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Prebiotic effect in the healthy infant -recent update
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).
Manado prebiotic 20114 16-7-2011
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)
Manado prebiotic 20115 16-7-2011
• 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
Manado prebiotic 20116 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
Manado prebiotic 20117 16-7-2011
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
Manado prebiotic 20118 16-7-2011
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
Manado prebiotic 20119 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 ???
Manado prebiotic 201110 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 11
The GUT: A Complex Organ
60 -70% of immune cells
Surface of approximately
300m2
100 million neurons
100 trillion bacteria
“ Gut Microbiota”
Manado prebiotic 2011
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
Manado prebiotic 201113 16-7-2011
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
Manado prebiotic 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)
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
Manado prebiotic 201115 16-7-2011
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 ?
Manado prebiotic 201116 16-7-2011
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
Manado prebiotic 201117 16-7-2011
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 [
%]
Manado prebiotic 2011
Distribution of the Lactobacillus Species (6 Weeks)
Breast-fed scGOS/lcFOS Standard
Formula formula
Haarman. M & J. Knol. 2005. AEM (72): 2359
Manado prebiotic 2011
Distribution of the Bifidobacterium Species (6 weeks)
Breast-fed scGOS/lcFOS Standard
Formula formula
Haarman. M & J. Knol. 2005 AEM (71):2318
Manado prebiotic 2011
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
Manado prebiotic 2011
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.
Manado prebiotic 201122 16-7-2011
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
Manado prebiotic 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.
Manado prebiotic 2011
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.
Manado prebiotic 201125 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 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)
Prebio Combination (n=102)
0
10
30
40
20
50
n=4n=1
P = 0.07
P = 0.18
P < 0.01
overall infections URTI GIT-infections
Prebio Combination (n=102)
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)
Manado prebiotic 2011
prebiotics 2010
27 16-7-2011
Bruzzese et al. (2006) JPGN 42: E95
Babies with ≥ 1 diarrhea episode
Standard (n = 145)
Prebio Combination (n=136)
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)
Prebio Combination (n=136)
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
Prebio Combination (n=136)
Reduction of infections during the first 12 months of life
(intervention during the first 6 months of life)
Manado prebiotic 201128 16-7-2011
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)
Prebio Combination (n=66)
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
Prebio Combination (n=66)
2.7
Prebio Combination (n=66)
Reduction of infections during the first 24 months of life
(intervention during the first 6 months of life)
Manado prebiotic 2011
Enteral supplementation with oligosaccharides decrease
serious infectious morbidity in preterm infants
Westerbeek 2010, AJCN 91 (3): 679-686
Manado prebiotic 201130 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 201131 16-7-2011
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?
Manado prebiotic 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
Manado prebiotic 201133 16-7-2011
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
Manado prebiotic 2011
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%
Manado prebiotic 201135 16-7-2011
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)
Manado prebiotic 2011
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
Manado prebiotic 2011
Results
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
• 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
Manado prebiotic 2011
Results
Atopic dermatitis
At 12 months lower incidence of AD
In control group:
earlier occurrence of AD
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
Manado prebiotic 2011
Synbiotics prevent asthma-like symptoms in infants with atopic dermatitisvan der Aa LB. Allergy 2011;66:170-7
Manado prebiotic 201140 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
Alterations of bacterial communities (Dysbiosis) is
associated with diseases (IBD, IBS, allergy, obesity, ...)
Round et al Nature Rev Immunol, 2009; 9: 313-323
Manado prebiotic 2011
• 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
Manado prebiotic 201143 16-7-2011
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
Manado prebiotic 2011prebiotics 201045 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 2011prebiotics 201046 16-7-2011
Inflammation
Microbiota
Immune system
Manado prebiotic 2011
• 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
Manado prebiotic 2011prebiotics 201048 16-7-2011
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
Manado prebiotic 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.
Manado prebiotic 2011
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.
Manado prebiotic 201151
MY FOOD MATTERS,
THANK YOU!
Manado prebiotic 2011
Manado prebiotic 2011prebiotics 201053 16-7-2011
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