Probiotics Update

Probiotics Update

Probiotics are defined as ‘live microorganisms that when administered in adequate amounts confer a health benefit on the host’ and categorized by microorganism (species) and strain.1Hill C, Guarner F, Reid G et al. Expert consensus document. The International Scientific Association for Probiotics and Prebiotics consensus statement on the scope and appropriate use of the term probiotic. Nat Rev Gastroenterol Hepatol 2014;11(8):506-14.^,2World Gastroenterology Organisation. Probiotics and prebiotics. 2017. https://www.worldgastroenterology.org/UserFiles/file/guidelines/probiotics-and-prebiotics-english-2017.pdf. Probiotic bacteria used consist largely of Lactobacillus, Bifidobacterium, Propionibacterium and Streptococcus.3Bonifait L, Chandad F, Grenier D. Probiotics for Oral Health: Myth or Reality? J Can Dent Assoc 2009;75(8):585-90. https://www.cda-adc.ca/jcda/vol-75/issue-8/585.pdf. While one or several strains may be effective for a specific health benefit other strains of the same species can be ineffective. The majority of probiotics are used for gastrointestinal disease, with limited use for potential oral health benefits.

Mechanisms of Action for Probiotics

Current research is supportive of several mechanisms of action for probiotics, including the following:2World Gastroenterology Organisation. Probiotics and prebiotics. 2017. https://www.worldgastroenterology.org/UserFiles/file/guidelines/probiotics-and-prebiotics-english-2017.pdf.^,4Stašková 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.^,5MacDonald 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.^,6Ritchie ML, Romanuk TN. A meta-analysis of probiotic efficacy for gastrointestinal diseases. PLoS One 2012;7(4):e34938. doi:10.1371/journal.pone.0034938.^,7Karczewski 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.

• Inhibition of microbial growth and biofilm formation.
• Alteration of the host flora – restoration of a healthy biofilm.
• Modulation of the inflammatory response and immune mechanisms.
• Protection of epithelial barriers. (Figure 1)

Mechanisms of action vary by species and strain. They variously involve the production of natural antimicrobial substances, metabolites and enzymes by probiotic bacteria; reduced adhesion of other microbes; direct competition; and changes in host cells and cell-to-cell communication.

Probiotics and Systemic Health

In a systematic review and meta-analysis of 84 randomized controlled trials (RCT), it was concluded that probiotics were generally beneficial in treating specific gastrointestinal diseases/conditions including ulcerative colitis, irritable bowel syndrome and acute diarrhea, and for the prevention of antibiotic-associated diarrhea.2World Gastroenterology Organisation. Probiotics and prebiotics. 2017. https://www.worldgastroenterology.org/UserFiles/file/guidelines/probiotics-and-prebiotics-english-2017.pdf.^,6Ritchie ML, Romanuk TN. A meta-analysis of probiotic efficacy for gastrointestinal diseases. PLoS One 2012;7(4):e34938. doi:10.1371/journal.pone.0034938. The efficacy of adjunctive probiotics together with a triple-therapy in eradicating Heliobacter pyloris in children has now also been confirmed, and research continues on the potential benefits of probiotics against auto-immune inflammatory diseases.8Feng JR, Wang F, Qiu X et al. Efficacy and safety of probiotic-supplemented triple therapy for eradication of Helicobacter pylori in children: a systematic review and network meta-analysis. Eur J Clin Pharmacol 2017;73(10):1199-208. doi: 10.1007/s00228-017-2291-6.^,9Sales-Campos H, Soares SC, Oliveira CJF. An introduction of the role of probiotics in human infections and autoimmune diseases. Crit Rev Microbiol 2019;45(4):413-32. doi: 10.1080/1040841X.2019.1621261.

Probiotics and Oral Health

Research is ongoing on the potential benefits of probiotics against dental caries, periodontal disease, halitosis, oral candidiasis and other conditions.10Inchingolo 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.^,11Lee 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.^,12Sang-Ngoen T, Czumbel LM, Sadaeng W et al. Orally Administered Probiotics Decrease Aggregatibacter actinomycetemcomitans but Not Other Periodontal Pathogenic Bacteria Counts in the Oral Cavity: A Systematic Review and Meta-Analysis. Front Pharmacol 2021;12:682656. doi:10.3389/fphar.2021.682656^,13Kaklamanos EG, Nassar R, Kalfas S et al. A single-centre investigator-blinded randomised parallel group clinical trial to investigate the effect of probiotic strains Streptococcus salivarius M18 and Lactobacillus acidophilus on gingival health of paediatric patients undergoing treatment with fixed orthodontic appliances: study protocol. BMJ Open 2019;9(9):e030638. doi:10.1136/bmjopen-2019-030638. Probiotic bacteria being researched/used for potential anti-caries benefits include Bifidobacteria, Lactobacilli, Streptococci, and strains of each of these (sometimes in combination).4Stašková 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.^,10Inchingolo 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.^,14Begić G, Badovinac IJ, Karleuša L et al. Streptococcus salivarius as an Important Factor in Dental Biofilm Homeostasis: Influence on Streptococcus mutans and Aggregatibacter actinomycetemcomitans in Mixed Biofilm. Int J Mol Sci 2023;24(8):7249. doi: 10.3390/ijms24087249.^,15Hale JDF, Jain R, Wescombe PA et al. Safety assessment of Streptococcus salivarius M18 a probiotic for oral health. Benef Microbes 2022;13(1):47-60. doi: 10.3920/BM2021.0107.^,16Tagg JR, Harold LK, Jain R, Hale JDF. Beneficial modulation of human health in the oral cavity and beyond using bacteriocin-like inhibitory substance-producing streptococcal probiotics. Front Microbiol 2023;14:1161155. doi: 10.3389/fmicb.2023.1161155.^,17Mahasneh SA, Mahasneh AM. Probiotics: A Promising Role in Dental Health. Dent J 2017;5:26. doi:10.3390/dj504002. Interestingly, microorganisms found in human colostrum, the breast milk produced shortly after giving birth, include Bifidobacteria and Lactobacilli.18Zaghloul SA, Hashem SN, El-Sayed SR et al. Evaluation of the Cariogenic and Anti-Cariogenic Potential of Human Colostrum and Colostrum-Derived Probiotics: Impact on S. mutans Growth, Biofilm Formation, and L. rhamnosus Growth. Life (Basel) 2023;13(9):1869. doi: 10.3390/life13091869.^,19Soto A, Martin V, Jiménez E et al. Lactobacilli and Bifidobacteria in Human Breast Milk: Influence of Antibiotherapy and Other Host and Clinical Factors. J Ped Gastroenterol Nutrition 2014;59(1):78-88. doi: 10.1097/MPG.0000000000000347. In one study, colostrum was sampled from 36 healthy mothers 1-3 days postpartum.15Hale JDF, Jain R, Wescombe PA et al. Safety assessment of Streptococcus salivarius M18 a probiotic for oral health. Benef Microbes 2022;13(1):47-60. doi: 10.3920/BM2021.0107. Potential probiotics were found in some samples, from which cell-free supernatants were obtained and found to inhibit the growth of S. mutans (SM).

Reviews and Recent Studies on Probiotics and Dental Caries

Several reviews on probiotics were conducted between 2012 and 2023, largely in children. In one review (2012), 12 of 19 papers reported reductions in mutans streptococci (SM and closely related species) in plaque or saliva with Bifidobacteria or Lactobacilli.20Twetman S, Keller MK. Probiotics for caries prevention and control. Adv Dent Res 2012;24:98-102. Only 3 studies addressed caries, with mixed results (or a confounder), and most studies were also of short duration. In systematic reviews, decreases in SM have been reported.21Laleman I, Detailleur V, Slot DE et al. Probiotics reduce mutans streptococci counts in humans: a systematic review and meta-analysis. Clin Oral Investig 2014;18(6):1539-52. doi: 10.1007/s00784-014-1228-z.^,22Gruner D, Paris S, Schwendicke F. Probiotics for managing caries and periodontitis: Systematic review and meta-analysis. J Dent 2016;48:16-25. ^,23Navidifar T, Mahdizade AM, Alipourkermani A et al. Clinical Efficacy of Probiotics on Oral Health: A Systematic Review of Clinical Trials. Curr Pharm Biotechnol 2023;24(15):1916-27. doi: 10.2174/1389201024666230405135457. In one of these (2023), 24 RCT were included with approximately 1600 participants and a 65% reduction in SM was found (p<0.05).23Navidifar T, Mahdizade AM, Alipourkermani A et al. Clinical Efficacy of Probiotics on Oral Health: A Systematic Review of Clinical Trials. Curr Pharm Biotechnol 2023;24(15):1916-27. doi: 10.2174/1389201024666230405135457. None reported adverse events. (Table 1)

Recent Clinical Studies
In a multicenter double-blind RCT with almost 500 pre-school children (mean age 37.6 months; caries prevalence 82%), the preventive effect of drinking reconstituted milk containing Lactobacillus paracasei SD1 (L. paracasei SD1) during a 6-month period was evaluated.24Piwat S, Teanpaisan R, Manmontri C et al. Efficacy of Probiotic Milk for Caries Regression in Preschool Children: A Multicenter Randomized Controlled Trial. Caries Res 2020;54(5-6):491-501. doi: 10.1159/000509926. One test group drank probiotic milk daily and the other test group drank this three days per week (with regular milk on other days). Compared to the control group drinking regular milk, caries risk was reduced in both test groups. At the 12-month endpoint, the likelihood of caries reversal was more than double and 92% greater, respectively, for children receiving the probiotic milk daily or thrice-weekly.

In a randomized parallel-group study, incremental caries was evaluated in children 3 to 6 years-of-age.25Staszczyk M, Jamka-Kasprzyk M, Kościelniak D et al. Effect of a Short-Term Intervention with Lactobacillus salivarius Probiotic on Early Childhood Caries-An Open Label Randomized Controlled Trial. Int J Environ Res Public Health 2022;19(19):12447. doi: 10.3390/ijerph191912447. At the one-year follow-up, 127 of 140 children could be evaluated. The test group chewed commercially available probiotic lozenges containing 10 mg of L. salivarius HM-6 Paradens twice-daily for two weeks. At 12 months, incremental caries was significantly lower in the children receiving probiotic lozenges (p<0.001) while there was no significant difference in risk for initial caries lesions. In an earlier study in children 2 to 3 years-of-age, the test group received milk containing L. rhamnosus SP1, 5 days per week for 10 months.26Rodríguez G, Ruiz B, Faleiros S et al. Probiotic Compared with Standard Milk for High-caries Children: A Cluster Randomized Trial. J Dent Res 2016;95:402-7. At the end of the study, a caries prevalence of 54.4% and 65.8% was found for the test and control groups, respectively, with new caries lesions experienced by 9.7% and 24.3%, respectively. It was concluded that drinking probiotic-supplemented milk over the long term may reduce caries in high-risk preschool children.

In a one-year RCT, again with children 2 to 3 years-of-age, the test group chewed commercially available tablets containing 3 strains of probiotic bacteria (S. rattus JH145, S. oralis KJ3sm, and S. uberis KJ2sm; ProBiora3) while the control group chewed placebo tablets. Incremental caries was reported to be significantly lower in the test group (0.2 vs 0.8), with a 47% lower likelihood of caries.27Hedayati-Hajikand T, Lundberg U, Eldh C, Twetman S. Effect of probiotic chewing tablets on early childhood caries-a randomized controlled trial. BMC Oral Health 2015;15:112. Conversely, in a 9-month RCT with more than 350 participants (3 to 4 years-of-age) no significant differences were found for the proportion of SM or the caries prevalence for the test group drinking milk containing L. rhamnosus and Bifidobacterium longum on weekdays and the control group drinking regular milk.28Villavicencio J, Villegas LM, Arango MC et al. Effects of a food enriched with probiotics on Streptococcus mutans and Lactobacillus spp. salivary counts in preschool children: A cluster randomized trial. J Appl Oral Sci 2018;26: e20170318. However, a reduced count of Lactobacillus was found for the test group. In another study with 38 children and a follow up at 6 and 12 months, five daily drops of Limosilactobacillus reuteri (DSM 17938 and ATCC PTA 5289) at bedtime were given to the test group and drops without the probiotic to the control group.29Hasslöf P, Granqvist L, Stecksén-Blicks C, Twetman S. Prevention of Recurrent Childhood Caries with Probiotic Supplements: A Randomized Controlled Trial with a 12-Month Follow-Up. Probiotics Antimicrob Proteins 2022;14(2):384-90. doi: 10.1007/s12602-022-09913-9. No difference between the groups was found, and recurrent caries rates were high. The COVID-19 pandemic was cited as a factor limiting the number of participants and power.

Numerous studies have evaluated SM counts, but not dental caries. In one RCT, two test groups received reconstituted milk containing L. paracasei SD1 once daily or three days per week for 6 weeks.30Wattanarat O, Nirunsittirat A, Piwat S et al. Significant elevation of salivary human neutrophil peptides 1-3 levels by probiotic milk in preschool children with severe early childhood caries: a randomized controlled trial. Clin Oral Investig 2021;25(5):2891-903. doi: 10.1007/s00784-020-03606-9. Based on analyses of samples available from 268 children at 6 and 12 months, significant reductions in SM and increases in human neutrophil peptides 1-3 levels were found for children with severe early childhood caries in the test groups compared to the control group. In another study in preschool children, the inclusion of L. rhamnosus GG, ATCC (LGG) in milk taken 5 days per week for 7 months significantly reduced SM levels in children 1 to 6 years-of-age.31Näse L, Hatakka K, Savilahti E et al. Effect of long-term consumption of a probiotic bacterium, Lactobacillus rhamnosus GG, in milk on dental caries and caries risk in children. Caries Res 2001;35(6):412-20. doi: 10.1159/000047484.

In two studies of up to 3 months’ duration with test and control groups, significant reductions in SM were observed in test groups compared to control groups after 28 days (L. reuteri in probiotic lozenges),32Alamoudi NM, Almabadi ES, El Ashiry EA, El Derwi DA. Effect of Probiotic Lactobacillus reuteri on Salivary Cariogenic Bacterial Counts among Groups of Preschool Children in Jeddah, Saudi Arabia: A Randomized Clinical Trial. J Clin Pediatr Dent 2018;42:331-8. and after 7 days (S. salivarius strain M18 as probiotic lozenges)33Salim 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.. In a double-blind RCT of 3 month’s duration with 100 caries-active children receiving S. salivarius strain M18, no overall difference in SM levels between the test and control group was found.34Burton 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. However, a significant difference was found for children in whom colonization with the probiotic was most effective. (Table 2)

Dental Biofilm, Probiotics and Recent Findings

Dental biofilm begins to form after pellicle formation, when bacteria (Gram-positive cocci) reversibly adhere to the surface then release adhesins and thereby adhere irreversibly. Extracellular polysaccharides (EPS) are produced, forming a matrix that binds the microorganisms together, retains bacterial chemicals, provides sites for other microorganisms to adhere to, and protects microorganisms in the biofilm.35Flemming H, Wingender J. The biofilm matrix. Nat Rev Microbiol 2010;8:623-33.^,36Marsh PD. Are dental diseases examples of ecological catastrophes? Microbiol 2003;149:279-94. Co-aggregation/co-adhesion of different species of microorganisms also occurs during biofilm formation, helping with microbial colonization. As the biofilm matures, a shift occurs in its composition when Gram-negative bacteria adhere and colonize the biofilm. Microorganisms within the biofilm share genetic information, compounds, and communicate by a number of mechanisms.37Senadheera D, Cvitkovitch DG. Quorum sensing and biofilm formation by Streptococcus mutans. Adv Exp Med Biol 2008;631:178-88. doi: 10.1007/978-0-387-78885-2_12. One of these is quorum sensing, whereby quorum sensing molecules monitor the bacterial population density, and regulate biofilm formation and virulence.38Suntharalingam P, Cvitkovitch DG. Quorum sensing in streptococcal biofilm formation. Trends Microbiol 2005;13:3-6.^,39Nagi M, Chapple ILC, Sharma P et al. Quorum Sensing in Oral Biofilms: Influence on Host Cells. Microorganisms 2023;11(7):1688. doi: 10.3390/microorganisms11071688.

Against this background, recent findings in in vitro studies for specific probiotics include the following:

• Live and heat-killed L. paracasei ET-22 can inhibit EPS production by SM.40Guo 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.
• Probiotic lactobacillus strains derived from commercially available products can co-aggregate with SM strains over a 24-hour period, and to varying degrees depending on the strain.41Twetman 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.
• Bacteriocins that target SM are produced by S. salivarius K 12 and M18.4Stašková 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.^,33Salim 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.^,34Burton 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. Bacteriocins, which are mainly active against Gram-positive bacteria,4Stašková 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. participate in the formation of pores in the cell membrane (salivaricin A) and interfere with cell wall development (salivaricin B).

 

Figure 2. Recent findings on probiotics and dental biofilm



In the caries process, acid production by cariogenic bacteria must be sufficient to create a low-pH environment that will cause demineralization. As such, since cariogenic bacteria create a low-pH environment they must be either acidogenic or at least acid tolerant (aciduric). Furthermore, low-pH conditions favor a shift to SM, lactobacilli and other acid-tolerant microorganisms, causing dysbiosis.36Marsh PD. Are dental diseases examples of ecological catastrophes? Microbiol 2003;149:279-94. Quorum sensing helps to regulate the acidogenicity and aciduricity of SM.37Senadheera D, Cvitkovitch DG. Quorum sensing and biofilm formation by Streptococcus mutans. Adv Exp Med Biol 2008;631:178-88. doi: 10.1007/978-0-387-78885-2_12. Looking at the research with respect to both dental biofilm and acid tolerance, in vitro tests showed that:

• Exposure to supernatants of 4 strains of lactobacilli reduced gene expression by SM – leading to reduced EPS production, reduced quorum sensing and reduced acid tolerance of the bacteria.42Wasfi R, Abd El-Rahman OA, Zafer MM, Ashour HM. Probiotic Lactobacillus sp. inhibit growth, biofilm formation and gene expression of caries-inducing Streptococcus mutans. J Cell Mol Med 2018;22(3):1972-83. doi: 10.1111/jcmm.13496.
• L. reuteri ATCC PTA5289 reduced the acid tolerance of SM, S. gordonii, and Actinomyces naeslundii (A. naeslundii).43Boisen G, Prgomet Z, Enggren G et al. Limosilactobacillus reuteri inhibits the acid tolerance response in oral bacteria. Biofilm 2023;6:100136. doi: 10.1016/j.bioflm.2023.100136. (Figure 2)

 

Other Considerations

In a recent analysis of 21 commercially available probiotic products promoted for oral health, approximately 75% contained many dead bacteria rather than the advertised count (CFU) of viable probiotic bacteria.44Van Holm W, Lauwens K, De Wever P et al. Probiotics for oral health: do they deliver what they promise? Front Microbiol 2023;14:1219692. doi: 10.3389/fmicb.2023.1219692. Some products did not provide information on the probiotic used, or information on CFU at time of use/expiry. Given that the CFU can decline between the time of manufacture and when the probiotic is actually used, it is recommended that consumers avoid products that only list the CFU based on manufacturing date.45National Institutes of Health. Probiotics. Fact Sheet for Health Professionals. https://ods.od.nih.gov/factsheets/Probiotics-HealthProfessional/. The International Scientific Association for Probiotics and Prebiotics advises manufacturers include the total CFU (ideally for each strain) at expiry/use by date on the labeling.

In addition, preparation methods that render probiotics temporarily dormant can increase their shelf life but can also reduce their adhesive properties.44Van Holm W, Lauwens K, De Wever P et al. Probiotics for oral health: do they deliver what they promise? Front Microbiol 2023;14:1219692. doi: 10.3389/fmicb.2023.1219692. Researchers have proposed that a consensus be reached on minimal adherent probiotic doses and called for improved probiotic delivery and thereby greater colonization and efficacy. Recently, in vitro research has been conducted on the potential of delivering Streptococcus salivarius in oro-dispersible films created using ink-jetting or as microencapsulated probiotics, to prolong their activity intra-orally.46Dodoo CC, Stapleton P, Basit AW, Gaisford S. The potential of Streptococcus salivarius oral films in the management of dental caries: An inkjet printing approach. Int J Pharm 2020;591:119962. doi: 10.1016/j.ijpharm.2020.119962.^,47Choudhary P, Kraatz HB, Lévesque CM, Gong SG. Microencapsulation of Probiotic Streptococcus salivarius LAB813. ACS Omega 2023;8(13):12011-8. doi: 10.1021/acsomega.2c07721.

It is recommended that consumers avoid products that only list the CFU based on manufacturing date.

Conclusions

The potential role of probiotics in helping to meet the challenges of dental caries is of considerable interest. Based on systematic reviews, there is insufficient evidence that probiotics can prevent caries. In a majority of studies, SM counts were evaluated as a proxy for a caries preventive effect. However as noted in reviews, and in studies on caries prevention, bacterial counts are not predictive of future caries experience.48van Palenstein Helderman WH, Mikx FH et al. The value of salivary bacterial counts as a supplement to past caries experience as caries predictor in children. Eur J Oral Sci 2001;109(5):312-5. doi: 10.1034/j.1600-0722.2001.00080.x.^,49Sánchez-Pérez L, Golubov J, Irigoyen-Camacho ME et al. Clinical, salivary, and bacterial markers for caries risk assessment in schoolchildren: a 4-year follow-up. Int J Paediatr Dent 2009;19(3):186-92. doi: 10.1111/j.1365-263x.2008.00941.x.^,50Zhang Q, Bian Z, Fan M, van Palenstein Helderman WH. Salivary mutans streptococci counts as indicators in caries risk assessment in 6-7-year-old Chinese children. J Dent 2007;35(2):177-80. doi: 10.1016/j.jdent.2006.07.004.^,51Hallett KB, O’Rourke PK. Oral biofilm activity, culture testing and caries experience in school children: O02-11. Oral Session O02/Cariology 2. Int J Paed Dent 2009;19(Suppl 1):4. Studies were often weak, with small sample sizes, low power, heterogeneity, and short follow-up periods. In addition, insufficient information is available on specific strains and doses.

Research is increasing knowledge on the mechanisms of action of probiotics, and innovations in the delivery and substantivity of probiotics are being researched. It is also suggested that screening of potential probiotics should include aggregation assays, since differences in co-aggregation have been found.42Wasfi R, Abd El-Rahman OA, Zafer MM, Ashour HM. Probiotic Lactobacillus sp. inhibit growth, biofilm formation and gene expression of caries-inducing Streptococcus mutans. J Cell Mol Med 2018;22(3):1972-83. doi: 10.1111/jcmm.13496. In the meantime, the results of some recent studies on probiotics and caries management are promising.24Piwat S, Teanpaisan R, Manmontri C et al. Efficacy of Probiotic Milk for Caries Regression in Preschool Children: A Multicenter Randomized Controlled Trial. Caries Res 2020;54(5-6):491-501. doi: 10.1159/000509926.^,25Staszczyk M, Jamka-Kasprzyk M, Kościelniak D et al. Effect of a Short-Term Intervention with Lactobacillus salivarius Probiotic on Early Childhood Caries-An Open Label Randomized Controlled Trial. Int J Environ Res Public Health 2022;19(19):12447. doi: 10.3390/ijerph191912447.^,26Rodríguez G, Ruiz B, Faleiros S et al. Probiotic Compared with Standard Milk for High-caries Children: A Cluster Randomized Trial. J Dent Res 2016;95:402-7.^,27Hedayati-Hajikand T, Lundberg U, Eldh C, Twetman S. Effect of probiotic chewing tablets on early childhood caries-a randomized controlled trial. BMC Oral Health 2015;15:112. Robust clinical trials are needed to ascertain the anti-caries efficacy and safety of probiotics.

References

• 1.Hill C, Guarner F, Reid G et al. Expert consensus document. The International Scientific Association for Probiotics and Prebiotics consensus statement on the scope and appropriate use of the term probiotic. Nat Rev Gastroenterol Hepatol 2014;11(8):506-14.
• 2.World Gastroenterology Organisation. Probiotics and prebiotics. 2017. https://www.worldgastroenterology.org/UserFiles/file/guidelines/probiotics-and-prebiotics-english-2017.pdf.
• 3.Bonifait L, Chandad F, Grenier D. Probiotics for Oral Health: Myth or Reality? J Can Dent Assoc 2009;75(8):585-90. https://www.cda-adc.ca/jcda/vol-75/issue-8/585.pdf.
• 4.Stašková 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.
• 5.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.
• 6.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.
• 7.Karczewski 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.
• 8.Feng JR, Wang F, Qiu X et al. Efficacy and safety of probiotic-supplemented triple therapy for eradication of Helicobacter pylori in children: a systematic review and network meta-analysis. Eur J Clin Pharmacol 2017;73(10):1199-208. doi: 10.1007/s00228-017-2291-6.
• 9.Sales-Campos H, Soares SC, Oliveira CJF. An introduction of the role of probiotics in human infections and autoimmune diseases. Crit Rev Microbiol 2019;45(4):413-32. doi: 10.1080/1040841X.2019.1621261.
• 10.Inchingolo 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.
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