probiotics and prebiotics for oral...

Probiotics and Prebiotics for Oral Health

Wim TEUGHELSBelgium

Rank Health condition

Affected people

(millions) %

1 Untreated caries of permanent teeth 2,431 35.29

2 Tension-type headache 1,431 20.77

3 Migraine 1,012 14.70

4 Fungal skin diseases 985 14.30

5 Other skin and subcutaneous diseases 803 11.66

6 Severe periodontitis 743 10.79

7 Mild hearing loss 724 10.52

8 Acne vulgaris 646 9.38

9 Low back pain 632 9.17

10 Untreated caries of deciduous teeth 621 9.02

36 Severe tooth loss 158 2.3

Prevalence of

oral diseases

Periodontitis Caries/Tooth decay

Most prevelant health conditions in the world

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Oral biofilms & plaque related periodontal diseases

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Solution

Fact: People leave dental biofilm after

brushing which is covered by a layer of

dead bacteria

MIC90 (µg/ml) Amoxicilin Spain vs. The Netherlands

32

256 256

0,38 1,5 0,0230

50

100

150

200

250

300

A.a Pi Fnbacterial species:

MIC

90

µg

/ml

Spain

The Netherlands

84 x

171 x 11130 x

MIC90 (µg/ml) Amoxicilin Spain vs. The Netherlands

32

256 256

0,38 1,5 0,0230

50

100

150

200

250

300

A.a Pi Fnbacterial species:

MIC

90

µg

/ml

Spain

The Netherlands

84 x

171 x 11130 x

33% R 33% R 20% R

Fact: Oral bacteria also become more

resistant to antibiotics when frequently

exposed to antibiotics

Fact: Antiseptics induce necrotrophy,

necrovirulence, resistance and can

increase antibiotic resistance

PRO

Evidence for probiotics in oral health is just emerging

Give it

time!

>30 studies

Probiotics & tooth decay

Author design n age vehicle time strain outcome test/ctl PF% NNTInfancyTaipele, 2013 RCT 106 0-2 pacifier/spoon 4y B. animalis BB-12 caries prevalence 31%/35% 11% 25Hasslöf, 2013 RCT 180 0-1 cereals 9y L. paracasei F19 caries prevalence 20%/26% 20% 17Stensson, 2014 RCT 188 0-1 drops 9y L. reuteri ATCC55730 caries prevalence 18%/42% 57% 4Toddlers & preschoolNäse, 2001 RCT 594 1-6 milk 7m L. rhamnosus GG caries prevalence 15%/19% 21% 25

164 3-4 milk 7m L. rhamnosus GG caries prevalence 10%/23% 56% 7Stecksén-B, 2009 CRCT 248 1-5 milk 21m L. rhamnosus LB21 +2.5 ppm F Δdmfs 0,3/1,6 48% 5H-Hajikand, 2015 RCT 138 2-3 tablets 12m Probiora Δds 0.2/0.8 49% 4Rodrigues, 2016 CRCT 261 2-3 milk 12m L. rhamnosus SP1 ΔIDAS(5-6) 9,7/24,3 61% 7AdultsPetersson, 2011 RCT 200 56-84 milk 15m L. rhamnosus LB21 rev rootcaries 54%/24% 55% 3

Jorgensen e.a. 2016

8 studies with true caries related outcome measure

preventive

fraction: 29%

Probiotics & tooth decay

Author design n age vehicle time strain outcome test/ctl PF% NNTInfancyTaipele, 2013 RCT 106 0-2 pacifier/spoon 4y B. animalis BB-12 caries prevalence 31%/35% 11% 25Hasslöf, 2013 RCT 180 0-1 cereals 9y L. paracasei F19 caries prevalence 20%/26% 20% 17Stensson, 2014 RCT 188 0-1 drops 9y L. reuteri ATCC55730 caries prevalence 18%/42% 57% 4Toddlers & preschoolNäse, 2001 RCT 594 1-6 milk 7m L. rhamnosus GG caries prevalence 15%/19% 21% 25

164 3-4 milk 7m L. rhamnosus GG caries prevalence 10%/23% 56% 7Stecksén-B, 2009 CRCT 248 1-5 milk 21m L. rhamnosus LB21 +2.5 ppm F Δdmfs 0,3/1,6 48% 5H-Hajikand, 2015 RCT 138 2-3 tablets 12m Probiora Δds 0.2/0.8 49% 4Rodrigues, 2016 CRCT 261 2-3 milk 12m L. rhamnosus SP1 ΔIDAS(5-6) 9,7/24,3 61% 7AdultsPetersson, 2011 RCT 200 56-84 milk 15m L. rhamnosus LB21 rev rootcaries 54%/24% 55% 3

8 studies with true caries related outcome measure

Jorgensen e.a. 2016

preventive

fraction: 29%

preventive

fraction: 47%

Probiotics & tooth decay

Author design n age vehicle time strain outcome test/ctl PF% NNTInfancyTaipele, 2013 RCT 106 0-2 pacifier/spoon 4y B. animalis BB-12 caries prevalence 31%/35% 11% 25Hasslöf, 2013 RCT 180 0-1 cereals 9y L. paracasei F19 caries prevalence 20%/26% 20% 17Stensson, 2014 RCT 188 0-1 drops 9y L. reuteri ATCC55730 caries prevalence 18%/42% 57% 4Toddlers & preschoolNäse, 2001 RCT 594 1-6 milk 7m L. rhamnosus GG caries prevalence 15%/19% 21% 25

164 3-4 milk 7m L. rhamnosus GG caries prevalence 10%/23% 56% 7Stecksén-B, 2009 CRCT 248 1-5 milk 21m L. rhamnosus LB21 +2.5 ppm F Δdmfs 0,3/1,6 48% 5H-Hajikand, 2015 RCT 138 2-3 tablets 12m Probiora Δds 0.2/0.8 49% 4Rodrigues, 2016 CRCT 261 2-3 milk 12m L. rhamnosus SP1 ΔIDAS(5-6) 9,7/24,3 61% 7AdultsPetersson, 2011 RCT 200 56-84 milk 15m L. rhamnosus LB21 rev rootcaries 54%/24% 55% 3

Jorgensen e.a. 2016

preventive

fraction: 29%

preventive

fraction: 47%

8 studies with true caries related outcome measure

Probiotics & tooth decay

8 studies with true caries related outcome measure

- 4 w 1 y 9 y

Control: placeboExperiment: L. reuteri ATCC 55730

Intervention: 5 drops / day

N=232

N=113

Total caries toothsurfaces

Plaque Index (%) Gingivitis index (%)

Probiotics & tooth decay

S. mutans numbers

Lo

wMedium High Lo

wMedium High

-70% *-19%

Probiotic

(n=18/746)

% o

f p

atie

nts

Control

(n=18/728)

+51% * +19% *

Probiotics & tooth decay

6th

Health Gingivitis

Health Gingivitis Periodontitis

Bleeding on probing

Probing pocket depth (PPD)

Boneloss

1 2 3 4 5 6 7 8 9 10 11 ...

mm

Health Gingivitis Periodontitis

Can probiotics prevent periodontitis?

Can probiotics prevent periodontitis?

Human studies10-40 years

Animal studies

Can probiotics prevent periodontitis?Relative bone level change Control Probiotic % reduction

Maekawa et al. L. brevis CD2 Mice Ligature -0,6 -0,22 -63%

Messora et al. B. subtilis Wistar rat Ligature -3,21 -2,38 -25%

Foureaux et al. B. subtilis Wistar rat Ligature -0,3 -0,12 -60%

Messora et al. B. subtilis + B. licheniformis Wistar rat Ligature -2,32 -1,07 -53%

Oliveira et al. B. animalis subsp. lactis Wistar rat Ligature -2,6 -1,6 -38%

Gatey et al. L. rhamnosus GG Mice Pg + Fn -0,06 -0,002 -96%

-56%

Irrespectively of mode of application(oral local or systemic) (Gatey et al 2018)

Ligature induced (foreign body): -48%Microbiologically induced: -96%

Can probiotics prevent periodontitis?

?

Evidence in Perio?

R/ ?

Heterogeneity

Optimism

Set-up Probiotic: Application: Outcome measure

- L. salivarius - tablets - PPD

- W. cibaria - chewing gum - GI

- L. reuteri - oral rinse - PI

- L. casei shirota - milk drink - BOP

- ……. - microbiology

Evidence in Perio?

>30 studies

+

+

+ ORPlacebo Probiotic

PPD

Baseline 21 days 3 months 6 months 12 months

Placebo 5.36±0.72 4.60±0.71 4.51±0.71 4.66±0.69 4.80±0.70

Probiotic 5.23±0.68 4.03±0.74* 3.80±0.75* 3.38±0.86* 3.49±0.87*

Teeth with PPD >= 5mm at 12 months

Baseline 12 months

Placebo 98,18% ± 4,07 89,34% ± 7,98

Probiotic 99,29% ± 1,6 29,91% ± 21,03 *-66.52%

Double blind placebo controlled 20 chronic periodontitis patients/armIntervention: SRP + placebo / probiotic(L. reuteri ATCC 55730 & PTA5289)lozenge 2/day for 3 weeksFollow-up: 12months

Study name Statistics for each study Difference in means and 95% CI

Difference Standard Lower Upper in means error Variance limit limit Z-Value p-Value

Teughels 2013 -0,020 0,075 0,006 -0,168 0,128 -0,266 0,790

Tekce 2015 -0,590 0,103 0,011 -0,791 -0,389 -5,740 0,000

Vivekananda -0,820 0,162 0,026 -1,137 -0,503 -5,071 0,000

-0,463 0,249 0,062 -0,951 0,025 -1,861 0,063

-1,00 -0,50 0,00 0,50 1,00

Favours probiotic Favours control

Meta Analysis

Evaluation copy

AZI: -0.32 [-0.53, -0.11]LDD: -0.28 [-0.45, -0.10]MET: -0.26 [-0.56, 0.04]MET+AMOX: -0.39 [-0.73, -0.05](Keestra et al 2014)WMD: -0,46 mm

Study name Statistics for each study Difference in means and 95% CI

Difference Standard Lower Upper in means error Variance limit limit Z-Value p-Value

Teughels 2013 -0,630 0,114 0,013 -0,854 -0,406 -5,520 0,000

Tekce 2015 -1,210 0,219 0,048 -1,640 -0,780 -5,521 0,000

-0,890 0,288 0,083 -1,455 -0,325 -3,085 0,002

-2,00 -1,00 0,00 1,00 2,00

Favours probiotic Favours control

Meta Analysis

Evaluation copy

WMD: -0,89 mm

PPD

PPD Deep AZI: -0.52 [-0.86, -0.18]]LDD: -0.62 [-0.84, -0.41]MET: -0.78 [-1.23, -0.33]MET+AMOX: -0.79 [-1.16, -0.42] (Keestra et al 2014)

How relevant are these differences?

Category Definition Placebo group Probiotic group

Low < 5 sites with PPD >4 2 (13.3%) 9 (60%)

Medium 5-8 sites with PPD > 4 3 (20%) 2 (13.3%)

High > 8 sites with PPD >4 10 (66.6%) 4 (26.6%)

Feres e.a. 2013

Risk for disease progression (Lang & Tonetti 2003)

How relevant are these differences?

Indirect, not yet direct

Category Definition Placebo group Probiotic group

None No teeth 2 (6%) 9 (26%)

Low 1-2 teeth 0 20 (57%)

Moderate-High >2 teeth 33 (94%) 6 (17%)

Need for surgery (Cionca et al. 2009 )

How relevant are these differences?

Tooth decay:49% preventive fraction

70% reduction in patients withhigh S. mutans counts

Oral Candida:48% reduction in patients with

high yeast counts

Gingivitis & periodontitis:> PPD reduction, CAL gain,

< need for surgery, Risk Disease Progression,

pathogens, Gi, Pi

Pregnancy gingivitis:58% ↓ Gi, 46% ↓ Pi

L. reuteri

Radiation mucositis:32% ↓ severe mucositis4x> without symptoms

Diabetes55% BOP reduction

Peri-implant diseases50% BOP reduction

Additional PPD reduction

Halitosis:15-60% reduction

Indirect causes

Probiotics in Dentistry

Are prebiotics an option?

Prebiotics

Oral health ≠ GI health?

3-5 min vs. 23 hours

Fast vs. Slow (fibers)

The quest for...

carbon

sources

nitrogen

sourcesP, S

sources

nutrient

supple

ments

peptide

nitrogen

sources

3/d, 3 min, 3d

7 9759

growth biofilm

11 9

27%

3%

3%

3%

The quest for...

Fiber prebiotic?

-1,20 mm +/- 0,14 -2,10 mm +/- 0,36 -1,78 mm +/- 0,35

-36%

N= 18 Wistar rats6: healthy 6: periodontitis induction (2 weeks) + ß-glucan 30mg/kg/day (4 weeks) via gavage6: periodontitis induction (2 weeks)

GI health – Oral health connection

Specific probiotics can help in the prevention and treatment of

oral diseases

Prebiotics are under development (very limited evidence)

When designing (clinical) trials, also consider oral health