Composition for preventing and / or treating skin disorders and diseases

Abstract

The present invention discloses a composition comprising oligosaccharides for use in the prevention and / or treatment of skin conditions and / or skin diseases by increasing SCFAs, in particular propionate and butyrate of the colon. The skin disease is in particular atopic dermatitis.

Description

[0001] This application is a divisional application of PCT application PCT / EP2017 / 051582, filed on January 26, 2017, entitled "Composition for the Prevention and / or Treatment of Skin Conditions and Skin Diseases". The date of entry into the Chinese national phase of the PCT application was July 25, 2018, and the application number was 201780008084.5.

[0002] This invention relates to compositions for the prevention and / or treatment of skin conditions and diseases (especially atopic dermatitis), such as those promoting skin health. Background Technology

[0003] Atopic dermatitis is a chronic, itchy skin condition that is common in children but can occur at any age. It is also known as eczema or atopic eczema.

[0004] The development of atopic dermatitis follows this process. Individuals with sensitive skin respond to certain triggers, resulting in large patches of rash. These triggers vary from person to person. For infants or young children, common triggers include other potentially allergenic ingredients in cow's milk and infant formula, such as wheat or soy. Atopic dermatitis can develop into a vicious cycle. Some triggers irritate a child's skin, causing redness and inflammation. This itching leads the child to scratch, worsening the dermatitis. The skin's protective outer layer is damaged, making the affected area more sensitive to irritants and more prone to dryness. The infant remains exposed to the trigger that initially caused these adverse reactions. The rash further develops, creating a vicious cycle.

[0005] There is no known single cause for atopic dermatitis, and it may involve allergens or non-allergens. Atopic dermatitis may present with more than one symptom. Various theories have been proposed to explain the underlying pathogenesis of this disease. Currently, the roles of filaggrin gene mutations, skin cell (keratinocyte) defects, the immune system, skin surface microbiota (bacteria, viruses, and yeast), and many other factors are being investigated.

[0006] People of all ages, those at risk of allergic reactions, or those with an allergic constitution (and therefore prone to illness) may suffer from various skin conditions and diseases.

[0007] Because infants, toddlers, and young children grow rapidly with fast cell division and proliferation, their skin is delicate and prone to skin diseases. Therefore, these skin conditions and diseases (especially atopic dermatitis) have a particularly severe impact on infants, toddlers, and young children. An increasing number of infants with allergic reactions are showing signs of allergies despite no family history of such reactions.

[0008] Short-chain fatty acids (SCFAs) are produced, in particular, by the fermentation of dietary fiber in the colon by microorganisms. Studies have shown that high abundance of SCFA-producing bacteria (especially butyrate) is associated with milder atopic eczema in infants (Nylund et al., " 特应性疾病的严重程度与肠道微生物群呈负相关 多样性和产丁酸细菌 “The severity of atopic diseases is inversely correlated with gut microbiota diversity and butyrate-producing bacteria,” European Journal of Allergy and Clinical Immunology, 2015 (Nylund et al., “The severity of atopic diseases is inversely correlated with gut microbiota diversity and butyrate-producing bacteria,” European Journal of Allergy and Clinical Immunology, 2015).

[0009] Therefore, increasing SCFA is a highly attractive approach for the prevention and / or treatment of skin conditions and diseases (especially atopic dermatitis), such as promoting skin health.

[0010] However, the taste of oral SCFAs may be unpalatable to some.

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

[0012] From the above, it can be seen that there is a need for an effective nutritional composition to promote skin health, especially for infants and young children, and that such an effective nutritional composition can be applied conveniently and safely.

[0013] Skin conditions or diseases (such as atopic dermatitis) require non-pharmacological interventions to improve, which are suitable for vulnerable individuals such as infants or babies.

[0014] A long-term effect is needed in reducing the frequency, incidence, severity, and / or duration of such skin conditions and diseases. An effect that becomes measurable "later in life," particularly in the years following the intervention, is also required.

[0015] Food interventions are needed for infants, young children, and children with or without allergic reactions to reduce the manifestations of allergic reactions, especially skin manifestations.

[0016] Such interventions are needed to maintain or improve skin health. Summary of the Invention

[0017] The inventors have surprisingly discovered that the application of a mixture of specific oligosaccharides is particularly effective in the prevention and / or treatment of skin conditions and diseases, and especially in the prevention and / or treatment of atopic dermatitis, and / or in promoting skin health.

[0018] The compositions according to the invention are advantageously nutritional compositions.

[0019] Therefore, in a first aspect, the present invention provides a composition comprising at least one fucoidylated oligosaccharide and at least one N-acetylated oligosaccharide for the prevention and / or treatment of skin conditions and skin diseases, preferably atopic dermatitis, in infants or young children by increasing the production of propionate, particularly propionate in the colon, in the body of such infants or young children.

[0020] In a particularly advantageous embodiment, the nutritional composition according to the invention comprises 2'-fucosyl lactose (2-FL) and lactate-N-neotetrasaccharide (LNnT) in a weight ratio of 1:10 to 12:1, and particularly 2FL:LNnT.

[0021] In a second aspect, the present invention provides a composition comprising at least one N-acetylated oligosaccharide, at least one galactooligosaccharide and at least one sialylated oligosaccharide, for the prevention and / or treatment of skin conditions and skin diseases, preferably atopic dermatitis, in infants or young children by increasing the production of SCFA in the colon (especially colonic SCFA production) in such infants or young children.

[0022] In one embodiment, the nutritional composition according to the invention comprises an oligosaccharide mixture comprising 0.1% to 4.0% by weight of N-acetylated oligosaccharides, 92.0% to 99.5% by weight of galactooligosaccharides, and 0.2% to 4.0% by weight of sialylated oligosaccharides.

[0023] The composition comprises three different types of uses as a nutritional composition. In the first case, the individual, and particularly the infant, is healthy and has no risk of allergic reaction because there is no history of allergic reactions in their family. In the second case, the individual, and particularly the infant, is healthy but has a risk of allergic reactions due to a family history of allergic reactions. In the third case, the individual, and particularly the infant, has an allergic reaction and is therefore ill. The first case is the preferred target group according to the invention.

[0024] The present invention also provides the following specific embodiments 1-15.

[0025] 1. A composition comprising a mixture of oligosaccharides for preventing and / or treating skin conditions and / or skin diseases, preferably atopic dermatitis, in infants or young children by increasing the production of SCFAs.

[0026] 2. The composition according to the foregoing embodiments, wherein the oligosaccharide mixture comprises at least one N-acetylated oligosaccharide, at least one galactooligosaccharide, and at least one sialylated oligosaccharide.

[0027] 3. The composition according to any one of the foregoing embodiments, wherein the oligosaccharide mixture comprises 0.1% to 4.0% by weight of N-acetylated oligosaccharides, 92.0% to 99.5% by weight of the galactooligosaccharides, and 0.2% to 4.0% by weight of the sialylated oligosaccharides.

[0028] 4. The composition according to any one of the foregoing embodiments, wherein the composition comprises at least 0.01% by weight of N-acetylated oligosaccharide, at least 2.0% by weight of galactooligosaccharide and at least 0.02% by weight of sialylated oligosaccharide.

[0029] 5. The composition according to any one of the foregoing embodiments, wherein the composition further comprises a prebiotic selected from human milk oligosaccharides, fructooligosaccharides, inulin, xylooligosaccharides, polydextrose, or any combination thereof.

[0030] 6. The composition according to any one of the foregoing embodiments, wherein the composition further comprises probiotics, wherein the probiotics are selected from the following probiotic strains: Lactobacillus acidophilus ( 嗜酸乳杆菌 ), Lactobacillus salivarius ( 唾液乳杆菌 Lactobacillus rhamnosus ( 鼠李糖乳杆菌 ), Lactobacillus paracasei ( 副干酪乳杆菌 Lactobacillus casei ( 干酪乳杆菌 Lactobacillus johnsonii ( 约氏乳杆菌 Lactobacillus plantarum ( 植物乳杆菌 ), Lactobacillus fermentum ( 发酵乳杆菌 Lactobacillus () 乳酸乳杆菌 Lactobacillus delbrueckii (), 德氏乳杆菌 Lactobacillus helveticus ( 瑞士乳杆菌 Lactobacillus bulgaricus () 保加利亚乳杆菌 ), Lactococcus lactis ( 乳酸乳球菌 Lactococcus lactis diacetyl subsp. 双乙酰乳球菌 Lactococcus lactis subsp. milk fat () 乳脂乳球菌 ), Streptococcus salivarius ( 唾液链球菌 Streptococcus thermophilus () 嗜热链球菌 ), Bifidobacterium lactis ( 乳酸双歧杆菌 Bifidobacterium animalis ( 动物双歧杆菌 ), Bifidobacterium longum ( 长双歧杆菌 ), Bifidobacterium breve 短双歧杆菌 ), Bifidobacterium infantis ( 婴儿双歧杆菌 ), or Bifidobacterium adolescentis ( 青春双歧杆菌 (or any mixture thereof)

[0031] 7. The composition according to any one of the foregoing embodiments, characterized in that the oligosaccharide mixture is derived from one or more animal milks, such as cow's milk, goat's milk, buffalo milk, or camel milk.

[0032] 8. The composition according to any one of the foregoing embodiments, wherein the SCFA is colonic propionate and / or butyrate.

[0033] 9. The composition according to embodiment 1, wherein the oligosaccharide mixture comprises at least one fucoidylated oligosaccharide and at least one N-acetylated oligosaccharide.

[0034] 10. The composition according to any one of embodiments 1 or 9, wherein the composition comprises 2'-fucosyllactose (2'FL) and lactose-N-neotetrasaccharide (LNnT), or comprises a mixture of oligosaccharides consisting of 2'-fucosyllactose (2'FL) and lactose-N-neotetrasaccharide (LNnT).

[0035] 11. The composition according to any one of embodiments 1, 9 or 10, wherein the composition comprises at least one additional oligosaccharide and / or one or more cellulose and / or one or more human milk oligosaccharide precursors, wherein the at least one additional oligosaccharide and / or one or more cellulose and / or one or more human milk oligosaccharide precursors are selected from GOS, FOS, XOS, inulin, polydextrose, sialylated oligosaccharides, sialic acid, fucose and any combination thereof.

[0036] 12. The composition according to any one of embodiments 1, 9, 10 or 11, wherein the composition does not contain any sialylated oligosaccharides.

[0037] 13. The composition according to any one of embodiments 1, 9, 10, 11 or 12, wherein the SCFA is a colonic propionate.

[0038] 14. The composition according to any one of embodiments 1 to 13, wherein the composition is a nutritional composition.

[0039] 15. The composition according to any one of embodiments 1 to 14, wherein the composition is a synthetic nutritional composition. Attached Figure Description

[0040] Figure 1 The figures indicate propionate production in the cecum of mice fed a low-fiber diet and a low-fiber diet rich in 5% of different experimental fibers.

[0041] Abbreviations: Pos ctr = positive control; HMO = human milk oligosaccharide, the tested 2FL+LNnT weight ratio was 1:1; PDX = polydextrose.

[0042] Figure 2 This represents the ratio of the median SCFA of each fiber-rich diet to the median of the positive control diet.

[0043] Abbreviations: Ctrl pos = positive control; HMO = human milk oligosaccharide, the tested 2FL+LNnT weight ratio was 1:1; PDX = polydextrose.

[0044] Figure 3 The results indicate butyrate production in the cecum of mice fed a low-fiber diet and a low-fiber diet rich in 5% of different experimental fibers.

[0045] Abbreviations: Pos ctr = positive control; BMO = milk oligosaccharide; PDX = polydextrose.

[0046] Figure 4 The figures indicate propionate production in the cecum of mice fed a low-fiber diet and a low-fiber diet rich in 5% of different experimental fibers.

[0047] Abbreviations: Pos ctr = positive control; BMO = milk oligosaccharide; PDX = polydextrose.

[0048] Figure 5 This represents the ratio of the median SCFA of each fiber-rich diet to the median of the positive control diet.

[0049] Abbreviations: Ctrl pos = positive control; BMO = milk oligosaccharide; PDX = polydextrose. Detailed Implementation

[0050] As used herein, the following terms have the following meanings.

[0051] The term "infant" refers to a child under 12 months of age.

[0052] The term "preschooler" refers to children aged between one and three years old, also known as toddlers.

[0053] "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.

[0054] "Vaginal delivery infants or toddlers" refers to infants or toddlers delivered vaginally rather than via cesarean section.

[0055] "Premature infant" refers to a baby or toddler born before full term. It usually refers to a baby or toddler born before 36 weeks of gestation.

[0056] The term "nutritional composition" refers to a composition that supplies nutrients to an individual. This nutritional composition is typically administered orally or intravenously. It may include 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.

[0057] 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.

[0058] 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 or a mixture containing components obtained by chemical and / or biological methods (including, for example, purification and separation methods), wherein the mixture may be chemically identical to compounds naturally present in mammalian milk, or the mixture may contain components identical to components naturally present in mammalian milk (i.e., the synthetic nutritional composition is not breast milk).

[0059] As used herein, the term "infant formula" refers to foods specifically designed to provide nutrition for infants in the first few months of life and that meet 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 specialties (including foods for specific medical purposes). The term "infant formula" encompasses both "Stage 1 infant formula" and "follow-up formula" or "follow-up formula."

[0060] Follow-up infant formula or "follow-up formula" is offered starting from the 6th month. Infant formula constitutes the main liquid element in the gradually diversifying diet of this group.

[0061] The term "infant food" refers to food specifically designed to provide nutrition for infants or toddlers under one year old.

[0062] The term "infant cereal composition" refers to food specifically designed to provide nutrition for infants or toddlers under one year of age.

[0063] The term "fortifier" refers to a liquid or solid nutritional composition suitable for mixing with breast milk or infant formula.

[0064] The term "weaning period" refers to the period during which other foods are used to replace breast milk or infant formula in the diet of infants or young children.

[0065] 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.

[0066] The expressions "in later life" and "in later stages of life" are used interchangeably. They refer to effects measured on individuals (infants or toddlers) a few weeks, months, or years after birth, such as after 6 months, 8 months, 10 months, 1 year, 2 years, preferably 4 years, more preferably 5 years, even more preferably 7 years, or even older, comparing the effect to the average observations of individuals of the same age. Preferably, it refers to effects observed at least 1 year after birth or at least 2, 5, 7, 10, or 15 years after birth. Therefore, the expression "in later life" could refer to observations during infancy, childhood, adolescence, or adulthood. Preferably, it refers to observations during childhood, adolescence, or adulthood.

[0067] The term "health disorder" encompasses any health condition and / or disease and / or functional disorder that affects an individual organism.

[0068] The term "SCFA" refers to short-chain fatty acids.

[0069] The statement "increased SCFA production" means that individuals fed the nutritional composition according to the invention have higher levels of systemic and / or colonic SCFAs compared to those fed a standard composition and / or a standard composition supplemented with common fiber (such as polydextrose or pectin). SCFAs can be propionate, butyrate, valerate, and / or acetate. In a specific embodiment of the invention, it is butyrate and / or propionate. SCFA production can be measured using techniques known to those skilled in the art, such as gas-liquid chromatography.

[0070] The statement "increased propionate production in the colon" means that, when measuring the amount of propionate in the colon (or large intestine) or a portion thereof (such as the cecum), the amount in individuals fed the nutritional composition according to the invention is higher than the amount in individuals fed the standard composition and / or the standard composition supplemented with common fiber (such as polydextrose or pectin). Propionate production can be measured using techniques known to those skilled in the art, such as by gas-liquid chromatography.

[0071] "Breast milk" should be understood as the mother's milk or colostrum.

[0072] The term "oligosaccharide" refers to carbohydrates with a degree of polymerization (DP) ranging from 2 to 20 (inclusive), but excluding lactose. In some embodiments of the invention, the DP of the carbohydrate is in the range of 3 to 20.

[0073] The expressions “at least one N-acetylated oligosaccharide, one galactooligosaccharide and one sialylated oligosaccharide” and “at least one N-acetylated oligosaccharide, at least one galactooligosaccharide and at least one sialylated oligosaccharide” are used interchangeably.

[0074] The terms "mixture of oligosaccharides" or "mixture of oligosaccharides" are used interchangeably. An oligosaccharide mixture according to one aspect of the invention comprises at least one N-acetylated oligosaccharide, at least one galactooligosaccharide, and at least one sialylated oligosaccharide. The mixture can be made from one or more of these different types of oligosaccharides, i.e., one or more N-acetylated oligosaccharides, one or more galactooligosaccharides, and one or more sialylated oligosaccharides. In some advantageous embodiments, the oligosaccharide in the oligosaccharide mixture is bovine milk oligosaccharide (or BMO).

[0075] The term "HMO" or "HMOs" refers to one or more human milk oligosaccharides. These carbohydrates are resistant to enzymatic hydrolysis by digestive enzymes such as the pancreas and / or brush border, suggesting 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 early infant and toddler development, 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 and diverse array of oligosaccharides in human milk; over 130 such structures have been identified to date. Almost all oligosaccharides have a lactose molecule at the reducing end, and the non-reducing terminal positions 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).

[0076] "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-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.

[0077] 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.

[0078] The phrase "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-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-decansaccharide.

[0079] 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”.

[0080] "HMO precursors" are key compounds used in the production of HMOs, such as sialic acid and / or fucose.

[0081] "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).

[0082] The terms "galactooligosaccharide" 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 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, "galactooligosaccharide" and "GOS" also comprise oligosaccharides (i.e., disaccharides) containing one galactose molecule and one glucose molecule linked by β-1,2, β-1,3, or β-1,6 bonds.

[0083] The nutritional compositions of the present invention may be in solid form (e.g., powder) or liquid form. The amounts of various ingredients (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 follow-up and subsequent infant formula, or infant cereal products, or any other formulations specifically designed for infant nutrition).

[0084] The terms "prebiotics" and "fiber" are used interchangeably. They refer 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 ( Gibson GR, Roberfroid Mb. Dietary regulation of the human colonic microbiota: introducing the concept of prebiotics, *Journal of Nutrition*, 1995, Vol. 125, pp. 1401-12.

[0085] 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 Food Sci. Technol. 1999:10 107-10 (Salminen S., Ouwehand A., Benno Y. et al., "How to Define Probiotics", Trends in Food Science and Technology, 1999, Vol. 10, pp. 107-110)). Microbial cells are generally bacteria or yeast.

[0086] The term "cfu" should be understood as colony-forming unit.

[0087] Unless otherwise specified, all percentages are by weight.

[0088] The term "skin disease" refers to eczema or atopic dermatitis and other related skin problems.

[0089] The terms “eczema” and “atopic dermatitis” (AD) are used interchangeably in this invention. Eczema is an inflammatory, chronically relapsing, non-contagious, and itchy (pruritic) skin disorder. Patients with eczema have skin that is prone to overreacting to irritants, food, and environmental allergens, becoming red, flaky, and extremely itchy (becoming reactive skin). It is also susceptible to bacterial infections of the skin. In individuals, the skin on the flexural surfaces of joints is often affected. Symptoms may vary from person to person, but they typically present as red, inflamed, and itchy rashes that can rapidly develop into raised and painful bumps. The skin tends to become more sensitive and may thicken, crack, dry out, or scale. Dysfunction of the epidermal barrier is considered the pathophysiological explanation for atopic dermatitis. Alterations in certain genes encoding structural proteins, epidermal proteases, and protease inhibitors can predispose to epidermal barrier defects and increase the risk of developing atopic dermatitis. The strong association between genetic barrier defects and environmental damage to the barrier and atopic dermatitis suggests that epidermal barrier dysfunction is a major factor in the development of this disease.

[0090] The term "prevention and / or treatment of skin diseases" refers to the prevention and reduction of the frequency and / or incidence and / or severity and / or duration of skin diseases (i.e., atopic dermatitis and other related skin problems, especially atopic dermatitis). Incidence is related to the number of any skin disease. Frequency is related to the number of the same skin disease. This prevention covers a reduction in the frequency and / or severity of the stated skin disease in later life. The term "in later life" covers the effect after the intervention ends. The effect "in later life" can be preferably an effect 2 to 4 weeks, 2 to 12 months, or 1 year (e.g., 2, 5, 10 years) after the intervention ends.

[0091] The term "dermatitis" refers to a condition that irritates, clogs, or inflames the skin. Dermatitis can cause symptoms such as redness, swelling, burning, and itching.

[0092] The term "prevention and / or treatment of skin conditions" refers to promoting skin health and / or preventing skin dehydration and / or enhancing skin hydration and / or strengthening skin barrier function and / or reducing rashes, roughness, and / or dryness. This prevention also includes establishing visible or hidden phenotypes that are associated with a reduction in the frequency, incidence, severity, and / or duration of the skin conditions later in life. "Barrier function," "skin barrier protection," or "skin barrier function" is the function of the (epidermal) barrier to prevent the migration of agents, allergens, microorganisms, or water through the epidermal layer.

[0093] As used herein, the term "enhanced skin barrier function" refers to strengthening the skin's barrier function. This reduces the migration of reagents, allergens, microorganisms, or water through the epidermal layer. Specifically, this enhancement of barrier function can be mediated by reducing the intercellular spaces between epidermal cell layers. This can be achieved by increasing the number and / or quality of tight junctions between epidermal cells and / or increasing the complexity of epidermal differentiation protein expression (such as filaggrin, small proline-rich proteins, NICE, epidermal proteins, and nautiloid proteins).

[0094] Furthermore, in the context of this invention, the terms "comprising" or "including" do not exclude other possible elements. The compositions mentioned in 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 described herein, and any other or optional (or as required) ingredients, components, or limitations described herein.

[0095] 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.

[0096] The invention will now be described 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.

[0097] The first aspect of the present invention

[0098] Therefore, in a first aspect, the present invention 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 skin conditions and / or skin diseases (preferably atopic dermatitis) in infants or young children by increasing propionate production in the colon of such infants or young children.

[0099] 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 propionate production in an individual and can therefore be used to prevent and / or treat skin conditions and skin diseases (preferably atopic dermatitis) in infants or young children by increasing propionate production in the colon.

[0100] The nutritional composition of the present invention comprises at least one fucoidan. One or more types of fucoidan may be present. One or more fucoidan may be selected from 2'-fucosylvose, 3'-fucosylvose, difucosylvose, 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, fucoidan-N-hexose, and fucoidan. Glycosyl-lactose-N-neohexoses (e.g., fucyl-lactose-N-neohexose I, fucyl-lactose-N-neohexose II), difucosyl-lactose-N-hexose I, difucosyl-lactose-N-neohexose, difucosyl-lactose-N-neohexose I, difucosyl-lactose-N-neohexose II, fucyl-para-lactose-N-hexose, trifucosyl-para-lactose-N-hexose I, and any combination thereof.

[0101] In some specific embodiments, the fucoidylated oligosaccharide comprises a 2'-fucosylation epitope. The fucoidylated oligosaccharide may be selected from, for example, 2'-fucosylation lactose, difucosylation lactose, lactose-N-fucopentose, lactose-N-fucohexose, lactose-N-difucohexose, fucosylation lactose-N-hexose, fucosylation lactose-N-neohexose, difucosylation lactose-N-hexose, difucosylation lactose-N-neohexose, difucosylation lactose-N-neohexose, fucosylation p-lactose-N-hexose, and any combination thereof.

[0102] 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 one specific embodiment, no other type of fucosylated oligosaccharide exists besides 2'-fucosylated lactose; that is, the nutritional composition of the invention comprises only 2'-fucosylated lactose as a fucosylated oligosaccharide.

[0103] One or more fucosylated oligosaccharides can be isolated from natural sources such as animal milk using chromatography or filtration techniques. Alternatively, fucosylated oligosaccharides can be prepared using biotechnological means, such as enzyme-based fermentation or microbial fermentation, employing specialized fucosyltransferases and / or fucosidases. 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.

[0104] 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 compositions of the present invention comprise both LNT and LNnT, wherein the LNT:LNnT ratio is between 5:1 and 1:2, or 2:1 to 1:1, or 2:1.2 to 2:1.6.

[0105] In a preferred embodiment, the nutritional composition according to the invention comprises lactose-N-neotetrasaccharide (LNnT). In a specific embodiment, no other type of N-acetylated oligosaccharide is contained other than lactose-N-neotetrasaccharide (LNnT), i.e., the nutritional composition of the invention contains only lactose-N-neotetrasaccharide (LNnT) as an N-acetylated oligosaccharide.

[0106] 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 ketohexoses (e.g., fructose) into N-acetylated hexosamine or oligosaccharides containing N-acetylated hexosamine, 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. N-acetylated oligosaccharides can also be produced through biotechnological means based on microbial fermentation technology.

[0107] In a particularly advantageous embodiment of the invention, the nutritional composition comprises 2'-fucosylated lactose (2FL) and lactose-N-neotetrasaccharide (LNnT).

[0108] 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.

[0109] 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.

[0110] The total amount of fucoidylated oligosaccharides and N-acetylated oligosaccharides present in the nutritional composition of the present invention may be from 0.1% to 10% by weight of the nutritional composition before reconstitution with water, such as from 0.5% to 7% by weight, or from 1% to 5% by weight. For the reconstituted ready-to-drink formulated food, the target ingredient is 0.01% to 1%, more preferably from 0.05% to 0.7% or from 0.1% to 0.5%.

[0111] The nutritional composition of the present invention may, for example, comprise: - Fucosylated oligosaccharides with a total dry weight of 0.2-5 g / L, for example 0.5-4.5 g / L or 1-4 g / L of the composition, or a total dry weight of 0.13-3.48 g / 100 g, for example 0.34-3.13 g / 100 g or 0.69-2.78 g / 100 g of the composition; and / or - A total amount of 0.05-5 g / L on dry weight, for example, 0.1-2 g / L or 0.1-1 g / L of the composition, or a total amount of 0.03-3.48 g / 100 g, for example, 0.07-1.4 g / 100 g or 0.07-0.7 g / 100 g of N-acetylated oligosaccharides.

[0112] The nutritional composition according to the invention may further comprise at least one additional oligosaccharide (i.e., in addition to one or more fucoidylated oligosaccharides and one or more N-acetylated oligosaccharides that are essential to be present in the composition) and / or at least one precursor of fiber and / or at least one human milk oligosaccharide. Another oligosaccharide and / or fiber and / or precursor may be selected from galactooligosaccharides (GOS), fructooligosaccharides (FOS), inulin, xylooligosaccharides (XOS), polydextrose, sialylated oligosaccharides, sialic acid, fucose, and any combination thereof. Their amounts may be between 0% and 10% by weight of the composition.

[0113] In addition to the oligosaccharides contained in the oligosaccharide mixture, suitable commercial products for preparing the nutritional compositions according to the invention include combinations of FOS and inulin, such as those sold by BENEO under the trademark Orafti, or by Tate & Lyle under the trademark STA-LITE. ® Polydextrose for sale.

[0114] In one specific embodiment, the composition according to the invention may comprise sialylated oligosaccharides. One or more sialylated oligosaccharides may be present. The one or more sialylated oligosaccharides 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 between 5:1 and 1:10, or between 3:1 and 1:1, or in the range of 1:1 to 1:10. In some specific embodiments, the sialylated oligosaccharide in the composition is 6'-sialyl lactose (6-SL).

[0115] One or more sialylated oligosaccharides 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 biotechnological means, such as 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. Sialic oligosaccharides can be formed starting with acceptor substrates initially having any degree of polymerization (DP), beginning with DP = 1. Alternatively, sialyl lactose can be produced via chemical synthesis from lactose and free N'-acetylneuraminic acid (sialic acid). Sial lactose is also commercially available, for example, from Kyowa HakkoKogyo in Japan.

[0116] In certain examples, the composition may contain sialylated oligosaccharides in a total amount of 0.05 to 5 g / L, such as 0.1 to 4 g / L, or 0.3 to 2 g / L of the composition on a dry weight basis, or in a total amount of 0.03 to 3.5 g / 100 g, such as 0.1 to 2 g or 0.2 to 1 g / 100 g of the composition.

[0117] In one embodiment, the nutritional composition may further comprise at least one BMO (milk oligosaccharide). In another embodiment, the nutritional composition may additionally comprise an oligosaccharide mixture (“BMO”) 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.

[0118] In a more specific embodiment, the nutritional composition may additionally comprise an oligosaccharide mixture (“BMO”) comprising 0.1% to 4.0% by weight of one or more N-acetylated oligosaccharides, 92.0% to 99.5% by weight of one or more galactooligosaccharides, and 0.2% to 4.0% by weight of one or more sialylated oligosaccharides.

[0119] 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.

[0120] 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.

[0121] 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.

[0122] The compositions according to the invention may contain 0 g to 2.1 g of one or more human milk oligosaccharide precursors per 100 g of composition on a dry weight basis, for example, 0 g to 1.5 g, or 0 g to 0.8 g, or 0 g to 0.15 g of one or more human milk oligosaccharide precursors per 100 g of composition on a dry weight basis.

[0123] The nutritional composition of the present invention may also contain at least one probiotic (or probiotic strain), such as a probiotic strain.

[0124] The most commonly used probiotics are mainly bacteria and yeasts belonging to the following genera: Lactobacillus ( Lactobacillus spp Streptococcus ( .), Streptococcus spp. Streptococcus spp .), Enterococcus spp. Enterococcus spp .), Bifidobacterium spp. Bifidobacterium spp .) and yeast ( Saccharomyces spp .).

[0125] In some specific embodiments, the probiotics are probiotic bacterial strains. In some specific embodiments, they are specifically Bifidobacterium and / or Lactobacillus (…). Lactobacilli ).

[0126] Suitable probiotic strains include Lactobacillus rhamnosus, trademarked LGG, from Valio Oy, Finland. Lactobacillus rhamnosus ATCC 53103, BLIS Technologies Limited, New Zealand, sells Lactobacillus rhamnosus CGMCC1.3724 and Lactobacillus casei under the trade name KI2. Lactobacillus paracasei CNCM I-2116, Lactobacillus johnsonii ( Lactobacillus johnsonii CNCM I-1225, Streptococcus salivarius ( Streptococcus salivariusDSM 13084, Bifidobacterium lactis specially marketed by Christian Hansen company (Denmark) under the trademark Bb 12. Bifidobacterium lactis CNCM 1-3446, Bifidobacterium longum sold by Morinaga Milk Industry Co., Ltd., Japan under the trademark BB536. Bifidobacterium longum ATCC BAA-999, and Bifidobacterium breve sold by Danisco under the trademark Bb-03. Bifidobacterium breve Bifidobacterium breve, sold by Morinaga under the trademark M-16V, and Bifidobacterium infantis, sold by Procter & Gamble Co. under the trademark Bifantis. Bifidobacterium infantis ), and Bifidobacterium breve sold by the Rosell Institute of Biology in Canada under the trademark R0070.

[0127] The nutritional composition according to the invention may contain 10e3 to 10e12 cfu of probiotic strains per gram of composition on a dry weight basis, more preferably containing probiotic strains between 10e7 and 10e12 cfu, for example between 10e8 and 10e10 cfu.

[0128] 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.

[0129] 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.

[0130] The nutritional compositions according to the invention may be, for example, infant formula, stage 1 infant formula, follow-up or later infant formula, baby food, infant cereal compositions, fortifiers (such as human milk fortifiers), or supplements. In some specific embodiments, the compositions of the 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 invention are infant formula.

[0131] 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 larger / follow-up formula fortifier).

[0132] When a nutritional composition is a supplement, it can be provided in unit dose form.

[0133] The nutritional compositions of the present invention may be in solid (e.g., powder), liquid or gel form.

[0134] 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 used in preterm infants, the amount of protein can be between 2.4 g / 100 kcal and 4 g / 100 kcal or greater than 3.6 g / 100 kcal. In some other embodiments, the amount of protein can be less than 2.0 g / 100 kcal, for example between 1.8 g / 100 kcal and 2 g / 100 kcal, or less than 1.8 g / 100 kcal.

[0135] 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.

[0136] 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%).

[0137] The protein may be intact or hydrolyzed, or a mixture of intact and hydrolyzed proteins. The term "intact" means that the major components of the protein are intact, i.e., the molecular structure is not altered, 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.

[0138] The term "hydrolyzed" means, in the context of this invention, that the protein has been hydrolyzed or broken down into its constituent amino acids.

[0139] The protein can be completely or partially hydrolyzed. For example, for infants or young children considered at risk of bovine milk allergy, providing partially hydrolyzed protein (with a degree of hydrolysis between 2% and 20%) 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 blockage during hydrolysis. This allows the degree of lysine blockage 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.

[0140] 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%, specifically at least 98%. In one specific embodiment, 100% of the protein is hydrolyzed.

[0141] 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 may be between 8 and 40, or between 20 and 60, or between 20 and 80, or greater than 10, 20, 40, 60, 80, or 90.

[0142] 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.

[0143] 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.

[0144] 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.

[0145] 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.

[0146] If necessary, the nutritional compositions of the present invention may contain emulsifiers and stabilizers, such as soybean, lecithin, monoglyceride citrate, and diglyceride citrate.

[0147] The nutritional compositions of the present invention may also contain other substances that may have beneficial effects, such as lactoferrin, nucleotides, nucleosides, etc.

[0148] 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.

[0149] The nutritional compositions according to the present invention can be prepared by any suitable means.

[0150] For example, formula foods such as infant formula can be prepared by blending protein sources, carbohydrate sources, and fat sources 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 reverse osmosis water) can then be added to form a liquid mixture. A suitable water temperature is between about 50°C and about 80°C to aid in the dispersion of the components. Commercially available liquefying agents can be used to form the liquid mixture.

[0151] 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.

[0152] The liquid mixture is then homogenized, for example, in two stages.

[0153] The liquid mixture can then be heat-treated to reduce the bacterial load, for example by rapidly heating the liquid mixture to a temperature between about 80°C and about 150°C and holding it for a duration between about 5 seconds and about 5 minutes. This can be done by steam injection, autoclaving, or a heat exchanger (e.g., a plate heat exchanger).

[0154] The liquid mixture can then be cooled, for example, to between approximately 60°C and approximately 85°C by rapid cooling. The liquid mixture is then homogenized again, for example, in two stages, with the pressure in the first stage between approximately 10 MPa and approximately 30 MPa, and the pressure in the second stage between approximately 2 MPa and approximately 10 MPa. The homogenized mixture can 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.

[0155] 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.

[0156] 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.

[0157] In another embodiment, the composition of the present invention may be a supplement.

[0158] 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.

[0159] In addition, supplements may 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.

[0160] The nutritional composition according to the present invention is for use with 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 for premature infants or young children.

[0161] The nutritional composition of the present invention can also be used for infants or young children delivered by cesarean section or vaginal delivery.

[0162] In some embodiments, the nutritional compositions according to the invention can be used before and / or during the weaning period.

[0163] In some embodiments, the nutritional compositions according to the invention are used for infants or young children at risk of developing allergies. In some embodiments, the nutritional compositions according to the invention are used for infants or young children born to women with allergies. Scientific evidence does indeed continue to suggest that infants born to mothers with allergies have a greater risk of developing allergies later in life than infants born to mothers without allergies.

[0164] The age and duration of administration (or provision or feeding) of the nutritional composition may be determined based on possibility and need.

[0165] Since the nutritional composition is primarily for preventative purposes, it can be provided, for example, immediately after birth. The composition of the 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.

[0166] 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.

[0167] 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 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, 4 months, or 6 months), for at least 1 month, 2 months, 4 months, or 6 months.

[0168] 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 used, for example, to supplement human milk or to supplement the nutrition of infant formula or follow-up formula.

[0169] The inventors have discovered that specific HMO interventions in animal models significantly increase propionate production in the cecum (part of the colon).

[0170] As mentioned in the background section, propionate is known to be used for protection against skin diseases.

[0171] Therefore, the nutritional composition according to the invention can be used to prevent and / or treat skin conditions and / or skin diseases in infants or young children by increasing the production of SFCA in the colon.

[0172] The health benefits of the present invention can be achieved by the nutritional composition through increasing propionate production in the colon, particularly the cecum, of the infant or young child. In one specific embodiment, propionate production is measured by gas-liquid chromatography and can be expressed as nmol / mg dry weight.

[0173] 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 by a nutrient composition that does not contain at least one fucoidylated oligosaccharide and at least one N-acetylated oligosaccharide.

[0174] 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 propionate production in the colon obtained by supplementing with a nutritional composition containing ordinary fiber (such as polydextrose or pectin).

[0175] This represents a new clinical development where new methods can be used to prevent allergic reaction symptoms.

[0176] Other purposes: Another object of the present invention is the use of at least one fucoidylated oligosaccharide and at least one N-acetylated oligosaccharide in the preparation of nutritional compositions for the prevention and / or treatment of skin conditions and / or skin diseases, preferably atopic dermatitis, in infants or young children by increasing the production of propionate, especially propionate in the colon.

[0177] Another object of the present invention is a pharmaceutical composition comprising at least one alginate oligosaccharide and at least one N-acetylated oligosaccharide for use in the prevention and / or treatment of skin conditions and / or skin diseases, preferably atopic dermatitis, in infants or young children by increasing the production of propionate, particularly in the colon.

[0178] Another object of the present invention is the use of at least one alginate oligosaccharide and at least one N-acetylated oligosaccharide for the prevention and / or treatment of skin conditions and / or skin diseases, preferably atopic dermatitis, in infants or young children by increasing propionate production, particularly in the colon.

[0179] Another object of the present invention relates to a method for preventing and / or treating skin conditions and skin diseases, preferably atopic dermatitis, in infants or young children by increasing propionate production, particularly in the colon, said 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.

[0180] In one embodiment, the eczema to be treated according to the invention has an allergen. In another embodiment, the eczema to be treated according to the invention has a non-allergen.

[0181] The different implementation schemes, details and examples described above (e.g., relating to the type and content of oligosaccharides, nutritional compositions, application, target populations) are also applicable to these other purposes.

[0182] The second aspect of the invention

[0183] Therefore, the first object of the present invention is a nutritional composition comprising a mixture of oligosaccharides, said oligosaccharide mixture comprising at least one N-acetylated oligosaccharide, at least one galactooligosaccharide and at least one sialylated oligosaccharide, for the prevention and / or treatment of skin conditions and / or skin diseases, preferably atopic dermatitis, in infants or young children by increasing the production of SCFAs, particularly acetate, propionate and / or butyrate in the colon.

[0184] As shown in Example 4, the inventors have found that supplementing with the oligosaccharide mixture according to the invention increases SCFA production in animal models, particularly propionate, butyrate, and acetate. Without being bound by theory, the inventors believe that these specific oligosaccharides synergistically provide a surprisingly significant increase in SCFA production in the colon. Due to the known properties of SCFAs, especially butyrate and propionate, such supplementation could be interestingly used for the prevention and / or treatment of skin conditions and / or skin diseases in infants or young children, preferably atopic dermatitis.

[0185] The oligosaccharide mixture in the nutritional composition according to the invention comprises at least one N-acetylated oligosaccharide, at least one galactooligosaccharide, and at least one sialylated oligosaccharide. As previously described, the mixture can be made from one or more of these different types of oligosaccharides, i.e., one or more N-acetylated oligosaccharides, one or more galactooligosaccharides, and one or more sialylated oligosaccharides. The oligosaccharide mixture in the nutritional composition of the invention can be prepared from one or more animal milks. The milk can be obtained from any mammal, especially cows, goats, buffalo, horses, elephants, camels, or sheep.

[0186] As an alternative, oligosaccharide mixtures can be prepared by purchasing and mixing various components.

[0187] N-acetylated oligosaccharides are oligosaccharides having N-acetylated residues. Suitable N-acetylated oligosaccharides in the oligosaccharide mixture of the nutritional compositions according to the invention include GalNAcβ1,3Galβ1,4Glc and Galβ1,6GalNAcβ1,3Galβ1,4Glc, and any mixtures thereof. N-acetylated oligosaccharides can be prepared by acting on N-acetylglucose and / or N-acetylglucosamine with glucosidase and / or galactosidase. Similarly, this can be achieved using N-acetyl-galactosyltransferase and / or N-acetyl-glycosyltransferase. N-acetylated oligosaccharides can also be obtained by fermentation techniques and / or microbial fermentation using the corresponding enzymes (recombinant enzymes or natural enzymes). 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 or mixed cultures can be used. The formation of N-acetylated oligosaccharides can be initiated by an acceptor substrate, starting at any degree of polymerization (DP) from DP=1. Alternatively, free or bound hexulose (fructose) can be chemically converted into N-acetylated hexosamine or oligosaccharides containing N-acetylated hexosamine, as described in Wrodnigg, TM, Dtutz, AE, Angew. Chem. Int. Ed. 1999: 38: 827-82.

[0188] Galacto-oligosaccharides are oligosaccharides comprising two or more galactose molecules that are uncharged and do not have N-acetyl residues. Suitable galacto-oligosaccharides in the oligosaccharide mixtures of the nutritional compositions according to the invention include Galβ1,3Galβ1,4Glc, Galβ1,6Galβ1,4Glc, Galβ1,3Galβ1,3Galβ1,4Glc, Galβ1,6Galβ1,6Galβ1,4Glc, Galβ1,3Galβ1,6Galβ1,4Glc, Galβ1,6Galβ1,3Galβ1,6Glc, Galβ1,6Galβ1,6Glc, Galβ1,3Galβ1,3Glc, Galβ1,4Galβ1,4Glc, and Galβ1,4Galβ1,4Glc, and any mixtures thereof. Synthetic galacto-oligosaccharides such as Galβ1,6Galβ1,4Glc, Galβ1,6Galβ1,6Galβ1,6Glc, Galβ1,3Galβ1,4Glc, Galβ1,6Galβ1,6Galβ1,4Glc, Galβ1,6Galβ1,3Galβ1,4Glc, Galβ1,3Galβ1,6Galβ1,4Glc, Galβ1,4Galβ1,4Glc, and Galβ1,4Galβ1,4Glc, as well as mixtures thereof, may be traded under the name Vivinal. ® and Elix'or ® Commercially available. Other suppliers of oligosaccharides include Dextra Laboratories, Sigma-Aldrich Chemie GmbH, and Kyowa Hakko Kogyo Co., Ltd. Alternatively, specific glycosyltransferases, such as galactosyltransferases, can be used to produce neutral oligosaccharides.

[0189] Sialized oligosaccharides are oligosaccharides containing sialic acid residues with associated charges. Suitable sialylated oligosaccharides in the oligosaccharide mixture of the nutritional compositions according to the invention include NeuAcβ2,3Galβ1,4Glc and NeuAcβ2,6Galβ1,4Glc, and any mixtures thereof. These sialylated oligosaccharides can be isolated from natural sources, such as animal milk, by chromatographic or filtration techniques. Alternatively, they can be prepared by biotechnological methods utilizing specific sialyl transferases, via enzyme-based fermentation techniques (recombinant or natural enzymes) or microbial fermentation techniques. In the latter case, the microorganisms may express their natural enzymes and substrates, or may be engineered to produce the corresponding substrates and enzymes. Single or mixed microbial cultures can be used. Sialized oligosaccharides can be formed by acceptor substrates, starting at any degree of polymerization (DP) from DP=1.

[0190] In one aspect of the invention, the nutritional composition comprises 2.5% to 15% by weight of an oligosaccharide mixture. Alternatively, the nutritional composition comprises 3% to 15% by weight, or 3% to 10% by weight, or 3.5% to 9.5% by weight, or 4% to 9% by weight, or 4.5% to 8.5% by weight, or 5.0% to 7.5% by weight, such as 5% by weight of an oligosaccharide mixture.

[0191] In some specific embodiments, the nutritional composition may comprise an amount of 0.5 to 3.1 g / 100 kcal, or 0.6 to 3.1 g / 100 kcal, or 0.6 to 2.0 g / 100 kcal, or 0.7 to 2.0 g / 100 kcal, or 0.8 to 1.8 g / 100 kcal, or 0.9 to 1.7 g / 100 kcal, or 1.0 to 1.5 g / 100 kcal of an oligosaccharide mixture.

[0192] The nutritional composition of the present invention may contain at least 0.01% by weight of N-acetylated oligosaccharides, at least 2.0% by weight of galactooligosaccharides and at least 0.02% by weight of sialylated oligosaccharides.

[0193] In some embodiments, the nutritional composition according to the invention may contain at least 0.005% by weight, or at least 0.01% by weight, or at least 0.02% by weight, or at least 0.03% by weight, or at least 0.04% by weight, or at least 0.05% by weight, or at least 0.06% by weight of N-acetylated oligosaccharides. In some embodiments, it may contain 0.005% to 0.06% by weight of N-acetylated oligosaccharides, such as 0.005% to 0.05% by weight, or 0.005% to 0.04% by weight, or 0.005% to 0.03% by weight, or 0.01% to 0.02% by weight of N-acetylated oligosaccharides. A specific example is 0.01% by weight of N-acetylated oligosaccharides.

[0194] In addition, the nutritional composition may contain at least 2% by weight, or at least 3% by weight, or at least 4% by weight, or at least 5% by weight, or at least 5.5% by weight, or at least 6% by weight, or at least 7% by weight, or at least 8% by weight of galactooligosaccharides. In some embodiments, the nutritional composition may contain 4.5% by weight to 8% by weight of galactooligosaccharides, such as 4.75% by weight to 6% by weight of galactooligosaccharides, or 4.9% by weight to 5% by weight, or 5.5% by weight to 6.5% by weight of galactooligosaccharides. A specific example is 4.965% by weight of galactooligosaccharides.

[0195] Finally, the nutritional composition may contain at least 0.01% by weight, or at least 0.02% by weight, or at least 0.03% by weight, or at least 0.04% by weight, or at least 0.05% by weight, or at least 0.06% by weight, or at least 0.07% by weight, or at least 0.08% by weight, or at least 0.09% by weight of sialylated oligosaccharides. In some embodiments, the nutritional composition may contain 0.02% to 0.09% by weight of sialylated oligosaccharides, such as 0.02% to 0.07% by weight, or 0.02% to 0.05% by weight, or 0.003% to 0.07% by weight. A specific example is 0.025% by weight of sialylated oligosaccharides.

[0196] In one specific embodiment, the nutritional composition according to the invention may comprise 0.01% to 0.07% by weight of N-acetylated oligosaccharides, 2.0% to 8.0% by weight of galactooligosaccharides, and 0.02% to 0.09% by weight of sialylated oligosaccharides.

[0197] In another specific embodiment, the nutritional composition according to the invention may comprise 0.01% to 0.03% by weight of N-acetylated oligosaccharides, 5.95% by weight of galactooligosaccharides, and 0.02% to 0.09% by weight of sialylated oligosaccharides.

[0198] In one specific embodiment, the nutritional composition may comprise 0.0015 g / 100 kcal to 0.005 g / 100 kcal of N-acetylated oligosaccharides, 0.70 g / 100 kcal to 1.5 g / 100 kcal of galactooligosaccharides, and 0.0045 g / 100 kcal to 0.0085 g / 100 kcal of sialylated oligosaccharides.

[0199] In another specific embodiment, the nutritional composition may comprise 0.0015 g / 100 kcal to 0.0045 g / 100 kcal of N-acetylated oligosaccharides, 0.74 g / 100 kcal to 1.2 g / 100 kcal of galactooligosaccharides, and 0.0045 g / 100 kcal to 0.0075 g / 100 kcal of sialylated oligosaccharides.

[0200] In one particular advantageous embodiment, the oligosaccharide mixture of the nutritional composition according to the invention comprises 0.1% to 4.0% by weight of N-acetylated oligosaccharides, 92.0% to 99.5% by weight of galactooligosaccharides, and 0.2% to 4.0% by weight of sialylated oligosaccharides.

[0201] In one particular advantageous embodiment, the oligosaccharide mixture of the nutritional composition according to the invention comprises 0.1% to 4.0% by weight of N-acetylated oligosaccharides, 92.0% to 99.5% by weight of galactooligosaccharides, and 0.2% to 4.0% by weight of sialylated oligosaccharides.

[0202] The nutritional compositions according to the invention may also contain other types of prebiotics (i.e., different from and supplemented by oligosaccharides contained in the oligosaccharide mixture as defined according to the invention). Examples of other types of prebiotics include human milk oligosaccharides (HMOs) such as fucoidan, fructooligosaccharides, fructooligosaccharides (FOS), inulin, xylooligosaccharides (XOS), polydextrose, or any mixture thereof.

[0203] In addition to the oligosaccharides contained in the oligosaccharide mixture, suitable commercial products for preparing the nutritional compositions according to the invention include combinations of FOS and inulin, such as those sold by BENEO under the trademark Orafti, or by Tate & Lyle under the trademark STA-LITE. ® Polydextrose for sale.

[0204] The nutritional composition of the present invention may also contain at least one probiotic (or probiotic strain), such as a probiotic strain.

[0205] The most commonly used probiotics are mainly bacteria and yeasts belonging to the following genera: Lactobacillus ( Lactobacillus species Streptococcus ( .), Streptococcus spp. Streptococcus spp. .), Enterococcus spp. Enterococcus spp. .), Bifidobacterium spp. Bifidobacterium spp. .) and yeast ( Saccharomyces spp. .).

[0206] In some specific embodiments, the probiotics are probiotic bacterial strains. In some specific embodiments, they are specifically Bifidobacterium and / or Lactobacillus (…). Lactobacilli ).

[0207] Suitable probiotic strains include Lactobacillus acidophilus ( Lactobacillus acidophilus ), Lactobacillus salivarius ( Lactobacillus salivarius Lactobacillus rhamnosus ( Lactobacillus rhamnosus ), Lactobacillus paracasei ( Lactobacillus paracasei Lactobacillus casei ( Lactobacillus casei Lactobacillus johnsonii ( Lactobacillus johnsonii Lactobacillus plantarum ( Lactobacillus plantarum ), Lactobacillus fermentum ( Lactobacillus fermentum Lactobacillus () Lactobacillus lactis Lactobacillus delbrueckii (), Lactobacillus delbrueckii Lactobacillus helveticus ( Lactobacillus helveticus Lactobacillus bulgaricus () Lactobacillus bulgaricus ), Lactococcus lactis ( Lactococcus lactis Lactococcus lactis diacetyl subsp. Lactococcus diacetylactis Lactococcus lactis subsp. milk fat () Lactococcus creameri ), Streptococcus salivarius ( Streptococcus salivarius Streptococcus thermophilus () Streptococcus thermophilus ), Bifidobacterium lactis ( Bifidobacterium lactis Bifidobacterium animalis ( Bifidobacterium animalum ), Bifidobacterium longum ( Bifidobacterium longum ), Bifidobacterium breve Bifidobacterium breve ), Bifidobacterium infantis ( Bifidobacterium infantis ), Bifidobacterium adolescentis ( Bifidobacterium adolescentis (or any mixture thereof)

[0208] Suitable probiotic strains include Lactobacillus rhamnosus, trademarked LGG, from Valio Oy, Finland. Lactobacillus rhamnosus ATCC 53103, BLIS Technologies Limited, New Zealand, sells Lactobacillus rhamnosus CGMCC1.3724 and Lactobacillus casei under the trade name KI2. Lactobacillus paracasei CNCM I-2116, Lactobacillus johnsonii ( Lactobacillus johnsonii CNCM I-1225, Streptococcus salivarius ( Streptococcus salivarius DSM 13084, Bifidobacterium lactis specially marketed by Christian Hansen company (Denmark) under the trademark Bb 12. Bifidobacterium lactis CNCM 1-3446, Bifidobacterium longum sold by Morinaga Milk Industry Co., Ltd., Japan under the trademark BB536. Bifidobacterium longum ATCC BAA-999, and Bifidobacterium breve sold by Danisco under the trademark Bb-03. Bifidobacterium breve Bifidobacterium breve, sold by Morinaga under the trademark M-16V, and Bifidobacterium infantis, sold by Procter & Gamble Co. under the trademark Bifantis. Bifidobacterium infantis ), and Bifidobacterium breve sold under the trademark R0070 by the Rosell Institute of Biology in Canada.

[0209] 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 containing probiotic strains between 10e7 and 10e12 cfu, such as between 10e8 and 10e10 cfu.

[0210] 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.

[0211] 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.

[0212] The nutritional compositions according to the invention may be, for example, infant formula, stage 1 infant formula, follow-up or later infant formula, baby food, infant cereal compositions, fortifiers (such as human milk fortifiers), or supplements. In some specific embodiments, the compositions of the 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 invention are infant formula.

[0213] 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 larger / follow-up formula fortifier).

[0214] When a nutritional composition is a supplement, it can be provided in unit dose form.

[0215] The nutritional compositions of the present invention may be in solid (e.g., powder), liquid or gel form.

[0216] The nutritional compositions of the present invention, and especially infant formula, typically contain protein sources, carbohydrate sources and lipid sources.

[0217] 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 used in preterm infants, the amount of protein can be between 2.4 g / 100 kcal and 4 g / 100 kcal or greater than 3.6 g / 100 kcal. In some other embodiments, the amount of protein can be less than 2.0 g / 100 kcal, for example between 1.8 g / 100 kcal and 2 g / 100 kcal, or less than 1.8 g / 100 kcal.

[0218] 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.

[0219] 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%).

[0220] The protein may be intact or hydrolyzed, or a mixture of intact and hydrolyzed proteins. The term "intact" means that the major components of the protein are intact, i.e., the molecular structure is not altered, 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.

[0221] The term "hydrolyzed" means, in the context of this invention, that the protein has been hydrolyzed or broken down into its constituent amino acids.

[0222] The protein can be completely or partially hydrolyzed. For example, for infants or young children considered at risk of bovine milk allergy, providing partially hydrolyzed protein (with a degree of hydrolysis between 2% and 20%) 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 blockage during hydrolysis. This allows the degree of lysine blockage 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.

[0223] 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%, specifically at least 98%. In one specific embodiment, 100% of the protein is hydrolyzed.

[0224] 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 may be between 8 and 40, or between 20 and 60, or between 20 and 80, or greater than 10, 20, 40, 60, 80, or 90.

[0225] 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.

[0226] 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.

[0227] 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.

[0228] 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.

[0229] If necessary, the nutritional compositions of the present invention may contain emulsifiers and stabilizers, such as soybean, lecithin, monoglyceride citrate, and diglyceride citrate.

[0230] The nutritional compositions of the present invention may also contain other substances that may have beneficial effects, such as lactoferrin, nucleotides, nucleosides, etc.

[0231] The nutritional composition of the present invention may also contain one or more carotenoids.

[0232] The nutritional compositions of the present invention (e.g., infant formula) can be prepared by blending protein sources, carbohydrate sources, and fat sources together in appropriate proportions. If necessary, emulsifiers can be added. Vitamins and minerals can be added at this time, but are usually added a little later to avoid thermal degradation. Before blending, any lyophilic vitamins, emulsifiers, etc., can be dissolved in the fat source. Water (preferably reverse osmosis water) can then be mixed in to form a liquid mixture.

[0233] The liquid mixture can then be heat-treated to reduce the bacterial load. For example, the liquid mixture can be rapidly heated to a temperature in the range of about 80°C to about 110°C and held for about 5 seconds to about 5 minutes. This can be done via steam injection or a heat exchanger such as a plate heat exchanger.

[0234] The liquid mixture can then be cooled to approximately 60°C to approximately 85°C, for example, by flash cooling. The liquid mixture can then be homogenized; for example, in two stages, the first stage at approximately 7 MPa to approximately 40 MPa, and the second stage at approximately 2 MPa to approximately 14 MPa. The homogenized mixture can then be further cooled to allow the addition of any heat-sensitive components, such as vitamins and minerals. At this point, it is convenient to standardize the pH and solids content of the homogenized mixture.

[0235] The homogenized mixture can be transferred to a suitable drying device (e.g., a spray dryer or freeze dryer) and converted into a powder. The moisture content of the powder should be less than about 5% by weight.

[0236] The oligosaccharide mixture can be prepared by any suitable method known in the art and added in different steps during the preparation of the nutritional composition of the present invention. The oligosaccharide mixture can be added directly to the nutritional composition (e.g., infant formula) by dry mixing (i.e., in the blending step). Alternatively, the oligosaccharide mixture can be added to the liquid mixture prior to heat treatment to reduce bacterial load. The individual components of the oligosaccharide mixture can also be added to the nutritional composition separately; in this case, the oligosaccharide mixture is preferably added to the liquid phase just before drying.

[0237] The nutritional composition according to the present invention is for use with 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 for premature infants or young children.

[0238] The nutritional composition of the present invention can also be used for infants or young children delivered by cesarean section or vaginal delivery.

[0239] In some embodiments, the nutritional compositions according to the invention can be used before and / or during the weaning period.

[0240] In some embodiments, the nutritional compositions according to the invention are used for infants or young children at risk of developing allergies. In some embodiments, the nutritional compositions according to the invention are used for infants or young children born to women with allergies. Scientific evidence does indeed continue to suggest that infants born to mothers with allergies have a greater risk of developing allergies later in life than infants born to mothers without allergies.

[0241] The age and duration of administration (or provision or feeding) of the nutritional composition may be determined based on possibility and need.

[0242] When the nutritional composition is used for preventative purposes (prevention of health impairments later in life), it may be provided, for example, immediately after the infant's birth. The compositions of the present invention may also be provided during the first week, or the first two weeks, or the first three weeks, or the first month, or the first two months, or the first three months, or the first four months, or the first six months, or the first eight months, or the first ten months, or the first year, or the first two years, or even longer. 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.

[0243] 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.

[0244] 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 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, 4 months, or 6 months), for at least 1 month, 2 months, 4 months, or 6 months.

[0245] 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 used, for example, to supplement human milk or to supplement the nutrition of infant formula or follow-up formula.

[0246] The oligosaccharide mixture present in the nutritional compositions of the present invention can be prepared from one or more animal milks. The milk can be obtained from any mammal, particularly cows, goats, buffalo, horses, elephants, camels, or sheep. In one specific embodiment, the oligosaccharides in the oligosaccharide mixture are bovine milk oligosaccharides and can be obtained from cow milk, goat milk, or buffalo milk. In an advantageous embodiment, the oligosaccharides are obtained from cow milk. WO2006087391 and WO2012160080 provide some examples of preparing BMO mixtures.

[0247] The inventors have discovered that BMO intervention in animal models increases SCFA production in the colon, particularly in the cecum, and especially butyrate and propionate. Since these SCFAs have been shown to protect against eczema, the nutritional compositions according to the invention could be used for the prevention and / or treatment of skin conditions and / or skin diseases in infants or young children, preferably atopic dermatitis.

[0248] There may be one or more SCFAs, with an increase in their production. SCFAs may be propionate, butyrate, valerate, and / or acetate. In one specific embodiment, the SCFA is propionate and / or butyrate (i.e., propionate, butyrate, or both).

[0249] Therefore, in one specific implementation, prevention and / or treatment of skin conditions and skin diseases, preferably atopic dermatitis, is achieved by increasing the production of propionate and / or butyrate in the colon of the infant or young child.

[0250] In one specific implementation, the production of propionate and / or butyrate is measured by gas-liquid chromatography and can be expressed in nmol / mg dry weight.

[0251] In one specific embodiment, colonic butyrate 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%, or at least 80%, or at least 90% compared to colonic butyrate production obtained by a nutrient composition that does not contain at least one N-acetylated oligosaccharide, at least one galactooligosaccharide, and at least one sialylated oligosaccharide.

[0252] In one specific embodiment, colonic butyrate 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%, or at least 80%, or at least 90%, or at least 100% or more, compared to colonic butyrate compositions obtained by supplementing with common fiber (such as polydextrose or pectin).

[0253] 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 by a nutrient composition that does not contain at least one N-acetylated oligosaccharide, at least one galactooligosaccharide, and at least one sialylated oligosaccharide.

[0254] 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 propionate production in the colon obtained by supplementing with a nutritional composition containing ordinary fiber (such as polydextrose or pectin).

[0255] Other purposes: Another object of the present invention is to use a mixture of oligosaccharides comprising at least one N-acetylated oligosaccharide, at least one galactooligosaccharide and at least one sialylated oligosaccharide in the preparation of nutritional compositions for the prevention and / or treatment of skin conditions and / or skin diseases, preferably atopic dermatitis, in infants or young children by increasing the content of SCFA, especially the butyrate and / or propionate content in the colon.

[0256] Another object of the present invention is to use a mixture of oligosaccharides comprising at least one N-acetylated oligosaccharide, at least one galactooligosaccharide and at least one sialylated oligosaccharide (or a nutritional composition comprising such a mixture of oligosaccharides) to increase the production of SCFAs in infants or young children, particularly SCFAs in the colon, especially butyrate and / or propionate.

[0257] Another object of the present invention is to use a nutritional composition comprising a mixture of oligosaccharides containing at least one N-acetylated oligosaccharide, at least one galactooligosaccharide and at least one sialylated oligosaccharide, for the prevention and / or treatment of skin conditions and / or skin diseases, preferably atopic dermatitis, in infants or young children by increasing the content of SCFAs, especially butyrate and / or propionate in the colon.

[0258] Another object of the present invention is a pharmaceutical composition comprising a mixture of oligosaccharides containing at least one N-acetylated oligosaccharide, at least one galactooligosaccharide, and at least one sialylated oligosaccharide, for the prevention and / or treatment of skin conditions and / or skin diseases, preferably atopic dermatitis, in infants or young children by increasing the content of SCFAs, particularly butyrate and / or propionate in the colon.

[0259] Another object of the present invention is a method for preventing and / or treating skin conditions and / or skin diseases, preferably atopic dermatitis, in infants or young children by increasing the content of SCFAs, particularly butyrate and / or propionate in the colon, the method comprising administering to the infant or young child a nutritional composition comprising a mixture of oligosaccharides containing at least one N-acetylated oligosaccharide, at least one galactooligosaccharide, and at least one sialylated oligosaccharide.

[0260] Another object of the present invention is a method for increasing SCFA production in infants or young children, particularly butyrate and / or propionate production in the colon, the method comprising administering to the infant or young child a nutritional composition comprising a mixture of oligosaccharides, the mixture comprising at least one N-acetylated oligosaccharide, at least one galactooligosaccharide and at least one sialylated oligosaccharide.

[0261] Another object of the present invention is a mixture of oligosaccharides comprising at least one N-acetylated oligosaccharide, at least one galactooligosaccharide and at least one sialylated oligosaccharide in a nutritional composition for infants or young children, the nutritional composition serving as a therapeutic agent for increasing SCFA production in said infants or young children, particularly butyrate and / or propionate production in the colon.

[0262] Another object of the present invention is a nutritional composition comprising at least one N-acetylated oligosaccharide, at least one galactooligosaccharide and at least one sialylated oligosaccharide, which is used as a therapeutic agent to increase SCFA production in infants or young children, especially butyrate and / or propionate production in the colon.

[0263] The aforementioned implementation schemes and examples (e.g., involving the type and amount of oligosaccharides, nutritional compositions, application, target populations, etc.) are also applicable to all these other purposes.

[0264] Therefore, the compositions according to the invention (as described in the first and second aspects) are preferably used to reduce the frequency and / or incidence and / or severity and / or duration of atopic dermatitis, and / or to promote skin health.

[0265] In one specific embodiment, the composition according to the invention is used to promote skin health and / or to prevent skin dehydration and / or to enhance skin hydration and / or to reduce rashes, roughness and dryness, and / or to enhance skin barrier function, and / or to enhance oral tolerance to allergens.

[0266] In one embodiment, the eczema to be treated according to the invention has an allergen. In another embodiment, the eczema to be treated according to the invention has a non-allergen.

[0267] The different implementation schemes, details and examples described above (e.g., relating to the type and content of oligosaccharides, nutritional compositions, application, target populations, etc.) are also applicable to these other purposes.

[0268] All of the above uses are specifically for infants and young children. The compositions and uses according to the invention are particularly suitable for infants and children who are at risk of allergic reactions, have a family history of allergies, or have experienced some allergic reactions (especially respiratory or skin allergies). In one embodiment, the compositions and uses of the invention are suitable for adolescents or adults who are at risk of allergic reactions or have experienced allergic reactions (especially respiratory or skin allergies).

[0269] The nutritional composition according to the invention modulates the metabolism of endogenous microorganisms, resulting in the production of short-chain fatty acids, particularly propionate and butyrate, which helps activate immune cells in the submucosal intestinal tract. Upon triggering the mucosal immune system, activated immune cells, immunomodulatory compounds, and / or immune mediators circulate to distal sites, including the skin, where they exert immunomodulatory activity. All these mechanisms together help balance potential inflammatory skin conditions, thereby improving associated clinical presentations such as dermatitis and eczema. Furthermore, the inventors believe that such carefully coordinated immunity reduces the skin's sensitivity to exogenous stimuli and leads to better skin barrier function, thereby reducing rashes and decreasing roughness and dryness associated with reactive skin.

[0270] examples

[0271] 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.

[0272] Example 1

[0273] 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.

[0274]

[0275] Table 1: Examples of the composition of nutritional compositions (e.g., infant formula) according to the present invention

[0276] Example 2

[0277] Research Description

[0278] Five-week-old female BALB / cByJ CRL mice from Charles River were divided into several groups and fed according to the following protocol for 6 weeks: - Week 1: All groups were fed a low-fiber diet (compositions are detailed in Table 2). - Weeks 2 to 6: Control group (Group A): Low-fiber diet (same as week 1) Test group (Group BD): 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).

[0279] Table 2: Composition of a low-fiber diet

[0280] Test the following fibers: HMO = Human milk oligosaccharides. The tested weight ratio of 2FL + LNnT was 1:1. PDX = Polydextrose pectin Table 3 provides a summary of the different test groups and diets.

[0281]

[0282] Table 3: Test group and diet in the study

[0283] Six weeks later, animals in each group were sacrificed, and contents from the cecum were collected. SCFA production was determined by gas-liquid chromatography (GLC; SCFA levels were expressed as nmol / mg dry weight). The following SCFAs were measured: propionate, butyrate, valerate, and acetate.

[0284] Measurements were performed according to the following protocol: SCFA in an acidic solution (pH 2.0 to 3.0) was separated on a GLC column coated with a polar stationary phase. This allows for minimal sample preparation (no derivatization) and straightforward basic FID detection. SCFA was extracted from the cecum using an acidic phosphate buffer containing HgCl2 and an internal standard (2,2-dimethylbutyric acid) for GLC analysis; the acidic phosphate buffer inactivated any residual bacterial activity. After centrifugation, the aseptically filtered supernatant was ready for analysis by GLC. SCFA was measured simultaneously.

[0285] Calculate the median ratio to compare the SCFA production of different fiber-rich diets.

[0286] Discover

[0287] A diet rich in HMOs significantly increases propionate production (see [link to article]). Figure 1 Compared to the positive control, its production increased by approximately 69%. Compared to pectin and PDX, its production increased by 73% and 75%, 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 microbiotacomposition and short chain fatty acid production).

[0288] Figure 2 This represents the ratio of the median SCFA for each test of each fiber-rich diet to the median SCFA of the positive control diet (i.e., the low-fiber diet only). A ratio of 1 (black line) means there is no difference between the fiber-rich diet and the control diet. A ratio below 1 means the corresponding SCFA is higher in the control diet compared to the fiber-rich diet, while a ratio above 1 means the corresponding SCFA is higher in the fiber-rich diet than in the control group.

[0289] Diets rich in PDX and pectin resulted in low release of all types of SCFAs. Conversely, diets rich in HMOs induced the release of more propionate and butyrate compared to low-fiber diets. Unlike other types of SCFAs and other tested fibers, diets rich in HMOs were the only ones that significantly increased propionate production.

[0290] Example 3

[0291] Table 4 below provides examples of compositions of infant formula containing an oligosaccharide mixture according to the present invention. The oligosaccharide mixture may, for example, contain 0.1% to 4.0% by weight of N-acetylated oligosaccharides, 92.0% to 99.5% by weight of galactooligosaccharides, and 0.2% to 4.0% by weight of sialylated oligosaccharides.

[0292]

[0293] Table 4: Examples of the composition of nutritional compositions (e.g., infant formula) according to the present invention

[0294] Example 4

[0295] Research Description

[0296] Five-week-old female BALB / cByJ CRL mice from Charles River were divided into several groups and fed according to the following protocol for 6 weeks: - Week 1: All groups were fed a low-fiber diet (compositions are detailed in Table 2). - Weeks 2 to 6: Control group (Group A): Low-fiber diet (same as week 1) Test group (Group BD): 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).

[0297] Table 5: Composition of a low-fiber diet

[0298] Test the following fibers: BMO = Milk Oligosaccharides: Tested to contain a mixture of oligosaccharides comprising 99.3% GOS, 0.2% N-acetylated oligosaccharides, and 0.5% sialylated oligosaccharides. PDX = Polydextrose pectin Table 6 provides a summary of the different test groups and diets.

[0299]

[0300] Table 3: Test group and diet in the study

[0301] Six weeks later, animals in each group were sacrificed, and contents from the cecum were collected. SCFA production was determined by gas-liquid chromatography (GLC; SCFA levels were expressed as nmol / mg dry weight). The following SCFAs were measured: propionate, butyrate, valerate, and acetate.

[0302] Measurements were performed according to the following protocol: SCFA in an acidic solution (pH 2.0 to 3.0) was separated on a GLC column coated with a polar stationary phase. This allows for minimal sample preparation (no derivatization) and straightforward basic FID detection. SCFA was extracted from the cecum using an acidic phosphate buffer containing HgCl2 and an internal standard (2,2-dimethylbutyric acid) for GLC analysis; the acidic phosphate buffer inactivated any residual bacterial activity. After centrifugation, the aseptically filtered supernatant was ready for analysis by GLC. SCFA was measured simultaneously.

[0303] Calculate the median ratio to compare the SCFA production of different fiber-rich diets.

[0304] Discover

[0305] Butyrate production is significantly increased through a diet rich in BMO (see [link to BMO diet]). Figure 3 Compared to the positive control, its production increased by approximately 99%. Compared to pectin and PDX, its production increased by 133% and 136%, respectively.

[0306] Propionate production is also significantly increased through a diet rich in BMO (see [link to BMO diet]). Figure 4 Compared to the positive control, its production increased by approximately 69%. Compared to pectin and PDX, its production increased by 74% and 75%, respectively.

[0307] These results are 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 production).

[0308] Figure 5 This 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) means there is no difference between the fiber-rich diet and the control diet. A ratio below 1 means the corresponding SCFA is higher in the control diet compared to the fiber-rich diet, while a ratio above 1 means the corresponding SCFA is higher in the fiber-rich diet than in the control group. Diets rich in PDX and pectin result in very low release of all types of SCFA. Conversely, diets rich in BMO result in greater release of all types of SCFA (acetate, propionate, butyrate, valerate) compared to low-fiber diets and other tested fibers. The BMO-rich diet is the only diet that enhances butyrate and propionate production in a highly efficient manner.

[0309] Therefore, the inventors were surprised to find that the cecum (and thus the colon) of mice fed a particular BMO mixture produced all the tested SCFAs, and especially butyrate and propionate, at higher levels.

[0310] Therefore, the inventors were surprised to find that mice fed with compositions containing oligosaccharides as described in this invention had significantly higher cecal (and therefore colonic) propionate / butyrate production.

[0311] Due to the known beneficial properties of SCFA, especially its beneficial properties in relation to eczema, a composition of either of the two aspects described in this invention will be effective for infants or young children for the prevention and / or treatment of skin conditions and / or skin diseases.

Claims

1. Use of a synthetic nutritional composition in the preparation of a product for the prevention and / or treatment of atopic dermatitis in infants or young children by increasing the production of SCFAs; The composition comprises an oligosaccharide mixture consisting of 2'-fucosylated lactose (2'FL) and lactose-N-neotetrasaccharide (LNnT), in a total amount of 0.1% to 10% by weight of the nutritional composition. The composition described herein does not contain any sialylated oligosaccharides, any GOS, and / or any milk oligosaccharides, and The SCFA is colonic propionate and / or butyrate.

2. The use according to claim 1, wherein the composition further comprises probiotics, wherein the probiotics are selected from the following probiotic strains: Lactobacillus acidophilus ( Lactobacillus acidophilus ), Lactobacillus salivarius ( Lactobacillus salivarius Lactobacillus rhamnosus ( Lactobacillus rhamnosus ), Lactobacillus paracasei ( Lactobacillus paracasei Lactobacillus casei ( Lactobacillus casei Lactobacillus johnsonii ( Lactobacillus johnsonii Lactobacillus plantarum ( Lactobacillus plantarum ), Lactobacillus fermentum ( Lactobacillus fermentum Lactobacillus () Lactobacillus lactis Lactobacillus delbrueckii (), Lactobacillus delbrueckii Lactobacillus helveticus ( Lactobacillus helveticus Lactobacillus bulgaricus () Lactobacillus bulgari ), Lactococcus lactis ( Lactococcus lactis Lactococcus lactis diacetyl subsp. Lactococcus diacetylactis Lactococcus lactis subsp. milk fat () Lactococcus cremoris ), Streptococcus salivarius ( Streptococcus salivarius Streptococcus thermophilus () Streptococcus thermophilus ), Bifidobacterium lactis ( Bifidobacterium lactis Bifidobacterium animalis ( Bifidobacterium animalis ), Bifidobacterium longum ( Bifidobacterium longum ), Bifidobacterium breve Bifidobacterium breve ), Bifidobacterium infantis ( Bifidobacterium infantis ), or Bifidobacterium adolescentis ( Bifidobacterium adolescentis (or any mixture thereof) 3. The use according to claim 1, wherein the SCFA is a colonic propionate.

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