Think outside the gut: Probiotics for oral health

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Abstract
The composition of an individual's microbiome significantly impacts their health and risk of developing intestinal and systemic diseases. The oral microbiome is a major contributor to our oral health, which in turn is intimately linked to systemic health, the ability to fend off disease, and our overall quality of life. The use of selected, orally-targeted probiotics now offers a highly complementary approach that promises to deliver the next generation of oral and throat healthcare. This article discusses recent published studies (2012-present) that highlight the clinical evaluation of selected probiotics for halitosis, throat infections, and dental health.
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S. salivarius K12 reduces S. pyogenes-mediated episodes of pharyngotonsillitis, days treated with antibiotics or antipyretics, and days missed from school or work. This was a multi-center open-labeled, non-randomized controlled study conducted on 61 school-aged (3-13) children in the Milan, Italy area. All but 1 child completed the study. The trial population that completed the study consisted of 32 males and 28 females who exhibited an average of not less than 3 episodes of pharyngotonsillitis (confirmed by rapid swab test for groups A and B streptococci) in the same quarter (February through April) as that of the study (2013) in the previous calendar year (2012). Thirty children were treated with one lozenge per day containing not less than 1 billion CFU S. salivarius K12 for 90 consecutive days, while the other thirty children served as the untreated control group. The treated and control groups did not differ significantly with respect to age, gender distribution, or episodes of pharyngotonsillitis per child. In the treated group, there were 19 males with a mean age 6.7 ± 2.5 [years ± standard deviation (SD)], 11 females with a mean age of 5.7 ± 1.9 (years ± SD), and a mean 3.1 episodes per child. In the untreated control group, there were 13 males with a mean age 6.1 ± 2.8 years, 17 females with a mean age of 5.7 ± 1.9, and a mean 3.0 episodes per child. Upper panel (A): Bars indicate total number of episodes of pharyngotonsillitis, and the values within the bars indicate the mean episodes per child during February through April for the indicated year. During the same quarter of the previous year (2012) in which they were not receiving K12, children assigned to the K12-treated group in this study (bars 1 and 2, respectively, on the left of graph) exhibited a total of 94 episodes of pharyngotonsillitis (mean of 3.1 episodes/child). After receiving K12 for 90 consecutive days in this study, the total episodes of pharyngotonsillitis were reduced to 3, corresponding to 0.1 episode per child and an approximate 97% decrease (P < 0.001 versus previous year (2012) and also versus untreated group in 2013). For the children in the untreated control group, there was no significant difference in total episodes of pharyngotonsillitis or episodes per child from 2012 vs 2013 (bars 3 and 4, respectively, on the right of graph). Lower panel (B): Bars and values with the bars indicate total number of days treated with antibiotics or antipyretics, along with days missed from school or work for the untreated control group (grey bars) and K12-treated group (blue bars) during the course of this study. Graphs were created for this article using data from (36).
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Agro FOOD Industry Hi Tech - vol. 27(3) - May/June 2016
KEYWORDS: Dental, halitosis, microbiome, mutans, pharyngitis, salivarius.
Abstract The composition of an individual’s microbiome significantly impacts their health and risk of developing
intestinal and systemic diseases. The oral microbiome is a major contributor to our oral health, which in
turn is intimately linked to systemic health, the ability to fend off disease, and our overall quality of life. The use of selected,
orally-targeted probiotics now offers a highly complementary approach that promises to deliver the next generation of oral and
throat healthcare. This article discusses recent published studies (2012-present) that highlight the clinical evaluation of selected
probiotics for halitosis, throat infections, and dental health.
Think outside the gut: Probiotics for oral health
INTRODUCTION TO THE ORAL MICROBIOME
The human microbiome (bacteria, fungi, and viruses) is
greater than ten times the number of our own mammalian
cells (1-4). To date, the majority of attention from the scientic,
health, and commercial perspectives has focused on the
microbiome of the gut. However, we have now entered
the era of appreciating the importance of the microbial
communities in other body regions, especially those that
inhabit the oral cavity (3-5). The microbiome of the oral cavity
is diverse, with over 700 different bacterial species identied
on the tongue, teeth, gums, inner cheeks, palate, and tonsils
(Figure 1). Although saliva contains no indigenous bacteria,
it contains the bacteria shed from biolms from other areas
of the oral cavity. Over 20% of these bacteria are members
of the genus Streptococcus, the most predominant genus in
the oral cavity (6) The oral microbiome also contains several
disease-associated viruses, two non-pathogenic protozoans,
approximately seven predominant fungi genera, and a
several species of non-bacterial prokaryotic organisms
termed Archaea (3-5). Oral health is determined, largely, by
the type and abundance of bacteria that reside in the oral
cavity, which in turn is determined, principally, by one’s age,
health status, nutritional status, lifestyle choices (ie tobacco
and alcohol use along with the quality of oral hygiene), and
geographic residence (Figure 1). The most authoritative
compilation of the constituents of the oral microbiome in
healthy and diseased individuals can be found in the Human
Oral Microbiome Database (HOMD; http://www.homd.
org/) (7). The purpose of this brief review is to discuss recent
published studies (2012-present) that highlight the clinical
evaluation of selected probiotics for halitosis, throat infections,
and dental health.
RELATIONSHIP OF ORAL MICROBIOME TO HEALTH AND DISEASE
The impact of the oral microbiome on affecting our health
and inuencing disease cannot be overstated. This inuence
applies not only to diseases of the oral cavity, but also
to many serious systemic diseases, including diabetes,
cardiovascular disease, and possibly Alzheimer’s disease
(Figure 1)(3-5, 8). Thus, the goal of supporting one’s oral health
should not be regarded, solely, as a primary defense to ward
off conditions such as halitosis, sore throats, dental caries, and
gum disease, but should be aggressively targeted to prevent
a life of misery, chronic disease, and premature mortality.
Halitosis (offensive breath) is due to the catabolism (of
sulphur-containing amino acids) and release of volatile
sulphur compounds (VSCs) by a variety of gram-negative
anaerobic bacterial species (9). The main molecular
culprits are hydrogen sulphide, dimethyl sulphide, and
methyl mercaptan, the most odoriferous of the group.
The causative bacteria are typically located in periodontal
pockets, between the teeth, and surface of the tongue.
The production of these compounds is exacerbated by
ingestion of certain foods with high sulphur content (ie garlic,
onions), alcohol, smoking, decreased saliva production,
excessive dental plaque, gingivitis, and periodontal disease.
Sore throats (acute pharyngitis) are typically caused
by either viral or bacterial infections, although allergies,
dryness, environmental irritants, muscle strain, excessive
alcohol consumption, and smoking also can be causative.
The principal bacterium that causes sore throats is the
ubiquitous organism Streptococcus pyogenes, a member of
Group A beta-haemolytic streptococci, accounting in the
PRE-PROBIOTICS
JOSEPH L. EVANS
Stratum Nutrition, 20 Research Park Drive, Saint Charles, MO 63304, USA
Joseph L. Evans
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Agro FOOD Industry Hi Tech - vol. 27(3) - May/June 2016
Gingivitis (inammation of the gums)
is the most common bacterial
infection in adults, with an estimated
worldwide prevalence of >90% (3-5,
14, 15). In the context of poor oral
hygiene, the amount of dental
plaque (bacterial biofilm on
dental surfaces) increases, and is
composed of aerobic, facultative
anaerobes, and anaerobic bacteria
species. This results in the increased
production of endotoxin and
inammatory cytokines into the gums
resulting in localized inammation.
This condition is most commonly
recognized by red, swollen gums
that bleed upon ossing, probing, or
even spontaneously. While no specic
bacterial species are consistently
associated with gingivitis, the severity
of inammation is positively correlated
with the amount of dental plaque.
Fortunately, gingivitis is reversible with
the reinstitution of good oral hygiene
leading to a reduction in dental
plaque.
If left untreated gingivitis can progress
to periodontitis (i.e. gum disease),
a much more severe microbially-
induced inammatory disease that
can result in the loss supporting tissues
around the tooth and, ultimately,
tooth loss (3-5, 14, 15). The process
typically begins with gingivitis resulting in the gradual localized
detachment of the gums from the teeth creating a pocket,
which is readily colonized by a number of anaerobic bacterial
species including Porphyromonas gingivalis, Treponema
denticola, and Tannerella forsythia (3, 5).
The bacteria of the oral cavity have ready access to the
bloodstream through gingival crevices and other loci, and
have been identied as either participants or causative
agents in a number of systemic diseases (4, 5). In the context
of the relationship between oral and systemic health, the
oldest link established is that between periodontal disease
and cardiovascular disease. On the basis of numerous
meta-analyses and other clinical research, it can be
concluded that an individual with periodontitis is at greater
risk of either having or developing cardiovascular disease.
Periodontitis can adversely affect glycemic control in patients
with diabetes and contribute to the development of its
complications. In patients with diabetes, there is a direct and
dose-dependent relationship between periodontitis severity
and diabetes complications. Emerging evidence supports
an increased risk for diabetes onset in patients with severe
periodontitis. Most recently, there is evidence that bacteria
from the oral cavity can weaken the blood brain barrier, enter
the brain, and accelerate the events leading to cognitive
decline and Alzheimer’s disease (8). Each of these serious
cardiovascular, metabolic, and neurological pathologies
exert a signicant cost to governments and society, but
most importantly, for aficted individuals which can result in
premature death.
United States for 15-30% of cases in children and 5-10% of
cases in adults (10). During the winter and spring in temperate
climates, up to 20% of asymptomatic school-aged children
may be Group A streptococcus carriers. Treatment includes
antibiotic(s); if left untreated, the infection can progress to
cause life-threatening rheumatic fever. Acute otitis media
(middle ear infection) is the most common bacterial infection
in young children and the predominant etiological agents
are S. pyogenes, Streptococcus pneumoniae, Moraxella
catarrhalis, and Haemophilus inuenzae.
Dental caries (tooth decay) has reached epidemic
proportions worldwide; according to the World Health
Organization (WHO), 60-90% of school-age children (varies
among different countries; see WHO data for specics) and
nearly 100% of adults (see WHO data for specics) have
dental caries (11, 12). This condition is a consequence of
inadequate exposure to uoride, poor oral hygiene, and the
chronic ingestion of carbohydrate-rich foods, drinks, and
snacks which offer a rich source of fermentable substrate
for oral bacteria. Elevated acid production overwhelms the
buffering capacity of saliva, leading to chronically reduced
pH. As a result, a shift in the microbial population favouring
the caries-associated bacteria such as Streptococcus
mutans, Lactobacilli, Bidobacteria, Proprionobacteria,
and others occurs. The positive association of S. mutans
with dental caries risk is so overwhelming that S. mutans is
proposed as an acceptable biomarker by the European
Food Safety Authority to support a disease risk reduction
claim (13).
Figure 1. Relationship of oral microbiome to oral and throat health and systemic health.
Major factors inuencing the composition of oral microbiome (green table). Oral microbiome has a
signicant impact not only on oral health but systemic health. Phylum and genus level classication
of bacteria colonizing the oral cavity of a composite human showing that the oral microbiome
diversity is dependent on the site sampled. Sites in the oral cavity share greater similarity in bacterial
composition than other locations, such as the gut, skin, and vagina. Bacterial distribution data were
obtained from (49), and are reproduced with permission of Annual Review of Genomics and Human
Genetics, Volume 13 © 2012 by Annual Reviews, http://www.annualreviews.org.
bacteria, inhibition of pathogen-induced production of
pro-inammatory cytokines, and enhancement of the host
immune system (17, 18). In this context and others, particularly
well studied bacterial strains are Streptococcus salivarius
K12 and M18 (18). About 15 years ago, the S. salivarius K12
strain was the rst S. salivarius to be commercialized and is
now marketed throughout the world for support of oral and
throat immune health along with halitosis (19). In January
2016, a letter of no objection was issued by the US Food and
Drug Administration regarding the S. salivarius K12 dossier
containing the scientic substantiation of self-afrmation of
GRAS (Generally Recognized as Safe)(20). S. salivarius K12
was isolated from the mouth of a healthy schoolchild in New
Zealand who had maintained an abundant indigenous
population of the K12 strain in their oral cavity for greater than
12 months, during which time no new S. pyogenes infections
were experienced.
Of note, S. salivarius
K12 produces two
bacteriocins, salivaricin
A2 and salivaricin B,
with inhibitory activity
against Group A beta-
haemolytic streptococci,
and other pathogenic
species (21). In contrast,
S. salivarius M18 produces
several bacteriocins,
including salivaricins
A2, B, M, and MPS (18).
In addition, S. salivarius
M18 also produces the
enzymes dextranase,
which antagonizes the
formation of biolms, and
urease, which serves to
elevate localized pH.
The hypothesized modes
of action of S. salivarius
K12 and S. salivarius M18
are depicted in Figure 2.
However, it should be kept
in mind that the modes
of action proposed in this
gure are based either on
in vitro studies or pilot clinical trials (17, 18).
Overview of scientic substantiation
A number of interesting reviews regarding the possible and
actual use of probiotics for oral health have been published
between 2010 and 2015 (17, 18, 22-27). Collectively, the authors
concluded that this approach holds great promise but that
the degree of clinical substantiation was still in the early stages.
The primary focus in this section will be to highlight more recent
published research in this area not covered in prior reviews,
with an emphasis on clinical trials. It should become apparent
that, for specic probiotics, substantiating clinical evidence
of efcacy is growing and will continue grow, in light of the
commercial potential available to orally targeted probiotics
with demonstrated clinical safety and efcacy.
Halitosis
Based on promising results in a pilot trial (28), Lactobacillus
salivarius WB21 was evaluated in a randomized, double-blind,
Thus, redirecting our thinking towards maintaining the health of the
oral cavity offers an incalculable potential return on investment.
PROBIOTICS FOR ORAL HEALTH
Market potential
Oral care products are typically included as a category
of personal care products, and can be further divided
into primary and secondary oral care products (16).
Primary products include toothpaste and tooth brushes.
More relevant to this article are the secondary products which
include mouthwash, dental oss, denture products, whitening
strips, and mouth fresheners. Globally, the oral health care
market was estimated to be $39.1 billion (US) in 2014 and
expected to reach approximately $51 billion (US) by 2020,
corresponding to a current
annual growth rate of 4.5%
(16). By comparison, the
oral care market in Brazil,
Russia, India, and China was
collectively estimated to
be $10.7 billion (US) in 2014
and expected to reach
approximately $17.3 billion
(US) by 2020, corresponding
to a current annual growth
rate of 8.4%. A major driver
of this expected growth is
the increased visibility of
oral care products coupled
with increased disposable
income in these countries.
Probiotics supporting
oral health, when used
in conjunction with
good oral hygiene, are
positioned nicely to t into
this secondary oral care
product category, as
they are compatible with
multiple delivery formats (eg
lozenges, gums, stick packs,
etc) and are, potentially,
available across multiple market channels. Successful
market growth of orally-targeted probiotics will depend on
1) consumer awareness of a) the overall importance of oral
health, b) the link between oral health and systemic health,
c) the ability to understand and differentiate between
probiotics for gut health and those for oral health; 2) clinical
substantiation of safety and efcacy; 3) awareness and
acceptance by health care practitioners; 4) economic
affordability; 5) availability and expansion of multiple delivery
formats; 6) strain stability over the life of the product; and 7)
regulatory acceptance.
Modes of action
Similar to probiotics that target the intestine, the modes
of action of probiotics that target the oral cavity can be
grouped into several categories: competition for adhesion,
competition for nutrients and growth factors, production
of inhibitory molecules that are lethal to pathogenic
bacteria, production of enzymes detrimental to pathogenic
Figure 2. Possible modes of action of S. salivarius K12 and M18 probiotics in the
oral cavity.
Reported health benets of S. salivarius K12 and M18 probiotics can occur
through multiple but not mutually exclusive modes of action including:
production of inhibitory molecules (ie salivaricins) that are lethal to pathogenic
bacteria, production of enzymes detrimental to pathogenic bacteria (eg
urease, dextranase), inhibition of pathogen-induced production of pro-
inammatory cytokines, enhancement of the host immune system, competition
for adhesion, and competition for nutrients and growth factors (18).
Reproduced with permission of Future Microbiology, Volume 7 © 2012 by Future
Medicine, http://www.futuremedicine.com.
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Agro FOOD Industry Hi Tech - vol. 27(3) - May/June 2016
salivarius K12 has been particularly well studied, and the
results consistently demonstrate the safety and efcacy of this
strain. In a clinical study reported in 2015, 22 children aged
3-9 years with a history of recurrent AOM with a diagnosis of
secretory otitis media were enrolled to determine the effect
of 90 days intervention with S. salivarius K12 (34). The authors
reported that daily administration of chewable lozenges
containing S. salivarius K12 (> 1 billion CFUs/lozenge) reduced
the incidence AOM by around 43% (P < 0.05), compared to
the incidence in the previous 12 months, with no reported
side effects (34). These results conrmed and extended
earlier ndings evaluating S. salivarius K12 in children. In
2012, S. salivarius K12 was shown to reduce the recurrence
of pharyngotonsillitis and AOM by around 90% and 40%,
respectively (35). More recently, it was reported that children
provided with S. salivarius K12 exhibited a 97% reduction in
the incidence of streptococcal sore throat (Figure 3)(36). In
addition, reductions in episodes of viral infections (by 80%)
and in the number of days requiring antibiotic (amoxicillin)
and/or antipyretic use (by 30-fold and 14-fold, respectively)
were also reported (Figure 3)(36). S. salivarius K12 has also
been reported to be effective in adults (aged 18-65), as
judged by its ability to reduce the incidence of streptococcal
sore throat by approximately 84% (37).
Most recently, 130 children with a history of group A beta-
hemolytic streptococci (GABHS) infections were evaluated:
76 of whom were enrolled to receive a once daily lozenge
with S. salivarius K12 (> 1 CFUs/lozenge), and the remaining 54
children served as the control group receiving no probiotic
(38). Each subject was monitored for the occurrence of
GABHS pharyngotonsillitis for at least 12 months following
their entry into the study. Results showed that 88% of the
treatment group experienced no pharyngotonsillar infections
compared to only 22% of the untreated group. Even nine
months after the use of S. salivarius K12 had been stopped,
the development of new pharyngotonsillitis infections was
signicantly lower when compared to the period before
treatment. The results from this study are supportive of the
previous studies discussed above, where prophylactic
administration of S. salivarius K12 to children with a history
of recurrent oral streptococcal infection resulted in
clinically meaningful reductions in the episodes of both
streptococcal and viral infections, along with concomitant
reductions in the number of days using an antibiotic and
days absent from school.
Dental health
The large number of subjects, prolonged duration of
treatment, and overall high study cost necessary to assess
the impact of a probiotic (or any) intervention on traditional
dental and periodontal clinical primary outcome measures
provides a major hurdle in the attempt to establish the
efcacy of a given strain (or combination of individual
probiotic strains). Therefore, the vast majority of published
clinical studies have typically employed one or more
surrogate endpoints to assess efcacy, including salivary
or plaque S. mutans counts; salivary ow, pH or buffering
capacity; plaque or gingival scores; periodontal pocket
depth; and, most recently, the Cariogram (39, 40).
A variety of probiotics have been reported to be benecial
for dental and periodontal health in children and adults.
placebo-controlled trial (29). Tablets containing either 2 billon
colony-forming units (CFUs/tablet; n=20) or placebo (n=6)
were administered for 14 days to male and female adults
with oral malodour in a crossover design. Organoleptic test
scores signicantly decreased in both the probiotic and
placebo periods compared with the respective baseline
scores, but there no signicant difference between periods.
In contrast, the concentration of volatile sulfur compounds
(P = 0.019) and the average probing pocket depth (P = 0.001)
decreased signicantly in the probiotic period compared
with the placebo period. Bacterial quantitative analysis found
signicantly lower levels of ubiquitous bacteria (P = 0.003) and
Fusobacterium nucleatum (P = 0.020) in the probiotic period.
The inability to detect a signicant difference between groups
for the organoleptic test scores was likely attributable to the
small sample size and uneven group distribution. S. salivarius
K12 is also effective at inhibiting the growth of bacteria in vitro
that cause halitosis (30, 31), and was reported to signicantly
(P = 0.008) reduce VSCs in humans (administration of daily
lozenges) within 7 days compared to placebo (n=23) (31).
Pharyngitis and Acute Otis Media (AOM)
Several probiotics have been evaluated for their efcacy
against respiratory tract infections. The impact of controlled
administration of Bidobacterium animalis subsp. lactis BB-12
(BB-12) on the risk of acute infectious diseases was studied in
healthy newborn infants (32). In this double-blind, placebo-
controlled study, 109 newborn one-month-old infants
were assigned randomly to a probiotic group receiving a
BB-12-containing tablet (n=55) or to a control group receiving
a control tablet (n=54). Test tablets were administered to
the infants twice a day (daily dose of BB-12 10 billion CFUs/
tablet) from the age of 1-2 months to 8 months with a novel
slow-release pacier or a spoon. Breastfeeding habits, pacier
use, dietary habits, medications and all signs and symptoms
of acute infections were registered. The daily duration of
pacier sucking was not associated with the occurrence of
AOM, nor was there any signicant differences between the
groups in reported AOM, use of antibiotics, or gastrointestinal
symptoms. However, the infants receiving BB-12 were reported
to have experienced fewer respiratory infections (65% v. 94%;
risk ratio 0.69; 95% CI 0.53, 0.89; P = 0.014) than the control
infants. The authors concluded that controlled administration
of BB-12 in early childhood may reduce respiratory infections.
Lactobacillus rhamnosus GG (LRGG) has also been evaluated
in multiple studies for possible efcacy in preventing
respiratory infections in children. A meta-analysis of four
randomized controlled trials (RCTs) involving 1805 participants
has been reported (33). Compared with placebo, LRGG
administration was associated with a reduced incidence
of AOM [four RCTs, n=1805; Relative Risk (RR)=0.76, 95%
condence interval (CI) 0.64-0.91], a reduced risk of upper
respiratory infections [one RCT, n=281; RR=0.62, 95% CI 0.50-
0.78], and reduced use of antibiotic treatments [four RCTs,
n=1805; RR 0.80, 95% CI 0.71-0.91]. There was no signicant
difference between the LRGG and the control groups in the
risk of overall respiratory infections or the incidence of lower
respiratory infections. Adverse effects were similar in both
groups. No serious adverse events were reported. The authors
concluded that administration of LRGG compared with
placebo has the potential to reduce the incidence of AOM,
upper respiratory infections, and antibiotic use in children
In the area of throat health (pharyngitis and AOM), S.
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Agro FOOD Industry Hi Tech - vol. 27(3) - May/June 2016
Pre-school children (2-3 years old; n = 261) given milk
supplemented with Lactobacillus rhamnosus SP1 (107 CFUs/
ml) for 10 months were at a lower risk for developing dental
caries (Odds Ratio, 3.5; P < 0.05)(41). Pre-school children
(2-3 years old; n = 138) given a chewable table containing
a combination of S. oralis KJ3, S. uberis KJ2, and S. rattus
JH145 for 1 year also exhibited a reduced risk for caries
development (Relative Risk, 0.47; P < 0.05)(42). Two-week
administration of L. salivarius WB21-containing tablets (2 billion
CFUs/tablet) to healthy adults (n=8) signicantly decreased
the number of S. mutans (P = 0.039)(43).
S. salivarius M18 is a closely related strain to S. salivarius
K12 and has been the subject of multiple clinical studies
evaluating its safety and efcacy in the context of dental
health (18, 39, 44, 45). In a randomized, double-blind
placebo controlled study conducted in 100 dental caries-
active children (mean age 8.5 years), lozenges containing
S. salivarius M18 (3.6 billion CFUs/lozenge) were administered
for 3 months. At treatment end, the plaque scores were
signicantly (P = 0.05) lower for children in the M18-treated
group, especially in subjects having high initial plaque
scores, in the absence of any signicant difference between
groups in adverse events (44). These promising results were
conrmed and extended in a study reported by Scariya et al
(45), who administered lozenges containing S. salivarius M18
(>100 million CFUs/lozenge) to healthy adults (n=14) for 30
days; the control group (n=14) did not receive the probiotic
lozenges. By day 30 (end of treatment) and persisting at days
45 and 60 in the group given S. salivarius M18, clinical indices
of dental health, including plaque index, gingival index,
sulcular bleeding index, and periodontal pocket depths, were
all signicantly improved compared to the control group.
Most recently, S. salivarius M18 administered in chewable
lozenges (>1 billion CFUs/lozenge) was evaluated for 90
days in children at high risk to develop dental caries (n=38);
the control group (n=38) did not receive the probiotic
lozenges (39). This study used the Cariogram, a validated,
algorithm-based software program developed in Sweden, as
a primary caries risk assessment tool (40). It is based on nine
different caries-related risk factors along with the professional
judgement of the dentist to provide objective and consistent
risk assessments for caries development. The results indicated
that administration of S. salivarius M18 produced a statistically
signicant and clinically meaningful reduction of risk of
avoiding new cavities by over 30%. Individual caries risk
factors that showed statistically signicant improvements
included plaque amount, S. mutans counts, saliva secretion,
and saliva buffering capacity. Although very promising, these
results need to be conrmed in a randomized, double-blind,
placebo controlled trial.
FUTURE DIRECTIONS AND CHALLENGES
As we enter the age of personalized nutrition, the stage
is set for probiotics that target the oral cavity to benet
those children and adults who desire a natural approach
to optimize their oral and throat health. In this regard, some
of the most promising probiotics have been highlighted
here. Due to the lucrative commercial potential of this
market, coupled with the signicance of potential health
benets, there are intensive efforts directed at identifying
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Agro FOOD Industry Hi Tech - vol. 27(3) - May/June 2016
Figure 3. S. salivarius K12 reduces S. pyogenes-mediated
episodes of pharyngotonsillitis, days treated with antibiotics or
antipyretics, and days missed from school or work.
This was a multi-center open-labeled, non-randomized
controlled study conducted on 61 school-aged (3-13) children
in the Milan, Italy area. All but 1 child completed the study.
The trial population that completed the study consisted of
32 males and 28 females who exhibited an average of not
less than 3 episodes of pharyngotonsillitis (conrmed by rapid
swab test for groups A and B streptococci) in the same quarter
(February through April) as that of the study (2013) in the
previous calendar year (2012). Thirty children were treated
with one lozenge per day containing not less than 1 billion CFU
S. salivarius K12 for 90 consecutive days, while the other thirty
children served as the untreated control group. The treated
and control groups did not differ signicantly with respect to
age, gender distribution, or episodes of pharyngotonsillitis per
child. In the treated group, there were 19 males with a mean
age 6.7 ± 2.5 [years ± standard deviation (SD)], 11 females
with a mean age of 5.7 ± 1.9 (years ± SD), and a mean 3.1
episodes per child. In the untreated control group, there were
13 males with a mean age 6.1 ± 2.8 years, 17 females with a
mean age of 5.7 ± 1.9, and a mean 3.0 episodes per child.
Upper panel (A): Bars indicate total number of episodes of
pharyngotonsillitis, and the values within the bars indicate the
mean episodes per child during February through April for
the indicated year. During the same quarter of the previous
year (2012) in which they were not receiving K12, children
assigned to the K12-treated group in this study (bars 1 and
2, respectively, on the left of graph) exhibited a total of 94
episodes of pharyngotonsillitis (mean of 3.1 episodes/child).
After receiving K12 for 90 consecutive days in this study,
the total episodes of pharyngotonsillitis were reduced to 3,
corresponding to 0.1 episode per child and an approximate
97% decrease (P < 0.001 versus previous year (2012) and
also versus untreated group in 2013). For the children in the
untreated control group, there was no signicant difference in
total episodes of pharyngotonsillitis or episodes per child from
2012 vs 2013 (bars 3 and 4, respectively, on the right of graph).
Lower panel (B): Bars and values with the bars indicate total
number of days treated with antibiotics or antipyretics, along
with days missed from school or work for the untreated control
group (grey bars) and K12-treated group (blue bars) during
the course of this study. Graphs were created for this article
using data from (36).
a.
b.
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Readers interested in a full list of references are invited to visit our
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and characterizing new probiotic strains (23, 46). Beyond
extending the clinical substantiation of existing probiotics
and introducing novel strains, the ability to have one’s oral
microbiome individually characterized to the genus level by
providing a saliva sample is easily attainable (47). Thinking
ahead, this personal microbiome prole could eventually
be accompanied by a list of potential probiotic strains
specically targeting the resident pathogenic bacteria.
Beyond that, look for saliva to become the new blood, in
the context of biomarkers. Aside from the ease of sample
collection, biomarkers in the blood are often present in
microgram quantities, while the same biomarkers are often
present in saliva at nanogram or even picogram levels.
This sort of laboratory testing is already commercially
available (48).
The main challenges will likely come from identifying
probiotics that do not pose any safety concerns, the ability
to colonize on one or more surfaces in the oral cavity, being
sufciently stable over time, and their compatibility with
multiple delivery formats. Adequate consumer education
regarding the need and benets of orally-targeted probiotics
is imperative. Finally, the uidity of worldwide regulatory
agencies and their statutes is unpredictable and merits
ongoing attention.
CONCLUSIONS
The oral microbiome is a major contributor to our oral health,
which in turn is closely linked to systemic health, the ability
to ward off disease, and a person’s overall quality of life.
A concerted effort to achieve regular exercise, high quality
nutrition, and good oral hygiene habits to promote our oral
health should be cornerstones of a healthy lifestyle. Good
oral hygiene includes proper diet, correct tooth brushing
techniques, use of dental oss, regular dental visits, and
regular teeth cleaning by a qualied dental hygienist. As we
have discussed, the use of selected orally-targeted probiotics
now offers a highly complementary approach to good oral
hygiene that promises to deliver the next generation of oral
and throat healthcare.
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53
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