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Anders Henriksson, PhD
Principal Application Specialist
July 10, 2019
A presentation with bite. Improving oral
health in an ageing population
Why Oral Health ?
2
A global issue
Mean percent of Community Periodontal Index (CPI)* scores in 35-44 year olds
by global World Health Organisation (WHO) offices
* CPI scores are defined by WHO protocol and is a standardized means of dental disease measurement used to compare reports
Modified from Petersen and Ogawa (2005) J Periodontol 76 (12):2187-2193
3
8 out of 10 people aged
35 years and over
suffer some kind of
gum complaint
Less than 10% of 35-44 year olds
have healthy gums
100 %
80 %
60 %
40 %
20 %
0 %
CPI 0 - healthy periodontal
conditions
CPI 1 - gingival bleeding
CPI 2 - gingival and calculus
bleeding
CPI 3 - shallow periodontal
pockets (4-5mm)
CPI 4 - deep periodontal
pockets (≥ 6mm)
Africa Americas Eastern
Mediterranean
Europe South
East Asia
Western
Pacific
Gingivitis and Periodontitis
▪ The oral cavity is home to more
than 700 different bacterial
species
▪ Biofilms are formed by bacterial
communities which reside in
saliva-covered soft and hard
tissues
▪ Oral biofilms are associated
with infectious diseases such
as tooth decay (caries) and
periodontal disease
Gingivitis
Gingivitis can cause dusky red, swollen,
tender gums that bleed easily, especially
when you brush your teeth.
Healthy gums Severe periodontitis(more than 6 mm pockets)
- Extensive bone and
tissue loss, teeth can
become loose
Gingivitis(2-3 mm pockets)
- gums become red
and bleed easily
Moderate
periodontitis(4-6 mm pockets)
- gum recession, bone
and tissue destruction
Periodontitis
Periodontitis is a severe gum infection
that can lead to tooth loss and other
serious health complications.
4
Untreated, can progress to
Increased prevalence of periodontitis in older age
FIGURE. Prevalence of total, mild, moderate, and severe periodontitis among adults aged ≥30 years, by age — National Health and Nutrition Examination Survey, United States, 2009–2010. This figure is a line graph that presents periodontitis in adults aged ≥30 years by level of severity (i.e., total mild, moderate, and severe). This figure demonstrates that the prevalence of mild and severe periodontitis remained relatively steady at <15% across all age groups.
Correlation between periodontitis and halitosis
Silva et al (2017) Journal of Clinical Periodontology
Link between periodontal disease and
non-communicable diseases
Nazir (2017) International Journal of Health Sciences
Gingivitis and Periodontitis – the importance of the oral biofilm
▪ The oral cavity is home to more
than 700 different bacterial
species
▪ Biofilms are formed by bacterial
communities which reside in
saliva-covered soft and hard
tissues
▪ Oral biofilms are associated
with infectious diseases such
as tooth decay (caries) and
periodontal disease
Gingivitis
Gingivitis can cause dusky red, swollen,
tender gums that bleed easily, especially
when you brush your teeth.
Healthy gums Severe periodontitis(more than 6 mm pockets)
- Extensive bone and
tissue loss, teeth can
become loose
Gingivitis(2-3 mm pockets)
- gums become red
and bleed easily
Moderate
periodontitis(4-6 mm pockets)
- gum recession, bone
and tissue destruction
Periodontitis
Periodontitis is a severe gum infection
that can lead to tooth loss and other
serious health complications.
8
Untreated, can progress to
Composition of biofilms
Periodontal disease Osteoimmunology
Silva et al (2015) J. Appl. Oral Sci.
receptor activator of nuclear factor-κB ligandreceptor activator of nuclear factor-κB osteoprotegerin
Probiotic Oral Therapy
Studies
11
Probiotic oral therapy studiesPre-clinical trials and important reviews in vitro and in animals
Evaluation – lactobacilli and/or bifidobacteria Authors / References
Oral adhesion and survival of probiotic and other lactobacilli and bifidobacteria in vitro Haukioja et al., Oral Microbiol Immunol. 2006
Do probiotics offer opportunities to manipulate the periodontal oral microbiota? Tueghels et al., J Clin Periodontol. 2011
Bifidobacteria inhibit the growth of Porphyromonas gingivalis but not of Streptococcus mutans
in an in vitro biofilm model
Jäsberg et al., Eur J Oral Sci. 2016
Clinical efficacy of probiotics as an adjunctive therapy to non-surgical periodontal treatment of
chronic periodontitis: a systematic review and meta-analysis.
Martin-Cabezas et al., J Clin Periodontol. 2016
Evaluation – Bifidobacterium lactis HN019™ Authors / References
Benefits of Bifidobacterium animalis subsp. lactis Probiotic in Experimental Periodontitis. Oliveira et al., J Periodontol. 2017
Effects of the probiotic Bifidobacterium animalis subsp. lactis on the non-surgical treatment of
periodontitis. A histomorphometric, microtomographic and immunohistochemical study in rats.
Ricoldi et al., PloS one 2017.
Effects of the probiotic Bifidobacterium animalis subsp. lactis on experimental periodontitis in
diabetic rats
Messora and Furlaneto, Conference
presentation at Vitafoods Europe, Geneva, 2017
12
Traditional treatment of periodontitis vs use of probiotics
New approach to improve treatment
outcomes: Probiotics
Teughels et al., (2011) J Clin Periodontol 38 (Suppl 11): 159-177
Invernici et al. (2018) J Clin Periodontol . 45(10):1198-1210.
Recent studies indicate that certain probiotics can have
positive effects in oral health including:
• Reduction in moderate and deep pockets
• Reduced probing depth
• Reduced bleeding upon probing
• Promotes a shift from periodontitis associated to healthy
oral microflora
• Decrease in pro-inflammatory markers
Traditional treatment for periodontal disease:
Scaling and Root Planing (SRP)
Planing
Scraping, smoothing of root surface
to allow gum tissue reattach better
to roots
Scaling
Cleaning that removes plaque
and tartar from gum line
13
Benefits of
B. lactis HN019™ in
experimental periodontitis
14
Benefits of B. lactis HN019™ in experimental periodontitis
Aim of the study
To evaluate microbiologic, histomorphometric, and
immunologic outcomes following topical administration of
B. lactis HN019™ in rats with ligature induced experimental
periodontitis in mandibular first molar (MFMs).
Study design
32 rats, divided to four groups of 8:
• control
• HN019™
• experimental periodontitis
• experimental periodontitis + HN019™
In probiotic groups each MFM were topically swabbed with 1
ml of 1.9 x 109 CFU B. lactis HN019™ on days 0, 3, and 7.
Oliveira et al., J Periodontol. 2017
15
Benefits of B. lactis HN019™ in experimental periodontitis
Experimental periodontitis + probiotic
▪ Group had more expression of
osteoprotegerin (OPG) and β-defensins vs.
experimental periodontitis –group
▪ Group showed decreased IL-1β and
receptor activator of nuclear factor-kappa B
ligand (RANKL) vs. experimental
periodontitis –group
Oliveira et al., J Periodontol. 2017
16
% DNA probe counts = percentage of the DNA count of each
species in relation to the total DNA count of the 40 bacterial species
evaluated. *Significant difference among groups (t test, P <0.05).
0
3
6
9
12
% D
NA
pro
be
co
un
ts
Group EP
Group EP + HN019™
Mean proportions of 40 species in the ligature biofilm
Effects of B. lactis HN019™ on non-surgical treatment of
periodontitis
Aim of the study
To evaluate the effect of B. lactis HN019™ together
with scaling and root planing (SRP) on ligature
induced experimental periodontitis.
Study design
32 rats, divided to four groups of 8:
• control,
• HN019™
• experimental periodontitis + SRP
• experimental periodontitis + SPR + HN019™
Probiotic groups received B. lactis HN019™ orally
in milk 109 CFU/10 ml for 15 days.
Ricoldi et al., PloS one 2017.
17
Effects of B. lactis HN019™ on the non-surgical treatment
of periodontitis
Experimental periodontitis + SPR + probiotic
▪ Group had reduced alveolar bone resorption
and attachment loss vs. experimental
periodontitis + SPR group.
▪ Group showed fewer osteoclasts, increased
expression of anti-inflammatory cytocines
and reduced expression of proinflammmatory
cytocines vs. experimental periodontitis +
SPR group.
* p<0.05
18
Ricoldi et al., PloS one 2017.
*
Ae
rob
ic/a
na
ero
bic
ba
cte
ria
ratio
Experimental groups
InterventionPlacebo
7.5
5.0
2.5
0.0
Effect of B. lactis HN019™ on ligature-associated microbiota.
B. lactis HN019™ gave greater bone volume,
reduced bone porosity and alveolar bone level
19
Ricoldi et al., PloS one 2017.
Table 1. Micro-CT analyses. Means and standard deviations (SD) of Bone Volume (BV), Bone Porosity (BP) and Alveolar Bone Level (ABL)
Human clinical trial
Effects of probiotic therapy in the
treatment of periodontitis: a study
of clinical, microbiological and
immunological profiles of the
host response
Invernici et al. (2018) J Clin Periodontol. 45(10):1198-1210.
AimTo evaluate the effects of the probiotic
therapy using Bifidobacterium lactis
HN019™ as an adjunct to non-surgical
periodontal treatment in patients diagnosed
with Generalized Chronic Periodontitis.
20
Effects of probiotic therapy in the treatment of periodontitis: a study of clinical, microbiological, and immunological profiles of the host response
Primary aim of the study
To evaluate the effects of the probiotic therapy using
Bifidobacterium lactis HN019™ as an adjunct to non surgical
periodontal treatment in patients diagnosed with Generalized
Chronic Periodontitis on clinical attachment loss (CAL).
Secondary aim of the study
To evaluate the following parameters before and after the treatment
of chronic periodontitis with oral administration of Bifidobacterium
lactis HN019™ associated with Scaling and Root Planing (SRP) or
SRP only.
• Probing pocking depth (PPD)
• Plaque index and bleeding on probing
• Microbial analysis of supra and subgingival plaque
• Quantification of IL-1ß, IL-8 and IL-10 in gingival crevicular fluid
21
Invernici et al. (2018) J Clin Periodontol. 45(10):1198-1210.
Study design
Randomized, double-blind, placebo-controlled and parallel
clinical trial.
Inclusion criteria
• Age over 30 years
• 30% or more the sites with Clinical Attachment Loss (CAL)
and Probing Pocket Depth (PPD) ≥4 mm
• Presence of Bleeding on Probing (BOP)
• At least 5 teeth with one site with CAL and PPD ≥5mm
• Otherwise healthy
Subjects41 adults with generalized chronic periodontitis, one lozenge
twice a day in the morning and before bedtime for 30 days
• Placebo N=21: Lozenge
• HN019™ N=20: Lozenge with 1 x 109 Bifidobacterium lactis
HN019™
Follow up - 30 days and 90 days.
Human clinical trial - periodontal measurements and dental
treatments used
Dental Treatment: Scaling and Root Planing (SRP)
PI: Plaque Index - percentage of total number of
tooth parts with plaque against number of teeth
present.
BOP: Bleeding On Probing - bleeding that is
induced by gentle manipulation of the tissue at the
depth of tooth and gingiva interface.
y = GR: Gingival Recession
x = CAL: Clinical Attachment Loss - measured from
a fixed point - usually the cementoenamel junction - to
the base of the sulcus or periodontal pocket.
z = PD: Probing Depths - from gingival to the base of
the sulcus or periodontal pocket. The margin may
change with tissue swelling or recession.
22
Effects of probiotic therapy in the treatment of periodontitis: a study of clinical, microbiological, and immunological profiles of the host response
Primary aim of the study
To evaluate the effects of the probiotic therapy using
Bifidobacterium lactis HN019™ as an adjunct to non surgical
periodontal treatment in patients diagnosed with Generalized
Chronic Periodontitis on clinical attachment loss (CAL).
Secondary aim of the study
To evaluate the following parameters before and after the treatment
of chronic periodontitis with oral administration of Bifidobacterium
lactis HN019™ associated with Scaling and Root Planing (SRP) or
SRP only.
• Probing pocking depth (PPD)
• Plaque index and bleeding on probing
• Microbial analysis of supra and subgingival plaque
• Quantification of IL-1ß, IL-8 and IL-10 in gingival crevicular fluid
23
Invernici et al. (2018) J Clin Periodontol. 45(10):1198-1210.
Study design
Randomized, double-blind, placebo-controlled and parallel
clinical trial.
Inclusion criteria
• Age over 30 years
• 30% or more the sites with Clinical Attachment Loss (CAL)
and Probing Pocket Depth (PPD) ≥4 mm
• Presence of Bleeding on Probing (BOP)
• At least 5 teeth with one site with CAL and PPD ≥5mm
• Otherwise healthy
Subjects41 adults with generalized chronic periodontitis, one lozenge
twice a day in the morning and before bedtime for 30 days
• Placebo N=21: Lozenge
• HN019™ N=20: Lozenge with 1 x 109 Bifidobacterium lactis
HN019™
Follow up - 30 days and 90 days.
Human clinical trial – study design
7 days
Inclusion
30 days
Intervention
60 days
Follow-up
Full mouth
supragingival
scaling
Proper home care
techniques
24
Invernici et al. (2018) J Clin Periodontol. 45(10):1198-1210.
• Scaling and Root Planing (SRP) – Day 0
• Clinical Attachment Loss (CAL)
• Probing Pocking Depth (PPD)
• Gingival Recession (GR)
• Plaque Index (PI)
• Bleeding on Probing (BOP)
• Adverse Event (AE)
• Samples of Gingival Crevicular Fluid (GCF)
• Samples of plaque and saliva
• Clinical Attachment Loss (CAL)
• Probing Pocking Depth (PPD)
• Gingival Recession (GR)
• Plaque Index (PI)
• Bleeding on Probing (BOP)
• Adverse Event (AE)
• Samples of Gingival Crevicular Fluid (GCF)
• Samples of plaque and saliva
Number of copies/μL of B. lactis HN019™ genome
25
Invernici et al. (2018) J Clin Periodontol. 45(10):1198-1210.
Test
Control
Only
probiotic group
had increased
numbers of
B. lactis HN019™
in subgingival
plaque samples at
30 days and 90
days.
HN
01
9™
ge
mo
me
co
pie
s/
l
Baseline
400000
300000
200000
100000
1000
800
600
400
200
0
(x102)
30 days 90 days
Aa
(9,064.9)
Aa
(13,828.8)
Ba
(13,353,018.9)
Ba
(23,477.6)
Ba
(2,884,499.1)
Ab
(137,009)
Positive changes in Clinical Attachment Loss (CAL)
at 60 days after intervention with HN019™
Bifidobacterium lactis HN019™ continues to improve Clinical Attachment Loss 60 days after the
intervention as an adjunct to non-surgical periodontal treatment in patients diagnosed with
Generalized Chronic Periodontitis
Probiotic B. lactis HN019™ Control p-value (delta)
Baseline (mm) 4.63 ± 0.42 4.70 ± 0.45 NS
30 days (change from baseline mm)
- 1.12 ± 0.44 - 1.01 ± 0.44 NS
90 days (change from baseline mm)
- 1.15 ± 0.45 - 0.76 ± 0.41 0.008
Probiotic B. lactis HN019™ Control p-value (delta)
Baseline (mm) 7.48 ± 0.53 7.62 ± 0.72 NS
30 days (change from
baseline mm) - 3.12 ± 1.27 - 2.54 ± 1.33 NS
90 days (change from
baseline mm)- 3.45 ± 1.21 - 2.07 ± 0.97 0.0004
X: CAL
26
Invernici et al. (2018) J Clin Periodontol. 45(10):1198-1210.
Moderate
pockets
Deep
pockets
Positive changes in Probing Pocking Depth (PPD)
at 60 days after intervention with HN019™
Bifidobacterium lactis HN019™ continues to improve Probing Pocket Depth 60 days after intervention
as an adjunct to non-surgical periodontal treatment in patients diagnosed with Generalized Chronic
Periodontitis
Moderate
pockets
Deep
pockets
Probiotic B. lactis HN019™ Control p-value (delta)
Baseline (mm) 4.47 ± 0.20 4.44 ± 0.27 NS
30 days (change from baseline mm)
- 1.18 ± 0.37 - 1.11 ± 0.41 NS
90 days (change from baseline mm)
- 1.28 ± 0.41 - 0.94 ± 0.42 0.01
Probiotic B. lactis HN019™ Control p-value (delta)
Baseline (mm) 7.27 ± 0.29 7.26 ± 0.35 NS
30 days (change from
baseline mm) - 3.20 ± 1.00 - 2.79 ± 1.11 NS
90 days (change from
baseline mm)- 3.52 ± 1.19 - 2.62 ± 0.88 0.01
Z: probing depth
27
Invernici et al. (2018) J Clin Periodontol. 45(10):1198-1210.
Oral microbiota profiles of mean counts (×105) in gingival plaque
Probing depth 4-7 mm –
moderate pockets
▪ The bacterial profiles of mean counts
indicate significant differences between
the HN019™ test group and control
group after 30 and 90 days.
▪ After 90 days the HN019™ test group
indicates a significant increase in
Actinomyces and Streptococcus and a
significant decrease in Porphyromonas
gingivalis and Treponema denticola
compared to baseline.
▪ P. gingivalis and T. denticola are
associated with periodontal diseases.
HN019™ Control 90 days baseline
28
Invernici et al. (2018) J Clin Periodontol. 45(10):1198-1210.
HN019™ induced positive changes in microbial complexes of
gingival plaque
Overall the test group
containing HN019™ indicates
significant changes in sub-
and supra- gingival plaque for
the following bacteria
compared to the control:
Red complex bacteria:
P. gingivalis and
T. denticola decreased
in probiotic group at 30
and still at 90 days(associated with periodontal
disease)
Blue complex bacteria:
Actinomyces and
Streptococcus
increased
29
Invernici et al. (2018) J Clin Periodontol. 45(10):1198-1210.
Conclusions - positive effects of
Bifidobacterium lactis HN019™
Probiotic Bifidobacterium
lactis HN019™ has positive
effects in oral health
▪ Reduction in moderate and
deep pockets
▪ Reduced bleeding upon
probing
▪ Promotes a shift from
periodontitis associated to
healthy microbiota
30
Invernici et al. (2018) J Clin Periodontol. 45(10):1198-1210.
Patients healing is
much improved after intervention
with Bifidobacterium
lactis HN019™.
This lowers the
cost of treatment
with less therapeutic
morbidity.
Low risk Moderate risk High risk
HN019™
100%
Control
30
5
65
52.5
4.7
42.8
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
Patients at risk for periodontitis progression
Excellent stability
With the blending of different carriers, the probiotic
chewable tablets stability
Opportunity:
Probiotic chewable tablet supply well over minimum cell
count of 1.0E+09 CFU/tablet before shelf life.
1.00E+09
1.00E+10
1.00E+11
Ac
tivit
y B
ac
teri
a(
CF
U/g)
Test time
Stability of probiotics
Delivery formats
Probiotic tablet
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