pre pro bio tics and immunity

8/6/2019 Pre Pro Bio Tics and Immunity

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Bringing immunity science in from

the cold.

Ger T. Rijkers

Utrecht, Nieuwegein, NijmegenThe Netherlands

[email protected]
mailto:[email protected]://www.gtrijkers.nl/http://www.gtrijkers.nl/mailto:[email protected]


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Health Claim Applications

44,000 applications

8% on probiotics284/284 rejected


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Probiotics

live microorganisms which, when administeredin adequate amounts, confer a health benefit on

the hostFAO/WHO 2001


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Probiotics

live microorganisms which, when administeredin adequate amounts, confer a health benefit on

the hostFAO/WHO 2001


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Surrounded by a world of micro-organisms


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Categories of micro-organisms


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Categories of micro-organisms

Gutmicrobiota

Measles

Tetanus


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Immune system

Infectious disease Allergic disease Autoimmunedisease

Malignancy

Functions of the immune system


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Immune system


Malignancy



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Immune system


Malignancy



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Immune system


Malignancy



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Immune system

Involvement of the immune systemin the most prevalent diseases

Excessive inflammationOveractiveMalfunctioning

ImpairedOut of control


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Immune system

Organisation of the immune system


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Immune system



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Immune system



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Immune system



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Health: a state of completephysical, mental, and social well-being and not merely the absenceof disease or infirmity.


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leaves no room for improvement ( astate of complete . . . well-being)

impossible for probiotics/prebioticsto have a beneficial effect in healthyindividuals.

This definition of health as a statelacks the temporal dimension anddoes not address its dynamics.


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Healthy: todaytomorrow morningcoming winterrest of your life


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Maintaining health Prevention of disease(Risk reduction)

Benificial effects of probiotics andprebiotics on the human immune system


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Food and food-supplementsBiomarkers

DrugsBiomarkers + Clinical endpoints


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Functional immune systemImmune dysfunction

R i s k o

f D i s e a s e

Physiological rangePathological range Suboptimal health

Target and study populations

Rijkers et al. Journal of Nutrition 140 (2010) 671-676S


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R i s k o

f D i s e a s e





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R i s k o

f D i s e a s e





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Confounding factorswithin the target population:Who is at risk?


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Age (years)

Age as a risk factor for infectiousdiseases

0.1 1.0 10 100

150

100

50

0

m e n

i n g

i t i s / 1 0 y e a r s

/ 1 0

5

a g e c a

t e g o r y

( )

s e p s i s

/

/ 1 0

5 /

( )

15

10

5

0

a g e c a

t e g o r y

1 0 y e a r s


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Confounding factorswithin the target population:Extrapolation from risk groups?


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Maintaining health: re-adjust (homeostasis)

Time (days, weeks)

G u t m i c r o b i o t a


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Time (days, weeks)

G u t m i c r o b i o t a

Antibiotics, (subclinical ) infectionLife event, Stress, Drivers exam


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Time (days, weeks)

G u t m i c r o b

i o t a



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Time (days, weeks)

G u t m i c r o b

i o t a



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Time (days, weeks)

G u t m i c r o b

i o t a



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Time (days, weeks)

G u t m i c r o b

i o t a

Antibiotics (amoxicillin)

0 3 7 14 35 63


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Time (days, weeks)

G u t m i c r o b

i o t a


0 3 7 14 35 63

*Probiotics: B. bifidum, B. lactis, B. longum, E. faecium, L. rhamnosus, L. paracasei

L. plantarum (2x), L. acidophilus (2x)


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Time (days, weeks)

G u t m i c r o b

i o t a


0 3 7 14 35 63

*Probiotics: B. bifidum, B. lactis, B. longum, E. faecium, L. rhamnosus, L. paracasei

L. plantarum (2x), L. acidophilus (2x)

Probiotics: mechanisms of action


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Probiotics: mechanisms of action



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Immune health claims for probiotics(not approved by EFSA)


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Bacillus bulgaricus


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Bacillus bulgaricus Eat this and live longer


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LGG from Vifit supports naturalimmunity


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DanActive help strenghten yourbodys defenses


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Yakult enhances our bodys immunityto reduce risk of infections


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S d d b ld f i g i


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Surrounded by a world of micro-organisms

Immune system protects against infection (= disease)

Common cold


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Common cold


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Establishing Cause-Effect Relationship


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Clinical efficacy in reducing common-cold

probiotic control PTotal symptom score 79.3 7.4 102.5 12.2 0.056Duration episode 7.0 0.5 8.9 1.0 0.045Days with fever 0.24 0.1 1.0 0.3 0.017


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CD8+ cytotoxic T lymphocytes


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64 15 19 19 0.035CD8+ cytotoxic T lymphocytes


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What is a biomarker?


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Validated biomarkers of the immune system

What is a biomarker?


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Increase in CD4 count in HIV + children

Excellent biomarker for the statusof the cellular immune system

Useless for healthy individuals

Biomarkers for the cellular immune system

Bi k f th h l i t


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Biomarkers for the humoral immune system

Albers R. et al, Br J Nutrition 2005;94:452-81

Ch ll h i


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Challenge the immune system

Challenge with either live or dead micro-organisms


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Challenge with live virus


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0 1 2 3 4 50

1

2

3

4

5

6

7

T o t a

l d a i l y s y m p t o m s c o r e

Study day

Benificial effects of probiotics and


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Benificial effects of probiotics andprebiotics on the human immune system:

Response to vaccination


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Antibody response to pneumococcal


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Antibody response to pneumococcal vaccination

Validated biomarker for response:

Specific antibody 0.35 g IgG/ml

Antibody response to pneumococcalvaccination

Benificial effects of probiotics and


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Benificial effects of probiotics andprebiotics on the human immune system:

Response to vaccination

Influenza and pneumococcal vaccination in order to Probe the function of the immune system Prevent infections; prevent disease



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Immune system


Malignancy


Allergic diseases


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Allergic diseases

Cows Milk Allergy


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Cow s Milk Allergy


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SCOring Atopic Dermatitis: SCORAD

Extent of dermatitisIntensity

ErythemaEdema/papulationOozing/crustingExcoriationLichenification

Quality of lifePruritisInsomnia

20%60%

20%

Mild 40

Extrinsic and Intrinsic Factors contribute to


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Mucosa,Epithelia

Nervoussystem

Gutmicrobiota

Immunesystem

GeneticEnvironment

Maternal-FetalInteraction

Clinical expressionof disease

M. Kalliomki, J-M Antoine, U Herz, GT Rijkers

JM Wells & A Mercenier (2010) J Nutrition 140, 713S

Development of Allergic diseases

Regulation by T lymphocytes


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TOO MUCH



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TOO MUCH

TOO LITTLE


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Reduction of eczema at 3 months


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-5

0

5

10

15

20

25

30

35

**

placebo Ecologic

PANDAB. bifidumB. lactisLc. lactis

% a

t o p i c e c z e m a

( 3 m o n t

h s )

L. Niers, R. Martin, G. Rijkers et al., Allergy 2009; 64: 1394-58


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Biomarkers for reduction of eczema?


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L. Niers, R. Martin, G. Rijkers et al., Allergy 2009; 64: 1394-58 and data unpublished

Total IgESpecific IgEEosinophils

CytokinesIL-4IL-5IL-13

-IFN

Probiotics Placebo4.41.3 3.80.8 IU/ml3/43 1/51 >0.35 IU/mlnd nd

0.40.3 0.10.1 pg/ml0.40.1 0.70.2 pg/ml2.01.0 0.90.3 pg/ml

5.94.6 0.30.3 pg/ml

NSNS

NSNSNSNS

Biomarkers for reduction of eczema?


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Selection of biomarkers

Validated?

In healthy children/adults?

Peer review scientific P i l t


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Peer review scientificliterature

Peer review regulatoryauthorities

Validated (and approved) biomarkers of


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Validated (and approved) biomarkers of response to vaccination

Clinical endpoints of infection(common cold, diarrhea)

Clinical endpoints of allergy(and autoimmune, inflammation etc)

[In vitro and experimental animals]

Immunity Health Claims


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Subterranean Homesick Blues, Bob Dylan


B fi i l ff t f bi tiImmunity Health Claims



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Get sick, get w ellHang around a ink wellRing bell, hard to tellIf anything is goin' to sellTry hard, get barredGet back, write brailleGet jailed, jump bail

Join the army, if you fail


Look out kidYou're gonna get hitBut users, cheatersSix-time losersHang around the theatersGirl by the whirlpoolLookin' for a new foolDon't follow leadersWatch the parkin' meters

Beneficial effects of probioticsImmunity Health ClaimsImmunity Health Claims

B fi i l ff t f bi tiImmunity Health Claims



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Look out kidYou're gonna get hitBut users, cheatersSix-time losersHang around the theatersGirl by the whirlpoolLookin' for a new fool

Don't follow leadersWatch the parkin' meters


Beneficial effects of probioticsImmunity Health Claims



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Look out kidYou're gonna get hitBut users, cheatersSix-time losersHang around the theatersGirl by the whirlpoolLookin' for a new fool

Don't follow leadersWatch the parkin' meters


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