REVIEW OF PROBIOTICS: ADJUNCTIVE
TREATMENT OF PERIODONTITIS
Fiona Collins BDS, MBA, MA, FPFA
2CE
CREDITS
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”. 1 While frequently used in the prevention and treatment
of gastrointestinal diseases, 2 probiotics are now also being researched and used for other purposes, including
the prevention and treatment of oral disease. 3 , 4 , 5 , 6 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. 3 , 4 , 7 , 8 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). 9 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. 10 , 11 , 12 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. 13 Keystone pathogens are noted to be a key component of CP progression. 14
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. 15 Additionally, the dental biofilm is inflammophilic and, as inflammation progresses,
further shifts in the microbial community occur, favoring an increased inflammatory response. 16 , 17 The
inflammatory response is host-dependent, and involves both pro- and anti-inflammatory mediators.
Based on the keystone pathogen hypothesis, even a
small amount of a specific bacteria (keystone) can
influence the microbial content of dental biofilm and
initiate an inflammatory response.
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. 18 , 19 , 20 The
most frequently researched probiotic as an adjunct for treating periodontal disease is Lactobacillus reuteri (L.
reuteri).
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.
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. 19 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. 20 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, 21 and conflicting results were also reported in
earlier systematic reviews. 22 , 23
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. 24 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. 25 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). 26 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. 27
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). 28 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. 29
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. 30 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. 31 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)
Table 1. Recent Studies on the effect of probiotics on CP parameters
Compared to the control group, significantly greater reductions for PI, GBI,
Hadžić et al. 24
2021 BOP, and CAL gains, in patients with advanced CP receiving SRP and
RCT
lozenges containing L. reuteri for 40 days.
Significantly greater improvements in PD, CAL and BOP for the test group
Sufaru et al. 25
2022 receiving SRP and adjunctive probiotic (L. reuteri) over a 30-day period
Split-mouth
compared to receiving SRP alone
No significant inter-group differences for reductions in PD or BOP, or CAL
Pelekos et al. 26
2019 gain, at 90 and 180 days after taking either L. reuteri lozenges twice-daily
Double-blind RCT
for 4 weeks (test group) or placebo.
At 90 days, significantly greater reductions in PD and greater CAL gain in the
Invernici 27 test group using lozenges containing B. lactis twice-daily for 30 days as an
2020
RCT adjunct to SRP compared to the control group receiving placebo lozenges
as the adjunct.
For molar sites with an initial PD ≥ 5 mm, greater improvements in CAL in the
Pelekos et al. 28 test group receiving adjunctive lozenges containing L. reuteri for 28 days
2020
RCT analysis compared with the group receiving placebo lozenges. Both groups received
periodontal therapy.
No significant inter-group differences for PD reductions or CAL gains overall
in patients receiving one-stage full-mouth disinfection plus lozenges
Teughels et al. 29
2013 containing L. reuteri twice-daily for 12 weeks or placebo. Significantly
RCT
greater reductions in PD for deeper pockets in the test group and greater
CAL gains.
Compared to control group (SRP and placebo lozenges), significantly
Laleman et al. 30
2020 greater reductions in overall residual PD for the test group (SRP plus twice-
RCT
daily probiotic lozenges (L. reuteri).
Greater reductions in PD in test group (maintenance treatment and
31 lozenges containing L. reuteri twice-daily for two 3-month periods over a
Grusovin.
2020 year), than for control group (maintenance treatment and placebo
Double-blind RCT
lozenges). No significant inter-group difference in the percentage of sites
with PD >4 mm.
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. 7 , 18 , 32 As noted in discussing probiotics and dental caries, in vitro studies have demonstrated that L.
paracasei inhibits EPS production by Streptococcus mutans (SM), 33 strains of Lactobacillus co-aggregate with
SM 34 and bacteriocins (antimicrobials) target SM – interfering with cell wall development and helping to form cell
membrane pores. 18 , 35 , 36 Some L. reuteri strains also secrete bacteriocins – reuterin and reutericyclin – which
inhibit the growth of numerous pathogens and compete for adhesion sites. 3 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. 37
Some L. reuteri strains secrete reuterin and
reutericyclin – bacteriocins that inhibit the growth of
numerous pathogens and compete for adhesion sites.
In one RCT, polymerase chain reaction (PCR) testing was performed to determine the effect of lozenges
containing L. reuteri in patients with advanced CP. 24 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. 38 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. 39 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. 30
In vitro studies
Figure 1. In vitro effects of select probiotics on microorganisms
B. lactis and B. infantis used alone or together have been found to inhibit Pg and Fn in biofilms, 40 and co-
culturing of S. salivarius K12 or M18 with periodontal pathogens found to inhibit Pg, Fn, Td, Tf, Parvimonas micra,
and Eikenella corrodens. 41 Additionally, S. salivarius M18 cell-free supernatant can inhibit growth of Pseudomonas
aeruginosa and Klebsiella pneumonia, as well as biofilm formation. 42 Furthermore, in a fourth study, cultures
containing S. dentisani 7746 supernatant were shown to inhibit Pg and Fn. 43
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. 44 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. 45
Significant reductions in salivary levels of prostaglandin E2 (PGE2) in patients receiving L. brevis. 3
Significant reductions in IL-1ß in patients receiving Bifidobacterium. 38
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. 7
In vitro reductions in the expression of interferon-γ induced by Fn when S. dentisani is incubated with Pg
and Fn. 43 (Figure 2)
Figure 2. Reductions in pro-inflammatory mediators in studies 3 , 7 , 38 , 43 , 45
Figure 3. Increases in anti-inflammatory mediators in studies 27 , 38 , 43 , 45
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. 45
Increased secretion of IL-10 (which downregulates MMPs as well as RANKL and upregulates TIMPs) in GCF in
patients receiving B. lactis HN019. 38
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. 27
In vitro, increased secretion of IL-10 through incubation of S. dentisani with Pg and Fn. 43 (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. 20 In one vitro study, strains of
Streptococcus salivarius and Lactobacillus were evaluated as probiotics for periodontal biofilms. 46 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. 21 , 47
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.
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