dr. anang.pkb bali_18 juli 2009_short version_role of prebio

8/3/2019 Dr. Anang.pkb Bali_18 Juli 2009_short Version_role of PREBIO

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Role of Prebiotics inRespiratory Immunity

Anang Endaryanto

Division of Allergy Immunology Department of Child HealthFaculty of Medicine - University of AirlanggaDr. Soetomo General Hospital


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What is immunity? (1)

Doan et. al.2008. Lippincotts Illustrated Reviews: Immunology


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Pathogens

Viruses

Parasites

Fungi

Proteins

mechanical defencee.g. skin, mucosa, mucus layer

chemical defencee.g. SCFA, acidic pH

biological defencehealthy flora prevents growth

of pathogens

immunological defence

e.g. antibodies, cytokines,white blood cells,macrophages


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Immune response = f (a) (b) (c) (d) (e)

a= immunogen stimuli

b= DC subsetc= recognition receptor

d= microenvironment

e= cytokines


Science 2001;293: 251-6


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What are major tasks of the immunesystem ?

1. Defence against pathogens: bacteria, viruses,

parasites, fungi

2. Assistance in anti-cancer responses

3. Removal of foreign / non-self compounds

4. Inhibition self-reactive / auto-reactive

responsiveness [Impairment of auto-immunity

(SLE, MS, RA,)]

5. Inhibition over-activity/allergy


Garssen J, 2009. Immune Modulating Effects of Prebiotic Carbohydrates


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How does the immune systemperform the major tasks ?

DCs

Th0Th1/Th17 Th2

AllergyResistance to infections

APC

By immune regulation



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What is the task of immune regulation?

Th0Th1/Th17 Th2

APC

Immune regulation

Th1/Th2 paradigm

Allergy

Antibody-mediatedautoimmunity

Resistance to intracellularinfections

Anti-cancer

Delayed typehypersensitivity reactions

Resistance toextracellular infections

Tolerance

T-cell mediatedautoimmunity

Graft rejection


f i l i f il


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If immune regulation failure,what happen?

Th0Th1/Th17 Th2

APC Allergy



Anti-cancer



Tolerance


Graft rejection

Immune regulation

Th1/Th2 paradigm


f i l i f il


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Th0Th1/Th17 Th2

APC Allergy



Anti-cancer



Tolerance


Graft rejection

Immune regulation

Th1/Th2 paradigm



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What is the goal of immune regulation?

Immune regulationThe extended Th1/Th2 paradigm

IFN-IL-12

IL-17IL-22

IL-4IL-5IL-13

IL-10TGF-

Th1 Th2Th17 Treg


If i l i f il


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Th1 , Th2 , Th1/Th2 Th1

Th2 (type I allergy)Th2 Th2 Th1 Th1 ?Th1 Th1

Th1 , Th2

Immune disorders diseases relation

HIV

COPD

Allergies

Asthma

Atopic eczema

Coeliac disease

Cystic Fibroses

Cancer

Elderly

Infants



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Immune disorders diseases relation

Hyperimmune- responsiveness:

Allergy

Autoimmunity

Chronic inflammatory diseases

Hypo immune- responsiveness:

Infections

Tumors/metastasis

Role in metabolic disorders/ syndrome X/ obesity

Role in neurological disorders: Autism, Alzheimer, Depression, Hyperactivity Syndrome, ...


h i h f l


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What is the consequence of naturalimbalance of immune system?

Immune disorders : Natural imbalance

Pregnancy and neonates

Th2 directed immune system: cytokines down regulate

cellular-immunity (Th1) > no rejection of the fetus and ormother tissues

After birth

Development of their own healthy Th1/ Th2 balanced immunesystem

Th 1 Th 2

Normal

Pregnancies

Recurrent

MiscarriagesFailure

CD 69+IL 2TNF TNF

CD 94+IL 4IL 5IL 10

Archives of Disease in Childhood 2004;89:97-102


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How does the Th1/Th2 balancedimmune system develop?

Th1 and Th2 activity as a function of age

years0 1 2 5 10 40 50 60 70 80 90

Th 1 Th 2

Genes

Hygiene

Drugs

Diets

Stress

Hormones



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RespiratorySystem

Respiratory Immunity


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Common Mucosal Immune System


S h ti t ti f i h t i i th i


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Schematic representation of immune homeostasis in the airway mucosa


Cantana A, 2008. Pediatric Allergy, Asthma & Immunology 1st ed : p728


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Where is the most active areaof immune regulation ?

Y

Y

Granulocyte

Macrophage / Monocyte

Dendritic cell

T Lymphocyte(Th1, Th2, Th3, Tr, ...)

B Lymphocyte / Antibodies

Natural Killer Cell

Epithelial cell

Bone marrow

Lymph nodes

Spleen

Thymus

Organs Cells

60 70 % of immune cells in the gastro- intestinal tract

Neurons, nerves


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What is the natural source of immuneregulator?

Field J Nutr 2005

Anti-microbial compounds Immune developmentImmunoglobiuines: sIgA, SIgG, compounds

SIgM MacrophagesLactoferrin, lactoferrin B and H NeutrophilsLysozyme LymphocytesLactoperoxidase CytokinesNucleotide-hydrolizing Growth factors

Antibodies Hormones-casein and -lactalbumin Milk peptidesHaptocorrin Long-chain polyunsaturatedMucins fatty acidsLactadherin NucleotidesFree secretory component Adhesion moleculesOligosaccharides and pre-

biotics Anti-inflammatory compoundsFatty acids Cytokines: Il-10 and TGFMaternal leukocytes and Il-1 receptor anatagonist

Cytokines TNF and Il-6 receptorssCD14 sCD14Complement and complement Adhesion molecules

receptors Long-chain polyunsaturated-defensin-1 fatty acidsToll-like receptors Hormones and growth factorsBifidus factor OsteoprotegerinTolerance/priming compounds Long-chain polyunsaturated

Cytokines: Il10 and TGF fatty acidsAnti-idiotypic antibodies Hormones and growth factors

Oligosaccharides

Compounds with immunological

properties in human milk

Th t ti l h i f i


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The potential mechanisms of immunemodulation by orally applied prebiotics.

THE OLD CONCEPT

Potential mechanisms of immune modulation

by orally applied non-digestible carbohydrates

ProbioticsPrebiotics

Prebiotics vs Probiotics

Roberfroid MB, Gibson GR, 2008. Handbook of Prebiotics

Th i l h i f i


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THE NEW CONCEPT

Major role for antigen-presenting cells

oligosaccharides

Th t ti l h i f i


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THE NEW CONCEPT

Paul Vos et al.,Critical Reviews Immunology, 2007

Potential mechanisms of immune modulation

by orally applied non-digestible carbohydrates


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Evidence 1:The potential mechanisms ofimmune modulation by orally applied prebiotics.Supplementation with oligosaccharides stimulate growth of bifidobacteria

and lactobacilli in the intestine

0.8g/100ml

(n=27)

0g/100ml(n=33)

0.4g/100ml(n=30)

log10of

CFU/gwetfaeces

(median,IQR)

log10of

CFU/gwetfaeces

(median,IQR)

0.8g/100ml

(n=27)

0g/100ml(n=33)

0.4g/100ml(n=30)

2

34

5

6

7

89

10

11

12

Reference range(IQR) ofbreastfedinfants (n=15)

10

0

12

3

4

5

67

8

9

Reference range

(IQR) ofbreastfed infants(n=15)

LactobacillusBifidus

Group differenceaccording to Mann-Whitney U-test: *p


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Evidence 2:The potential mechanisms ofimmune modulation by orally applied prebiotics.

scGOS/lcFOS increases the faecal sIgA level during the first 6months of life

P. Alliet et al., J. Pediatric Gastroenterology Nutr. 2007, 44 (ESPGHAN)

A. Bakker-Zierikzee et al., Pediatric Allergy Immunol 2006; 17: 134-140

P. Scholtens et al., J Nutr 2008; 138: 1141-1147

0

100

200

300

400

500

600

700

800

sIgA g/g faeces after 26 weeks

control

scGOS/lcFOS

breastmilk

p


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Control

G/lcF/l

vP

0

10

20

30

40

50

60

70

P


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lcFOS stimulates NO2 production by murine macrophages

Jeurink et al, unpublished observations

Medium 0 0.02 0.1 0.5 2.5 5 12.50

10

20

30

40

50

60

lcFOS/scFOS (mg/ml) + IFN-

lcFOS

scFOS

NO2

- production(uM)

E id Th i l h i f


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TLR9 ligand supports a regulatory Th1 type effector response;potential new synbiotic concepts

Contro

l

TLR2

TLR

4

TLR9

Contro

l

TLR2

TLR

4

TLR9

10 010 110 2

10 010 110 2

**

10 3

10 4

10 5

10 3

10 4

10 5

I

FN-(

pg/mL)

TNF-

(pg/m

L)

Con

trol

TLR2

TLR4

TLR9

Con

trol

TLR2

TLR4

TLR9

10 0

10 1

*

10 0

10 1

*

**

10 2

10 3

10 4

10 2

10 3

10 4

IL-10(pg/mL) IL

-6(pg/mL)

Kivit et al: submitted april 2009


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Evidence 6:The potential mechanisms of immunemodulation by orally applied prebiotics.

scGOS/lcFOS stimulates TLR9 induced IFN- production byhuman blood cells in co-culture systems with human gut

epithelial cells

Kivit et al: submitted april 2009

Control

scGOS/lcFO

S

TLR4

TLR9

TLR4+

scGOS/lcFO

S

TLR9+

scGOS/lcFO

S10010

1102103

104

*** *

***

**

IFN-(

pg/mL)


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scGOS/lcFOS affects Th1/Th2via DC/T-cell interaction

Ratio IFN-/IL-4(positive cells)

Control

GOS/lcFOS

**

0,0

1,0

2,0

3,0

4,0

5,0

6,0

Stimulation ofanti-allergic profile

Wh i h f i l


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What is the new concept of potentialmechanisms of immune modulation by

orally applied prebiotics?

Immune skewing

Microbes TLRs

Oligos. C-type lect.DC-sign

!


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What is the role of FOS & GOSprebiotics in the child immunity ?

GOS

FOS GOS/lcFOS can affect systemicimmunity (Th1/Th2/Treg)

There is synergy betweendifferent types of

oligosaccharidesNot all oligosaccharides affect the

immune system

What about improved resistanceto infections ?

What about reduced risk for IgE

mediated allergy?


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Evidence 1:Defence against pathogens.

Vaccination study

Blood samplePrimary influenza

immunization

Blood sampleBooster influenza

immunization

Study parameters:

DTH

Influenza specific antibodytiters

Ex-vivo lymphocyte restimulation

0 7 14 302821-20

Start dietaryintervention

DTHEnd

Vos et al. International Immunopharmacology 2006; 6: 1277-1286


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GOS/lcFOS improves vaccination

0

50

100

150

Earswelling(10

-3m

m)

Vos et al. International Immunopharmacology 2006; 6: 1277-1286



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Infectious virus detection in C57BL/6J liver

0

20

40

60

80

100

120

0 2 4 6

Time postinfection (days)

Positiv

eplaqueassay(%) Control

Oligo

Oligosaccharides decrease MCMV load in vivo



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Healthy infants

GA37 -42 weeks

BW appropriate

for GA

Sample342 infants

Improved

Not improved

Not improved

Improved

12 months

Standard formula +0.4 g/100 ml scGOS/lcFOSper 100 ml (n=169)

Control :Standard formula

P Population

C Comparator

OOutcomes

I Interventions

Incidence1. acute diarrhoea

2. upper& lower RTI3. use of antibiotics,4. number of hospital

admissions

Open, placebo-controlled, randomised, prospective study

Bruzzese et al., 2009,

Clinical Nutrition, in press


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pre-term infants

GA < 32

BW 1500 gram

Sample324 preterminfants

Improved

Not improved

Not improved

Improved

27 days

Breast milk or Standard formula

+ 1.5 g/kg/day

sc GOS /lcFOS/ AOS (n=54)

Control :Breast milk or Standard

formula

P Population

C Comparator

OOutcomes

I Interventions

Primary outcome:

serious infectionmorbidity

Sepsis

Meningitis

Pyelonephritis

Pneumonia

Open, placebo-controlled, randomised, prospective study

Westerbeek et al., 2009,

submitted to ESPR Enteral supplementation with oligosaccharides decreaseserious infectious morbidity in preterm infants


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Protective effect on infectious episodesin High-Risk infants at 6 months

Arslanoglu et al, 2007, J .Nutr. 137: 2420-2424

0

10

20

30

40

50

All Infections URTI

infec

tiousepidsode

s

placebo

GOS/lcFOS

p=0.01

trend,

p=0.07

E id 6


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Evidence 6:Inhibition over-activity/allergy

Non-

sens

Sens

P


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GOS/lcFOS impairs IgE levels

P


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Early dietary intervention with a mixture of prebiotic oligosaccharides

reduce the incidence of allergic manifestations

during the first 2 years of life

Arslanoglu et al., 2008, J. of Nutr. 138:1091-1095

Evidence 9: Defence against pathogens &


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Infants (FH+ > 1)

GA : 37- 42

BW appropriate for GA

Sample1187healthyinfants

Improved

Not improved

Not improved

Improved

12 mos

Non-hydrolyzedformula + 0.8gGOS/FOS/AOS per100ml (n=416)

1. Non-hydrolyzedformula (n=414)

2. Exclusive BF(n=300)

P Population

C Comparator

OOutcomes

I Interventions 1st Outcome:Incidence of

Atopic

dermatitis

2nd Outcome:

Number of febrileepisodes with a peak

rectal temp 38.5C

Evidence 9:Defence against pathogens &inhibition over-activity/allergy

Eisses et al., 2008,

Arch Dis Child. 93:A133-A135

Double blind, placebo controlled, randomized prospective study


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Summary

Pathogens

Viruses

Parasites

Fungi

Proteins

mechanical defencee.g. skin, mucosa, mucus layer

chemical defencee.g. SCFA, acidic pH

biological defencehealthy flora prevents growth

of pathogens

immunological defencee.g. antibodies, cytokines,

white blood cells,macrophages

Non-digestibleoligosaccharides

(GOS/lcFOS)

Doan et al 2008Summary


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Doan et. al. 2008.Lippincotts IllustratedReviews: Immunology

GOS/lcFOS

GOS/lcFOS

GOS/lcFOS

GOS/lcFOS

GOS/lcFOS

GOS/lcFOS

GOS/lcFOS

Summary


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... What isthe role of FOS & GOS prebiotics

in the respiratory immunity ?

Immune response = f (a) (b) (c) (d) (e)

a= immunogen stimuli

b= DC subset

c= recognition receptor

d= microenvironment

e= cytokines

FOS & GOSPrebiotics


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dr. anang.pkb bali_18 juli 2009_short version_role of prebio

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