Prebiotic Effect in The Healthy Infant - Recent Update: Yvan - Vandenplas@uzbrussel - Be

Prebiotic effect
in the healthy infant recent update
yvan.vandenplas@uzbrussel.be
Outline of presentation
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
Manado prebiotic 2011
16-7-2011
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)
16-7-2011
The first few years in life is a vulnerable period, in which a childs

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

5
16-7-2011
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
16-7-2011
Poor immune system affects the Window of Opportunity for:
Physical Growth and Development

Under-nutrition
has negative impact

on physical growth2
High
incidence of
diarrhea &
infection
Poor
immune system
Infection
& diarrhea lead to appetite

loss, nutrient loss, malabsorption and
increased metabolism of energy &
nutrients1,2
Undernutrition
Repeated diarrhea
impairs weight &
height gains, and
physical
development1
Window of Opportunity
16-7-2011
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
High
incidence of
diarrhea &
infection
Poor
immune system
Under-nutrition
has negative impact

on cognitive
function2
Under-nutrition
Likely due to the compounded effects

of otitis media (middle ear infection) discomforts & poor hearing that
deter the learning process.
Repeated diarrhea
impairs cognitive
development1
Otitis media
affects language
and literacy skill
development3
Children with otitis
media have poorer
attention skills5
Window of Opportunity
16-7-2011
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 ???
16-7-2011

6. Conclusion
10
16-7-2011
The GUT: A Complex Organ

60 -70% of immune cells
Surface of approximately
300m2
100 million neurons
100 trillion bacteria

Gut Microbiota
11
Intestinal Flora Development
prepartal
birth
Oral inoculation
with maternal
intestinal/vaginal
flora
4 days
20 days
4-6 months
Dietary influence
Breast-fed:
Bifidobacteria-dominated flora
aseptic
Weaning:
Transition to adult-like
flora
Diverse flora
Formula-fed:
Diverse flora
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
13
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
16-7-2011
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)
[Gal( 1-]1- 4 3/4/6)Gal( 1-4)Glc

Lactose
10% lcFOS:
high molecular weight (long chain)

Fructo-OligoSaccharides
(fraction from chicory)
[Frc( 2-]n>8 1)Frc(
-1)Glc
Sucrose
Why is this Prebiotic Combination so Special ?

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

15
16-7-2011
Intestinal Flora
of Breast- and Formula-fed Infants
Formula-fed infant
100
% of total faecal micro-organisms
% of total faecal micro-organisms
Breast-fed infant
90
80
70
60
50
40
30
20
Bifidobacteria
90
E. coli
80
Bacteroides
70
60
50
40
30
20
10
10
0
100
10
15
Days
20
25
10
15
Days
20
25
According to Harmsen et al., 2000

16
16-7-2011
Reduction of potential pathogens

- Term Infants after 6 weeks-
Proportion of total bacteria [%]
18
16
Prebio Combination Formula (n=16)

Standard Formula (n=18)
p < 0.05
14
p < 0.05
12
10
p < 0.05
8
6
4
2
0
E. Coli
Clostridia
Eubacteria
Knol et al., 2003
17
16-7-2011
Distribution of the Lactobacillus Species (6 Weeks)
Breast-fed
scGOS/lcFOS
Formula
Standard
formula
Haarman. M & J. Knol. 2005. AEM (72): 2359
Distribution of the Bifidobacterium Species (6 weeks)
Breast-fed
scGOS/lcFOS
Formula
Standard
formula
Haarman. M & J. Knol. 2005 AEM (71):2318
Intestinal Flora Development
prepartal
birth
Oral inoculation
with maternal
intestinal/vaginal
flora
4 days
20 days
4-6 months
Dietary influence
Breast-fed:
aseptic
Weaning:
Transition to adult-like
flora
Diverse flora
GOS/FOS Formula-fed:
Effect of a whey-predominant starter formula containing

LCPUFAs and oligosaccharides (FOS/GOS) on GI comfort
Vivatvakin 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)
Hard stools
Soft stools
% bifidobacteria
Experimental
7.5
82.3
78.1
Control
0.7 %
90.8 %
63.7
BF
p
p<0.001
p<0.05
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 microbiota

of 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
22
16-7-2011
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
25
16-7-2011
Reduction of infections during the first 12 months of life

(intervention during the first 6 months of life)
overall infections
50
GIT-infections
URTI
Standard (n = 104)
Prebio Combination (n=102)
Standard (n = 104)
Standard (n = 104)
50
50
40
40
n=47
40
P < 0.01
30
20
30
20
n=21
10
10
30
n=30
P = 0.07
n=14
20
10
n=4
P = 0.18
n=1
0
Babies with 1 infection episode
0
Babies with 1 URTI episode
Babies with 1 GITI episode
Arslanoglu et al. (2007) J Nutr 137: 2420-2424

26
16-7-2011

recurrent URTI
diarrhea
50
Standard (n = 145)
Standard (n = 145)
50
antibiotic courses
Standardl (n = 145)
50
n=49
40
40
40
P < 0.05
30
n=34
P < 0.05
30
n=35
P < 0.05
30
n=30
20
20
20
n=19
n=17
10
10
10
Babies with 1 diarrhea episode
Babies with > 3 URTI episodes
Babies with >2 antibiotocs courses
prebiotics 2010
Bruzzese et al. (2006) JPGN 42: E95

27
16-7-2011

Overall # URTI epidsodes

per child
Overall # infection
episodes per child
Standard (n = 68)
5.9
Standard (n = 68)
Overall # antiobiotic
prescriptions per child
Standard (n = 68)
Oligosaccharide
Prebio
Combination (n=66)
Mixture (n=66)
P < 0.05
P < 0.01
3.3
P < 0.01
3
2.7
2.1
2
1.8
Arslanoglu et al. (2008) J Nutr 138 : 1091-1095

28
16-7-2011
Enteral supplementation with oligosaccharides decrease

serious infectious morbidity in preterm infants
Westerbeek 2010, AJCN 91 (3): 679-686

6. Conclusion
30
16-7-2011
Microflora and Development of Atopy

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
Colonisation with
Bifidobacteria at 3 weeks
Atopic
Non-atopic
180 x
Clostridia at 3 weeks
9.3 x
Ratio Bifidobacteria to Clostridia
107
107
610 x 107
P
< 0.11
3.3 x 107
< 0.05
= 0.03
Kalliomki et al., 2001
Relation between intestinal microflora and maturation of

human immunity to a non-atopic mode?
31
16-7-2011
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
36
p=0.014
30
P<0.001
24
18
12
23.1%
mean
(95% CI)
9.8%
6
0
mean
(95% CI)
Standard
(n=24/104)
Prebiotic
(n=10/102)
Bifodobacteria count (log cfu/g stool)
cumulative incidence of atopic dermatitis
Atopic Dermatitis and fecal bifidobacteria

in high-atopy risk Infants at age 6 months
18
15
12
P<0.001
10.28
8.65
median (IQR)
median (IQR)
3
0
Standard
(n=44)
Prebiotic
(n=50)
Moro G et al. (2006) Arch Dis Child 91: 814-819

33
16-7-2011
The protective effect of reduction of atopic dermatitis

lasts beyond the intervention period
30
p < 0.05
Cumulative incidence of
atopic dermatitis (%)
Scored by SCORAD index
20
HA formula with
GOS/lcFOS
(n=68)
25.0%
Control
HA formula
(n=66)
10
12.1%
0
Arslanoglu et al., 2007
Reduced incidence of atopic dermatitis during 24 months follow-up

of infants at risk of developing an allergy
after 6 months feeding a GOS/lcFOS supplemented HA formula
Reduction of further symptoms

20
20
p < 0.05
HA formula with
GOS/lcFOS (n=68)
10
Incidence [%]
Incidence [%]
p < 0.05
Control
HA formula
(n=66)
6.3%
HA formula with
GOS/lcFOS (n=68)
10
17.6%
Control
HA formula
(n=66)
0.0%
11.8%
Bronchial symptoms
Acute Allergic Cutaneous reactions
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
35
16-7-2011
Reduced occurrence of early atopic dermatitis because of immunoactive

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

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 dermatitis

van der Aa LB. Allergy 2011;66:170-7

6. Conclusion
40
16-7-2011
Alterations of bacterial communities (Dysbiosis) is

associated with diseases (IBD, IBS, allergy, obesity, ...)
Round et al Nature Rev Immunol, 2009; 9: 313-323
Bacteria Support Gut Barrier and Immune Function

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)
Composition and function of the Intestinal Flora

Health promoting functions
Harmful/pathogenic effects
Production of
toxins.
Diarrhoea /
obstipation
Infections
Liver damage
Cancer
Encephalopathy
Production of
carcinogens
Intestinal
putrefaction
Ps-Aeruginosa
Proteus
Inhibition of
growth of
exogenous and/or
harmful bacteria
Staphylococci
Clostridia
Veillonellae
Enterococci
E. coli
Lactobacilli
Streptococci
Eubacteria
Bifidobacteria
Bacteroides
Stimulation of
immune functions
Aid in digestion
and/or absorption
of food
ingredients/
minerals
Synthesis of
vitamins
11
Gibson, GR & Roberfroid, MB; 1994
43
Number/g faeces Log 10 scale
16-7-2011
Fecal secretory IgA is increased in healthy infants who receive a

formula with GOS/lcFOS
PAMJ Scholtens. J Nutr 2008;138:1141-7
Fecal sIgA
at age wk 8 and wk 26 of life
mg/g wet feces
2
1,6
P < 0.001
1,2
0,8
0,4
0
44
wk
wk
Standard (n=24)
Manado prebiotic
prebiotics
2010 2011
wk
wk
12
wk
16
wk
20
wk
26
Reference (n=31)
16-7-2011

6. Conclusion
45
Manado prebiotic
prebiotics
2010 2011
16-7-2011
Microbiota
Inflammation
46
Manado prebiotic
prebiotics
2010 2011
Immune system
16-7-2011
SUPPLEMENTATION OF INFANT FORMULA

WITH PROBIOTICS AND/OR PREBIOTICS: A SYSTEMATIC REVIEW
AND COMMENT BY THE ESPGHAN COMMITTEE ON NUTRITION
ESPGHAN Committee on Nutrition: C. Braegger, A. Chmielewska, T. Decsi; S. Kolacek,
W. Mihatsch, L. Moreno, M. Piecik; J. Puntis, R. Shamir, H. Szajewska, D. Turck, J. van Goudoever.
JPGN 2011;52:238-50
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.
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

48
Manado prebiotic
prebiotics
2010 2011
16-7-2011
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!
51
The combination of GOS/lcFOS induces

a beneficial immunoglobulin profile
in infants (age 6 months) at high risk for allergy
Total IgE
CMP-specific IgG1
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
Standard
HA formula
(n=35)
HA formula
with GOS/lcFOS
(n=33)
Standard
HA formula
(n=35)
HA formula
with GOS/lcFOS
(n=41)
Van Hoffen et al., 2008
The serum samples are from a subgroup of the Moro-Arslanoglu study
53
Manado prebiotic
prebiotics
2010 2011
total IgE, IgG1, IgG2 and IgG3, ~ no effect on IgG4

CMP-specific IgG1
DTP-specific Ig levels were not affected !
(hexavac vaccination was at age 3 months)
16-7-2011

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Prebiotic effect

in the healthy infant recent update

2. GI flora composition in infants

Manado prebiotic 2011

The burden of suboptimal breastfeeding in the US: a pediatric cost analysis.

Manado prebiotic 2011

The first few years in life is a

(e.g. weight & height gain)

Manado prebiotic 2011

The first few years in life is a vulnerable period, in which a childs

*otitis media = middle ear infection

Manado prebiotic 2011

Ulijaszek S. Transdisciplinarity in the

Manado prebiotic 2011

Poor immune system affects the Window of Opportunity for:

Physical Growth and Development

has negative impact

Manado prebiotic 2011

& diarrhea lead to appetite

Poor immune system affects the Window of Opportunity for:

Infection & diarrhea lead to appetite loss,

has negative impact

Likely due to the compounded effects

Manado prebiotic 2011

First few years of life

= Window of Opportunity and also the Vulnerable Period

??? How can a prebiotic combination

Manado prebiotic 2011

2. GI flora composition in infants

Manado prebiotic 2011

The GUT: A Complex Organ

100 million neurons

100 trillion bacteria

Intestinal Flora Development

Oligosaccharides in human milk

Unique for human milk

Manado prebiotic 2011

The Specific GOS/FOS Prebiotic Mixture:

low molecular weight (short chain)

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

high molecular weight (long chain)

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

Manado prebiotic 2011

Why is this Prebiotic Combination so Special ?

Extensive portfolio of experimental research and clinical studies

Manado prebiotic 2011

% of total faecal micro-organisms

% of total faecal micro-organisms

According to Harmsen et al., 2000

Manado prebiotic 2011

Reduction of potential pathogens

Proportion of total bacteria [%]

Prebio Combination Formula (n=16)

Manado prebiotic 2011

Distribution of the Lactobacillus Species (6 Weeks)

Distribution of the Bifidobacterium Species (6 weeks)

Manado prebiotic 2011

Intestinal Flora Development

Effect of a whey-predominant starter formula containing

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

Gastric transit time

Effect of a milk formula with prebiotics on the intestinal microbiota

RDBPC clinical trial, 140 infants (1-2 years)