Composition comprising 2fl and lnnT for controlling food intake and growth of infants or young children

Abstract

This invention relates to a nutritional composition comprising at least one fucoidylated oligosaccharide and at least one N-acetylated oligosaccharide, the nutritional composition being used to reduce and / or control food intake in infants or young children, and / or to promote healthy growth in infants or young children.

Description

Technical Field

[0001] This invention relates to nutritional compositions containing specific oligosaccharides for reducing and / or controlling food intake in infants or young children, and / or for promoting healthy growth in infants or young children. Background Technology

[0002] For various reasons, breastfeeding is recommended for all infants. It has been widely reported that breastfed infants exhibit different growth patterns compared to formula-fed infants. In fact, breastfed infants have lower weight gain and lower body fat percentage in the first year of life compared to formula-fed infants. Furthermore, breastfed infants have different gut microbiota distributions compared to formula-fed infants. In summary, these factors influence the physiological development of infants, including metabolism, immunity, and overall growth.

[0003] It has also been reported that infant and toddler feeding patterns vary depending on the type of milk consumed and the method of feeding, for example, based on the frequency and amount of food digested according to their satiety response. Previous studies have reported that formula-fed infants consume significantly more food than breastfed infants starting from the 6th week after birth (Sievers et al., "Feeding patterns in breast-fed and formula-fedinfants", 2002). Another study showed that breastfed children had a stronger satiety response in the first year of life than in the second year, compared to formula-fed children (A Brown et al., "Breastfeeding during the first year promotes satiety responsiveness in children aged 18–24 months", 2012). These studies suggest that breast milk may contain factors that induce satiety. Furthermore, compared to infants exclusively breastfed, bottle-fed infants in early infancy are more likely to empty their bottles or cups in later infancy (Li et al., “Do Infants Fed From Bottles Lack Self-regulation of Milk Intake Compared With Directly Breastfed Infants?”, 2010).

[0004] However, in some cases, due to medical reasons, breastfeeding is insufficient or unsuccessful, or the mother does not choose to breastfeed. Infant formula has been developed for these situations. Fortifiers, which enrich mother's breast milk or infant formula with special ingredients, have also been developed.

[0005] Short-chain fatty acids (SCFAs) are produced, in particular, through the microbial fermentation of dietary fiber in the colon. Propionate has been shown to be an SCFA involved in regulating food intake and enhancing satiety. (Arora et al., “Propionate: Anti-obesity and satiety enhancing factor?”, 2011; Lin et al., “Butyrate and Propionate Protect against Diet-Induced Obesity and Regulate Gut Hormones via Free Fatty Acid Receptor 3-Independent Mechanisms”, 2012; Chambers et al., “Effects of targeted delivery of propionate to the human colon on appetite regulation, body weight maintenance and adiposity in overweight adults”, 2014; Canfora et al., “Short-chain fatty acids in control of body weight and insulin”.) "Sensitivity", Nature Reviews Endocrinology, Vol. 11, pp. 577-591, 2015.

[0006] Therefore, increasing colonic propionate levels is attractive for appetite regulation and weight management. However, oral SCFAs are unpalatable and rapidly absorbed by the small intestine. Consequently, specific delivery systems for releasing propionate in the proximal colon have been developed for several studies. In the 2014 paper "Effects of targeted delivery of propionate to the human colon on appetite regulation, body weight maintenance, and adiposity in overweight adults" by Chambers et al., scientists developed a specific carrier molecule in which propionate is chemically bound to inulin (a natural polymer primarily composed of fructose) via ester bonds. This inulin-propionate ester is chemically synthesized. Only when the inulin polymer is fermented by the colonic microbiota is most of the propionate chemically bound to the inulin released, thus providing targeted colonic delivery. However, such carriers have some drawbacks; for example, this type of chemically synthesized substance may face regulatory issues if used to design compositions for infants or young children. This study was specifically designed for adults. Therefore, some more "natural" solutions (e.g., components found in breast milk) will be preferred for infants or young children.

[0007] Therefore, alternative solutions that are more suitable for infants and young children should be developed.

[0008] All human milk oligosaccharides (HMOs) are the third largest solid component of human milk after lactose and fat. HMOs typically contain lactose at the reducing end and a carbohydrate core at the non-reducing end, which usually contains fucose or sialic acid. More than one hundred HMOs have been isolated and characterized in human milk.

[0009] Compositions using HMO components (such as fucoidylated oligosaccharides, lactose-N-tetrasaccharides, lactose-N-neotetrasaccharides, and / or sialylated oligosaccharides) for various health purposes (primarily immune purposes) have been described.

[0010] However, the use of HMOs to control food intake in infants or toddlers has not been explored. The role of HMOs in promoting healthy growth is also limited; for example, the growth rate of infants using HMOs is similar to that of breastfed infants.

[0011] To enable infants or young children to obtain these health benefits, it is clear that appropriate methods need to be developed.

[0012] Furthermore, because these infants or young children are particularly vulnerable, the way to deliver this health benefit should be in a way that is particularly suitable for young individuals (infants and young children) and does not involve traditional drug interventions.

[0013] These health benefits need to be delivered to these infants or young children in a way that does not cause side effects and / or is not only easy to deliver but also widely accepted by parents or healthcare professionals.

[0014] Furthermore, the price of the means by which this benefit is delivered should be fair and reasonable for most people, and affordable for most people. Summary of the Invention

[0015] The inventors have discovered that compositions containing at least one fucosylated oligosaccharide and at least one N-acetylated oligosaccharide can increase colonic propionic acid production in animal models.

[0016] Since propionic acid is known to be used to control food intake and enhance satiety, this composition can be advantageously used to reduce and / or control food intake in infants or young children.

[0017] The nutritional composition can also be used to promote healthy growth in infants or young children, as the inventors have found that this composition can also increase lean body mass in animal models, improve relative intake, promote growth, and reduce fat content.

[0018] In a particularly advantageous embodiment, the nutritional composition according to the invention comprises 2'-fucosylated lactose (2-FL) and lactose-N-neotetrasaccharide (LNnT), specifically in a weight ratio of 2FL to LNnT of 1:2 to 2:1. Attached Figure Description

[0019] Figure 1 The results indicate the propionic acid production in the cecum of mice fed a low-fiber diet and a low-fiber diet rich in 5% of the different test fibers.

[0020] Abbreviations: Pos ctr = positive control; HMO = human milk oligosaccharide, tested at a weight ratio of 1:1 2FL+LNnT; PDX = polydextrose.

[0021] Figure 2 This represents the ratio of the median SCFA of a fiber-rich diet to the median of a positive control diet.

[0022] Abbreviations: Ctrl pos = positive control; HMO = human milk oligosaccharide, tested at a weight ratio of 1:1 for 2FL+LNnT; PDX = polydextrose.

[0023] Figure 3The lean body mass (in grams) of 3-week-old (d=22 days) rats is expressed.

[0024] Normal rats: Reference, rats nursed by females

[0025] IUGR rats: IUGR (Intrauterine Growth Restricted) rats, nursed by female rats.

[0026] IUGR rat / HMO mixture: IUGR rats, fed by female rats and supplemented with human milk oligosaccharides (2FL+LNnT in a weight ratio of 2:1).

[0027] *Compared to normal rats, P<0.001; #Compared to IUGR rats, P<0.001

[0028] Figure 4 shows the following groups from day 22 to day 29 ( Figure 4A *Compared to normal rats, P<0.001; #Compared to IUGR rats, P<0.01) and from day 22 to 36 ( Figure 4B *Compared to normal rats, P<0.001; #Compared to IUGR rats, P=0.03) Relative intake (total food intake / average body weight):

[0029] Normal rats: Reference, rats fed with a control diet

[0030] IUGR rats: IUGR (Intrauterine Growth Restricted) rats; fed with a control diet.

[0031] IUGR rat / HMO mixture: IUGR rats were fed a diet supplemented with 4.5% by weight of a mixture of human milk oligosaccharides (2FL+LNnT in a weight ratio of 2:1).

[0032] Figure 5 shows the following groups from day 22 to day 29 ( Figure 5A ) and from day 22 to day 36 ( Figure 5B Relative intake (total food intake / average body weight):

[0033] Normal rats: Reference, rats fed with a control diet

[0034] IUGR rats: IUGR (Intrauterine Growth Restricted) rats; fed with a control diet.

[0035] IUGR rats / 2FL: IUGR rats fed a diet supplemented with 4.5% human milk oligosaccharide 2FL.

[0036] IUGR rats / LNnT: IUGR rats fed a diet supplemented with 4.5% by weight of human milk oligosaccharide LNnT

[0037] IUGR rat / HMO mixture: IUGR rats fed a diet supplemented with 4.5% human milk oligosaccharides (2FL+LNnT in a 2:1 weight ratio).

[0038] Figure 6 This indicates the growth of IUGR pups from p2 to p157 when fed different diets (2FL, LNnT, 2FL+LNnT) or maltodextrin (reference / control).

[0039] Figure 7 This represents the average body weight of piglets from p2 to p32 fed with a milk substitute supplemented with 1.5 g / L HMO (1 g of 2FL + 0.5 g of LNnT) or with a control milk substitute.

[0040] Figure 8 This indicates the fat content of piglets fed with milk substitutes supplemented with 1.5 g / L HMO (1 g of 2FL + 0.5 g of LNnT) or with control milk substitutes at day 33. Detailed Implementation

[0041] As used herein, the following terms have the following meanings.

[0042] The term "infant" refers to a child under 12 months of age.

[0043] The term "preschooler" refers to children aged between one and three years old, also known as toddlers.

[0044] "Cesarean section baby or toddler" refers to a baby or toddler delivered via cesarean section. This means that the baby or toddler was not delivered vaginally.

[0045] "Vaginal delivery infants or toddlers" refers to infants or toddlers delivered vaginally rather than via cesarean section.

[0046] Premature infants are babies or toddlers born before full term. This typically refers to infants or toddlers born before 36 weeks of gestation.

[0047] The term "nutritional composition" refers to a composition that supplies nutrients to an individual. This nutritional composition is typically ingested orally or intravenously. It may contain lipid or fat sources, carbohydrate sources, and / or protein sources. In one specific embodiment, the nutritional composition is a ready-to-drink composition, such as a ready-to-drink formula food.

[0048] In one specific embodiment, the composition of the present invention is a hypoallergenic nutritional composition. The term "hypoallergenic nutritional composition" refers to a nutritional composition that is unlikely to cause an allergic reaction.

[0049] In one specific embodiment, the nutritional composition of the present invention is a "synthetic nutritional composition". The term "synthetic nutritional composition" refers to a mixture obtained by chemical and / or biological methods, the chemical properties of which may be the same as those naturally present in mammalian milk (that is, the synthetic nutritional composition is not breast milk).

[0050] As used herein, the term "infant formula" refers specifically to food intended to provide nutrition for infants in the first few months of life and which meets the diverse nutritional needs of this population (in accordance with Article 2(c) of European Commission Directive 91 / 321 / EEC 2006 / 141 / EC of 22 December 2006 concerning infant formula and follow-up formula). It also refers to nutritional compositions intended for use in infants, as defined in the Codex Alimentarius Commission (STAN 72-1981) and for infant-specific products (including foods for specific medical purposes). The term "infant formula" encompasses both "Stage 1 infant formula" and "Stage 2 infant formula" or "follow-up formula."

[0051] Stage 2 infant formula or follow-up formula is offered starting from the 6th month. Infant formula constitutes the main liquid component of this group's gradually diversifying diet.

[0052] The term "infant food" refers to food designed to provide specific nutrition to infants or young children under one year of age.

[0053] The term "infant cereal composition" refers to food designed to provide specific nutrition to infants or young children under one year of age.

[0054] The term "fortifier" refers to a liquid or solid nutritional composition suitable for mixing with breast milk or infant formula.

[0055] The term "weaning period" refers to the period during which breast milk is gradually replaced by other foods in the diet of infants or young children.

[0056] The expressions “age in days / weeks / months / age”, “number of days / weeks / months / years after birth”, and “number of days / weeks / months / years after birth” can be used interchangeably.

[0057] The term "SCFA" refers to short-chain fatty acids.

[0058] The statement "increased colonic propionic acid production" refers to a higher propionic acid content measured in the colon (or large intestine) or a portion thereof (such as the cecum) of an individual fed with the nutritional composition according to the invention (i.e., a nutritional composition containing at least one fucoidylated oligosaccharide and at least one N-acetylated oligosaccharide) compared to a standard composition (i.e., a nutritional composition not containing at least one fucoidylated oligosaccharide and at least one N-acetylated oligosaccharide) and / or a standard composition supplemented with common fiber (such as polydextrose or pectin). Propionic acid production can be measured using techniques known to those skilled in the art, such as gas-liquid chromatography.

[0059] The phrase "reducing and / or controlling food intake" means that when an infant or young child consumes the nutritional composition of the present invention (i.e., a nutritional composition containing at least one fucoidylated oligosaccharide and at least one N-acetylated oligosaccharide), the amount of food they consume will be reduced or adjusted so that when they consume the standard nutritional composition (i.e., a nutritional composition not containing at least one fucoidylated oligosaccharide and at least one N-acetylated oligosaccharide), the amount of food they consume is even less. In some embodiments, the intake of the nutritional composition of the present invention is close to or equivalent to the intake of breast milk. Intake or amount may refer to the amount per meal or per day.

[0060] The term "growth" refers to the increase in an infant's or toddler's weight, height, and / or head circumference. In one specific implementation, it refers to weight. Growth should be understood as the changes in an infant's or toddler's weight, height, and / or head circumference as they grow older. These parameters do not simply increase during infancy; in fact, as shown by the standard growth curves published by the WHO, an infant's weight may decrease in the first few days after birth. Therefore, growth should be understood as the overall increase in an infant's weight during the first few months after birth. Therefore, the expressions "growth rate" and "rate of growth" can also be used in place of the term "growth."

[0061] The statements “promoting healthy growth” and “promoting optimal growth” are used interchangeably. They include promoting a growth rate that is close to or equivalent to that of breastfed infants. They include promoting normal growth as confirmed by a pediatrician to prevent it from being associated with health problems. These statements also include preventing possible overgrowth or excessive weight gain in formula-fed infants, especially in the first few months after birth. The statement “promoting healthy growth” may also include controlling weight management and / or avoiding weight gain (especially excessive weight gain), and / or promoting lean body mass gain (especially when total weight or fat mass increases), and / or reducing body fat percentage.

[0062] "Satisfaction" is the feeling of fullness after a meal, suppressing the urge to eat for a period of time after eating. The expression "enhancing the satiety response" (or "inducing satiety") includes administering the nutritional composition according to the invention (i.e., a nutritional composition containing at least one fucoidylated oligosaccharide and at least one N-acetylated oligosaccharide) to an infant or young child, compared to administering a conventional nutritional composition (i.e., a nutritional composition not containing at least one fucoidylated oligosaccharide and at least one N-acetylated oligosaccharide), causing the infant or young child to experience satiety earlier (i.e., more quickly), meaning the infant or young child will digest a smaller amount of food and feel full. It can also refer to "regulating (e.g., reducing / weakening) appetite." Satisfaction may occur at a time close to or equivalent to the time at which satiety is achieved through breastfeeding.

[0063] "Breast milk" should be understood as breast milk or the mother's colostrum.

[0064] The term "HMO" refers to one or more human milk oligosaccharides. These carbohydrates are resistant to enzymatic hydrolysis by digestive enzymes such as pancreatic enzymes and / or chorionic villus enzymes, indicating that they can perform functions not directly related to their calorific value. It has been specifically noted in the art that these carbohydrates play a crucial role in the early development of infants and young children, such as immune system maturation. Many different types of HMOs have been found in human milk. Each individual oligosaccharide is based on a variety of combinations of glucose, galactose, sialic acid (N-acetylneuraminic acid), fucose, and / or N-acetylglucosamine with these molecules, resulting in a large number of diverse oligosaccharides in human milk; more than 130 such structures have been identified to date. Almost all oligosaccharides have a lactose moiety at the reducing end, while the non-reducing terminal sites are occupied by sialic acid and / or fucose (if present). HMOs can be acidic (e.g., oligosaccharides containing charged sialic acid) or neutral (e.g., fucoidylated oligosaccharides). Some examples of HMOs are fucoidylated oligosaccharides, N-acetylated oligosaccharides, and / or sialylated oligosaccharides.

[0065] "Fucosylated oligosaccharides" are oligosaccharides containing fucose residues. These oligosaccharides are neutral. Some examples are 2'-FL (2'-fucosyllactose or 2-fucosyllactose or 2FL or 2-FL), 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-fucohexasose, lactose-N-difucohexasose I, fucosyllacto-N-hexasose, fucosyllacto-N-neohexose, difucosyllacto-N-hexasose I, difucosyllacto-N-neohexose II, and any combination thereof.

[0066] The terms “fucosylated oligosaccharides containing 2'-fucosylation epitopes” and “2-fucosylated oligosaccharides” encompass fucosylated oligosaccharides with certain homologous forms. These homologous fucosylated oligosaccharides all contain 2'-fucosylation epitopes, thus suggesting that they have certain homologous functions.

[0067] The term "(one or more) N-acetylated oligosaccharides" encompasses both "N-acetyllactoside" and "(one or more) oligosaccharides containing N-acetyllactoside". Such oligosaccharides are neutral oligosaccharides having N-acetyllactoside residues. Suitable examples are: LNT (lactose-N-tetrasaccharide), para-lactose-N-neohexose (para-LNnH), LNnT (lactose-N-neohexose), or any combination thereof. Other examples are: lactose-N-hexasaccharide, lactose-N-neohexose, para-lactose-N-hexasaccharide, para-lactose-N-neohexose, lactose-N-octasaccharide, lactose-N-neohexose, isol-lactose-N-octasaccharide, para-lactose-N-octasaccharide, and lactose-N-decansaccharide.

[0068] The expressions “at least one fucoidylated oligosaccharide” and “at least one N-acetylated oligosaccharide” refer to “at least one type of fucoidylated oligosaccharide” and “at least one type of N-acetylated oligosaccharide”.

[0069] "HMO precursors" are key compounds used in the preparation of HMOs, such as sialic acid and / or fucose.

[0070] "Sialinated oligosaccharides" are oligosaccharides containing charged sialic acid, that is, oligosaccharides with sialic acid residues. These oligosaccharides are acidic. Some examples are 3-SL (3'-sialyl-lactose) and 6-SL (6'-sialyl-lactose).

[0071] The terms "galacto-oligosaccharide," "galacto-oligosaccharide," and "GOS" are used interchangeably. They refer to oligosaccharides containing two or more galactose molecules that are uncharged and do not contain N-acetyl residues (i.e., they are neutral oligosaccharides). In one embodiment, the two or more galactose molecules are linked by β-1,2, β-1,3, β-1,4, or β-1,6 bonds. In another embodiment, "galacto-oligosaccharide" and "GOS" also comprise oligosaccharides containing one galactose molecule and one glucose molecule linked by β-1,2, β-1,3, or β-1,6 bonds (i.e., a disaccharide).

[0072] The nutritional compositions of the present invention may be in solid form (e.g., powder) or liquid form. When the composition is in solid form (e.g., powder), the amount of each component (e.g., oligosaccharides) may be expressed as g / 100g composition on a dry weight basis; or when the composition refers to a liquid form, it may be expressed as a concentration of g / L composition (the latter also covers liquid compositions that can be obtained by reconstituted powder with liquids such as milk, water, etc., such as reconstituted infant formula or follow-up formula / stage 2 infant formula, or infant cereal products, or any other formulations specifically designed for infant nutrition).

[0073] The term "prebiotic" refers to non-digestible carbohydrates that exert a beneficial effect on the host by selectively stimulating the growth and / or activity of healthy 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).

[0074] The term "probiotics" refers to microbial cell preparations or microbial cell components that have beneficial effects on the health or well-being of the host. (Salminen S, Ouwehand A, Benno Y. et al., "Probiotics: how should they be defined," Trends in Food Science and Technology, 1999, Vol. 10, pp. 107-110). The microbial cells are generally bacteria or yeast.

[0075] The term "cfu" should be understood as colony-forming unit.

[0076] Unless otherwise specified, all percentages are by weight.

[0077] Furthermore, in the context of this invention, the terms "comprising" or "including" do not exclude other possible elements. The compositions of this invention (including the various embodiments described herein) may comprise, consist of, or be substantially composed of the following elements: the essential elements and necessary limitations of the invention as described herein, and any other or optional ingredients, components, or limitations as described herein or as required.

[0078] Any references to prior art documents in this specification should not be construed as an admission that such prior art is well-known or constitutes part of common general knowledge in the art.

[0079] The present invention will now be described in more detail. It should be noted that the various aspects, features, embodiments, and implementations described in this application are compatible and / or can be combined together.

[0080] Therefore, the present invention relates to a nutritional composition comprising at least one fucoidylated oligosaccharide and at least one N-acetylated oligosaccharide for reducing and / or controlling food intake in infants or young children.

[0081] It can also be used to promote the healthy growth of infants or toddlers.

[0082] Unbound by theory, the inventors of this invention believe that fucoidylated oligosaccharides and N-acetylated oligosaccharides work synergistically to unexpectedly provide the aforementioned health benefits. This particular combination of oligosaccharides will significantly increase an individual's propionic acid production, and therefore can be used to reduce and / or control food intake and / or promote healthy growth in infants or young children.

[0083] The nutritional composition of the present invention comprises at least one fucoidan. One or more types of fucoidan may be present. The fucoidan (one or more) may be selected from a list including: 2'-fucosylvose, 3'-fucosylvose, difucosylvose, lactose-N-fucopentose (such as lactose-N-fucopentose I, lactose-N-fucopentose II, lactose-N-fucopentose III, lactose-N-fucopentose V), lactose-N-fucohexaose, lactose-N-difucohexaose I, fucoidan-N... - Hexasaccharides, fucoidyl-lactose-N-neohexoses (such as fucoidyl-lactose-N-neohexose I, fucoidyl-lactose-N-neohexose II), difucosyl-lactose-N-hexasaccharide I, difucosyl-lactose-N-neohexose, difucosyl-lactose-N-neohexose I, difucosyl-lactose-N-neohexose II, fucoidyl-para-lactose-N-hexasaccharide, trifucosyl-para-lactose-N-hexasaccharide I, and any combination thereof.

[0084] In some specific embodiments, the fucoidylated oligosaccharide contains a 2'-fucosylation epitope. For example, the fucoidylated oligosaccharide may be selected from a list including: 2'-fucosylation lactose, difucosylation lactose, lactose-N-fucopentose, lactose-N-fucohexasose, lactose-N-difucohexasose, fucoidyllacto-N-hexasose, fucoidyllacto-N-neohexose, difucosylation lactose-N-hexasose, difucosylation lactose-N-hexasose, difucosylation lactose-N-neohexose, difucosylation lactose-N-neohexose, fucoidyl-p-lacto-N-hexasose, and any combination thereof.

[0085] In a preferred embodiment, the nutritional composition according to the invention comprises 2'-fucosylated lactose (or 2FL, or 2'FL, or 2-FL or 2'-FL). In a specific embodiment, no other type of fucosylated oligosaccharide is present besides 2'-fucosylated lactose; that is, the nutritional composition of the invention comprises only 2'-fucosylated lactose as a fucosylated oligosaccharide.

[0086] Fucosylated oligosaccharides (one or more) can be isolated from natural sources such as animal milk using chromatography or filtration techniques. Alternatively, fucosylated oligosaccharides can be prepared using specialized fucosyltransferases and / or fucosidases via biotechnological means, employing enzyme-based fermentation techniques (recombinant or natural enzymes) or microbial fermentation techniques. In the latter case, the microorganisms can express their natural enzymes and substrates, or can be engineered to produce the corresponding substrates and enzymes. Single microbial cultures and / or mixed cultures can be used. Fucosylated oligosaccharides can be formed starting with acceptor substrates initially having any degree of polymerization (DP), beginning with DP = 1. Alternatively, fucosylated oligosaccharides can be prepared by chemical synthesis from lactose and free fucose. Fucosylated oligosaccharides are also available from, for example, Kyowa Hakko Kogyo Co., Ltd.

[0087] The compositions of the present invention further comprise at least one N-acetylated oligosaccharide. One or more types of N-acetylated oligosaccharides may be present. One or more N-acetylated oligosaccharides may be, for example, lactose-N-tetrasaccharide (LNT), lactose-N-neotetrasaccharide (LNnT), or any combination thereof. In some embodiments, the N-acetylated oligosaccharide is lactose-N-neotetrasaccharide (LNnT), para-lactose-N-neohexasaccharide (para-LNnH), or any combination thereof. In some embodiments, the N-acetylated oligosaccharide is LNnT. In some embodiments, the N-acetylated oligosaccharide is LNT. In some other embodiments, the N-acetylated oligosaccharide is a mixture of LNT and LNnT. In some embodiments, the composition comprises both LNT and LNnT, with an LNT:LNnT ratio of 5:1 to 1:2, or 2:1 to 1:1, or 2:1.2 to 2:1.6.

[0088] In a preferred embodiment, the nutritional composition according to the invention comprises lactose-N-neotetrasaccharide (LNnT). In a specific embodiment, no other types of N-acetylated oligosaccharides are contained besides lactose-N-neotetrasaccharide (LNnT), i.e., the nutritional composition of the invention contains only lactose-N-neotetrasaccharide (LNnT) as an N-acetylated oligosaccharide.

[0089] (One or more) N-acetylated oligosaccharides can be chemically synthesized by enzymatic transfer, i.e., by using glycosyltransferases to transfer sugar units from the donor moiety to the acceptor moiety, as described, for example, in U.S. Patent 5,288,637 and WO 96 / 10086. Alternatively, LNT and LNnT can be prepared by chemically converting free or oligosaccharide-bound ketohexasaccharides (e.g., fructose) into N-acetylated hexasaccharides or oligosaccharides containing N-acetylated hexasaccharides, as described in Wrodnigg, TM; Stutz, AE (1999) Angew. Chem. Int. Ed. 38: 827-828. The N-acetylated lactoside obtained in this manner can then be transferred to lactose, which serves as the acceptor moiety. (One or more) N-acetylated oligosaccharides can also be obtained through biotechnological means based on microbial fermentation technology.

[0090] In a particularly advantageous embodiment of the invention, the nutritional composition comprises 2'-fucosylated lactose (2FL) and lactose-N-neotetrasaccharide (LNnT).

[0091] In another specific embodiment, the nutritional composition of the present invention comprises a mixture of oligosaccharides consisting of 2'-fucosylated lactose (2-FL) and lactose-N-neotetrasaccharide (LNnT). In other words, the nutritional composition of the present invention contains only 2'-fucosylated lactose (2-FL) as a fucosylated oligosaccharide and only lactose-N-neotetrasaccharide (LNnT) as an N-acetylated oligosaccharide.

[0092] In some embodiments, the weight ratio of fucoidylated oligosaccharides to N-acetylated oligosaccharides (e.g., 2FL and LNnT) in the nutritional composition of the present invention is 1:10 to 12:1, such as 1:7 to 10:1, 1:5 to 5:1, 2:1 to 5:1, 1:3 to 3:1, 1:2 to 2:1, 1:1 to 3:1, or 1:5 to 1:0.5, for example 1:1 or 2:1; for example 1:1, 2:1, or 10:1.

[0093] The total amount of fucoidylated oligosaccharides and N-acetylated oligosaccharides present in the nutritional compositions of the present invention may be from 0.1% to 10% by weight of the nutritional composition before water reconstruction, such as from 0.5% to 7% by weight or from 1% to 5% by weight. For reconstituted ready-to-drink formulations, the total amount may be from 0.01% to 1%, more preferably from 0.05% to 0.7% or from 0.1% to 0.5%.

[0094] The nutritional composition of the present invention may, for example, comprise:

[0095] - Fucosylated oligosaccharides, on a dry weight basis, comprising a total amount of 0.2 g / L to 5 g / L of the composition, for example 0.5 g / L to 4.5 g / L or 1 g / L to 4 g / L, or a total amount of 0.13 g / 100 g to 3.48 g / 100 g of the composition, for example 0.34 g / 100 g to 3.13 g / 100 g or 0.69 g / 100 g to 2.78 g / 100 g; and / or

[0096] -N-acetylated oligosaccharides, on a dry weight basis, are present in a total amount of 0.05 g / L to 5 g / L of the composition, for example 0.1 g / L to 2 g / L or 0.1 g / L to 1 g / L, or in a total amount of 0.03 g / 100 g to 3.48 g / 100 g of the composition, for example 0.07 g / 100 g to 1.4 g / 100 g or 0.07 g / 100 g to 0.7 g / 100 g.

[0097] The nutritional composition according to the invention may further comprise at least one other oligosaccharide (i.e., in addition to the fucoidylated oligosaccharide and N-acetylated oligosaccharide which are essential to be present in the composition) and / or at least one fiber and / or at least one human milk oligosaccharide precursor. The other oligosaccharide and / or fiber and / or precursor may be selected from a list including: galactooligosaccharides (GOS), fructooligosaccharides (FOS), inulin, xylooligosaccharides (XOS), polydextrose, sialylated oligosaccharides, sialic acid, fucose, and any combination thereof. Their amounts may be from 0% to 10% by weight of the composition.

[0098] In addition to the oligosaccharides contained in the oligosaccharide mixture, suitable commercial products, including combinations of FOS and inulin, can be used to prepare the nutritional compositions according to the invention. These commercial products include those sold by BENEO under the trademark Orafti, or by Tate & Lyle under the trademark STA. Polydextrose for sale.

[0099] In one specific embodiment, the composition according to the invention may comprise sialylated oligosaccharides. One or more sialylated oligosaccharides may be present. The sialylated oligosaccharide(s) may be selected from 3'-sialyl lactose (3-SL), 6'-sialyl lactose (6-SL), and any combination thereof. In some embodiments of the invention, the composition comprises 3-SL and 6-SL. In some specific embodiments, the ratio between 3'-sialyl lactose (3-SL) and 6'-sialyl lactose (6-SL) may be in the range of 5:1 to 1:10, or 3:1 to 1:1, or 1:1 to 1:10. In some specific embodiments, the sialylated oligosaccharide in the composition is 6'-sialyl lactose (6-SL).

[0100] Sialized oligosaccharides (one or more) can be isolated from natural sources (such as animal milk) using chromatography or filtration techniques. Alternatively, sialylated oligosaccharides can be prepared using specialized sialyltransferases or sialic acid sialidases via biotechnology, through enzyme-based fermentation (recombinant or natural enzymes), chemical synthesis, or microbial fermentation. In the latter case, the microorganisms can express their natural enzymes and substrates, or can be engineered to produce the corresponding substrates and enzymes. Single or mixed microbial cultures can be used. Sialized oligosaccharides can be formed starting with acceptor substrates initially having any degree of polymerization (DP), beginning with DP = 1. Alternatively, sialyl lactose can be prepared via chemical synthesis from lactose and free N'-acetylneuraminic acid (sialic acid). Sial lactose is also commercially available, for example, from KyowaHakko Kogyo in Japan.

[0101] In a specific example, the composition may contain one or more sialylated oligosaccharides in a total amount of 0.05 g / L to 5 g / L, such as 0.1 g / L to 4 g / L or 0.3 g / L to 2 g / L, or in a total amount of 0.03 g / 100 g to 3.5 g / 100 g, such as 0.1 g / 100 g to 2 g / 100 g or 0.2 g / 100 g to 1 g / 100 g, based on a dry weight of the composition.

[0102] In a specific embodiment, the nutritional composition may further comprise at least one BMO (milk oligosaccharide). In one specific embodiment, the nutritional composition may additionally comprise an oligosaccharide mixture (“BMOS”) comprising 0.1 wt% to 4.0 wt% of one or more N-acetylated oligosaccharides, 92.0 wt% to 99.5 wt% of one or more galactooligosaccharides, and 0.2 wt% to 4.0 wt% of one or more sialylated oligosaccharides. WO2006087391 and WO2012160080 provide some examples of preparing BMO mixtures.

[0103] In some specific embodiments of the present invention, the nutritional composition does not contain any one or more sialylated oligosaccharides, any GOS and / or any milk oligosaccharides.

[0104] The compositions according to the invention may optionally also contain at least one precursor of human milk oligosaccharides. One or more precursors may be present. For example, human milk oligosaccharide precursors are sialic acid, fucose, or mixtures thereof. In some specific embodiments, the composition contains sialic acid.

[0105] In a specific example, the composition comprises 0 g / L to 3 g / L of human milk oligosaccharide precursor, or 0 g / L to 2 g / L, or 0 g / L to 1 g / L, or 0 g / L to 0.7 g / L, or 0 g / L to 0.5 g / L, or 0 g / L to 0.3 g / L, or 0 g / L to 0.2 g / L of human milk oligosaccharide precursor.

[0106] The composition according to the invention may contain 0 to 2.1 g of human milk oligosaccharide precursor per 100 g of composition on a dry weight basis, for example, 0 to 1.5 g, or 0 to 0.8 g, or 0 to 0.15 g of human milk oligosaccharide precursor per 100 g of composition on a dry weight basis.

[0107] The nutritional composition of the present invention may also contain at least one probiotic (or probiotic strain), such as a probiotic strain.

[0108] The most commonly used probiotics are mainly bacteria and yeasts belonging to the following genera: Lactobacillus spp., Streptococcus spp., Enterococcus spp., Bifidobacterium spp., and Saccharomyces spp.

[0109] In some specific implementations, the probiotics are probiotic bacterial strains. In some specific implementations, they are specifically Bifidobacteria and / or Lactobacilli.

[0110] Suitable probiotic strains include *Lactobacillus rhamnosus* ATCC 53103 (trademarked LGG), *Lactobacillus rhamnosus* CGMCC 1.3724, *Lactobacillus paracasei* CNCM I-2116, *Lactobacillus johnsonii* CNCM I-1225 (trademarked KI2), *Streptococcus salivarius* DSM 13084 (trademarked KI2), sold by BLIS Technologies Limited, New Zealand; and especially *Bifidobacterium lactis* CNCM 1-3446 (trademarked Bb 12), sold by Christian Hansen company, Denmark. Also included are strains from Morinaga Milk Industry Co., Ltd., Japan. Bifidobacterium longum ATCC BAA-999 sold by Co., Ltd. (Japan), Bifidobacterium breve ATCC Bb-03 sold by Danisco, Bifidobacterium breve ATCC M-16V sold by Morinaga Milk Co., Ltd., Bifidobacterium infantis ATCC Bifantis sold by Procter & Gamble Co., Ltd., and Bifidobacterium breve ATCC R0070 sold by Institut Rosell (Lallemand) Co., Ltd.

[0111] The nutritional composition according to the invention may contain 10e3 to 10e12 cfu probiotic strains per gram of composition on a dry weight basis, more preferably 10e7 to 10e12 cfu, such as 10e8 to 10e10 cfu probiotic strains per gram of composition.

[0112] In one embodiment, the probiotics are live. In another embodiment, the probiotics are non-replicating or inactivated. In some other embodiments, both live and inactivated probiotics may be present simultaneously.

[0113] The nutritional compositions of the present invention may also contain at least one bacteriophage (bacterial bacteriophage) or a mixture of bacteriophages, which are preferably targeted at pathogenic streptococci, Haemophilus, Moraxella and Staphylococci.

[0114] The nutritional compositions according to the present invention may be, for example, infant formula, stage 1 infant formula, follow-up formula, or stage 2 infant formula, baby food, infant cereal composition, fortifier (such as human milk fortifier), or supplement. In some specific embodiments, the compositions of the present invention are infant formula, fortifiers, or supplements intended for use in infants aged 4 months or 6 months. In a preferred embodiment, the nutritional compositions of the present invention are infant formula.

[0115] In some other embodiments, the nutritional composition of the present invention is a fortifier. The fortifier may be a breast milk fortifier (e.g., human milk fortifier) ​​or a formula food fortifier (such as an infant formula fortifier or a follow-up formula fortifier / stage 2 infant formula fortifier).

[0116] When a nutritional composition is a supplement, it can be provided in unit dose form.

[0117] The nutritional compositions of the present invention may be in solid (e.g., powder), liquid or gel form.

[0118] The nutritional compositions according to the invention typically contain a protein source. The amount of protein can be from 1.5 g / 100 kcal to 3 g / 100 kcal. In some embodiments, particularly when the composition is specifically designed for preterm infants, the amount of protein can be from 2.4 g / 100 kcal to 4 g / 100 kcal or higher than 3.6 g / 100 kcal. In some other embodiments, the amount of protein can be lower than 2.0 g / 100 kcal, for example from 1.8 g / 100 kcal to 2 g / 100 kcal, or lower than 1.8 g / 100 kcal.

[0119] The type of protein is considered irrelevant to this invention, provided that the minimum requirements for essential amino acid content are met and satisfactory growth is ensured. Therefore, protein sources based on whey, casein, and mixtures thereof, as well as soy-based protein sources, can be used. Regarding the whey protein of interest, the protein source can be based on acidic whey, sweet whey, or mixtures thereof, and can contain any desired proportions of α-lactalbumin and β-lactoglobulin.

[0120] In some advantageous implementations, the protein source is whey-based (i.e., more than 50% of the protein comes from whey protein, such as 60% or 70%).

[0121] The protein can be a whole protein, a hydrolyzed protein, or a mixture of both. The term "whole" means that the major components of the protein are intact, i.e., the molecular structure is unchanged, for example, at least 80% of the protein is unchanged, such as at least 85% of the protein is unchanged, preferably at least 90% of the protein is unchanged, and even more preferably at least 95% of the protein is unchanged, such as at least 98% of the protein is unchanged. In one specific embodiment, 100% of the protein is unchanged.

[0122] The term "hydrolyzed" means, in the context of this invention, that the protein has been hydrolyzed or broken down into its constituent amino acids.

[0123] The protein can be completely or partially hydrolyzed. For example, for infants or young children considered at risk of bovine milk allergies, providing partially hydrolyzed protein (2% to 20% hydrolysis) may be preferable. If a hydrolyzed protein is required, the hydrolysis process can be carried out as needed and as is known in the art. For example, whey protein hydrolysates can be prepared by enzymatic hydrolysis of whey fractions in one or more steps. If the whey fraction used as a raw material is substantially lactose-free, it has been found that the protein undergoes much less lysine blocking during hydrolysis. This allows the degree of lysine blocking to be reduced from about 15% by weight of total lysine to less than about 10% by weight of lysine; for example, about 7% by weight of lysine, which greatly improves the nutritional quality of the protein source.

[0124] In one embodiment of the invention, at least 70% of the protein is hydrolyzed, preferably at least 80%, such as at least 85%, and even more preferably at least 90%, such as at least 95%, particularly at least 98%. In one specific embodiment, 100% of the protein is hydrolyzed.

[0125] In one specific embodiment, the protein in the nutritional composition is hydrolyzed, fully hydrolyzed, or partially hydrolyzed. The degree of hydrolysis (DH) of the protein can be 8 to 40, or 20 to 60, or 20 to 80, or greater than 10, 20, 40, 60, 80, or 90.

[0126] In one embodiment, the nutritional composition according to the invention is a hypoallergenic composition. In another embodiment, the composition according to the invention is a hypoallergenic nutritional composition.

[0127] The nutritional compositions according to the invention typically contain a carbohydrate source. This is particularly preferred when the nutritional compositions of the invention are for infant formula. In this case, any carbohydrate source commonly found in infant formula can be used, such as lactose, sucrose, saccharin, maltodextrin, starch, and mixtures thereof, but one of the preferred carbohydrate sources is lactose.

[0128] The nutritional compositions according to the invention typically contain a lipid source. This is particularly relevant when the nutritional compositions of the invention are for infant formula. In this case, the lipid source can be any lipid or fat suitable for use in infant formula. Some suitable fat sources include palm oil, high-oleic sunflower oil, and high-oleic safflower oil. The essential fatty acids linoleic acid and α-linolenic acid may also be added, as well as small amounts of oils containing large amounts of pre-formed arachidonic acid and docosahexaenoic acid, such as fish oil or microbial oil. The ratio of n-6 fatty acids to n-3 fatty acids in the fat source can be from about 5:1 to about 15:1, for example from about 8:1 to about 10:1.

[0129] The nutritional compositions of the present invention may also contain all vitamins and minerals considered essential for a daily diet, present in significant amounts in the composition. Minimum requirements for certain vitamins and minerals have been determined. Examples of minerals, vitamins, and other nutrients optionally present in the compositions of the present invention include vitamin A, vitamin B1, vitamin B2, vitamin B6, vitamin B12, vitamin E, vitamin K, vitamin C, vitamin D, folic acid, inositol, niacin, biotin, pantothenic acid, choline, calcium, phosphorus, iodine, iron, magnesium, copper, zinc, manganese, chlorine, potassium, sodium, selenium, chromium, molybdenum, taurine, and L-carnitine. Minerals are typically added in the form of salts. The presence and amounts of specific minerals and other vitamins will vary depending on the target population.

[0130] If necessary, the nutritional compositions of the present invention may contain emulsifiers and stabilizers, such as soybean, lecithin, monoglyceride citrate, and diglyceride citrate.

[0131] The nutritional compositions of the present invention may also contain other substances that may have beneficial effects, such as lactoferrin, nucleotides, nucleosides, etc.

[0132] The nutritional compositions of the present invention may also contain one or more carotenoids. In some specific embodiments of the present invention, the nutritional compositions of the present invention do not contain any carotenoids.

[0133] The nutritional compositions according to the invention can be prepared by any suitable means. The compositions will now be described by way of example.

[0134] For example, formula foods such as infant formula can be prepared by blending protein sources, carbohydrate sources, and fat sources together in appropriate proportions. If an emulsifier is used, it can be added at this stage. Vitamins and minerals can be added at this stage, but are usually added later to avoid thermal degradation. Before blending, any lipophilic vitamins, emulsifiers, etc., can be dissolved in the fat source. Water (preferably water that has undergone reverse osmosis) can then be added to form a liquid mixture. A suitable water temperature is in the range of about 50°C to about 80°C to aid in the dispersion of the components. Commercially available liquefying agents can be used to form the liquid mixture.

[0135] Especially if the final product is in liquid form, one or more fucoidylated oligosaccharides and one or more N-acetylated oligosaccharides can be added at this stage. If the final product is a powder, these components can also be added at this stage as needed.

[0136] Then, the liquid mixture is homogenized in, for example, in two stages.

[0137] 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 and holding it for a duration of about 5 seconds to about 5 minutes. This can be done by steam injection, autoclaving, or a heat exchanger (e.g., a plate heat exchanger).

[0138] The liquid mixture is then cooled, for example, to about 60°C to about 85°C by rapid cooling. It is then homogenized again, for example, in two stages, where the pressure in the first stage is about 10 MPa to about 30 MPa, and the pressure in the second stage is about 2 MPa to about 10 MPa. The homogenized mixture can then be further cooled to add any heat-sensitive components, such as vitamins and minerals. The pH and solids content of the homogenized mixture can then be conveniently adjusted.

[0139] If the final product is to be a powder, the homogenized mixture is transferred to a suitable drying apparatus, such as a spray dryer or freeze dryer, and then converted into a powder. The moisture content of the powder should be less than about 5% by weight. Alternatively, one or more fucoidylated oligosaccharides and one or more N-acetylated oligosaccharides may be added at this stage by dry mixing them with one or more probiotic strains (if used), or by blending them in the form of crystalline syrup with one or more probiotic strains, followed by spray drying or freeze drying of the mixture.

[0140] If a liquid composition is preferred, the homogenized mixture can be sterilized and then packaged into a suitable container under aseptic conditions, or it can be packaged into a container first and then sterilized.

[0141] In another embodiment, the composition of the present invention may be a supplement.

[0142] Supplements may be in the form of tablets, capsules, lozenges, or liquids. Supplements may also contain protective hydrocolloids (such as gums, proteins, modified starches), binders, film-forming agents, encapsulation agents / materials, wall / shell materials, matrix compounds, coatings, emulsifiers, surfactants, solubilizers (oils, fats, waxes, lecithin, etc.), adsorbents, carriers, fillers, co-compounds, dispersants, wetting agents, processing aids (solvents), flow agents, flavor masking agents, weighting agents, gelling agents, and gelling agents. Supplements may also contain conventional pharmaceutical additives and adjuvants, excipients, and diluents, including but not limited to: water, gelatin of any origin, plant gums, lignin sulfonates, talc, sugars, starches, gum arabic, vegetable oils, polyalkylene glycols, flavoring agents, preservatives, stabilizers, emulsifiers, buffers, lubricants, coloring agents, wetting agents, fillers, etc.

[0143] In addition, supplements may contain organic or inorganic carrier materials suitable for oral or parenteral administration, as well as vitamins, minerals, trace elements, and other micronutrients recommended by government agencies such as the USRDA.

[0144] The nutritional composition according to the present invention is for use in infants or young children. The infants or young children may be full-term or premature. In one specific embodiment, the nutritional composition of the present invention is used in premature infants or young children. Premature infants have an increased risk of nutrient misutilization, lean body mass syndrome, visceral fat accumulation, and metabolic diseases later in life. Therefore, in a specific embodiment, the nutritional composition of the present invention is used in premature infants.

[0145] The nutritional composition of the present invention can also be used for infants or young children delivered by cesarean section or vaginal delivery.

[0146] In some embodiments, the nutritional compositions according to the invention can be used before and / or during the weaning period.

[0147] In some embodiments, the nutritional compositions according to the invention are used for infants or young children who are at risk and / or in need.

[0148] Infants or young children who are at risk and / or in need may be bottle-fed and / or formula-fed.

[0149] Infants or young children who are at risk and / or in need may be eligible if they meet at least one of the following criteria:

[0150] - They have difficulty controlling their food intake, or they have abnormal (especially high) food intake (e.g., they have a better appetite), for example:

[0151] i) They eat more compared to other infants or toddlers of the same age and body size (weight and height); and / or

[0152] ii) Their sense of satiety has changed, such as a delayed satiety response (possibly due to physiological or anatomical reasons); and / or

[0153] - Their weight increases excessively in the first few months after birth.

[0154] In one specific example, the nutritional composition of the present invention can be used for infants or toddlers with IUGR (intrauterine growth restriction). This particular group faces risks and / or needs because they will have a better appetite to compensate for their growth retardation. However, they may not consume food in a healthy manner using standard formulas; for example, they may have a higher total weight or fat mass gain compared to lean body mass gain, which could contribute to the development and regulation of future health conditions, including later-onset obesity or related complications. The nutritional composition of the present invention is believed to provide for healthy growth.

[0155] The age and duration of administration (providing or feeding) of the nutritional composition can be determined based on availability and need.

[0156] Nutritional compositions may be used for preventive and / or therapeutic purposes.

[0157] For example, the nutritional composition can be administered to the infant immediately after birth, particularly when used for preventative purposes. The compositions of the present invention can also be provided within one week, two weeks, three weeks, one month, two months, three months, four months, six months, eight months, ten months, one year, two years, or even longer after birth. In some particularly advantageous embodiments of the invention, the nutritional composition is provided (or administered) to the infant during the first four or six months after birth. 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 a few weeks (e.g., 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks…) or a few 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 specifically refer to cases where the infant is premature, but it is not necessary.

[0158] For therapeutic purposes, this composition may be administered once symptoms appear, such as when a mother or pediatrician notices that her infant or toddler is frequently hungry and / or requires unusually large amounts of food before feeling full, and / or particularly during the first few months after birth when there is excessive growth / weight gain. The composition may be discontinued after the symptoms have disappeared, or several days / weeks / months after the disappearance process.

[0159] In one embodiment, the composition of the present invention is provided to an infant or young child as a supplementary composition to breast milk. In some embodiments, the infant or young child receives breast milk for at least the first 2 weeks, the first 1 month, 2 months, 4 months, or 6 months. In one embodiment, the nutritional composition of the present invention is provided to the infant or young child after this period of breast milk nutrition, or is provided to the infant or young child together with breast milk during this period of breast milk nutrition. In another embodiment, the composition is provided to the infant or young child as the sole or primary nutritional composition for at least a period of time (e.g., after at least 1 month, 2 months, or 4 months), for at least 1 month, 2 months, 4 months, or 6 months.

[0160] In one embodiment, the nutritional composition of the present invention is a complete nutritional composition (meeting all or most of an individual's nutritional needs). In another embodiment, the nutritional composition is a supplement or fortifier intended for use, for example, as a supplement to human milk or to supplement infant formula or follow-up formula.

[0161] The inventors have discovered that, in animal models, intervention with specific HMOs significantly increases propionic acid production in the cecum (part of the colon).

[0162] As described in the background section, propionic acid is known to be a satiety enhancer and to control food intake.

[0163] They also found that, in animal models, intervention with this specific HMO increased lean body mass, improved relative intake, promoted growth, and reduced fat content.

[0164] Therefore, the nutritional compositions according to the present invention can be used to reduce and / or control the food intake of infants or young children and / or promote their healthy growth.

[0165] By enhancing the satiety response of the infant or toddler, the health benefits targeted by this invention can be achieved.

[0166] These health benefits can be obtained by using the nutritional composition according to the invention by increasing the production of propionic acid in the colon of the infant or young child, particularly in the cecum.

[0167] This indicates a new clinical situation in which food intake and growth can be focused on in new ways.

[0168] In one specific implementation, propionic acid production is measured by gas-liquid chromatography and can be expressed in nmol / mg dry weight.

[0169] In one specific embodiment, the colonic propionic acid yield is increased by at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50%, or at least 60% compared to the colonic propionic acid yield obtained using a nutrient composition that does not contain at least one fucoidylated oligosaccharide and at least one N-acetylated oligosaccharide.

[0170] In one specific embodiment, the production of colonic propionic acid is increased by at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, or at least 70% compared to the production obtained using a nutritional composition supplemented with common fiber (such as polydextrose or pectin).

[0171] The nutritional compositions according to the invention can also be used specifically to prevent excessive weight gain in infants or young children and / or to promote lean body mass gain (or increase lean body mass).

[0172] Other purposes :

[0173] Another object of the present invention is to provide a nutritional composition comprising at least one fucoidylated oligosaccharide and at least one N-acetylated oligosaccharide for enhancing the satiety response of infants or young children.

[0174] Another object of the present invention is to prepare a nutritional composition using at least one fucoidylated oligosaccharide and at least one N-acetylated oligosaccharide to reduce and / or control the food intake of infants or young children.

[0175] Another object of the present invention is to prepare a nutritional composition using at least one fucoidylated oligosaccharide and at least one N-acetylated oligosaccharide to promote the healthy growth of infants or young children.

[0176] Another object of the present invention is to prepare a nutritional composition using at least one fucoidylated oligosaccharide and at least one N-acetylated oligosaccharide to enhance the satiety response of infants or young children.

[0177] Another object of the present invention is a pharmaceutical composition comprising at least one fucoidylated oligosaccharide and at least one N-acetylated oligosaccharide, the pharmaceutical composition being used to reduce and / or control food intake in infants or young children.

[0178] Another object of the present invention is a pharmaceutical composition comprising at least one fucoidylated oligosaccharide and at least one N-acetylated oligosaccharide, the pharmaceutical composition being used to promote the healthy growth of infants or young children.

[0179] Another object of the present invention is a pharmaceutical composition comprising at least one fucoidylated oligosaccharide and at least one N-acetylated oligosaccharide, the pharmaceutical composition being used to enhance the satiety response of infants or young children.

[0180] Another object of the present invention is to use at least one fucoidylated oligosaccharide and at least one N-acetylated oligosaccharide to reduce and / or control the food intake of infants or young children.

[0181] Another object of the present invention is to promote the healthy growth of infants or young children by using at least one fucoidylated oligosaccharide and at least one N-acetylated oligosaccharide.

[0182] Another object of the present invention is to enhance the satiety response of infants or young children by using at least one fucoidylated oligosaccharide and at least one N-acetylated oligosaccharide or a nutritional composition containing the thereof.

[0183] Another object of the present invention relates to a method for reducing and / or controlling food intake in infants or young children, the method comprising applying a nutritional composition comprising at least one fucoidylated oligosaccharide and at least one N-acetylated oligosaccharide to the infant or young child.

[0184] Another object of the present invention relates to a method for enhancing the satiety response of an infant or young child, the method comprising applying a nutritional composition comprising at least one fucoidylated oligosaccharide and at least one N-acetylated oligosaccharide to the infant or young child.

[0185] The different implementation schemes, specific methods and examples described above (e.g., relating to the type and amount of oligosaccharides, nutritional compositions, application, target populations, etc.) are also applicable to these other purposes.

[0186] Example

[0187] The following examples illustrate some specific embodiments of the compositions used according to the present invention. These examples are given for illustrative purposes only and should not be construed as limiting the invention, as various changes can be made thereto without departing from the spirit of the invention.

[0188] Example 1

[0189] Table 1 below provides examples of the composition of nutritional compositions (e.g., infant formula) according to the present invention. These compositions are given by way of example only.

[0190]

[0191]

[0192] Table 1: Examples of the composition of nutritional compositions (e.g., infant formula) according to the present invention

[0193] Example 2

[0194] Research Description

[0195] Five-week-old female BALB / cByJ CRL mice from the Charles River were divided into several groups and fed for 6 weeks according to the following protocol:

[0196] - Week 1: All groups were fed a low-fiber diet (see Table 2 for details).

[0197] -Weeks 2 to 6:

[0198] • Control group (Group A): Low-fiber diet (same as week 1)

[0199] • Test group (Groups B to D): Supplemented with a low-fiber diet containing 5% test fiber (same as week 1) (5% of the total low-fiber diet was replaced by 5% test fiber)

[0200]

[0201]

[0202] Table 2: Composition of a low-fiber diet

[0203] Test the following fibers:

[0204] HMO = Human milk oligosaccharides. The test sample was 2FL+LNnT at a weight ratio of 1:1.

[0205] PDX = Polydextrose

[0206] pectin

[0207] Table 3 provides a summary of the different test groups and diets.

[0208]

[0209] Table 3: Test group and diet in the study

[0210] Six weeks later, animals from each group were sacrificed, and the contents of the cecum were collected. SCFA production was measured by gas-liquid chromatography (GLC; amount of SCFA in nmol / mg dry weight). The following SCFAs were measured: propionic acid, butyric acid, valeric acid, and acetic acid.

[0211] Measurements were performed using the following protocol: SCFA in acidic solutions (pH 2.0 to 3.0) was separated on a GLC column coated with a polar stationary phase. This allows for minimal sample preparation (without derivatives) and simple, basic FID detection. SCFA was extracted from the cecum using acidic phosphate buffer containing HgCl2 to inactivate any residual bacterial activity, and GLC analysis was performed using an internal standard (2,2-dimethyl-butyric acid). After centrifugation, the sterilely filtered supernatant was analyzed by GLC. SCFA was measured simultaneously.

[0212] The median ratio was calculated to compare the effects of different fiber-rich diets on SCFA production.

[0213] Discover

[0214] A diet rich in HMOs significantly increases propionic acid production (see HMO-rich diets). Figure 1 Compared to the positive control, its yield increased by approximately 69%. Compared to pectin and PDX, its yield increased by 73% and 75%, respectively.

[0215] This is quite surprising, because pectin is generally considered a high inducer of SCFAs (Stark et al., J Nutr., 1993, In vitro production of short-chain fatty acids by bacterial fermentation of dietary fiber compared with effects of those fibers on hepatic sterol synthesis in rats; Yang et al., Anaerobe, 2013, In vitro characterization of the impact of selected dietary fibers on fecal microbiota composition and short chain fatty acid production).

[0216] Figure 2This represents the ratio of the median SCFA for each tested dietary fiber-rich diet to the median SCFA for the positive control diet (i.e., the low-fiber diet only). A ratio of 1 (black line) indicates no difference between the fiber-rich and control diets. A ratio below 1 indicates that the corresponding SCFA is higher in the control diet compared to the fiber-rich diet, while a ratio above 1 indicates that the corresponding SCFA is higher in the fiber-rich diet than in the control diet.

[0217] Diets rich in PDX and pectin induced less release of various SCFAs. Conversely, diets rich in HMOs induced greater release of propionic and butyric acids compared to low-fiber diets. HMO-rich diets were the only ones that caused such a significant difference in propionic acid release compared to other types of SCFAs and other tested fibers.

[0218] Therefore, the inventors were surprised to find that mice fed with a composition containing at least one fucoidylated oligosaccharide and at least one N-acetylated oligosaccharide had significantly higher propionic acid production in the cecum (and thus in the colon).

[0219] Due to the known properties of propionic acid, particularly its ability to regulate food intake and increase satiety, compositions containing at least one fucoidylated oligosaccharide and at least one N-acetylated oligosaccharide are effective for infants or young children for reducing and / or controlling food intake and / or promoting healthy growth.

[0220] Example 3

[0221] Research Description

[0222] A large number of pregnant female rats were purchased from Charles River Laboratories. Some of them had 60% of their food restricted during the last 10 days of their pregnancy.

[0223] The experimental subjects – newborn mice – were immediately divided into several groups (d=1) after birth:

[0224] • Normal rats (reference): whose mothers did not have IUGR (intrauterine growth restriction) during pregnancy (n=20).

[0225] • IUGR rats (control): Their mothers had IUGR during pregnancy, meaning that the pregnant women had 60% of their food restricted during the last 10 days of pregnancy (n=20)

[0226] • IUGR rats + HMO (test group): 3 different groups:

[0227] IUGR rats + 2FL (n=20)

[0228] IUGR rats + LNnT (n=20)

[0229] IUGR rats + 2FL / LNnT (also known as IUGR rats + HMO mixture) (n=20) whose mothers had IUGR during pregnancy, meaning that the pregnant rat mothers had 60% of their food restricted during the last 10 days of pregnancy.

[0230] During the experiment, they were fed milk and a standard diet supplemented with HMO and 2FL, LNnT or 2FL+LNnT (weight ratio of 2:1); see details below.

[0231] Normal rats were selected as the reference model.

[0232] IUGR (intrauterine growth restricted) rats were chosen as a control model because they would have a better appetite to compensate for their growth retardation, and therefore they might not consume a standard diet in a healthy way (e.g., they might have a higher total weight and / or fat mass gain compared to their lean body mass gain), which could contribute to the development and regulation of future health conditions, including obesity or related complications later in life.

[0233] Feed all pups from birth (d=1) to up to day 57 (d=57) according to the following protocol:

[0234] - Days 1 to 6: Rats in all groups were nursed by female mice (breast milk only).

[0235] - Days 7 to 21: All rats were nursed by females (breast milk only). However, in the test groups, HMO or a mixture of HMOs at 3 g / kg body weight was also administered by gavage.

[0236] 2FL: 3g / kg body weight, for group IUGR rats + 2FL

[0237] LNnT: 3 g / kg body weight, for group IUGR rats + LNnT

[0238] 2FL: 2 g / kg body weight + LNnT: 1 g / kg body weight, for group IUGR rats + 2FL / LNnT

[0239] - Days 22 to 57: Rats were separated from their mothers, and they followed the following protocol:

[0240] Normal rats and IUGR rats: fed with the control diet (compositions detailed in Table 4) without HMO supplementation.

[0241] Test group: fed the same diet, but supplemented with 4.5% by weight of HMO or HMO mixture (maltodextrin in the total control diet was replaced by the corresponding HMO):

[0242] 4.5% by weight of 2FL, for group IUGR rats + 2FL

[0243] 4.5% by weight LNnT, for group IUGR rats + LNnT

[0244] 3% by weight 2FL + 1.5% by weight LNnT, for group IUGR rats + 2FL / LNnT

[0245] ％ corn starch 53.4 Casein 20 sucrose 10 soybean oil 7 Mineral mixture AIN-93-G* 3.5 Choline tartrate 0.25 L-cysteine 0.3 tert-butylhydroquinone 0.0014 Vitamin mixture AIN-93-VX* 1 Maltodextrin 4.5

[0246] *From Research Diets, Inc.

[0247] Table 4: Compositions of the control diet

[0248] To evaluate the efficiency of feeding these rats, particularly to observe whether feeding indicated healthy growth, several parameters were calculated, including:

[0249] Lean body mass: This corresponds to the weight of the body that is not overweight. It is measured using magnetic resonance imaging (MRI).

[0250] - Relative intake: This corresponds to the total food intake over a specified period divided by the average body weight. It is assessed in several phases throughout the experiment (therefore, the total food intake is measured continuously over several days for calculation).

[0251] The significance of the type II error assessment was analyzed using the Wilcoxon two-tailed t-test.

[0252] Discover

[0253] Although the lean body mass of IUGR rats was significantly lower than that of normal rats, the inventors were surprised to find that on day 22 (approximately 3 weeks of age), the lean body mass of IUGR rats + HMO mixtures increased significantly and was closer to that of the reference group (normal rats). Figure 3 This situation is illustrated in the text.

[0254] like Figure 4A (The cycle from day 22 to day 29) and Figure 4B As shown in the cycle from day 22 to day 36, the relative intake of IUGR rats was significantly higher than that of normal rats. These rats had better appetites and ate more. However, when the HMO mixture was administered, the appetite of the rats was modulated (weakened): the relative intake of IUGR rats with the HMO mixture (2FL+LNnT) was significantly lower than that of the IUGR rats and was close to that of the control group (normal rats), see Figures 4 and 5.

[0255] Even more surprisingly, there appears to be a genuine synergistic effect between 2FL and LNnT in the HMO mixture, because the relative intake of IUGR rats supplemented with a single HMO (2FL alone or LNnT alone) did not decrease but significantly increased compared to the relative intake of IUGR rats (control, without HMO), such as... Figure 5A (The cycle from day 22 to day 29) and Figure 5B (The cycle is shown as day 22 to day 36).

[0256] Throughout the experiment, the same trend was observed at other times using the HMO mixture (2FL+LNnT).

[0257] Therefore, the inventors were surprised to find that, compared with IUGR rats, rats in need / at risk (i.e., rats with a better appetite and therefore more susceptible to future health conditions) fed with a composition containing at least one fucoidylated oligosaccharide and at least one N-acetylated oligosaccharide had higher lean body mass, regulated appetite, and significantly reduced relative intake, which tended to be close to the reference group.

[0258] Therefore, the compositions according to the invention are effective for infants or young children in reducing and / or controlling food intake and / or promoting healthy growth.

[0259] Example 4

[0260] In the same experience performed in Example 3, another parameter (growth) was also measured. Briefly, during lactation (p7 to p21), intrauterine growth-retarded pups (born of females who received only 40% of the recorded intake of the reference pregnant female) and reference pups (born of reference females) were gavaged with a mixture of 2FL, LNnT, and HMO (2FL:LNnT; 2:1 ratio) or maltodextrin (IUGR & reference). At weaning (p21), rats were given random access to a semi-purified diet supplemented with the appropriate treatment (4.5% by weight) until day 57. From day 57, all rats were fed an arbitrary amount of a normal diet until the end of the experiment on day 157.

[0261] like Figure 6 As shown, the HMO mixture (2FL+LNnT) promoted the growth of IUGR mouse pups compared with those mixtures supplemented with 2FL and LNnT or the control IUGR mouse pups.

[0262] Example 5

[0263] Two-day-old piglets were randomly assigned to receive either a fixed-volume milk substitute supplemented with 1.5 g / L HMO (1 g of 2FL + 0.5 g of LNnT) or a control milk substitute (285 ml / kg or 325 ml / kg body weight, respectively, on days p2–p5 and p6–p33) until day p32 at the end of the study. Body weight was measured daily. Figure 7 As shown. At the end of the study, viscera were removed, and soft tissue was collected from the carcass after removal of skin, feet, and bones. The protein and lipid content of the soft tissue was chemically analyzed. Lipid content is expressed as... Figure 8 Percentage of total body weight.

[0264] Piglets supplemented with a mixture of 2FL and LNnT had similar body weight and weight gain to control animals. However, these piglets had a lower percentage of fat content at the end of the 33-day experimental period.

[0265] Therefore, nutritional compositions containing at least one fucoidylated oligosaccharide and at least one N-acetylated oligosaccharide are effective for infants or young children to prevent excessive fat accumulation or related health problems later in life, such as obesity.

Claims

1. Use of a nutritional composition in the preparation of a product for reducing and / or controlling food intake in infants or young children, said nutritional composition comprising at least one fucoidylated oligosaccharide and at least one N-acetylated oligosaccharide, wherein the at least one fucoidylated oligosaccharide is 2'-fucosylated lactose (2'FL) and the at least one N-acetylated oligosaccharide is lactose-N-neotetrasaccharide (LNnT).

2. The use according to claim 1, wherein the nutritional composition further comprises a fucosylated oligosaccharide selected from the list of the following: 3'-fucosylvose, difucosylvose, lactose-N-fucopentose I, lactose-N-fucopentose II, lactose-N-fucopentose III, lactose-N-fucopentose V, lactose-N-fucohexasaccharide, lactose-N-difucohexasaccharide I, fucosylvose-N-hexasaccharide, fucosylvose-N-neohexose I, fucosylvose-N-neohexose II, difucosylvose-N-hexasaccharide I, difucosylvose-N-neohexose I, difucosylvose-N-neohexose II, fucosylvose-P-lactose-N-hexasaccharide, and any combination thereof.

3. The use according to any one of claims 1-2, wherein the nutritional composition further comprises an N-acetylated oligosaccharide selected from lactose-N-tetrasaccharide (LNT).

4. The use according to any one of claims 1-2, wherein the nutritional composition further comprises an N-acetylated oligosaccharide selected from p-lactose-N-neohexose (p-LNnH).

5. The use according to any one of claims 1-2, wherein the nutritional composition comprises a mixture of oligosaccharides consisting of 2'-fucosylated lactose (2'FL) and lactose-N-neotetrasaccharide (LNnT).

6. The use according to any one of claims 1-2, wherein the weight ratio of the fucoidylated oligosaccharide to the N-acetylated oligosaccharide is 1:10 to 12:

1.

7. The use according to any one of claims 1-2, wherein the weight ratio of the fucoidylated oligosaccharide to the N-acetylated oligosaccharide is 1:2 to 2:

1.

8. The use according to any one of claims 1-2, wherein the at least one fucoidylated oligosaccharide and the at least one N-acetylated oligosaccharide are present in a total amount of 0.1% to 10% by weight of the nutritional composition.

9. The use according to any one of claims 1-2, wherein the at least one fucoidylated oligosaccharide and the at least one N-acetylated oligosaccharide are present in a total amount of 0.5% to 7% by weight of the nutritional composition.

10. The use according to any one of claims 1-2, wherein the at least one fucoidylated oligosaccharide and the at least one N-acetylated oligosaccharide are present in a total amount of 1% to 5% by weight of the nutritional composition.

11. The use according to any one of claims 1-2, wherein the nutritional composition comprises at least one other oligosaccharide and / or fiber and / or human milk oligosaccharide precursor selected from the list of the following: galactooligosaccharide (GOS), fructooligosaccharide (FOS), xylooligosaccharide (XOS), inulin, polydextrose, sialylated oligosaccharide, sialic acid, fucose, and any combination thereof.

12. The use according to any one of claims 1-2, wherein the composition further comprises at least one probiotic, said probiotic being present in an amount of 10... 3 cfu / g up to 10 12 The composition described in cfu / g (dry weight).

13. The use according to any one of claims 1-2, wherein the nutritional composition is an infant formula, baby food, infant cereal composition, fortifier, or supplement.

14. The use according to any one of claims 1-2, wherein the nutritional composition is stage 1 infant formula, follow-up formula, or stage 2 infant formula.

15. The use according to any one of claims 1-2, wherein the infant or toddler is an infant or toddler at risk and / or in need.

16. The use according to claim 15, wherein the infant or toddler meets at least one of the following criteria: - They have difficulty controlling their food intake, or they have abnormal food intake. and / or - Their weight increases excessively in the first few months after birth.

17. The use according to claim 16, wherein the infant or toddler having difficulty controlling their food intake or having abnormal food intake means: i) They eat more compared to other infants or toddlers of the same age and size; and / or ii) Their sense of fullness has changed.

18. The use according to any one of claims 1-2, wherein the nutritional composition is used for the purpose by enhancing the satiety response of the infant or young child.

19. The use according to any one of claims 1-2, wherein the nutritional composition is used for the purpose by increasing the production of propionic acid in the colon of the infant or young child.

20. The use according to any one of claims 1-2, wherein the nutritional composition is used to prevent excessive weight gain in infants or young children and / or to promote lean body mass gain.

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