Patent Description:
Mother's milk is recommended for all infants. However, in some cases breast feeding is inadequate or unsuccessful for medical reasons or the mother chooses not to breast feed. Infant formula have been developed for these situations. Fortifiers have also been developed to enrich mother's milk or infant formula with specific ingredients. Infants and young children may suffer from constipation or hard stool due, especially, to the immaturity of their gut, the lack of activity at this young age and the undiversified content of their feeding. Because of their beneficial effects, prebiotics are therefore often incorporated into infant formula, fortifiers or any other synthetic nutritional compositions and nutritional supplements.

Prebiotics are non-digestible carbohydrates that contribute to the well-being of their host. They are typically compounds that pass undigested through the upper part of the gastrointestinal tract and stimulate the growth and/or activity of advantageous bacteria such as bifidobacteria that colonize the large bowel by acting as substrate for them. They will form the basis for stool.

However, some fibers including the beneficial prebiotics inulin and oligofructose, produce gases that fertilize the healthy bacteria that live in the lower gut. This may lead to flatulence, bloating, colics and/or gut discomfort in the individual. These associated effects may be particularly problematic in infants and young children and can lead to crying periods, feeding difficulties, irritability, pain, especially abdominal pain, abdominal cramping, poor sleep.

Human milk oligosaccharides (HMOs) are, collectively, the third largest solid constituents in human milk, after lactose and fat. HMOs usually consist of lactose at the reducing end with a carbohydrate core that often contains a fucose or a sialic acid at the non-reducing end. There are over one hundred milk oligosaccharides that have been isolated and characterized in human milk.

Some compositions using HMO ingredients, such as fucosylated oligosaccharides, lacto-N-tetraose, lacto-N-neotetraose and/or sialylated oligosaccharides, have been developed and for different purposes.

For example <CIT> describes a pharmaceutical composition comprising a molecule comprising a fucose group in an alpha-<NUM> linkage, an alpha-<NUM> linkage or an alpha-<NUM> linkage to a galactose group and a pharmaceutically acceptable carrier. Various molecules are described such as <NUM>'-fucosyllactose. This application is quite general since several infections can be prevented or treated, including respiratory or enteric infections, and there is a large target of patients (infants, children or adults). In addition, this document suggests that providing 2FL in medium or high amounts decreases the incidence of Campylobacter diarrhea.

<CIT>relates to compositions containing at least one fucose residue in an alpha <NUM>-<NUM> linkage such as 2FL and uses thereof. In particular, such compositions can be used in the treatment and prevention of gastrointestinal infections like diarrhoea and enterocolitis.

<CIT> describes an oligosaccharide-containing substance or receptor binding to diarrheagenic Escherichia coli and/or zoonotic Helicobacter species, and use thereof in, e.g., pharmaceutical, nutritional and other compositions for prophylaxis and treatment of diarrhea, hemorrhagic colitis or haemolytic uremic syndrome.

<CIT> refer to nutritional composition comprising HMOs but for a wide list of health benefits including feeding tolerance and especially reduction of diarrhea and loose stools (so the opposite of constipation), as well as reduction of the associated gas and colics.

<CIT> describes human milk oligosaccharides (HMOs) for improving gastrointestinal function and tolerance in infants, toddlers, and children.

<CIT> and <CIT> relate to an oligosaccharide mixture and to a food product comprising said oligosaccharide mixture, especially infant formula.

<CIT> discloses a composition for stimulating health of an infant by administering the composition to a pregnant woman.

Moreover, Albrecht et al. states that in the feces of breast-fed babies, characteristic human milk oligosaccharide (HMO) profiles, showing genetic fingerprints known for human milk of secretors and non-secretors, were recognized. Alternatively, advanced degradation and bioconversion of HMOs, resulting in an accumulation of acidic HMOs or HMO bioconversion products was observed (<NPL>).

<CIT> provides a composition for promoting growth of intestinal bifidobacteria, comprising oligosaccharide as an active ingredient.

Furthermore, <CIT> describes oligosaccharides and oligosaccharides linked to backbones such as proteins, methods for making such oligosaccharides and method for using them to treat and/ or prevent various disorders.

Indeed, as indicated in <NPL>, prebiotic cabohydrates (e.g. HMOs, GOS) have an impact on the neonatal gut development. However, the effects are specific to the types of fibers (HMOs and GOS are structurally different). For example, HMOs have been shown to facilitate a protective gut colonization in newborn infants (Riccardo Locascio et al, <NUM>, reference <NUM> of this publication) and also to confer a protection against diarrhea (Newburg et al, <NUM>, reference <NUM> of this publication).

None of the previous work is therefore focused on the prevention and/or treatment of constipation and/or the improvement of stool consistency/frequency without the above-mentioned associated problems of flatulence, bloating, colics and/or gut discomfort that can be particularly painful in infants and young children.

There is clearly a need for developing suitable methods to decrease the incidence of these health conditions/problems in infants and young children and especially there is a need for nutritional compositions such as infant formula that can provide softer stool without increasing flatulence, bloating, colics and/or gut discomfort.

There is also a need to deliver such health benefits in a manner that is particularly suitable for the young subjects (infants and young children), in a manner that does not involve a classical pharmaceutical intervention as these infants or young children are particularly fragile.

There is a need to deliver such health benefits in these infants or young children in a manner that does not induce side effects and/or in a manner that is easy to deliver, and well accepted by the parents or health care practitioners.

There is also a need to deliver such benefits in a manner that does keep the cost of such delivery reasonable and affordable by most.

The present inventors have found that a composition comprising at least one fucosylated oligosaccharide and at least one N-acetylated oligosaccharide can advantageously be used to improve stool consistency in an infant or a young child, especially by reducing stool hardness.

As used herein, the following terms have the following meanings.

The term "infant" means a child under the age of <NUM> months.

The expression "young child" means a child aged between one and three years, also called toddler.

An "infant or young child born by C-section" means an infant or young child who was delivered by caesarean. It means that the infant or young child was not vaginally delivered.

An "infant or young child vaginally born" means an infant or young child who was vaginally delivered and not delivered by caesarean.

A "preterm" or "premature" means an infant or young child who was not born at term. Generally it refers to an infant or young child born prior <NUM> weeks of gestation.

The expression "nutritional composition" means a composition which nourishes a subject. This nutritional composition is usually to be taken orally or intravenously, and it usually includes a lipid or fat source and a protein source.

The composition may be a hypoallergenic nutritional composition. The expression "hypoallergenic nutritional composition" means a nutritional composition which is unlikely to cause allergic reactions.

The composition is a "synthetic nutritional composition". The expression "synthetic nutritional composition" means a mixture obtained by chemical and/or biological means, which can be chemically identical to the mixture naturally occurring in mammalian milks (i.e. the synthetic composition is not breast milk).

The expression "infant formula" as used herein refers to a foodstuff intended for particular nutritional use by infants during the first months of life and satisfying by itself the nutritional requirements of this category of person (Article <NUM>(c) of the European Commission Directive <NUM>/<NUM>/EEC <NUM>/<NUM>/EC of <NUM> December <NUM> on infant formulae and follow-on formulae). It also refers to a nutritional composition intended for infants and as defined in Codex Alimentarius (Codex STAN <NUM>-<NUM>) and Infant Specialities (incl. Food for Special Medical Purpose). The expression "infant formula" encompasses both "starter infant formula" and "follow-up formula" or "follow-on formula".

A "follow-up formula" or "follow-on formula" is given from the 6th month onwards. It constitutes the principal liquid element in the progressively diversified diet of this category of person.

The expression "baby food" means a foodstuff intended for particular nutritional use by infants or young children during the first years of life.

The expression "infant cereal composition" means a foodstuff intended for particular nutritional use by infants or young children during the first years of life.

The term "fortifier" refers to liquid or solid nutritional compositions suitable for mixing with breast milk or infant formula.

The expression "weaning period" means the period during which the mother's milk is substituted by other food in the diet of an infant or young child.

The expressions "days/weeks/months/years of life" and "days/weeks/months/years of birth" can be used interchangeably.

The expression "preventing and/or treating constipation and/or improving stool consistency/frequency" encompasses one or several of the following:.

The expression "preventing and/or treating flatulence, bloating, colics and/or gut discomfort" encompasses one or several of the following:.

The expressions "in preventing constipation/flatulence/bloating/colics/gut discomfort", "to prevent constipation/flatulence/bloating/ colics/gut discomfort", "in the prevention of constipation/flatulence/bloating/ colics/gut discomfort" and "for the prevention of constipation/flatulence/bloating/ colics/gut discomfort" can be used interchangeably.

These expressions mean avoiding that these health conditions/issues (constipation/flatulence/bloating/colics/gut discomfort) occur and/or decreasing the incidence of said health conditions/issues (reduction of the frequency, i.e. the number of these health conditions/issues). In some embodiments the prevention of these health conditions/issues occurs during the treatment (i.e. during the administration of the composition of the present invention, either immediately after the start of the administration or some time after, e.g. some days or weeks after the start). It can also encompass the prevention of these health conditions/issues later in life. The term "later in life" encompasses the effect after the termination of the intervention or treatment. The effect "later in life" can be from <NUM> week to several months, for example from <NUM> to <NUM> weeks, from <NUM> to <NUM> weeks, from <NUM> to <NUM> weeks, from <NUM> to <NUM> months or from <NUM> to <NUM> months.

The expressions "in treating constipation/flatulence/bloating/colics/gut discomfort", "to treat constipation/flatulence/bloating/ colics/gut discomfort", "in the treatment of constipation/flatulence/bloating/ colics/gut discomfort" and "for the treatment of constipation/flatulence/bloating/ colics/gut discomfort" can be used interchangeably.

They should be understood as comprising the decrease of the duration of these health conditions/issues (constipation/flatulence/bloating/colics/gut discomfort) (e.g. number of days/weeks/years the infants or young children will suffer from these health conditions/issues), the decrease of the severity (or level) of these health conditions/issues (e.g. the consequences and/or the seriousness of these health conditions/issues). These expressions also encompass the relieve of the symptoms or consequences such as blocking stool, crying periods, feeding difficulties, irritability, pain, especially abdominal pain, abdominal cramping, poor sleep and any combinations thereof, and/or the decrease of complications caused by these health conditions/issues on the infant or young child health, such as anal fissure, rectal bleeding, the need of a surgical intervention, the use of medication, the use of stool softeners, and/or the decrease of pain, and/or the decrease of tiredness, and/or the ease of the sleep and/or the stabilization of the activity of the infants or young children suffering from these health conditions/issues.

The expressions "no or a limited level" and "no particular issue" of flatulence, bloating, colics and/or gut discomfort can be used interchangeably. They have to be understood in the context of the present invention that infants or young children fed the composition of the present invention will have no flatulence, bloating, colics and/or gut discomfort episodes or they will have a low level of flatulence, bloating, colics and/or gut discomfort or they will have less (e.g. at least <NUM>% less, or at least <NUM>% less, or at least <NUM>% less, or at least <NUM>% less, or at least <NUM>% less or at least <NUM>% less. ) flatulence, bloating, colics and/or gut discomfort episodes in comparison with infants or young children fed with a standard composition (e.g. the same composition but without any fucosylated oligosaccharide and N-acetylated oligosaccharide). The expressions "a limited level" and "a lower level" can be used interchangeably. They may refer to the frequency and/or the occurrence and/or the severity.

The terms "gut", "GUT" and "gastrointestinal" can be used interchangeably.

The expression "gut discomfort" includes abdominal pain and/or cramping.

The expressions "in improving stool consistency/frequency", "in improving stool consistency and/or frequency" and "in improving stool consistency and/or stool frequency" can be used interchangeably. They encompass the improvement of stool consistency, the improvement of stool frequency and/or both. The expression "improving stool consistency" means that the stool of an infant or young child feeding a nutritional composition has a softer consistency than the stool of an infant or young child not feeding a nutritional composition. The expression "improving stool consistency" may especially encompass or mean "reducing stool hardness", "softening stool" and/or "providing softer stool", e.g. there will be less hard lumps, like nuts, that are hard to pass. The expression "improving stool frequency" means that the stool of an infant or young child will become more frequent, i.e. the transit will be regulated and/or faster. It may therefore also encompass or mean "improving/increasing the transit speed" or "avoiding a slow transit" or "regulating the transit". The improvement of stool consistency/frequency may especially allow avoiding pain, especially abdominal pain, abdominal cramping and also further complications like anal fissure, rectal bleeding, the need of a surgical intervention, the use of medication, the use of stool softeners.

The "mother's milk" should be understood as the breast milk or the colostrum of the mother.

An "oligosaccharide" is a saccharide polymer containing a small number (typically three to ten) of simple sugars (monosaccharides).

The term "HMO" or "HMOs" refers to human milk oligosaccharide(s). These carbohydrates are highly resistant to enzymatic hydrolysis, indicating that they may display essential functions not directly related to their caloric value. It has especially been illustrated that they play a vital role in the early development of infants and young children, such as the maturation of the immune system. Many different kinds of HMOs are found in the human milk. Each individual oligosaccharide is based on a combination of glucose, galactose, sialic acid (N-acetylneuraminic acid), fucose and/or N-acetylglucosamine with many and varied linkages between them, thus accounting for the enormous number of different oligosaccharides in human milk - over <NUM> such structures have been identified so far. Almost all of them have a lactose moiety at their reducing end while sialic acid and/or fucose (when present) occupy terminal positions at the non-reducing ends. The HMOs can be acidic (e.g. charged sialic acid containing oligosaccharide) or neutral (e.g. fucosylated oligosaccharide).

A "fucosylated oligosaccharide" is an oligosaccharide having a fucose residue. It has a neutral nature. Some examples are <NUM>-FL (<NUM>'-fucosyllactose), <NUM>-FL (<NUM>-fucosyllactose), difucosyllactose, lacto-N-fucopentaose (e.g. lacto-N-fucopentaose I, lacto-N-fucopentaose II, lacto-N-fucopentaose III, lacto-N-fucopentaose V), lacto-N-fucohexaose, lacto-N-difucohexaose I, fucosyllacto-N-hexaose, fucosyllacto-N-neohexaose, difucosyllacto-N-hexaose I, difucosyllacto-N-neohexaose II and any combination thereof.

The expressions "fucosylated oligosaccharides comprising a <NUM>'-fucosyl-epitope" and "<NUM>-fucosylated oligosaccharides" encompass fucosylated oligosaccharides with a certain homology of form since they contain a <NUM>'-fucosyl-epitope, therefore a certain homology of function can be expected.

The expression "N-acetylated oligosaccharide(s)" encompasses both "N-acetyl-lactosamine" and "oligosaccharide(s) containing N-acetyl-lactosamine". They are neutral oligosaccharides having an N-acetyl-lactosamine residue. Suitable examples are LNT (lacto-N-tetraose), para-lacto-N-neohexaose (para-LNnH), LNnT (lacto-N-neotetraose) or any combination thereof. Other examples are lacto-N-hexaose, lacto-N-neohexaose, para-lacto-N-hexaose, para-lacto-N-neohexaose, lacto-N-octaose, lacto-N- neooctaose, iso- lacto-N-octaose, para- lacto-N-octaose and lacto-N-decaose.

The expression "at least one fucosylated oligosaccharide" and "at least one N-acetylated oligosaccharide" means "at least one type of fucosylated oligosaccharide" and "at least one type of N-acetylated oligosaccharide".

A "precursor of HMO" is a key compound that intervenes in the manufacture of HMO, such as sialic acid and/or fucose.

A "sialylated oligosaccharide" is a charged sialic acid containing oligosaccharide, i.e. an oligosaccharide having a sialic acid residue. It has an acidic nature. Some examples are <NUM>-SL (<NUM>' sialyllactose) and <NUM>-SL (<NUM>' sialyllactose).

The nutritional composition can be in solid form (e.g. powder) or in liquid form. The amount of the various ingredients (e.g. the oligosaccharides) can be expressed in g/<NUM> of composition on a dry weight basis when it is in a solid form, e.g. a powder, or as a concentration in g/L of the composition when it refers to a liquid form (this latter also encompasses liquid composition that may be obtained from a powder after reconstitution in a liquid such as milk, water. , e.g. a reconstituted infant formula or follow-on/follow-up formula or infant cereal product or any other formulation designed for infant nutrition).

The term "prebiotic" means non-digestible carbohydrates that beneficially affect the host by selectively stimulating the growth and/or the activity of healthy bacteria such as bifidobacteria in the colon of humans (<NPL>).

The term "probiotic" means microbial cell preparations or components of microbial cells with a beneficial effect on the health or well-being of the host. The microbial cells are generally bacteria or yeasts.

The term "cfu" should be understood as colony-forming unit.

All percentages are by weight unless otherwise stated.

In addition, in the context of the invention, the terms "comprising" or "comprises" do not exclude other possible elements. The composition of the present invention, including the many embodiments described herein, can comprise, consist of, or consist essentially of the essential elements and limitations of the invention described herein, as well as any additional or optional ingredients, components, or limitations described herein or otherwise depending on the needs.

The invention will now be described in further details. It is noted that the various aspects, features, examples and embodiments described in the present application may be compatible and/or combined together.

The inventors of the present invention believe that the fucosylated oligosaccharide(s) and the N-acetylated oligosaccharide(s) as defined in the appended claims act synergically to surprisingly provide the above-mentioned health benefits. Without being bound by theory, the inventors believe that the observed effect is mediated via an alteration of the intestinal ecosystem, thus indirectly affecting stool consistency/frequency, bowel movements and eventually gut discomfort.

The composition of the present invention comprises at least one fucosylated oligosaccharide. The fucosylated oligosaccharide is <NUM>'-fucosyllactose.

The nutritional composition comprises <NUM>'-fucosyllactose (or 2FL, or <NUM>'FL, or <NUM>-FL or <NUM>'-FL). There is no other type of fucosylated oligosaccharide than <NUM>'-fucosyllactose, i.e. the nutritional composition of the invention comprises only <NUM>'-fucosyllactose as fucosylated oligosaccharide.

The fucosylated oligosaccharide may be isolated by chromatography or filtration technology from a natural source such as animal milks. Alternatively, it may be produced by biotechnological means using specific fucosyltransferases and/or fucosidases either through the use of enzyme-based fermentation technology (recombinant or natural enzymes) or microbial fermentation technology. In the latter case, microbes may either express their natural enzymes and substrates or may be engineered to produce respective substrates and enzymes. Single microbial cultures and/or mixed cultures may be used. Fucosylated oligosaccharide formation can be initiated by acceptor substrates starting from any degree of polymerization (DP), from DP = <NUM> onwards. Alternatively, fucosylated oligosaccharides may be produced by chemical synthesis from lactose and free fucose. Fucosylated oligosaccharides are also available for example from Kyowa, Hakko, Kogyo of Japan.

The composition of the present invention also comprises at least one the N-acetylated oligosaccharide. The N-acetylated oligosaccharide(s) is lacto-N-tetraose (LNT).

There is no other type of N-acetylated oligosaccharide than lacto-N-neotetraose (LNnT), i.e. the nutritional composition of the invention comprises only lacto-N-neotetraose (LNnT) as N-acetylated oligosaccharide.

The N-acetylated oligosaccharide may be synthesised chemically by enzymatic transfer of saccharide units from donor moieties to acceptor moieties using glycosyltransferases as described for example in <CIT> and <CIT>. Alternatively, LNT and LNnT may be prepared by chemical conversion of Keto-hexoses (e.g. fructose) either free or bound to an oligosaccharide (e.g. lactulose) into N-acetylhexosamine or an N-acetylhexosamine-containing oligosaccharide as described in <NPL>. N-acetyl-lactosamine produced in this way may then be transferred to lactose as the acceptor moiety.

The nutritional composition comprises <NUM>'-fucosyllactose (2FL) and lacto-N-neotetraose (LNnT).

The nutritional composition of the present invention comprises an oligosaccharide mixture that consists of <NUM>'-fucosyllactose (<NUM>-FL) and lacto-N-neotetraose (LNnT). The nutritional composition of the invention may comprise only <NUM>'-fucosyllactose (<NUM>-FL) as fucosylated oligosaccharide and only lacto-N-neotetraose (LNnT) as N-acetylated oligosaccharide.

In the present invention, the fucosylated oligosaccharide(s) and N-acetylated oligosaccharide(s) are present in the nutritional composition in some particular amounts that will be below detailed. The term "amount" refers to the total amount of each of these <NUM> components in the nutritional composition unless otherwise specified. It therefore does not refer to an individual amount except when there is a single type of these components (in that case both the total and individual amounts equal).

The fucosylated oligosaccharideis present in the nutritional composition in a total amount <NUM>-<NUM>/L of the composition, such as <NUM>-<NUM>/L or <NUM>-<NUM>/L or <NUM>-<NUM>/L or <NUM>-<NUM>/L or <NUM>-<NUM>/L of the composition. The fucosylated oligosaccharide may be in a total amount of <NUM>/L of the composition. The fucosylated oligosaccharide may be in a total amount of <NUM>/L of the composition.

The fucosylated oligosaccharide is present in the nutritional composition in a total amount of <NUM>-<NUM>/<NUM> of the composition, such as <NUM>-<NUM>/<NUM>, or <NUM>-<NUM>/<NUM> or <NUM>-<NUM>/<NUM> or <NUM>-<NUM>/<NUM> or <NUM>-<NUM>/<NUM> of the composition. The fucosylated oligosaccharide may be in a total amount of <NUM>/<NUM> of the composition. The fucosylated oligosaccharide may be in a total amount of <NUM>/<NUM> of the composition.

The N-acetylated oligosaccharide is present in the nutritional composition in a total amount of <NUM>-<NUM>/L of the composition, such as <NUM>-<NUM>/L or <NUM>-<NUM>/L of the compositionThe N-acetylated oligosaccharide may be in a total amount of <NUM>/L of the composition. The N-acetylated oligosaccharide may be in a total amount of <NUM>/L of the composition.

The N-acetylated oligosaccharide is present in the nutritional composition in a total amount of <NUM>-<NUM>/<NUM> of composition, such as <NUM>-<NUM>/<NUM> or <NUM>-<NUM>/<NUM>. The N-acetylated oligosaccharide may be in a total amount of <NUM>/<NUM> of the composition. The N-acetylated oligosaccharide can be in a total amount of <NUM>/<NUM> of the composition.

The nutritional composition comprises the at least one fucosylated oligosaccharide and the at least one N-acetylated oligosaccharide wherein:.

The nutritional composition may comprise the at least one fucosylated oligosaccharide and the at least one N-acetylated oligosaccharide wherein:.

The nutritional composition may comprises the at least one fucosylated oligosaccharide and the at least one N-acetylated oligosaccharide wherein:.

The fucosylated oligosaccharide and the N-acetylated oligosaccharide comprised in the nutritional composition are typically present in a ratio fucosylated oligosaccharide:the N-acetylated oligosaccharide of from <NUM>:<NUM> to <NUM>:<NUM> such as from <NUM>:<NUM> to <NUM>:<NUM>, for example <NUM>:<NUM> to <NUM>:<NUM>, or <NUM>:<NUM> - <NUM>:<NUM> or <NUM>:<NUM> - <NUM>:<NUM>. In a particularly advantageous embodiment, this ratio is <NUM>:<NUM> or around <NUM>:<NUM>.

The nutritional composition may also comprise at least another oligosaccharide(s) (i.e. other than the fucosylated oligosaccharide(s) and N-acetylated oligosaccharide(s) necessarily present in the composition) and/or at least a fiber(s) and/or at least a precursor(s) thereof. The other oligosaccharide and/or fiber and/or precursor thereof may be selected from the list comprising galacto-oligosaccharides (GOS), fructo-oligosaccharides (FOS), inulin, xylooligosaccharides (XOS), polydextrose, sialylated oligosaccharides, sialic acid, fucose and any combination thereof. They may be in an amount between <NUM> and <NUM>% by weight of composition.

Suitable commercial products that can be used in addition to the oligosaccharides comprised in the oligosaccharide mixture to prepare the nutritional compositions include combinations of FOS with inulin such as the product sold by BENEO under the trademark Orafti, or polydextrose sold by Tate & Lyle under the trademark STA-LITEO.

The composition can comprise sialylated oligosaccharide(s). There can be one or several sialylated oligosaccharide(s).

The sialylated oligosaccharide(s) can be selected from the group comprising <NUM>' sialyllactose (<NUM>-SL), <NUM>' sialyllactose (<NUM>-SL), and any combination thereof. In some embodiments of the invention the composition comprises <NUM>-SL and <NUM>-SL. In some particular embodiments the ratio between <NUM>'-sialyllactose (<NUM>-SL) and <NUM>'-sialyllactose (<NUM>-SL) can be in the range between <NUM>:<NUM> and <NUM>:<NUM>, or from <NUM>:<NUM> and <NUM>:<NUM>, or from <NUM>:<NUM> to <NUM>:<NUM>. In some specific embodiments the sialylated oligosaccharide of the composition is <NUM>' sialyllactose (<NUM>-SL).

The sialylated oligosaccharide(s) may be isolated by chromatographic or filtration technology from a natural source such as animal milks. Alternatively, they may be produced by biotechnological means using specific sialyltransferases or sialidases, neuraminidases, either by an enzyme based fermentation technology (recombinant or natural enzymes), by chemical synthesis or by a microbial fermentation technology. In the latter case microbes may either express their natural enzymes and substrates or may be engineered to produce respective substrates and enzymes. Single microbial cultures or mixed cultures may be used. Sialyl-oligosaccharide formation can be initiated by acceptor substrates starting from any degree of polymerisation (DP), from DP=<NUM> onwards. Alternatively, sialyllactoses may be produced by chemical synthesis from lactose and free N'-acetylneuraminic acid (sialic acid). Sialyllactoses are also commercially available for example from Kyowa Hakko Kogyo of Japan.

In particular examples the composition may comprise from <NUM> to <NUM>/L of sialylated oligosaccharide(s), or from <NUM> to <NUM>/L, or from <NUM> to <NUM>/L, or from <NUM> to <NUM>/L, or from <NUM> to <NUM>/L, for example <NUM> or <NUM>/L of sialylated oligosaccharide(s). The composition can comprise from <NUM> to <NUM>/l of sialylated oligosaccharide(s).

The composition can contain from <NUM> to <NUM> of sialylated oligosaccharide(s) per <NUM> of composition on a dry weight basis, e.g. from <NUM> to <NUM> or from <NUM> to <NUM> or form <NUM> to <NUM> of sialylated oligosaccharide(s) per <NUM> of composition on a dry weight basis.

The nutritional composition may comprise sialylated oligosaccharide(s) in an amount of below <NUM>/<NUM> of composition on a dry weight basis.

The nutritional composition may not contain any sialylated oligosaccharide(s).

The nutritional composition may not contain any galacto-oligosaccharides (GOS).

The nutritional composition can also contain at least one BMO (bovine milk oligosaccharide). The nutritional composition may not not comprise any bovine milk oligosaccharide.

The composition may optionally also comprise at least one precursor of oligosaccharide. There can be one or several precursor(s) of oligosaccharide. For example the precursor of human milk oligosaccharide is sialic acid, fucose or a mixture thereof. In some particular embodiments the composition comprises sialic acid.

In particular examples the composition comprises from <NUM> to <NUM>/L of precursor(s) of oligosaccharide, or from <NUM> to <NUM>/L, or from <NUM> to <NUM>/L, or from <NUM> to <NUM>/L, or from <NUM> to <NUM>/L or from <NUM> to <NUM>/L, or from <NUM> to <NUM>/L of precursor(s) of oligosaccharide.

The composition can contain from <NUM> to <NUM> of precursor(s) of oligosaccharide per <NUM> of composition on a dry weight basis, e.g. from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> of precursor(s) of oligosaccharide per <NUM> of composition on a dry weight basis.

The nutritional composition of the present invention can further comprise at least one probiotic (or probiotic strain), such as a probiotic bacterial strain.

The probiotic microorganisms most commonly used are principally bacteria and yeasts of the following genera: Lactobacillus spp. , Streptococcus spp. , Enterococcus spp. , Bifidobacterium spp. and Saccharomyces spp.

The probiotic may be a probiotic bacterial strain. It may be Bifidobacteria and/or Lactobacilli.

Suitable probiotic bacterial strains include Lactobacillus rhamnosus ATCC <NUM> available from Valio Oy of Finland under the trademark LGG, Lactobacillus rhamnosus CGMCC <NUM>, Lactobacillus paracasei CNCM I-<NUM>, Lactobacillus johnsonii CNCM I-<NUM>, Streptococcus salivarius DSM <NUM> sold by BLIS Technologies Limited of New Zealand under the designation KI2, Bifidobacterium lactis CNCM <NUM>-<NUM> sold inter alia by the Christian Hansen company of Denmark under the trademark Bb <NUM>, Bifidobacterium longum ATCC BAA-<NUM> sold by Morinaga Milk Industry Co. of Japan under the trademark BB536, Bifidobacterium breve sold by Danisco under the trademark Bb-<NUM>, Bifidobacterium breve sold by Morinaga under the trade mark M-16V, Bifidobacterium infantis sold by Procter & Gamble Co. under the trademark Bifantis and Bifidobacterium breve sold by Institut Rosell (Lallemand) under the trademark R0070.

The nutritional composition may contain from 10e3 to 10e12 cfu of probiotic strain, more preferably between 10e7 and 10e12 cfu such as between 10e8 and 10e10 cfu of probiotic strain per g of composition on a dry weight basis.

The probiotics may be viable. The probiotics may be non-replicating or inactivated. There may be both viable probiotics and inactivated probiotics in some other embodiments.

The nutritional composition can further comprise at least one phage (bacteriophage) or a mixture of phages, preferably directed against pathogenic Streptococci, Haemophilus, Moraxella and Staphylococci.

The nutritional composition can be for example an infant formula, a starter infant formula, a follow-on or follow-up formula, a baby food, an infant cereal composition, a fortifier such as a human milk fortifier, or a supplement. In some particular embodiments, the composition of the invention is an infant formula, a fortifier or a supplement that may be intended for the first <NUM> or <NUM> months of age. In a preferred embodiment the nutritional composition of the invention is an infant formula.

The nutritional composition of the present invention can be a fortifier. The fortifier can be a breast milk fortifier (e.g. a human milk fortifier) or a formula fortifier such as an infant formula fortifier or a follow-on/follow-up formula fortifier.

When the nutritional composition is a supplement, it can be provided in the form of unit doses.

The nutritional composition can be in solid (e.g. powder), liquid or gelatinous form.

The nutritional composition generally contains a protein source. The protein can be in an amount of from <NUM> to <NUM> per <NUM> kcal. In some embodiments, especially when the composition is intended for premature infants, the protein amount can be between <NUM> and <NUM>/100kcal or more than <NUM>/100kcal. In some other embodiments the protein amount can be below <NUM> per <NUM> kcal, e.g. between <NUM> to <NUM>/100kcal, or in an amount below <NUM> per <NUM> kcal.

The type of protein is not believed to be critical provided that the minimum requirements for essential amino acid content are met and satisfactory growth is ensured. Thus, protein sources based on whey, casein and mixtures thereof may be used as well as protein sources based on soy. As far as whey proteins are concerned, the protein source may be based on acid whey or sweet whey or mixtures thereof and may include alpha-lactalbumin and beta-lactoglobulin in any desired proportions.

The protein source may be whey predominant (i.e. more than <NUM>% of proteins are coming from whey proteins, such as <NUM>% or <NUM>%).

The proteins may be intact or hydrolysed or a mixture of intact and hydrolysed proteins. By the term "intact" is meant that the main part of the proteins are intact, i.e. the molecular structure is not altered, for example at least <NUM>% of the proteins are not altered, such as at least <NUM>% of the proteins are not altered, or at least <NUM>% of the proteins are not altered, or at least <NUM>% of the proteins are not altered, such as at least <NUM>% of the proteins are not altered. <NUM>% of the proteins may not be altered.

The term "hydrolysed" means in the context of the present disclosure a protein which has been hydrolysed or broken down into its component amino acids.

The proteins may be either fully or partially hydrolysed. It may be desirable to supply partially hydrolysed proteins (degree of hydrolysis between <NUM> and <NUM>%), for example for infants or young children believed to be at risk of developing cow's milk allergy. If hydrolysed proteins are required, the hydrolysis process may be carried out as desired and as is known in the art. For example, whey protein hydrolysates may be prepared by enzymatically hydrolysing the whey fraction in one or more steps. If the whey fraction used as the starting material is substantially lactose free, it is found that the protein suffers much less lysine blockage during the hydrolysis process. This enables the extent of lysine blockage to be reduced from about <NUM>% by weight of total lysine to less than about <NUM>% by weight of lysine; for example about <NUM>% by weight of lysine which greatly improves the nutritional quality of the protein source.

At least <NUM>% of the proteins are hydrolysed, or at least <NUM>% of the proteins are hydrolysed, such as at least <NUM>% of the proteins are hydrolysed, or at least <NUM>% of the proteins are hydrolysed, such as at least <NUM>% of the proteins are hydrolysed, or at least <NUM>% of the proteins are hydrolysed. <NUM>% of the proteins may be hydrolysed.

The proteins of the nutritional composition may be hydrolyzed, fully hydrolyzed or partially hydrolyzed. The degree of hydrolysis (DH) of the protein can be between <NUM> and <NUM>, or between <NUM> and <NUM> or between <NUM> and <NUM> or more than <NUM>, <NUM>, <NUM>, <NUM>, <NUM> or <NUM>.

The nutritional composition may be a hypoallergenic composition. The composition may be a hypoallergenic nutritional composition.

The nutritional composition generally contains a carbohydrate source. This is particularly preferable in the case where the nutritional composition of the invention is an infant formula. In this case, any carbohydrate source conventionally found in infant formulae such as lactose, sucrose, saccharose, maltodextrin, starch and mixtures thereof may be used although one of the preferred sources of carbohydrates is lactose.

The nutritional composition generally contains a source of lipids. This is particularly relevant if the nutritional composition is an infant formula. In this case, the lipid source may be any lipid or fat which is suitable for use in infant formulae. Some suitable fat sources include palm oil, high oleic sunflower oil and high oleic safflower oil. The essential fatty acids linoleic and α-linolenic acid may also be added, as well small amounts of oils containing high quantities of preformed arachidonic acid and docosahexaenoic acid such as fish oils or microbial oils. The fat source may have a ratio of n-<NUM> to n-<NUM> fatty acids of about <NUM>:<NUM> to about <NUM>:<NUM>; for example about <NUM>:<NUM> to about <NUM>:<NUM>.

The nutritional composition may also contain all vitamins and minerals understood to be essential in the daily diet and in nutritionally significant amounts. Minimum requirements have been established for certain vitamins and minerals. Examples of minerals, vitamins and other nutrients optionally present in the composition of the invention include vitamin A, vitamin B1, vitamin B2, vitamin B6, vitamin B12, vitamin E, vitamin K, vitamin C, vitamin D, folic acid, inositol, niacin, biotin, pantothenic acid, choline, calcium, phosphorous, iodine, iron, magnesium, copper, zinc, manganese, chlorine, potassium, sodium, selenium, chromium, molybdenum, taurine, and L-carnitine. Minerals are usually added in salt form. The presence and amounts of specific minerals and other vitamins will vary depending on the intended population.

If necessary, the nutritional composition may contain emulsifiers and stabilisers such as soy, lecithin, citric acid esters of mono- and diglycerides, and the like.

The nutritional composition may also contain other substances which may have a beneficial effect such as lactoferrin, nucleotides, nucleosides, and the like.

The nutritional composition may also contain carotenoid(s). In some particular embodiments of the invention, the nutritional composition of the invention does not comprise any carotenoid.

The nutritional composition may be prepared in any suitable manner. A composition will now be described by way of example.

For example, a formula such as an infant formula may be prepared by blending together the protein source, the carbohydrate source and the fat source in appropriate proportions. If used, the emulsifiers may be included at this point. The vitamins and minerals may be added at this point but they are usually added later to avoid thermal degradation. Any lipophilic vitamins, emulsifiers and the like may be dissolved into the fat source prior to blending. Water, preferably water which has been subjected to reverse osmosis, may then be mixed in to form a liquid mixture. The temperature of the water is conveniently in the range between about <NUM> and about <NUM> to aid dispersal of the ingredients. Commercially available liquefiers may be used to form the liquid mixture. The fucosylated oligosaccharide(s) and the N-acetylated oligosaccharide(s) may be added at this stage, especially if the final product is to have a liquid form. If the final product is to be a powder, they may likewise be added at this stage if desired.

The liquid mixture is then homogenised, for example in two stages.

The liquid mixture may then be thermally treated to reduce bacterial loads, by rapidly heating the liquid mixture to a temperature in the range between about <NUM> and about <NUM> for a duration between about <NUM> seconds and about <NUM> minutes, for example. This may be carried out by means of steam injection, an autoclave or a heat exchanger, for example a plate heat exchanger.

Then, the liquid mixture may be cooled to between about <NUM> and about <NUM> for example by flash cooling. The liquid mixture may then be again homogenised, for example in two stages between about <NUM> MPa and about <NUM> MPa in the first stage and between about <NUM> MPa and about <NUM> MPa in the second stage. The homogenised mixture may then be further cooled to add any heat sensitive components, such as vitamins and minerals. The pH and solids content of the homogenised mixture are conveniently adjusted at this point.

If the final product is to be a powder, the homogenised mixture is transferred to a suitable drying apparatus such as a spray dryer or freeze dryer and converted to powder. The powder should have a moisture content of less than about <NUM>% by weight. The fucosylated oligosaccharide(s) and the N-acetylated oligosaccharide(s) may also or alternatively be added at this stage by dry-mixing or by blending them in a syrup form of crystals, along with the probiotic strain(s) (if used), and the mixture is spray-dried or freeze-dried.

If a liquid composition is preferred, the homogenised mixture may be sterilised then aseptically filled into suitable containers or may be first filled into the containers and then retorted.

The supplement may be in the form of tablets, capsules, pastilles or a liquid for example.

The supplement may further contain protective hydrocolloids (such as gums, proteins, modified starches), binders, film forming agents, encapsulating agents/materials, wall/shell materials, matrix compounds, coatings, emulsifiers, surface active agents, solubilizing agents (oils, fats, waxes, lecithins etc.), adsorbents, carriers, fillers, cocompounds, dispersing agents, wetting agents, processing aids (solvents), flowing agents, taste masking agents, weighting agents, jellifying agents and gel forming agents. The supplement may also contain conventional pharmaceutical additives and adjuvants, excipients and diluents, including, but not limited to, water, gelatine of any origin, vegetable gums, lignin-sulfonate, talc, sugars, starch, gum arabic, vegetable oils, polyalkylene glycols, flavouring agents, preservatives, stabilizers, emulsifying agents, buffers, lubricants, colorants, wetting agents, fillers, and the like.

Further, the supplement may contain an organic or inorganic carrier material suitable for oral or parenteral administration as well as vitamins, minerals trace elements and other micronutrients in accordance with the recommendations of Government bodies such as the USRDA.

The nutritional composition may be for use in infants or young children. The infants or young children may be born term or preterm. The nutritional composition may be for use in infants or young children that were born preterm. The nutritional composition may be for use in preterm infants.

The nutritional composition may also be used in an infant or a young child that was born by C-section or that was vaginally delivered.

The composition can be for use before and/or during the weaning period.

The nutritional composition can be administered (or given or fed) at an age and for a period that depends on the needs. The nutritional composition of the present invention is used for prevention or treatment purposes:.

The nutritional composition may be used for prevention purposes. The nutritional composition can be for example given immediately after birth of the infants. The composition can also be given during the first week of life of the infant, or during the first <NUM> weeks of life, or during the first <NUM> weeks of life, or during the first month of life, or during the first <NUM> months of life, or during the first <NUM> months of life, or during the first <NUM> months of life, or during the first <NUM> months of life, or during the first <NUM> months of life, or during the first <NUM> months of life, or during the first year of life, or during the first two years of life or even more. The nutritional composition may be given (or administered) to an infant within the first <NUM> or <NUM> months of birth of said infant.

The nutritional composition may be given few days (e.g. <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>. ), or few weeks (e.g. <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>. ), or few months (e.g. <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>. ) after birth. This may be especially the case when the infant is premature, but not necessarily.

The composition may be given to the infant or young child as a supplementary composition to the mother's milk. In some embodiments the infant or young child receives the mother's milk during at least the first <NUM> weeks, first <NUM>, <NUM>, <NUM>, or <NUM> months. The nutritional composition may be given to the infant or young child after such period of mother's nutrition, or is given together with such period of mother's milk nutrition The composition is given to the infant or young child as the sole or primary nutritional composition during at least one period of time, e.g. after the <NUM>st, <NUM>nd or <NUM>th month of life, during at least <NUM>, <NUM>, <NUM> or <NUM> months.

The nutritional composition may be a complete nutritional composition (fulfilling all or most of the nutritional needs of the subject). The nutrition composition may be a supplement or a fortifier intended for example to supplement human milk or to supplement an infant formula or a follow-on formula.

The nutritional composition may be given for treatment purposes, e.g. when the composition is used for the treatment of constipation.

In these cases, the nutritional composition can be given for some days (<NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>. ), or for some weeks (<NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> or even more), or for some months (<NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> or even more), depending on the needs. It may be given once the symptoms appear or once these health diseases/conditions have been diagnosed. It may be given up to the symptoms of the treated diseases/conditions disappear, or several days/weeks/months after said disappearance.

The health benefits/effects may be observed during the first few weeks or months of life and/or during the first few weeks or months after administration of the nutritional composition, e.g. during the first week, the first <NUM> weeks, the first month, the first <NUM> months, the first <NUM> months or the first <NUM> months. Effects at longer term may be less important. The nutritional composition may be for use in improving stool consistency/frequency in an infant during the first month or first <NUM> months of life and/or after administration of the nutritional composition. The nutritional composition may be for use in preventing and/or treating colics in infants during the first month, the first <NUM> months or the first <NUM> months of life and/or after administration of the nutritional composition, especially in C-section infants.

The nutritional composition was also particularly efficient in terms of flatulence, bloating, colics and gut discomfort since no or a limited level was observed in said infant or young child.

The following examples illustrate some specific embodiments of the composition for use according to the present invention. The examples are given solely for the purpose of illustration and are not to be construed as limitations of the present invention.

An example of the composition of a nutritional composition (e.g. an infant formula) according to the present invention is given in the below table <NUM>. This composition is given by way of illustration only.

A controlled, single-blind, randomized, multi-center, interventional clinical trial of <NUM> groups in parallel was made. Infants were recruited and randomized to one of the <NUM> study arms within <NUM> days after birth. The study arms consisted of a classical infant starter formula without HMO [Control] or this classical infant starter formula supplemented with <NUM> HMOs [HMO]. The composition of the tested infant formula with or without the addition of HMOs was equivalent to the composition shown in table <NUM>, except that:.

Introduction of weaning food was from <NUM> months onwards.

The study consists of a <NUM> months ± <NUM> days treatment period with one of the two treatments and a <NUM> months follow-up period without treatment.

The inventors surprisingly observed that infants of the HMO group (i.e. those fed a classical formula supplemented with <NUM>/L of <NUM>'-fucosyllactose and <NUM>/L lacto-N-neotetraose had less hard stools, both at <NUM> month (<FIG>) and <FIG> months (<FIG>) of age. In the same time, no particular issue of flatulence, bloating, colics and gut discomfort was reported in said infant or young child.

In particular, there was also a significant lower level of colics in infants fed the HMOs born form C-section at <NUM> months of age, see <FIG>.

Claim 1:
A synthetic nutritional composition comprising at least one fucosylated oligosaccharide and at least one N-acetylated oligosaccharide for use in preventing and/or treating constipation and /or preventing and/or treating flatulence, bloating, colics and/or gut discomfort in an infant or a young child,
wherein the fucosylated oligosaccharide is <NUM>'-fucosyllactose and
wherein the N-acetylated oligosaccharide is lacto-N-neotetraose (LNnT), and
- the fucosylated oligosaccharide is in a total amount of <NUM>-<NUM>/L of the composition and/or in a total amount of <NUM>-<NUM>/<NUM> of composition on a dry weight basis; and
- the N-acetylated oligosaccharide is in a total amount of <NUM>-<NUM>/L of composition on a dry weight basis and/or in a total amount of <NUM>-<NUM>/<NUM> of composition on a dry weight basis; and
wherein an infant is a child under the age of <NUM> month and a young child is a child aged between one year and three years.