prebiotik

Prebiotic effect in the healthy infant -recent update

[email protected]

Manado prebiotic 20112 16-7-2011

1. Window of opportunity

2. GI flora composition in infants

3. Prebiotic OS and infections

4. Prebiotic OS and allergy

5. Prebiotic OS and gut immune function

6. Conclusion

Outline of presentation

Manado prebiotic 2011

The burden of suboptimal breastfeeding in the US: a pediatric cost analysis. Bartick M. Pediatrics. 2010;125:e1048-56

Pediatric diseases for which the Agency for Healthcare Research and Quality

reported risk ratios that favored breastfeeding:

necrotizing enterocolitis, otitis media, gastroenteritis,

hospitalization for lower respiratory tract infections,

atopic dermatitis, sudden infant death syndrome,

childhood asthma, childhood leukemia, type 1 diabetes mellitus,

and childhood obesity.

If 90% of US families could comply with medical recommendations to breastfeed

exclusively for 6 months, the US would save $13 billion per year and prevent an

excess 911 deaths, nearly all of which would be in infants

($10.5 billion and 741 deaths at 80% compliance).


The first few years in life is a Window of Opportunity* for:

• Physical growth and development

(e.g. weight & height gain)

• Cognitive development

(e.g. semantic fluency, language, non-verbal learning,

attention, problem solving, IQ)

• Emotion and social development

(e.g. emotional control, behavioral adaptation, social interaction)

*A period of time in which suitable action can achieve success (critical periods)


• The first few years in life is a vulnerable period, in which a child’s

immature immune system is constantly exposed to

over one billion of germs per year.

• A child with a poor immune system will be more vulnerable to infection,

including respiratory tract infection, otitis media* and gastroenteritis

(causing diarrhea).

• A child with frequent infections and diarrhea will miss the window of

opportunity to develop his full potential.

*otitis media = middle ear infection


Ulijaszek S. Transdisciplinarity in the study of undernutrition-infection interactions. Coll Antropol. 1997 Jun;21(1):3-15.

Key Takeout:

Infections can lead to appetite lose, malabsorption and elevated metabolism of energy and other nutrients


High

incidence of

diarrhea &

infection

Poor immune system affects the Window of Opportunity for:

Physical Growth and Development

• Under-nutrition has negative impact on physical growth2

• Repeated diarrhea impairs weight & height gains, and physical development1

• Infection & diarrhea lead to appetite loss, nutrient loss, malabsorption and increased metabolism of energy & nutrients1,2

Under-nutrition

Window of Opportunity

Poor immune system


High

incidence of

diarrhea &

infection

Poor immune system affects the Window of Opportunity for:

Cognitive Development

• Infection & diarrhea lead to appetite loss, nutrient loss, malabsorption and increased metabolism of energy & nutrients1,2

Under-nutrition

Window of Opportunity

Poor immune system

Likely due to the compounded effects of otitis media (middle ear infection) -discomforts & poor hearing that deter the learning process.

• Under-nutrition has negative impact on cognitive function2

• Repeated diarrhea impairs cognitive development1

• Otitis media affects language and literacy skill development3

Children with otitis media have poorer attention skills5


First few years of life= Window of Opportunity and also the Vulnerable Period

Poor immune system (with frequent infection & diarrhea) affects the window of opportunity

??? How can a prebiotic combination have a role in immune-modulation ???







6. Conclusion


Manado prebiotic 2011 11

The GUT: A Complex Organ

60 -70% of immune cells

Surface of approximately

300m2

100 million neurons

100 trillion bacteria

“ Gut Microbiota”


Intestinal Flora Development

birth 4 days 4-6 months

Oral inoculation

with maternal

intestinal/vaginal

flora

20 days

Dietary influence

Formula-fed:

Diverse flora

Weaning:

Transition to adult-like

flora

Breast-fed:

Bifidobacteria-dominated flora

Diverse flora

prepartal

aseptic

After Stark & Lee, 1982; Heine, 1998; Harmsen et al., 2000


Oligosaccharides in human milk

Br J Nutr 1999; Ped Clin N Am 2001; J Clin Gastroenterol 2004

Unique for human milk

Partially digested,

act as prebiotic stimulating bifidogenic flora

At least 130 different structures

Changing composition between mothers,

during lactation, during breastfeeding

Some resemble epithelial pathogen receptors


The Specific GOS/FOS Prebiotic Mixture:

Mimicking Size, Linkage, partly Building Blocks and Prebiotic function of HMOS

90 % scGOS: low molecular weight (short chain)

Galacto-OligoSaccharides

(enzymatic from lactose)

10% lcFOS: high molecular weight (long chain)

Fructo-OligoSaccharides

(fraction from chicory)

[Gal( 1-]1- 4 3/4/6)Gal( 1-4)GlcLactose

[Frc( 2-]n>8 1)Frc( -1)GlcSucrose


GOS

Comprise the most natural “lactose-derived” oligosaccharide

Showing the lowest incidence of side effects (gas production /

bloating) compared to similar short-chain oligosacharides

lcFOS

Comprise a more slowly fermentable substrate to allow

fermentation all over the full length of the large intestine

Extensive portfolio of experimental research and clinical studies

Why is this Prebiotic Combination so Special ?


Intestinal Flora

of Breast- and Formula-fed Infants

Breast-fed infant

0

10

20

30

40

50

60

70

80

90

100

0 5 10 15 20 25

Days

% o

f to

tal fa

ec

al m

icro

-org

an

ism

s

Formula-fed infant

0 5 10 15 20 25

Days

0

10

20

30

40

50

60

70

80

90

100

% o

f to

tal fa

ec

al m

icro

-org

an

ism

s

Bifidobacteria

E. coli

Bacteroides

According to Harmsen et al., 2000


Knol et al., 2003

Reduction of potential pathogens

- Term Infants after 6 weeks-

0

2

4

6

8

10

12

14

16

18

E. Coli Clostridia Eubacteria

Prebio Combination Formula (n=16)

Standard Formula (n=18)

p < 0.05

p < 0.05

p < 0.05

Pro

po

rtio

n o

f to

tal b

ac

teri

a [

%]


Distribution of the Lactobacillus Species (6 Weeks)

Breast-fed scGOS/lcFOS Standard

Formula formula

Haarman. M & J. Knol. 2005. AEM (72): 2359


Distribution of the Bifidobacterium Species (6 weeks)

Breast-fed scGOS/lcFOS Standard

Formula formula

Haarman. M & J. Knol. 2005 AEM (71):2318


Intestinal Flora Development

birth 4 days 4-6 months

Oral inoculation

with maternal

intestinal/vaginal

flora

20 days

Dietary influence

GOS/FOS Formula-fed:

Bifidobacteria-dominated flora !

Weaning:

Transition to adult-like

flora

Breast-fed:

Bifidobacteria-dominated flora

Diverse flora

prepartal

aseptic


Effect of a whey-predominant starter formula containing

LCPUFAs and oligosaccharides (FOS/GOS) on GI comfortVivatvakin B. Asia Pac J Clin Nutr. 2010;19:473-80

Single-centre, DBPCR trial in full-term infants (n=144)

1 to 4 months old

Group of exclusively breast-fed infants: reference (n=80)

Experimental Control BF p

Hard stools 7.5 0.7 % p<0.001

Soft stools 82.3 90.8 % p<0.05

% bifidobacteria 78.1 63.7 74.3

Gastric transit time 59.6 61.4 55.9

Intestinal transit time (data not shown) closer to that of the breast-fed group.

Growth parameter values were similar for all groups.


Effect of a milk formula with prebiotics on the intestinal microbiotaof infants after an antibiotic treatment.Brunser O. Pediatr Res. 2006;59:451-6

RDBPC clinical trial, 140 infants (1-2 years) after a 1-wk amoxicillin (50 mg/kg/d) for acute bronchitis

3 weeks; >500 mL/day formula with prebiotics (Prebio 1 70/30 inulin/FOS; 4.5 g/L) or control Fecal samples: day -7 (beginning AB)

day 0 (end of AB / before formula)day 7 and day 21

fluorescent in situ hybridization (FISH) and flow cytometry

• Amoxicillin total fecal bacteria (<.00001) but E. coli (<0.02) • Bifidobacteria prebiotic control

Day 0 8.17 + 1.46 8.22 + 1.24 Day 7 8.54 + 1.20 7.95 + 1.54

0.014 NS• Lactobacilli similar tendency // other bacteria unaffected


A randomized, double-blind, controlled trial of the effect of prebiotic

oligosaccharides on enteral tolerance in preterm infants (ISRCTN77444690).Modi N. Pediatr Res. 2010;68:440-5.

• After covariate adjustment,

significant benefit from trial formula in principal secondary outcome(proportion of time between birth and 28 d/discharge that a

total milk intake of ≥ 150 mL/kg/d was tolerated)

with increasing infant immaturity

(2.9% improved tolerance for a baby born at 28-wk gestation and

9.9% at 26-wk gestation; p < 0.001)

but decreased or no benefit in babies >31-wk gestation.

• Prebiotic supplementation appears safe

and may benefit enteral tolerance in the most immature infants.


A specific prebiotic mixture added to starting infant formula has

long-lasting bifidogenic effects.Salvini FJ. Nutr. 2011 (in press)

Prebiotic supplementation resulted in

more fecal bifidobacteria (P < 0.0001)

and lactobacilli (P = 0.0044)

compared with the placebo group.

These differences between the groups

were maintained during the

second half of the first year

without any prebiotic supplementation.







6. Conclusion


Manado prebiotic 201126 16-7-2011Arslanoglu et al. (2007) J Nutr 137: 2420-2424

Standard (n = 104)

Prebio Combination (n=102)

0

10

30

40

20

50

n=47

n=21

Standard (n = 104)

0

10

30

40

20

50

n=30

n=14

Standard (n = 104)


0

10

30

40

20

50

n=4n=1

P = 0.07

P = 0.18

P < 0.01

overall infections URTI GIT-infections


Babies with ≥ 1 infection episode Babies with ≥ 1 URTI episode Babies with ≥ 1 GITI episode

Reduction of infections during the first 12 months of life

(intervention during the first 6 months of life)


prebiotics 2010

27 16-7-2011

Bruzzese et al. (2006) JPGN 42: E95

Babies with ≥ 1 diarrhea episode

Standard (n = 145)


0

10

30

40

20

50

n=34

n=17

Babies with > 3 URTI episodes

Standard (n = 145)

0

10

30

40

20

50

n=35

n=19

Standardl (n = 145)


0

10

30

40

20

50

* *

Babies with >2 antibiotocs courses

n=49

n=30

P < 0.05

P < 0.05

P < 0.05

diarrhea recurrent URTI antibiotic courses





Arslanoglu et al. (2008) J Nutr 138 : 1091-1095

Oligosaccharide

Mixture (n=66)

Overall # infection

episodes per child

Overall # URTI epidsodes

per child

Overall # antiobiotic

prescriptions per child

Standard (n = 68)


1

2

4

5

3

65.9

4

Standard (n = 68)

0

1

3

4

2

5

3.3

2.1

Standard (n = 68)

0

1

3

4

2

5

1.8

P < 0.01

P < 0.01 P < 0.05


2.7





Enteral supplementation with oligosaccharides decrease

serious infectious morbidity in preterm infants

Westerbeek 2010, AJCN 91 (3): 679-686







6. Conclusion



Analysis of intestinal flora of 76 infants at high risk of atopy at 3

weeks and 3 months of life

Infants grouped at age of 12 months as atopic if at least one

positive skin prick test

Kalliomäki et al., 2001

Microflora and Development of Atopy

Colonisation with Atopic Non-atopic P

Bifidobacteria at 3 weeks-

180 x 107

+610 x 107 < 0.11

Clostridia at 3 weeks+

9.3 x 107-

3.3 x 107 < 0.05

Ratio Bifidobacteria to Clostridia - + = 0.03

Relation between intestinal microflora and maturation of

human immunity to a non-atopic mode?


A mixture of prebiotic oligosaccharides reduces the incidence of

atopic dermatitis during the first six months of age.Moro G. Arch Dis Child. 2006;91:814-9


Prebiotic

(n=10/102)

Standard

(n=24/104)

cu

mu

lati

ve

in

cid

en

ce

of

ato

pic

de

rma

titi

s

0

6

12

18

24

30

36

p=0.014

Moro G et al. (2006) Arch Dis Child 91: 814-819

Prebiotic

(n=50)

Standard

(n=44)

Bif

od

ob

ac

teri

a c

ou

nt

(lo

g c

fu/g

sto

ol)

0

3

6

9

12

15

18

P<0.001

10.28

8.65

9.8%

23.1%

mean

(95% CI)

median (IQR)mean

(95% CI) median (IQR)

Atopic Dermatitis and fecal bifidobacteria

in high-atopy risk Infants at age 6 months

P<0.001


The protective effect of reduction of atopic dermatitis

lasts beyond the intervention period

Arslanoglu et al., 2007

Reduced incidence of atopic dermatitis during 24 months follow-upof infants at risk of developing an allergy

after 6 months feeding a GOS/lcFOS supplemented HA formula

Cu

mu

lative

in

cid

en

ce

of

ato

pic

de

rma

titis (

%)

0

10

30

20

HA formula with

GOS/lcFOS

(n=68)

Control

HA formula

(n=66)

p < 0.05Scored by SCORAD index

12.1%

25.0%


Reduction of further symptoms

Arslanoglu, Moro et al 2007

Reduced incidence of further symptoms during 24 months follow-up

of infants at risk of developing an allergy

fed 6 months with a GOS/lcFOS supplemented HA formula

0

10

20

p < 0.05

6.3% 17.6%

Inc

ide

nc

e [

%]

0

10

20

p < 0.05

0.0% 11.8%

Bronchial symptoms Acute Allergic Cutaneous reactions

Inc

ide

nc

e [

%]

HA formula with

GOS/lcFOS (n=68)

Control

HA formula

(n=66)

HA formula with

GOS/lcFOS (n=68)

Control

HA formula

(n=66)


Study population

1187 healthy term infants without family history of atopy

1130 infants intention-to-treat analysis

IMMUNOFORTIS+ : 414

control: 416

Breastfeeding: 300

835 infants per protocol

IMMUNOFORTIS+ : 292

control: 300

breastfeeding: 243

Reduced occurrence of early atopic dermatitis because of immunoactive

prebiotics among low-atopy-risk infants.Grüber C. J Allergy Clin Immunol. 2010;126:791-7


Results



• Safety of IMMUNOFORTIS

Safety confirmed

• Febrile episodes

Lower in IMMUNOFORTIS + group at 6 months

No difference at 12 months

Low incidence in both groups

Dilution effect of IMMUNOFORTIS +

during 2nd half year of life


Results

Atopic dermatitis

At 12 months lower incidence of AD

In control group:

earlier occurrence of AD




Synbiotics prevent asthma-like symptoms in infants with atopic dermatitisvan der Aa LB. Allergy 2011;66:170-7







6. Conclusion



Alterations of bacterial communities (Dysbiosis) is

associated with diseases (IBD, IBS, allergy, obesity, ...)

Round et al Nature Rev Immunol, 2009; 9: 313-323


• Gut microbiota help support gut barrier function:

↑ Mucin production

↓ Permeability

• Gut microflora help support the adaptive immune response:

Generate IgA activity (humoral)

Balance in T helper cell subclasses (cellular)

Bacteria Support Gut Barrier and Immune Function


Composition and function of the Intestinal Flora

Harmful/pathogenic effects

Lactobacilli

Eubacteria

Bifidobacteria

Health promoting functions

Ps-Aeruginosa

Proteus

Staphylococci

Veillonellae

Enterococci

E. coli

Streptococci

Bacteroides

Clostridia

Production of

toxins.

Diarrhoea /

obstipation

Infections

Liver damage

Cancer

Encephalopathy

Production of

carcinogens

Intestinal

putrefaction

Inhibition of

growth of

exogenous and/or

harmful bacteria

Stimulation of

immune functions

Aid in digestion

and/or absorption

of food

ingredients/

minerals

Synthesis of

vitamins

2

4

8

Number/g faeces Log 10 scale

11

Gibson, GR & Roberfroid, MB; 1994

Manado prebiotic 2011prebiotics 201044 16-7-2011

0

0,4

0,8

1,2

1,6

2

wk 1wk 4

wk 8wk 12

wk 16wk 20

wk 26

Standard (n=24) Prebio Combination (n=22) Reference (n=31)

mg/g wet feces

Fecal sIgA

at age wk 8 and wk 26 of life

P < 0.001

Fecal secretory IgA is increased in healthy infants who receive a formula with GOS/lcFOSPAMJ Scholtens. J Nutr 2008;138:1141-7







6. Conclusion



Inflammation

Microbiota

Immune system


• Based on this review, available scientific data suggest that the

administration of probiotic- and/or prebiotic-supplemented formula

to healthy infants is safe with regards to growth and adverse effects.

• The safety and clinical effects of one product should not be

extrapolated to other products.

SUPPLEMENTATION OF INFANT FORMULA

WITH PROBIOTICS AND/OR PREBIOTICS: A SYSTEMATIC REVIEW

AND COMMENT BY THE ESPGHAN COMMITTEE ON NUTRITIONESPGHAN Committee on Nutrition: C. Braegger, A. Chmielewska, T. Decsi; S. Kolacek,

W. Mihatsch, L. Moreno, M. Pieścik; J. Puntis, R. Shamir, H. Szajewska, D. Turck, J. van Goudoever.

JPGN 2011;52:238-50


Prebiotics in infant nutrition

Effect on GI flora composition and development

Effect on GI metabolites (pH, SCFA)

Prevention of adhesion of pathogens

Tolerance and safety

Induction of specific and unspecific immune response

and maturation of immune system

Reducing infections and allergic manifestations

Concept of Immune-Programming

Prebiotics are not generic / GOS/lcFOS is specific


Cost-effectiveness model for a specific mixture of prebiotics in The Netherlands.Lenoir-Wijnkoop I. Eur J Health Econ. 2010

Infant formula with prebiotics (IMMUNOFORTIS(®))

additional cost of 51 € /year

increase in Quality Adjusted Life Years (QALY) of 0.108,

when compared with no prebiotics.

Incremental cost-effectiveness ratio (ICER) of 472 €.

This study shows that the favourable health benefit of the use of a

specific mixture of prebiotics results in positive short- and long-term

health economic benefits.

In addition, this study demonstrates that the use of infant formula with

a specific mixture of prebiotics is a highly cost-effective way of

preventing atopic dermatitis in The Netherlands.


Probiotics and prebiotics in pediatrics.Thomas DW. Pediatrics. 2010;126:1217-31

Prebiotics are supplements or foods that contain a nondigestible food

ingredient that selectively stimulates the favorable growth

and/or activity of indigenous probiotic bacteria.

Human milk contains substantial quantities of prebiotics.

… there may be some long-term benefit of prebiotics for the

prevention of atopic eczema and common infections in healthy infants.

Confirmatory well-designed clinical research studies are necessary.


MY FOOD MATTERS,

THANK YOU!


Van Hoffen et al., 2008

The serum samples are from a subgroup of the Moro-Arslanoglu study

total IgE, IgG1, IgG2 and IgG3, ~ no effect on IgG4CMP-specific IgG1

DTP-specific Ig levels were not affected !(hexavac vaccination was at age 3 months)

Total IgE CMP-specific IgG1

HA formula

with GOS/lcFOS

(n=33)

Standard

HA formula

(n=35)

Data represent individual

results and median of

the placebo group (n=43) and

the GOS/lcFOS group (n=41)

** p<0.01; * p<0.05

HA formula

with GOS/lcFOS

(n=41)

Standard

HA formula

(n=35)

The combination of GOS/lcFOS induces a beneficial immunoglobulin profile

in infants (age 6 months) at high risk for allergy

prebiotik

Documents

prebiotic os

prebiotic effect

nutrientsmanado prebiotic

immune function6

appetite loss

infection interactions

childs immature immune

nutrient loss