RU2793556C2 - Breast milk oligosaccharides for health beneficial effects through prevention of early fat ricochet - Google Patents

Abstract

FIELD: pharmaceutical industry.

SUBSTANCE: invention relates to the use of artificial nutritional compositions for infants and young children. Use of an artificial nutritional composition containing at least one fucosylated oligosaccharide for the prevention of a later life disorder in an infant or young child at risk of developing obesity by preventing early fat rebound, the later life disorder being selected from overweight, obesity, and/or obesity-related comorbidities, wherein at least one fucosylated oligosaccharide is fucosylated by FUT3, and wherein at least one fucosylated oligosaccharide is present in the said nutritional composition in an amount effective to achieve the desired effect later in life in the said infant or a young child.

EFFECT: above composition allows to prevent health problems and disorders in later life, chosen from the group consisting of type 2 diabetes, fasting hyperglycemia, insulin resistance, visceral obesity, hyperinsulinemia, hypertension, cardiovascular disease, cerebrovascular disease, arthrosis, dyslipidemia, hyperuricemia, fatty liver, osteoarthritis and sleep apnea, after the specified person reaches the age over 36 months.

8 cl, 2 dwg, 3 tbl, 2 ex

Description

Technical field

The present invention relates to nutritional compositions for use in an infant or young child for the prevention of health problems later in life through the prevention of early fat rebound (adiposity rebound).

Prerequisites for the creation of the invention

Over the past 30 years worldwide, the prevalence of obesity and overweight in adults, children and adolescents has risen dramatically and continues to rise. Globally, the incidence of obesity has more than doubled since 1980, according to WHO. It has become a global health problem as it is associated with reduced life expectancy, altered quality of life and in addition it is responsible for additional health conditions. Globally, overweight and obesity are associated with more deaths than underweight. Childhood obesity is indeed associated with a higher likelihood of obesity, premature death and disability in adulthood. But in addition to increased future risks, obese children experience breathing difficulties, increased risk of fractures, hypertension, early markers of cardiovascular disease, insulin resistance, and physiological 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 incapacitating degenerative joint disease); and even some types of malignant tumors (endometrium, breast and colon).

Mother's milk is recommended for all babies for various reasons. Breastfeeding has been specifically reported to be particularly beneficial for obesity prevention compared to formula feeding (Owen et al., Effect of Infant Feeding on the Risk of Obesity Across the Life Course: A Quantitative Review of Published Evidence, 2005). Evidence suggests that infancy may be a critical period in the development and programming of obesity or future metabolic disorders. Many sources have reported that breastfed babies have a growth pattern that is different from formula fed babies. Indeed, breastfed infants have lower weight gain and lower body fat mass during the first year of life compared to formula fed infants. In addition, breastfed infants have a different gut microbiota profile compared to a formula fed infant. In general, these factors influence the development of an infant's physiology, including metabolism, immunity, and overall growth.

However, in some cases, breastfeeding is insufficient or unfavorable for medical reasons, or the mother refuses to breastfeed. Infant formulas have been developed for these situations. Fortifiers have also been developed to fortify mother's milk or infant formula with certain ingredients. It is known that growth rate in infants has an impact on the risk of subsequent excess accumulation of adipose tissue mass and associated metabolic disorders and cardiovascular diseases. In particular, a faster growth rate during infancy may predispose such an infant to obesity later in life.

Therefore, nutritional compositions that promote normal growth in the infant and young child and that can help prevent excessive accumulation of adipose tissue mass will be preferred.

There is a clear need to provide such health benefits in a way that is particularly suitable for young subjects (infants and young children), and such a way should not include classical pharmaceutical intervention, since these subjects are particularly vulnerable.

There is a need to provide these health benefits to infants and young children in a manner that does not cause side effects and/or is easy to carry out and is acceptable to parents or healthcare professionals.

There is also a need to provide such benefits in a manner that will keep the cost of such provision reasonable and affordable to the majority.

Statement of the Invention

Therefore, one aspect of the present invention relates to a nutritional composition containing at least one fucosylated oligosaccharide, for use in an infant or young child in the prevention of a health disorder in later life, such as excessive accumulation of adipose tissue in later life; and/or health disorders associated with excessive accumulation of adipose tissue mass, such as overweight, obesity and/or obesity-related comorbidities in later life, through the prevention of early fat rebound.

Another aspect of the present invention relates to the use of a nutritional composition according to the present invention to reduce the risk of developing overweight in later life in an infant or young child through the prevention of early fat rebound.

Brief description of the figures

In FIG. 1 shows sex-specific conditional LMS z-score of abdominal circumference for ages 6-12 months relative to the FUT3 rs3894326 polymorphism.

In FIG. 2 shows a sex-specific conditional z-score for LMS abdominal circumference for 2-3 years of age relative to the FUT3 rs3894326 polymorphism.

Description of the invention

Definitions

Before a more detailed discussion of the present invention, the following terms, expressions and conventions will first be defined:

Fucose is a hexose deoxysugar with the chemical formula C ₆ H ₁₂ O _5. It corresponds to 6-deoxy-L-galactose.

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

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. HomoloGene: 55438 ChEMBL: 3269 GeneCards: FUT3 Gene.

The FUT3 gene encodes an enzyme with alpha-(1,3)-fucosyltransferase and alpha-(1,4)-fucosyltransferase activities.

Fucosyltransferase 2 (abbreviated FUT2 in this document) also known as galactoside-2-alpha-L-fucosyltransferase 2, EC 2.4.1.69, SE 2, SEC2, fucosyltransferase-2 (secretor gene), GDP-L-fucose:beta -D-galactoside-2-alpha-L-fucosyltransferase 2, galactoside-2-alpha-L-fucosyltransferase 2, alpha-2-fucosyltransferase linked to secretor gene for blood group antigens, secretor gene factor and transmembrane protein 2. In the prior art, the FUT2 gene is also referred to as the secretor (Se) gene.

SNP (Single Nucleotide Polymorphism) is a single nucleotide variation that can occur at a specific position in the genome, with each variation present in a measurable amount in a population. Functional SNPs, such as those described in the present invention, affect protein expression.

The term "infant" means a person under the age of 12 months.

The expression "young child" means a person between the ages of one and three years, also called a toddler.

The term "child" means a person between the ages of three and 12 years.

A person between the ages of 12 and 18 is called a teenager, and a person over the age of 18 is called an adult.

The term "nutritional composition" means a composition fed to a subject. This nutritional composition will generally be taken orally or intravenously. It may include a lipid or fat source, a carbohydrate source, and/or a protein source.

In a specific embodiment, the composition of the present invention is a hypoallergenic nutritional composition. The expression "hypoallergenic nutritional composition" means a nutritional composition that is unlikely to cause allergic reactions.

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

The expression "infant formula" as used herein refers to a food product that is specifically intended to be consumed by infants during the first months of life (such as 0 to 12 months, 0 to 10 months, 0 to 8 months, 0 to 6 months, 0 to 4 months) and which by itself satisfies the nutritional needs of this category of persons (Article 2(c) of European Commission Directive 91/321/EEC 2006/141/EC of 22 December 2006 on infant formula and infant formula for complementary foods). It also refers to a nutritional composition intended for infants as defined in the Codex Alimentarius (Codex STAN 72-1981) and the "Special Foods for Infants" standard (including the article "Foods for Special Medical Purposes"). The expression "infant formula" covers both "initial formula" and "formula for formula feeding".

"Mixture for feeding children" is given starting from the 6th month. It constitutes the main liquid element in the gradually increasing variety of diets for this category of individuals.

"Milk formula for children from 1 to 3 years" (or GUM) is usually a milk-based formula adapted to the specific nutritional needs of a toddler or toddler.

The expression "infant food" means a food product specifically intended for use by infants or young children during the first years of life.

The term "cereal-based infant formula" means a food product specifically intended for use by infants or young children during the first years of life.

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

The term "supplement" refers to a nutritional composition intended to provide nutrients that may not otherwise be consumed in sufficient amounts. It is taken in addition to another food/food product. It may, for example, be in the form of tablets, capsules, lozenges or liquids. The additive may additionally contain protective hydrocolloids (such as gums, modified starches), binders, film-forming agents, encapsulating agents/materials, wall/shell materials, matrix compounds, coatings, emulsifiers, surface active agents, solubilizing agents (oils, fats, waxes, lecithins, etc.), adsorbents, carriers, fillers, auxiliary compounds, dispersing agents, wetting agents, processing aids (solvents), anti-caking agents, taste masking agents, weighting agents, gelling agents and gelling agents. The additive may also contain conventional pharmaceutical additives and adjuvants, excipients and diluents, including, but not limited to, water, gelatin of any origin, vegetable gums, lignin sulfonate, talc, sugars, starch, gum arabic, vegetable oils, polyalkylene glycols, flavoring agents, preservatives. , stabilizers, emulsifying agents, buffers, lubricants, colorants, wetting agents, fillers, and the like. The term "supplement" means the same as the additive, and these terms can be used interchangeably in this document.

The expressions "accumulation of adipose tissue mass" and "accumulation of fat" can be used interchangeably.

The expression "excessive accumulation of adipose tissue mass" refers to an abnormal amount of adipose tissue mass in the body, for example, an amount that can be detrimental to health and can lead to health disorders. Overweight or obesity are examples of excess fat accumulation.

The body mass index (BMI) is a simple weight-for-height measure that is widely 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 indicates overweight; A BMI greater than or equal to 30 indicates obesity.

The expressions "reducing (excessive) accumulation of adipose tissue mass" and "avoiding (excessive) accumulation of adipose tissue mass" refer to reducing or limiting the amount of fat in the body of an individual.

The expression "health disorder(s)" encompasses any health condition and/or disease and/or dysfunction that affects an individual's body, including metabolic dysfunctions.

The expressions "prevention of disorder in later life" or "prevention of disorder in later life" can be used interchangeably. They mean avoiding the occurrence of a health disorder (eg obesity) later in life and/or reducing the frequency and/or severity of a health disorder later in life. Prevention occurs "later in life", therefore, preferably after the completion of the intervention or treatment (ie, after administration of the nutritional composition of the present invention).

The expression "health disorder in later life associated with excessive accumulation of mass of adipose tissue" refers to a health disorder in later life due to (ie direct relationship) or associated (ie indirect relationship) with excess fat. It covers overweight, obesity and obesity-related comorbidities.

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 cancers.

Prevention occurs "later in life", for example, after administration of a nutritional composition according to the present invention, or, for example, after completion of an intervention or treatment.

The expression "in the later life" and "in the afterlife" can be used interchangeably. Effects that occur "later life"/"later life" refer to effects measured in an individual (infant or young child) after administration of the nutritional composition of the present invention and at least 8 months or several years after birth e.g. after the age of 8 months after birth, for example after the age of 10 months after birth, for example after the age of 1 year after birth, for example after the age of 2 years, preferably after the age of 4 years, more preferably after the age of 5 years, even more preferably after the age of 7 years after birth or even more, and compared with the average observational data for subjects of the same age. Preferably, it 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, "later in life" may refer to observation during infancy, early childhood, childhood, adolescence, or adulthood. Preferably, it refers to observation in childhood, adolescence or adulthood.

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

The expression "HMO" refers to the oligosaccharide(s) of breast milk. These carbohydrates are resistant to enzymatic hydrolysis by digestive enzymes (eg, pancreas and/or brush border), indicating that they may exhibit functions not directly related to their calorie content. First of all, they have been shown to play a vital role in the early development of infants and young children, such as the development of the immune system. Many different types of HMO have been found in breast milk. Each individual oligosaccharide is based on a combination of glucose, galactose, sialic acid (N-acetylneuraminic acid), fucose, and/or N-acetylglucosamine, forming numerous and varied bonds between them, resulting in the presence of a huge number of different oligosaccharides in breast milk - at the moment it was more than 130 such structures have been identified. Nearly all of them have a lactose group at their reducing end, while sialic acid and/or fucose (if present) end up at the non-reducing ends. HMOs can be acidic (eg, an oligosaccharide containing a charged sialic acid) or neutral (eg, a fucosylated oligosaccharide).

"Fucosylated oligosaccharide" is an oligosaccharide having a fucose residue. It has a neutral character. Some examples are 2-FL (2'-fucosyllactose), 3-FL (3'-fucosyllactose), difucosyllactose, lacto-N-fucopentaose (e.g. lacto-N-fucopentaose I, lacto-N-fucopentaose II, lacto-N -fucopentaose III, lacto-N-fucopentaose V), lacto-N-fucohexaose, lacto-N-difucohexaose I, fucosyllacto-N-hexaose, fucosyllacto-N-neohexaose, difucosyllacto-N-hexaose I, difucosyllacto-N-neohexaose II and any combination of them.

An "alpha-1,3-fucosylated oligosaccharide" is an oligosaccharide having a fucose linked via a C1 fucose in alpha conformation to a C3 monosaccharide unit of a mono- or oligosaccharide (2 or more monosaccharides).

An "alpha-1,4-fucosylated oligosaccharide" is an oligosaccharide having a fucose linked via a C1 fucose in alpha conformation to a C4 monosaccharide unit of a mono- or oligosaccharide (2 or more monosaccharides).

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

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

A "sialylated oligosaccharide" is an oligosaccharide containing a charged sialic acid, i. e. an oligosaccharide having a sialic acid residue. It has an acidic character. Some examples are 3-SL (3'-sialyllactose) and 6-SL (6'-sialyllactose).

The nutritional composition of the present invention may be present in solid form (eg powder) or in liquid form. The amount of various ingredients (e.g. oligosaccharides) can be expressed as g/100 g of the composition on a dry weight basis if the composition is in solid form, e.g. powder, or as a concentration in g/l of the composition when referring to a liquid form (the latter also covers a liquid composition that can be obtained from a powder after reconstitution into a liquid such as milk, water, etc., e.g. , or any other formula intended for baby food).

The term "prebiotic" refers to non-digestible carbohydrates that benefit 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; 125:1401-12).

The term "probiotic" means preparations from microbial cells or components of microbial cells that have a beneficial effect on the health or well-being of the host organism. (Salminen S, Ouwehand A. Benno Y. et al. "Probiotics: how should they be defined" Trends Food Sci. Technol. 1999:10 107–10). Microorganism cells are essentially bacteria or yeast.

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

Unless otherwise indicated, all percentages given are by weight.

Additionally, in the context of the invention, the terms "comprising" or "comprises" do not exclude other possible elements. The composition according to the present invention, including many of the embodiments described herein, may contain the essential elements and limitations of the present invention described herein, as well as any additional or optional ingredients, components or limitations described herein, or otherwise depending on from needs, consist or actually consist of them.

Any reference to prior art documents in this specification should not be construed as an admission that such prior art is widely known or forms part of the common knowledge in the field.

Description of the invention

The essence of the invention

The present invention is based on the understanding of the importance of fucosylated oligosaccharides in the infant's diet for the timing of the onset of fat rebound (defined below). Mothers who develop single nucleotide polymorphisms (SNPs) that disrupt the expression of FUT3 (the gene encoding fucosyltransferase 3) also show reduced amounts of alpha-1,3- and alpha-1,4-fucosylated oligosaccharides in breast milk. The present inventors have shown that, surprisingly, the presence of this particular SNP is significantly associated with measurements of abdominal circumference in infants and young children (see Example and Table 3).

The link is that fucosylated human milk oligosaccharides, such as alpha-1,3-fucosylated oligosaccharides and alpha-1,4-fucosylated oligosaccharides (such as fucosylated oligosaccharide fucosylated with FUT3), affect infant growth by affecting time of occurrence of fat rebound.

Fat rebound is defined in the context of the present invention as the point in an individual's development when BMI begins to rise after infancy. Typically, an infant will gain mass during the earliest period of life. This is followed by a period in the development of the infant/young child when BMI declines. A decrease in BMI is usually due to increased length growth and possibly also reduced fat accumulation. At some point in development, BMI stops declining and starts rising again. This point in time when BMI starts to rise after infancy is known as fat rebound (AR). The term "fat rebound" is an accepted term in the art and has been described, for example, in Rolland-Cahera et al., Am J Clin Nutr. 1984 Jan;39(1):129-35.

Early fat rebound is associated with excess fat accumulation later in life, such as during adolescence and/or adulthood. Young children who exhibit early fat rebound (i.e., fat rebound that occurs earlier than expected) are at increased risk of being overweight, obese, and obesity-related comorbidities later in life.

There are prior studies regarding fucosylated human milk oligosaccharides and growth. For example, Alderete et al. investigated human milk oligosaccharides during early development (Alderete et al, Am J Clin Nutr. 2015 Dec;102(6):1381-8). However, the conclusions that can be drawn from this study are limited to the period of 0 to 6 months studied, and no conclusions can be drawn regarding the effect of human milk oligosaccharides on the risks of developing excess body fat later in life, nor in relation to the timing of the occurrence of fat rebound. Indeed, the authors themselves made the same conclusion.

Moreover, the effect of fucosylated oligosaccharides, documented in Alderete et al., varies depending on the type of fucosylated oligosaccharides. For example, alpha-1,3-fucosylated oligosaccharides and alpha-1,4-fucosylated oligosaccharides such as LNFPII are associated with increased body fat at 6 months. The opposite result was obtained for fucosylated oligosaccharides without this type of linkage (eg LNFPI, LNnT). The person skilled in the art therefore had no incentive to select alpha-1,3-fucosylated oligosaccharides and alpha-1,4-fucosylated oligosaccharides (such as a fucosylated oligosaccharide fucosylated with FUT3) to avoid health problems later in life by prevention of early fat rebound. However, the present inventors have shown that these particular oligosaccharides are indeed capable of avoiding early fat rebound and therefore provide prevention of later life excess fat accumulation or disorders associated with it.

The impact on early fat rebound presents new clinical situations in which the goal of prevention of health problems later in life can be achieved in a new way.

Nutritional composition for use

Thus, the present invention in a first aspect relates to a nutritional composition comprising at least one fucosylated oligosaccharide for use in an infant or young child in the prevention of a health disorder later in life, such as excess accumulation of adipose tissue in later life; and/or health disorders associated with excessive accumulation of adipose tissue mass, such as obesity in later life and/or obesity-related comorbidities, through the prevention of early fat rebound.

The nutritional compositions of the present invention prevent early fat rebound and thereby protect the subject from excessive accumulation of adipose tissue mass and/or from health disorders later in life associated with excessive accumulation of adipose tissue mass, such as obesity in later life and associated comorbidities.

The nutritional compositions of the present invention are typically administered to an infant or young child; however, the effect of preventing subsequent health problems can be seen for the first time later in life.

In the context of this application, "later in life" means in later life of the same infant or young child who is administered the nutritional composition. Thus, a nutritional composition for use according to the present invention may be administered to an infant or young child and may help prevent health disorders that may otherwise occur later in life in that infant or young child. Later in life in this context can mean, for example, at any time when an infant or young child is no longer a child, for example, an infant or young child may become a child, adolescent or adult. See also the definitions for further discussion of the expression "in later life".

In one embodiment, the nutritional composition of the present invention may be for use in reducing and/or preventing excessive accumulation of adipose tissue mass in an infant or young child through the prevention of early fat rebound. By this is meant that the nutritional composition of the present invention is administered to an infant or young child and provides for the prevention of excessive accumulation of adipose tissue mass in said infant or young child by preventing early fat rebound.

In another embodiment, the nutritional composition of the present invention may be for use in an infant or young child to reduce and/or prevent excess accumulation of adipose tissue later in life by preventing early fat rebound. By this is meant that the nutritional composition of the present invention is administered to an infant or young child and provides for the prevention of excess accumulation of adipose tissue later in life in said infant or young child through the prevention of early fat rebound.

In a further embodiment, the nutritional composition of the present invention may be for use in an infant or young child for use in the prevention of a health disorder later in life, e.g., a health disorder associated with excessive accumulation of adipose tissue mass, through the prevention of early fat rebound. By this is meant that the nutritional composition of the present invention is administered to an infant or young child and provides for the prevention of a health disorder, for example, a health disorder associated with excessive accumulation of adipose tissue mass, said health disorder occurring later in life in said infant or young child, through the prevention of early fat rebound.

Fucosylated oligosaccharides

As mentioned above, the nutritional composition for use according to the present invention contains at least one fucosylated oligosaccharide.

One particular embodiment relates to the case where said fucosylated oligosaccharide has at least one fucose group attached via an alpha-2 bond, an alpha-1,2 bond, an alpha-1,3 bond, an alpha-1,4- bonds or combinations thereof.

In a particular embodiment, said fucosylated oligosaccharide is fucosylated with FUT3 and/or with FUT2. Therefore, in specific embodiments, the present invention relates to a nutritional composition for use according to the present invention, comprising at least one fucosylated oligosaccharide that is fucosylated by FUT3, for use in an infant or young child to reduce and/or avoid excessive accumulation of adipose tissue mass. through the prevention of early fat rebound; and/or for use in an infant or young child for the prevention of a health disorder later in life, such as a health disorder associated with excessive accumulation of adipose tissue mass, such as obesity and associated comorbidities later in life, through the prevention of early fat rebound.

In one embodiment of the present invention, at least one fucosylated oligosaccharide in the nutritional composition of the present invention is one or more selected from the group consisting of 3'-fucosylated lactose (3FL), DFL, LNFP II, LNFP III, LNFP V, LNDFH I, LNDFH II, 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-LNnO II, DF-iso-LNO I, 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-LNH II, 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-LNO II, DFS-LNO, TFS-iso-LNO, FDS-LNT I, FDS-LNH II, FDS-LNH III, FDS-LNnH, FS-new-LNP I, DF-para-LNH sulfate I, DF-pair-LNH sulfate II, TF-pair-LNH sulfate, and combinations thereof (see Table 1 for explanation of abbreviations). Reference is also made to ‘Oligosaccharides: Sources, Properties and Applications’, Nova Science Publishers, 2011; Editor Nicole S Gordon; chapter 1 relating to milk oligosaccharides, and in particular to table 4 of that chapter, which details the structures of the oligosaccharides mentioned).

Specific embodiments of the nutritional composition for use according to the present invention relate to the case where at least one fucosylated oligosaccharide is selected from the group consisting of 3'-fucosylated lactose (3'FL), DFL, LNFP II, LNFP III, LNFP V.

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

The following fucosylated oligosaccharides will be referred to below by their respective abbreviations.

Table 1. Trivial names and abbreviations of fucosylated oligosaccharides

Reduction Full title Alpha 1,3 bond Alpha 1,4 bond 3FL 3'-fucosylated lactose Yes DFL Difucosyllactose = lactodifucotetraose Yes LNFP II Lacto-N-fucopentaose II Yes LNFP III Lacto-N-fucopentaose III Yes LNFP V Lacto-N-fucopentaose V Yes LNDFH I Lacto-N-difucohexaose I Yes LNDFH II Lacto-N-difucohexaose I Yes Yes F-LNH II F-lacto-N-hexaose II Yes F-pair-LNH I F-para-lacto-N-hexaose II Yes F-pair-LNH II F-para-lacto-N-hexaose II Yes DF-LNH II Difucosyllacto-N-hexaose II Yes Yes DF-LNH I Difucosyllacto-N-hexaose I Yes DF-LNnH Difucosyllacto-N-neohexaose Yes DF-pair-LNH Difucosyl-para-lactohexaose Yes Yes DF-pair-LNnH Difucosyl-para-lacto-N-neohexaose Yes Yes TF-LNH Trifucosyllacto-N-hexaose Yes Yes TF-pair-LNH I Trifucosyl-para-lacto-N-hexaose I Yes Yes TF-para-LNH II Trifucosyl-para-lacto-N-hexaose II Yes Yes TF-pair-LNnH Trifucosyl-para-lacto-N-neohexaose I Yes F-LNO Fucosyl-lacto-N-octaose Yes F-LNnO Fucosyl-lacto-N-neooctose Yes DF-LNO I Difucosyl-lacto-N-octaose I Yes DF-LNO II Difucosyl-lacto-N-octaose II Yes Yes DF-LNnO I Difucosyl-lacto-N-neooctose I Yes Yes DF-LNnO II Difucosyl-lacto-N-neooctose II Yes DF-iso-LNO I Difucosyl-iso-lacto-N-octaose I Yes Yes DF-iso-LNO II Difucosyl-iso-lacto-N-octaose II Yes TF-LNO Trifucosyl-lacto-N-octaose Yes Yes TF-LNnO Trifucosyl-lacto-N-neooctose Yes Yes TF-iso-LNO I Trifucosyl-iso-lacto-N-octaose I Yes TF-iso-LNO II Trifucosyl-iso-lacto-N-octaose II Yes Yes Tetra-F-iso-LNO Tetra-fucosyl-iso-lacto-N-octaose Yes Yes Tetra-F-para-LNO Tetra-fucosyl-para-lacto-N-octaose Yes Yes Penta-F-iso-LNO Penta-fucosyl-iso-lacto-N-octaose Yes Yes F-LND I Fucosyl-lacto-N-decasaccharide Yes F-SL 3'-Sialyl-3-fucosyllactose Yes F-LSTa Fucosyl-LS-tetrasaccharide a / sialyl-lacto-N-tetraose a Yes F-LSTc Fucosyl-LS-tetrasaccharide c / sialyl-lacto-N-tetraose c Yes FS-LNH I Fucosyl-sialyl-lacto-N-hexaose I Yes FS-LNH II Fucosyl-sialyl-lacto-N-hexaose II Yes FS-LNH III Fucosyl-sialyl-lacto-N-hexaose III Yes FS-LNH IV Fucosyl-sialyl-lacto-N-hexaose IV Yes FS-LNnH I Fucosylsialyl lacto-N-neohexaose I Yes DFS-LNH I Difucosyl-sialyl-lacto-N-hexaose I Yes DFS-LNH II Difucosyl-sialyl-lacto-N-hexaose II Yes Yes DFS-LNnH Difucosyl-sialyl-lacto-N-neohexaose Yes FS-LNO Fucosyl-sialyl-lacto-N-octaose Yes FS-iso-LNO Fucosyl-sialyl-iso-lacto-N-octaose Yes DFS-iso-LNO I Difucosyl-sialyl-iso-lacto-N-octaose I Yes Yes FS-iso-LNO II Fucosyl-sialyl-iso-lacto-N-octaose II Yes DFS-LNO Difucosyl-sialyl-lacto-N-octaose Yes Yes TFS-iso-LNO Trifucosyl-sialyl-lacto-N-octaose Yes Yes FDS-LNT I Fuco-disialyllacto-N-tetraose I Yes FDS-LNHII Fuco-disialyl lacto-N-hexaose II Yes FDS-LNH III Fuco-disialyl lacto-N-hexaose II Yes FDS-LNnH Fuco-disialyllacto-N-neohexaose II Yes FS-new-LNP I Fucosyl-sialyl-novo-lacto-N-pentaose i Yes DF-para-LNH sulfate I Difucosyl-para-lacto-N-hexaose sulfate I Yes DF-pair-LNH sulfate II Difucosyl-para-lacto-N-hexaose sulfate I Yes Yes TF-para-LNH sulfate Trifucosyl-para-lacto-N-hexaose sulfate Yes Yes

Yes indicates presence, empty cell indicates absence.

Health Disorders and Fat Rebound

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

Examples of obesity-related comorbidities include one or more of insulin resistance, impaired glucose tolerance, diabetes mellitus, hypertension, dyslipidemia, sleep apnea, arthritis, hyperuricemia, gallbladder disease and certain types of cancer, coronary artery disease, heart failure, cardiac arrhythmia, stroke and menstrual irregularities.

Fat rebound normally occurs at the age of 6 years, for example, after the age of 6 years, or after 7 years, or, for example, at 7 years; for example, in the range of 6 to 9 years, eg 6 to 8 years, eg 6 to 7 years.

In contrast, early fat rebound in the context of this application is defined as a fat rebound that occurs earlier than it would normally occur. Accordingly, early fat rebound can be said, for example, when fat rebound (i.e. the time when BMI begins to increase after infancy) occurs before the age of 6 years, for example in the interval from 2 to 6 years, for example from 3 to 6 years, or, for example, from 4 to 6 years, or at the age of 5 to 6 years, or, for example, from 2 to 5 years, from 3 to 5 years, from 4 to 5 years.

Target groups

The nutritional composition according to the present invention is intended for use in infants or young children.

In some embodiments, the nutritional composition of the present 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 adipose tissue mass.

Infants or young children may be born at term or may be premature. In a specific embodiment, the nutritional composition of the invention is for use in preterm infants. Premature infants are at increased risk for insulin resistance, hyperglycemia, nutritional deficiencies, growth failure in lean body mass, fat accumulation in the viscera, and metabolic disorders later in life. Therefore, one embodiment of this aspect of the present invention relates to a nutritional composition for use according to the present invention, wherein the infant or young child is at risk of obesity, for example, one or more selected from the group consisting of preterm infants, infants born to overweight mothers and obese, and/or infants born to mothers carrying the SNP rs3894326.

The nutritional composition of the present invention may also be administered to an infant or young child who has been delivered by caesarean section or by vaginal delivery.

The time of occurrence of fat rebound may vary in subpopulations or, for example, in different target groups. Therefore, as an alternative, early fat rebound can be defined as fat rebound that occurs at least 6 months earlier than the subpopulation mean time of onset of fat rebound. For example, early fat rebound can be defined as fat rebound that occurs 8 months earlier, 12 months earlier, 18 months earlier, 24 months earlier than the average time point for the subpopulation. In additional examples, early fat rebound can be defined as fat rebound that occurs between 6 months and 36 months earlier than the subpopulation average, e.g., 6 months to 30, 7 months to 24 months, 7 to 20 months, 7 to 18 months, 7 to 16 months, 8 to 12 months earlier than the subpopulation average.

The subpopulation may be, for example, a selected target group such as a subpopulation of infants identified as being at risk of being overweight and/or obese later in life. In one embodiment, the subpopulation may be infants born to mothers who exhibit one or more of the SNPs. In another embodiment, the subpopulation may be infants or young children born to overweight and obese women. Indeed, scientific evidence consistently confirms that infants born to overweight and obese mothers have a higher risk of becoming overweight or obese later in life than infants born to mothers who are not overweight or obese.

Nutritional composition

Additional embodiments of this aspect of the present invention relate to a nutritional composition for use according to the present invention, in which at least one fucosylated oligosaccharide, for example, at least one fucosylated oligosaccharide with alpha-1,3- and/or alpha-1,4- bond (or a fucosylated oligosaccharide fucosylated by FUT3) is present in an amount of 0.02 to 10 wt.%, for example 0.1 to 5 wt.% or 0.2 to 1.5 wt.% of the nutritional composition, when All percentages herein are expressed on a dry weight basis. In some embodiments, at least one fucosylated oligosaccharide is present in a total amount of 0.05 to 1.5 g/l, such as 0.1 g/l or 0.8 g/l of the composition.

In additional embodiments, the implementation of the nutritional composition for use according to the present invention contains or preferably additionally contains at least one fucosylated oligosaccharide with alpha-2-linkage and/or alpha-1,2-linkage; and/or which is fucosylated by FUT2. In some embodiments, this nutritional composition contains one or more fucosylated oligosaccharides selected from the group consisting of alpha-1,2'-fucosylated lactose and alpha-2'-fucosylated lactose. In a specific embodiment, the nutritional composition for use according to the present invention further comprises 2-FL (2'-fucosyllactose).

Adapted nutritional compositions

The nutritional composition of the present invention may be adapted to meet the needs of an infant or young child. For example, a nutritional composition for use according to the present invention may be an infant formula, initial infant formula, infant formula for formula fed children or follow-up formula, infant formula, cereal-based infant formula, formula for infants 1 to 3 years of age, fortifier, or additive.

For example, the nutritional composition for use may be a powdered infant formula that is diluted with water to form a finished liquid product. In other examples, the nutritional composition for use according to the present invention may also be a concentrated liquid that is diluted with water to form a finished liquid product. The nutritional composition for use according to the present invention may be a liquid product that is consumed by the infant directly as is. The nutritional composition of the present invention may be a breast milk fortifier that is added to or diluted with breast milk. In this case, the values of the concentration of components already present in breast milk (to which a human milk fortifier is added) should be taken as average values for lactating mothers, which are known or predicted from published clinical data.

The nutritional composition for use according to the present invention may contain a source of lipids. The lipid source can be any lipid or fat that is suitable for use in infant formula. Preferred fat sources include palm olein, high oleic acid sunflower oil and high oleic acid sunflower oil. You can also add essential fatty acids, linoleic and α-linolenic acid. In the composition, the ratio of n-6 to n-3 fatty acids in the fat source (including LC-PUFAs such as arachidonic acid (ARA) and/or docosahexaenoic acid (DHA)) is preferably from about 1:2 to about 10: 1, preferably from about 5:1 to 10:1, even more preferably from about 7:1 to about 9:1.

The nutritional composition according to the present invention is preferably such that the fat consists essentially of a mixture of 0 to 20% milk fat; 10 to 30% coconut oil; 10 to 40% canola oil; from 10 to 25% sunflower oil; from 10 to 30% sunflower oil with a high content of oleic acid; from 2 to 10% palmitic acid, mainly in the form of triglycerides; and 1.5 to 2.5% of a blend of ARA and DHA polyunsaturated fatty acids (such as a 1:1 blend of ARASCO® and DHASCO® from Martek), preferably in an ARA:DHA ratio of about 1:1 relative to total fat .

Milkfat can effectively replace Betapol® or Infat® from AAK/Enzymotec.

Each of these fat sources is a refined oil suitable for use in baby food.

Other standard ingredients known to the person skilled in the art in formulating infant formula, initial infant formula, infant formula for feeding children or follow-up formula, infant formula, cereal-based infant formula, milk formula for infants 1 to 3 years old, fortifier or supplement, also may be present in nutritional compositions for use according to the present invention.

Thus, the nutritional composition for use according to the present invention may contain other ingredients, the action of which can reinforce the technical effect of the components, in particular in accordance with Commission Directive 2006/141/EC of 22 December 2006 on infant formulas and infant formulas. fed children.

The nutritional composition for use according to the present invention may also contain a carbohydrate source, preferably in the form of prebiotics or in addition to prebiotics. Any carbohydrate source conventionally present in infant formulas can be used, such as lactose, sucrose, maltodextrin, starch, and mixtures thereof, although lactose is the preferred carbohydrate source.

Prebiotics that can be included in accordance with the present invention are not particularly limited and include all food substances that promote the growth of probiotics or beneficial microorganisms in the intestine. Preferably they can be selected from the group consisting of 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), galactooligosaccharides (GOS), isomaltooligosaccharides (IMO), xylooligosaccharides (XOS), arabinoxylooligosaccharides (AXOS), mannanoligosaccharides (MOS), inulin, polydextrose soy oligosaccharides, glycosyl sucrose (GS), lactosucrose (LS), lactulose (LA), palatinozooligosaccharides (PAO), maltooligosaccharides, gums and/or their hydrolysates, pectins and/or their hydrolysates. In a particular embodiment, the prebiotics may be fructooligosaccharides and/or inulin. In a particular embodiment, the prebiotics are a combination of FOS with inulin, such as the product sold by BENEO-Orafti under the trademark Orafti® oligofructose (formerly Raftilose®) or the product sold by BENEO-Orafti under the trademark Orafti® inulin (formerly Raftiline ®). Another example is the combination of 70% short chain fructooligosaccharides and 30% inulin, registered by Nestle under the trademark "Prebio 1".

Prebiotics can also be BMO (Bovine Milk Oligosaccharide) and/or HMO (Breast Milk Oligosaccharide), such as N-acetylated oligosaccharides, sialylated oligosaccharides, other fucosylated oligosaccharides, and any mixtures thereof.

Specific embodiments relate to a nutritional composition according to the present invention, further comprising at least one additional(s) oligosaccharide(s), and/or fiber(s), and/or precursor(s) of breast milk oligosaccharides, selected from the list containing GOS, FOS, KOS, inulin, polydextrose, sialylated oligosaccharides, sialic acid, fucose, N-acetylated oligosaccharides and any combination thereof.

A specific example of a prebiotic is a mixture of galactooligosaccharide(s), N-acetylated oligosaccharide(s) and sialylated oligosaccharide(s), wherein the N-acetylated oligosaccharide(s) is (s) from 0.5 to 4.0% of the mixture of oligosaccharides, galactooligosaccharide(s) constitute(s) from 92.0 to 99.5% of the mixture of oligosaccharides, and sialylated(s) oligosaccharide(s) comprise (-yut) from 1.0 to 4.0% of a mixture of oligosaccharides. This mixture of oligosaccharides is preferably a mixture of BMOS (cow's milk oligosaccharides). For example, a composition for use according to the present invention may contain from 2.5 to 15.0 wt.% of this mixture of BMOS based on dry matter, provided that the composition contains at least 0.02 wt.% N-acetylated oligosaccharide, according to at least 2.0 wt.% galactooligosaccharide and at least 0.04 wt.% sialylated oligosaccharide. Publications WO2006087391 and WO2012160080 present some examples of the preparation of this BMO mixture.

The nutritional composition for use according to the present invention may further comprise one or more probiotics. In specific embodiments, one or more probiotics for this purpose may 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, Lactobacillus lactis, Lactobacillus rhamnosus, Lactobacillus johnsonii, Lactobacillus plantarum, Lactobacillus salivarius, Lactococcus lactis, Enterococcus faecium, Saccharomyces cerevisiae, Saccharomyces boulardii или their mixtures. 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; their mixtures.

The nutritional composition for use according to the present invention may also contain a protein source. The type of protein is not considered critical to the present invention, provided that the minimum requirements for the content of essential amino acids are met and satisfactory growth is ensured. Thus, protein sources based on whey, casein and mixtures thereof, as well as protein sources based on soy, can be used. With respect to whey proteins, the protein source may be based on acid whey or sweet whey, or mixtures thereof, and may include alpha-lactalbumin and beta-lactoglobulin in any desired ratios. Proteins can be at least partially hydrolyzed to enhance oral tolerance to allergens, especially food allergens. In such a case, the composition may be a hypoallergenic composition.

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) infant formula in which cow's milk proteins are hydrolyzed (partially or heavily). The mixture may also be a soy milk formula or a non-allergenic formula, such as a free amino acid formula.

The protein may be present in an amount of 1.5 to 3 g per 100 kcal. A specific embodiment relates to a nutritional composition for use according to the present invention, wherein the protein content is less than 2 g/100 kcal, eg 1 to 2 g/100 kcal; for example, not more than 1.8 g/100 kcal, for example from 1 to 1.8 g/100 kcal; for example, in the range of 1.5 to 1.8 g protein/100 kcal.

The nutritional composition for use according to the present invention may also contain all of the vitamins and minerals, as well as other micronutrients known to be indispensable in the daily diet and present in nutritionally significant amounts. Some vitamins and minerals have minimum requirements. Examples of minerals, vitamins and other nutrients that are optionally present in the composition of the present invention include vitamin A, vitamin B1, vitamin B2, vitamin B6, vitamin B12, vitamin E, vitamin K, vitamin C, vitamin D, folate 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 amounts of specific minerals and other vitamins may vary depending on the intended population.

If necessary, the nutritional composition for use according to the present invention may contain emulsifiers and stabilizers such as soy, lecithin, citric acid mono- and diglycerides, and the like.

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

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

This mixture can be obtained by any suitable method. For example, it can be obtained by mixing a protein source, a carbohydrate source and a fat source in appropriate proportions. At this stage, emulsifiers can be included if they are used. Vitamins and minerals can be added at this stage, but they are usually added later to avoid thermal decomposition. Any lipophilic vitamins, emulsifiers, and the like may be dissolved prior to mixing. at the source of the fat. Water, preferably reverse osmosis water, can then be mixed in to form a liquid mixture. The water temperature conveniently ranges between about 50°C and about 80°C to facilitate dispersion of the ingredients. Commercially available thinners can be used to form the liquid mixture.

Fucosylated oligosaccharide(s) may be added at this stage, especially if the final product is to be in liquid form. If the final product is to be a powder, they can also be added at this stage if necessary.

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

The liquid mixture can then be thermally treated to reduce bacterial load by rapidly heating the liquid mixture to a temperature in the range of about 80° C. to about 150° C. over a period of time, for example, from about 5 seconds to about 5 minutes. This can be done by steam injection or by using an autoclave or a heat exchanger such as a plate heat exchanger.

Then the liquid mixture can be cooled to a temperature of from about 60°C to about 85°C, for example, by flash cooling. The liquid mixture can then be homogenized again, for example in two stages: under a pressure ranging from about 10 MPa to about 30 MPa in the first stage and from about 2 MPa to about 10 MPa in the second stage. The homogenized mixture can then be further cooled to add any heat sensitive components such as vitamins and minerals. At this stage, it is convenient to adjust the pH and solids content of the homogenized mixture.

The homogenized mixture is transferred to a suitable drying apparatus such as a spray dryer or freeze dryer and powdered. The moisture content of the powder should be less than about 5% wt. The fucosylated oligosaccharide(s) may also or alternatively be added at this stage by dry blending together with the optional probiotic bacterial strain(s) or by blending them in the form of a syrup from crystals together with optional(s) probiotic(s) bacterial(s) strain(s) and spray drying (or freeze drying).

If a liquid composition is preferred, then the homogenized mixture can be sterilized and then filled into suitable containers under aseptic conditions, or it can be first filled into containers and then sterilized in an autoclave.

In another embodiment, the composition of the invention may be an additive in an amount sufficient to achieve the desired effect in the infant. This form of administration is usually more suitable for preterm infants.

The supplement may, for example, be in the form of a powder, tablet, capsule, lozenge or liquid, as long as it is suitable as a nutritional composition for an infant. The additive may additionally contain protective hydrocolloids (such as gums, proteins, modified starches), binders, film-forming agents, encapsulating agents/materials, wall/shell materials, matrix compounds, coatings, emulsifiers, surfactants, solubilizing agents (oils, fats, waxes, lecithins, etc.), adsorbents, carriers, fillers, auxiliary compounds, dispersing agents, wetting agents, processing aids (solvents), anti-caking agents, taste masking agents, weighting agents, gelling agents and gelling agents. The additive may also contain conventional pharmaceutical additives and adjuvants, excipients and diluents, including, but not limited to, water, gelatin of any origin, vegetable gums, lignin sulfonate, talc, sugars, starch, gum arabic, vegetable oils, polyalkylene glycols, flavoring agents, preservatives. , stabilizers, emulsifying agents, buffers, lubricants, colorants, wetting agents, fillers, and the like.

The supplement can be incorporated into an acceptable consumer (infant) product, such as an edible carrier or base, respectively. Examples of such carriers or bases are a pharmaceutical composition or a food composition. Examples of such compositions are infant formulas, including formulas for premature babies.

Additionally, the supplement may contain an organic or inorganic carrier material suitable for enteral or parenteral administration, as well as vitamins, minerals, trace elements and other micronutrients in accordance with the recommendations of government authorities, such as European Commission Directive 2006/141/EC of 22 December 2006 on infant formula and complementary formula.

Dosing regimen

The nutritional composition for use according to the present invention may be given at any time during infancy and early childhood. The age for administration (or use or feeding) of the nutritional composition, as well as the duration of such administration, depends on the possibilities and needs.

In one embodiment of this aspect of the present invention, the nutritional composition for use according to the present invention is administered when the infant or young child is from birth to 3 years of age, e.g., 6 months to 3 years, 7 months to 3 years, 8 months to 3 years, 9 months to 3 years, 10 months to 3 years, 12 months to 3 years, or, for example, 1 to 3 years or 2 to 3 years. Specific embodiments relate to the case where the infant or young child is between 8 months and 3 years of age.

Since the nutritional composition is predominantly used for prophylactic purposes (avoiding excessive accumulation of adipose tissue mass, prevention of health disorders in later life associated with excessive accumulation of adipose tissue mass, such as obesity in later life), it can be given, for example, immediately after the birth of babies. The composition according to the present invention can also be given during the first week of an infant's life, or during the first 2 weeks of life, or during the first 3 weeks of life, or during the first month of life, or during the first 2 months of life, or during the first 3 months of life, or during the first 4 months of life, or during the first 6 months of life, or during the first 8 months of life, or during the first 10 months of life, or during the first year of life, or during the first two years of life, or even longer. In some particularly advantageous embodiments of the present invention, the nutritional composition is given (or administered) to an infant during the first 4 or 6 months after the birth of said infant.

In some other embodiments, the nutritional composition of the present invention is given several days (e.g., 1, 2, 3, 5, 10, 15, 20...) or several weeks (e.g., 1, 2, 3, 4, 5, 6 ,7, 8, 9, 10...), or a few months (for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10...) after birth. First of all, this may be relevant, but not necessarily, in the case when the baby was born prematurely.

In one embodiment, the composition of the invention is given to an infant or young child as a composition in addition to mother's milk. In some embodiments, the infant or young child receives breast milk for at least the first 2 weeks, the first 1, 2, 4, or 6 months. In one embodiment, the nutritional composition of the invention is given to an infant or young child after such a breast milk feeding period, or is given during such a breast milk feeding period. In another embodiment, the composition is given to an infant or young child as the sole or main nutritional composition for at least one period of time, for example after the 1st, 2nd or 4th month of life, for at least 1, 2, 4 or 6 months.

Application for overweight

In another aspect, the present invention relates to the use of a nutritional composition, as defined herein in the context of the nutritional composition aspect for use, to reduce the risk of later life overweight in an infant or young child by preventing early fat rebound.

Nutritional composition for use in promoting normal growth

In a further aspect, the present invention relates to a nutritional composition comprising at least one fucosylated oligosaccharide for use in promoting normal growth by preventing early fat rebound.

One embodiment relates to a nutritional composition according to the present invention comprising one or more of a fucosylated oligosaccharide having at least one fucose group attached via an alpha 1,3 bond, an alpha 1,4 bond, and/or an alpha -1,2- or alpha-2 bonds.

One embodiment relates to a nutritional composition according to the present invention having at least one fucose group attached via an alpha 1,3 bond, at least one fucose group attached via an alpha 1,4 bond, or combinations thereof, for use to promote normal growth in an infant or young child.

The expression "height" refers to the increase in weight, body length, head circumference and/or abdomen in an infant or young child. In a particular embodiment, it refers to weight. Growth should be understood as the process of change in weight, body length, head circumference and/or abdomen as an infant or young child matures. Therefore, the expressions "growth rate" and "growth rate" can be used as alternatives to the term "growth". In the process of developing an infant, these parameters not only increase. As the standard growth curves published by WHO show, the weight of an infant may decrease in the first days of an infant's life. Thus, height should be understood as the total growth of an infant during the first months of life, for example, in particular, 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.

The expressions "promoting normal growth" and "promoting optimal growth" can be used interchangeably. They cover promoting a growth rate that approaches or approximates that of a breastfed infant. They cover the promotion of growth, which is defined by pediatricians as normal, provided that it is not associated with health problems. These expressions also cover the prevention of overgrowth or overweight, which may occur in formula-fed infants, especially in the first few months of life. The term "promoting normal growth" can also encompass treatment to control weight and/or avoid weight gain, especially overweight gain, and/or promote lean mass gain, especially as compared to gain in total or adipose tissue mass.

One embodiment of this aspect relates to a nutritional composition comprising at least one fucosylated oligosaccharide that is fucosylated with FUT3 for use in promoting normal growth in an infant or young child by preventing early fat rebound.

In specific embodiments, the nutritional composition of the present invention is for use in promoting normal growth in an infant or young child, the infant or young child being as described herein under the heading Target Groups.

In additional embodiments, the implementation of the nutritional composition for use according to this aspect may be as described above in this document in relation to the previous aspects of the present invention.

Ways to identify target groups

The presence of a FUT3 polymorphism that disrupts FUT3 expression leads to reduced amounts of fucosylated oligosaccharide having at least one fucose group attached via a 1,3 bond and/or at least one fucose group attached via a 1,4 bond. Based on the association between abdominal circumference and this FUT3 polymorphism, such infants may be identified as at risk of early fat rebound and/or excess fat mass accumulation.

Accordingly, in a further aspect, the present invention relates to a method for identifying whether an infant or young child is at risk of excessive accumulation of adipose tissue mass and/or one or more health disorders, such as a health disorder associated with excessive accumulation of fat, either in infancy/ at a younger age or later in life; moreover, this method involves determining the presence of the following single nucleotide polymorphism in the FUT3 gene in the mother of the infant:

a) rs3894326 (record number in the SNP database, MCBI),

wherein the presence of said polymorphism is associated with an increased risk of early fat rebound, excessive accumulation of adipose tissue mass, and one or more health disorders, such as a health disorder associated with excessive accumulation of fat, in infancy and/or later in the life of the infant.

The polymorphism number refers to the entry number in the NCBI database of single nucleotide polymorphisms and is available online.

Method of treatment

Mothers who exhibit a disrupted FUT3 gene will produce less fucosylated oligosaccharide with at least one fucose attached via alpha-1,3 and/or alpha-1,4 linkages. In order to compensate for this deficiency, it will be preferable to identify mothers who have this deficiency and supplement the diet of their offspring with at least one such fucosylated oligosaccharide.

Thus, a further aspect of the present invention relates to a method for the prevention of early fat rebound, excess fat accumulation and/or ill health associated with excessive accumulation of adipose tissue later in life in an infant or young child, comprising the steps of:

i. Determining whether the mother has a functional FUT3 enzyme or not,

And

ii. Administering to said infant or young child a nutritional composition as defined above in the context of a nutritional composition of the present invention, for example a nutritional composition comprising at least one fucosylated oligosaccharide, said fucosylated oligosaccharide having at least one fucose group attached via an alpha 1,3 bonds, at least one fucose group attached via an alpha 1,4 bond, or combinations thereof, thereby preventing early fat rebound.

An FUT3 enzyme is functional if it results in alpha-1,3 and/or alpha-1,4-fucosylation of its substrates. Methods for determining whether a mother has a functional FUT3 enzyme or not are known in the art. For example, a gene may be detected by PCR, or a functional protein may be analyzed using immunological methods such as Western blotting.

In one embodiment, the present invention relates to a method for the prevention of early fat rebound, excess fat accumulation and/or health disorder associated with excessive accumulation of adipose tissue later in life, in an infant or young child, comprising the steps

i. Determine if the mother has the following single nucleotide polymorphism in the FUT3 gene:

a) rs3894326

And

ii. Administering to said infant or young child a nutritional composition as defined above in the context of a nutritional composition of the present invention, for example a nutritional composition comprising at least one fucosylated oligosaccharide, said fucosylated oligosaccharide having at least one fucose group attached via an alpha 1,3 bonds, at least one fucose group attached via an alpha 1,4 bond, or combinations thereof, thereby preventing early fat rebound.

For use in production

An aspect of the present invention relating to a nutritional composition for use according to the present invention can alternatively be described as the use of a fucosylated oligosaccharide for the manufacture of a nutritional composition for administration to an infant or young child to reduce and/or avoid excess accumulation of adipose tissue mass later in life. ; and/or for the prevention of a health disorder later in life, such as a health disorder associated with fat accumulation, by preventing early fat rebound and/or by controlling the timing of the occurrence of fat rebound.

An additional embodiment relates to the use of a fucosylated oligosaccharide that is fucosylated with FUT3 for the manufacture of a nutritional composition for administration to an infant or young child to reduce and/or avoid excess accumulation of adipose tissue mass later in life; and/or for the prevention of a health disorder in later life, such as a health disorder in later life associated with the accumulation of fat, through the prevention of early fat rebound.

A further embodiment relates to the use of a fucosylated oligosaccharide that is fucosylated with FUT3 for the manufacture of a nutritional composition for the reduction and/or prevention of excess body fat mass in an infant or young child; and/or for the prevention of a health disorder later in life associated with the accumulation of fat in an infant or young child, through the prevention of early fat rebound.

Additional embodiments relate to said use of a fucosylated oligosaccharide, wherein the nutritional composition is defined as described herein above in relation to the nutritional composition for use according to the present invention.

It should be noted that the embodiments and elements described in the context of one aspect of the present invention are also applicable to other aspects of the invention.

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

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

Examples

Example 1

Table 2 below shows an example of the composition of a nutritional composition (eg, infant formula) in accordance with the present invention. This composition is for illustrative purposes only.

Table 2. An example of the composition of the nutritional composition (for example, infant formula) in accordance with the present invention

Nutrients Per 100 kcal per liter Energy value (kcal) 100 670 Protein (g) 1.83 12.3 Fat (g) 5.3 35.7 Linoleic acid (g) 0.79 5.3 α-Linolenic acid (mg) 101 675 lactose (g) 11.2 74.7 Minerals (g) 0.37 2.5 Na (mg) 23 150 K (mg) 89 590 Cl (mg) 64 430 Ca (mg) 62 410 P (mg) 31 210 Mg (mg) 7 50 Mn (mcg) 8 50 Se (mcg) 2 13 Vitamin A (µg RE) 105 700 Vitamin D (µg) 1.5 10 Vitamin E (mg TE) 0.8 5.4 Vitamin K1 (mcg) 8 54 Vitamin C (mg) 10 67 Vitamin B1 (mg) 0.07 0.47 Vitamin B2 (mg) 0.15 1.0 Niacin (mg) 1 6.7 Vitamin B6 (mg) 0.075 0.50 Folic acid (mcg) 9 60 Pantothenic acid (mg) 0.45 3 Vitamin B12 (mcg) 0.3 2 Biotin (mcg) 2.2 15 Choline (mg) 10 67 Fe (mg) 1.2 8 I (µg) 15 100 Cu (mg) 0.06 0.4 Zn (mg) 0.75 5 Oligosaccharides
(OGM) DFL (g) 0.015 0.1

Example 2: Linking SNPs to Growth

The oligosaccharide profile in breast milk depends on genetic variations, such as enzymes involved in glycosylation. The authors of the present invention studied whether the variation in the oligosaccharide has an impact on the health of the child. A study was made of the relationship between SNP FUT3 and child health outcomes. SNP analysis was performed in maternal samples from a population cohort and logistic regression analysis was used to determine associations between FUT3 SNPs and child health outcomes. A significant relationship was uncovered between LMS growth scores and FUT3 SNPs. The LMS method for assessing growth is known in the art (see Eur J Clin Nutr. 1990 Jan;44(1):45-60, The LMS method for constructing normalized growth standards, Cole TJ). Although LMS is generally thought of as a cross-sectional technique, it can be applied to long-term data.

The relationship between LMS growth scores and SNP FUT3 was examined in relation to abdominal circumference growth over time periods and the results are shown in Table 3 below.

When SNP was considered to be significantly associated with outcomes, the regression models were further adjusted (see Table 3) for the number of births in history, mode of delivery, and breastfeeding.

There is an association between LMS abdominal circumference growth scores from 6 to 12 months and SNP FUT3 rs3894326 (p=0.043). This relationship remains significant when adjusted for breastfeeding, number of births, and mode of delivery; moreover, the duration of breastfeeding (0, <= 3m, >3m) also shows a significant relationship with the measured AC increase by the LMS method.

An increase in abdominal circumference from 2 to 3 years was also significantly associated with the SNP FUT3 rs3894326 (p=0.018), and this relationship remains significant when adjusted for duration of breastfeeding, number of births in history, and method of delivery. The results show that the presence of the rs3894326 form of the FUT3 SNP that disrupts the FUT3 gene (carrying the mutation) is associated with reduced abdominal circumference at 6 months and increased abdominal circumference at 2 to 3 years of age compared with the FUT3 gene-neutral form of the SNP ( wild type). This means that the absence of a functional FUT3 enzyme and, as a result, the absence of the production of alpha-1,3- and -1,4-fucosylated HMOs is associated with greater abdominal circumference, a measure of body fat, at 2-3 years of age. Early high fat rebound at 2-3 years of age in a group of infants fed with reduced alpha-1,3- and -1,4-fucosylated HMO (non-functional FUT3 enzyme) breast milk predisposes to future fat storage disorders ; thus, it can be concluded that alpha-1,3- and -1,4-fucosylated HMOs are essential for optimal infant growth and that their presence leads to the prevention of early fat rebound.

In FIG. 1 shows a conditional z-score of abdominal circumference at 6-12 months of age in infants whose mothers carry a fully functional form of FUT3 (SNP rs3894326: AA, wild type) and infants carrying an altered form of FUT3 (SNP rs3894326: TA, carrying a mutation) . In FIG. 2 shows conditional z-scores for abdominal circumference for the same groups of infants aged 2-3 years. It is clear that in the case of infants born to mothers with FUT3 that is not fully functional, and therefore a reduced amount of 1,3- and alpha-1,4-fucosylated HMOs in milk, the normal growth of the infant may be disturbed.

As a conditional z-score for height or size outcomes, such as belly fat, this size is substituted into a regression equation against total body size as described (Keijzer-Veen et al., 2005).

Table 3 shows data for both the unadjusted and adjusted models.

Abbreviations and comments:

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

SNP means single nucleotide polymorphism, in this case it is rs3894326.

N is the number of participants in the study.

Beta is the value of the beta coefficient in the regression model used in the analysis. A negative beta value for AC at 6-12 months indicates that a group of infants whose mothers carry the SNP type mutation are associated with lower AC compared to those whose mothers carry wild-type SNPs, while a positive beta value for AC at 2-3 years shows that a group of infants whose mothers carry the SNP type mutation are associated with higher AC compared to those whose mothers carry the wild-type SNP, as depicted in FIG. 1 and 2.

AC = abdominal circumference; m = months; years = years. Adjusted = see description from Example above.

Table 3

LMS Growth Estimation SNP No Beta P-value N (corrected) Beta (adjusted) P-value (corrected) Other significant prognostic factors AC
from 6 to 12 m rs3894326
(FUT3) 564 -0.988 0.043 659 -1.014 0.043 Breast-feeding AC
2 to 3 years rs3894326
(FUT3) 450 1.363 0.018 518 1.313 0.023 No

Claims (9)

1. Use of an artificial nutritional composition containing at least one fucosylated oligosaccharide for the prevention of later life health disorder in an infant or young child at risk of developing obesity by preventing early fat rebound, the later life health disorder being selected from overweight, obesity and/or obesity-related comorbidities, wherein at least one fucosylated oligosaccharide is fucosylated by FUT3, and wherein at least one fucosylated oligosaccharide is present in said nutritional composition in an amount effective to achieve the desired effect later in life in said infant or young child age. 2. The use according to claim 1, wherein at least one fucosylated oligosaccharide has at least one fucose group attached via an alpha 1,3 bond, at least one fucose group attached via an alpha 1,4 bond, or their combinations. 3. Use according to any of the preceding claims, 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 and combinations thereof. 4. Use according to any one of the preceding claims, wherein said nutritional composition further comprises alpha-1,2-fucosylated lactose and/or 2'-fucosylated lactose. 5. Use according to any one of the preceding claims, wherein said nutritional composition further comprises at least one fucosylated oligosaccharide fucosylated by FUT2. 6. Use according to any one of the preceding claims, wherein the health disorder is selected from the group consisting of overweight, obesity, type 2 diabetes, insulin resistance, hypertension, cardiovascular disease, or metabolic syndrome. 7. Use according to any of the preceding claims, wherein said nutritional composition further comprises at least one additional(s) oligosaccharide(s) and/or fiber(s) and/or precursor(s) of breast milk oligosaccharides selected from a list containing GOS, FOS, XOC, inulin, polydextrose, sialylated oligosaccharides, sialic acid, fucose, N-acetylated oligosaccharides and any combination thereof. 8. Use according to any one of the preceding claims, wherein said nutritional composition further comprises at least one probiotic in an amount of 10 ³ to 10 ¹² CFU/g based on the dry weight of said composition. 9. The use according to any one of the preceding claims, wherein said nutritional composition is an infant formula, initial infant formula, infant formula for feeding infants or follow-up formula, infant formula, cereal-based infant formula, milk formula for children from 1 to 3 years of age , enricher or additive.

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