Human milk oligosaccharides beneficial to health by preventing premature obesity rebound

Abstract

The present invention relates to a nutritional composition comprising at least one fucosylated oligosaccharide for use in infants or young children to prevent later-day health disorders by preventing premature obesity rebound. The invention also relates to a nutritional composition for promoting healthy growth.

Description

[0001] This application is a divisional application of PCT application PCT / EP2017 / 051589, which was filed on January 26, 2017 and whose invention name is “Human milk oligosaccharides beneficial to health by preventing premature obesity rebound”. The date on which the PCT application entered the Chinese national phase is July 23, 2018, and the application number is 201780007746.7. Technical Field

[0002] The present invention relates to a nutritional composition for infants or young children that prevents health disorders later in life by preventing premature obesity rebound. 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 WHO, obesity has more than doubled worldwide since 1980. It has become a global health problem because it is associated with a shortened lifespan, altered quality of life and its link to further health conditions. Overweight and obesity are more likely to contribute to increased mortality worldwide than underweight. In fact, childhood obesity increases the odds of obesity, premature death and disability in adulthood. But in addition to increasing future risks, obese children also experience breathing difficulties, increased risk of fractures, high blood pressure, early markers of cardiovascular disease, insulin resistance and psychological effects. Elevated BMI is a major risk factor for non-communicable diseases such as 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 of the joints); 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 conducive to preventing obesity (Owen et al., "Effect of Infant Feeding on the Risk of Obesity Across the Life Course: A Quantitative Review of Published Evidence", 2005). There is evidence that infancy may be a critical period for the development and regulation 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 from 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 to breastfeed due to certain medical reasons. Infant formulas have been developed for these situations. Fortifiers that enrich the mother's milk or infant formula with special ingredients have also been developed. It is known that the growth rate of an infant affects the risk of excessive accumulation of fat mass and related metabolic and cardiovascular diseases in the later period. In particular, a faster growth rate during infancy may lead to obesity in the infant later in life.

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

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

[0008] There is a need to deliver such health benefits to these 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 delivering 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, which is used in infants or young children to prevent future health disorders, such as excessive accumulation of fat mass in the future, by preventing premature obesity rebound; and / or for health disorders associated with excessive accumulation of fat mass, such as overweight, obesity and / or comorbidities associated with obesity in the future.

[0011] Another aspect of the invention relates to the use of a nutritional composition according to the invention for reducing the risk of an infant or young child to later develop overweight by preventing premature obesity rebound. BRIEF DESCRIPTION OF THE DRAWINGS

[0012] Figure 1 Shown are the gender-specific LMS conditional z scores for abdominal circumference of the polymorphism FUT3 rs3894326 in infants aged 6-12 months.

[0013] Figure 2 Shown are the gender-specific LMS conditional z scores for abdominal circumference of the polymorphism FUT3 rs3894326 in infants aged 2-3 years. DETAILED DESCRIPTION

[0014] definition

[0015] Before discussing the present invention in further detail, the following terms, expressions and conventions are first defined:

[0016] Fucose is a kind of 12 Hexodeoxy sugar at O5. It corresponds to 6-deoxy-L-galactose.

[0017] Fucosyltransferases (also known as glycosyltransferase family 10) are enzymes that transfer L-fucose from a GDP-fucose (guanylate diphosphate-fucose) donor substrate to an acceptor substrate.

[0018] Fucosyltransferase 3 (abbreviated herein as FUT3) is also known as galactoside 3(4)-L-fucosyltransferase. Other synonyms include CD174; FT3B, FucT-III, LE; and Les. The EC number is 2.4.1.65, and the OMIM number is: 111100. HomoloGene: 55438, ChEMBL: 3269, GeneCards: FUT3 gene.

[0019] The FUT3 gene encodes an enzyme with α(1,3)-fucosyltransferase and α(1,4)-fucosyltransferase activities.

[0020] 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).

[0021] A SNP (Single Nucleotide Polymorphism) is a variation in a single nucleotide that may occur at a certain position in the genome, where each variation exists to some measurable degree within a population. Functional SNPs, such as those described in the present invention, affect protein expression.

[0022] The term "infant" refers to a person under the age of 12 months.

[0023] The expression "young child" refers to a person between the ages of one and three, also known as a toddler.

[0024] The term "child" refers to a person between the ages of three and 12.

[0025] People between the ages of 12 and 18 are called adolescents, and people over the age of 18 are called adults.

[0026] The expression "nutritional composition" refers to a composition that supplies nutrients to an individual. Such a nutritional composition is usually taken orally or intravenously. It may include a lipid or fat source, a carbohydrate source and / or a protein source.

[0027] In a particular embodiment, the composition of the invention is a hypoallergenic nutritional composition.The expression "hypoallergenic nutritional composition" refers to a nutritional composition which is unlikely to cause an allergic reaction.

[0028] In a specific embodiment, the nutritional composition of the invention is a "synthetic nutritional composition". The expression "synthetic nutritional composition" refers to a mixture obtained by chemical and / or biological methods, the chemical properties of which may be identical to the mixture naturally present in mammalian milk (i.e., the synthetic nutritional composition is not human milk).

[0029] The expression "infant formula" as used herein refers to a food intended specifically for the nutrition of infants in the first few months of life (such as 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 various nutritional requirements of this group of people (in accordance with Article 2(c) of Council Directive 91 / 321 / EEC 2006 / 141 / EC 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 in special products for infants (including foods for special medical purposes). The expression "infant formula" covers both "stage 1 infant formula" and "follow-up formula" or "stage 2 infant formula".

[0030] "Follow-on formula" or "step 2 formula" is offered from the 6th month onwards. Infant formula constitutes the main liquid element in the gradually diversified diet of this population.

[0031] "Growing-up milk" (or GUM) is generally a milk-based beverage adapted for the special nutritional needs of a toddler or young child.

[0032] The expression "baby food" means food intended specifically for the nutrition of infants or young children under one year of age.

[0033] The expression "infant cereal composition" refers to a foodstuff which is intended specifically for the nutrition of infants or young children under one year of age.

[0034] The term "fortifier" refers to a liquid or solid nutritional composition suitable for mixing with breast milk or infant formula.

[0035] The term "supplement" refers to a nutritional composition intended to provide nutrients that would otherwise be insufficient for nutrient intake. In addition to the intake of other nutrients / foods, the nutritional composition is also taken in. Supplements can be, for example, tablets, capsules, lozenges or liquid forms. Supplements can also include 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.

[0036] The expressions "fat mass accumulation" and "fat accumulation" are used interchangeably.

[0037] The expression "excessive accumulation of fat mass" refers to an abnormal amount of fat mass, for example, an amount that may be detrimental to health and may lead to health disorders. Being overweight or obese are examples of excessive accumulation of fat.

[0038] 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 greater than or equal to 25 is considered overweight; a BMI greater than or equal to 30 is considered obese.

[0039] 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.

[0040] The expression "health disorder" encompasses any health condition and / or disease and / or functional disorder affecting an individual organism, including metabolic disorders.

[0041] The expressions "preventing a health disorder at a later date" or "preventing a health disorder at a later date" are used interchangeably. They refer to 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. Preventing the occurrence "at a later date" therefore preferably occurs after the intervention or treatment has ended (i.e. after the administration of the nutritional composition according to the invention).

[0042] The expression "health disorders later in life related to excessive accumulation of fat mass" refers to health disorders later in life that are due to (ie, directly related to) or associated with (ie, indirectly related to) excess fat. It encompasses overweight, obesity, and obesity-related comorbidities.

[0043] The expression "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.

[0044] Prevention occurs "later", for example after administration of the nutritional composition according to the invention, or for example after the end of an intervention or treatment.

[0045] The expressions "later" and "later period" are used interchangeably. The effect occurring "later" / "later period" refers to the effect measured in an individual (infant or young child) after applying the nutritional composition according to the present invention, and at least 8 months or several years after birth, such as after 8 months of birth, such as after 10 months of birth, such as after 1 year of birth, 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 birth, even longer, and compared with the average observation of individuals of the same age. Preferably, it refers to the effect observed after at least 1 year of age, or after at least 2 years of age, 5 years of age, 7 years of age, 10 years of age or 15 years of age. Therefore, the expression "later" may refer to the effect observed in infancy, in early childhood, in childhood, in adolescence or in adulthood. Preferably, it refers to the effect observed in childhood, in adolescence or in adulthood.

[0046] The expression "breast milk" is to be understood as mother's breast milk or colostrum.

[0047] The expression "HMO" refers to human milk oligosaccharides. These carbohydrates are resistant to enzymatic hydrolysis by digestive enzymes (e.g., pancreatic and / or brush border), indicating that they may exhibit functions that are not directly related to their caloric value. It has been specifically noted in the art that these carbohydrates play a key role in the early development of infants and young children (such as, immune system maturation). 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 variety of bonds between these molecules, so human milk contains a large number of different types of oligosaccharides, and more than 130 such structures have been identified to date. Almost all oligosaccharides have a lactose moiety at the reducing end, and the terminal position of the non-reducing end is occupied by sialic acid and / or fucose (if present). HMOs can be acidic (e.g., oligosaccharides containing charged sialic acid) or neutral (e.g., fucosylated oligosaccharides).

[0048] "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-fucopentose (e.g., lactose-N-fucopentose I, lactose-N-fucopentose II, lactose-N-fucopentose III, lactose-N-fucopentose V), lactose-N-fucohexose, lactose-N-difucohexose I, fucosyllactose-N-hexose, fucosyllactose-N-neohexose, difucosyllactose-N-hexose I, difucosyllactose-N-neohexose II, and any combination of these substances.

[0049] "α1,3 fucosylated oligosaccharide" is an oligosaccharide having fucose linked via C1 of the fucose in the α configuration to C3 of a monosaccharide unit of a monosaccharide or oligosaccharide (2 or more monosaccharides).

[0050] "α1,4 fucosylated oligosaccharide" is an oligosaccharide having fucose linked via C1 of the fucose in the α configuration to C4 of a monosaccharide unit of a monosaccharide or oligosaccharide (2 or more monosaccharides).

[0051] The expression "N-acetylated oligosaccharide" encompasses "N-acetyllactosamine" and "oligosaccharides comprising N-acetyllactosamine". Such oligosaccharides are neutral oligosaccharides having an N-acetyllactosamine residue. Suitable examples are: LNT (lactose-N-tetraose), p-lactose-N-neohexose (p-LNnH), LNnT (lactose-N-neotetraose) or any combination thereof. Other examples are lactose-N-hexose, lactose-N-neohexose, p-lactose-N-hexose, p-lactose-N-neohexose, lactose-N-octose, lactose-N-neooctose, iso-lactose-N-octose, p-lactose-N-octose and lactose-N-decasaccharide.

[0052] "HMO precursors" are key compounds used to prepare HMOs, such as sialic acid and / or fucose.

[0053] "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).

[0054] The nutritional composition of the present invention may be in solid form (e.g., powder) or liquid form. The amount of various ingredients (e.g., oligosaccharides) may be expressed as g / 100 g composition on a dry weight basis when the composition is in solid form (e.g., powder); or as a concentration g / L composition when the composition refers to a liquid form (the latter also encompasses liquid compositions that can be obtained by reconstituted the powder with liquids such as milk, water, etc., such as reconstituted infant formula or 2-stage infant formula / older infant formula, or infant cereal products, or any other formulations designed specifically for infant nutrition).

[0055] 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 (such as Bifidobacteria in the human colon) (Gibson GR, Roberfroid MB. Dietary modulation of the human colonic microbiota: introducing the concept of prebiotics. J Nutr. 1995; Vol. 125, pp. 1401-1412).

[0056] The term "probiotic" refers to a microbial cell preparation or microbial cell component that has 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", Trend Food Sci. Technol., 1999, Vol. 10, pp. 107-110). Microbial cells are generally bacteria or yeast.

[0057] The term "cfu" is to be understood as colony forming units.

[0058] Unless otherwise indicated, all percentages are by weight.

[0059] In addition, in the context of the present invention, the term "comprising" or "including" does not exclude other possible elements. The composition of the present invention (including the multiple embodiments described herein) may comprise, consist of or consist essentially of the following elements: the basic elements and necessary limitations of the present invention described herein, and any other or optional ingredients, components or limitations described herein or determined as required.

[0060] 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.

[0061] Description of the Invention

[0062] Invention basis

[0063] The present invention is based on the recognition of the importance of fucosylated oligosaccharides in infant diets on the timing of obesity rebound (defined below). Mothers who display a single nucleotide polymorphism (SNP) that disrupts the expression of FUT3 (the gene encoding fucosyltransferase 3) also display reduced amounts of α1,3 and α1,4 fucosylated oligosaccharides in breast milk. The inventors have shown that, surprisingly, the presence of this particular SNP is significantly correlated with abdominal circumference measurements in infants and young children (see Examples and Table 3).

[0064] This suggests that fucosylated human milk oligosaccharides, such as α1,3 fucosylated oligosaccharides and α1,4 fucosylated oligosaccharides (such as fucosylated by FUT3), affect infant growth by affecting the timing of adiposity rebound.

[0065] In the context of the present invention, obesity rebound is defined as the time point at which BMI begins to rise after infancy in individual development. Usually infants gain weight in the earliest stage of life. This is followed by an infant / toddler development period in which BMI decreases. The decline in BMI is usually due to an increase in length growth, and may also lead to a decrease in fat accumulation. At a certain time point in development, BMI will stop declining and start to rise again. This time point at which BMI begins to rise after infancy is called obesity rebound (AR). The term "obesity rebound" is a recognized term in the art and has been described in, for example, Rolland-Caher et al., Am J Clin Nutr., January 1984, Vol. 39, No. 1, pp. 129-135.

[0066] Premature adiposity rebound is associated with excessive fat accumulation later in life, such as during adolescence and / or adulthood. Young children who show premature adiposity rebound (ie, adiposity rebound that occurs earlier than expected) are at increased risk for overweight, obesity, and obesity-related comorbidities later in life.

[0067] Fucosylated human milk oligosaccharides and growth have been studied before. 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 0 to 6-month-old infants studied, and the effects of human milk oligosaccharides on the risk of excessive fat accumulation in the future, nor the time of obesity rebound, cannot be inferred. In fact, the author himself has also summarized a lot.

[0068] Furthermore, the effects of fucosylated oligosaccharides documented by 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 were associated with fat gain at 6 months. The opposite results were obtained for fucosylated oligosaccharides that do not have this type of bond (e.g. LNFPI, LNnT). Therefore, one skilled in the art would not be instigated to select α1,3 fucosylated oligosaccharides and α1,4 fucosylated oligosaccharides (such as fucosylated oligosaccharides fucosylated by FUT3) to avoid health disorders in the future by preventing premature obesity rebound. However, the inventors of the present invention have shown that these specific oligosaccharides are actually able to avoid premature obesity rebound and thus prevent excessive fat accumulation or its related disorders in the future.

[0069] Actions targeting premature adiposity rebound represent novel clinical scenarios that could be targeted in new ways to prevent future health disorders.

[0070] Nutritional composition for use

[0071] Therefore, a first aspect of the present invention relates to a nutritional composition comprising at least one fucosylated oligosaccharide, which is used in infants or young children to prevent future health disorders, such as excessive accumulation of fat mass in the future, by preventing premature obesity rebound; and / or for health disorders associated with excessive accumulation of fat mass, such as obesity in the future and / or comorbidities associated with obesity.

[0072] The nutritional composition according to the present invention prevents premature obesity rebound, thereby protecting the individual from excessive accumulation of fat mass and / or later health disorders associated with excessive accumulation of fat mass, such as later obesity and related comorbidities.

[0073] The nutritional compositions of the present invention are typically administered to infants or young children; however, the effects of preventing future health disorders may first be seen later in life.

[0074] In the context of the present application, "later" refers to the later life of the same infant or young child to whom the nutritional composition is administered. Therefore, the nutritional composition for use according to the present invention can be administered to an infant or young child and can help prevent other health disorders that may occur in the infant or young child in the future. "Later" in the context of this article refers to, for example, any time when the infant or young child is no longer a young child, such as when the infant or young child may have become a child, a teenager or an adult. For further discussion of the expression "later", see also the definition.

[0075] In one embodiment, the nutritional composition according to the present invention can be used to reduce and / or prevent excessive accumulation of fat mass in infants or young children by preventing premature obesity rebound. 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 infant or young child by preventing premature obesity rebound.

[0076] In another embodiment, the nutritional composition according to the invention can be used for infants or young children to reduce and / or prevent excessive accumulation of fat mass in the future by preventing premature obesity rebound. 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 future by preventing premature obesity rebound.

[0077] In another embodiment, the nutritional composition according to the invention can be used for infants or young children for preventing health disorders in the future, such as health disorders associated with excessive accumulation of fat mass, by preventing premature obesity rebound. This means that the nutritional composition according to the invention is administered to an infant or young child and prevents health disorders, such as health disorders associated with excessive accumulation of fat mass, said health disorders occurring in the future of the infant or young child, by preventing premature obesity rebound.

[0078] Fucosylated oligosaccharides

[0079] As stated above, the nutritional composition for use according to the invention comprises at least one fucosylated oligosaccharide.

[0080] A specific embodiment relates to wherein the fucosylated oligosaccharide has at least one fucose group attached via an α2 bond, an α1,2 bond, an α1,3 bond, an α1,4 bond or a combination thereof.

[0081] In a specific embodiment, the fucosylated oligosaccharide is fucosylated by FUT3 and / or FUT2. Thus, in a specific embodiment, the present invention relates to a nutritional composition for use according to the invention, comprising at least one fucosylated oligosaccharide, which is fucosylated by FUT3, for use in infants or young children to reduce and / or avoid excessive accumulation of fat mass by preventing premature obesity rebound; and / or for use in infants or young children to prevent future health disorders, such as health disorders associated with excessive accumulation of fat mass, such as obesity and related comorbidities in the future, by preventing premature obesity rebound.

[0082] In one embodiment of the invention, the at least one fucosylated oligosaccharide in the nutritional composition according to the invention is chosen from 3'-fucosylated lactose (3FL), DFL, LNFP II, 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-LNH II, TF-para-LNnH, F-LNO, F-LNnO, F-iso-LNO, DF-LNO I, BF-LNO II, DF-LNnO I, DF-LNO II, DF-iso-LNO I, DF-iso-LNO II, TF-LNO, TF-LNnO, TF-iso-LNO I, TF-iso-LNOII, 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-LNH II, FS-LNH III, FS-LNH IV, FS-LNnH I, FS-LNnHII, DFS-LNH I, DFS-LNH II, DFS-LNnH, FS-LNO, FS-iso-LNO, DFS-iso-LNO I, FS-iso-LNO II, DFS-LNO, TFS-iso-LNO, FDS-LNT I, FDS-LNH II, FDS-LNH III, FDS-LNnH, FS-neo-LNP One or more of the group consisting of I, DF-para-LNH sulfate I, DF-para-LNH sulfate II, TF-para-LNH sulfate and combinations thereof (for explanation of abbreviations, see Table 1). Reference is also made to Chapter 1 of "Oligosaccharides: Sources, Properties and Applications" (Nova Science Publishers, 2011, editor Nicole S Gordon) on human milk oligosaccharides, in particular Table 4 of the chapter, which details the structures of the oligosaccharides mentioned.

[0083] A specific embodiment of the nutritional composition for use according to the invention relates to one wherein at least one fucosylated oligosaccharide is selected from the group consisting of 3'fucosylated lactose (3'FL), DFL, LNFP II, LNFP III, LNFP V.

[0084] In other specific embodiments of the present invention, the at least one fucosylated oligosaccharide is selected from the group consisting of 3' fucosylated lactose (3' FL) and DFL.

[0085] The following fucosylated oligosaccharides will be referred to hereinafter by their abbreviations.

[0086] Table 1: Common names and abbreviations of fucosylated oligosaccharides

[0087]

[0088]

[0089]

[0090] "Yes" means it exists, and a blank box means it does not exist.

[0091] Health disorders and obesity rebound

[0092] Other embodiments relate to the nutritional composition for use according to the invention, wherein the health disorder is a health disorder associated with excessive accumulation of fat mass. The health disorder associated with excessive accumulation of fat mass can be selected from the group consisting of: overweight, obesity, type 2 diabetes, insulin resistance, hypertension, cardiovascular disease or metabolic syndrome.

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

[0094] Obesity rebound typically occurs at age 6, for example after age 6, or after age 7, or for example at age 7; such as between age 6 and 9, such as between age 6 and 8, for example between age 6 and 7.

[0095] In contrast, in the context of the present application, premature obesity rebound is defined as obesity rebound that occurs earlier than normal. Therefore, for example, when obesity rebound (i.e., the time when BMI starts to rise after infancy) occurs before 6 years old, for example, between 2 years old and 6 years old, for example, between 3 years old and 6 years old, or for example, between 4 years old and 6 years old, or 5 years old to 6 years old, or for example, 2 years old to 5 years old, 3 years old to 5 years old, 4 years old to 5 years old, it can be considered as obesity rebound.

[0096] Target Group

[0097] The nutritional composition according to the invention is intended for infants or young children.

[0098] In some embodiments, the nutritional composition according to the invention is for use in infants or young children who are at risk of developing a health disorder later in life, such as a health disorder associated with excessive accumulation of fat mass.

[0099] The baby or young child can be a full-term baby or a premature baby. In a specific embodiment, the nutritional composition of the present invention is used for premature babies. Premature babies will have increased risk of insulin resistance, hyperglycemia, poor nutrient utilization, impaired lean body growth, visceral fat accumulation and metabolic diseases 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 the baby or young child has a risk of suffering from obesity, such as one or more of the group consisting of premature babies, overweight babies, babies born to obese mothers and / or babies born to mothers carrying SNP rs3894326.

[0100] The nutritional composition of the present invention can also be used for infants or young children born by caesarean section or vaginal delivery.

[0101] The time of obesity rebound may be different in subgroups, or for example, different in different target groups. Therefore, alternatively, premature obesity rebound can be defined as the obesity rebound of at least 6 months earlier than the average obesity rebound time of the subgroup. For example, premature obesity rebound can be defined as the obesity rebound of 8 months, 12 months, 18 months, 24 months earlier than the average time point of the subgroup. In other examples, premature obesity rebound can be defined as the obesity rebound of 6 months to 36 months earlier than the average time point of the subgroup, such as 6 months to 30 months earlier than the average time point of the subgroup, 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.

[0102] The subpopulation may be, for example, a selected target population, such as a subpopulation of infants determined to be at risk of developing overweight and / or obesity later in life. In one embodiment, the subpopulation may be infants born to mothers that display one or more SNPs. In another embodiment, the subpopulation may be infants or young children born to overweight and obese women. Indeed, scientific evidence continues to show that infants born to overweight and obese mothers are at a greater risk of developing overweight or obesity later in life than infants born to mothers who are not overweight or obese.

[0103] Nutritional composition

[0104] Other embodiments of this aspect of the invention relate to nutritional compositions for use according to the invention, wherein at least one fucosylated oligosaccharide, e.g. at least one fucosylated oligosaccharide having α1,3 bonds and / or α1,4 bonds (or a fucosylated oligosaccharide fucosylated by FUT3) 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, 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, e.g. 0.1 g / L or 0.8 g / L of the composition.

[0105] In other embodiments, the nutritional composition for use according to the invention comprises or preferably further comprises at least one fucosylated oligosaccharide having an α2 bond and / or an α1,2 bond; and / or a fucosylated oligosaccharide fucosylated by FUT2. In some embodiments, the nutritional composition comprises one or more fucosylated oligosaccharides selected from the group consisting of α1,2'fucosylated lactose and α2'fucosylated lactose. In a specific embodiment, the nutritional composition for use according to the invention further comprises 2-FL (2'fucosylated lactose).

[0106] Adjusted nutritional composition

[0107] 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 stage 2 or older infant formula, a baby food, an infant cereal composition, a growing-up milk, a fortifier or a supplement.

[0108] For example, the nutritional composition used may be a powdered infant formula which is diluted with water to obtain a final liquid product. In other examples, the nutritional composition for use according to the invention may also be a concentrated liquid which is diluted with water to obtain a final liquid product. The nutritional composition for 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 known or predicted from published clinical data.

[0109] The nutritional composition for purposes according to the present invention may include 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 ratio of n-6 fatty acids to n-3 fatty acids in a fat source (including optional LC-PUFA, such as ARA and / or DHA) is 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.

[0110] 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 (such as 1:1 from Martek). and A mixture of ARA and DHA, preferably in a ratio of about 1:1.

[0111] Milk fat can be made from Or from AAK / Enzymotec Effective replacement.

[0112] Each of these fat sources is a refined oil suitable for use in infant nutrition.

[0113] Other standard ingredients known to the person skilled in the art for formulating infant formulas, step 1 infant formulas, step 2 infant formulas or follow-on formulas, baby foods, infant cereal compositions, growing-up milks, fortifiers or supplements are also present in the nutritional composition for use according to the invention.

[0114] 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 stage 2 infant formulae.

[0115] 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 present in infant formulas may be used, such as lactose, sucrose, maltodextrin, starch and mixtures thereof, but the preferred carbohydrate source is lactose.

[0116] Prebiotics that can be included according to the present invention are not specifically limited, including all food substances that promote the growth of probiotics or beneficial microorganisms in the intestine. Preferably, prebiotics can be selected from the group consisting of the following items: 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), arabinoxylan oligosaccharides (AXOS), manno-oligosaccharides (MOS), inulin, soy polydextrose oligosaccharides, glycosylsucrose (GS), lactosucrose (LS), lactulose (LA), palatinose oligosaccharides (PAO), maltooligosaccharides, gums and / or hydrolysates thereof, pectin and / or hydrolysates thereof. In a specific embodiment, the prebiotics can be fructooligosaccharides and / or inulin. In one embodiment, the prebiotic is a combination of FOS and inulin, such as that 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".

[0117] 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.

[0118] A specific embodiment relates to a nutritional composition according to the invention further comprising at least one other oligosaccharide and / or fiber and / or precursor of human milk oligosaccharides selected from the list comprising GOS, FOS, XOS, inulin, polydextrose, sialylated oligosaccharides, sialic acid, fucose, N-acetylated oligosaccharides and any combination thereof.

[0119] 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. The oligosaccharide mixture is preferably a mixture of BMOS (milk oligosaccharides). For example, a composition for use according to the present invention may contain 2.5% to 15.0% by weight of the BMOS 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.

[0120] The nutritional composition for use according to the invention may also comprise one or more probiotics. In a particular embodiment, the one or more probiotics may for this purpose be chosen from the group consisting of Bifidobacterium, Lactobacillus, Lactococcus, Enterococcus, Streptococcus, Kluyveromyces, Saccharoymces, Candida, in particular from the group consisting of Bifidobacterium longum, Bifidobacterium lactis, Bifidobacterium animalis, Bifidobacterium breve, Bifidobacterium infantis, Bifidobacterium adolescentis, Lactobacillus acidophilus, Lactobacillus casei, casei, Lactobacillus paracasei, Lactobacillus 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.

[0121] The nutritional composition for use according to the invention may also contain a protein source. The type of protein is considered to be immaterial to the 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 whey proteins are 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 to enhance oral tolerance to allergens, in particular food allergens. In this case, the composition is a hypoallergenic composition.

[0122] 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, such as a formula based on free amino acids.

[0123] The amount of protein may be 1.5 g / 100 kcal 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, for example 1 g / 100 kcal to 2 g / 100 kcal; such as less than 1.8 g / 100 kcal, for example 1 g / 100 kcal to 1.8 g / 100 kcal; for example, in the range of 1.5 g / 100 kcal to 1.8 g protein / 100 kcal.

[0124] 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 nutritional demand in large quantities. 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 amount of specific minerals and other vitamins will vary according to the applicable population.

[0125] 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.

[0126] 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.

[0127] The preparation of a nutritional composition for use according to the invention will now be described by way of example.

[0128] 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 that has been subjected to 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.

[0129] 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 as needed.

[0130] The liquid mixture is then homogenized, for example in two stages.

[0131] 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 to about 150°C for a period of about 5 seconds to about 5 minutes. This can be done by steam injection, autoclave, or heat exchanger (e.g., plate heat exchanger).

[0132] The liquid mixture is then cooled to about 60°C to about 85°C, for example by flash cooling. The liquid mixture is then homogenized again, for example in two stages, with a pressure of about 10 MPa to about 30 MPa in the first stage and a pressure of about 2 MPa to about 10 MPa in the second stage. The homogenized mixture may then be further cooled to allow for the addition of any heat-sensitive components, such as vitamins and minerals. The pH and solids content of the homogenized mixture are conveniently adjusted at this point.

[0133] 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 can 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).

[0134] 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 sterilisation.

[0135] 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.

[0136] Supplement can be in the form of, for example, powder, tablet, capsule, lozenge or liquid, as long as it is a suitable nutritional composition for infants. Supplement can also include protective hydrophilic colloid (such as gum, protein, modified starch), binder, film former, encapsulant / material, wall / shell material, matrix compound, coating, emulsifier, surfactant, solubilizer (oil, fat, wax, lecithin, etc.), adsorbent, carrier, filler, co-compound, dispersant, wetting agent, processing aid (solvent), flow agent, taste masking agent, weighting agent, gelling agent and gel forming agent. Supplement can also include conventional pharmaceutical additives and adjuvants, excipients and diluents, including but not limited to: water, gelatin from any source, vegetable gum, lignin sulfonate, talc, sugar, starch, gum arabic, vegetable oil, polyalkylene glycol, flavoring agent, preservative, stabilizer, emulsifier, buffer, lubricant, coloring agent, wetting agent, filler, etc.

[0137] The supplements can be added separately to a product (e.g., an ingestible carrier or support) that is acceptable to the consumer (which is an infant). Examples of such carriers or supports are pharmaceutical or food compositions. Examples of such compositions are infant formulas, including formulas for premature infants.

[0138] In addition, the supplement may also 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 (such as European Commission Directive 2006 / 141 / EC of 22 December 2006 on infant formula and step 2 infant formula).

[0139] Dosage regimen

[0140] The nutritional composition for use according to the invention may be provided at any time during infancy and early childhood. The age and duration of administration (or provision or feeding) of the nutritional composition may be determined according to possibilities and needs.

[0141] In one embodiment of this aspect of the invention, the nutritional composition for use according to the invention is administered to infants or young children from birth to 3 years of age, such as 6 months to 3 years of age, 7 months to 3 years of age, 8 months to 3 years of age, 9 months to 3 years of age, 10 months to 3 years of age, 12 months to 3 years of age, or for example 1 year to 3 years of age or 2 years to 3 years of age. A specific embodiment relates to infants or young children of 8 months to 3 years of age.

[0142] Since the nutritional composition is mainly used for preventive purposes (avoiding excessive accumulation of fat mass, thereby preventing the health disorders associated with excessive accumulation of fat mass such as obesity in the future), it can be provided, for example, after the baby is born. The composition of the present invention can also be provided within 1 week after the baby is born, or within 2 weeks after birth, or within 3 weeks after birth, or within 1 month after birth, or within 2 months after birth, or within 3 months after birth, or within 4 months after birth, or within 6 months after birth, or within 8 months after birth, or within 10 months after birth, or within 1 year after birth, or within 2 years after birth, or even within a longer time. In some particularly advantageous embodiments of the present invention, the nutritional composition is provided (or applied) to the baby before 4 or 6 months after the baby is born.

[0143] In some other embodiments, the nutritional composition of the present invention is provided 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 a premature baby, but this is not required.

[0144] In one embodiment, the composition of the present invention is provided to an infant or young child as a supplementary composition of breast milk. In some embodiments, an infant or young child receives breast milk during at least the first 2 weeks, first 1 month, 2 months, 4 months or 6 months. In one embodiment, the nutritional composition of the present invention is provided to an infant or young child after this period of time when breast milk is used to provide nutrition, or is provided to an infant or young child together with breast milk during this period of time when breast milk is used to provide nutrition. In another embodiment, at least for a period of time (for example, after at least 1 month, 2 months or 4 months), at least 1 month, 2 months, 4 months or 6 months, the composition is provided to an infant or young child as a unique or main nutritional composition.

[0145] Uses for overweight

[0146] In another aspect the invention relates to the use of a nutritional composition as defined herein, in the context of a nutritional composition for use, for reducing the risk of an infant or young child later developing overweight by preventing premature obesity rebound.

[0147] Nutritional composition for promoting healthy growth

[0148] In another aspect, the present invention relates to a nutritional composition comprising at least one fucosylated oligosaccharide for promoting healthy growth by preventing premature obesity rebound.

[0149] One embodiment relates to a nutritional composition according to the invention comprising one or more fucosylated oligosaccharides having at least one fucosyl group attached via an α1,3 bond, via an α1,4 bond and / or via an α1,2 bond or an α2 bond.

[0150] One embodiment relates to a nutritional composition according to the present invention, which has at least one fucose group linked via an α1,3 bond, at least one fucose group linked via an α1,4 bond, or a combination thereof, for promoting healthy growth of an infant or young child.

[0151] The expression "growth" refers to the growth of the weight, height, head circumference and / or abdominal circumference of an infant or 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 young child as the age increases. Therefore, the expressions "growth rate" and "growth velocity" can also be used in place of the term "growth". These parameters do not just increase during infant development, in fact, the standard growth curves announced by the WHO show that the weight of the infant may decrease in the first few days after the birth of the infant. Therefore, "growth" must be understood as the overall growth of the infant in the first few months after birth, such as particularly from birth to 8 months old, from birth to 10 months old, from birth to 12 months old, or from birth to 24 months old, or from birth to 36 months old.

[0152] The expressions "promote healthy growth" and "promote optimal growth" are used interchangeably. They encompass promoting a growth rate that is close to or approximates the growth rate of a breastfed infant. They encompass promoting growth that is considered normal by a pediatrician, so that the infant grows without 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 of life. The expression "promote 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 in terms of an increase in total weight or fat mass.

[0153] One embodiment of the present aspect relates to a nutritional composition comprising at least one fucosylated oligosaccharide fucosylated by FUT3 for promoting healthy growth of an infant or young child by preventing premature obesity rebound.

[0154] In a particular 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 above under the heading Target Group.

[0155] In other embodiments, the nutritional composition for use according to the present aspect may be as described above in relation to the preceding aspects of the invention.

[0156] Methods for identifying target groups

[0157] 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 via a 1,3 linkage and / or at least one fucosyl group linked via a 1,4 linkage. Based on the identified association between abdominal circumference and such FUT3 polymorphism, such infants may be identified as being at risk for premature obesity rebound and / or excessive accumulation of fat mass.

[0158] Thus, another aspect of the invention relates to a method of identifying whether an infant or young child is at risk for excess accumulation of fat mass and / or one or more health disorders, such as health disorders associated with excess accumulation of fat in the infant / young child or later in life; the method comprising determining the presence of the following single nucleotide polymorphisms in the FUT3 gene of the infant's mother:

[0159] a) rs3894326 (SNP database accession number, MCBI)

[0160] The presence of the polymorphism is associated with an increased risk of premature obesity relapse, excess accumulation of fat mass, and one or more health disorders, such as health disorders related to excess fat accumulation during infancy and / or later in life.

[0161] The polymorphism numbers refer to the accession numbers in the single nucleotide polymorphism database of NCBI and are available online.

[0162] Treatment

[0163] Mothers showing a disruption in the FUT3 gene will produce fewer fucosylated oligosaccharides having at least one fucose linked by α1,3 and / or α1,4 bonds. 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 such fucosylated oligosaccharide.

[0164] Therefore, another 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

[0165] i. Determine if the mother has a functional FUT3 enzyme,

[0166] as well as

[0167] ii. administering to the infant or young child a nutritional composition in the context of a nutritional composition according to the present invention as defined above, e.g. a nutritional composition comprising at least one fucosylated oligosaccharide, wherein the fucosylated oligosaccharide has at least one fucose group linked via an α1,3 bond, at least one fucose group linked via an α1,4 bond, or a combination thereof, thereby preventing premature obesity rebound.

[0168] If the FUT3 enzyme causes α1,3 and / or α1,4 fucosylation of its substrate, it 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 analyzed by immuno-based methods such as Western blot.

[0169] In one embodiment, 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 following steps

[0170] i. Determine whether the mother has the following single nucleotide polymorphisms in the FUT3 gene:

[0171] a)rs3894326

[0172] as well as

[0173] ii. administering to the infant or young child a nutritional composition in the context of a nutritional composition according to the present invention as defined above, e.g. a nutritional composition comprising at least one fucosylated oligosaccharide, wherein the fucosylated oligosaccharide has at least one fucose group linked via an α1,3 bond, at least one fucose group linked via an α1,4 bond, or a combination thereof, thereby preventing premature obesity rebound.

[0174] Uses in preparation

[0175] Aspects of the invention relating to nutritional compositions for use according to the invention may alternatively be described as using fucosylated oligosaccharides to prepare a nutritional composition for administration to an infant or young child to reduce and / or avoid excessive accumulation of fat mass in later life; and / or for preventing later health disorders, such as health disorders associated with fat accumulation, by preventing premature obesity rebound, and / or by regulating the timing of obesity rebound.

[0176] Another embodiment relates to the use of fucosylated oligosaccharides fucosylated by FUT3 to prepare a nutritional composition for administration to an infant or young child to reduce and / or avoid excessive accumulation of fat mass in the future; and / or to prevent future health disorders, such as future health disorders associated with fat accumulation, by preventing premature obesity rebound.

[0177] Another embodiment relates to the use of fucosylated oligosaccharides fucosylated by FUT3 to prepare a nutritional composition for reducing and / or preventing excessive accumulation of fat mass in infants or young children; and / or preventing future health disorders associated with fat accumulation in infants or young children by preventing premature obesity rebound.

[0178] This application also discloses the following technical solutions.

[0179] 1. A nutritional composition comprising at least one fucosylated oligosaccharide for use in preventing health disorders in infants or young children later in life by preventing premature obesity rebound.

[0180] 2. The nutritional composition for use according to technical solution 1, wherein the future health disorder involves excessive accumulation of fat mass, such as future overweight, obesity and / or obesity-related complications.

[0181] 3. A nutritional composition for use according to technical solution 1 or 2, wherein the at least one 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.

[0182] 4. The nutritional composition for use according to any one of the preceding technical solutions, wherein the at least one fucosylated oligosaccharide is fucosylated by FUT3.

[0183] 5. The nutritional composition for use according to any one of the preceding technical solutions, wherein the at least one fucosylated oligosaccharide is selected from the group consisting of: 3' fucosylated

[0184] Lactose (3'FL), DFL, LNFP II, LNFP III, LNFP V and combinations thereof.

[0185] 6. The nutritional composition for use according to any one of the preceding technical solutions, which comprises or further comprises α1,2-fucosylated lactose and / or 2-fucosylated lactose.

[0186] 7. The nutritional composition for use according to any one of the preceding technical solutions, comprising or further comprising at least one fucosylated oligosaccharide fucosylated by FUT2.

[0187] 8. The nutritional composition for use according to any one of the preceding technical solutions, wherein the health disorder is selected from the group consisting of overweight, obesity, type 2 diabetes, insulin resistance, hypertension, cardiovascular disease or metabolic syndrome.

[0188] 9. A nutritional composition for use according to any one of the preceding technical solutions, wherein the at least one fucosylated oligosaccharide 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.

[0189] 10. A nutritional composition for use according to any one of the preceding technical solutions, wherein the composition further comprises at least one additional oligosaccharide and / or fiber and / or a precursor of human milk oligosaccharides selected from the list comprising the following items: GOS, FOS, XOS, inulin, polydextrose, sialylated oligosaccharides, sialic acid, fucose, N-acetylated oligosaccharides and any combination thereof.

[0190] 11. The nutritional composition for use according to any one of the preceding technical solutions, wherein the composition further comprises at least one probiotic, wherein the amount of the probiotic is 10 3 cfu / g of the composition to 10 12 cfu / g of the composition (dry weight).

[0191] 12. A nutritional composition for use according to any one of the preceding technical solutions, wherein the nutritional composition is an infant formula, a stage 1 infant formula, a follow-on infant formula or a stage 2 infant formula, a baby food, an infant cereal composition, a growing-up milk, a fortifier or a supplement.

[0192] 13. The nutritional composition for use according to any one of the preceding technical solutions, wherein the infant or young child is at risk of obesity.

[0193] 14. Has at least one fucose group linked via an α1,3 bond and at least one α1,4

[0194] Use of fucosylated oligosaccharides containing fucose groups linked to the oligosaccharide or a combination thereof for preventing premature obesity rebound.

[0195] 15. The use of the nutritional composition defined in any one of the above technical solutions 1 to 13, which is used to reduce the risk of overweight in infants or young children in the future by preventing premature obesity rebound. Other embodiments relate to the use of the fucosylated oligosaccharide, wherein the nutritional composition is defined as described above for the nutritional composition for use according to the present invention.

[0196] 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.

[0197] All patent and non-patent references cited in this application are hereby incorporated by reference in their entirety.

[0198] The present invention will now be described in further detail in the following non-limiting examples.

[0199] Example

[0200] Example 1

[0201] An example of the composition of a nutritional composition (eg an infant formula) according to the invention is given in Table 2 below. The composition is given by way of example only.

[0202]

[0203]

[0204] Table 2: Examples of compositions of nutritional compositions (eg infant formula) according to the invention

[0205] Example 2: Relationship between SNP and growth

[0206] Human milk oligosaccharide distribution pattern depends on genetic variation, such as genetic variation related to glycosylated enzymes. The inventors have studied whether the change of oligosaccharides affects children's health. The association study between FUT3 SNP and children's health outcomes was carried out. Maternal samples from population cohorts were analyzed for SNP, 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 found. The LMS growth score method is known in the art (see Eur J Clin Nutr., January 1990, Vol. 1, No. 44, pp. 45-60, "The LMSmethod for constructing normalized growth standards", Cole TJ). Although LMS is generally regarded as a crossover / segmentation method, it can be used for longitudinal data.

[0207] The association between LMS growth score and FUT3 SNPs has been investigated to determine the growth of abdominal circumference over time and the results are shown in Table 3 below.

[0208] In cases where a SNP was found to be significantly associated with the outcome, the regression model was further adjusted for parity, mode of delivery, and breastfeeding (see Table 3).

[0209] There was an association between LMS abdominal circumference growth score at 6 to 12 months and FUT3 SNP rs3894326 (p = 0.043). This association remained significant when adjusting for breastfeeding, parity, and mode of delivery; breastfeeding duration (0, <= 3 months, > 3 months) also showed a significant association with LMS AC growth.

[0210] Abdominal circumference growth at 2 to 3 years was also significantly associated with FUT3 SNP rs3894326 (p = 0.018), and the association remained significant when adjusting for breastfeeding duration, parity, and mode of delivery. The results showed that the presence of the FUT3 SNP rs3894326 form that disrupts the FUT3 gene (carrying the mutation) was associated with reduced abdominal circumference at 6 months and increased abdominal circumference at 2 to 3 years of age compared with the unaffected SNP form of the FUT3 gene (wild type). This means that there is no functional FUT3 enzyme, and therefore no α1,3-fucosylated HMOs and α1,4-fucosylated HMOs are produced at 2 to 3 years, which is associated with a larger abdominal circumference (a measure of obesity). The group of infants with early high adiposity rebound at 2 to 3 years of age who were fed human milk with reduced amounts of α1,3 and 1,4-fucosylated HMOs (non-functional FUT3 enzymes) were susceptible to future fat accumulation-related disorders; we therefore conclude that α1,3-fucosylated HMOs and α1,4-fucosylated HMOs are required for optimal growth of infants and their presence prevents premature adiposity rebound.

[0211] exist Figure 1 In Figure 2, conditional z scores for abdominal circumference at 6 to 12 months are shown for infants whose mothers carry the fully functional FUT3 form (SNP rs3894326:AA, wild type) versus infants whose mothers carry the altered FUT3 form (SNP rs3894326:TA, carrying a mutation). Figure 2 , conditional z scores for abdominal circumference at 2 to 3 years of age are shown for the same group of infants. Clearly, normal infant growth may be disrupted if mothers have non-fully functional FUT3 and therefore reduced amounts of α1,3-fucosylated HMOs and α1,4-fucosylated HMOs in their breast milk.

[0212] The conditional z-score of a growth outcome or dimension (such as abdominal fat) was defined as the regression of that dimension on total body size as described by Keijzer-Veen et al. (2005).

[0213] In Table 3, data from the unadjusted and adjusted models are shown.

[0214] Abbreviations and notes:

[0215] The LMS growth score is a measure of abdominal circumference (AC) as defined above.

[0216] SNP refers to single nucleotide polymorphism, which in this case is rs3894326.

[0217] N is the number of participants in this study.

[0218] β is the β value coefficient of the regression model used in this analysis. The β value of AC is negative, indicating that the group of infants whose mothers carry the mutant SNP is associated with lower AC compared with the group of infants whose mothers carry the wild-type SNP (positive β value of AC) in the 6- to 12-month-old infant group, and in the 2- to 3-year-old infant group, indicating that the group of infants whose mothers carry the mutant SNP is associated with higher AC compared with the group of infants whose mothers carry the wild-type SNP, as shown in Figure 1 and Figure 2 shown.

[0219] AC = abdominal circumference; m = months; yrs = years. Adjusted = See description of examples above.

[0220] Table 3

[0221]

Claims

1. Use of a synthetic nutritional composition comprising at least one fucosylated oligosaccharide for the preparation of a non-therapeutic product for preventing future overweight and / or obesity in infants or young children at risk of obesity by preventing premature obesity rebound, wherein the at least one fucosylated oligosaccharide is fucosylated by FUT3, wherein the infant or child is born to a mother carrying SNP rs3894326, wherein the at least one fucosylated oligosaccharide has at least one fucose group linked via an α1,3 bond, at least one fucose group linked via an α1,4 bond, or a combination thereof, 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, LNDFHI, LNDFH II and combinations thereof.

2. The use according to claim 1 or 2, wherein the nutritional composition further comprises α1,2-fucosylated lactose and / or 2-fucosylated lactose.

3. The use according to claim 1 or 2, wherein the nutritional composition further comprises at least one fucosylated oligosaccharide fucosylated by FUT2.

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 composition further comprises at least one additional oligosaccharide and / or fiber and / or a precursor of human milk oligosaccharides selected from the list comprising: GOS, FOS, XOS, inulin, polydextrose, sialylated oligosaccharides, sialic acid, fucose, N-acetylated oligosaccharides and any combination thereof.

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

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

10. 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 following steps: 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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