Human milk oligosaccharides against future excessive fat mass accumulation and related health disorders

Abstract

The present invention relates to human milk oligosaccharides against future excessive fat mass accumulation and related health disorders, in particular to nutritional compositions comprising at least one fucosylated oligosaccharide for use in infants or young children, the present invention relates to a fucosylated oligosaccharide having at least one fucose group linked by an alpha 1, 3 bond, at least one fucose group linked by an alpha 1, 4 bond, or a combination thereof, for use in reducing and / or preventing future excessive accumulation of fat mass and / or health disorders associated with excessive accumulation of fat mass, in which the fucosylated oligosaccharide has at least one fucose group linked by an alpha 1, 3 bond, at least one fucose group linked by an alpha 1, 4 bond, or a combination thereof. The invention also relates to a nutritional composition for use in promoting healthy growth.

Description

[0001] The applicant submitted a PCT application PCT / EP2017 / 051587 entitled “Human milk oligosaccharides against excessive fat accumulation and related health disorders” on January 26, 2017. The PCT application entered the Chinese national phase on July 23, 2018 with application number 201780007742.9. This application is a divisional application of the Chinese application. Technical Field

[0002] The present invention relates to a nutritional composition for infants or young children to avoid excess fat accumulation later in life. In particular, the present invention relates to preventing health disorders associated with excess fat accumulation later in life. Background Art

[0003] The prevalence of obesity and overweight in adults, children and adolescents has increased rapidly worldwide over the past 30 years and continues to rise. According to the World Health Organization, obesity has more than doubled worldwide since 1980. Obesity has become a global health concern because it is associated with reduced life expectancy, altered quality of life and is a cause of additional health conditions. Overweight and obesity are associated with more deaths worldwide than underweight. In fact, childhood obesity is associated with a higher likelihood of obesity, premature death and disability in adulthood. However, in addition to an increased risk of future illness, obese children also experience an increased risk of breathing difficulties, fractures, high blood pressure, early markers of cardiovascular disease, insulin resistance and psychological effects. An elevated BMI is a major risk factor for noncommunicable diseases, including cardiovascular disease (mainly heart disease and stroke), which was the leading cause of death in 2012; diabetes; musculoskeletal disorders (especially osteoarthritis - a highly disabling degenerative disease); and even some cancers (endometrial, breast and colon cancer).

[0004] For various reasons, it is recommended that all infants adopt breastfeeding. It is reported that compared with formula feeding, breastfeeding is particularly beneficial to the prevention of obesity (Owen et al., Effect of Infant Feeding on the Risk of Obesity Across the Life Course: A Quantitative Review of Published Evidence, 2005). Evidence shows that infancy may be a critical period for the occurrence and programming of obesity or future metabolic diseases. It is widely reported that breastfed infants have different growth patterns from infants fed with infant formula. In fact, compared with infants fed with formula, breastfed infants have lower weight gain and lower body fat in the first year after birth. In addition, breastfed infants have different intestinal microbial population distributions compared with infants fed with infant formula. In a word, these factors affect the physiological development of infants, including metabolism, immunity and overall growth.

[0005] However, in some cases, breastfeeding is not sufficient or successful, or the mother does not choose breastfeeding due to certain medical reasons. Infant formulas have been developed for these situations. Fortifiers that enrich breast milk or infant formulas with special ingredients have also been developed. It is known that the growth rate of infants affects the risk of excessive accumulation of fat mass and related metabolic and cardiovascular diseases in the future. In particular, a faster growth rate in infancy can make infants prone to obesity in the future.

[0006] Therefore, a nutritional composition that aids in the healthy growth of infants and young children and that can help prevent excessive accumulation of fat mass would be advantageous.

[0007] Since these individuals are particularly fragile and not amenable to traditional pharmacological interventions, it is obvious that the means of providing such health benefits should be non-pharmacological interventions that are particularly suitable for young individuals (infants and young children).

[0008] There is a need to deliver such health benefits to infants or young children in a manner that does not induce side effects and / or in a manner that is not only easily delivered but also widely accepted by parents or health care providers.

[0009] Furthermore, the means of providing this benefit should be priced reasonably and affordable to most people. Summary of the invention

[0010] Therefore, one aspect of the present invention relates to a nutritional composition comprising at least one fucosylated oligosaccharide for infants or young children for reducing and / or avoiding excessive fat mass accumulation in the future and / or health disorders associated with excessive fat mass accumulation in the future, such as obesity and obesity-related comorbidities in the future; wherein the fucosylated oligosaccharide has at least one fucose group linked by a 1,3 linkage, at least one fucose group linked by a 1,4 linkage, or a combination thereof.

[0011] Another aspect of the invention relates to the use of a nutritional composition as defined in any of the preceding claims for reducing the risk of an infant or young child becoming overweight later in life.

[0012] Another aspect of the invention relates to the use of the nutritional composition according to the invention by preventing premature obesity rebound.

[0013] In a further aspect, the present invention relates to a nutritional composition comprising at least one fucosylated oligosaccharide having at least one fucose group linked by an α1,3 linkage, at least one fucose group linked by an α1,4 linkage, or a combination thereof, for promoting healthy growth of an infant or young child.

[0014] Another aspect of the present invention is to provide a method for identifying whether an infant has excessive fat mass accumulation and / or a risk of one or more health disorders associated with excessive fat accumulation during infancy or later in life; the method comprises determining the presence of the following single nucleotide polymorphism in the FUT3 gene of the infant's mother:

[0015] a) rs3894326 (accession number in the NCBI single nucleotide polymorphism database)

[0016] The presence of the polymorphism is associated with an increased risk of excess fat mass accumulation during infancy and later in life and of one or more health disorders associated with excess fat mass. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Figure 1 Shown are the gender-specific LMS conditional z scores for abdominal circumference for the 6-12 month polymorphism FUT3 rs3894326.

[0018] Figure 2 Shown are the gender-specific LMS conditional z scores for abdominal circumference for the 2-3 years polymorphism FUT3 rs3894326. DETAILED DESCRIPTION

[0019] definition

[0020] Before discussing the present invention in further detail, the following terms, expressions and conventions are first defined:

[0021] Fucose has the chemical formula C6H 12 Hexasaccharide deoxysugar of O5. It corresponds to 6-deoxy-L-galactose.

[0022] Fucosyltransferases (also known as glycosyltransferase family 10) are enzymes that transfer L-fucose from a GDP-fucose (guanosine diphosphate-fucose) donor substrate to an acceptor substrate.

[0023] Fucosyltransferase 3 (abbreviated herein as FUT3) is also known as galactoside 3(4)-L-fucosyltransferase. Additional synonyms include CD174; FT3B, FucT-III, LE; and Les. The EC number is 2.4.1.65, and the OMIM number is 111100. Homologous genes: 55438 ChEMBL: 3269 GeneCards: FUT3 gene.

[0024] The FUT3 gene encodes an enzyme with α(1,3)-fucosyltransferase and α(1,4)-fucosyltransferase activities.

[0025] Fucosyltransferase 2 (abbreviated herein as FUT2) is also known as galactoside 2-α-L-fucosyltransferase 2, EC 2.4.1.69, SE 2, SEC2, fucosyltransferase-2 (secreted), GDP-L-fucose:β-D-galactoside 2-α-L-fucosyltransferase 2, galactoside 2-α-L-fucosyltransferase 2, secretory blood group α-2-fucosyltransferase, secretory factor, and transmembrane protein 2. The FUT2 gene is also referred to in the art as a secretory gene (Se).

[0026] SNPs (single nucleotide polymorphisms) are variations of a single nucleotide that can occur at some specific positions in the genome, where each variation is present in a population to some significant degree. Functional SNPs (such as those described in the present invention) affect protein expression.

[0027] The term "infant" refers to persons under the age of 12 months.

[0028] The term "young children" refers to those aged one to three years old, also known as toddlers.

[0029] The term "child" refers to persons aged three years and up to 12 years.

[0030] People aged 12 to 18 are called adolescents, and people aged 18 and above are called adults.

[0031] The expression "nutritional composition" means a composition that supplies nutrients to an individual. The nutritional composition is usually taken orally or intravenously. It may include a lipid or fat source, a carbohydrate source and / or a protein source.

[0032] In a particular embodiment, the composition of the invention is a hypoallergenic nutritional composition.The expression "hypoallergenic nutritional composition" means a nutritional composition which is less likely to cause an allergic reaction.

[0033] In a specific embodiment, the nutritional composition of the invention is a "synthetic nutritional composition". The expression "synthetic nutritional composition" means a mixture obtained by chemical and / or biological methods, the chemical properties of which mixture may be identical to the mixture naturally occurring in mammalian milk (i.e., the synthetic nutritional composition is not breast milk).

[0034] As used herein, the expression "infant formula" refers to a food intended for specific nutritional use for infants during the first few months after birth (such as from 0 to 12 months, 0 to 10 months, 0 to 8 months, 0 to 6 months or 0 to 4 months), and which itself meets the multiple nutritional needs of this group of people (in accordance with Article 2 (c) of Directive 91 / 321 / EEC 2006 / 141 / EC of the European Commission of 22 December 2006 on infant formula and follow-on formula). It also relates to nutritional compositions intended for infants, as defined in the Codex Alimentarius Commission (Codex STAN 72-1981) and special products for infants (including foods for special medical purposes). The expression "infant formula" covers both "stage 1 infant formula" and "stage 2 infant formula" or "follow-on formula".

[0035] "Step 2 infant formula" or "follow-on formula" is given from the 6th month onwards. Infant formula constitutes the main liquid element in the gradually diversified diet of such people.

[0036] "Growing-up milk" (or GUM) is generally a milk-containing beverage adapted for the special nutritional needs of a toddler or young child.

[0037] The expression "baby food" means a foodstuff intended for special nutritional use for infants or young children during the first year of life.

[0038] The expression "infant cereal composition" means a foodstuff intended for special nutritional use for infants or young children during the first year of life.

[0039] The term "fortifier" refers to a liquid or solid nutritional composition suitable for mixing with breast milk or infant formula.

[0040] The term "supplement" refers to a nutritional composition intended to provide nutrients that may not be consumed in sufficient amounts. It is consumed with other nutrients / foods. Supplements can be, for example, tablets, capsules, lozenges or liquid forms. Supplements can also contain protective hydrophilic colloids (such as gums, modified starches), binders, film formers, encapsulating agents / materials, wall / shell materials, matrix compounds, coatings, emulsifiers, surfactants, solubilizers (oils, fats, waxes, lecithins, etc.), adsorbents, carriers, fillers, co-compounds, dispersants, wetting agents, processing aids (solvents), flow agents, taste masking agents, weighting agents, gelling agents and gel forming agents. Supplements may also contain conventional pharmaceutical additives and adjuvants, excipients and diluents, including but not limited to: water, gelatin from any source, vegetable gums, lignin sulfonates, talc, sugars, starches, gum arabic, vegetable oils, polyalkylene glycols, flavors, preservatives, stabilizers, emulsifiers, buffers, lubricants, colorants, wetting agents, fillers, etc. The term "supplement" has the same meaning as supplement, and the two terms are used interchangeably herein.

[0041] The expressions "fat mass accumulation" and "fat accumulation" are used interchangeably. The expression "excessive accumulation of fat mass" refers to an abnormal amount of body fat, for example, an amount that may be detrimental to health and may lead to health disorders. Being overweight or obese are examples of having excessive accumulation of fat.

[0042] The body mass index (BMI) is a simple index of weight-for-height that is commonly used to classify overweight and obesity. BMI is defined as a person's weight in kilograms divided by the square of their height in meters (kg / m2). According to the WHO, a BMI of 25 or more is considered overweight; a BMI of 30 or more is considered obese.

[0043] The expressions "reducing (excess) fat mass accumulation" and "avoiding (excess) fat mass accumulation" refer to reducing or limiting the body fat mass of an individual.

[0044] The expression "health disorder" encompasses any health condition and / or disease and / or malfunction affecting an individual organism, including metabolic diseases.

[0045] The expressions "preventing a health disorder later in life" or "preventing a later in life health disorder" are used interchangeably. They mean avoiding the occurrence of a health disorder (e.g. obesity) at a later date and / or reducing the incidence and / or severity of a health disorder at a later date. This prevention occurs "later", thus preferably after the intervention or treatment has ended (i.e. after the administration of the nutritional composition according to the invention).

[0046] The expression "future health disorders associated with excess accumulation of fat mass" refers to future health disorders caused by (ie, directly related to) or associated with (ie, indirectly related to) excess fat. It encompasses overweight, obesity, and obesity-related comorbidities.

[0047] The term "obesity-related comorbidities" includes hypertension, dyslipidemia, insulin resistance, type 2 diabetes, sleep apnea, arthritis, hyperuricemia, gallbladder disease, cardiovascular disease, metabolic syndrome, and certain types of cancer.

[0048] This prevention takes place "later", for example after administration of the nutritional composition according to the invention, or for example after the end of an intervention or treatment.

[0049] The expressions "later in life" and "in later life" are used interchangeably. An effect occurring "later in life" refers to an effect measured in an individual (infant or toddler) after a few weeks, months or years of age, such as after 6 months of age, such as after 8 months of age, such as after 10 months of age, such as after 1 year of age, such as after 2 years of age, preferably after 4 years of age, more preferably after 5 years of age, even more preferably after 7 years of age or even longer, and the results are compared with the average observations of individuals of the same age. It preferably refers to an effect observed after at least 1 year of age or after at least 2, 5, 7, 10 or 15 years of age. Thus, the expression "later" may refer to observations during infancy, during early childhood, during childhood, during adolescence or during adulthood. Preferably, it refers to observations during childhood, during adolescence or during adulthood.

[0050] The expression "breast milk" is to be understood as mother's breast milk or colostrum.

[0051] The expression "HMO" or "HMOs" refers to human milk oligosaccharides. These carbohydrates are resistant to enzymatic hydrolysis by digestive enzymes (e.g. pancreatic and / or brush border), which indicates that they can exhibit functions that are not directly related to their caloric value. In particular, it has been suggested in the art that these carbohydrates play a key role in the early development of infants and young children, such as the maturation of the immune system. Many different types of HMO are found in human milk. Each individual oligosaccharide is based on a combination of glucose, galactose, sialic acid (N-acetylneuraminic acid), fucose and / or N-acetylglucosamine with a wide variety of bonds between these molecules, so that human milk contains a large number of different types of oligosaccharides, with more than 130 such structures identified to date. Almost all oligosaccharides have a lactose molecule at the reducing end, and the terminal position of the non-reducing end is occupied by sialic acid and / or fucose (if any). HMOs can be acidic (e.g., oligosaccharides containing charged sialic acid) or neutral (e.g., fucosylated oligosaccharides).

[0052] "Fucosylated oligosaccharides" are oligosaccharides containing fucose residues. Such oligosaccharides are neutral. Some examples are 2-FL (2'fucosyllactose), 3-FL (3-fucosyllactose), difucosyllactose, lactose-N-fucopentaose (e.g., lactose-N-fucopentaose I, lactose-N-fucopentaose II, lactose-N-fucopentaose III, lactose-N-fucopentaose V), lactose-N-fucohexaose, lactose-N-difucohexaose I, fucosyllactose-N-hexaose, fucosyllactose-N-neohexaose, difucosyllactose-N-hexaose I, difucosyllactose-N-neohexaose II, and any combination of these substances.

[0053] "α1,3 fucosylated oligosaccharides" are oligosaccharides having fucose linked to C3 of a monosaccharide unit of a monosaccharide or oligosaccharide (2 or more monosaccharides) via C1 of the fucose in the α conformation.

[0054] "α1,4 fucosylated oligosaccharides" are oligosaccharides having fucose linked to C4 of a monosaccharide unit of a monosaccharide or oligosaccharide (2 or more monosaccharides) via C1 of the fucose in the α conformation. The expression "N-acetylated oligosaccharide" encompasses "N-acetyllactosamine" and "oligosaccharides containing N-acetyllactosamine". Such oligosaccharides are neutral oligosaccharides having N-acetyllactosamine residues. Suitable examples are: LNT (lactose-N-tetraose), p-lactose-N-neohexaose (p-LNnH), LNnT (lactose-N-neotetraose) or any combination thereof. Other examples are: lactose-N-hexaose, lactose-N-neohexose, p-lactose-N-hexaose, p-lactose-N-neohexose, lactose-N-octaose, lactose-N-neooctaose, iso-lactose-N-octaose, p-lactose-N-octaose and lactose-N-decaose.

[0055] "HMO precursors" are key compounds for the production of HMOs, such as sialic acid and / or fucose.

[0056] "Sialyl oligosaccharides" are oligosaccharides containing charged sialic acid, i.e. oligosaccharides containing sialic acid residues. Such oligosaccharides are acidic. Some examples are 3-SL (3'-sialyllactose) and 6-SL (6'-sialyllactose).

[0057] The nutritional composition of the present invention may be in solid form (e.g., powder) or in liquid form. The amount of each ingredient (e.g., oligosaccharide) may be expressed as g / 100 g of the composition on a dry weight basis when the composition is in solid form (e.g., powder), or as a concentration of g / L of the composition when the composition is in liquid form (the latter also encompasses liquid compositions obtained after reconstitution of the powder in a liquid (such as milk or water), such as reconstituted infant formula or larger / stage 2 infant formula or infant cereal products or any other formulation designed to provide nutrition to infants).

[0058] The term "prebiotic" refers to non-digestible carbohydrates that have a beneficial effect on the host by selectively stimulating the growth and / or activity of beneficial bacteria (e.g., Bifidobacteria in the human colon) (Gibson GR, Roberfroid MB. Dietary modulation of the human colonic microbiota: introducing the concept of prebiotics. J Nutr. 1995; 125: 1401-1412).

[0059] The term "probiotics" refers to microbial cell preparations or microbial cell components that have a beneficial effect on the health or well-being of the host. (Salminen S, Ouwehand A. Benno Y. et al. "Probiotics: how should they be defined" Trends Food Sci. Technol. 1999, Vol. 10, pp. 107-110). Microbial cells are generally bacteria or yeast.

[0060] The term "cfu" is to be understood as colony forming units.

[0061] Unless otherwise indicated, all percentages are by weight.

[0062] In addition, in the context of the present invention, the term "comprising" or "including" does not exclude other possible elements. The composition mentioned in the present invention (including the multiple embodiments described herein) may include the following elements, be composed of or consist essentially of the following elements: the basic elements and necessary restrictions described herein, and any other or optional (or depending on the needs) ingredients, components or restrictions described herein.

[0063] Any reference to prior art documents in this specification is not to be taken as an admission that such prior art is well known or forms part of the common general knowledge in the art.

[0065] Basis of the Invention

[0066] The present invention is based on the recognition of the importance of fucosylated oligosaccharides in the diet of infants for timed obesity rebound (as defined below). Mothers showing a single nucleotide polymorphism (SNP) that disrupts the expression of FUT3 (the gene encoding fucosyltransferase 3) also show reduced amounts of α1,3 and α1,4 fucosylated oligosaccharides in breast milk. The inventors have surprisingly shown that the presence of this particular SNP is significantly correlated with abdominal circumference measurements in infants and young children (see Examples and Table 3).

[0067] This implies that fucosylated human milk oligosaccharides such as α1,3 fucosylated oligosaccharides and α1,4 fucosylated oligosaccharides (such as those fucosylated by FUT3) affect infant growth and promote timed adiposity rebound.

[0068] Obesity rebound is defined as a stage in individual development in the context of the present invention, in which BMI begins to rise after infancy. Usually infants gain weight during the earliest period of life. Afterwards is a period of infant / toddler development in which BMI decreases. The reduction of BMI is usually due to increased height growth, and may also be due to reduced fat accumulation. At a certain time point in development, BMI will stop decreasing and start to rise again. This time point when BMI begins to rise after infancy is called obesity rebound (AR). The term obesity rebound is an accepted term in the art, and has been described in, for example, Rolland-Cahera et al., Am J Clin Nutr. January 1984, Vol. 39, No. 1: 129-135 pages.

[0069] Premature adiposity rebound is associated with excessive accumulation of fat mass later in life, such as during adolescence and / or adulthood. Young children who exhibit premature adiposity rebound (ie, adiposity rebound that occurs earlier than expected) are at increased risk for later overweight, obesity, and obesity-related comorbidities.

[0070] Previously, fucosylated human milk oligosaccharides and growth have been studied. For example, Alderete et al. studied human milk oligosaccharides in early development (Alderete et al., Am J Clin Nutr. December 2015, Vol. 102, No. 6: pp. 1381-1388). However, the conclusions that can be drawn from this study are limited to the time period from birth (0 months) to 6 months studied, and it is impossible to infer the effect of human milk oligosaccharides on the risk of excessive accumulation of fat mass in the future, nor the timing of obesity rebound. In fact, the authors themselves also draw these conclusions.

[0071] Furthermore, the effects of fucosylated oligosaccharides recorded in Alderete et al. vary depending on the type of fucosylated oligosaccharide. For example, α1,3 fucosylated oligosaccharides and α1,4 fucosylated oligosaccharides (such as LNFPII) are associated with fat gain at 6 months. Fucosylated oligosaccharides that do not contain such bonds (e.g., LNFPI, LNnT) obtain the opposite results. Therefore, one skilled in the art would not choose α1,3 fucosylated oligosaccharides and α1,4 fucosylated oligosaccharides (such as fucosylated oligosaccharides fucosylated by FUT3) to avoid future fat mass accumulation. However, the inventors of the present invention have shown that these specific oligosaccharides can actually avoid premature obesity rebound, thus preventing excessive accumulation of fat in the future or its associated disorders.

[0072] Acting on premature adiposity rebound represents new clinical scenarios in which prevention of later health disorders can be targeted in new ways.

[0073] Nutritional composition for said use

[0074] Therefore, the present invention relates in a first aspect to a nutritional composition comprising at least one fucosylated oligosaccharide for infants or young children for reducing and / or avoiding excessive fat mass accumulation in the future and / or health disorders associated with excessive fat mass accumulation in the future, such as obesity and related comorbidities in the future; wherein the fucosylated oligosaccharide has at least one fucose group linked by an α1,3 bond, at least one fucose group linked by an α1,4 bond, or a combination thereof.

[0075] The nutritional composition of the present invention is typically administered to an infant or young child; however, the effect of preventing future excess fat mass accumulation and / or the effect of preventing future health disorders associated with excess fat mass accumulation (such as future obesity and related comorbidities) may first be observed in the infant or young child later in life.

[0076] In the context of this patent application, "later" means the same infant or toddler to whom the nutritional composition is applied later. Therefore, the nutritional composition for use according to the present invention can be applied to an infant or toddler, and can help prevent excessive accumulation of fat mass and / or health disorders associated with excessive accumulation of fat mass, which otherwise may occur later in the life of the infant or toddler. In this context, "later" may mean, for example, any stage when an infant or toddler is no longer an infant, such as an infant or toddler may have become a child, a teenager or an adult. Also see the "definition" section for further discussion of the expression "later".

[0077] In one embodiment, the nutritional composition according to the invention can be used to reduce and / or prevent excessive accumulation of fat mass in infants or young children. This means that the nutritional composition according to the invention is administered to an infant or young child and prevents excessive accumulation of fat mass in the infant or young child.

[0078] In another embodiment, the nutritional composition according to the present invention can be used for infants or young children for reducing and / or preventing excessive accumulation of fat mass in the future. This means that the nutritional composition according to the present invention is administered to an infant or young child and prevents excessive accumulation of fat mass in the future of the infant or young child.

[0079] In a further embodiment, the nutritional composition according to the invention can be used for infants or young children for preventing health disorders associated with excessive accumulation of fat mass in the future. This means that the nutritional composition according to the invention is administered to an infant or young child and prevents health disorders associated with excessive accumulation of fat mass, which occur in the future of the infant or young child.

[0080] Fucosylated oligosaccharides

[0081] As mentioned above, the nutritional composition for use according to the present invention comprises at least one fucosylated oligosaccharide, wherein the fucosylated oligosaccharide has at least one fucose group linked via an α1,3 linkage, at least one fucose group linked via an α1,4 linkage, or a combination thereof.

[0082] In a specific embodiment, the fucosylated oligosaccharide is fucosylated by FUT3. Thus, in a specific embodiment, the present invention relates to a nutritional composition for use according to the present invention, comprising at least one fucosylated oligosaccharide fucosylated by FUT3, for reducing and / or avoiding excessive accumulation of fat mass in an infant or young child; and / or for preventing health disorders in an infant or young child later in life that are associated with excessive accumulation of fat mass, such as later obesity and related comorbidities.

[0083] In one embodiment of the invention, the at least one fucosylated oligosaccharide in the nutritional composition according to the invention is one or more fucosylated oligosaccharides selected from the group consisting of: 3'-fucosylated lactose (3FL), DFL, LNFPII, LNFP III, LNFP V, LNDFH I, LNDFHII, F-LNH II, F-para-LNH I, F-para-LNH II, DF-LNH II, DF-LNH I, DF-LNnH, DF-para-LNH, DF-para-LNnH, TF-LNH, TF-para-LNH I, TF-para-LNHII, TF-para-LNnH, F-LNO, F-LNnO, F-iso-LNO, DF-LNO I, BF-LNO II, DF-LNnO I, DF-LNnO II, DF-iso-LNOI, DF-iso-LNO II, TF-LNO, TF-LNnO, TF-iso-LNO I, TF-iso-LNO II, tetra-F-iso-LNO, tetra-F-para-LNO, penta-F-iso-LNO, F-LND, F-SL, F-LSTa, F-LSTb, F-LSTd, FS-LNH I, FS-LNHII, FS-LNH III, FS-LNH IV, FS-LNnH I, FS-LNnH II, DFS-LNH I, DFS-LNH II, DFS-LNnH, FS-LNO, FS-iso-LNO, DFS-iso-LNO I, FS-iso-LNOII, DFS-LNO, TFS-iso-LNO, FDS-LNT I, FDS-LNH II, FDS-LNHIII, FDS-LNnH, FS-neo-LNP I, DF-p-LNH sulfate I, DF-p-LNH sulfate II, TF-p-LNH sulfate and combinations thereof (for explanation of abbreviations, see Table 1). For milk oligosaccharides, reference is also made to "Oligosaccharides: Sources, Properties and Applications", Nova Science Publishers, 2011; Editor Nicole S Gordon; Chapter 1, and in particular to Table 4 of Chapter 1, which details the structures of the above oligosaccharides).

[0084] A specific embodiment of the nutritional composition for use according to the invention relates to one wherein the at least one fucosylated oligosaccharide is selected from the group consisting of: 3' fucosylated lactose (3' FL), DFL, LNFP II, LNFP III, LNFP V.

[0085] In a further specific embodiment of the present invention, the at least one fucosylated oligosaccharide is selected from the group consisting of: 3' fucosylated lactose (3' FL) and DFL.

[0086] The abbreviation of fucosylated oligosaccharides will be used hereinafter to refer to the following fucosylated oligosaccharides.

[0087] Table 1: Common names and abbreviations of fucosylated oligosaccharides

[0088]

[0089]

[0090] Yes means it exists, and an empty box means it does not exist.

[0091] Health disorders and obesity rebound

[0092] A further embodiment relates to a nutritional composition for use according to the invention, wherein the health disorder associated with excessive accumulation of fat mass is selected from: overweight, obesity, type 2 diabetes, insulin resistance, hypertension, cardiovascular disease or metabolic syndrome and premature obesity rebound.

[0093] Examples of obesity-related comorbidities include one or more of insulin resistance, glucose intolerance, diabetes, hypertension, dyslipidemia, sleep apnea, arthritis, hyperuricemia, gallbladder disease and certain types of cancer, coronary artery disease, heart failure, arrhythmia, stroke, and menstrual disorders.

[0094] A specific embodiment relates to a nutritional composition for use according to the invention, wherein the health disorder associated with excessive accumulation of fat mass is premature obesity rebound.

[0095] Obesity rebound typically occurs from age 6, for example after age 6, or after age 7, or for example at age 7; such as in the time period of 6 to 9 years, such as 6 to 8 years, for example 6 to 7 years.

[0096] In contrast, premature obesity rebound is defined in the context of the present patent application as obesity rebound that occurs earlier than it normally would. Thus, for example, when obesity rebound (i.e., the time when BMI begins to rise after infancy) occurs before the age of 6, for example, in a time period of 2 to a maximum of 6 years, for example, 3 to a maximum of 6 years, or for example, 4 to a maximum of 6 years, or 5 to a maximum of 6 years, or for example, 2 to 5 years, 3 to 5 years, 4 to 5 years, it can be said to be premature obesity rebound.

[0097] Preventing premature obesity rebound

[0098] As mentioned above, premature obesity rebound is associated with excessive accumulation of fat mass in the future, such as in adolescence and / or adulthood. The risk of overweight, obesity and obesity-related comorbidities in the future of young children who show premature obesity rebound (i.e., obesity rebound occurring earlier than expected) increases. Therefore, the present invention relates in another aspect to a nutritional composition for use according to the present invention by preventing premature rebound.

[0099] In further embodiments, the nutritional composition for use according to this aspect may be as described above with respect to the previous aspects of the invention, in particular, wherein the infant or young child may be as described herein under the heading Target Group.

[0100] Target Group

[0101] The nutritional composition according to the invention is intended for infants or young children.

[0102] In some embodiments, the nutritional composition according to the invention is for use in infants or young children who are at risk of later developing health disorders related to excessive accumulation of fat mass.

[0103] Infants or young children can be full-term or premature births. In a specific embodiment, the nutritional composition of the present invention is used for premature infants. Premature infants may have insulin resistance, hyperglycemia, poor nutrient utilization, impaired lean body growth, visceral fat accumulation and metabolic disease in the future. Therefore, an embodiment of this aspect of the present invention relates to a nutritional composition for purposes according to the present invention, wherein an infant or young child has a risk of obesity, such as selected from: premature infants, overweight and obese mothers born of infants and / or infants born of mothers carrying SNP rs3894326.

[0104] The nutritional composition of the present invention can also be used for infants or young children born by caesarean section or vaginal delivery.

[0105] The timing of obesity rebound may change in subgroups, or for example change in different target groups.Therefore, as an alternative, premature obesity rebound can be defined as the obesity rebound that occurs at least 6 months earlier than the average timing of the obesity rebound of the subgroup.For example, premature obesity rebound can be defined as the obesity rebound that occurs 8 months earlier, 12 months earlier, 18 months earlier, and 24 months earlier than the average time point of the subgroup.In another example, premature obesity rebound can be defined as the obesity rebound that occurs in the time period of 6 months to 36 months earlier than the average time point of the subgroup, such as the obesity rebound that occurs in the time period of 6 months to 30 months, 7 months to 24 months, 7 months to 20 months, 7 months to 18 months, 7 months to 16 months, 8 months to 12 months earlier than the average time point of the subgroup.

[0106] The subgroup may be, for example, a selected target population, such as a subgroup of infants determined to be at risk of overweight and / or obesity in the future. In one embodiment, the subgroup may be infants born to mothers showing the SNPs according to the present invention. In another embodiment, the subgroup may be infants or young children born to overweight and obese women. In fact, scientific evidence continues to show that infants born to overweight and obese mothers are at greater risk of becoming overweight or obese in the future than infants born to mothers who are not overweight or obese.

[0107] Nutritional composition

[0108] Further embodiments of this aspect of the invention relate to nutritional compositions for use according to the invention, wherein at least one fucosylated oligosaccharide having α1,3 and / or α1,4 bonds (or fucosylated oligosaccharides fucosylated by FUT3) is present in an amount of 0.02 wt% to 10 wt%, such as 0.1 wt% to 5 wt%, or 0.2 wt% to 1.5 wt% of the nutritional composition, all percentages being by dry weight. In some embodiments, at least one fucosylated oligosaccharide is present in a total amount of 0.05 g / L to 1.5 g / L, for example 0.1 g / L or 0.8 g / L of the composition.

[0109] In a further embodiment, the nutritional composition for use according to the invention further comprises at least one fucosylated oligosaccharide having an α2 bond and / or a 1,2α bond; and / or a fucosylated oligosaccharide fucosylated by FUT2. In some embodiments, the nutritional composition comprises one or more fucosylated oligosaccharides selected from: 1,2'fucosylated lactose and 2'fucosylated lactose. In a specific embodiment, the nutritional composition for use according to the invention further comprises 2-FL (2'fucosyllactose). At least one fucosylated oligosaccharide having an α2 bond and / or a 1,2α bond; and / or a fucosylated oligosaccharide fucosylated by FUT2 may be present in a total amount of 0.1 g / L-5 g / L, e.g., 0.5 g / L-4.5 g / L or 1 g / L-4 g / L of the composition, or 0.05 g / 100 g-3.48 g / 100 g, e.g., 0.34 g / 100 g-3.13 g / 100 g or 0.69 g / 100 g-2.78 g / 100 g of the composition on a dry weight basis.

[0110] Adjusted nutritional composition

[0111] The nutritional composition according to the invention may be suitable for meeting the needs of an infant or young child. For example, the nutritional composition for use according to the invention may be an infant formula, a stage 1 infant formula, a follow-on or stage 2 infant formula, a baby food, an infant cereal composition, a growing-up milk, a fortifier or a supplement.

[0112] For example, the nutritional composition for the use according to the invention may be a powdered infant formula which is diluted with water to give a final liquid product. In other examples, the nutritional composition for the use according to the invention may also be a concentrated liquid which is diluted with water to give a final liquid product. The nutritional composition for the use according to the invention may be a liquid product which is directly consumed by infants as is. The nutritional composition according to the invention may be a human milk fortifier which is added to human milk or diluted with human milk. In this case, the concentration of the components already present in human milk (to which the human milk fortifier is added) is considered to be the average value for lactating mothers obtained or predicted from published clinical data.

[0113] The nutritional composition for purposes according to the present invention may contain a lipid source. The lipid source may be any lipid or fat suitable for use in infant formula. Preferred fat sources include palmitoleic acid, high oleic sunflower oil and high oleic safflower oil. Essential fatty acids, i.e. linoleic acid and alpha-linolenic acid, may also be added. In this composition, the fat source (including optional LC-PUFA, such as ARA and / or DHA) has a ratio of preferably about 1:2 to about 10:1, preferably about 5:1 to about 10:1, even more preferably about 7:1 to about 9:1 n-6 to n-3 fatty acids.

[0114] The nutritional composition according to the invention is preferably such that the fat consists essentially of a mixture of the following ingredients (relative to the total fat): 0% to 20% milk fat; 10% to 30% coconut oil; 10 to 40% canola oil; 10 to 25% sunflower oil; 10 to 30% high oleic sunflower oil; 2% to 10% palmitic acid, mainly in the form of triglycerides; and 1.5% to 2.5% of a mixture of the polyunsaturated fatty acids ARA and DHA (e.g., 1:1 from Martek). and A mixture of ARA and DHA), preferably with a ratio of about 1:1 relative to total fat.

[0115] Milk fat can be Or from AAK / Enzymotec Effective replacement.

[0116] Each of these fat sources is a refined oil suitable for use in infant nutrition.

[0117] Other standard ingredients known to the person skilled in the art for formulating infant formulas, step 1 infant formulas, follow-on or step 2 infant formulas, baby foods, infant cereal compositions, growing-up milks, fortifiers or supplements may also be present in the nutritional composition for use according to the invention.

[0118] Therefore, the nutritional composition for use according to the invention may contain further ingredients which may serve to enhance the technical effect of the components, in particular in accordance with European Commission Directive 2006 / 141 / EC of 22 December 2006 on infant formulae and follow-on formulae.

[0119] The nutritional composition for use according to the invention may also contain a carbohydrate source, preferably as a prebiotic or in addition to a prebiotic. Any carbohydrate source commonly found in infant formulas may be used, such as lactose, sucrose, maltodextrin, starch and mixtures thereof, but the preferred carbohydrate source is lactose.

[0120] The prebiotics that may be included in the invention are not particularly limited and include all food substances that promote the growth of intestinal probiotics or beneficial microorganisms. Preferred prebiotics may be selected from: oligosaccharides, optionally containing fructose, galactose and mannose; dietary fiber, in particular soluble fiber, soy fiber; inulin; or mixtures thereof. Some examples of prebiotics are fructooligosaccharides (FOS), galacto-oligosaccharides (GOS), isomaltooligosaccharides (IMO), xylo-oligosaccharides (XOS), arabinoxy-oligosaccharides (AXOS), manno-oligosaccharides (MOS), inulin, soy oligosaccharides, glycosylsucrose (GS), lactosucrose (LS), lactulose (LA), palatinose oligosaccharides (PAO), maltooligosaccharides, gums and / or their hydrolysates, pectins and / or their hydrolysates. In a specific embodiment, the prebiotic may be fructooligosaccharides and / or inulin. In a specific embodiment, the prebiotic is a combination of FOS and inulin, for example in the product sold by BENEO-Orafti under the trademark Fructo-oligosaccharides (formerly ) or sold by BENEO-Orafti under the trademark Inulin (formerly Another example is the combination of 70% short-chain oligofructose and 30% inulin, which is registered by Nestle under the trademark "Prebio 1".

[0121] Prebiotics may also be BMOs (bovine milk oligosaccharides) and / or HMOs (human milk oligosaccharides), such as N-acetylated oligosaccharides, sialylated oligosaccharides, other fucosylated oligosaccharides, and any mixtures thereof.

[0122] A specific embodiment relates to a nutritional composition according to the invention, further comprising at least one additional oligosaccharide and / or fiber and / or a precursor of a human milk oligosaccharide selected from the list consisting of GOS, FOS, XOS, inulin, polydextrose, sialylated oligosaccharides, sialic acid, fucose, N-acetylated oligosaccharides and any combination thereof.

[0123] A specific example of a prebiotic is a mixture of galacto-oligosaccharides, N-acetylated oligosaccharides and sialylated oligosaccharides, wherein N-acetylated oligosaccharides account for 0.5% to 4.0% of the oligosaccharide mixture, galacto-oligosaccharides account for 92.0% to 99.5% of the oligosaccharide mixture, and sialylated oligosaccharides account for 1.0% to 4.0% of the oligosaccharide mixture. This oligosaccharide mixture is preferably a mixture of BMO (milk oligosaccharides), for example, the composition for use according to the present invention may contain 2.5% to 15.0% by weight of this BMO mixture based on dry matter, provided that the composition contains at least 0.02% by weight of N-acetylated oligosaccharides, at least 2.0% by weight of galacto-oligosaccharides and at least 0.04% by weight of sialylated oligosaccharides. WO2006087391 and WO2012160080 provide some examples of preparing such BMO mixtures.

[0124] The nutritional composition for use according to the invention may also comprise one or more probiotics. In a specific embodiment, the one or more probiotics may for this purpose be selected from the group consisting of: Bifidobacterium, Lactobacillus, Lactococcus, Enterococcus, Streptococcus, Kluyveromyces, Saccharoymces, Candida, in particular selected from the group consisting of: Bifidobacterium longum, Bifidobacterium lactis, Bifidobacterium animalis, Bifidobacterium breve, Bifidobacterium infantis, Bifidobacterium adolescentis, Lactobacillus acidophilus, Lactobacillus casei, Lactobacillus paracasei, Lactobacillus salivarius ... salivarius, Lactobacillus lactis, Lactobacillus rhamnosus, Lactobacillus johnsonii, Lactobacillus plantarum, Lactobacillus salivarius, Lactococcus lactis, Enterococcus faecium, Saccharomyces cerevisiae, Saccharomyces boulardii, or a mixture thereof.Some suitable examples of probiotics are selected from the group consisting of Bifidobacterium longum NCC3001 (ATCC BAA-999), Bifidobacterium longum NCC2705 (CNCM I-2618), Bifidobacterium longum NCC490 (CNCM I-2170), Bifidobacterium lactis NCC2818 (CNCM I-3446), Bifidobacterium breve strain A, Lactobacillus paracasei NCC2461 (CNCM I-2116), Lactobacillus johnsonii NCC533 (CNCM I-1225), Lactobacillus rhamnosus GG (ATCC53103), Lactobacillus rhamnosus NCC4007 (CGMCC 1.3724), Enterococcus faecium SF 68 (NCC2768; NCIMB10415), and mixtures thereof.

[0125] The nutritional composition for use according to the invention may also contain a protein source. The type of protein is considered to be immaterial for the present invention, as long as the minimum requirements for the 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 the whey protein concerned is concerned, the protein source may be based on acid whey or sweet whey or mixtures thereof, and may contain alpha-lactalbumin and beta-lactoglobulin in any desired proportion. The protein may be at least partially hydrolyzed in order to enhance oral tolerance to allergens, in particular food allergens. In this case, the composition is a hypoallergenic composition.

[0126] In a preferred embodiment, the composition may be an infant formula based on cow's milk whey. The formula may also be a hypoallergenic (HA) formula in which cow's milk proteins are (partially or fully) hydrolyzed. The formula may also be based on soy milk or be a non-allergenic formula, for example a formula based on free amino acids.

[0127] The amount of protein may be 1.5 to 3 g / 100 kcal. A specific embodiment relates to a nutritional composition for use according to the invention, wherein the protein content is less than 2 g / 100 kcal, e.g. 1 to 2 g / 100 kcal, such as less than 1.8 g / 100 kcal, e.g. 1 to 1.8 g / 100 kcal, e.g. in the range of 1.5 to 1.8 g protein / 100 kcal.

[0128] The nutritional composition for purposes according to the present invention may also contain all vitamins and minerals and other micronutrients that are considered to be necessary for daily diet and in large quantities in nutrition. The minimum requirement of some vitamins and minerals has been determined. The example of minerals, vitamins and other nutrients optionally present in the composition of the present invention includes 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, phosphorus, iodine, iron, magnesium, copper, zinc, manganese, chlorine, potassium, sodium, selenium, chromium, molybdenum, taurine and L-carnitine. Minerals are usually added in the form of salts. The presence and content of specific minerals and other vitamins will vary according to the applicable population.

[0129] If necessary, the nutritional composition for use according to the present invention may contain emulsifiers and stabilizers such as soybean, lecithin, citric acid monoglyceride, citric acid diglyceride, and the like.

[0130] The nutritional composition for use according to the invention may also contain other substances which may have a beneficial effect, such as lactoferrin, nucleotides, nucleosides, gangliosides, polyamines and the like.

[0131] The preparation of a nutritional composition for use according to the invention will now be described by way of example.

[0132] The formula food can be prepared in any suitable manner. For example, it can be prepared by blending a protein source, a carbohydrate source, and a fat source in a suitable ratio. If an emulsifier is used, it can be added at this time. Vitamins and minerals can be added at this time, but in order to avoid thermal degradation, they are usually added a little later. Before blending, any lipophilic vitamins, emulsifiers, etc. can be dissolved in the fat source. Then water (preferably water through reverse osmosis) can be mixed to form a liquid mixture. Suitable water temperatures are in the range of about 50° C. to about 80° C. to help disperse the ingredients. Commercially available liquefiers can be used to form a liquid mixture.

[0133] Especially when the final product is in liquid form, fucosylated oligosaccharides can be added at this stage. If the final product is a powder, these ingredients can also be added at this stage if necessary.

[0134] The liquid mixture is then homogenized, for example in two stages.

[0135] The liquid mixture can then be heat treated to reduce the bacterial load, for example by rapidly heating the liquid mixture to a temperature in the range of about 80°C and about 150°C for a period of time between about 5 seconds and about 5 minutes. This can be done by steam injection, autoclave, or heat exchanger (e.g., plate heat exchanger).

[0136] The liquid mixture is then cooled to between about 60° C. and about 85° C., for example by flash cooling. The liquid mixture can then be homogenized again, for example in two stages, with the pressure in the first stage being between about 10 MPa and about 30 MPa, and the pressure in the second stage being between about 2 MPa and about 10 MPa. The homogenized mixture can then be further cooled in order to add any heat-sensitive components, such as vitamins and minerals. It is convenient at this point to adjust the pH and solids content of the homogenized mixture.

[0137] The homogenized mixture is transferred to a suitable drying device (such as a spray dryer or freeze dryer) and converted into a powder. The moisture content of the powder should be less than about 5% by weight. Fucosylated oligosaccharides may also or alternatively be added at this stage by dry mixing them with the optional probiotic strains, or blending them in the form of a crystalline syrup with the optional probiotic strains and spray drying (or freeze drying).

[0138] If a liquid composition is preferred, the homogenised mixture may be sterilised and then filled into suitable containers under aseptic conditions, or it may be filled into containers prior to retorting.

[0139] In another embodiment, the composition of the invention may be a supplement in an amount sufficient to achieve the desired effect in an infant. This form of administration is generally more suitable for premature infants.

[0140] Supplements can be in the form of, for example, powders, tablets, capsules, lozenges or liquids, as long as they are suitable nutritional compositions for infants. Supplements can also contain protective hydrophilic colloids (such as gums, proteins, modified starches), binders, film formers, encapsulating agents / materials, wall / shell materials, matrix compounds, coatings, emulsifiers, surfactants, solubilizers (oils, fats, waxes, lecithins, etc.), adsorbents, carriers, fillers, co-compounds, dispersants, wetting agents, processing aids (solvents), flow agents, taste masking agents, weighting agents, gelling agents and gel forming agents. Supplements can also contain conventional pharmaceutical additives and adjuvants, excipients and diluents, including but not limited to: water, gelatin from any source, vegetable gums, lignin sulfonates, talc, sugars, starches, gum arabic, vegetable oils, polyalkylene glycols, flavors, preservatives, stabilizers, emulsifiers, buffers, lubricants, colorants, wetting agents, fillers, etc.

[0141] The supplements can be added to a product (e.g., an ingestible carrier or support) that is acceptable to the consumer (infant), respectively. Examples of such carriers or supports are pharmaceutical or food compositions. Examples of such compositions are infant formulas, including formulas for premature infants.

[0142] In addition, 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 recommended by governmental agencies (e.g., Commission Directive 2006 / 141 / EC of 22 December 2006 on infant formula and follow-on formula).

[0143] Dosage regimen

[0144] The nutritional composition for use according to the invention can be administered at any time during infancy and early childhood. The age and duration of administration (giving or feeding) of the nutritional composition can be determined according to possibilities and needs.

[0145] In one embodiment of this aspect of the invention, the nutritional composition for use according to the invention is administered when the infant or toddler is from birth to 3 years old, such as from 6 months to 3 years old, from 7 months to 3 years old, from 8 months to 3 years old, from 9 months to 3 years old, from 10 months to 3 years old, from 12 months to 3 years old, or for example from 1 year to 3 years old or from 2 years to 3 years old. A specific embodiment relates to wherein the infant or toddler is 8 months to 3 years old.

[0146] Since the nutritional composition is mainly used for preventive purposes (avoiding excessive accumulation of fat mass, preventing future health disorders related to excessive accumulation of fat mass such as future obesity), it can be given, for example, immediately after the baby is born. The composition of the present invention can also be given during the first 1 week after the baby is born, or during the first 2 weeks after birth, or during the first 3 weeks after birth, or during the first 1 month after birth, or during the first 2 months after birth, or during the first 3 months after birth, or during the first 4 months after birth, or during the first 6 months after birth, or during the first 8 months after birth, or during the first 10 months after birth, or during the first 1 year after birth, or during the first 2 years after birth, or even longer. In some particularly advantageous embodiments of the present invention, the nutritional composition is given (or applied) to the baby within the first 4 or 6 months after birth.

[0147] In some other embodiments, the nutritional composition of the present invention is administered a few days (e.g., 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 20 days...), or weeks (e.g., 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks...) or months (e.g., 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months...) after birth. This may especially refer to the case where the infant is premature, but this is not required.

[0148] In one embodiment, the composition of the present invention is given to an infant or young child as a supplementary composition of breast milk. In some embodiments, the infant or young child receives breast milk during at least the first 2 weeks, the first 1 month, the first 2 months, the first 4 months or the first 6 months. In one embodiment, the nutritional composition of the present invention is given to an infant or young child after this period of time of giving nutrition with breast milk, or is provided to an infant or young child together with breast milk during this period of time of providing nutrition with breast milk. In another embodiment, during at least a period of time (e.g., in the 1st month after birth, the 2nd month or the 4th month), during at least 1 month, 2 months, 4 months or 6 months, the composition is given to an infant or young child as the only or main nutritional composition.

[0149] For overweight

[0150] The invention in another aspect relates to the use of a nutritional composition as defined herein in the context of one aspect of a nutritional composition for use for reducing the risk of developing overweight later in life in an infant or young child.

[0151] Nutritional composition for promoting healthy growth

[0152] In a further aspect, the present invention relates to a nutritional composition comprising at least one fucosylated oligosaccharide having at least one fucose group linked by an α1,3 linkage, at least one fucose group linked by an α1,4 linkage, or a combination thereof, for promoting healthy growth of an infant or young child.

[0153] The expression "growth" refers to the growth of the weight, height, head circumference and / or abdominal circumference of an infant or a young child. In a specific embodiment, it refers to body weight. Growth should be understood as the change in the weight, height, head circumference and / or abdominal circumference of an infant or a young child as the age increases. Therefore, the expressions "growth rate" and "rate of growth" can also be replaced by the term "growth". These parameters do not just increase during infant development. In fact, the standard growth curve published by the World Health Organization shows that the weight of an infant may decrease in the first few days after birth of the infant. Therefore, growth should be understood as the overall growth of an infant in the first few months after birth, such as particularly from birth to 8 months, from birth to 10 months, from birth to 12 months, or from birth to 24 months, or from birth to 36 months.

[0154] The expressions "promoting healthy growth" and "promoting optimal growth" are used interchangeably. They encompass promoting a growth rate that is close to or approaching the growth rate of a breastfed infant. They encompass promoting growth that is identified as normal by a pediatrician, so that it is not associated with causing health problems. These expressions also encompass preventing excessive growth or excessive weight gain that may occur in formula-fed infants, especially in the first few months after birth. The expression "promoting healthy growth" may also encompass controlling weight management and / or avoiding weight gain, especially excessive weight gain, and / or promoting an increase in lean body mass (especially by increasing total body weight or fat mass) and / or reducing fat content.

[0155] One embodiment of the present aspect relates to a nutritional composition comprising at least one fucosylated oligosaccharide fucosylated by FUT3 for use in promoting healthy growth in an infant or young child.

[0156] In a specific embodiment, the nutritional composition according to the invention is used to promote healthy growth of an infant or a young child, wherein the infant or young child may be as described herein under the heading Target Group.

[0157] In further embodiments, the nutritional composition for use according to this aspect may be as described above with respect to the previous aspects of the invention.

[0158] Methods for identifying target groups

[0159] The presence of a FUT3 polymorphism that interferes with FUT3 expression results in a reduced amount of fucosylated oligosaccharides having at least one fucosyl group linked by an α1,3 linkage and / or at least one fucosyl group linked by an α1,4 linkage. Based on the association identified between abdominal circumference and this FUT3 polymorphism, such infants can be identified as being at risk for excessive accumulation of fat mass.

[0160] Thus, the invention relates in a further aspect to identifying an infant or young child at risk for premature obesity relapse, excess accumulation of fat mass and / or one or more health disorders, such as health disorders associated with excess fat accumulation, during infancy / early childhood or later in life; the method comprising determining the presence of the following single nucleotide polymorphism in the FUT3 gene of the mother of the infant or young child:

[0161] a) rs3894326 (Accession number in NCBI SNP database)

[0162] The presence of the polymorphism is associated with an increased risk of premature obesity relapse, excessive accumulation of fat mass, and / or one or more health disorders associated with excessive fat accumulation during infancy / early childhood and / or later in infancy or early childhood.

[0163] The polymorphism numbers refer to the accession numbers in the single nucleotide polymorphism database of NCBI and are available online.

[0164] Treatment

[0165] Mothers displaying a disrupted FUT3 gene will produce fewer fucosylated oligosaccharides having at least one fucose linked via an α1,3 and / or α1,4 bond. To compensate for this deficiency, it would be advantageous to identify mothers deficient in this regard and supplement the diet of their offspring with at least one of these fucosylated oligosaccharides.

[0166] Therefore, a further aspect of the present invention relates to a method for preventing premature obesity rebound, excessive fat accumulation and / or health disorders associated with excessive fat mass accumulation in infants or young children in the future, the method comprising the steps of:

[0167] i. Determine if the mother has a functional FUT3 enzyme,

[0168] and

[0169] ii. administering to the infant or young child a nutritional composition as defined above in the context of the nutritional composition according to the present invention, e.g. a nutritional composition comprising at least one fucosylated oligosaccharide, wherein the fucosylated oligosaccharide has at least one fucose group linked via a 1,3 linkage, at least one fucose group linked via a 1,4 linkage, or a combination thereof.

[0170] If the FUT3 enzyme causes 1,3 and / or 1,4 fucosylation of its substrate, the FUT3 enzyme is functional. Methods for determining whether a mother has a functional FUT3 enzyme are known in the art. For example, the gene can be detected by PCR, or the functional protein can be determined by immunological methods such as Western blot.

[0171] In one embodiment, the present invention relates to a method for preventing premature obesity relapse, excessive fat accumulation and / or health disorders associated with excessive fat mass accumulation in infants or young children in the future, the method comprising the steps of:

[0172] i. Determine whether the mother has the following single nucleotide polymorphisms in the FUT3 gene:

[0173] a)rs3894326

[0174] and

[0175] ii. administering to the infant or young child a nutritional composition as defined above in the context of the nutritional composition according to the present invention, e.g. a nutritional composition comprising at least one fucosylated oligosaccharide, wherein the fucosylated oligosaccharide has at least one fucose group linked via a 1,3 linkage, at least one fucose group linked via a 1,4 linkage, or a combination thereof.

[0176] For preparation

[0177] The aspect of the invention relating to the nutritional composition for use according to the invention may alternatively be described as the use of a fucosylated oligosaccharide having at least one fucose group linked by an α1,3 bond, at least one fucose group linked by an α1,4 bond or a combination thereof for the preparation of a nutritional composition for administration to an infant or young child, the composition being used to reduce and / or avoid premature obesity rebound, excessive accumulation of fat mass in the future; and / or for preventing health disorders associated with excessive accumulation of fat mass in the future.

[0178] Further embodiments relate to the use of fucosylated oligosaccharides fucosylated by FUT3 for the preparation of a nutritional composition for reducing and / or preventing excess accumulation of fat mass in an infant or young child; and / or for preventing health disorders associated with excess accumulation of fat mass in an infant or young child in the future.

[0179] Further embodiments relate to the use of fucosylated oligosaccharides fucosylated by FUT3 for the preparation of a nutritional composition for reducing and / or preventing excessive accumulation of fat mass in an infant or young child; and / or for preventing health disorders associated with fat accumulation in the infant or young child later in life.

[0180] A further embodiment relates to said use of fucosylated oligosaccharides, wherein the nutritional composition is defined as described above for the nutritional composition for use according to the invention.

[0181] The present invention also provides the following embodiments:

[0182] 1. A nutritional composition comprising at least one fucosylated oligosaccharide for reducing and / or avoiding excessive fat mass accumulation in infants or young children in the future and / or health disorders associated with excessive fat mass accumulation in the future, such as obesity and obesity-related comorbidities in the future; wherein the fucosylated oligosaccharide has at least one fucose group linked by an α1,3 bond, at least one fucose group linked by an α1,4 bond, or a combination thereof.

[0183] 2. The nutritional composition for use according to embodiment 1, comprising at least one fucosylated oligosaccharide, wherein the fucosylated oligosaccharide is fucosylated by FUT3.

[0184] 3. The nutritional composition for use according to embodiment 1 or 2, wherein the at least one fucosylated oligosaccharide is selected from the group consisting of: 3'fucosylated lactose (3FL), DFL, LNFPII, LNFP III, LNFP V, and combinations thereof.

[0185] 4. The nutritional composition for use according to any one of the preceding embodiments, wherein the at least one fucosylated oligosaccharide is selected from the group consisting of: 3'-fucosylated lactose, DFL and combinations thereof.

[0186] 5. The nutritional composition for use according to any one of the preceding embodiments, wherein the health disorder associated with excessive accumulation of fat mass is selected from: overweight, obesity, type 2 diabetes, insulin resistance, hypertension, cardiovascular disease or metabolic syndrome and premature obesity rebound.

[0187] 6. The nutritional composition for use according to any one of the preceding embodiments, wherein the health disorder associated with excessive accumulation of fat mass is premature obesity rebound.

[0188] 7. The nutritional composition for use according to any one of the preceding embodiments, wherein the at least one fucosylated oligosaccharide is present in an amount of 0.02 to 10 wt.-%, such as 0.1 to 5 wt.-% or 0.2 to 1.5 wt.-% of the nutritional composition.

[0189] 8. The nutritional composition for use according to any one of the preceding embodiments, further comprising at least one fucosylated oligosaccharide consisting of 1,2-fucosylated lactose and / or 2-fucosylated lactose.

[0190] 9. The nutritional composition for use according to any one of the preceding embodiments, further comprising at least one additional oligosaccharide and / or fiber and / or a precursor of a human milk oligosaccharide selected from the list consisting of GOS, FOS, XOS, inulin, polydextrose, sialylated oligosaccharides, sialic acid, fucose, N-acetylated oligosaccharides and any combination thereof.

[0191] 10. The nutritional composition for use according to any one of the preceding embodiments, further comprising at least one probiotic, wherein the amount of the probiotic is 10 3 cfu / g to 10 12 cfu / g of the composition (dry weight).

[0192] 11. The nutritional composition for use according to any one of the preceding embodiments, wherein the nutritional composition is an infant formula, a step 1 infant formula, a follow-on or step 2 infant formula, a baby food, an infant cereal composition, a growing-up milk, a fortifier or a supplement.

[0193] 12. Nutritional composition for use according to any one of the preceding embodiments by preventing premature obesity rebound.

[0194] 13. A nutritional composition as defined in any one of the preceding embodiments for use in promoting healthy growth of an infant or young child.

[0195] 14. Use of a nutritional composition as defined in any one of the preceding embodiments for reducing the risk of an infant or young child becoming overweight later in life.

[0196] 15. A method for identifying an infant or young child at risk for premature obesity relapse, excessive accumulation of fat mass, and / or one or more health disorders associated with excessive fat accumulation during infancy / early childhood or later in life; the method comprising determining the presence of the following single nucleotide polymorphisms in the FUT3 gene of the mother of the infant or young child:

[0197] a) rs3894326 (accession number in the single nucleotide polymorphism database of NCBI),

[0198] The presence of the polymorphism is associated with an increased risk of premature obesity relapse, excessive accumulation of fat mass, and / or one or more health disorders associated with excessive fat accumulation during the infancy / early childhood and later in the infant or early childhood.

[0199] 16. Use of a fucosylated oligosaccharide having at least one fucose group linked by an α1,3 bond, at least one fucose group linked by an α1,4 bond, or a combination thereof for preparing a nutritional composition for administration to infants or young children, wherein the composition is used to reduce and / or avoid premature obesity rebound, excessive fat mass accumulation in the future; and / or to prevent health disorders associated with excessive fat mass accumulation in the future.

[0200] It should be noted that embodiments and features described in the context of one aspect of the invention are also applicable to the other aspects of the invention.

[0201] All patent and non-patent references cited in this application are hereby incorporated by reference in their entirety.

[0202] The present invention will now be described in further detail in the following non-limiting examples.

[0203] Example

[0204] Example 1

[0205] An example of the composition of a nutritional composition (eg an infant formula) according to the invention is given in the following Table 2. The composition is given by way of example only.

[0206]

[0207]

[0208] Table 2: Examples of compositions of nutritional compositions (eg infant formula) according to the invention

[0209] Example 2: Association between SNPs and growth

[0210] The oligosaccharide distribution of human milk depends on the genetic variation of enzymes involved in, for example, glycosylation. The inventors have studied whether the variation of oligosaccharides affects children's health. An association study between FUT3 SNP and children's health outcomes was performed. SNP analysis of maternal samples from a population group was performed, and logistic regression analysis was used to determine the association between FUT3 SNP and children's health outcomes. The significant association between LMS growth score and FUT3 SNP was revealed. The LMS growth score method is known in the art (see, Eur J Clin Nutr. January 1990, Vol. 44, No. 1: 45-60 pages, The LMS method for constructing normalized growth standards, Cole TJ). However, LMS is generally regarded as a cross-sectional method, which can be used for longitudinal data.

[0211] The association between the LMS growth score of abdominal circumference growth over a period of time and FUT3 SNPs has been investigated, and the results are shown in Table 3 below.

[0212] Where a SNP was found to be significantly associated with the outcome, the regression models were further adjusted for parity, mode of delivery and breastfeeding (see Table 3).

[0213] There was a certain association between LMS abdominal circumference growth score and FUT3 SNP rs3894326 (p=0.043) at 6 to 12 months. This association remained significant when adjusted for breastfeeding, parity and delivery mode; among which breastfeeding duration (0, <=3 months, >3 months) also showed a significant association with LMS AC growth.

[0214] Abdominal circumference growth from 2 to 3 years of age was also significantly associated with FUT3 SNP rs3894326 (p = 0.018), which remained significant when adjusted for breastfeeding duration, parity, and delivery mode. The results showed that the presence of the FUT3 SNP rs3894326 form that disrupts the FUT3 gene (carrying the mutation) was associated with a decrease in abdominal circumference at 6 months and an increase in abdominal circumference at 2 to 3 years of age compared to the SNP form that does not affect the FUT3 gene (wild type). This means that the absence of a functional FUT3 enzyme and therefore the lack of production of α1,3 and α1,4 fucosylated HMOs is associated with a higher abdominal circumference (a measure of obesity) at 2 to 3 years of age. For the group of infants fed human milk containing reduced amounts of α1,3 and α1,4-fucosylated HMOs (non-functional FUT3 enzyme), an early higher adiposity rebound at 2 to 3 years of age induced impairments associated with future fat accumulation; thus, it was concluded that α1,3 and α1,4-fucosylated HMOs are necessary for optimal growth of infants and their presence prevents premature adiposity rebound.

[0215] exist Figure 1 In , conditional z scores for abdominal circumference at 6 to 12 months are shown between infants born to mothers carrying a fully functional FUT3 form (SNP rs3894326: AA, wild type) and infants carrying an altered FUT3 form (SNP rs3894326: TA, carrying a mutation). Figure 2 , conditional z scores for abdominal circumference are shown for the same group of infants aged 2 to 3 years. Clearly, normal infant growth can be impaired in infants born to mothers with incompletely functional FUT3 and thus reduced amounts of 1,3 and α1,4 fucosylated HMOs in their milk.

[0216] When a conditional z score is given for a growth outcome or size (such as abdominal wall obesity), it is defined as that size regressed on total body size as described by (Keijzer-Veen et al., 2005).

[0217] In Table 3, data for both the unadjusted model and the adjusted model are shown.

[0218] Abbreviations and notes:

[0219] The LMS growth score is a measure of abdominal circumference (AC) as defined above.

[0220] SNP means single nucleotide polymorphism, which in this case is rs3894326.

[0221] N is the number of participants in this study.

[0222] β is the beta coefficient of the regression model used in the analysis. Negative beta values ​​for AC at 6 to 12 months showed that the group of infants whose mothers carried the mutant SNP was associated with lower AC compared with those whose mothers carried the wild-type SNP, while positive beta values ​​for AC at 2 to 3 years showed that the group of infants whose mothers carried the mutant SNP was associated with higher AC compared with those whose mothers carried the wild-type SNP, as shown in Figure 1 and 2 shown.

[0223] AC = abdominal circumference

[0224] m = month

[0225] yr = year

[0226] Adjusted = see the description of the above embodiment

[0227] Table 3

[0228]

Claims

1. Use of a nutritional composition comprising at least one fucosylated oligosaccharide in the preparation of a non-therapeutic product for preventing excessive fat accumulation and / or overweight, obesity and premature obesity rebound in infants or young children in the future; wherein the fucosylated oligosaccharide has at least one fucose group connected by an α1,3 bond, at least one fucose group connected by an α1,4 bond, or a combination thereof, wherein the infant or young child is born to a mother carrying SNP rs3894326, wherein the at least one fucosylated oligosaccharide is selected from: 3'fucosylated lactose (3FL), DFL, LNFP II, LNFPIII, LNFP V, and a combination thereof.

2. The use according to claim 1, wherein the at least one fucosylated oligosaccharide is selected from the group consisting of: 3'-fucosylated lactose, DFL and combinations thereof.

3. The use according to claim 1 or 2, wherein the health disorder associated with excessive accumulation of fat mass is premature obesity rebound.

4. Use according to claim 1 or 2, wherein the at least one fucosylated oligosaccharide is present in an amount of 0.02% to 10% by weight of the nutritional composition.

5. Use according to claim 1 or 2, wherein the at least one fucosylated oligosaccharide is present in an amount of 0.1% to 5% by weight of the nutritional composition.

6. Use according to claim 1 or 2, wherein the at least one fucosylated oligosaccharide is present in an amount of 0.2% to 1.5% by weight of the nutritional composition.

7. The use according to claim 1 or 2, wherein the nutritional composition further comprises at least one fucosylated oligosaccharide consisting of 1,2-fucosylated lactose and / or 2-fucosylated lactose.

8. The use according to claim 1 or 2, wherein the composition further comprises at least one additional oligosaccharide and / or fiber and / or human milk oligosaccharide precursor selected from the list consisting of GOS, FOS, XOS, inulin, polydextrose, sialylated oligosaccharides, sialic acid, fucose, N-acetylated oligosaccharides and any combination thereof.

9. The use according to claim 1 or 2, wherein the composition further comprises at least one probiotic, wherein the amount of the probiotic is 10 3 cfu / g to 10 12 cfu / g of the composition (dry weight).

10. The use according to claim 1 or 2, wherein the nutritional composition is an infant formula, a step 1 infant formula, a follow-on or step 2 infant formula, a baby food, an infant cereal composition, a growing-up milk, a fortifier or a supplement.

11. The use according to claim 1 or 2, wherein the nutritional composition is used to promote healthy growth of infants or young children.

12. Non-therapeutic use of a nutritional composition as defined in any one of claims 1 to 12 for reducing the risk of an infant or young child becoming overweight later in life.

13. A method of preparing a nutritional composition for an infant or young child comprising: providing a fucosylated oligosaccharide having at least one fucosylated group linked by an α1,3 bond, at least one fucosylated group linked by an α1,4 bond, or a combination thereof, wherein the composition is used to reduce and / or avoid premature obesity rebound, excessive fat accumulation in the future; and / or to prevent overweight and obesity in the future, wherein the infant or young child is born to a mother carrying SNP rs3894326, wherein the at least one fucosylated oligosaccharide is selected from: 3'-fucosylated lactose (3FL), DFL, LNFP II, LNFP III, LNFP V, and a combination thereof.

14. A method for preventing premature obesity relapse, excessive fat accumulation and / or health disorders associated with excessive fat mass accumulation in infants or young children in the future, the method comprising the steps of: i. Determine whether the mother has the following single nucleotide polymorphisms in the FUT3 gene: a)rs3894326 and ii. administering to the infant or young child a nutritional composition as defined above in the context of the nutritional composition according to the present invention, e.g. a nutritional composition comprising at least one fucosylated oligosaccharide, wherein the fucosylated oligosaccharide has at least one fucosyl group linked via a 1,3 bond, at least one fucosyl group linked via a 1,4 bond, or a combination thereof, wherein the infant or young child is born to a mother carrying SNP rs3894326, wherein the at least one fucosylated oligosaccharide is selected from: 3' fucosylated lactose (3FL), DFL, LNFP II, LNFP III, LNFP V, and combinations thereof.

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