WO2013062402A1

WO2013062402A1 - Allergy treatment with non- digestible oligosaccharide

Info

Publication number: WO2013062402A1
Application number: PCT/NL2011/050721
Authority: WO
Inventors: Günther Boehm; Guido MORO; Frank WIENS
Original assignee: N.V. Nutricia
Priority date: 2011-10-24
Filing date: 2011-10-24
Publication date: 2013-05-02
Also published as: CN104039175A; EP2770854A1

Abstract

The present invention relates to the treatment of subjects in order to reduce the incidence and or severity of allergic disease and/or manifestations in subjects during (early) childhood. The present inventors have found that the administration of certain non-digestible oligosaccharides, especially lc-FOS and/or sc-GOS, during infancy, as secondary intervention in subjects who develop allergy, especially atopic dermatitis, produces a reduction in the incidence and/or severity of allergic disease and/or manifestations later in life, i.e. far beyond the intervention period. Hence, one aspect of the present invention concerns a the treatment of an infant that develops allergy or atopic dermatitis before the age of 6 months, for reducing the incidence of allergic diseases and/or manifestation in said individual during (early) childhood, said treatment comprising administering a composition comprising non-digestible oligosaccharides to said infant.

Description

ALLERGY TREATMENT WITH NON- DIGESTIBLE OLIGOSACCHARIDE Field of the Invention

The present invention relates to reducing the incidence and or severity of allergic disease and/or manifestations in subjects during (early) childhood. More in particular, the invention entails the use of non-digestible oligosaccharides, especially lc-FOS and/or sc-GOS, during infancy, as secondary intervention in subjects who develop allergy, especially atopic dermatitis, during infancy, so as to reduce the incidence and or severity of allergic disease and/or manifestations in subjects during (early) childhood.

Background of the Invention

Over the past several decades, Atopic diseases, including atopic dermatitis (also known as eczema), allergic rhinitis and asthma, have become more frequent in the Western societies, a phenomenon also called "epidemic of allergy". Atopic diseases now affect approximately 20% of the population in the developed countries. Atopic disease is generally classified into 3 sequential phases: infantile, childhood, and adult, each with characteristic physical findings. Atopic diseases can have a tremendous impact on the quality of life of patients. It also creates a great financial burden for both the family and society.

Atopic dermatitis is the commonest chronic cutaneous disease in the first years of life. Atopic dermatitis is often the first manifestation of allergic diseases. Literature data show a progression from atopic dermatitis to other atopic diseases later in life. Progression of infant allergy to atopic diseases such as atopic dermatitis, allergic rhinoconjunctivitis, wheezing and finally asthma is defined in the art as "allergic march" or "atopic march". The cutaneous manifestations of atopy often represent the beginning of the atopic march. On the basis of several longitudinal studies, approximately half of atopic dermatitis patients will develop asthma and two thirds will develop allergic rhinitis. Epicutaneous sensitization has been thought to be responsible. It is now well-established that atopic dermatitis in the first 3 months is a risk factor for aeroallergen sensitization at 5 years. The risk increases with a positive family history for atopic diseases. One study showed that seventy-seven per cent of children with two atopic parents and early atopic dermatitis were sensitized against aeroallergens at 5 years. Although these risk factors were also significantly associated with the manifestation of allergic airway disease, the positive predictive value for this outcome at age 5 years was not yet as high, i.e. 50%. In atopic disease management and research, a distinction can usually be made between interventions that aim to avoid the onset of the allergic march ("primary prevention/intervention") and interventions that attempt to modulate the progression of the atopic march ("Secondary prevention/intervention"). So far, research has focused mainly on primary prevention, i.e. to shape and optimize early immune development and, in doing so, override other aspects of risk. Such interventions are aimed at a population that is still healthy, but is at risk of the disease. Unfortunately, all predictors investigated so far are insufficiently sensitive and specific. Therefore, possible preventive measures should be recommended only if they are applicable to the whole population, present no risk, and are low cost.

Kukkonen et al. ("Probiotics and prebiotic galacto-oligosaccharides in the prevention of allergic diseases: a randomized, double-blind, placebo-controlled trial", J Allergy Clin Immunol 2007; 119(1): 192- 195) describe a study amongst 1223 pregnant women carrying high-risk children, who used a probiotic preparation or a placebo for 2 to 4 weeks before delivery. Their infants received the same probiotics plus galacto- oligosaccharides (n 5 461) or a placebo (n 5 464) for 6 months. Probiotic treatment showed no effect on the incidence of all allergic diseases by the age 2 years. A preventive effect of probiotics on atopic eczema at age 2 was shown however.

Kuitunen et al. ⁽^'Airway inflammation in probiotic-treated children at 5 years ", Pediatric allergy and immunology 2011; 22(2): 249-51) describe a study amongst 1223 pregnant mothers carrying children at increased risk for allergy on the effects of probiotics. Of the 1018 intention-to-treat infants, 160 were randomized to have their FENO (Fractional exhaled nitric oxide) measured at age 5. In the probiotic group, from 36th wk of gestation, mothers took twice daily Lactobacillus rhamnosus GG, L. rhamnosus LC705, Bifidobacterium breve Bb99 and Propionibacterium freudenreichii ssp. shermanii JS in capsules. Their newborn infants received the same probiotics plus 0.8 g galacto-oligosaccharides once daily for 6 months after birth. Treatment during the first 6 months of life had no effect on airway inflammation at the age of 5 years measured by FENO. In these same infants, a preventive effect of probiotics on atopic eczema at age 2 was shown. However, the effect had disappeared by the age of 5.

Kukkonen et al. ⁽^'Probiotics prevent IgE- associated allergy until age 5 years in cesarean-delivered children but not in the total cohort", J Allergy Clin Immunol 2009;123:335-4 L> describes a placebo controlled study amongst 1223 mothers with infants at high risk for allergy who received a probiotic mixture (2 lactobacilli, bifidobacteria, and propionibacteria) or placebo during the last month of pregnancy. Their infants received the probiotic mixture from birth until the age of 6 months. Infants also received a prebiotic galactooligosaccharide or placebo. At the age of 5 years, the cumulative incidence of allergic disease (eczema, food allergy, allergic rhinitis and asthma) and IgE sensitization was evaluated. Frequencies of allergic and IgE-associated allergic disease and sensitization in the probiotic and placebo groups were similar: 52.6% versus 54.9% and 29.5% versus 26.6%, respectively, and 41.3% in both. No significant difference appeared in frequencies of eczema (39.3% vs 43.3%), atopic eczema (24.0% vs 25.1%), allergic rhinitis (20.7% vs 19.1%), or asthma (13.0% vs 14. P/o) between groups. It was concluded that no allergy-preventive effect extending to the age of 5 years was achieved with perinatal supplementation to high-risk mothers and children.

The ETAC (Early Treatment of the Atopic Child) was a prospective study of 817 infants 1-2 years of age, which had atopic eczema and a family history of atopy. These infants were treated with cetirizine (0.25 mg/kg, twice daily) or placebo. In the subset of children sensitized to pollen or dust mites, there was a 50% reduction in the development of asthma symptoms compared to the placebo group. The overall analysis failed to reach statistical significance though. As will be understood by those skilled in the art, secondary intervention is of particular interest because it is extremely difficult to identify the at risk subjects before the first manifestations of atopic disease become noticeable. Secondary intervention, as stated before, should be aimed at (early) reversal of the allergic phenotype in subjects already sensitized so as to prevent or modulate further progression of the atopic march.

It is an objective of the present invention to provide such treatment for infants developing manifestations of atopic disease during the first months of life, which is effective far beyond the intervention period. It is in particular an object of the invention to provide effective treatment which is applicable to the whole population of atopic infants, presenting no risk and is low cost

Summary of the Invention

The present inventors have found that the administration of certain non-digestible oligosaccharides to an infant that develops atopic dermatitis or allergy before the age of 6 months produces a reduction in the incidence of allergic disease and/or manifestations at the age of 5 years.

Without wishing to be bound by theory, it is considered by many that the positive effect on atopic dermatitis is cause through an effect on the intestinal microbiota of the infant. Modification of this microbiota, e.g. the increase of bifidobacteria and lactobaccili, is needed to induce the positive effects on allergy.

The present inventors have now found that the administration of non-digestible oligosaccharides in a group of infants who developed atopic dermatitis in the first 6 months of life produces positive effects on allergic disease and/or manifestation later in life. This is very surprising for several reasons. It was surprising to observe that administration of non-digestible oligosaccharides in a first 6 months of life has an effect several years later in life, exactly in the population which developed atopic dermatitis during infancy. It was found that positive results could be obtained even in subjects that developed atopic dermatitis during infancy in spite of having been administered non-digestible oligosaccharides.

The appending example describes the results of 5 y follow-up study on (i) the cumulative incidence of allergic manifestations during 5 y, and (ii) the prevalence of allergic and persistent allergic manifestations at 5 y. The example shows that a positive effect can be achieved in subjects that developed atopic dermatitis during infancy and that the positive effect persists up to the age of 5 years. The effect is not caused by a direct effect of oligosaccharides, as the subjects in treatment and control groups received distinct treatment, i.e. with the non-digestible oligosaccharide composition of the invention, only during the first months or first one or two years of life. More in particular, at the age of 5, the children in the treatment group had not been treated with the non-digestible oligosaccharide composition of the invention anymore for at least two or, most likely, at least 3 years.

Hence, one aspect of the present invention concerns a the treatment of an infant that develops allergy or atopic dermatitis before the age of 6 months, for reducing the incidence of allergic diseases and/or manifestation in said individual during (early) childhood, said treatment comprising administering a composition comprising non- digestible oligosaccharides to said infant.

Another aspect of the invention concerns the use of non-digestible oligosaccharide in the manufacture of a composition for the treatment of an infant that develops allergy or atopic dermatitis before the age of 6 months, for reducing the incidence of allergic diseases and/or manifestation in said individual during (early) childhood, said treatment comprising administering the composition to said infant.

Yet, another aspect of the invention concerns a composition comprising non-digestible oligosaccharide for use in the treatment of an infant that develops allergy or atopic dermatitis before the age of 6 months, for reducing the incidence of allergic diseases and/or manifestation in said individual during (early) childhood, said treatment comprising administering the composition to said infant. Detailed description of the Invention

The invention defined above and certain preferred aspects and embodiments thereof are described in more detail in the following sections.

For a proper understanding of this document and its claims, it is to be understood that the verb "to comprise" and its conjugations are used in its non-limiting sense to mean that items following the word are included, but items not specifically mentioned are not excluded. In addition, reference to an element by the indefinite article "a" or "an" does not exclude the possibility that more than one of the element is present, unless the context clearly requires that there be one and only one of the elements. The indefinite article "a" or "an" thus usually means "at least one". Subjects to be treated in accordance with the invention

The present invention entails the treatment of infants. As used herein, the term "infant", unless otherwise specified, refers to human subjects aged 0-36 months of age. In a preferred embodiment of the invention the subject to be treated is an infant not more than about one year of age. Particular embodiments of the invention entail the treatment of subjects of less than 12 months of age, preferably less than 6 months of age.

In one embodiment of the invention, the infant to be treated develops or has developed allergy or atopic dermatitis during the first year of life. In a further embodiment of the invention, the infant to be treated develops or has developed allergy or atopic dermatitis within the first 6 months from birth. In a further embodiment, the infant to be treated develops or has developed allergy or atopic dermatitis within 3 months from birth.

As described herein before it was entirely unexpected that infants that already have developed allergy or atopic dermatitis before treatment with non-digestible oligosaccharides is commenced or infants that develop atopic dermatitis in spite of prior treatment with non-digestible oligosaccharides benefit from (further) treatment with non-digestible oligosaccharide, i.e. in terms of reduced severity and/or incidence of allergic manifestations later in life, particularly at the age of 5 years. Hence, in an embodiment of the invention, the infant to be treated is an infant that already has developed allergy or atopic dermatitis at the time of treatment, particularly atopic dermatitis. Furthermore, in an embodiment of the invention, the infant to be treated is an infant that has developed allergy or atopic dermatitis after prior treatment with non- digestible oligosaccharides.

Medical indications

As stated herein before, the present invention entails the treatment of a subject as defined in the foregoing section, in order to reduce the incidence and/or severity of allergic diseases and/or manifestations in early childhood and childhood.

The term "allergic disorder" generally refers to a disease state or syndrome whereby the body produces an immune response which is strongly related to exposure to environmental antigens, said immune response typically involving IgE antibody production. Such an immune response evokes allergic symptoms such as itching, sneezing, coughing, respiratory congestion, rhinorrhea, skin eruptions and the like, as well as severe reactions, such as asthma attacks. The term "allergic manifestations" is used to more loosely refer to symptoms, effects and conditions that are the result of or related to allergic disease. Examples of allergic diseases and disorders which can be treated by the methods of this invention include, but are not limited to, drug hypersensitivity, allergic rhinitis, bronchial asthma, ragweed pollen hayfever, anaphylactic syndrome, urticaria, angioedema, atopic dermatitis, erythema nodosum, erythema multiforme, Stevens Johnson Syndrome, cutaneous necrotizing venulitis, bullous skin diseases, wheezing, allergy to food substances and insect venom-induced allergic reactions, as well as any other allergic disease or disorder.

In one particularly preferred embodiment of the invention, the treatment is for reducing the incidence and/or severity of atopic dermatitis in early childhood or childhood. The term early childhood preferably refers to a human in the age of 4-6 years. Atopic dermatitis is considered a specific form of eczema. In one particularly preferred embodiment of the invention, the treatment is for reducing the incidence and/or severity of wheezing in early childhood or childhood. As used herein the term 'wheezing' refers to the occurrence of a high-pitched, whistling sound when smaller airways are narrowed. This narrowing may occur for various reasons and is usually associated with atopic or allergic diseaese, although other causes can exist, such as viral infection. There are two main forms of presentation depending upon onset and age acute onset of wheezing in an infant and recurrent or persistent wheeze. The present invention in particular entails the treatment for reducing the incidence and/or severity of wheezing, especially recurrent or persistent wheezing, particularly associated with atopic disease.

In one particularly preferred embodiment of the invention, the treatment is for reducing the incidence and/or severity of allergic rhinoconjunctivitis in early childhood or childhood.

Atopic dermatitis, wheezing and allergic rhinoconjunctivitis, in certain subjects, may be associated components of the same condition. Not every component has to be present at the same time, but subjects may be prone to all of these three related conditions. Hence, in an embodiment of the invention, the treatment of the invention is for reducing the severity and incidence of atopic dermatitis, wheezing and allergic rhinoconjunctivitis in early childhood or childhood.

As will be understood by those skilled in the art, the term 'reducing the incidence and or severity of , generally stated, means that the treatment has the purpose of somehow bringing about a significant improvement in the quality of life in early childhood and/or childhood, as compared to non-treated subjects. This improvement may result from a reduction in the number of periods during which subjects experience inconvenience or burden as a consequence of allergic disease, from a shortening of the duration of such periods, and/or from amelioration of the inconvenience or burden experienced during such periods, or a combination of two or all of these effects. The expression thus also encompasses the complete absence of any period during which the subject experiences manifestations of allergic disease during early childhood and/or childhood, as well as the complete absence of allergic disease during early childhood and/or childhood. As will be clear from the foregoing, the treatment aims at achieving an effect in the subject during early childhood or childhood. In an embodiment, the invention entails treatment of a subject to accomplish any or all of the above described effects at the age of above 3, 4, 5, 6, or 7 years. Furthermore, the present invention typically entails the treatment of a subject to accomplish any or all of the above described effects at the age of below 10, 9, 8 or 7 years. At this age the subject typically is not receiving the treatment anymore. Preferably, at this age, the subject has not received any specific treatment with non-digestible olisaccharides anymore for at least 1, 2 or 3 years.

Thus, the present treatment specifically aims to achieve a long-term effect, which does not imply that an immediate or short-term effect does or does not occur.

The occurrence of this long-term effect is assumed to relate to what is known as the 'atopic march' or 'allergic march', meaning that allergic manifestations or diseases infnacy, early childhood, childhood and even adulthood may be related in such a way that immunological developments during infancy at least in part determine the occurrence of allergic disease and/or manifestations later in life. Accordingly, in atopic disease management, a distinction can be made between interventions that aim to avoid the onset of this atopic march and interventions that attempt to modulate the progression of the allergic or atopic march. The present invention typically aims to achieve the latter. One particularly preferred embodiment entails the treatment for modulating the progression of the atopic march in a subject as defined in the foregoing sections, especially in a subject that develops or has developed atopic dermatits during the first six months of life.

The present invention may result in the immediate or short-term relieve of atopic dermatitis in infants that had developed atopic dermatitis prior to treatment, but the invention is not particularly limited in this respect. The present invention in any case encompasses an embodiment wherein the treatment does not result in prevention, curing, suppression or disappearance of atopic dermatitis during infancy, e.g. during the first two years after birth, during the first year after birth, or during the first six months after birth. Non-digestible oligosaccharides

The present composition comprises a non-digestible or non-digestible oligosaccharide, which preferably stimulates the growth of the intestinal lactic acid producing bacteria, particularly Bifidobacteria and/or the Lactobacilli.

The term "oligosaccharide" as used in the present invention refers to saccharides with a degree of polymerization (DP) of 2 to 250, preferably a DP 2 to 100, more preferably 2 to 60, even more preferably 2 to 10. If the oligosaccharide with a DP of 2 to 100 is included in the present composition, this includes compositions which contain oligosaccharides with a DP between 2 and 5, a DP between 50 and 70 and a DP of 7 to 60.

"Degree of polymerisation" or "DP" refers to the total number of saccharide units in an oligo- or polysaccharide chain. The "average DP" refers to the average DP of oligosaccharides or polysaccharide chains in a composition, without taking possible mono- or disaccharides into account (which are preferably removed if present). The average DP of a composition is used to distinguish between compositions. In addition the % saccharide units, such as the % glucose and % fructose units, in a composition are distinguishing.

The term "non-digestible oligosaccharide" as used in the present invention refers to oligosaccharides which are not or only partially digested in the intestine by the action of acids or digestive enzymes present in the human upper digestive tract (small intestine and stomach) but which are fermented by the human intestinal flora. For example, sucrose, lactose, maltose and maltodextrins are considered digestible. Preferably the non-digestible oligosaccharide is a non-digestible neutral oligosaccharide. The term "neutral oligosaccharide" as used in the present invention refers to oligosaccharides wherein more than 75% of the saccharides units are selected from the group consisting of glucose, fructose, galactose, mannose, ribose, rhamnose, arabinose, and xylose, preferably more than 85%, more preferably more than 95%, even more preferably more than 99%. Preferred neutral oligosaccharides are transgalacto-oligosacharides and fructo-oligosaccharides. Preferably the present non-digestible oligosaccharide is a prebiotic oligosaccharide. The term "prebiotic oligosaccharide" refers to a non-digestible oligosaccharide that beneficially affects the host by selectively stimulating the growth and/or activity of one or a limited number of probiotic bacterial species in the colon.

Preferably the present non-digestible oligosaccharide is soluble. The term "soluble" as used herein, when having reference to a polysaccharide, fiber or oligosaccharide, means that the substance is at least soluble according to the method described by L. Prosky et al, J. Assoc. Off. Anal. Chem. 71, 1017-1023 (1988).

Preferably the present composition comprises at least one non-digestible oligosaccharide selected from the group consisting of galacto-oligosaccharides, non- digestible dextrins, xylo-oligosaccharides, arabino-oligosaccharides, gluco- oligosaccharides (including gentio-oligosaccharides and cyclodextrins), chito- oligosaccharides, fuco-oligosaccharides, manno-oligosaccharides, isomalto- oligosaccharides fructo-oligosaccharides (including inulin), galactomanno- oligosaccharides, glucomanno-oligosaccharides, and arabinogalacto-oligosaccharides; more preferably at least galacto-oligosaccharides and/or fructo-oligosaccharides, most preferably at least galacto-oligosaccharides.

Preferably the present composition comprises at least one non-digestible oligosaccharide selected from the group consisting of galacto-oligosaccharide, fucosylactose, sialyllactose, fructooligosaccharide.

The term "fructo-oligosaccharide" as used herein refers to a non-digestible polysaccharide carbohydrate comprising a chain of at least 2 β-linked fructose units, with a DP of 2 to 250, preferably 7 to 100, more preferably 20 to 60. Preferably inulin is used. Inulin is available under the tradename "Raftilin HP^®", (Orafti). The average DP of the present fructo-oligosaccharide is preferably at least 7, more preferably at least 10, preferably below 100. The fructo-oligosaccharide used preferably has the (majority of) fructose units linked with a β(2— »1) linkage. Other terms for fructooligosaccharides include inulin, fructopolysaccharide, polyfructose, fructans and oligofructose. The present composition preferably comprises fructo-oligosaccharides with a DP of 2 to 100.

Non-digestible dextrins refer to digestion-resistant (malto)dextrins or digestion- resistant polydextrose which preferably have a DP of 10 to 50, preferably between 10 and 20. The non-digestible dextrins preferably comprise a(l— >4), a(l— >6) glucosidic bonds and 1—2 and 1—3 linkages Non-digestible dextrins are for example available under the tradename "Fibersol 2^®" from Matsutami Industries or Litesse^® from Danisco.

The present inventors found that galacto-oligosaccharides can be advantageously used in the present composition, because these oligosaccharides where particularly effective in stimulating the growth of Bifidobacteria. Hence, in a preferred embodiment the present composition comprises galacto-oligosaccharides. The term "galacto- oligosaccharide" as used herein refers to a non-digestible oligosaccharide, wherein at least 30% of the saccharide units are galactose units, preferably at least 50%, more preferably at least 60%. The present composition preferably comprises galacto- oligosaccharides with a DP of 2-100, more preferably a DP of 2-10. Preferably the saccharides of the galacto-oligosaccharide are β-linked, as is the case in human milk oligosaccharides.

Preferably the present composition comprises a galacto-oligosaccharide selected from the group consisting of transgalacto-oligosaccharides, lacto-N-tetraose (LNT) and lacto-N-neotetraose (neo-LNT). In a particularly preferred embodiment the present method comprises the administration of transgalacto-oligosaccharide ([galactose]_n- glucose; wherein n is an integer between 1 and 60, i.e. 2, 3, 4, 5, 6, 59, 60; preferably n is 2, 3, 4, 5, 6, 7, 8, 9 and/or 10). Transgalacto-oligosaccharides (TOS) are for example sold under the trademark Vivinal™ (Borculo Domo Ingredients, Netherlands).

The present composition preferably comprises 0.5 to 75 grams of the non-digestible oligosaccharides per 100 gram dry weight, preferably between 0.5 and 50 grams. The present composition preferably comprises 0.1 to 75 grams of the oligosaccharides per 100 gram dry weight, preferably between 0.1 and 50 grams

The present method preferably comprises the administration of a serving comprising between 0.05 and 25 grams non-digestible oligosaccharide, preferably between 0.1 and 5 grams. The present method preferably comprises the administration of a serving comprising between 0.05 and 25 grams galacto-oligosaccharides, preferably between 0.1 and 5 gram galacto-oligosaccharides.

The present inventors have also found that a mixture of a long chain non-digestible (neutral) oligosaccharides and short chain non-digestible (neutral) oligosaccharides synergistically stimulate the growth of a healthy intestinal flora, particularly Bifidobacteria and reduces the occurrence of E. coli in infants delivered via caesarean section .

The present composition thus preferably comprises at least two non-digestible (neutral) oligosaccharides with different average degrees of polymerization (DP). Preferably the weight ratios:

a. (non-digestible (neutral) oligosaccharides with DP 2 to 5) : (non-digestible (neutral) oligosaccharides with DP 6, 7, 8, and/or 9) > 1; and/or

b. (non-digestible (neutral) oligosaccharides with DP 10 to 60) : (non-digestible (neutral) oligosaccharides with DP 6, 7, 8, and/or 9) > 1

Preferably both weight ratios are above 2, even more preferably above 5. For further improvement, the present non-digestible oligosaccharide preferably has a relatively high content of short chain oligosaccharides, as these strongly stimulate the growth of Bifidobacteria. Hence, preferably at least 10 wt.% of the non-digestible oligosaccharides in the present composition has a DP of 2 to 5 (i.e. 2, 3, 4, and/or 5) and at least 5 wt.% has a DP of 10 to 60. Preferably at least 50 wt.%, more preferably at least 75 wt.% of the non-digestible neutral oligosaccharides have a DP of 2 to 9 (i.e. 2, 3, 4, 5, 6, 7, 8, and/or 9). To improve the biodiversity and stimulate the growth of multiple intestinal organisms, the present composition preferably comprises two non-digestible oligosaccharides with a different structure. The present composition preferably comprises at least two different non-digestible (neutral) oligosaccharides, wherein the oligosaccharides have a homology in saccharide units below about 90%, preferably below 50%, even more preferably below 25%, even more preferably below 5%. The term "homology" as used in the present invention is the cumulative of the percentage of same saccharide unit in the different oligosaccharides. For example, oligosaccharide 1 (OLl) has the structure fruc-fruc-glu-gal, and thus comprises 50% fruc (fructose), 25% gal (galactose) and 25% glu (glucose). Oligosaccharide 2 (OL2) has the structure fruc-fruc-glu, and thus comprises 66% fruc, 33% glu. The different oligosaccharides thus have a homology of 75% (50% fruc + 25% glu).

The present composition preferably comprises galacto-oligosaccharides and fructo- oligosaccharides, more preferably transgalacto-oligosacharides with a DP of 2-7 and fructo-oligosaccharides with a DP of 10-100.

Preferably, the non-digestible oligosaccharide used as the active ingredient in the present treatments is not a human milk oligosaccharide.

Compositions

The present composition is preferably enterally administered, more preferably orally. The present composition is thus preferably an oral composition, more preferably an infant formula. The present composition is preferably a synthetic formula, prepared by admixing different ingredients. The present composition can be advantageously used as a complete nutrition for infants.

The composition according to the present invention is not human milk or breast milk. Furthermore, the present composition is not a naturally occurring mammalian milk. Furthermore, in case the composition comprises animal milk or is based on animal milk, the composition typically comprises at least one non-digestible oligosaccharide that is not normally present in the naturally occurring animal milk. The present composition preferably comprises lipid, protein and carbohydrate and is preferably administered as a liquid food. The term "liquid food" as used in the present invention includes dry food (e.g. powders) which are accompanied with instructions so as to admix said dry food mixture with a suitable liquid (e.g. water).

The present composition preferably provides nutrition to the infant, and comprises a lipid component, a protein component and a carbohydrate component. The lipid component preferably provides 5 to 50% of the total calories, the protein component preferably provides 5 to 50% of the total calories, and the carbohydrate component preferably provides 15 to 90% of the total calories. The present composition is preferably used as an infant formula, wherein the lipid component provides 35 to 50% of the total calories, the protein component provides 7.5 to 12.5% of the total calories, and the carbohydrate component provides 40 to 55% of the total calories. For calculation of the % of total calories for the protein component, the total of energy provided by the proteins, peptides and amino acids needs to be taken.

Preferably the lipid component comprises a combination of at least one lipid selected from the group consisting of vegetable lipids and animal lipids and at least one oil selected from the group consisting of fish, animal, vegetable, algae, fungal and bacterial oil. Preferably, the lipid comprises at least 12 mg/100 kcal a-linolenic acid (ALA). Preferably the lipid composition has a wt/wt ratio of linoleic acid (LA) and ALA between 5 and 15, more preferably 5 to 10. Preferably the amount of trans fatty acids is below 4 wt.% based on total lipid. A high content of trans fatty acids compromises the intestinal barrier.

The protein component used in the present composition preferably comprises at least one selected from the group consisting of non-human animal proteins (such as milk proteins, meat proteins and egg proteins), vegetable proteins (such as soy protein, wheat protein, rice protein, potato protein and pea protein), free amino acids and mixtures thereof. Cow's milk derived nitrogen source, particularly cow milk protein proteins such as casein and whey proteins are particularly preferred. Preferably the protein component comprises intact proteins, more preferably intact bovine whey proteins and/or intact bovine casein proteins. As the present composition is suitably used to reduce the allergic reaction in an infant, the protein of the infant formula is preferably selected from the group consisting of hydrolyzed milk protein (e.g. hydrolyzed casein and/or hydrolyzed whey protein), vegetable protein and/or amino acids. The use of these hydrolyzed proteins further reduces the allergic reactions of the infant. The use of these hydrolyzed proteins advantageously improves the absorption of the dietary protein component by the immature intestine of caesarean delivered infants.

Preferably the composition comprises digestible carbohydrates. The digestible carbohydrates used in the present composition are preferably selected from the group consisting of sucrose, lactose, glucose, fructose, corn syrup solids, starch and maltodextrins, and mixtures thereof, more preferably lactose.

Compositions according to the invention may additionally comprise other active ingredients, such as vitamins (A, Bl, B2, B3, B5, B12, C, D, E, K, etc.), probiotics (e.g. bifidobacteria, lactobacilli, etc.), other prebiotics, fibres, lactoferrin, immunoglobulins, nucleotides, and the like. Nutrients such as proteins, lipids and other carbohydrates (e.g. digestible carbohydrates, non-digestible carbohydrates, soluble or insoluble carbohydrates) may be present in various amounts. Typical in- soluble non-digestible carbohydrates present in infant nutrition are soy polysaccharides, resistant starch, cellulose and hemicellulose. Typical soluble and digestible carbohydrates for use in infant nutrition are for example maltodextrin, lactose, maltose, glucose, fructose, sucrose and other mono- or disaccharides or mixtures thereof. The composition may also comprise other inactive ingredients and carriers, such as e.g. glucose, lactose, sucrose, mannitol, starch, cellulose or cellulose derivatives, magnesium stearate, stearic acid, sodium saccharin, talcum, magnesium carbonate and the like. The compositions may also comprise water, electrolytes, essential and non-essential amino acids, trace elements, minerals, fibre, sweeteners, flavorings, colorants, emulsifiers and stabilisers (such as soy lecithin, citric acid, esters of mono- or di-glycerides), preservatives, binders, fragrances, and the like.

In another embodiment, the present inventions provides a method wherein a composition containing oligosaccharides, preferably a concentrated compositions containing high amounts of oligosaccharides, is admixed to the nutrition to be administered to the infant. Providing a concentrated form enables the addition of the present non-digestible oligosaccharides to both synthetic infant milk formula but also breast milk. The composition comprising non-digestible oligosaccharide suitable for used in such a method, which is preferably a concentrated composition, preferably comprises at least 5 wt.%, preferably at least 10 wt.%, more preferably at least 25 wt.% non-digestible oligosaccharide based on dry weight of the composition, wherein the non-digestible oligosaccharide is preferably selected from the group consisting of galacto- oligosaccharides, non-digestible dextrins, xylo-oligosaccharides, arabino- oligosaccharides, gluco-oligosaccharides (including gentio-oligosaccharides and cyclodextrins), chito-oligosaccharides, fuco-oligosaccharides, manno-oligosaccharides, isomalto-oligosaccharide and fructo-oligosaccharide (including inulins). This composition can be improved by combining it with one or more of the components as disclosed above, preferably one or more or all selected from the group of uronic acid oligosaccharides, LC-PUFA (long chain polyunsaturated fatty acids), nucleotides and probiotic bacteria.

The concentrated composition is preferably designed to be added to a single serving of infant nutrition. The cumulative weight of the non-digestible oligosaccharide in such a composition is preferably between 0.1 and 10 gram, preferably between 0.2 and 5 gram per serving. The composition is preferably packed per serving, i.e. in a unit dose of one serving, preferably in the form of a sachet. On serving of the composition preferably has a dry weight of 0.5 to 25 grams, preferably between 1 and 10 grams.

Treatment

As will be understood by those skilled in the art, in a preferred embodiment of the invention, the treatment comprises enteral administration of the composition. "Enteral" refers herein to the delivery directly into the gastrointestinal tract of a subject (e.g. orally or via a tube, catheter or stoma). Oral administration is particularly preferred.

In an embodiment of the invention, the treatment comprises repeated administration of the composition within a certain treatment period. In a preferred embodiment of the invention, during the treatment period, a serving of the composition is administered at least 1, at least 2, at least 3 or at least 4 times a month. In another preferred embodiment of the invention, during the treatment period, a serving of the composition is administered at least 1, at least 2, at least 3, at least 4, at least 5, at least 6 or at least 7 times a week. Still more preferably, during the treatment period, a serving of the composition is administered at least once every 3 days, at least once every 2 days or at least once every day. In a most preferred embodiment of the invention the treatment comprises daily administration of 1, 2 or 3 servings of the composition comprising the non-digestible oligosaccharide.

Preferably, each serving is adapted for administration of these regimens comprises amount of 0.1 and 10 gram, preferably between 0.2 and 5 gram, cumulative weight of non-digestible oligosaccharides. Hence in a preferred embodiment of the invention, the present treatment comprises administration of non-digestible oligosaccharides in a dosage of 0.1 and 10 gram, preferably between 0.2 and 5 gram, with the above frequencies, preferably it comprises the daily administration of 0.1 and 10 gram, preferably between 0.2 and 5 gram oligosaccharides.

Preferably the treatment period lasts at least a week, at least two weeks, at least a month, at least two months, at least three months, at least four months at least five months or at least six months. Furthermore it is preferred that the treatment is started within 6 months after birth, within 5 months after birth, within four months after birth, or within three months after birth. Preferably, the subject receives the treatment before the age of 2 years, preferably before the age of 1 year, more preferably before the age of 6 months, most preferably before the age of 3 months.

In a particularly preferred embodiment of the invention, the treatment is stopped before the age of 2 years, or before the age of 1 year or before the age of 6 months, administration of the composition is discontinued at the age of 2 years, for a period of at least 1 year, preferably at least 2 years. As already mentioned above, an embodiment of the invention, concerns the treatment of infants that receive human breast milk. The present invention thus provides a method of treatment as defined in any of the foregoing sections, said method comprising the steps of:

a) admixing a composition comprising non-digestible oligosaccharide with a nutrition to be administered to the infant, preferably human breast milk; and

b) administering the mixture obtained in step a) to the infant.

Thus, the invention has been described by reference to certain embodiments discussed above. It will be recognized that these embodiments are susceptible to various modifications and alternative forms well known to those of skill in the art. Accordingly, although specific embodiments have been described, these are examples only and are not limiting upon the scope of the invention. All patent and literature references cited in the present specification are hereby incorporated by reference in their entirety.

The following examples serve to illustrate the invention described in the foregoing. Experimental

introduction

It was the objective of the present study to evaluate if a protective effect against allergy lasted beyond the intervention period until 5 y of age in the group of infants that did develop atopic dermatitis during infancy. methods

Study Design

The original study was a randomised, double-blind, placebo-controlled trial as described elsewhere (1, 2). Briefly, 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 months of life (1). To evaluate the possible long-term protective effect of the prebiotic intervention on allergy, the study cohort was followed up to 5 y. Follow-up was performed by investigators who were blind to formula assignment. The study protocol was approved by the Ethical Committee of the Macedonio Melloni Hospital, Milan, Italy. Informed written consent was obtained from parents. Nutritional Intervention

Nutritional intervention was for the first 6 months of the study and explained in detail in Mora et al (1).

Five-year Follow-up Protocol

Data were collected throughout (i) follow-up visits, (ii) diaries written by parents, and (iii) telephone calls by trained personal.

Endpoints and Definitions

Main endpoints of interest were

· cumulative incidence of allergic manifestations in 5y, and

• prevalence of allergic and persistent allergic manifestations at 5 y of age.

We evaluated also

• prevalences of allergic manifestations at 5 y in relation to the presence of AD within the first 6mo of life to assess if early AD occurrence has been a predictor persistent allergic manifestations.

Monitored allergic manifestations were AD, recurrent wheezing, allergic rhinoconjunctivitis, and urticaria. Atopic dermatitis (AD) was diagnosed according to the criteria described by Harrigan and Rabinowitz (3) and Muraro et al (4). After 2 y the diagnosis of AD was confirmed in the presence of an itchy skin condition with a minimal duration of 4 weeks if there were following features: involvement of the cheeks, or forehead and outer limbs, general dry skin in the past year. Recurrent wheezing was defined as 3 or more physician-diagnosed wheezing episodes during each follow-up period (4). Allergic urticaria was defined as (5) 2 or more episodes of itching eruptions or swelling with typical appearance seen by a physician and provoked by the same allergen. Allergic rhinoconjunctivitis was considered as repeated physician diagnosed nasal and ocular symptoms (itching,sneezing, increased secretion, and nasal blockage) not related to common cold or infection (6, 7).

50 % of the cases with AD at 6 mo in the placebo group continued to have allergy in terms of AD, persistent wheezing, and rhinoconjunctivitis at 5 y compared to 16.7 % in the intervention group (p<0.05). The children who had AD during the first 6 mo in the whole group developed more persistent allergic manifestations and allergic rhinoconjunctivitis at 5 y of life (Table 1). Prevalences of any persistent allergic manifestation, AD, and allergic rhinoconjunctivitis at 5 y were significantly higher in AD-6mo(+) children (40, 30, 25 %, respectively) in the whole group, compared to AD- 6mo(-) ones (9,7, 1.4, 4.2 %, respectively) (pO.01, pO.0001, p=0.01 with odds ratios 6.2, 30.4, 7.7 respectively). AD-6mo(+) children tended to have also more persistent wheezing at 5 y (20 vs 5.6 %, p=0.065 with odds ratio 4.3) Table 1.Prevalence of the persistent allergic manifestations and rhinoconjunctivitis at 5y in relation to the presence of AD at 6 months (placebo-intervantion groups combined)

References

1 . Mora G, Arslanoglu S, Stahl B, Jelinek J, Wahn U, Boehm G. A mixture of prebiotic oligosaccharides reduces the incidence of atopic dermatitis durig the first six months of age. Arch Dis Child. 2006;91 :814-9. Arslanoglu S, Moro GE, Schmitt J, Tandoi L, Rizzardi S, Boehm G. Early dietary intervention with a mixture of prebiotic oligosaccharides reduces the incidence of allergic manifestations and infections during the first two years of life. J Nutr 2008; 138 (6): 1091-5.

Harrigan E, Rabinowitz LG. Atopic dermatitis. Pediatr Allergy Immunol. 1999;19:383-9.

Muraro A, Dreborg S, Halken S, Host et al. Dietary prevention of allergic diseases in infants and small children. Part II: Evaluation of methods in allergy prevention studies and sensitization markers. Definitions and diagnostic criteria for allergic diseases. Pediatr Allergy Immunol. 2004;14: 196-205.

von Berg A, Koletzko S, Grubl A, Filipiak-Pittroff B, Wichmann HE, Bauer CP, Reinhardt D, Berdel D; German Infant Nutritional Intervention Study Group. The effect of hydro lyzed cwow's milk formula for allergy prevention in the first year of life: the German Infant Nutritional Intervention Study, a randomized double-blind trial. J Allergy Clin Immunol. 2003 Mar;l 11(3):533-40.

Johansson SG, Bieber T, Dahl R, Friedmann PS, Lanier BQ, Lockey RF, Motala C, Ortega Martell JA, Platts-Mills TA, et al. Revised nomenclature for allergy for global use: report of the Nomenclature Review Committee of the World Allergy Organization, October 2003. J Allergy Clin Immunol. 2004;113:832-6.

Kulig M, Klettke U, Wahn V, Forster J, Bauer CP, Wahn U. Development of seasonal allergic rhinitis during the first 7 years of life. J Allergy Clin Immunol. 2000 Nov;106(5):832-9.

Claims

1. Use of composition comprising non-digestible oligosaccharide in the manufacture of a composition for the treatment of an infant that develops allergy or atopic dermatitis before the age of 6 months, for reducing the incidence of allergic diseases and/or manifestation in said individual during (early) childhood, said treatment comprising administering the composition to said infant.

2. Use according to claim 1, wherein the treatment is for reducing the incidence of persisting atopic dermatitis, allergic rhinoconjunctivitis and/or wheezing in (early) childhood.

3. Use according to claim 1 or 2, wherein the treatment is for reducing the incidence of allergic diseases and/or manifestation in said individual at the age of >4 years.

4. Use according to any one of claims 1-3, wherein the treatment is for reducing the incidence of allergic diseases and/or manifestation in said individual at the age of 5 years.

5. Use according any one of the preceding claims, wherein the treatment comprises administering the composition to said infant within two years after birth.

6. Use according to any one of the preceding claims, wherein the treatment comprises administering the composition to said infant within one year after birth.

7. Use according to any one of the preceding claims, wherein the treatment comprises administering the composition to said infant within 6 months after birth.

8. Use according to any one of the preceding claims, wherein the treatment comprises daily administration for a period of at least 1 month.

9. Use according to any one of the preceding claims, wherein the administration of the composition is discontinued at the age of 2 years, for a period of at least 1 year, preferably at least 2 years.

10. Use according to any one of the preceding claims, wherein the composition comprises galactooligosaccharides.

11. Use according to any one of the preceding claims, wherein the composition comprises fructooligosaccharides.

12. Use according to any one of the preceding claims, wherein the composition is an infant formula.

13. Use according to any one of the preceding claims, wherein the non-digestible oligosaccharide is not a human milk oligosaccharide.

14. Use according to any one of the preceding claims, wherein the composition is not human milk.

15. Use according to any one of the preceding claims, wherein the infant receives human breast milk and the treatment comprises mixing the composition with human breast milk before administering it.

16. Use according to any one of the preceding claims, wherein the infant has developed atopic dermatitis or allergy at the age of 3 months.

17. Use according to preceding claims, wherein the composition is administered to an infant which developed atopic dermatitis or allergy in the first year of life.

18. Composition comprising non-digestible oligosaccharide for use in the treatment of an infant that develops allergy or atopic dermatitis before the age of 6 months, for reducing the incidence of allergic diseases and/or manifestation in said individual during (early) childhood, said treatment comprising administering the composition to said infant.