Compositions comprising human milk oligosaccharides for use in infants or young children to prevent or treat allergies

Abstract

The present invention relates to a composition comprising human milk oligosaccharides for use in infants or young children for the prevention or treatment of allergies, said composition comprising at least one fucosylated oligosaccharide and at least one N-acetylated oligosaccharide, the invention relates to a composition for preventing and / or treating allergy symptoms in an infant or a young child by increasing propionate production in the body of the infant or the young child.

Description

(19) State Intellectual Property Office (12) Invention Patent Application (10) Application Publication Number (43) Application Publication Date (21) Application Number 202610040273.1 (22) Application Date 2017.01.26 (30) Priority Data 16152753.6 2016.01.26 EP (62) Divisional Application Data 201780005821.6 2017.01.26 (71) Applicant Nestlé Products Ltd. Address Switzerland (72) Inventor C. Brancat C. Nanbrini (74) Patent Agency Beijing Zhongzi Law Firm 11247 Patent Attorney An Peidong Huang Gesheng (51) Int.Cl. A23L 33 / 21 (2016.01) A23L 33 / 00 (2016.01) A61K 31 / 702(2006.01) A61K 39 / 35(2006.01) A61P 37 / 08(2006.01) A61P 3 / 02(2006.01) (54) Invention Title Composition Containing Human Milk Oligosaccharides for the Prevention or Treatment of Allergic Reactions in Infants or Young Children (57) Abstract This invention relates to a composition containing human milk oligosaccharides for the prevention or treatment of allergic reactions in infants or young children, the composition comprising at least one fucoidylated oligosaccharide and at least one N-acetylated oligosaccharide for the prevention and / or treatment of allergic symptoms in said infants or young children by increasing propionate production in said infants or young children. Claims (2 pages), Description (19 pages), Drawings (3 pages), CN 121890762 A 2026.04.21 CN 1 21 89 07 62 A 1. A nutritional composition comprising at least one fucoidylated oligosaccharide and at least one N-acetylated oligosaccharide, for preventing and / or treating allergic symptoms in an infant or young child by increasing propionate production in the body of said infant or young child. 2. The nutritional composition according to claim 1, wherein the nutritional composition is used to prevent and / or treat allergic symptoms in an infant or young child by increasing colonic propionate production in the body of said infant or young child.3. A nutritional composition for use according to any one of the preceding claims, wherein the fucosylated oligosaccharide is selected from the list consisting of: 2'-fucosylvose, 3'-fucosylvose, difucosylvose, lactose-N-fucopentose I, lactose-N-fucopentose II, lactose-N-fucopentose III, lactose-N-fucopentose V, lactose-N-fucohexose, lactose-N-difucohexose I, fucosylvose-N-hexose, fucosylvose-N-neohexose I, fucosylvose-N-neohexose II, difucosylvose-N-hexose I, difucosylvose-N-neohexose I, difucosylvose-N-neohexose II, fucosylvose-P-lactose-N-hexose, and any combination thereof. 4. A nutritional composition for use according to any one of the preceding claims, wherein the fucoidylated oligosaccharide comprises a 2'-fucosylate epitope. 5. A nutritional composition for use according to any one of the preceding claims, wherein the fucoidylated oligosaccharide is 2'-fucosylate (2'FL). 6. A nutritional composition for use according to any one of the preceding claims, wherein the N-acetylated oligosaccharide is selected from the list consisting of: lactose-N-tetrasaccharide (LNT), lactose-N-neotetrasaccharide (LNnT), and any combination thereof. 7. A nutritional composition for use according to any one of the preceding claims, wherein the N-acetylated oligosaccharide is lactose-N-neotetrasaccharide (LNnT), p-lactose-N-neohexose (p-LNnH), or any combination thereof, preferably wherein the N-acetylated oligosaccharide is lactose-N-neotetrasaccharide (LNnT). 8. A nutritional composition for use according to any one of the preceding claims, comprising 2'-fucosylated lactose (2'FL) and lactose-N-neotetrasaccharide (LNnT), or comprising a mixture of oligosaccharides consisting of 2'-fucosylated lactose (2'FL) and lactose-N-neotetrasaccharide (LNnT). 9. A nutritional composition for use according to any one of the preceding claims, wherein the weight ratio of the fucoidylated oligosaccharide to the N-acetylated oligosaccharide is 1:10 to 12:1, such as 1:2 to 2:1. 10. A nutritional composition for use according to any one of the preceding claims, wherein the at least one fucoidylated oligosaccharide and the at least one N-acetylated oligosaccharide are present in an amount of 0.1% to 10% by weight, such as 0.5% to 7% by weight or 1% to 5% by weight, of the nutritional composition.11. A nutritional composition for use according to any one of the preceding claims, comprising at least one other oligosaccharide and / or fiber and / or human milk oligosaccharide precursor, selected from the list including: GOS, FOS, XOS, inulin, polydextrose, sialylated oligosaccharides, N-acetylated oligosaccharides, sialic acid, fucose, and any combination thereof. 12. A nutritional composition for use according to any one of the preceding claims, wherein it does not contain any sialylated oligosaccharides. 13. A nutritional composition for use according to any one of the preceding claims, wherein the composition further comprises at least one probiotic in an amount of 10³ cfu / g of the composition to 10¹² cfu / g of the composition (dry weight). 14. A nutritional composition for use according to any one of the preceding claims, wherein the nutritional composition is infant formula, stage 1 infant formula, stage 2 infant formula, or follow-up formula, baby food, infant cereal composition, fortifier, or supplement. Claims 1 / 2 Page 2 CN 121890762 A 15. A nutritional composition for use according to any one of the preceding claims, wherein the infant or young child is at risk of developing an allergic reaction, wherein the allergic reaction is selected from the group consisting of: allergic sensitization, food allergy, atopic dermatitis or eczema, asthma, wheezing, allergic rhinitis, rhinoconjunctivitis, eosinophilic esophagitis, hypersensitivity, allergy, urticaria, angioedema, food intolerance; and allergic reactions derived from allergenic proteins in food, pollen, animal dander, house dust mites, or venom. 16. A nutritional composition for use according to any one of the preceding claims, wherein the nutritional composition is a synthetic nutritional composition. Claims 2 / 2 Page 3 CN 121890762 A Composition containing human milk oligosaccharides for use in infants or young children to prevent or treat allergic reactions

[0001] This application is a divisional application of international application filed on January 26, 2017, with application number PCT / EP2017 / 051580 and the invention title "Composition containing human milk oligosaccharides for use in infants or young children to prevent or treat allergic reactions". This international application entered the Chinese national phase on July 5, 2018, with application number 201780005821.6. Technical Field

[0002] The present invention relates to nutritional compositions containing specific oligosaccharides for preventing and / or treating allergic reactions in infants or young children by increasing the production of propionate (especially colonic propionate) in the body of said infants or young children. The nutritional compositions of the present invention are intended to prevent and treat allergic reactions. In the first scenario, the infant or young child is healthy and has a normal risk of developing an allergic reaction, or has a higher risk of developing an allergic reaction because a first-degree family member has or has had an allergic reaction.In the second scenario, the infant or toddler has an allergic reaction or is at risk and therefore becomes ill. Background Art

[0003] Allergic reactions are one of the most common health problems, affecting the lives of patients of all ages. Allergic diseases are recognized as an epidemic by the World Health Organization today. It has been shown that the prevalence of allergic reactions has increased in recent decades. Modern lifestyles, especially urban lifestyles, are associated with a high prevalence and severity of allergic manifestations.

[0004] It has been confirmed that the development of an “allergic phenotype” or “atopic sensitivity” can lead to subsequent sensitization to other allergens and the occurrence of allergic reactions. Therefore, allergic sensitization (especially food allergen sensitization) during childhood, especially early childhood, is dangerous and has attracted much attention. Thus, allergic reactions in childhood may be the first step in an allergic cascade that can later trigger multiple allergic reactions (this process is often referred to as the “Atopic March”). For example, it has been shown that children with persistent food hypersensitivity in early childhood have a significantly increased risk of developing allergic rhinitis (hay fever) or asthma later in childhood (Ostblöm et al., 2008). Children with mild food hypersensitivity also have an increased risk of respiratory allergies, but to a lesser extent than those with persistent food hypersensitivity. Therefore, alleviating the severity of food hypersensitivity may be crucial to slowing the “atopic process.”

[0005] In this context, managing the onset of allergies and preventing allergies during childhood and infancy is extremely important.

[0006] In the first few years after birth, an infant’s immune system is actively developing. Intervening in, preventing, avoiding, managing, reducing, or modulating allergies in such young patients can affect not only their short-term allergic condition but also their long-term allergic condition later in life.

[0007] Evidence suggests that infancy may be a critical period for developing allergies. For various reasons, breastfeeding is recommended for all infants. In particular, it has been reported that breastfeeding reduces the risk of allergic reactions in offspring (Lodge, CJ, Breastfeeding and asthma and allergies: a systematic review and meta-analysis, Acta Paediatrica, 2015).

[0008] However, in some cases, breastfeeding is insufficient or unsuccessful due to certain medical reasons, or the mother does not choose to breastfeed. Infant formula has been developed for these situations. Fortifiers have also been developed to enrich mother's breast milk or infant formula with special ingredients.

[0009] Short-chain fatty acids (SCFAs) are produced, in particular, by the fermentation of dietary fiber in the colon by microorganisms. Propionate is an SCFA that has been shown to protect against allergic inflammation in the lungs and reduce allergic sensitization (the presence of total IgE) (Trompette et al., “Gut Microbiota metabolism of dietary fiber influences allergic airway disease and hematopoiesis”, Nature Medicine, 2013). Allergic sensitization (the presence of total IgE) is a marker of increased risk of developing allergic symptoms, therefore a reduction shown in total IgE should be understood as an indicator of the efficacy of propionate in preventing and / or treating allergic reactions other than allergic inflammation in the lungs, i.e., general allergic reactions.

[0010] Therefore, increasing propionate is a very meaningful target for protecting against allergic reactions and allergic symptoms. However, oral SCFAs may be unpalatable.

[0011] Therefore, alternative solutions more suitable for infants and young children should be developed.

[0012] 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 human milk oligosaccharides have been isolated and characterized.

[0013] For various health purposes (primarily immune purposes), several compositions using HMO components (such as fucoidylated oligosaccharides, lactose-N-tetrasaccharides, lactose-N-neotetrasaccharides, and / or sialylated oligosaccharides) have been described.

[0014] However, the use of HMOs for the prevention of allergic reactions and allergic symptoms has not been adequately studied.

[0015] It is clear that there is a need to develop suitable methods for the prevention and / or treatment of allergic reactions in infants and young children.

[0016] Moreover, since infants or young children are particularly vulnerable and not suitable for traditional drug interventions, the delivery of such health benefits should be through non-drug interventions particularly suitable for young individuals (infants and young children).

[0017] There is a need to deliver such health benefits to infants or young children in a manner that does not cause side effects and / or is not only easy to deliver but also widely accepted by parents or healthcare professionals.

[0018] Furthermore, the price of such a delivery method should be reasonable and affordable for most people. Summary of the Invention

[0019] The inventors have discovered that compositions comprising at least one fucoidylated oligosaccharide and at least one N-acetylated oligosaccharide can increase the production of colonic propionate in animal models.

[0020] Because propionate is known to defend against allergic reactions, such compositions are therefore advantageous for the prevention and / or treatment of allergic symptoms in infants or young children.

[0021] In a particularly advantageous embodiment, the nutritional composition according to the invention comprises 2'-fucosylated lactose (2-FL) and lactose-N-neotetrasaccharide (LNnT), and particularly the 2FL:LNnT weight ratio is 1:2 to 2:1.

[0022] Figure 1 shows the propionate production in the cecum of mice fed a low-fiber diet and a low-fiber diet rich in 5% of different test fibers.

[0023] Abbreviations: Pos ctr = positive control; HMO = human milk oligosaccharide, tested 2FL+LNnT weight ratio 1:1; PDX specification 2 / 19 page 5 CN 121890762 A = polydextrose.

[0024] Figure 2 shows the ratio of the median of each SCFA in the fiber-rich diet to the median of the positive control diet.

[0025] Abbreviations: Ctrl pos = positive control; HMO = human milk oligosaccharide, the weight ratio of 2FL+LNnT tested was 1:1; PDX = polydextrose.

[0026] Figure 3 shows the IgE levels measured in mice from different groups of the experiments recorded in Example 3.

[0027] Figure 4 shows the cecal propionate levels measured in mice from different groups of the experiments recorded in Example 3.

[0028] Figure 5 shows the propionate levels in the feces of mice from different groups of the experiments recorded in Example 3. Detailed Description

[0029] As used herein, the following terms have the following meanings.

[0030] The term “infant” refers to a child under 12 months of age.

[0031] The expression “toddler” refers to a child between one and three years of age, also known as a toddler.

[0032] “Cesarean section infant or toddler” refers to an infant or toddler delivered by cesarean section. This means that the infant or toddler was not delivered vaginally.

[0033] “Vaginal delivery infant or toddler” refers to an infant or toddler delivered vaginally rather than by cesarean section.

[0034] “Premature infant” refers to an infant or toddler born before full term. This typically refers to an infant or toddler born before 36 weeks of gestation.

[0035] The term “nutritional composition” refers to a composition that provides nutrients to an individual. This nutritional composition is typically ingested orally or intravenously. It may include lipid or fat sources, carbohydrate sources, and / or protein sources. In one embodiment, the nutritional composition is a ready-to-drink composition, such as a ready-to-drink formula food.

[0036] In one 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.

[0037] In one specific embodiment, the nutritional composition of the present invention is a “synthetic nutritional composition.” The term “synthetic nutritional composition” means a mixture obtained by chemical and / or biological means, or a mixture comprising components obtained by chemical and / or biological means (including, for example, purification and separation means), which may be chemically identical to a mixture naturally present in mammalian milk, or may contain components identical to those naturally present in mammalian milk (i.e., the synthetic nutritional composition is not breast milk).

[0038] As used herein, the term “infant formula” refers to a food intended specifically for the nutrition of infants in the first few months after birth, and which itself 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 for infant formula and Stage 2 infant formula). It also refers to nutritional compositions intended for use in infants, as defined in the Codex Alimentarius Commission (Codex STAN 72-1981) and infant specialties (including foods for specific medical purposes). The term "infant formula" encompasses both "Stage 1 infant formula" and "follow-up formula" or "Stage 2 infant formula."

[0039] "Follow-up formula" or "Stage 2 infant formula" is provided from the 6th month onwards. Infant formula constitutes a major liquid element in the gradually diversifying diet of this group.

[0040] The term "infant food" refers to food designed specifically for supplying nutrition to infants or toddlers under one year of age.

[0041] The term "infant cereal composition" refers to food designed specifically for supplying nutrition to infants or toddlers under one year of age.

[0042] The term "fortifier" refers to a liquid or solid nutritional composition suitable for mixing with breast milk or infant formula.

[0043] The term "weaning period" refers to the period during which breast milk or infant formula is gradually replaced in the diet of an infant or toddler with other foods.

[0044] 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” are used interchangeably.

[0045] The terms “prevention and / or treatment of allergic reactions / allergic responses / allergic symptoms / allergic diseases” mean preventing and / or reducing the frequency and / or incidence and / or severity and / or duration of “allergic reactions” or “allergic responses” or “allergic symptoms” or “allergic diseases.” Incidence is related to the number of “allergic reactions” or “allergic responses” or “allergic symptoms” or “allergic diseases.” Frequency is related to the number of the same “allergic reactions” or “allergic responses” or “allergic symptoms” or “allergic diseases.”This prevention covers reducing the frequency and / or severity of the “allergic reaction” or “allergic response” or “allergic symptoms” or “allergic disease” after the intervention ends. The term “after” covers the effect after the intervention ends.

[0046] The expressions “after” and “later” are used interchangeably. They refer to the effect measured in individuals (infants or toddlers) after several weeks, months, or years of age, such as after 6 months of age, such as after 8 months of age, such as after 10 months of age, such as after 1 year of age, such as after 2 years of age, preferably after 4 years of age, more preferably after 5 years of age, even more preferably after 7 years of age, or even older, and comparing the effect to the average observation of individuals of the same age. Preferably, it involves the effect observed after at least 1 year of age or after at least 2, 5, 7, 10, or 15 years of age. Thus, the expression “after” may refer to the observation during infancy, during childhood, during adolescence, or during adulthood. Preferably, it refers to observations during childhood, adolescence, or adulthood. The term “post-intervention” covers effects after the intervention has ended.

[0047] The expression “health disorder” covers any health condition and / or disease and / or functional impairment affecting an individual organism.

[0048] The expressions “allergic reaction” or “allergic response” or “allergic symptoms” or “allergic disease” are used interchangeably. Such terms include, but are not limited to, allergic sensitization, food allergy, atopic dermatitis and eczema, asthma, wheezing, allergic rhinitis, rhinoconjunctivitis, eosinophilic esophagitis, hypersensitivity, allergy, and urticaria. Allergic reactions can develop into various allergens, all of which are included within the scope of this invention; non-limiting examples include proteins derived from foods such as milk, eggs, grains, nuts, or from pollen, animal dander, or house dust mites.

[0049] The term “SCFA” refers to short-chain fatty acids.

[0050] The expression "increased propionate production" means that, compared with individuals fed a standard composition (i.e., a nutritional composition not containing at least one fucoidylated oligosaccharide and at least one N-acetylated oligosaccharide) and / or individuals fed a standard composition supplemented with common fiber (such as polydextrose or pectin), the amount of systemic propionate and / or colonic propionate is higher in individuals fed the nutritional composition according to the invention (i.e., containing at least one fucoidylated oligosaccharide and at least one N-acetylated oligosaccharide). Propionate production can be measured by techniques known to those skilled in the art, such as by gas-liquid chromatography.

[0051] The expression “increased colonic propionate production” means that, compared to individuals fed a standard composition (i.e., a nutritional composition not containing at least one fucoidylated oligosaccharide and at least one N-acetylated oligosaccharide) and / or individuals fed a standard composition supplemented with common fiber (such as polydextrose or pectin), the amount of propionate in the colon (or large intestine) or a portion thereof, such as the cecum, is higher in individuals fed a nutritional composition according to the invention (i.e., containing at least one fucoidylated oligosaccharide and at least one N-acetylated oligosaccharide). Propionate production can be measured by techniques known to those skilled in the art, such as by gas-liquid chromatography.

[0052] “Breast milk” should be understood as the mother’s milk or colostrum.

[0053] The term “HMO” refers to (one or more) human milk oligosaccharides. These carbohydrates are resistant to enzymatic hydrolysis by digestive enzymes (e.g., the pancreas and / or brush border, as described on page 4 / 19 of the specification, CN 121890762 A), indicating that they may exhibit 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 the maturation of the immune system. Many different types of HMOs have been found in human milk. Each individual oligosaccharide is based on a combination of glucose, galactose, sialic acid (N-acetylneuraminic acid), fucose, and / or N-acetylglucosamine with a wide variety of bonds between these molecules, thus human milk contains a large number of diverse oligosaccharides, with over 130 such structures identified to date. Almost all oligosaccharides have a lactose moiety at the reducing end, and the non-reducing end is occupied by sialic acid and / or fucose (if present). HMOs can be acidic (e.g., oligosaccharides containing charged sialic acid) or neutral (e.g., fucoidylated oligosaccharides).

[0054] “Fucoidylated oligosaccharides” are oligosaccharides containing fucose residues. Such 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-fucohexose, lactose-N-difucohexose I, fucosyllactose-N-hexose, fucosyllactose-N-neohexose, difucosyllactose-N-hexose I, difucosyllactose-N-neohexose II, and any combination of these substances.

[0055] The terms “fucosylated oligosaccharides containing 2'-fucosylation epitopes” and “2-fucosylated oligosaccharides” cover fucosylated oligosaccharides with certain homologous forms. These homologous fucosylated oligosaccharides all contain 2'-fucosylation epitopes, so it can be inferred that they have certain homologous functions.

[0056] The term “N-acetylated oligosaccharide” encompasses both “N-acetyl-lactoside” and “oligosaccharide containing N-acetyl-lactoside”. Such oligosaccharide is a neutral oligosaccharide having N-acetyl-lactoside 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-hexose, lactose-N-neohexose, para-lactose-N-hexose, para-lactose-N-neohexose, lactose-N-octasaccharide, lactose-N-neoctasaccharide, isol-lactose-N-octasaccharide, para-lactose-N-octasaccharide, and lactose-N-decanose.

[0057] 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”.

[0058] “HMO precursor” is a key compound used to prepare HMO, such as sialic acid and / or fucose.

[0059] “Sialylated oligosaccharide” is an oligosaccharide containing charged sialic acid, i.e., an oligosaccharide with sialic acid residues. Such oligosaccharides are acidic. Some examples are 3-SL (3'-sialyl lactose) and 6-SL (6'-sialyl lactose).

[0060] The expressions “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 have N-acetyl residues (i.e., they are neutral oligosaccharides). In one specific 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 include oligosaccharides containing one galactose molecule and one glucose molecule (i.e., disaccharide) linked by β-1,2, β-1,3, or β-1,6 bonds.

[0061] The nutritional compositions of the present invention may be in solid form (e.g., powder) or liquid form. The content of various components (e.g., oligosaccharides) may be expressed as g / 100g composition on dry weight when the composition is in solid form (e.g., powder); or as a concentration g / L composition when the composition refers to a liquid form (the latter also covers liquid compositions that can be obtained by reconstituted powder with liquids such as milk, water, etc., such as reconstituted infant formula or stage 2 infant formula / follow-up formula or infant cereal products or any other formulations specifically designed for infant nutrition).

[0062] The terms “prebiotic”, “fiber(s)” and “fiber(s)” are used interchangeably.These refer to non-digestible carbohydrates that produce beneficial effects 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).

[0063] The term "probiotics" refers to microbial cell preparations or microbial cell components that have beneficial effects on the health or good condition of the host (Salminen S, Ouwehand A. Benno Y. et al. "Probiotics: how should they be defined" Trends Food Sci. Technol. 1999:10 107-10). Microbial cells are generally bacteria or yeast.

[0064] The term "cfu" should be understood as colony-forming unit.

[0065] Unless otherwise specified, all percentages are by weight.

[0066] Additionally, in the context of this invention, the terms “comprising” or “including” do not exclude other possible elements. The compositions of the present 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.

[0067] Any references to prior art literature in this specification should not be construed as an admission that such prior art is well-known or constitutes part of common knowledge in the art.

[0068] The invention will now proceed in more detail. It should be noted that the various aspects, features, embodiments, and implementations described herein are compatible and / or can be combined together.

[0069] The present invention therefore relates to a nutritional composition comprising at least one fucoidylated oligosaccharide and at least one N-acetylated oligosaccharide for the prevention and / or treatment of allergic symptoms in infants or young children by increasing propionate production in the body (especially the colon).

[0070] In one embodiment, the present invention therefore relates to a nutritional composition comprising at least one fucoidylated oligosaccharide and at least one N-acetylated oligosaccharide for preventing and / or treating allergic symptoms in infants or young children by increasing the production of colonic propionate (especially propionate) in the body of said infants or young children.

[0071] Unbound by theory, the inventors of the present invention believe that (one or more) fucosylated oligosaccharides and (one or more) N-acetylated oligosaccharides work synergistically to unexpectedly provide the aforementioned health benefits. This particular combination of oligosaccharides will significantly increase propionate production in an individual and can therefore be used to prevent and / or treat allergic symptoms in infants or young children by increasing propionate (especially colonic propionate) production in the body of said infants or young children.

[0072] The nutritional composition of the present invention comprises at least one fucosylated oligosaccharide. One or more types of fucosylated oligosaccharides may be present. (One or more) fucosylated oligosaccharides are actually selected from a list including the following: 2'-Fucosyllactose, 3'-Fucosyllactose, Difucosyllactose, Lactose-N-fucopentose (such as lactose-N-fucopentose I, lactose-N-fucopentose II, lactose-N-fucopentose III, lactose-N-fucopentose V), Lactose-N-fucohexose, Lactose-N-difucohexose I, Fucosyllactose-N-hexose, Fucosyllactose-N-neohexose (such as fucosyllactose-N-neohexose I, fucosyllactose-N-neohexose II), difucosyllactose-N-hexose I, difucosyllactose-N-neohexose, difucosyllactose-N-neohexose I, difucosyllactose-N-neohexose II, fucosyl-p-lactose-N-hexose, trifucosyl-p-lactose-N-hexose I, and any combination thereof.

[0073] In some specific embodiments, the fucosylated oligosaccharide contains a 2'-fucosyl epitope. The fucoidyl oligosaccharide may be selected from, for example, a list including the following: 2'-fucosyllactose, difucosyllactose, lactose-N-fucopentose, lactose-N-fucohexose, lactose-N-difucohexose, fucoidyllactose-N-hexose, fucoidyllactose-N-neohexose, difucosyllactose-N-hexose, difucosyllactose-N-neohexose, difucosyllactose-N-neohexose, fucoidyl-p-lactose-N-hexose, and any combination thereof.

[0074] In a preferred embodiment, the nutritional composition according to the invention comprises 2'-fucosyllactose (or 2FL, or 2'FL, or 2-FL or 2'-FL). In one specific embodiment, no other type of fucosylated oligosaccharide exists besides 2'-fucosylated lactose; that is, the nutritional composition of the present invention contains only 2'-fucosylated lactose as a fucosylated oligosaccharide.

[0075] Fucosylated oligosaccharides (one or more) can be separated from natural sources such as animal milk by chromatography or filtration techniques.Alternatively, fucosylated oligosaccharides can be prepared by biotechnological means using special fucosyltransferases and / or fucosidases, through enzyme-based fermentation techniques (recombinant enzymes 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), starting from 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.

[0076] The compositions of the present invention further comprise at least one of N-acetylated oligosaccharides. 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-neohexose (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, wherein the LNT:LNnT ratio is 5:1 to 1:2, or 2:1 to 1:1, or 2:1.2 to 2:1.6.

[0077] In a preferred embodiment, the nutritional composition according to the invention comprises lactose-N-neotetrasaccharide (LNnT). In one specific embodiment, no other type of N-acetylated oligosaccharide is contained except for lactose-N-neotetrasaccharide (LNnT), that is, the nutritional composition of the present invention contains only lactose-N-neotetrasaccharide (LNnT) as an N-acetylated oligosaccharide.

[0078] (One or more) N-acetylated oligosaccharides can be chemically synthesized by enzymatic transfer, that is, by using glycosyltransferases to transfer sugar units from the donor portion to the acceptor portion, 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 ketohexoses (e.g., fructose) into N-acetylglucosamine or oligosaccharides containing N-acetylglucosamine, as described in Wrodnigg, T.M.; Stutz, AE (1999) Angew. Chem. Int. Ed. 38:827-828.The N-acetylglucosinolate obtained in this way can then be transferred to lactose, which serves as the acceptor moiety. N-acetylated oligosaccharides can also be produced by biotechnological means based on microbial fermentation.

[0079] In a particularly advantageous embodiment of the invention, the nutritional composition comprises 2'-fucosylated lactose (2FL) and lactose-N-neotetrasaccharide (LNnT).

[0080] In another specific embodiment, the nutritional composition of the invention comprises a mixture of oligosaccharides consisting of 2'-fucosylated lactose (2FL) and lactose-N-neotetrasaccharide (LNnT). In other words, the nutritional composition of the invention comprises only 2'-fucosylated lactose (2FL) as a fucosylated oligosaccharide and only lactose-N-neotetrasaccharide (LNnT) as an N-acetylated oligosaccharide.

[0081] In some embodiments, the weight ratio of fucoidylated oligosaccharide to N-acetylated oligosaccharide (e.g., 2FL:LNnT) in the nutritional composition of the present invention is 1:10 to 12:1, such as 1:7 to 10:1 or 1:5 to 5:1, or 2:1 to 5:1 or 1:3 to 3:1, or 1:2 to 2:1, or 1:1 to 3:1, or 1:5 to 1:0.5. Specification 7 / 19 pages 10 CN 121890762 A

[0082] Before being mixed with water, the total amount of (one or more) fucoidylated oligosaccharides and (one or more) N-acetylated oligosaccharides present in the nutritional composition of the present invention may be 0.1% to 10% by weight of the nutritional composition, such as 0.5% to 7% by weight or 1% to 5% by weight. For ready-to-drink formula foods, the target is 0.01% to 1%, more preferably 0.05% to 0.7% or 0.1% to 0.5%.

[0083] The nutritional composition of the present invention may, for example, comprise: - fucoidylated oligosaccharides, the total amount of which is 0.2 g / L composition - 5 g / L composition, for example 0.5 g / L composition - 4.5 g / L composition or 1 g / L composition - 4 g / L composition, or the total amount on dry weight is 0.13 g / 100 g composition - 3.48 g / 100 g composition, for example 0.34 g / 100 g composition - 3.13 g / 100 g composition or 0.69 g / 100 g composition - 2.78 g / 100 g composition; and / or - N-acetylated oligosaccharides, the total amount of which is 0.05 g / L composition - 5 g / L composition, for example 0.1 g / L composition - 2 g / L composition or 0.1 g / L composition - 1 g / L composition, or the total amount on dry weight is 0.003 g / 100 g composition - 3.48g / 100g composition, for example, 0.07g / 100g composition - 1.4g / 100g composition or 0.07g / 100g composition - 0.7g / 100g composition.

[0084] The nutritional composition according to the invention may further comprise at least additional oligosaccharides (i.e., in addition to (one or more) fucoidylated oligosaccharides and (one or more) N-acetylated oligosaccharides that are required to be present in the composition) and / or at least one or more fiber and / or at least one or more human milk oligosaccharide precursors. Another 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.

[0085] In addition to the oligosaccharides contained in the oligosaccharide mixture, suitable commercial products for preparing the nutritional composition according to the invention include combinations of FOS and inulin, such as products sold by BENEO under the trademark Orafti, or polydextrose sold by Tate & Lyle under the trademark STA-LITE®.

[0086] 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 the group consisting of 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).

[0087] Sialidized oligosaccharides(s) may be separated from natural sources such as animal milk by chromatography or filtration techniques. Alternatively, sialylated oligosaccharides can be prepared using specialized sialyltransferases or sialiosides 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. Sialylated oligosaccharides can be formed starting with acceptor substrates initially having any degree of polymerization (DP), beginning with DP = 1. Alternatively, sialylated lactose can be prepared via chemical synthesis from lactose and free N'-acetylneuraminic acid (sialic acid). Sialylated lactose is also commercially available, for example, from Kyowa Hakko Kogyo in Japan.

[0088] In a specific example, the composition may contain fucoidylated oligosaccharides in total amounts of 0.05 g / L to 5 g / L, for example 0.1 g / L to 4 g / L or 0.3 g / L to 2 g / L, or in total amounts on a dry weight basis of 0.03 g / 100 g to 3.5 g / 100 g, for example 0.1 g / 100 g to 2 g / 100 g or 0.2 g / 100 g to 1 g / 100 g as described on page 8 / 19 of the specification, CN 121890762 A.

[0089] In one specific embodiment, the nutritional composition may also contain 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.

[0090] In some specific embodiments of the invention, the nutritional composition does not contain any one or more sialylated oligosaccharides, any GOS, and / or any bovine milk oligosaccharides.

[0091] The composition according to the invention may optionally also comprise at least one precursor of human milk oligosaccharides. One or more precursors may be present. For example, the human milk oligosaccharide precursor is sialic acid, fucose, or a mixture thereof. In some specific embodiments, the composition comprises sialic acid.

[0092] 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.

[0093] The composition according to the invention may comprise 0 g to 2.1 g of (one or more) human milk oligosaccharide precursor / 100 g composition on a dry weight basis, for example, 0 g to 1.5 g, 0 g to 0.8 g, or 0 g to 0.15 g of (one or more) human milk oligosaccharide precursor / 100 g composition on a dry weight basis.

[0094] The nutritional composition of the invention may also comprise at least one probiotic (or probiotic strain), such as a probiotic strain.

[0095] 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.

[0096] In some specific embodiments, the probiotics are probiotic bacterial strains. In some specific embodiments, they are specifically Bifidobacteria and / or Lactobacillus.

[0097] Suitable probiotic strains include Lactobacillus rhamnosus ATCC 53103, Lactobacillus rhamnosus CGMCC 1.3724, Lactobacillus paracasei CNCM I-2116, Lactobacillus johnsonii CNCM I-1225, Streptococcus salivarius DSM 13084, sold under the trade name KI2 by BLIS Technologies Limited, New Zealand, Bifidobacterium lactis CNCM 1-3446, specially sold under the trademark Bb 12 by Christian Hansen company, Denmark, and Morinaga Milk Industry Co., Ltd., Japan. Bifidobacterium longum ATCC BAA-999 sold by Procter & Gamble Ltd. (Japan) under the trademark BB536; Bifidobacterium breve sold by Danisco under the trademark Bb-03; Bifidobacterium breve sold by Morinaga under the trademark M-16V; Bifidobacterium infantis sold by Procter & Gamble Co. under the trademark Bifantis; and Bifidobacterium breve sold by the Rosell Institute of Biological Sciences, Canada under the trademark R0070.

[0098] The nutritional composition according to the invention may comprise 10e3 to 10e12 cfu of probiotic strains / g composition by dry weight, more preferably 10e7 to 10e12 cfu of probiotic strains / g composition, such as 10e8 to 10e10 cfu of probiotic strains / g composition.

[0099] 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.

[0100] The nutritional composition 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 Staphylococcus.

[0101] The nutritional composition according to the present invention may be, for example, infant formula, stage 1 infant formula, stage 2 infant formula, or follow-up formula, baby food, infant cereal composition, fortifier (such as human milk fortifier), or supplement. In some specific embodiments, the composition of the present invention is an infant formula, fortifier, or supplement intended for use in infants aged 4 months or 6 months. In a preferred embodiment, the nutritional composition of the present invention is an infant formula.

[0102] 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 fortifier (such as an infant formula fortifier or a stage 2 / follow-up formula fortifier).

[0103] When the nutritional composition is a supplement, it may be provided in unit dose form.

[0104] The nutritional compositions of the present invention may be in solid (e.g., powder), liquid, or gel form.

[0105] The nutritional compositions according to the present invention typically contain a protein source. The amount of protein may be from 1.5 g / 100 kcal to 3 g / 100 kcal. In some embodiments, particularly when the composition is intended for preterm infants, the amount of protein may 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 may be less than 2.0 g / 100 kcal, for example from 1.8 g / 100 kcal to 2 g / 100 kcal, or less than 1.8 g / 100 kcal.

[0106] The type of protein is considered irrelevant to the present 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 may be used, as well as soy-based protein sources. Regarding the whey protein of interest, the protein source may be based on acidic whey or sweet whey or a mixture thereof, and may contain any desired proportions of α-lactalbumin and β-lactoglobulin.

[0107] In some advantageous embodiments, the protein source is whey-based (i.e., more than 50% of the protein is derived from whey protein, such as 60% or 70%).

[0108] The protein may be a whole protein or a hydrolyzed protein, or a mixture of whole and hydrolyzed proteins.The term "intact" means that the major portion of the protein is intact, i.e., the molecular structure is not altered, for example, at least 80% of the protein is not altered, such as at least 85% of the protein is not altered, preferably at least 90% of the protein is not altered, and even more preferably at least 95% of the protein is not altered, such as at least 98% of the protein is not altered. In one specific embodiment, 100% of the protein is not altered.

[0109] The term "hydrolyzed" means, in the context of this invention, that the protein has been hydrolyzed or broken down into its constituent amino acids.

[0110] The protein may be completely hydrolyzed or partially hydrolyzed. For example, for infants or young children considered to be at risk of developing bovine milk allergies, providing partially hydrolyzed protein (with a degree of hydrolysis of 2% to 20%) may be desirable. 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 is found that the protein undergoes far less lysine blocking during hydrolysis (lysine specification 10 / 19 pages 13 CN 121890762 A blockage). 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.

[0111] In one embodiment of the invention, at least 70% of the protein is hydrolyzed, preferably at least 80% of the protein is hydrolyzed, such as at least 85% of the protein is hydrolyzed, and even more preferably at least 90% of the protein is hydrolyzed, such as at least 95% of the protein is hydrolyzed, particularly at least 98% of the protein is hydrolyzed. In one specific embodiment, 100% of the protein is hydrolyzed.

[0112] In one specific embodiment, the protein of the nutritional composition is hydrolyzed, completely hydrolyzed, or partially hydrolyzed. The degree of protein hydrolysis (DH) can be 8 to 40, or 20 to 60, or 20 to 80, or greater than 10, 20, 40, 60, 80, or 90.

[0113] In one specific embodiment, the nutritional composition according to the invention is a hypoallergenic composition. In another specific embodiment, the composition according to the invention is a hypoallergenic nutritional composition.

[0114] The nutritional composition according to the invention generally contains a carbohydrate source. This is particularly preferred in the case where the nutritional composition of the invention is an 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.

[0115] The nutritional compositions according to the invention generally contain a lipid source. This is particularly relevant in the case that the nutritional compositions of the invention are 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.

[0116] The nutritional compositions of the invention may also contain all vitamins and minerals considered essential for a daily diet, which are present in the composition in significant nutritional amounts. 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 usually added in the form of salts. The presence and content of specific minerals and other vitamins will vary depending on the target population.

[0117] If necessary, the nutritional compositions of the present invention may contain emulsifiers and stabilizers, such as soybean, lecithin, monoglyceride citrate, and diglyceride citrate.

[0118] The nutritional compositions of the present invention may also contain other substances that may have beneficial effects, such as lactoferrin, nucleotides, nucleosides, etc.

[0119] 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.

[0120] The nutritional compositions according to the invention can be prepared by any suitable method. The compositions will now be described by way of example.

[0121] For example, formulated foods such as infant formula can be prepared by blending a protein source, a carbohydrate source, and a fat source together in appropriate proportions. If an emulsifier is used, it can be added at this time. Vitamins and minerals can be added at this time, but they 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 been subjected to reverse osmosis) can then be mixed in to form a liquid mixture. The water temperature is in the range of about 50°C to about 80°C to facilitate dispersion of the components. Commercially available liquefying agents can be used to form the liquid mixture.

[0122] Especially if the final product is in liquid form, one or more fucoidylated oligosaccharides and one or more N-acetylated oligosaccharides may be added at this stage. If the final product is a powder, these components may also be added at this stage as needed.

[0123] The liquid mixture is then homogenized, for example, in two stages.

[0124] The liquid mixture may then be heat-treated to reduce bacterial load, for example, by rapidly heating the liquid mixture to a temperature in the range of about 80°C to about 150°C for a 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).

[0125] The liquid mixture is then cooled, for example, to about 60°C to about 85°C by rapid cooling. The liquid mixture is then homogenized again, for example, in two stages, wherein the pressure of the first stage is about 10 MPa to about 30 MPa, and the pressure of the second stage is about 2 MPa to about 10 MPa. The homogenized mixture may then be further cooled to add any heat-sensitive components, such as vitamins and minerals. At this point, the pH and solids content of the homogenized mixture can be conveniently adjusted.

[0126] If the final product will 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 with one or more probiotic strains (if used), or by blending with one or more probiotic strains in the form of crystalline syrup, and then spray-drying or freeze-drying the mixture.

[0127] If a liquid composition is preferred, the homogenized mixture may be sterilized and then filled into a suitable container under aseptic conditions, or it may be filled into a container first and then sterilized.

[0128] In another embodiment, the composition of the present invention may be a supplement.

[0129] The supplement may be, for example, in tablet, capsule, lozenge, or liquid form. Supplements may also include 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.The supplement 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, starch, gum arabic, vegetable oils, polyalkylene glycols, flavoring agents, preservatives, stabilizers, emulsifiers, buffers, lubricants, coloring agents, wetting agents, fillers, etc.

[0130] In addition, the supplement may also contain organic or inorganic carrier materials suitable for oral or parenteral administration, as well as vitamins, trace minerals and other micronutrients recommended by government agencies (such as the USRDA).

[0131] The nutritional composition according to the invention is for use in infants or young children. The infant or young child may be a full-term or premature infant. In one specific embodiment, the nutritional composition of the invention is for use in premature infants or young children.

[0132] The nutritional composition of the invention may also be used in infants or young children delivered by cesarean section or vaginally.

[0133] In some embodiments, the nutritional composition according to the invention may be used before and / or during weaning.

[0134] In some embodiments, the nutritional composition according to the invention is used for infants or young children at risk of developing allergies. In some embodiments, the nutritional composition according to the invention is used for infants or young children born to mothers who have allergies. Indeed, scientific evidence continues to show that infants born to mothers who have allergies have a greater risk of developing allergies later in life than infants born to mothers who do not have allergies. Specification 12 / 19 pages 15 CN 121890762 A

[0135] The age and duration of administration (providing or feeding) of the nutritional composition may be determined according to possibility and need.

[0136] Because the nutritional composition is also used for preventative purposes (prevention of future health disorders), it may be provided, for example, immediately after the birth of the infant. The compositions of the present invention may 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 compositions are provided (or administered) to the infant during the first four or six months after birth.

[0137] 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.

[0138] 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 nutrition provided by breast milk, or provided to the infant or young child together with breast milk during this period of nutrition provided by breast milk. 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.

[0139] 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, to supplement human milk or to supplement infant formula or stage 2 infant formula.

[0140] The inventors have discovered that specific HMO interventions in animal models significantly increase propionate production in the cecum (part of the colon) of animals.

[0141] As mentioned in the background section, propionate is known to protect against allergic reactions.

[0142] The nutritional composition according to the invention can therefore be used to prevent and / or treat allergic symptoms in infants or young children by increasing propionate production in the body (especially colonic propionate production).

[0143] The target health benefits of the invention can be obtained using a nutritional composition that increases colonic propionate production in the body of the infant or young child, especially propionate production in the cecum. In one specific embodiment, propionate production is determined by gas-liquid chromatography and can be expressed as nmol / mg dry weight.

[0144] In one specific embodiment, colonic propionate production is increased by at least 10%, or at least 15%, or at least 20%, or at least 30%, or at least 40%, or at least 50%, or at least 60% compared to colonic propionate production obtained using a nutritional composition that does not contain at least one fucoidylated oligosaccharide and at least one N-acetylated oligosaccharide.

[0145] In one specific embodiment, colonic propionate production is increased by at least 10%, or at least 15%, or at least 20%, or at least 30%, or at least 40%, or at least 50%, or at least 60%, or at least 70% compared to colonic propionate production obtained using a nutritional composition supplemented with common fiber (such as polydextrose or pectin).

[0146] This represents a new clinical situation in which the prevention of allergic symptoms can be achieved in a new way.

[0147] Other objectives: Another objective of the present invention is to prepare a nutritional composition for preventing and / or treating allergic symptoms in infants or young children by increasing propionate production (especially colonic propionate production) using at least one fucoidylated oligosaccharide and at least one N-acetylated oligosaccharide. Specification 13 / 19 pages 16 CN 121890762 A

[0148] Another objective of the present invention is a pharmaceutical composition comprising at least one fucoidylated oligosaccharide and at least one N-acetylated oligosaccharide for preventing and / or treating allergic symptoms in infants or young children by increasing propionate production (especially colonic propionate production) in infants or young children.

[0149] Another objective of the present invention is to use at least one fucoidylated oligosaccharide and at least one N-acetylated oligosaccharide for preventing and / or treating allergic symptoms in infants or young children by increasing propionate production (especially colonic propionate production) in infants or young children.

[0150] Another object of the present invention relates to a method for preventing and / or treating allergic symptoms in an infant or young child by increasing propionate production (especially colonic propionate production) in the infant or young child, the method comprising administering to the infant or young child a nutritional composition comprising at least one fucoidylated oligosaccharide and at least one N-acetylated oligosaccharide.

[0151] The foregoing different embodiments, details and examples in the specification (e.g., relating to the type and content of oligosaccharides, nutritional compositions, administration, target populations, etc.) are also applicable to all these other objects.

[0152] Examples

[0153] The following examples illustrate some specific embodiments of compositions for use according to the 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.

[0154] Example 1

[0155] Table 1 below gives examples of the composition of a nutritional composition (e.g., infant formula) according to the invention. This composition is given by way of example only. Instruction manual, pages 14 / 19, 17 CN 121890762 A

[0156]

[0157] Table 1: Examples of the composition of nutritional compositions (e.g., infant formula) according to the present invention.

[0158] Example 2 Instruction manual 15 / 19 pages 18 CN 121890762 A

[0159] Study description

[0160] Five-week-old female BALB / cByJ CRL mice from Charles River were divided into several groups and fed for 6 weeks according to the following protocol: - Week 1: All groups were fed a low-fiber diet (composition detailed in Table 2) - Week 2 to 6: Control group (Group A): Low-fiber diet (same as Week 1) Test group (Group B to Group D): Low-fiber diet (same as Week 1), supplemented with 5% test fiber by weight (5% of the total low-fiber diet was replaced by 5% test fiber) Instruction manual 16 / 19 pages 19 CN 121890762 A

[0161] Table 2: Composition of the low-fiber diet

[0162] The following fiber was tested: HMO = human milk oligosaccharide. 2FL+LNnT was tested at a weight ratio of 1:1.

[0163] PDX = Polydextrose

[0164] Pectin

[0165] Table 3 provides a summary of the different test groups and diets.

[0166]

[0167] Table 3: Test groups and diets of this study

[0168] After 6 weeks, animals in 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: propionate, butyrate, valerate, and acetate.

[0169] Measurements were performed based on the following protocol: SCFAs in acidic solutions (pH 2.0 to 3.0) were separated on a GLC column coated with a polar stationary phase. This allowed for minimal sample preparation (no derivatization) and simple, basic FID detection. Any residual bacterial activity was inactivated using an acidic phosphate buffer containing HgCl2 and SCFAs were extracted from the cecum using an internal standard (2,2-dimethylbutyrate) for GLC analysis. After centrifugation, the supernatant, after sterile filtration, was prepared for GLC analysis. SCFA was measured simultaneously.

[0170] Median ratios were calculated to compare the effects of diets rich in different fibers on SCFA production.

[0171] It was found

[0172] that diets rich in HMOs significantly increased propionate production (see Figure 1). Propionate production increased by approximately 69% compared to the positive control. It increased by 73% and 75% compared to pectin and PDX, respectively.This is quite surprising, as 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, manual 17 / 19 pages 20 CN 121890762 A production).

[0173] Figure 2 shows the ratio of the median of each tested SCFA in each fiber-rich diet to the median of the positive control diet (i.e., low-fiber diet only). A ratio of 1 (black line) indicates no difference between the fiber-rich diet and the control diet. 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.

[0174] Diets rich in PDX and pectin induced less release of various SCFAs. Conversely, diets rich in HMO induced more propionate release than low-fiber diets. The HMO-rich diet was the only one that promoted propionate release, showing a very large difference compared to other types of SCFAs and other tested fibers.

[0175] The inventors were therefore surprised to find that mice fed with a composition containing at least one fucosylated oligosaccharide and at least one N-acetylated oligosaccharide had significantly higher cecal (and therefore colonic) propionate production.

[0176] Due to the known properties of propionate, particularly in the prevention and treatment of allergic reactions, compositions containing at least one fucosylated oligosaccharide and at least one N-acetylated oligosaccharide would therefore be effective for the prevention and / or treatment of allergic symptoms in infants or young children.

[0177] Example 3

[0178] Method: Female Balb / c mice aged 5 to 8 weeks were given 50-200 µL of Aspergillus allergen extract for epidermal application to induce allergy. A small portion of the back of the mice was shaved.A sterile gauze patch (1×1 cm) containing the allergen was fixed to the skin using a bio-occlusive transparent dressing and a bandage. The patch was left on the skin for a 7-day sensitization period until it detached or was removed on day 8. This process was repeated twice, with a 2-week rest period in between.

[0179] A few days after the last sensitization, mice were exposed to 100 µL of the allergen by applying one drop of the allergen to each nostril.

[0180] HMO (more specifically a 2:1 mixture of 2 FL and LNnt) was incorporated into the low-fiber diet of the HMO group up to 5%. The volume and calories of the control diets of the other groups were adjusted with maltodextrin and cellulose.

[0181] The diet was started 3 weeks before the first sensitization and continued throughout the experiment. Feces were collected 3 weeks after feeding and before the first sensitization occurred. At harvest, cecum and blood were collected, and immunoglobulins were measured by ELISA as described previously by Holvoet et al. (Holvoet S. Allergy 2016 Dec;71(12):1753–1761): Specific IgE levels were quantified as follows: Aspergillus allergen (Greer Laboratories) was resuspended in distilled water containing antiprotease (Sigma) and Triton X100 (Sigma). The solution was sonicated on ice for 5 minutes and centrifuged at 1000 rpm for 10 minutes. The supernatant was collected, and total protein content was measured using the BCA Protein Assay Kit (Thermo Scientific; Zug, Switzerland) according to the manufacturer's protocol. Following the manufacturer's protocol, total Aspergillus protein was labeled using digoxigenin-3-O-methylcarbonyl-e-aminohexanoic acid-N-hydroxysuccinimide ester (DIG; Roche, Basel, Switzerland). 96-well plates were coated with 100 µL of carbonate buffer containing 2 µg / mL rat anti-mouse IgE (BD-Bioscience) and incubated overnight at 4°C. The plates were washed with 0.05% Tween PBS and blocked for 1 h at room temperature with 200 µL PBS containing 10% fetal bovine serum (FCS; Bioconcept). The diluted serum was incubated for 2 h at room temperature. After washing, the DIG-labeled antigen was incubated for 90 min at room temperature. The plates were washed and incubated for 1 h at room temperature with HRP-labeled anti-DIG antibody (Roche, Switzerland). The color was developed using TMB, and the reaction was stopped using 1N HCl (Merck).Read the instruction manual pages 18 / 19, 21 CN 121890762 A at 450 nm. Take the plate and the results are expressed as OD.

[0182] Specific IgE levels measured in mice from different experimental groups are reported in Figure 3.

[0183] Colonic propionate levels were measured as follows. After ionization with an electron bombardment source, propionate present in the cecum and feces of mice fed HMOs was analyzed by gas chromatography-mass spectrometry (GC-MS) using an Agilent Technologies 6890 Series XL MSD 5975 C (Santa Clara, CA). Briefly, the cecum and feces were first homogenized in a solution of orthophosphate and mercuric acetate D3 corresponding to 4 times the fecal weight. The sample was then homogenized with glass beads for 20 minutes using a multivortex. The preparation was centrifuged at 2,000 g for 15 minutes at 4 °C. The supernatant was collected and weighed. Add 10 μL of 37% HCl and 3 mL of chloroform, and homogenize for 20 minutes. After centrifugation at 1,800 g for 10 minutes at 4 °C, remove the supernatant. Add 10 µL of tert-butyldimethylsilylimidazole, and heat the sample at 60 °C for 30 minutes, then cool and inject. Freeze-dry to determine the humidity, and the humidity content was used to calculate the SCFA per gram of dry material.

[0184] Specific SCFA levels measured in mice from different experimental groups are reported in Figures 4 and 5.

[0185] Results: Figures 4 and 5 show a significant increase in propionate when mice were supplemented with HMO. Based on IgE measurements, specific IgE levels in these mice were significantly lower than in the positive control that did not receive HMO supplementation, highlighting the association between increased colonic propionate and reduced allergic sensitization.Instruction Manual 19 / 19 Page 22 CN 121890762 A Figure 1 Figure 2 Instruction Manual Drawings 1 / 3 Page 23 CN 121890762 A Figure 3 Figure 4 Instruction Manual Drawings 2 / 3 Page 24 CN 121890762 A Figure 5 Instruction Manual Drawings 3 / 3 Page 25 CN 121890762 A Abstract The present invention relates to a composition comprising human milk oligosaccharides for use in infants or young children to prevent or treat allergic reactions, the composition comprising at least one fucosylated oligosaccharide and at least one N-acetylated oligosaccharide, for use in preventing and / or treating allergy reaction symptoms in infants or young children, by increasing propionate production, in said infants or young children.

Claims

1. A nutritional composition comprising at least one fucoidylated oligosaccharide and at least one N-acetylated oligosaccharide for preventing and / or treating allergic symptoms in an infant or young child by increasing propionate production in the infant or young child.

2. The nutritional composition according to claim 1, wherein the nutritional composition is used to prevent and / or treat allergic symptoms in an infant or young child by increasing the production of colonic propionate in the infant or young child.

3. A nutritional composition for use according to any one of the preceding claims, wherein the fucosylated oligosaccharide is selected from the list consisting of: 2'-fucosylvose, 3'-fucosylvose, difucosylvose, lactose-N-fucopentose I, lactose-N-fucopentose II, lactose-N-fucopentose III, lactose-N-fucopentose V, lactose-N-fucohexose, lactose-N-difucohexose I, fucosylvose-N-hexose, fucosylvose-N-neohexose I, fucosylvose-N-neohexose II, difucosylvose-N-hexose I, difucosylvose-N-neohexose I, difucosylvose-N-neohexose II, fucosylvose-P-lactose-N-hexose, and any combination thereof.

4. A nutritional composition for use according to any one of the preceding claims, wherein the fucoidylated oligosaccharide comprises a 2' fucoidyl epitope.

5. A nutritional composition for use according to any one of the preceding claims, wherein the fucoidylated oligosaccharide is 2'-fucosylated lactose (2'FL).

6. A nutritional composition for use according to any one of the preceding claims, wherein the N-acetylated oligosaccharide is selected from the list of the following: lactose-N-tetrasaccharide (LNT), lactose-N-neotetrasaccharide (LNnT), and any combination thereof.

7. A nutritional composition for use according to any one of the preceding claims, wherein the N-acetylated oligosaccharide is lactose-N-neotetrasaccharide (LNnT), p-lactose-N-neohexose (p-LNnH), or any combination thereof, preferably wherein the N-acetylated oligosaccharide is lactose-N-neotetrasaccharide (LNnT).

8. A nutritional composition for use according to any one of the preceding claims, comprising 2'-fucosyllactose (2'FL) and lactose-N-neotetrasaccharide (LNnT), or comprising a mixture of oligosaccharides consisting of 2'-fucosyllactose (2'FL) and lactose-N-neotetrasaccharide (LNnT).

9. A nutritional composition for use according to any one of the preceding claims, wherein the weight ratio of the fucoidylated oligosaccharide to the N-acetylated oligosaccharide is 1:10 to 12:1, such as 1:2 to 2:

1.

10. A nutritional composition for use according to any one of the preceding claims, wherein the at least one fucoidylated oligosaccharide and the at least one N-acetylated oligosaccharide are present in an amount of 0.1% to 10% by weight, such as 0.5% to 7% by weight or 1% to 5% by weight, of the nutritional composition.

11. A nutritional composition for use according to any one of the preceding claims, comprising at least one other oligosaccharide and / or fiber and / or human milk oligosaccharide precursor, selected from the list including: GOS, FOS, XOS, inulin, polydextrose, sialylated oligosaccharides, N-acetylated oligosaccharides, sialic acid, fucose, and any combination thereof.

12. A nutritional composition for use according to any one of the preceding claims, wherein it does not contain any sialylated oligosaccharides.

13. A nutritional composition for use according to any one of the preceding claims, said composition further comprising at least one probiotic, said probiotic being present in an amount of 10... 3 cfu / g of the composition up to 10 12 The composition described in cfu / g (dry weight) 14. A nutritional composition for use according to any one of the preceding claims, wherein the nutritional composition is infant formula, stage 1 infant formula, stage 2 infant formula or follow-up formula, baby food, infant cereal composition, fortifier or supplement.

15. A nutritional composition for use according to any one of the preceding claims, wherein the infant or young child is at risk of developing an allergic reaction, wherein the allergic reaction is selected from the group consisting of: allergic sensitization, food allergy, atopic dermatitis or eczema, asthma, wheezing, allergic rhinitis, rhinoconjunctivitis, eosinophilic esophagitis, hypersensitivity, allergy, urticaria, angioedema, food intolerance; and allergic reactions derived from allergenic proteins in food, pollen, animal dander, house dust mites, or venom.

16. A nutritional composition for use according to any one of the preceding claims, wherein the nutritional composition is a synthetic nutritional composition.

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