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Probiotics in Oral Health and Disease: A Systematic Review

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  • Instituto Universitário Egas Moniz (IUEM)

Abstract

Abstract: Purpose: Probiotics may exclude or antagonize oral pathogens and be useful to prevent oral dysbiosis and treat oral diseases. The objective of this review was to assess the benefits of probiotics in oral health and disease, and in dental practice; Methods: Primary articles published between January 2012 and 30 December 2020 with full text available were searched in PubMed, ClinicalTri- als.gov, ScienceDirect, Google Scholar, B-on, and SciELO; Results: The electronic search identified 361 references of which 91 (25.2%) met all the inclusion criteria. In total, data from 5374 participants with gingivitis, periodontitis, peri-implantitis, caries, orthodontic conditions, halitosis, or oral condi- tions associated with chemo-radiotherapy were included. Despite major inconsistencies between clinical trials, probiotics have been found to contribute to reduce S. mutans counts (L. paracasei SD1), reduce probing depth in chronic periodontitis (B. animalis subsp. lactis DN-173010 with L. reuteri), reduce levels of volatile sulfur compounds and halitosis (L. salivarius WB21), treat oral mucositis and improve the quality of life of patients undergoing cancer chemo-radiotherapy (L. brevis CD2). Com- binations of probiotic bacteria tend to lead to higher clinical efficacy than any individual probiotic agent; Conclusion: Oral probiotics influence favorably the oral microbiota and provide benefits to the oral ecosystem in periodontal diseases, cariology, halitosis, orthodontics and management of oral mucositis resulting from cancer treatment. However, the use of probiotics in dental practice or in self-management preventive strategies requires additional well controlled clinical trials to determine the most effective probiotic combinations, the most appropriate probiotic vehicle, and the frequency of administration.
applied
sciences
Review
Probiotics in Oral Health and Disease: A Systematic Review
Perrine Saïz, Nuno Taveira * and Ricardo Alves


Citation: Saïz, P.; Taveira, N.; Alves,
R. Probiotics in Oral Health and
Disease: A Systematic Review. Appl.
Sci. 2021,11, 8070. https://doi.org/
10.3390/app11178070
Academic Editor: Bruno Chrcanovic
Received: 15 July 2021
Accepted: 26 August 2021
Published: 31 August 2021
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Attribution (CC BY) license (https://
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4.0/).
Centro de Investigação Interdisciplinar Egas Moniz (CiiEM), Instituto Universitário Egas Moniz,
2829-511 Monte de Caparica, Portugal; perrinesaiz.psz@gmail.com (P.S.); ralves@egasmoniz.edu.pt (R.A.)
*Correspondence: ntaveira@ff.ulisboa.pt; Tel.: +351-966147563
Abstract:
Purpose: Probiotics may exclude or antagonize oral pathogens and be useful to prevent oral
dysbiosis and treat oral diseases. The objective of this review was to assess the benefits of probiotics
in oral health and disease, and in dental practice; Methods: Primary articles published between
January 2012 and 30 December 2020 with full text available were searched in PubMed, ClinicalTri-
als.gov, ScienceDirect, Google Scholar, B-on, and SciELO; Results: The electronic search identified
361 references
of which 91 (25.2%) met all the inclusion criteria. In total, data from
5374 participants
with gingivitis, periodontitis, peri-implantitis, caries, orthodontic conditions, halitosis, or oral condi-
tions associated with chemo-radiotherapy were included. Despite major inconsistencies between
clinical trials, probiotics have been found to contribute to reduce S. mutans counts (L. paracasei SD1),
reduce probing depth in chronic periodontitis (B. animalis subsp. lactis DN-173010 with L. reuteri),
reduce levels of volatile sulfur compounds and halitosis (L. salivarius WB21), treat oral mucositis and
improve the quality of life of patients undergoing cancer chemo-radiotherapy (L. brevis CD2). Com-
binations of probiotic bacteria tend to lead to higher clinical efficacy than any individual probiotic
agent; Conclusion: Oral probiotics influence favorably the oral microbiota and provide benefits to
the oral ecosystem in periodontal diseases, cariology, halitosis, orthodontics and management of oral
mucositis resulting from cancer treatment. However, the use of probiotics in dental practice or in
self-management preventive strategies requires additional well controlled clinical trials to determine
the most effective probiotic combinations, the most appropriate probiotic vehicle, and the frequency
of administration.
Keywords: probiotics; oral microbiota; oral health; oral diseases; dental practice
1. Introduction
The oral cavity is a dynamic ecosystem, with environmental changes and permanent
interactions in which commensal bacteria limit the colonization of pathogenic microorgan-
isms. The oral microbiota is heterogeneous and diverse, and its imbalance leads to the
onset of major oral diseases such as periodontitis and dental caries [
1
]. Conventional treat-
ment of these diseases involves removal of the bacterial plaque by mechanical means and
antimicrobial drug therapy which may have limited efficacy due to drug resistance [
2
]. It is
necessary to look for alternatives and adjuvants to conventional therapeutic and prevention
approaches and probiotics may play an important role in this context.
According to the World Health Organization (WHO) and the Food and Agriculture
Organization of the United Nations (FAO), probiotics are “living microorganisms that,
when administered in adequate amounts, confer benefits to host health” [
3
]. Probiotic-based
intervention strategies are widely used for intestinal diseases but not yet for oral diseases
due to the limited scientific evidence of usefulness. Probiotics can outcompete pathogenic
bacteria and increase the proportion of beneficial bacteria in the mouth thereby contributing
for the prevention and therapy of oral diseases [
4
6
]. In order to be effective in the oral
cavity, probiotics must support oral environmental conditions, adhere to and colonize oral
surfaces, inhibit oral pathogens [7,8], and/or delay colonization by pathogenic strains [5].
Furthermore, they must not ferment the sugars in order to avoid the pH decrease and
Appl. Sci. 2021,11, 8070. https://doi.org/10.3390/app11178070 https://www.mdpi.com/journal/applsci
Appl. Sci. 2021,11, 8070 2 of 19
demineralization of the enamel, they should hamper the organization of the extracellular
matrix responsible for biofilm formation, limit the production of cytotoxic products by
pathogenic bacteria, and beneficially alter the biochemical parameters that influence the
dental plaque (e.g., salivary components, buffer capacity) (Figure 1) [
9
]. In addition, oral
probiotics must be safe for the host [10,11].
Figure 1.
Potential mechanisms of action of probiotics in oral health and disease: (
A
) direct interaction with pathogens to
prevent pathogen colonization; (
B
) antagonistic activity on pathogens cytotoxic metabolites, oral biofilm, and extracellular
matrix; (
C
) synthesis of antibacterial agents (e.g., bacteriocins) against oral pathogens; (
D
) alter adhesion, aggregation,
colonization, and proliferation of pathogens in oral tissues due to mechanisms of exclusion and competition; (
E
) coating oral
tissues to protect oral surfaces from pathogens action; (
F
) maintain oral ecosystem balance by synthetizing cytoprotective
proteins, antioxidant products, and regulatory metabolites on surface of oral cells; (G) competition for nutrients.
Appl. Sci. 2021,11, 8070 3 of 19
The therapeutic and prophylactic potential of probiotics has been explored with
promising results in major oral diseases like periodontitis and dental caries [
12
15
]. How-
ever, questions remain regarding the best probiotic species or strains for each oral disease or
condition and for each population or individual [
16
], and regarding the most appropriate
probiotic vehicles, dose, and frequency of administration. To determine the usefulness of
probiotics in current dental practice we make a critical review of clinical studies assessing
the potential benefits of probiotics in oral health and disease.
2. Material and Methods
2.1. Protocol
This systematic review used the Preferred Reporting Items for Systematic reviews
and Meta-analysis (PRISMA) guidelines [
17
]. The PRISMA checklist is available as a
Supplementary file (Table S1).
2.2. Focused Question and Eligibility Criteria
The following question was set: “Is there scientific evidence that the use of probiotics
confers benefits to human oral health?” The PICOS criteria that allowed the elaboration of
the research question are presented in Table S2.
The eligibility criteria of the studies to be included in the review were:
1.
Types of study: randomized clinical trials, without any information of blinding, blind
(single, double, or triple), placebo controlled, or non-placebo controlled (compared to
another intervention), including cross-over studies.
2.
Type of participants: of any age (adults, children, the elderly), without gender restric-
tion, healthy or not.
3. Type of intervention: use of any probiotic (alone or in combination).
4.
Considering any dosage regimen, vehicle of delivery or frequency of intervention.
Comparators may consist of placebo or other active intervention without probiotics
(with or without prebiotic/synbiotic vs. placebo/other intervention). Prebiotics are a
group of nutrients that are degraded by gut microbiota. Synbiotic is a mixture of pre-
and probiotics. Studies including an auxiliary to the active treatment were analyzed.
5.
Primary outcomes: clinical, microbiological, immunological, and
biochemical parameters
.
6. Secondary outcomes: any adverse effects, rate of adherence, quality of life.
2.3. Search Strategy and Study Selection
The bibliographic search was carried out in the following electronic databases PubMed,
ClinicalTrials.gov, ScienceDirect, Google Scholar, B-on, SciELO using the keywords “pro-
biotics”, “dental practice”, “oral health”, “oral diseases” and “oral microbiota” and the
conjugation of these keywords. Articles published between January 2012 and 30 Decem-
ber 2020 with full text available were selected. Duplicate references, articles available in
2011 published in 2012, theses, reviews, and articles related to oral probiotics intake with
only systemic repercussion were excluded. Further research was done after reading the
references of all relevant articles. The full texts of all articles corresponding to the inclusion
criteria were obtained and examined for final inclusion. The selection process was included
in a PRISMA flow diagram (Figure S1).
3. Results
The electronic search identified 361 references. After removing the duplicates,
308 references
were selected for eligibility based on the titles and abstracts, excluding
in vitro
studies,
animal studies, and ongoing and unpublished clinical trials. After searching in the ref-
erences, 28 additional articles were identified. For the full text review, 129 articles were
selected. Of these, 38 clinical trials were excluded because oral health was not the focus of
the study, because the study design was unclear, there was no information about allocation,
the intake of probiotics was evaluated in animals, and studies were performed
in vitro
.
The 91 randomized controlled trials (RTCs) included in the review involve data from
Appl. Sci. 2021,11, 8070 4 of 19
5374 participants
with gingivitis (n= 14), periodontitis (n= 21), peri-implantitis (n= 8),
carie (n= 23), orthodontic conditions (n= 6), halitosis (n= 4), oral conditions associated
with chemo-radiotherapy (n= 6) and changes in the oral ecosystem (n= 9). Sample sizes
range from 10 and 321 participants. The duration of interventions varied between 7 days
and up to 2 years. There were 59 studies performed in adults, 24 in children, and 8 in more
than one age group. Regarding the probiotic/s administered, 53 studies have implemented
a combination of probiotics and 37 have administered a single probiotic. Two studies used
symbiotic/prebiotic (1 with a single probiotic and 1 with a combination). The concentra-
tions of the probiotics were not reported in 29 studies and one study did not specify the
probiotic that was used. In two studies the duration of administration of probiotic(s) was
not given. Adverse effects were reported in 13 trials.
Regarding the study design, there are 11 cross-over trials, 80 placebo-controlled trials
and 11 trials compared with another intervention. Regarding the blinding, there are
18 studies
without indication of blinding, five single blinding, 61 double-blind, six triple-
blind and one with no blinding. The primary results of the studies are mainly focused on
clinical, microbiological, and immunological parameters. No data were analyzed regarding
financing, for-profit bias, and location of studies.
4. Discussion
4.1. Impact of Probiotics in the Oral Microbiota
The community of microorganisms that colonizes the mouth and forms the dental
plaque mainly plays a protective role against pathogens. Dental plaque consists of bacterial
cells (mainly streptococci and lactobacilli), bacterial metabolites/products/toxins, salivary
polymers/proteins, and food debris [
1
]. Probiotic lactobacilli may inhibit the adhesion of
pathogenic bacteria to the oral tissues, reducing the amount of biofilm formed (
Figure 1
).
On the other hand, lactobacilli probiotics may potentiate dental plaque acidogenicity and
increase the load of acid tolerant bacteria such as S. mutans and viridans streptococci,
making the dental biofilm more pathogenic [
18
]. The following 9 trials studied the impact
of probiotics in the oral ecosystem (Table S3
)
. In Thakkar et al. [
19
], dental plaque accumu-
lation in children was significantly reduced after 14 days of tablet consumption containing
L. acidophilus, L. rhamnosus, Bifidobacterium longum and S. boulardii, and after three weeks of
intervention. In a study by Burton et al. [
20
], administration of Streptococcus salivarius M18
to children for 3 months caused a significant decrease in dental plaque scores. Non-target
microorganisms, S. salivarius, Lactobacillus spp., hemolytic streptococci and Candida spp.
levels were not changed during the study. Despite a high adhesion rate (>80%), only
22% of the children were colonized by S. salivarius M18 and this lasted until 4 months
after discontinuation. S. mutans counts were reduced, especially in colonized children,
suggesting that S. salivarius M18 may have anti-carie activity and that colonization helps
the probiotic effect.
A significant reduction of salivary Aggregatibacter actynomycetancomitans, P. gingivalis
and Streptococcus mutans counts, and total number of microorganisms was achieved in
children after 2-weeks ingestion of Petit-Suisse (cream cheese) with L. casei [
21
]. However,
the reduction of total number of microorganisms and Streptococcus mutans was attributed
to Petit-Suisse alone as it occurred in both the probiotic and control groups.
A significant decrease in S. mutans counts and in the total number of microorganisms
occurred after once daily consumption of fermented milk containing L. rhamnosus SD11 in
adults during 4-weeks and after 4-weeks discontinuation [
22
]. In contrast, Lactobacillus spp.
counts increased significantly at week 4 in all patients, and the probiotic was detected up
to 8 weeks in 80% of the individuals. In a study by Toiviainen et al. [
23
], a combination of
L. rhamnosus GG and B. lactis BB-12 administered over 4 weeks to adults caused no change
in the salivary S. mutans or Lactobacillus spp. counts. Similarly, L. reuteri DSM 17938 and
ATCC PTA 5289 administered during 2–12 weeks to adults had no impact on salivary S.
mutans count and microbial profile and diversity [
24
26
]. Administration of L. rhamnosus
GG or L. reuteri D2112 and PTA 5289, also did not impact salivary S. mutans count [
18
].
Appl. Sci. 2021,11, 8070 5 of 19
However, there was a significant increase in lactobacilli in volunteers taking L. reuteri but
not L. rhamnosus.
In summary, most probiotic strains analyzed in these trials are safe, as they do not sig-
nificantly and definitively affect the commensal oral microbiota, and some can transiently
colonize the dental surfaces and have the potential to prevent dental caries.
4.2. Probiotics in Periodontology
Periodontitis is caused by periodontopathogenic bacteria (Porphyromonas gingivalis,
Treponema denticola, Tannerella forsythia and Aggregatibacter actinomycetancomitans) that are
organized in biofilms at the supragingival and subgingival levels in susceptible hosts
[1,27]
.
Treatment consists of the mechanical removal of pathogenic biofilm and the use of antisep-
tics or antibiotics [
28
]. The main objective of the treatments is to avoid recolonization by
pathogenic bacteria. Probiotics as adjuvants to mechanical treatment could modify and
occupy the subgingival niche susceptible to recolonization by pathogenic bacteria and
allow a new equilibrium with the oral environment (Figure 1) [
7
]. Probiotics could also
alter the bacterial profile of the biofilm adjacent to implants [
29
]. In addition, they could
act as immunomodulators in the oral cavity by decreasing pro-inflammatory cytokines
IL-1
β
, TNF-
α
and matrix metalloproteinases (MMP) levels, and increasing IL-10, TGF-
β
1
and tissue inhibitor of metalloproteinases (TIMP) levels [3032].
4.2.1. Probiotics in Gingival Health and Gingivitis
Fourteen randomized clinical trials related to the use of probiotics in gingivitis and
gingival health were analyzed (Table S4). In a study by Kuru et al. [
33
], 4-week use of
yogurt supplemented with Bifidobacterium animalis subsp. lactis DN-173010 had a posi-
tive effect on gingival inflammatory parameters after a 5-day non-brushing period. In a
study by
Yousuf et al. [9]
, plaque index (PI) and gingival index (GI) scores were reduced
in adolescents after two weeks administration of a probiotic combination containing Bifi-
dobacterium longum, Lactobacillus acidophilus, Bifidobacterium bifidum, Bifidobacterium lactis
and acid lactic bacillus. Dhawan and Dhawan [
11
] showed a significant reduction of PI up
to 4 weeks with the probiotic combination Lactobacillus sporogenes,Streptococcus faecalis PC,
Clostridium butyrium TO-A, and Bacillus mesentericus TO-A in patients with gingivitis. In
studies by Desmukh et al. [
34
] and Nadkerny et al. [
7
], individuals with gingival health
and gingivitis were administered with a probiotic combination for two weeks. Control
group used chlorhexidine. The probiotic combination reduced gingival inflammation and
plaque accumulation in the same way as chlorhexidine in both studies suggesting it could
serve as an adjuvant in plaque control. Alkaya et al. [
35
] tested three modes of application
of Bacillus subtilis, Bacillus megaterium, and Bacillus pumulus in patients with gingivitis after
mechanical therapy and no significant difference was observed between the probiotic and
placebo groups.
Similar negative results were obtained by Keller et al. [
36
] when using Lactobacillus
rhamnosus and Lactobacillus curvatus tablets in patients with gingivitis.
Contrasting results were obtained when using Lactobacillus reuteri (DSM17938 and
ATCC PTA 5289) probiotic for gingivitis. In a study by Hallstrom et al. [
30
], there were
no clinical, microbiological, and immunological benefits in women with experimental
gingivitis. In a study by Iniesta et al. [
37
], there was a significant reduction in salivary counts
of total anaerobes after 4 weeks of intervention, and Prevotella intermedia counts after 4 and
8 weeks in patients with gingivitis relative to the placebo group. Porphyromonas gingivalis
counts also decreased significantly in a subgingival sample up to 4 weeks. However, there
was no difference between PI and GI scores in the test and placebo groups. In contrast,
Sabatini et al. [
4
] showed a significant reduction in PI and GI scores in patients with
controlled diabetes type II after 30 days on probiotic. Likewise, Schagenhauf et al. [
38
]
showed a significant reduction of clinical parameters and a complete resolution of sites
with mild inflammation in pregnant women. The results suggest that L. reuteri-based
probiotics may help to manage gingivitis in individuals more susceptible to oral infections.
Appl. Sci. 2021,11, 8070 6 of 19
Lee et al. [
39
] evaluated the effects of Lactobacillus brevis CD2 in experimental gingivitis.
Significant differences at the bleeding on probing (BOP) level were found on day 10 in favor
of the probiotic group but no longer on day 14 suggesting that this strain can delay the
onset of gingivitis over a short period of time. Consistent with this, there was a progressive
increase in nitric oxide (NO), an inflammatory mediator, in the gingival crevicular fluid
(GCF) of the placebo group unlike the probiotic group in which there was no change.
Alanzi et al. [
40
] evaluated the 4-weeks administration of probiotic tablets containing
Lactobacillus rhamnosus, Bifidobacterium lactis on adolescents with gingival health. There was
a significant reduction in Aggregatibacter actynomycetancomitans and F. nucleatum counts in
saliva and plaque, and P. gingivalis count in plaque in the probiotic group. GI scores also
improved in the probiotic group. In Montero et al. [
41
] administration of tablets containing
Lactobacillus plantarum, Lactobacillus brevis, and Peiococcus acidilactici for 6-weeks to patients
with gingivitis led to a significant reduction of severe gingival inflammation scores when
compared to placebo. In addition, the average number of sites per patient with moderate
inflammation was reduced from 56 to 4 after the probiotic intervention period. There was
a decrease in T. forsythia counts which the authors correlated with the decrease of severe
inflammation scores.
Overall, these studies suggest that long term use of some probiotics may aid in oral
hygiene, promote gingival health, and help to treat gingivitis. This effect is more significant
when there is no mechanical removal of the plaque [
4
,
7
,
9
,
11
,
38
,
40
] than when the plaque
is removed [
35
]. Additional long-term studies are needed in larger population across all
age ranges and ethnic groups to obtain more consistent clinical results, and to determine if
probiotics need to colonize the oral cavity to cause a beneficial effect.
4.2.2. Probiotics in Periodontitis
The uncontrolled expansion of periodontopathogenic bacteria (Porphyromonas gingi-
valis, Treponema denticola, Tannerella forsythia, Filifactor alocis, Parvimonas micra, Aggregatibac-
ter actinomycetemcomitans and species of Fusobacterium and Prevotella) along with dysregula-
tion of the immune barriers and tissue damage leads to periodontitis [
1
]. Remodeling of
the periodontal extracellular matrix depends on the balance between proteolytic enzymes
responsible for the degradation and remodeling of extracellular matrix proteins (MMPs),
present in saliva, dental plaque and GCF and tissue inhibitors of MMPs, TIMP-1 and
TIMP-2 [
42
,
43
]. In case of periodontal diseases, an imbalance in the ratio of MMPs/TIMPs
(e.g., TIMP-1 reduction and MMP 8–9 increase) leads to periodontal destruction.
The conventional treatment of periodontitis involves the mechanical removal of the
subgingival plaque. Scaling and root planing (SRP) is the standard control method and
can be complemented by the addition of antibiotics which can lead to development of
resistance, modifications of the commensal flora and risk of dysbiosis [
28
]. On the other
hand, bacterial plaque is difficult to remove in low access sites, and remaining bacteria can
cause periodontitis relapse and can invade adjacent tissues (i.e., mucosa, tongue, tonsils)
and cause new infections [1].
Probiotics were proposed as adjuncts to the mechanical therapy of periodontitis
aiming at restoring the commensal microbiota and reduce inflammation and tissue dam-
age [44,45]. For this review, 21 randomized clinical trials related to the implementation of
probiotics in periodontal conditions were selected (Table S5). Most trials have used species
of Lactobacillus because it is a commensal bacterium that antagonizes P. gingivalis [10,46].
In Vicario et al. [
10
], tablets containing L. reuteri ATCC 55,730 and L. reuteri ATCCPTA
5289 were administered to patients with chronic periodontitis for 30 days. All clinical
parameters improved significantly in the test group, suggesting a possible synergy between
the strains used. In a study by Imran et al. [
47
], ingestion of milk with Lactobacillus casei for
one month provided no clinical benefit to patients with chronic periodontitis in spite of a
significant decrease in P. gingivalis counts in the first months after the intervention. Aggre-
gatibacter actynomycetancomitans and P. intermedia counts showed no significant reduction.
Appl. Sci. 2021,11, 8070 7 of 19
Iwasaki et al. [
48
] evaluated the use for 12 weeks of heat-killed Lactobacillus plantarum
in patients undergoing supportive periodontal therapy. Mechanical control of plaque
was performed and improved clinical parameters in both the test and placebo groups. A
significant decrease in favor of the probiotic group was observed at 12 weeks in bleeding
on probing (BOP), number of teeth with periodontal pocket depth (PD) >4 mm and number
of sites with PD >4 mm, suggesting that this probiotic can prevent a possible recurrence
and/or disease progression.
Grusovin et al. [
8
] evaluated for 12 months the effects of a Lactibacillus reuteri DSM
17938 and PTA 5389 probiotic combination in patients treated for a stage III-IV periodontitis,
grade C. In the probiotic group, there was a higher reduction of mean PD throughout the
study, higher clinical attachment level (CAL) gain at 6 months, and higher reduction of
BOP at 6 and 9 months.
In a study by Penala et al. [
46
], probiotics L. salivarius and L. reuteri were evaluated
as an adjunct to SRP in the treatment of patients with chronic periodontitis. The test
group received subgingival delivery of probiotics and probiotic mouthwash for 14 days.
A significant difference in favor of the test group was observed after 3 months in the
number of moderate periodontal pockets. Moreover, there was a significant reduction in
the benzoyl-DL arginine-naphthylamide (BANA) test for detecting digesting peptidase in
the test group after 1 month, compared to the placebo group, but the difference was no
longer observed at 3 months.
Chandra et al. [
49
] tested a subgingival combination of probiotics Saccharomyces
boulardii with a prebiotic (fructo-oligosaccharide) in patients with chronic periodontitis
as adjuvant to SRP. Despite a short-term colonization by Saccharomyces boulardii (until
day 7
), there was significant clinical improvement (as measured by the reduction of PI,
GI, CAL, and PD) in the test group at 3 and 6 months after the mechanical treatment.
The results suggest that S. boulardii may be a good auxiliary agent in the treatment of
chronic periodontitis.
In a study by Boyeena et al. [
50
], the effects of a probiotic combination were compared
to the application of tetracycline fibers directly in the periodontal pocket after mechanical
removal of the plaque. Use of probiotics caused a significant reduction of BOP and PD
when compared to the tetracycline fibers. The combination of both approaches showed
a significant improvement of BOP and PD when compared to tetracycline fibers alone
illustrating the benefits of using tetracycline fibers and probiotics to treat periodontitis.
Shah et al. [
51
] tested L. brevis, with or without doxycycline, for the treatment of
patients with aggressive periodontitis after mechanical plaque removal. After 2 weeks,
there was a significantly higher reduction of PD in patients on L. brevis and doxycycline
relative to the other patients. At 2 months Lactobacillus spp. count (CFU/mL) increased
significantly in patients on L. brevis and all patients had significantly improved clinical
parameters when compared to baseline.
In a study by Morales et al. [
52
], the effects of daily administration of Lactobacillus
rhamnosus SP1 or azithromycin tablets for 3 months were studied as an adjunct to SRP in
patients with chronic periodontitis. Clinical and microbiological outcomes (as determined
by the presence and levels of Tannerella forsythia, Porphyromonas gingivalis and Aggregatibacter
actinomycetemcomitans) improved over the study period but there were no significant
differences between groups.
Yuki et al. [
53
] compared the effects of consumption for 90 days of yogurt containing
L. rhamnosus
L820 with placebo yogurt in individuals with mental deficiency and periodon-
tal disease. The PMA (papillary-marginal-attached) score was significantly reduced in the
probiotic group at 90 days suggesting that L. rhamnosus L820 may have a beneficial effect
on periodontal disease as an adjunct to mechanical oral hygiene.
Ikram et al. [
44
] compared L. reuteri with metronidazole as adjuvant to SRP in patients
with chronic periodontitis. There was a significant improvement in the clinical parameters
at all evaluation periods with no difference between groups, indicating that the efficacy of
probiotic and antibiotic was similar.
Appl. Sci. 2021,11, 8070 8 of 19
In a study by Laleman et al. [
54
], the use of Streptococcus oralis KJ3, Streptococcus uberis
KJ2, and Streptococcus rattus JH14 was not effective as adjunctive treatment of periodontitis
despite lower PI at the end of the monitoring period (24 weeks) and the decrease of salivary
P. intermedia at 12 weeks.
Murugesan et al. [
55
] evaluated the efficacy of co-administration of doxycycline
and synbiotic tablet (consisting of prebiotic Streptococcus faecalis T-110 JPC and probiotics
Clostridium butyricum TO-A, Bacillus mesentericus TO-A and L. sporogenes) as adjuvant to SRP
in patients with periodontitis. Four weeks after the end of the intervention, a significant
reduction of PD, CAL and BOP was observed in the test group indicating that this prebiotic-
probiotic mixture can be a complement to the mechanical removal and doxycycline to
improve clinical parameters, reduce bacterial load and repopulate the treated niche.
Three different trials studied the impact of L. reuteri in patients with chronic peri-
odontitis using comparable study design (administration for 3 weeks of probiotic tablets
containing L. reuteri compared to placebo) and obtained similar results [
5
,
31
,
56
]. Most
clinical and microbiological parameters (as evidenced by a delay of recolonization up to
6 months
) were significantly improved during the study period and the probiotic groups
had fewer patients at high risk of disease progression and more patients at low risk. In one
study the probiotic was found until day 90 in 11 patients and was no longer found on day
180, indicating temporary colonization [31].
Residual periodontal pockets are associated with an increased risk of periodontal
disease progression and therefore require additional treatment. The effect of probiotic
combination L. reuteri ATCC PTA 5289 and DSM 17938 as an adjunct to the SRP treat-
ment of residual pockets was evaluated in patients with chronic periodontitis previously
treated [
57
]. The use of L. reuteri after re-instrumentation did not affect colonization by pe-
riodontopathogens. While no significant clinical improvement was observed after
12-week
consumption of probiotics and after 12 weeks of discontinuation, at 24 weeks after discon-
tinuation PD was significantly reduced in moderate and deep pockets, and more pockets
were sealed in the probiotic group. Taken together, these studies suggest that probiotic
L. reuteri
may serve as an effective complement to mechanical therapy in the treatment of
chronic and relapsing periodontitis.
In a study by Sajedinejad et al. [
45
], use of L. salivarius NK02 in mouthwash for
28 days
significantly improved clinical parameter (reduced PD, GI, and BOP) in patients
with chronic periodontitis. In addition, Aggregatibacter actynomycetancomitans counts in
saliva and gingival crevicular fluid were significantly reduced in the test group which also
presented more commensal bacteria than the placebo group.
Bifidobacterium animalis subsp. lactis HN019 was evaluated for 30 days in patients
with chronic periodontitis [
58
]. The probiotic colonized the subgingival flora for 60 days.
There was a significant reduction of IL-1
β
at the end of 30–90 days, and IL-8 at the end
of 30 days as compared to the control group. Likewise, there was a higher reduction
of periodontopathogens (P. gingivalis, T. denticola, F. nucleatum sub spp. vincentii) in the
test group up to 90 days. Clinical parameters improved significantly in the test group as
determined by CAL and PD (in moderate and deep pockets at 90 days), and the risk of
disease progression was also lower in the test group relative to the control group.
In a study by Butera et al. [
59
], the use of probiotics combinations for 6 months as
an adjunct to SRP in patients with periodontitis improved clinical parameters in both
probiotics groups (group 2: toothpaste with Bifidobacterium and Lactobacillus and group
3: toothpaste + chewing-gum with L. reuteri,L. salivarius, and L. plantarum), except for
adherent gingiva and RG. Hence, BOP, PI, number of bleeding sites, pathological site, and
sulcus bleeding index improved significantly at month 3 in both groups (also at month 6
in group 3). PD and CAL also improved significantly at month 3 in both groups. There
was a significant reduction of orange complex pathogens P. intermedia and F. nucleatum
between 3 and 6 months in both probiotics groups. Overall, group 3 presented better and
more durable effects than group 2 suggesting a synergistic effect between the probiotic
strains present in toothpaste and chewing-gum.
Appl. Sci. 2021,11, 8070 9 of 19
4.2.3. Probiotics in Peri-Implant Diseases
Peri-implant mucositis is a reversible soft tissue inflammation around the implants
with no bone loss, caused by bacteria biofilm [
60
]. Its evolution leads to peri-implantitis,
characterized by bone resorption and potential implant loss, increased levels of IL-6, IL-1
β
,
and IL-8 and increased GCF volume [
61
]. The mechanical control of the biofilm and the
use of antiseptics and antibiotics may be insufficient for the complete cure. Probiotics may
aid in the formation of a new protective biofilm compatible with peri-implant health.
Eight randomized clinical trials investigating the effects of different species of Lacto-
bacillus in peri-implant inflammation in otherwise healthy adults were analyzed (
Table S6
).
Laleman et al. [
62
], studied the use of L. reuteri ATCC PTA 5289 and DSM 17938 in initial
peri-implantitis. After SRP, probiotics were administered in drops directly to the site of
peri-implantitis and afterwards in lozenges consumed for 12 weeks twice a day. There
were no clinical and microbiological benefits from the administration of the probiotics.
Similar negative results were obtained by Lauritano et al. [
63
], who evaluated the daily
consumption of L. reuteri tablets for 28 days in patients with peri-implant mucositis, by
Peña et al. [
64
] who studied the addition for 1 month of L. reuteri DSM 17938 and ATCC
PTA in patients with peri-implant mucositis who received mechanical therapy and 0.12%
chlorhexidine 15 days before the start of probiotic intervention, by Galofréet al. [
65
]
who also evaluated the effects of administration of L. reuteri DSM 17938 and ATCC PTA
5289 in patients with peri-implant mucositis and peri-implantitis for 30 days, and by
Hallström et al. [29]
who administered L. reuteri DSM 17938 and ATCC PTA 5289 in pa-
tients with peri-implant mucositis for
3 months
. Mongardini et al. [
66
] also found no
clinical benefits after 14-days administration of L. plantarum and L. brevis on patients with
experimental peri-implant mucositis.
In contrast, Flichy-Fernández et al. [
67
] found that administration of L. reuteri DSM
17938 and ATCC PTA 5289 for 30 days was useful to treat and prevent peri-implant
mucositis. At the end of the study, a single patient developed mucositis and most (17 of
23) of the patients with mucositis were cured. Accordingly, PI, GI, PD and GCF volume
were significantly reduced in the probiotic group when compared with placebo. IL-6 and
IL-8 levels were also significantly reduced in the mucositis group taking the probiotics.
The severity of peri-implant mucositis was also reduced significantly in a more recent trial
using a probiotic combination (L. reuteri DSM 26866, L. rhamnosus DSM 21690, L. bulgaricus
DSM21690, and Bifidobacterium animalis ssp. lactis DSM 17741) [
68
]. Clinical parameters
(as determined by PI, GI, BOP, and PD) improved significantly in the test group relative
to the control group after 1 month of consumption of probiotics. Salivary flow increased
after 1 month in test group, with a significant difference between groups. Immunological
parameters (salivary cytokines Il-1
β
, Il-4, TNF-
α
) decreased significantly at 1 and 6 months
after the start of the intervention. Finally, the pathogenic species Prevotella intermedia,
Treponema denticola,Aggregatibacter actinomycetemcomitans,Porphyromonas gingivalis, and
Fusobacterium nucleatum, decreased after 1 month of probiotic consumption. The positive
results obtained in these two trials may be related with a better removal of the subgingival
plaque prior to the application of probiotics. On the other hand, the lack of results in
the remaining trials may be related with small sample sizes and short administration
times [
69
]. Clearly, further standardized clinical trials are indispensable to determine the
usefulness of probiotics in prevention, management, and treatment of gingival, periodontal
and peri-implant conditions, and to develop practical recommendations and adequate
clinical protocols.
4.3. Probiotics in Cariology
Dental caries is a multifactorial disease, related to acidogenic and acid tolerant bacteria
such as S. mutans and Lactobacillus spp. [
70
]. These bacteria produce acids from fermen-
tation of carbohydrates that demineralize dental tissues. The prevention of dental caries
involves the administration of fluoride, the use of sealants and modification of dietary
habits (lower consumption of sucrose) [
71
]. The treatment and control of dental caries
Appl. Sci. 2021,11, 8070 10 of 19
requires mechanical removal of the carious lesions which should be combined with an
antimicrobial in the case of high-risk children. Probiotics have been proposed as an adjunct
method to dental caries management strategies as they adhere to oral tissues, prevent adhe-
sion/colonization/proliferation of caries pathogens and formation of pathogenic biofilm,
produce inhibitors of cell adhesion and antibacterial agents, and consume nutrients before
caries pathogens can use them (Figure 1) [33,7275].
Seventeen clinical trials evaluated the effect of different probiotics on cariology in
children and infants (Table S7). Overall, it was easier to modify the immature dental biofilm
of children through colonization with probiotics than the established biofilm of adults.
Six trials in adults assessed whether permanent integration of probiotics into the mature
biofilm can be achieved in a cariogenic environment.
In a study by Rodriguez et al. [
76
], administration of L. rhamnosus SP1 strain in milk to
children for 10 months led to a lower prevalence of dental caries relative to the placebo
group (54.5% vs. 65.8%), lower incidence of cavitated lesions (9.7% vs. 24.3%), and lower
incidence of new lesions. Administration of tablets containing Streptococcus uberis KJ2TM,
Streptococcus oralis KJ3TM and Streptococcus rattus JH145TM to children for 3 months,
caused a significant reduction in dental caries at the end of one year with prevention of
enamel demineralization [
77
]. In a study by Di Pierro et al. [
78
], Streptococcus salivarius
M18 probiotic in tablets was evaluated for 90 days in children with high risk of caries.
There was a significant reduction in the overall cariogram result. In the probiotic group, PI
and
S. mutans
counts were significantly reduced indicating that the consumption of this
probiotic may help to prevent the development of new caries in high-risk children.
The daily and triweekly consumption of probiotic milk containing L. paracasei SD1 on
Streptococcus mutans and lactobacilli counts in saliva and plaque samples was evaluated in
preschool children for 6 months [
79
]. Probiotic administration reduced S. mutans counts and
increased total lactobacilli counts in the saliva and plaque samples that persisted at least
6 months
after discontinuation. Similar results were obtained by Pahumunto et al. [
72
] after
3-months consumption of milk containing L. paracasei SD1, and by Teanpaisan et al. [
75
]
after 6-months consumption. In the latter study, there was colonization by the probiotic
strain already at month 3 which decreased progressively with time to undetectable levels
at month 12. Overall, the results suggest that in children with high risk of caries, daily
consumption of probiotic L. paracasei SD1 may be recommended to control the amount of
S. mutans responsible for the initial process of tooth decay.
Stensson et al. [80] administered L. reuteri as drops to pregnant women (from the 9th
month of pregnancy) and their infants (up to 1 year old). At 9 years of age, the infants in
the test group showed significant improvements in GI and dental caries prevalence relative
to placebo (82% children free of carious lesions vs. 58%). L. reuteri was detected in only two
children from each group. Diet, oral hygiene, fluoride supplementation and socioeconomic
factors were similar in both groups at baseline but were not documented at the end of the
study preventing the identification of potential contributors for the benefit of probiotics in
dental caries development in early age.
In a study by Campus et al. [
81
], administration of L. brevis CD2 lozenges for
6 weeks
in children led to significant reduction in salivary S. mutans mean counts (log
10
CFU/mL), a
significant reduction in the dental plaque pH, and a significant reduction in gingival bleed-
ing at week 6. The benefits were also significant 2 weeks after probiotic discontinuation.
Bhalla et al. [
82
] evaluated Bifidobacterium animalis subsp. lactis BB-12 administered
in curds to children. A significant reduction in the S. mutans count in saliva occurred
after 1 h of ingestion and after 7 days of intervention. In a study by Sudhir et al. [
83
], L.
acidophilus administered in curds to children for 30 days led to a significant reduction in
the S. mutans count in saliva in the test group. A probiotic combination of L. acidophilus
LA5 and B. lactis BB12 also caused a significant reduction of salivary S. mutans counts in
children at days 7 and 30 after ingestion [
73
]. However, after 6 months of discontinuation, S.
mutans values returned to the initial values indicating that the colonization was temporary.
Tablet consumption of L. reuteri DSM 17938 and ATCC PTA 5289 for 28 days also caused
Appl. Sci. 2021,11, 8070 11 of 19
a significant reduction in salivary S. mutans and Lactobacillus spp. counts in children [
84
].
In contrast, L. paracasei F19 given as a dietary supplement for 9 months had no significant
effect at the microbiological and clinical levels at 3, 6 and 9 years of age [
74
]. Consistent
with this, the probiotic did not colonize the oral flora. Likewise, in Taipale et al. [
85
],
Bifidobacterium animalis subsp. lactis BB-12, administered by slow release or tablet from
the age of 1–2 months to 2 years, had no significant effect in the occurrence of dental
caries in children with low caries risk up to 4 years old when compared to xylitol and
sorbitol. Administration in children of L. rhamnosus and Bifidobacterium longum in milk for
9 months
[
86
] or Bifidobacterium lactis in yogurt for two weeks [
87
] also caused no significant
impact on S. mutans counts, dental caries prevalence, or pH and plaque accumulation.
Finally, in Cildir et al. [
88
], L. reuteri administration in drops for 25 days in children with
cleft palate (population with higher food retention, and higher levels of dental caries and
cariogenic bacteria than healthy children) caused no significant reduction in salivary S.
mutans and Lactobacillus spp. levels.
In adults, consumption of yogurt with L. acidophilus LA5 and/or Bifidobacterium lactis
BB12 for 2 weeks caused a significant temporary reduction of S. mutans count in saliva after
2 weeks [
89
,
90
]. This effect was lost 2 weeks after discontinuation. Similar results were
obtained in adults who consumed white cheese with L. casei LAFTI L26 for 2 weeks [
91
].
Administration for 4 weeks of L. paracasei SD1 in milk allowed a significant reduction
of S. mutans quantities at all monitoring times [
92
]. Lactobacillus spp. count increased
significantly in most (75%) of the patients up to week 4 suggestive of probiotic colonization.
Ingestion of ice cream containing B. infantis for 28 days, caused a significant reduction in
S. mutans counts when compared to baseline and to the control group [
93
]. There was no
effect in Lactobacillus spp. levels.
The topical application of Streptococcus dentisani in an adhesive gel on dental surfaces
in single and multiple doses was evaluated in healthy adults [94]. There was a significant
increase of the number of S. dentisani in dental plaque at day 14 after the first application
which was no longer observed on day 28. In dental plaque samples, S. mutans count
decreased significantly in the single dose group on day 28.
In summary, L. acidophilus, L. reuteri, S. dentisani, S. salivarius, B. lactis and L. para-
casei may be effective as an adjunct method to restorative treatment in children at any
risk of caries especially when used in conjunction with changes in dietary habits. Dairy
products (yogurt, milk) appear to be the favorite vehicles for oral probiotics in children.
Besides being easy to ingest, they contain essential nutrients: calcium, phosphorus, vitamin,
protein, casein phosphopeptides that promote enamel remineralization, neutralize acids,
participate in buffering, and interfere with the acidity of the probiotics Lactobacillus spp. or
Bifidobacterium spp. The mixture of probiotic(s) with dairy products induces a synergistic
effect. The heterogeneity of the trials (variability in study design, range of administration,
strains used, dosage, vehicle) likely explains variations in results and prevents significant
comparisons. Overall, however, these studies suggest that short term consumption of
probiotics may reduce cariogenic bacteria counts, prevent dental plaque formation, and
thus control the progression of dental caries. These effects seem to require the temporary
colonization of the oral ecosystem which may lead to the exclusion of bacterial pathogens
(Figure 1). However, probiotics are unable to definitively eliminate pathogenic bacteria and
a reduction in salivary counts does not imply a reduction of bacterial plaque virulence [
24
].
Future trials should not only evaluate the cariogenic bacteria counts but also the dental
caries progression/incidence because, as already mentioned, virulence and counting are
not synonymous [72,75,81].
4.4. Probiotics in Orthodontics
The orthodontic treatment causes dysbiosis of the oral microbiome due to difficulty in
hygienizing the orthodontic appliance [
95
]. Probiotics may be useful as supplements to
hinder bacterial colonization and render the dental biofilm less virulent in patients with
Appl. Sci. 2021,11, 8070 12 of 19
fixed or removable orthodontic appliances. Six studies related to the effect of probiotics on
orthodontics were analyzed (Table S8).
Jose et al. [
96
] found a significant reduction of S. mutans levels in dental plaque around
the bracket evaluated after probiotic (undisclosed composition) administration with curd
or toothpaste. In a study by Ritthagol et al. [
97
], four weeks ingestion of milk containing
L. paracasei SD1 in adolescents with non-syndromic lip-palatine cleft led to a significant
increase of salivary Lactobacillus spp. count and decrease of S. mutans count at all times of
evaluation when compared with baseline data. L. paracasei SD1 temporarily colonized the
oral microbiota, being detected in saliva up to 4 weeks after cessation. The results suggest
that this probiotic may help to prevent caries after orthodontic treatment in this population.
The effectiveness of 14-days milk consumption of L. casei or L. reuteri lozenges was
investigated in young adults undergoing orthodontic treatment [
98
]. Periodontal condition
was improved in both probiotic groups, better results being observed in the L. reuteri
group. Alp and Baka [
99
] assessed the effect of a systemic probiotic (Lactococcus lactis
subsp, Leuconostoc spp., Lactobacillus spp. and S. thermophilus and yeasts isolated from
cereal grains) or local intervention (bacteriocin extracted from lactic acid bacteria), for
6 weeks
on salivary microbial colonization in orthodontic patients. There was a significant
reduction in S. mutans count at weeks 3 and 6 in both intervention groups. Lactobacillus spp.
counts decreased significantly at week 3 in the probiotic group and at week 6 in the local
intervention group. In contrast, in a study by Pinto et al. [
100
] there were no oral benefits
after two-weeks consumption of yogurt containing B. animalis subsp. lactis DN-173010,
and in Gizani et al. [
101
] there were no clinical and microbiological advantages to the
use of L. reuteri lozenges in patients with maxillary orthodontic appliance. In summary,
daily consumption of some but not all probiotics may help to prevent caries and improve
periodontal condition in patients on orthodontic treatment.
4.5. Probiotics in Halitosis
Halitosis has multiple etiologies, and may be caused by ingestion of certain foods,
poor oral hygiene, periodontitis, respiratory infections, tobacco consumption, genetic
predisposition, dry mouth and oral microbiome dysbiosis [
102
]. Volatile sulfur compounds
(VCS) responsible for halitosis include hydrogen sulfide, methyl mercaptan and dimethyl
sulfide. In the oral cavity, these substances essentially result from the metabolic activity of
oral microorganisms [
102
]. Several factors contribute to the production of these compounds,
such as higher prevalence of gram-negative anaerobic bacteria, alkaline salivary pH, low
redox potential, and the presence of sulfuric substrates (cysteine and methionine) [
103
,
104
].
Four studies have looked at the impact of probiotics in reducing halitosis by decreasing the
density of the bacteria responsible by VCS production (Table S9).
Lee et al. [
105
] assessed the effect of consumption of Weissella cibaria tablets for 8 weeks
on halitosis in healthy adults. W. cibaria counts were higher in the probiotic group at 4 and
8 weeks, and there was a significant reduction in VCS levels at week 4, and a significant
reduction in bad breath improvement (BBI) score at week 8. The results suggest that W.
cibaria tablets can be a useful oral hygiene product to control bad breath.
Streptococcus salivarius M18 has also been shown to reduce halitosis in patients with
orthodontic treatment [
106
]. This required a month of consumption of two probiotic
lozenges per day. Only Rothia spp. levels were significantly reduced in the probiotic group.
The VCS score decreased significantly throughout the study in the probiotic group and
placebo groups after 1 month but, after 3 months of follow-up, the VCS levels returned
to the baseline value in the placebo group whereas in the probiotic group the VCS levels
decreased significantly. A reduction in halitosis levels was also observed 1 and 3 months
after ingestion of L. salivarius and L. reuteri for 14 days in patients with chronic periodontitis
and halitosis [
46
]. In a similar study performed with L. salivarius WB21 only, VCS levels
were significantly reduced and there was a significant reduction of PD [
107
]. Also, bacteria
known to produce malodourous compounds like F. nucleatum were reduced in the probiotic
Appl. Sci. 2021,11, 8070 13 of 19
group. Finally, in Keller et al. [
108
]L. reuteri reduced the organoleptic scores in patients
who had a subjective feeling of bad breath.
In summary, regular consumption of probiotics L. salivarius, S. salivarius, W. cibaria or
L. reuteri may complement mechanical oral care in controlling halitosis.
4.6. Probiotics in Oral Wound Healing and Oral Mucositis Related with Cancer Therapy
Wound healing in the oral mucosa involves several inflammatory mediators/molecules
and is impacted by several factors such as age, dietary habits, and the oral microbiome
[109,110]
.
Cancer therapy affects salivary quality and reduce salivary glycoproteins that cover and
protect oral mucosa against microorganism’s adherence and irritation. In addition, it
induces oral mucositis that may favor the emergence of opportunistic infections, fever,
anorexia, hemorrhage, severe pain, dysphagia and dysgeusia [
111
]. Oral glutamine has
been recommended to mitigate radiotherapy-induced oral mucositis in head and neck
cancer patients but other effective interventions are needed [
112
]. As mentioned previously,
probiotics may participate indirectly in re-epithelization and tissue regeneration due to
their potential to: (1) influence immune-regulating factors (e.g., kB nuclear factor, toll-like
receptors in dendritic cells), (2) modulate inflammatory mediator levels (e.g., cytokines
such as IL-1
β
, TNF-
α
, IL-6 and IL-15 and chemokines such as IL-8); and (3) induce the
production of proteolytic enzymes involved in tissue remodeling (MMPs).
A few clinical trials have investigated the role of topical administration of probiotics
in oral wound healing and in the treatment of oral mucositis in patients undergoing chemo-
radiotherapy (Table S10). In a study by Twetman et al. [
113
], the application of L. reuteri
in adults with healthy mucosa one week before standardized biopsy of the oral mucosa
and one week later showed no improvement in healing. However, patients in the probiotic
group had lower pain, less erythema/edema and the fibrin more rapidly covered the
wound. There was no change in the levels of MMP1-3 and IFN-
α
2, IFN-
β
and IFN-
γ
in the
wound exudate during the first healing week [114].
Walivaara et al. [
115
] evaluated the effects of L. reuteri supplements administered
3 times
a day for 2 weeks on the healing of wounds after surgical extraction of lower third
molars. Probiotic had no effect on the healing process as determined by extra-oral swelling,
level of salivary oxytocin, and presence of bacteria. However, in patients on probiotic
the subjective perception of pain, discomfort and swelling was significantly reduced and
leading to improved quality of life during the healing process.
Limaye et al. [
116
] assessed the safety and tolerability of a 1, 3 or 6 mouthwash/day
containing Lactococcus lactis (AG013, a strain that produces human trefoil factor 1) in
patients newly diagnosed with advanced squamous cell head and neck cancer who were
to start chemotherapy. The mean number of days with oral mucositis was reduced by 35%
in the probiotic group, and there were fewer emergency visits (36% vs. 60%). The placebo
patients had at least 2 days with oral mucositis while 29% of those taking AG013 had oral
mucositis for 0 or 1 day. Lactococcus lactis AG013 was detected in mucosa and saliva shortly
after the mouthwash, and up to 14 days after the mouthwash in equivalent number in the
test groups. The probiotic was safe as there was no infection in neutropenic patients.
In a study by Jiang et al. [
117
], a significant improvement in oral mucositis was
observed in patients with nasopharyngeal carcinoma undergoing chemoradiotherapy
taking a probiotic combination of Bifidobacterium longum, Lactobacillus lactis, and Enterococcus
faecium. Finally, Sharma et al. [
118
] evaluated the effect of L. brevis CD2 taken in lozenges in
patients with squamous cell carcinoma of head and neck submitted to chemo-radiotherapy.
The incidence and severity of oral mucositis was reduced in the probiotic group. In the
probiotic group, more patients completed the cancer treatment, and fewer patients needed
adjuvant medications to control the pain associated with mucositis. In summary, while
probiotics seem to have no direct effect on oral wound healing, they can contribute to
attenuate oral mucositis and improve quality of life in patients undergoing cancer therapy.
Appl. Sci. 2021,11, 8070 14 of 19
5. Conclusions
The use of probiotic bacteria is an expanding area of research in dentistry. Oral
probiotics are safe, influence favorably the oral microbiota and provide benefits to the
oral ecosystem in periodontal diseases, cariology, halitosis, orthodontics and manage-
ment of oral mucositis resulting from cancer treatment. The areas in which probiotics
should be further developed are endodontics, dental traumatology, and healing of chronic
oral wounds.
Probiotics likely act without colonization or by transient colonization of the oral cavity,
so a daily intake is advised. In addition, synergistic combinations of probiotic bacteria
should lead to higher clinical efficacy than any individual probiotic agent.
Before recommending probiotic use in daily dental practice and considering probi-
otics as a self-management preventive strategy or adjuvant/alternative therapy, additional
large-scale, long-term, randomized, placebo-controlled clinical trials studies are needed to
determine the most effective probiotic strain combinations, the most suitable probiotic ve-
hicles, and the most appropriate dosage and frequency of administration. Further research
is also needed on product compliance and acceptance by different age groups. Finally, a
better understanding of the mechanisms of action of probiotics and of the host response
to probiotics is needed. Algorithms matching person-specific data and known factors
interfering with probiotic efficacy will allow the identification of the optimal probiotic
modality for stratified populations or individuals [16].
Supplementary Materials:
The following are available online at https://www.mdpi.com/article/
10.3390/app11178070/s1, Figure S1: Preferred Reporting Items for Systematic Reviews and Meta-
Analysis (PRISMA) flow diagram, Table S1: PRISMA checklist, Table S2: PICOS criteria, Table
S3: Characteristics of clinical trials of probiotics in the oral ecosystem, Table S4: Characteristics
of clinical trials of probiotics in gingivitis and gingival health, Table S5: Characteristics of clinical
trials of probiotics in periodontal diseases, Table S6: Characteristics of clinical trials of probiotics
in peri-implantitis, Table S7: Characteristics of clinical trials of probiotics in cariology, Table S8:
Characteristics of clinical trials of probiotics in orthodontics, Table S9: Characteristics of clinical
trials of probiotics in halitosis, Table S10: Characteristics of clinical trials of probiotics in oral wound
healing and treatment of oral mucositis related to cancer treatment.
Author Contributions:
Conceptualization, P.S., N.T. and R.A.; formal analysis, P.S., N.T. and R.A.;
investigation, P.S., N.T. and R.A.; data curation, P.S., N.T. and R.A.; writing—original draft prepara-
tion, P.S., N.T. and R.A.; writing—review and editing, P.S., N.T. and R.A.; supervision, N.T.; project
administration, N.T.; funding acquisition, N.T. All authors have read and agreed to the published
version of the manuscript.
Funding:
This work was funded by national funds through the FCT-Foundation for Science and
Technology, I.P., under the project UIDB/04585/2020.
Conflicts of Interest:
The authors declare no conflict of interest. The funders had no role in the design
of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or
in the decision to publish the results.
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... Probiotics like Lactobacillus brevis CD2 have also been shown to alleviate oral mucositis, a painful condition that commonly affects cancer patients undergoing chemotherapy and radiotherapy, while simultaneously improving their overall quality of life. Furthermore, combining different probiotic strains often leads to better clinical outcomes than using single probiotic agents, highlighting the enhanced therapeutic potential of probiotic mixtures in oral health care [81]. Oral probiotics positively affect the oral microbiota and confer advantages to the oral microbiome in the context of periodontal diseases, dental caries, bad breath, orthodontic treatment, and the management of oral mucositis induced by cancer therapies. ...
... Today, probiotics are commonly used to support general health and well-being, with a well-established reputation for promoting gastrointestinal health. Increasing evidence also suggests that probiotics play an effective role in preventing and treating various oral diseases, including dental caries, oral mucositis, and halitosis [65]. ...
... These probiotics reduce the number of (quantity) oral S. mutans 250 . Oral probiotics, e.g., Lactobacillus and Bifidobacterium, improve the oral ecosystem by influencing oral microbiota, thereby mitigating PDs, candidal fungal infections, oral mucositis, dental caries, and halitosis 210,212 . ...
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Periodontal disorders (PD), also known as gum disease, involve inflammation and infection of the gum and bone tissue, which are preventable and treatable. Many worldwide suffer from such conditions, particularly in low- and middle-income countries. Risk factors related to periodontitis include poor oral cleanliness, regular alcohol consumption, betel quid chewing, and intake of tobacco. PD also raises the risk of fatal systemic diseases by provoking systemic inflammation. Oral homeostasis and prevention of periodontitis require healthy microbiota. PD results from alteration of the oral and gut microbiome environment. This host-microbe equilibrium interruption leads to inflammation, and tissue breakdown further acts to nourish the pathogens. There are several surgical and non-surgical means for managing PD. However, the positive impact of probiotics, which include the genera Lactobacillus and Bifidobacterium, on PD has been noted. Probiotics kindle the immune system and synthesize antiinflammatory cytokines that activate T regulatory cells. They also build antimicrobial molecules and inhibit oral pathogens. This narrative review was done to note the effects of probiotics on PD. The research used electronic search engines, including PubMed, Scopus, and Google Scholar. This study indicates that probiotics may be used as adjuvant therapy for gum disease. This may aid in faster healing, and since probiotics are found in accessible food sources like yogurt, the wider population may benefit. Thus, the global population may enjoy excellent oral health and an improved quality of life.
... Large doses of commercial probiotics (≥10 8 CFU mL −1 organisms per day) taken for 2-6 months can significantly alter the oral microbiome, promoting beneficial bacteria but potentially masking disease-related microbial changes [140,141]. The use of probiotics has shown promise in managing conditions like gingivitis, periodontitis, and even halitosis by enhancing the beneficial microbial population and inhibiting the growth of harmful bacteria [142,143]. Beyond reversing dysbiosis, probiotics play a crucial role in host modulation and biofilm control, highlighting their therapeutic potential in managing inflammatory oral diseases, including periodontal and peri-implant conditions. Probiotics can inhibit pathogenic biofilm formation, enhance the host immune response, and restore microbial balance, thereby mitigating inflammation and tissue destruction associated with these diseases, therefore possibly contributing to oral carcinogenesis [144]. ...
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Introduction The effectiveness of nonsurgical periodontal treatment is related to patient- and tooth-related factors. To overcome the limitations of the conventional approach, probiotics are one of the adjunct therapies that have been studied. Objectives This umbrella review answered the focused question: in adult patients with periodontal diseases or peri-implant diseases, does the use of probiotic therapy as an adjuvant to nonsurgical periodontal treatment when compared with nonsurgical periodontal treatment alone affect treatment effectiveness and clinical disease parameters? Methods A systematic electronic search to identify systematic reviews according to PICOS criteria, defined a priori, was used, and 5 electronic databases were searched (Medline, LILACS, Cochrane Central Registry of Controlled Trials, Google Scholar, and DANS EASY). Included systematic reviews were rated using quality assessment tools by 2 independent reviewers. Results Thirty systematic reviews were identified evaluating the effectiveness of probiotics in periodontal and peri-implant disease treatment. A quantitative analysis of the results was not possible due to the high heterogeneity of clinical data. Seventeen of 31 reviews reported clinically relevant benefits of probiotic therapy as an adjuvant to scaling and root planning. Twenty-two reviews had a low risk of bias, 7 had a moderate risk, and 2 had a high risk. Conclusion The evidence from the available studies is conflicting, which means that no definitive conclusions can be made about the effectiveness of probiotic therapy as an adjuvant to nonsurgical periodontal treatment. High-quality primary research studies are needed that control for known confounding variables. Knowledge Transfer Statement This umbrella review provides some evidence regarding the efficacy of probiotics as an adjunct to nonsurgical periodontal therapy, despite some equivocal findings. However, short-term probiotic use alongside therapy appears to be advantageous; there is currently no evidence supporting their long-term benefits. We have also identified that probiotic research is primarily constrained by its origins in gastrointestinal applications, resulting in a lack of approved probiotics for dental use. This review highlights the need for extensive clinical research to ascertain their effectiveness in the oral environment. Nevertheless, the utilization of probiotics alongside periodontal treatment seems safe, with no reported adverse effects in patients. Thus, further clinical validations in oral health care settings are crucial.
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Background/Objectives: Periodontal disease is caused by oral infections, biofilms, persistent inflammation, and degeneration of cell barrier integrity, allowing pathogens to invade host cells. Probiotics have been extensively studied for the treatment of periodontal disease. However, research on the involvement of beneficial substances produced by probiotics, called “postbiotics,” in periodontal diseases remains in its early stages. The present study aimed to evaluate the effect of a postbiotic metabolite (PM) from Lactiplantibacillus plantarum PD18 on immunomodulation and maintenance of cell barrier integrity related to periodontal disease. Method: The main substance in PM PD18 was analyzed by GC-MS. The cytotoxic effect of PM PD18 was performed using the MTT assay, wound healing through the scratch assay, cell permeability through TEER value, modulation of inflammatory cytokines through ELISA, and gene expression of inflammatory cytokines and tight junction protein was determined using qRT-PCR. Results: The main substance found in PM PD18 is 2,3,5,6-tetramethylpyrazine. PM PD18 did not exhibit cytotoxic effects on RAW 264.7 cells but promoted wound healing and had an antiadhesion effect on Porphyromonas gingivalis concerning SF-TY cells. This postbiotic could maintain cell barrier integrity by balancing transepithelial electrical resistance (TEER) and alkaline phosphatase (ALP) activity. In addition, the gene and protein expression levels of zonula occludens-1 (ZO-1) increased. PM PD18 was found to have immunomodulatory properties, as demonstrated by regulated anti- and pro-inflammatory cytokines. Interleukin-10 (IL-10) increased, while IL-6 and IL-8 were reduced. Conclusions: This study demonstrated that PM PD18 is efficient as a natural treatment for maintaining cell barrier integrity and balancing inflammatory responses associated with periodontal disease.
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Introduction Numerous noninvasive strategies are used to prevent dental caries. Remineralization can take place by the use of milk and milk products. Another approach to bacterially mediated diseases has been the use of probiotics. The classic food containing probiotic is yogurt (curd) and consumption of dairy products on daily basis seems to be most natural and effective way to ingest probiotic bacteria. Aim The aim of this study is to evaluate the effect of probiotic homemade curd and yogurt on salivary pH, calcium level, and buffering capacity. Materials and Methods A total of 52 students aged 12 years, who met the inclusion criteria were randomly selected from two different schools and were divided into two groups. Test and control group consumed 200 mL of probiotic yogurt and curd for a period of 30 days. Baseline and 30 days of unstimulated salivary sample (2 ml) was collected and salivary pH, buffering capacity and salivary calcium level was assessed. The data were statistically analyzed. Results The mean salivary pH and buffering capacity was found to be same in both groups and salivary calcium levels increased with the use of probiotic yogurt at the end of 30 days compared to control group. Conclusion The consumption of probiotic yogurt for a short period of time can prevent dental caries by increasing salivary calcium levels.
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Background: Peri-implant mucositis (PiM) is an inflammation of the soft tissues surrounding the dental implant and is the precursor of the destructive inflammatory peri-implantitis. PiM is usually reversible, but difficult to eradicate. Mechanical debridement (MD) is the conventional procedure to treat PiM although not enough to reach a complete resolution. Recently, probiotics have been considered in the treatment of peri-implant disease. Therefore, the aim of this systematic review and meta-analysis was to investigate the efficacy of the probiotic therapy combined with MD compared with MD alone or MD + placebo in patients with PiM. Methods: A search using electronic databases (MEDLINE, Science Direct databases, and Cochrane Central Register of Controlled Trials) and a manual search were performed up to November 2019 by two reviewers independently of each other. Eligible randomized controlled trials (RCTs) comparing MD + probiotic vs. MD were included. The quality assessment for all the selected RCTs was conducted according to the Cochrane Handbook for Systematic Reviews of Interventions. Probing depth reduction was selected as the primary outcome. Weighted mean difference (WMD) and 95% confidence interval (CI) were calculated for continuous outcomes, and odds ratio (OR) and 95% CI were calculated for dichotomous outcomes, using random effect models. This review was registered on the PROSPERO database (CRD42020213625). Results: Five eligible publications were included in this systematic review and four in the meta-analysis. As regards the implant, the WMD in the probing depth reduction between the test and control group was −0.12 mm [95% CI (−0.38, 0.14), p = 0.38], meaning that the adjunctive probiotic therapy was not improving PiM compared with MD alone or MD + placebo. The meta-analysis also showed no statistically significant results in the secondary outcomes (reduction of full mouth plaque index and full mouth bleeding on probing, absence of bleeding on probing at implant level, and changes in microorganism load and species). Conclusion: The findings of this systematic review and meta-analysis suggested that the additional use of probiotics did not improve the efficacy of MD in PiM treatment regarding clinical and microbial outcomes, at least in a short-term.
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To determine the diagnostic value of inflammatory cytokines in periodontal disease, we performed a systematic review of the changes in inflammatory cytokines after non-surgical periodontal therapy and a meta-analysis of the utility of interleukin (IL)-1β and matrix metalloproteinase (MMP)-8 as salivary biomarkers. All available papers published in English until 20 August 2020, were searched in the MEDLINE and EMBASE databases. Population, intervention, comparison, and outcome data were extracted from the selected studies, and the roles of IL-1β and MMP-8 were assessed in a meta-analysis. Eleven studies, including two meta-analyses, were assessed in the systematic review. Biomarkers showing high levels in periodontal disease were salivary IL-1β, IL-4, IL-6, MMP-8, and tissue inhibitor of matrix metalloproteinases (TIMP)-2, and those in the controls were tumor necrosis factor (TNF)-α, IL-10, IL-17, and IL-32. Biomarkers that decreased after scaling and root planning (SRP) and oral hygiene instruction (OHI) in periodontitis patients were IL-1β, MMP-8, MMP-9, prostaglandin E2 (PGE2), and TIMP-2. The pooled standardized mean difference of IL-1β and MMP-8 was −1.04 and 35.90, respectively, but the differences between periodontitis patients and healthy controls were not significant. Although the changes in salivary IL-1β and MMP-8 levels after non-surgical periodontal therapy were not significant, salivary cytokines could be used to confirm the effect of periodontal therapy or diagnose periodontal disease.
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Dental caries, the most common chronic infectious disease worldwide, has a complex etiology involving the interplay of microbial and host factors that are not completely understood. In this study, the oral microbiome, and 38 host cytokines and chemokines, were analyzed across 23 children with caries and 24 children with healthy dentition. De novo assembly of metagenomic sequencing obtained 527 metagenome-assembled genomes (MAGs), representing 150 bacterial species. 42 of these species had no genomes in public repositories, therefore representing novel taxa. These new genomes greatly expanded the known pangenomes of many oral clades, including the enigmatic Saccharibacteria clades G3 and G6, which had distinct functional repertoires compared to other oral Saccharibacteria. Saccharibacteria are understood to be obligate epibionts, which are dependent on host bacteria. This data suggests that the various Saccharibacteria clades may rely on their hosts for highly distinct metabolic requirements, which would have significant evolutionary and ecological implications. Across the study group, Rothia, Neisseria, and Haemophilus spp. were associated with good dental health, while Prevotella spp., Streptococcus mutans, and Human herpesvirus 4 (Epstein-barr virus/EBV) were more prevalent in children with caries. Finally, ten of the host immunological markers were significantly elevated in the caries group, and co-occurrence analysis provided an atlas of potential relationships between microbes and host immunological molecules. Overall, this study illustrated the oral microbiome at an unprecedented resolution, and contributed several leads for further study that will increase the understanding of caries pathogenesis and guide therapeutic development.
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Background: Oral mucositis is a debilitating consequence of radiotherapy in patients with head and neck cancers. Radiation-induced oral mucositis (RIOM) can cause pain and weight loss, reduce quality of life and affect treatment outcomes. Methods: A systematic review was undertaken to identify and examine the efficacy of low-cost interventions to mitigate RIOM and to develop clinical guidelines based on the evidence. Results: The author identified three interventions: benzydamine hydrochloride mouth rinse (BHM), honey and oral glutamine (OG). The search identified twenty-four studies in total. Four studies examined BHM; all findings were favourable, although only one had moderate methodological quality, and the rest were low. The product was poorly tolerated by some participants in one study. Twelve studies examined honey. Eleven of these had favourable results; two studies had moderate methodological quality, and the rest were low. Eight studies examined OG. Six of these had favourable results; two studies had moderate methodological quality, and the rest were low. Conclusion: The author cannot recommend BHM to mitigate RIOM due to the overall low quality of the studies and poor tolerance to the product. The author cannot recommend honey to mitigate RIOM due to weak evidence supporting the intervention. The author can recommend OG to mitigate RIOM. There is a need for high-quality studies with a consensus of the methodology to reduce heterogeneity and examination of the cost-effectiveness of the interventions.
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Halitosis is a common ailment concerning 15% to 60% of the human population. Halitosis can be divided into extra-oral halitosis (EOH) and intra-oral halitosis (IOH). The IOH is formed by volatile compounds, which are produced mainly by anaerobic bacteria. To these odorous substances belong volatile sulfur compounds (VSCs), aromatic compounds, amines, short-chain fatty or organic acids, alcohols, aliphatic compounds, aldehydes, and ketones. The most important VSCs are hydrogen sulfide, dimethyl sulfide, dimethyl disulfide, and methyl mercaptan. VSCs can be toxic for human cells even at low concentrations. The oral bacteria most related to halitosis are Actinomyces spp., Bacteroides spp., Dialister spp., Eubacterium spp., Fusobacterium spp., Leptotrichia spp., Peptostreptococcus spp., Porphyromonas spp., Prevotella spp., Selenomonas spp., Solobacterium spp., Tannerella forsythia, and Veillonella spp. Most bacteria that cause halitosis are responsible for periodontitis, but they can also affect the development of oral and digestive tract cancers. Malodorous agents responsible for carcinogenesis are hydrogen sulfide and acetaldehyde.
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This review provides a detailed description of matrix metalloproteinases (MMPs), focusing on those that are known to have critical roles in bone and periodontal disease. Periodontal disease is an inflammatory process initiated by anaerobic bacteria, which promote the host immune response in the form of a complex network of molecular pathways involving proinflammatory mediators such as cytokines, growth factors, and MMPs. MMPs are a family of 23 endopeptidases, collectively capable of degrading virtually all extracellular matrix (ECM) components. This study critically discusses the available research concerning the involvement of the MMPs in periodontal disease development and progression and presents possible therapeutic strategies. MMPs participate in morphogenesis, physiological tissue turnover, and pathological tissue destruction. Alterations in the regulation of MMP activity are implicated in the manifestation of oral diseases, and MMPs comprise the most important pathway in tissue destruction associated with periodontal disease. MMPs can be considered a risk factor for periodontal disease, and measurements of MMP levels may be useful markers for early detection of periodontitis and as a tool to assess prognostic follow-ups. Detection and inhibition of MMPs could, therefore, be useful in periodontal disease prevention or be an essential part of periodontal disease therapy, which, considering the huge incidence of the disease, may greatly improve oral health globally.
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Background and Objectives Dental caries, caused by oral microbial flora, is considered as one of the most common infectious diseases in human. The aim of this study was to determine the effect of short-term consumption of PROBIOTIC YOGURT containing BIFIDOBACTERIUM LACTIS on salivary STREPTOCOCCUS MUTANS and LACTOBACILLI in students with initial stages of dental caries. Materials and Methods 66 students (18-30 years old) with initial stages of dental caries were selected in this single blind randomized clinical trial. The subjects were randomly assigned into two groups: intervention group received 300g/d PROBIOTIC YOGURT, and control group received 300 g/d conventional yogurt for 2 weeks. Unstimulated fasting saliva sample was collected pre-and post-intervention. Bacterial counting was performed for salivary STREPTOCOCCUS MUTANS and LACTOBACILLI. Salivarius Mitis agar and Rogosa agar were used as culture media for STREPTOCOCCUS MUTANS and LACTOBACILLI, respectively. Results The number of STREPTOCOCCUS MUTANS in saliva was significantly reduced in the intervention group post-intervention (P< 0.001); however, it was not changed in the control group (P= 0.71). STREPTOCOCCUS MUTANS was also significantly lower in the intervention group compared with the control group post-intervention (P< 0.001). Although salivary LACTOBACILLI was reduced significantly in both groups post-intervention (P< 0.001), this reduction was not significantly greater in the intervention group compared with the control group (P= 0.594). Conclusions It is suggested that consumption of PROBIOTIC …
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A precision approach to probiotics could address the heterogeneity inherent to probiotic strains, the hosts and their microbiomes. Here, we discuss the steps required to develop precision probiotics: mechanistic studies, phenotypic and target-based discovery strategies, and person-centric trials.
Article
Halitosis is referred to as an unpleasant odor coming from the mouth. Recently, probiotics have been studied as an alternative prevention for halitosis. The aim of this study was to evaluate the effects of probiotic bacterium Weissella cibaria Chonnam Medical University (CMU)-containing tablets (1 × 108 colony forming units [CFU]/g) on oral malodor. The randomized, double-blind, placebo-controlled trial was conducted in 92 healthy adults (20-39 years of age) with bad breath. All subjects were randomly assigned to a test (probiotic, n = 49) or control (placebo, n = 43) group after dental scaling and root planing. The tablets were taken once daily for 8 weeks. Measurements included an organoleptic test (OLT), volatile sulfur compounds (VSC), bad breath improvement (BBI) scores, and the oral colonization of W. cibaria CMU. This study also assessed safety variables of adverse reactions, vital signs, and the findings of hematology and blood chemistry. Most of the variables were measured at baseline, 4, and 8 weeks. Safety-related variables were measured at baseline and 8 weeks. At week 4, a significant decrease in OLT and VSC results was observed in the test group while BBI scores were significantly reduced at week 8 (P < .05). Statistically significant intergroup differences were observed for changes in W. cibaria number at weeks 4 and 8. No safety issues were encountered in either group. These results indicate that W. cibaria CMU tablets could be a safe and useful oral care product for controlling bad breath.