The Journal of Nutrition
Nutrition and Disease
Early Dietary Intervention with a Mixture of
Prebiotic Oligosaccharides Reduces the
Incidence of Allergic Manifestations and
Infections during the First Two Years of Life1,2
Sertac Arslanoglu,3* Guido E. Moro,3Joachim Schmitt,4Laura Tandoi,3Silvia Rizzardi,3
and Gunther Boehm4,5
3Center for Infant Nutrition, Macedonio Melloni Hospital, University of Milan, Milan 20129, Italy;4Numico Research,
Friedrichsdorf 61381, Germany; and5Sophia Children’s Hospital, Erasmus University, Rotterdam 3015 GE, The Netherlands
A mixture of neutral short-chain galactooligosaccharides (scGOS) and long-chain fructooligosaccharides (lcFOS) has been
shown to reduce the incidence of atopic dermatitis (AD) and infectious episodes during the first 6 mo of life. This dual
protection occurred through the intervention period. The present study evaluated if these protective effects were lasting
beyondtheinterventionperiod.In aprospective, randomized,double-blind,placebo-controlleddesign,healthyterminfants
with a parental history of atopy were fed either a prebiotic-supplemented (8 g/L scGOS/lcFOS) or placebo-supplemented
(8 g/L maltodextrin) hypoallergenic formula during the first 6 mo of life. Following this intervention period, blind follow-up
continued until 2 y of life. Primary endpoints were cumulative incidence of allergic manifestations. Secondary endpoints
were number of infectious episodes and growth. Of 152 participants, 134 infants (68 in placebo, 66 in intervention group)
completed the follow-up. During this period, infants in the scGOS/lcFOS group had significantly lower incidence of allergic
manifestations. Cumulative incidences for AD, recurrent wheezing, and allergic urticaria were higher in the placebo group,
(27.9, 20.6, and 10.3%, respectively) than in the intervention group (13.6, 7.6, and 1.5%) (P , 0.05). Infants in the scGOS/
lcFOS group had fewer episodes of physician-diagnosed overall and upper respiratory tract infections (P , 0.01), fever
episodes (P , 0.00001), and fewer antibiotic prescriptions (P , 0.05). Growth was normal and similar in both groups. Early
dietary intervention with oligosaccharide prebiotics has a protective effect against both allergic manifestations and
infections. The observed dual protection lasting beyond the intervention period suggests that an immune modulating
effect through the intestinal flora modification may be the principal mechanism of action.J. Nutr. 138: 1091–1095, 2008.
Human milk oligosaccharides (HMO),6after lactose and lipids,
represent the third largest component in human milk (20–23 g/L
in colostrum and 12–14 g/L in mature milk). They are important
prebiotic potential and the direct interaction with the immune
cells (1–6). HMO are structurally very complex with a huge
diversity and so, identical structures are not available in infant
formulas (6–8). Searching for alternatives to mimic the prebiotic
effect of human milk, a prebiotic mixture of 90% short-chain
galactooligosaccharides (scGOS) and 10% long-chain fructooli-
gosaccharides (lcFOS) (IMMUNOFORTIS) has been developed
(9). Although these oligosaccharides are not identical to HMO,
studies in preterm (10) and term infants (11–13) have shown that
a formula supplemented with this prebiotic scGOS/lcFOS mix-
ture results in an intestinal microbiota similar to that found in
breast-fed infants. Because a balanced intestinal microbiota domi-
nated by bifidobacteria and lactobacilli is crucial for the expan-
sion and education of the immune system early in life (14,15), it
could be expected that such a prebiotic mixture might modulate
the immune system in bottle-fed infants.
Our hypothesis was that this mixture of prebiotic oligosaccha-
rides could mimic the immune modulatory function of HMO,
leading to a reduction in the incidence of allergic manifestations
on a prospective, randomized, double-blind, placebo-controlled
nutritional intervention design, we planned a series of prospective
trials addressing different outcomes at different time points.
1Supported by the European Union EARNEST (Early Nutrition Programming)
Project (FOOD-CT-2005-007036). Numico Research provided the scGOS/lcFOS
mixture utilized in this study.
2Author disclosures: S. Arslanoglu, G. E. Moro, L. Tandoi, and S. Rizzardi, no
conflicts of interest; G. Boehm is the Director of Infant Nutrition Research at
Numico Research; J. Schmitt is the Head of Research Cooperation at Numico
* To whom correspondence should be addressed. E-mail: email@example.com.
6Abbreviations used: AD, atopic dermatitis; HMO, human milk oligosaccharides;
lcFOS, long-chain fructooligosaccharides; scGOS, short-chain galactooligosac-
charides; URTI, upper respiratory tract infection.
0022-3166/08 $8.00 ª 2008 American Society for Nutrition.
Manuscript received 3 February 2008. Initial review completed 6 March 2008. Revision accepted 2 April 2008.
at Moldova, Republic of: ASNA Sponsored on June 2, 2013
The population consisted of healthy term infants with a
parental history of atopy and the intervention was early scGOS/
lcFOS supplementation (8 g/L of formula) during the first 6 mo
of life. The first trials addressed the cumulative incidence of
atopic dermatitis (AD) (16) and infections (17) during the inter-
vention period and showed that the mixture led to a significant
reduction in the incidence of AD and had a preventive effect
against infections during the first 6 mo of life.
We report here the results of a further study aimed at moni-
toring if these allergy and infection prevention effects are long
lasting. This is a 2-y follow-up trial with a double-blind follow-up
design evaluating the cumulative incidence of allergic manifesta-
tions,episodesofinfections,and growthduringthefirst2y oflife.
Study design. The study was planned as a randomized, double-blind,
placebo-controlled trial. Term infants with a parental history of atopy
received either prebiotic-supplemented (8 g/L scGOS/lcFOS) or placebo-
supplemented (8 g/L maltodextrin) hypoallergenic formula during the
first 6 mo of life (16). The study hypothesis was that the prebiotic-
supplemented formula could be protective against allergic manifesta-
tions and infections during the first 2 y of life. Infants were enrolled and
randomly assigned to 1 of the 2 study groups, scGOS/lcFOS or placebo,
according to a preprepared randomization numbers table. For this
purpose, the random permuted block method was used with a block size
of 4. For blinding, 2 trial formulas were coded by adding the suffix N or
O to the product name. Follow-up to the age of 2 y was performed by 2
investigators who were unaware of the formula assignments. Distribu-
tion of the formulas to the infants was done by the nurses who were not
involved in the first 6 mo of the study.
Subjects. Healthy term infants with a parentalhistory of atopic eczema,
allergic rhinitis, or asthma in either mother or father were eligible for the
study. In all cases, the parental diagnosis was based on a documented
physician’s certification. Inclusion criteria were: gestational age between
37 and 42 wk, birth weight appropriate for gestational age, and start of
formula feeding within the first 2 wk of life. According to the hospital’s
policy, breast-feeding was recommended to all mothers. The parents were
informed about the study at discharge from the maternity ward and were
asked to contact the hospital if they started formula feeding. The study
protocol was approved by the Ethical Committee of the Macedonio
Melloni Hospital, Milan, Italy. Informed written consent was obtained
from parents. Two hundred and fifty-nine term infants were enrolled and
206 infants completed the first 6-mo part of the study (16,17). Parents of
152 completers gave consent to participate for the 2-y follow-up trial.
Nutritional intervention. Infants whose mothers started formula feed-
ing within the first 2 wk of life were randomly assigned to be fed 1 of the
2 study formulas. The recipe of both formulas was based on a hypo-
allergenic formula with extensively hydrolyzed cow milk whey protein
(Aptamil HA). In the intervention group, this formula was supplemented
with 8 g/L scGOS/lcFOS (IMUNOFORTIS) and in the placebo group the
same formula was supplemented with 8 g/L maltodextrin (Glucodex 12).
Mixed breast- and bottle-feeding was accepted until wk 6 of life. When
the motherstarted formulafeeding according to the inclusioncriteria but
continued breast-feeding for more than 6 wk, the infant was excluded
from the study. Duration of feeding with the study formulas was 6 mo.
Weaning was startedin a standard way for all the infants in the study at 5
mo with fruit followed by weaning purees. Probiotic or prebiotic food
supplements were not allowed throughout this period.
Follow-up protocol. Data were collected through follow-up visits,
diaries written by parents, and telephone calls by trained personal.
Follow-up visits consisted of a detailed physical examination, evalua-
tion of growth, and structured interviews by the study physicians. These
visits were scheduled at 1, 2, 3, 4, 5, 6, 9, 12, 18, and 24 mo of age. Any
sign or symptom related to allergy (AD, wheezing episodes, and allergic
urticaria) and infection (fever, cough, runny nose, watery stools) was
recorded. Medical documents and reports were noted. Unscheduled
visits were conducted when the investigators were contacted by the fam-
ily regarding the occurrence of symptoms related to allergy or infections.
Diaries and telephone calls were used to collect the data between 2
scheduled visits and to increase the compliance. Parents were instructed
to record allergic and infectious symptoms, every episode of fever
($38.5?C), clinic visits, tests, physician’s diagnosis, prescription of med-
ications, particularly antibiotics, and were asked to contact the inves-
tigators and bring these reports and medical documents at each visit.
Endpoints and definitions. Primary endpoints were cumulative inci-
dence of allergic manifestations: AD, recurrent wheezing, and allergic
urticaria at 2 y of age.
AD was diagnosed accordingto the criteria described byHarrigan and
Rabinowitz (18) and Muraro et al. (19). The diagnosis of AD was
confirmedifthe following featureswere detected: pruritus, involvement of
the face, skull facial, and/or extensor part of the extremities, and a
minimal duration of the symptoms of 4 wk. Severity of AD was scored by
using the SCORAD index based on extension and intensity of the skin
symptoms,aswellasonthe subjective symptomsofpruritusandsleep loss
as recommended by the European Task Force on AD (20,21). The extent
of AD was determined by using the SCORAD figure for infants ,2 y.
Recurrent wheezing was defined as 3 or more physician-diagnosed
wheezing episodes (19). Allergic urticaria was defined as (22) 2 or more
episodes of itching eruptions or swelling with typical appearance
provoked by the same allergen.
Secondary endpoints were the number of infectious episodes and
growth. To define infectious episodes, 2 different criteria were used:
physician-diagnosed infections and episodes of fever ($38.5?C) wit-
nessed by the parents. The reason to select a second definition was to
have an objective criterion for the diagnosis of infection.
Physician-diagnosed infections included overall, upper respiratory
tract infections (URTI), lower respiratory tract infections, otitis media,
gastrointestinal infections, and urinary tract infections. Antibiotic pre-
scriptions were recorded separately to determine the infectious episodes
requiring antibiotic therapy.
Body weight and length were measured at each clinic visit by expe-
rienced nurses and the growth data were assessedat 12, 18, and 24 mo of
life. Birth data were derived from the birth records.
Statistical analysis. The data were analyzed on a per protocol basis.
Time-balanced randomization was performed with the software
RANCODE (IDV; seed numbers randomized by reaction time) with a
random permuted block size of 4. Sample size was calculated based on
analysis of the previous years’ incidence of AD in the hospital and
assuming an effect size similar to that reported for probiotics at that time
(16). Based on this assumption, 108 subjects per group completing the
protocol were calculated to provide a power of 80%. The study was
completed after a full 2-y enrollment period to exclude seasonal effects.
One-way ANOVA and t tests were used to compare continuous
variables between 2 treatment groups. When equality of variances were
not present, we used Mann-Whitney U nonparametric tests. Categorical
data were compared by using the chi-square test. Fisher’s exact test was
performed for the analysis. Differences were considered significant at
P , 0.05. Statistical analyses were performed using the SPSS 10.0 soft-
ware for Windows.
Parents of 152 infants agreed to participate in the follow-up
study. A total of 134 infants (68 in the placebo, 66 in the scGOS/
lcFOS group) completed the 2-y follow-up period (Fig. 1).
Baseline characteristics and demographic data of the completers
were similar (Table 1).
During the follow-up, the growth expressed as mean body
weight and length at 12, 18, and 24 mo was adequate and
similar in the placebo and intervention groups (data not shown).
The cumulative incidences of AD, recurrent wheezing, and
allergic urticaria were lower in the scGOS/lcFOS group (13.6,
1092Arslanoglu et al.
at Moldova, Republic of: ASNA Sponsored on June 2, 2013
7.6, 1.5%, respectively) than in the placebo group (27.9, 20.6,
and 10.3%, respectively; P , 0.05) (Fig. 2).
As previously mentioned, 2 different criteria were used to
define the infectious episodes for this study: physician-diagnosed
infections and fever episodes witnessed by the parents. The
number of overall infections was lower in the scGOS/lcFOS
group than in the placebo group as assessed by both physician-
diagnosed infections (P ¼ 0.01) and the number of fever epi-
sodes (P , 0.0001) (Table 2).
Infants in the scGOS/lcFOS group had fewer episodes of
infections (P ¼ 0.06). Similarly, infants in the intervention group
had fewer episodes of infections requiring antibiotic treatment
compared with infants in the placebo group (P , 0.05) (Table 2).
In a subgroup of 98 infants with a complete set of stool
samples, supplementation with scGOS/lcFOS resulted in a sig-
nificant increase in the number of bifidobacteria compared with
the placebo group at 6 mo (16). The median bifidobacteria count
as colony-forming units/g stool at 6 mo of life was 10.3 in the
scGOS/lcFOS group and 8.7 in the placebo group (P , 0.0001).
This is the first follow-up study, to our knowledge, showing that
an early dietary intervention results in dual prevention for
infection and allergy and that both effects last beyond the
intervention period. We have previously shown that prebiotic
oligosaccharides significantly reduce the incidence of AD (16)
and infections (17) in infants at high-risk for allergy during the
6-mo intervention period. The hypothesis of the present study
was that this observed dual preventive effect could last longer,
beyond the intervention period through the modulation of the
immune system. The rationale for this expectation was that the
dietary intervention started very early (within the first 2 wk of
life) and went on for 6 mo, a time corresponding to a critical
period of life when long-lasting effects can be induced (pro-
Confirming this hypothesis, the scGOS/lcFOS mixture led to
significant reductions in the cumulative incidence of allergic
manifestations (AD, recurrent wheezing episodes, and allergic
urticaria) and in the number of infectious episodes (overall,
URTI, infections requiring antibiotic therapy, fever episodes)
during 18 mo after the termination of oligosaccharide supple-
During the last decades, we have become aware of a dramatic
increase in allergic diseases throughout the world, a so-called
subjects throughout the study.
Flow chart showing enrollment and disposition of the
Baseline characteristics and demographic data of
subjects who completed the 2-y follow-up1
Gender ratio (male:female)
Birth weight, g
Mother's age, y
Atopy in the family, %
Vaginal delivery, %
Maternal smoking, %
Age at onset of day care, mo
Furred pets at home, %
3314 6 455
32.6 6 4.7
3282 6 505
33.6 6 4.9
1.4 6 0.8
13.1 6 4.1
1.4 6 0.7
11.7 6 4.2
1Values are means 6 SD or %.
end of 2-y follow-up period in the scGOS/lcFOS and placebo groups.
n ¼ 68 (placebo) or 66 (scGOS/lsFOS). *Different from placebo, P ,
0.05. Atopic dermatitis was diagnosed according to the criteria de-
scribed (18,19). Recurrent wheezing was defined as 3 or more
physician-diagnosed wheezing episodes (19). Allergic urticaria was
defined as 2 or more episodes of itching eruptions or swelling with
typical appearance provoked by the same allergen (22).
Cumulative incidence of allergic manifestations at the
Episodes of infections and fever during the 2-y
follow-up period in the scGOS/lcFOS
and placebo groups1
Overall (any kind of infection)**
Lower respiratory tract infections
Urinary tract infections
Infections requiring antibiotic prescriptions*
Fever episodes recorded by parentsz
5.9 6 4.1
3.2 6 2.2
1.3 6 0.8
0.7 6 1.2
0.6 6 0.9
0.1 6 0.5
2.7 6 2.4
3.9 6 2.5
4.1 6 3.1
2.1 6 1.8
0.9 6 1.1
0.5 6 1.0
0.4 6 0.7
0.0 6 0.0
1.8 6 2.3
2.2 6 1.9
1Values are means 6 SD. *Different from placebo, P , 0.05, **P ¼ 0.01,yP , 0.01,
zP , 0.0001.
Prebiotics and immunomodulation 1093
at Moldova, Republic of: ASNA Sponsored on June 2, 2013
‘‘epidemic of allergy.’’ In fact, recent data suggest that the
incidence of atopic disease in children with 1 atopic family
member has reached almost 50% by the age of 2 y (23). The
cumulative incidence of AD changes between 13–44% in the
literature (24). Moreover, Kuehni et al. (25) reported a signif-
icant increase in wheezing disorders in preschool children in
the UK. The etiology of allergic diseases is multifactorial. The list
of lifestyle-related factors that might be associated with this
epidemic of the century is long. Although there is no marker that
is capable with certainty to predict the development of allergic
disease later on, the family history remains the best predictor
(24). At this point, primary prevention in high-risk infants
becomes crucial as a public health priority. Recently among the
primary prevention measures (22,24–32) gut microbiota mod-
ifying agents, i.e. probiotics and prebiotics, offer promising
Evidence shows that differences in the gut microbiota com-
position during the neonatal period and early infancy precede
the development of atopy. Bjorkstein et al. (37) have demon-
strated that the presence of fewer bifidobacteria and lactobacilli
in the neonatal microbiota precedes the development of atopic
diseases. Recently, the KOALA Birth Cohort Study (38) revealed
that thepresence of Escherichia coli wasassociated with ahigher
risk of developing eczema, whereas colonization with Clostrid-
ium difficile was associated with higher risk of developing
eczema as well as recurrent wheeze and allergic sensitization.
Human milk is considered the gold standard nutrient in the
first 6 mo of life. It promotes a microbiota rich in bifidobacteria
and its oligosaccharides play an important role in establishment
of this health benefit promoting flora (prebiotic effect). Recently,
a prebiotic mixture of scGOS and lcFOS in a 9:1 ratio has been
designed for formula-fed infants (9) to provide a prebiotic effect
comparable to that of human milk. It has been demonstrated
that this mixture has prebiotic activities in infants (10–13) and
immunomodulatory effects in animal models (39,40). Also dur-
ing the 6-mo intervention period of this follow-up study, sup-
plementation with this mixture resulted in a significant increase
in the number of bifidobacteria compared with the placebo
There are only a few published follow-up studies addressing
the prevention of allergic disease in infants at high risk by means
of intestinal flora modification (33–36,41). In the first preven-
tion trial of Kalliomaki et al. (33), probiotics (Lactobacillus GG)
were given to the mothers of infants at high risk prenatally and
then to the infants for 6 mo. In the next trial conducted by
Kukkonen et al. (34), both probiotics (mothers plus infants) and
prebiotics (infants) were used as intervention. Both trials showed
a reduction in the cumulative incidence of AD by 2 y of age,
although the effect sizes were quite different (a reduction of 50%
in the first study and 20% in the latter). Our study is the first
follow-up trial in which prebiotic oligosaccharide intervention
has been applied alone and exclusively to the infants postnatally.
In this prevention trial of 134 high-risk infants, the cumulative
incidence of AD has been successfully reduced by .50% in 2 y
(27.9% in the placebo vs. 13.6% in the scGOS/lcFOS group).
This reduction is similar to thereduction obtained byKalliomaki
et al. (46% in the placebo and 23% in the intervention group).
AD is typically the first manifestation of the allergic disorder
followed by subsequent respiratory allergic disease (atopic
march) (42). In our study, the cumulative incidence of other
allergy-associated symptoms, like recurrent wheezing and aller-
gic urticaria, was also significantly lower in the sGOS/lcFOS
group compared with the placebo group. We think that the
3-fold reduction in the incidence of recurrent wheezing episodes
(20.6% in the placebo vs. 7.6% in the sGOS/lcFOS groups)
might have important clinical implications, because we used
very strict definition criteria (3 or more physician-diagnosed
episodes in 2 y). Recent literature underlines the importance of
recurrent early wheeze in the later development of asthma. Ly
et al. (43) showed in a group of 440 children with parental
history of allergy that the frequency of recurrent early wheeze
was 26.0% and was associated with a 4-fold increase in the odds
of asthma at 7 y of age. In this study, recurrent early wheeze was
defined as $2 reports of wheezing in the first 3 y of life. Very
recently it has been reported by Saglani et al. (44) that the
characteristic pathological features of adult asthma have already
been developed in preschool children with confirmed wheeze
between the ages of 1 and 3 y.
Our data show that the use of this prebiotic oligosaccharide
mixture (scGOS/lcFOS) also results in a significant reduction of
the total number of infections, respiratory tract infections, fever
episodes, and antibiotic prescriptions during the first 2 y of life.
Although we cannot determine the specific mechanism
through which this dual prevention occurred, it might be
through the modification of the intestinal flora. This interpre-
tation is also supported by the fact that a relationship between
allergic diseases and intestinal microbiota early in life has been
reported (45,46). As shown in this study, it is possible to have
fewer infections and allergic symptoms at the same time through
the bifidogenic modification of the intestinal flora soon after
birth. However, any potential direct effect of the studied
prebiotics on the immune cells and target receptors like lectins
(1,47,48) cannot be excluded.
We conclude that early nutritional intervention with prebi-
otic oligosaccharides seems to be effective in priming the infant’s
immune system in a balanced way, providing a substantial
protection both for allergy and infection. This dual effect can be
considered as a typical example of immunological program-
ming. When mother’s milk is not available, the supplementation
of formulas with prebiotic oligosaccharides early in life may
have promising clinical implications.
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