group. In a split-mouth study evaluating adjunctive use of L. reuteri over a 40-day period in patients with advanced CP receiving SRP, significantly greater improvements in PD, CAL and BOP were again found for the test group.25Sufaru I-G, Lazar L, Sincar D-C et al. Clinical Effects of Locally Delivered Lactobacillus reuteri as Adjunctive Therapy in Patients with Periodontitis: A Split-Mouth Study. Applied Sci 2022;12(5):2470. https://doi.org/10.3390/app12052470. In a double-blind RCT (2019), patients with moderate-severe CP received non-surgical periodontal therapy plus either L. reuteri lozenges twice-daily for 4 weeks (test group) or placebo lozenges (control).26Pelekos G, Ho SN, Acharya A et al. A double-blind, paralleled-arm, placebo-controlled and randomized clinical trial of the effectiveness of probiotics as an adjunct in periodontal care. J Clin Periodontol 2019;46(12):1217-27. doi: 10.1111/jcpe.13191. At follow-up on Days 90 and 180, no significant inter-group differences were found for reductions in PD or BOP, or for CAL gains. In another study, lozenges containing B. lactis were used twice-daily for 30 days as an adjunct to SRP in the test group while the control group received SRP and placebo lozenges. At 90 days, significantly greater reductions in PD and greater CAL gain were observed for the test group.27Invernici MM. Bifidobacterium animalis Subsp Lactis HN019 Presents Antimicrobial Potential against Periodontopathogens and Modulates the Immunological Response of Oral Mucosa in Periodontitis Patients. PLoS ONE 2020;15:e0238425.

Evaluation of moderate and/or deep pockets and residual pockets
Other studies evaluated overall improvements and those specifically for moderate and/or deep pockets. In a report on outcomes for molar sites with an initial PD ≥ 5 mm, patients received periodontal therapy (surgical/non-surgical) and either adjunctive lozenges containing L. reuteri for 28 days (test group ) or placebo lozenges (control group).28Pelekos G, Acharya A, Eiji N et al. Effects of adjunctive probiotic L. reuteri lozenges on S/RSD outcomes at molar sites with deep pockets. J Clin Periodontol 2020;47(9):1098-107. doi: 10.1111/jcpe.13329. Greater improvements in CAL were observed for the test group, and a greater likelihood of PD reductions. Similarly, outcomes were compared in a 12-week study for patients receiving one-stage full-mouth disinfection and then lozenges containing L. reuteri twice-daily for 12 weeks (test group) or placebo lozenges.29Teughels W, Durukan A, Ozcelik O et al. Clinical and microbiological effects of Lactobacillus reuteri probiotics in the treatment of chronic periodontitis: a randomized placebo-controlled study. J Clin Periodontol 2013;40(11):1025-35. Significant reductions were found overall for PD and CAL gains with no significant inter-group differences. However, significantly greater reductions in PD were found for deep pockets in the test group and greater CAL gains for moderate or deep pockets.

With respect to residual periodontal pockets, in one RCT patients received SRP plus 12 weeks of either adjunctive twice-daily adjunct probiotic lozenges containing L. reuteri or placebo lozenges, and with/without probiotic drops administered at the time of SRP.30Laleman I, Pauwels M, Quirynen M, Teughels W. A dual-strain Lactobacilli reuteri probiotic improves the treatment of residual pockets: A randomized controlled clinical trial. J Clin Periodontol 2020;47(1):43-53. doi: 10.1111/jcpe.13198. No effect was observed for the probiotic drops. Significantly greater reductions in overall PD were observed for the test group compared to the placebo group, especially for pockets 4 to 6 mm and ≥7 mm deep, and resulted in 67% and 54% of pockets, respectively, becoming <4 mm in depth. In another RCT, greater reductions in PD were obtained in patients with severe periodontitis receiving maintenance treatment and taking lozenges containing L. reuteri twice-daily for two 3-month periods over a year, than for the group using placebo lozenges.31Grusovin MG, Bossini S, Calza S et al. Clinical efficacy of Lactobacillus reuteri-containing lozenges in the supportive therapy of generalized periodontitis stage III and IV, grade C: 1-year results of a double-blind randomized placebo-controlled pilot study. Clin Oral Investig 2020;24(6):2015-24. doi: 10.1007/s00784-019-03065-x. However, in this study there were no significant inter-group difference in the percentage of sites with PD >4 mm, and CAL gain was greater for the test group only at the 6-month timepoint. (Table 1)

Mechanisms of Action and Pathways

Several pathways exist for altering oral flora using probiotics, including co-aggregation, competition for adhesion, and production of antimicrobials and other substances, e.g., lactic acid, hydrogen peroxide, and enzymes.7MacDonald KW, Chanyi RM, Macklaim JM et al. Streptococcus salivarius inhibits immune activation by periodontal disease pathogens. BMC Oral Health 2021;21(1):245. doi: 10.1186/s12903-021-01606-z.^,18Stašková A, Sondorová M, Nemcová R et al. Antimicrobial and Antibiofilm Activity of the Probiotic Strain Streptococcus salivarius K12 against Oral Potential Pathogens. Antibiotics (Basel) 2021;10(7):793. doi: 10.3390/antibiotics10070793.^,32Inchingolo F, Inchingolo AM, Malcangi G et al. The Benefits of Probiotics on Oral Health: Systematic Review of the Literature. Pharmaceuticals (Basel) 2023;16(9):1313. doi: 10.3390/ph16091313. As noted in discussing probiotics and dental caries, in vitro studies have demonstrated that L. paracasei inhibits EPS production by Streptococcus mutans (SM),33Guo M, Wu J, Hung W et al. Lactobacillus paracasei ET-22 Suppresses Dental Caries by Regulating Microbiota of Dental Plaques and Inhibiting Biofilm Formation. Nutrients 2023;15(15):3316. https://doi.org/10.3390/nu15153316. strains of Lactobacillus co-aggregate with SM34Twetman L, Larsen U, Fiehn NE et al. Coaggregation between probiotic bacteria and caries associated strains: An in vitro study. Acta Odontol Scand 2009;67:284-8. and bacteriocins (antimicrobials) target SM – interfering with cell wall development and helping to form cell membrane pores.18Stašková A, Sondorová M, Nemcová R et al. Antimicrobial and Antibiofilm Activity of the Probiotic Strain Streptococcus salivarius K12 against Oral Potential Pathogens. Antibiotics (Basel) 2021;10(7):793. doi: 10.3390/antibiotics10070793.^,35Salim HP, Mallikarjun SB, Raju S et al. Randomized Clinical Trial of Oral Probiotic Streptococcus salivarius M18 on Salivary Streptococcus mutans in Preprimary Children. Int J Clin Pediatr Dent 2023;16(2):259-63.^,36Burton JP, Drummond BK, Chilcott CN et al. Influence of the probiotic Streptococcus salivarius strain M18 on indices of dental health in children: A randomized double-blind, placebo-controlled trial. J Med Microbiol 2013;62:875-84. Some L. reuteri strains also secrete bacteriocins – reuterin and reutericyclin – which inhibit the growth of numerous pathogens and compete for adhesion sites.3Bonifait L, Chandad F, Grenier D. Probiotics for Oral Health: Myth or Reality? www.cda-adc.ca/jcda 2009;75(8):585-90. In addition, L. lactis secretes nisin which along with the probiotic inhibits Pg, Tf and Fn, and reduces the host inflammatory response and loss of alveolar bone.37Gao L, Kuraji R, Zhang MJ et al. Nisin probiotic prevents inflammatory bone loss while promoting reparative proliferation and a healthy microbiome. NPJ Biofilms Microbiomes 2022;8(1):45. doi: 10.1038/s41522-022-00307-x.

In one RCT, polymerase chain reaction (PCR) testing was performed to determine the effect of lozenges containing L. reuteri in patients with advanced CP.24Hadžić Z, Pašić E, Gojkov-Vukelić M, Hadžić S. Effects of Lactobacillus reuteri lozenges (Prodentis) as adjunctive therapeutic agent in non-surgical therapy of periodontitis. Balk J Dent Med 2021;25:41-5. At the end of 40 days significant reductions in Aa, Pg and Prevotella intermedia were found for the test group and control group (placebo lozenges). In patients receiving adjunctive treatment with Bifidobacterium, statistically higher levels of A. naeslundii and S. mitis, and lower levels of Pg, Td, Fn, C. showae, and E. nodatum were found in deep periodontal pockets.38Invernici MM, Salvador SL, Silva PHF et al. Effects of Bifidobacterium probiotic on the treatment of chronic periodontitis: A randomized clinical trial. J Clin Periodontol 2018;45(10):1198-210. Fewer periodontal pathogens were found in the test group. In other research, the total count of five periodontopathic bacteria at baseline was compared at the end of 4 and 8 weeks for a test group taking tablets containing L. salivarius WB21 and a control group taking placebo tablets.39Mayanagi G, Kimura M, Nakaya S et al. Probiotic effects of orally administered Lactobacillus salivarius WB21-containing tablets on periodontopathic bacteria: a double-blinded, placebo-controlled, randomized clinical trial. J Clin Periodontol 2009;36(6):506-13. doi: 10.1111/j.1600-051X.2009.01392.x. Using quantitative real-time PCR, a more than three-fold reduction in total periodontopathogens was found, and for Tf in the test group at 4 weeks, compared to the placebo group. In contrast, in a study with adjunctive use of L. reuteri in the treatment of residual pockets, no effect on pathogen counts was found.30Laleman I, Pauwels M, Quirynen M, Teughels W. A dual-strain Lactobacilli reuteri probiotic improves the treatment of residual pockets: A randomized controlled clinical trial. J Clin Periodontol 2020;47(1):43-53. doi: 10.1111/jcpe.13198.

In vitro studies

B. lactis and B. infantis used alone or together have been found to inhibit Pg and Fn in biofilms,40Argandoña Valdez RM, Ximenez-Fyvie LA, Caiaffa KS et al. Antagonist effect of probiotic bifidobacteria on biofilms of pathogens associated with periodontal disease. Microb Pathog 2021;150:104657. doi: 10.1016/j.micpath.2020.104657. and co-culturing of S. salivarius K12 or M18 with periodontal pathogens found to inhibit Pg, Fn, Td, Tf, Parvimonas micra, and Eikenella corrodens.41Park JA, Lee GR, Lee JY, Jin BH. Oral Probiotics, Streptococcus salivarius K12 and M18, Suppress the Release of Volatile Sulfur Compounds and a Virulent Protease from Oral Bacteria: An In-Vitro Study. Oral Health Prev Dent 2023;21(1):259-70. doi: 10.3290/j.ohpd.b4328987. Additionally, S. salivarius M18 cell-free supernatant can inhibit growth of Pseudomonas aeruginosa and Klebsiella pneumonia, as well as biofilm formation.42Tunçer S, Karaçam S. Cell-free supernatant of Streptococcus salivarius M18 impairs the pathogenic properties of Pseudomonas aeruginosa and Klebsiella pneumonia. Arch Microbiol 2020;202(10):2825-840. doi: 10.1007/s00203-020-02005-8. Furthermore, in a fourth study, cultures containing S. dentisani 7746 supernatant were shown to inhibit Pg and Fn.43Esteban-Fernández A, Ferrer MD, Zorraquín-Peña I et al. In vitro beneficial effects of Streptococcus dentisani as potential oral probiotic for periodontal diseases. J Periodontol 2019;90(11):1346-55. doi: 10.1002/JPER.18-0751.

Since microorganisms within the biofilm interact, some antagonistically and some synergistically, the impact of a given probiotic could have a broader effect. For example, co-aggregation of Td and Pg may increase the virulence of both species.44Zhu w, Lee S-W. Surface interactions between two of the main periodontal pathogens: Porphyromonas gingivalis and Tannerella forsythia, J Perio Impl Sci 2016;46(1):2-9. As such, greater virulence might be avoided if lower levels of one or both of these periodontopathogens were reduced by use of a probiotic. (Figure 1)

Modulation of the inflammatory response and immune mechanisms
Given the role of the host response in the onset and progression of CP, modulation of the inflammatory and immune response favoring health is desirable. In addition, periodontal destruction depends on the balance between destructive and protective inflammatory mediators and their interactions. While it is beyond the scope of this article to address all inflammatory mediators and interactions involved in CP, changes in the levels of inflammatory mediators have been observed in in vivo and in vitro research.

Examples of changes in pro-inflammatory mediators observed following use of a probiotic include the following:

• Significant reductions in IL-6, IL-8, and matrix metalloproteinase 8 (MMP8) which is associated with bone destruction, in gingival crevicular fluid in patients receiving L. reuteri.45İnce G, Gürsoy H, İpçi ŞD et al. Clinical and biochemical evaluation of lozenges containing Lactobacillus reuteri as an adjunct to non-surgical periodontal therapy in chronic periodontitis. J Periodontol 2015;86(6):746-54.
• Significant reductions in salivary levels of prostaglandin E2 (PGE2) in patients receiving L. brevis.3Bonifait L, Chandad F, Grenier D. Probiotics for Oral Health: Myth or Reality? www.cda-adc.ca/jcda 2009;75(8):585-90.
• Significant reductions in IL-1ß in patients receiving Bifidobacterium.38Invernici MM, Salvador SL, Silva PHF et al. Effects of Bifidobacterium probiotic on the treatment of chronic periodontitis: A randomized clinical trial. J Clin Periodontol 2018;45(10):1198-210.
• In vitro inhibition of IL-6 and IL-8 production when gingival fibroblasts are pre-treated with S. salivarius K12 or M18 or the probiotic is administered along with Pg, Aa and Fn.7MacDonald KW, Chanyi RM, Macklaim JM et al. Streptococcus salivarius inhibits immune activation by periodontal disease pathogens. BMC Oral Health 2021;21(1):245. doi: 10.1186/s12903-021-01606-z.
• In vitro reductions in the expression of interferon-γ induced by Fn when S. dentisani is incubated with Pg and Fn.43Esteban-Fernández A, Ferrer MD, Zorraquín-Peña I et al. In vitro beneficial effects of Streptococcus dentisani as potential oral probiotic for periodontal diseases. J Periodontol 2019;90(11):1346-55. doi: 10.1002/JPER.18-0751. (Figure 2)

Examples of increases in the levels of anti-inflammatory mediators after use of a probiotic include the following:

• Significant increases in tissue inhibitor of matrix metalloprotease (TIMP-1), which inhibits MMPs, in patients receiving L. reuteri.45İnce G, Gürsoy H, İpçi ŞD et al. Clinical and biochemical evaluation of lozenges containing Lactobacillus reuteri as an adjunct to non-surgical periodontal therapy in chronic periodontitis. J Periodontol 2015;86(6):746-54.
• Increased secretion of IL-10 (which downregulates MMPs as well as RANKL and upregulates TIMPs) in GCF in patients receiving B. lactis HN019.38Invernici MM, Salvador SL, Silva PHF et al. Effects of Bifidobacterium probiotic on the treatment of chronic periodontitis: A randomized clinical trial. J Clin Periodontol 2018;45(10):1198-210.
• Increased levels of beta-defensin (BD)-3, toll-like receptor 4 (TLR4), and cluster of differentiation (CD)-57 and CD-4 in periodontal tissues in patients receiving B. lactis HN019.27Invernici MM. Bifidobacterium animalis Subsp Lactis HN019 Presents Antimicrobial Potential against Periodontopathogens and Modulates the Immunological Response of Oral Mucosa in Periodontitis Patients. PLoS ONE 2020;15:e0238425.
• In vitro, increased secretion of IL-10 through incubation of S. dentisani with Pg and Fn.43Esteban-Fernández A, Ferrer MD, Zorraquín-Peña I et al. In vitro beneficial effects of Streptococcus dentisani as potential oral probiotic for periodontal diseases. J Periodontol 2019;90(11):1346-55. doi: 10.1002/JPER.18-0751. (Figure 3)

Other Considerations

The research and use of probiotics as an adjunct to periodontal therapy continues to evolve, and the most researched probiotic used for this purpose is by far L. reuteri. However, as noted in several systematic reviews, there is considerable heterogeneity in studies including for patient selection, probiotic(s), study duration, frequency of use and delivery vehicle.

In addition, it is recognized that results for a given probiotic bacteria are strain-dependent, and different strains of the same probiotic can modulate their inhibitory capacity against pathogens.20Ochôa C, Castro F, Bulhosa JF et al. Influence of the Probiotic L. reuteri on Periodontal Clinical Parameters after Nonsurgical Treatment: A Systematic Review. Microorganisms 2023;11(6):1449. doi: 10.3390/microorganisms11061449. In one vitro study, strains of Streptococcus salivarius and Lactobacillus were evaluated as probiotics for periodontal biofilms.46Van Holm W, Carvalho R, Delanghe L et al. Antimicrobial potential of known and novel probiotics on in vitro periodontitis biofilms. NPJ Biofilms Microbiomes 2023;9(1):3. doi: 10.1038/s41522-023-00370-y. Some strains of Lactobacillus were effective in reducing A. actinomycetemcomitans, while others were not, and S. salivarius was ineffective. Conversely, some S. salivarius strains offered greater efficacy against other periodontal pathogens, specifically P. intermedia, P. gingivalis, and F. nucleatum. Conversely, it has been shown that pathogens can increase or inhibit the growth of different probiotics.21Canut-Delgado N, Giovannoni ML, Chimenos-Küstner E. Are probiotics a possible treatment of periodontitis? Probiotics against periodontal disease: a systematic review. Br Dent J 2021;Nov 23. doi: 10.1038/s41415-021-3624-5.^,47Jansen PM, Abdelbary MMH, Conrads G. A concerted probiotic activity to inhibit periodontitis-associated bacteria. PLoS ONE 2021;16(3):e0248308. https://doi.org/10.1371/journal. pone.0248308.

Conclusions

Further research with robust RCTs and standardized protocols is required to determine the efficacy of probiotic bacteria and strains for adjunctive treatment of periodontal disease, and the most effective combinations. In the meantime, the results of recent studies are promising. While there is as yet insufficient evidence, depending on the specific probiotic strain and protocol, adjunctive probiotics may provide additional treatment benefits and can be considered for patients with periodontitis.

References

• 1.Food and Agricultural Organization of the United Nations and World Health Organization. Health and nutritional properties of probiotics in food including powder milk with live lactic acid bacteria. World Health Organization [online], (2001).
• 2.Ritchie ML, Romanuk TN. A meta-analysis of probiotic efficacy for gastrointestinal diseases. PLoS One 2012;7(4):e34938. doi:10.1371/journal.pone.0034938.
• 3.Bonifait L, Chandad F, Grenier D. Probiotics for Oral Health: Myth or Reality? www.cda-adc.ca/jcda 2009;75(8):585-90.
• 4.Mahasneh SA, Mahasneh AM. Probiotics: A Promising Role in Dental Health. Dent J (Basel) 2017;5(4):26. doi:10.3390/dj5040026.
• 5.Lee DS, Kim M, Nam SH et al. Effects of Oral Probiotics on Subjective Halitosis, Oral Health, and Psychosocial Health of College Students: A Randomized, Double-Blind, Placebo-Controlled Study. Int J Environ Res Public Health 2021;18(3):1143. doi:10.3390/ijerph18031143.
• 6.Cheng B, Zeng X, Liu S et al. The efficacy of probiotics in management of recurrent aphthous stomatitis: a systematic review and meta-analysis. Sci Rep 2020;10(1):21181. doi:10.1038/s41598-020-78281-7.
• 7.MacDonald KW, Chanyi RM, Macklaim JM et al. Streptococcus salivarius inhibits immune activation by periodontal disease pathogens. BMC Oral Health 2021;21(1):245. doi: 10.1186/s12903-021-01606-z.
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