WO2022226311A1

WO2022226311A1 - Nutritional compositions comprising human milk oligosaccharides and a designed lipid component for improving lung function

Info

Publication number: WO2022226311A1
Application number: PCT/US2022/025955
Authority: WO
Inventors: Rachael Buck; Tapas Das; David Hill; Mustafa Vurma
Original assignee: Abbott Laboratories
Priority date: 2021-04-23
Filing date: 2022-04-22
Publication date: 2022-10-27

Abstract

Disclosed are methods of and nutritional compositions for treating or improving at least one marker of lung health in an individual. The nutritional compositions include a combination of a human milk oligosaccharide component and a designed lipid component.

Description

NUTRITIONAL COMPOSITIONS COMPRISING HUMAN MILK OLIGOSACCHARIDES AND A DESIGNED LIPID COMPONENT FOR

IMPROVING LUNG FUNCTION

CROSS-REFERENCE TO RELATED APPLICATION

[0001] This application is claims priority to and any benefit of U.S. Provisional Patent Application No. 63/178,644, filed April 23, 2021, the content of which is hereby incorporated by reference as if fully recited herein.

FIELD

[0002] The present disclosure relates to a mixture of human milk oligosaccharides (HMOs) and a designed lipid component for nutritionally benefitting an individual consumer, including improving one or more aspects of the individual’s health. More particularly, the present disclosure relates to nutritional compositions comprising HMOs and a designed lipid component that can modulate or improve the health of an individual consumer by improving one or more markers of lung function as described in greater detail herein.

BACKGROUND

[0003] Breast milk containing HMOs has been associated with enhanced development and balanced growth and maturation of infant's respiratory, gastrointestinal, and immune systems, among others, thereby providing protection to the infant from a variety of diseases. There are more than 200 known oligosaccharides present in human milk, with various individual classes having been shown to promote health in a variety of ways. Further, breast milk includes HMOs that not only act as pathogen receptor analogues, but certain structures activate immune factors as well as acting as metabolic fuel in the gut microbiome to preferentially benefit certain beneficial bacteria.

[0004] Due to the accepted safety of HMOs as a component of an infant’s diet, efforts have been extended to develop the use of HMOs in other therapeutic regimes, including those for adults and the elderly. However, these efforts have yet to develop fully effective therapies in many areas. Accordingly, there is an unmet need for nutritional solutions that are effective to treat one or more of the conditions or diseases described herein, including but not, limited to lung function and health.

SUMMARY

[0005] Lung function and lung health are integral to infant development and overall health throughout life. By providing compositions comprising HMO(s) and a designed lipid component in products for daily consumption, the present invention would provide a nutritional means for improving various types of lung function in an individual, allowing for a nutritional means of therapeutically improving lung health without the need for more aggressive (e.g., pharmaceutical) interventions. The general inventive concepts are based, in part, on the discovery of an unexpected synergy between lipid containing components and HMOs at improving one or more markers of lung health in an individual.

[0006] The general inventive concepts are directed to nutritional compositions including at least one HMO (e.g., combinations of neutral and acidic HMOs), in combination with a designed lipid component, for use in modulating or treating the conditions or diseases described herein, including but not limited to: improving lung function in an individual; immunity (e.g., viral immunity);improving lung elasticity (or treating a lack of lung elasticity or conditions characterized by hampered lung elasticity) in an individual; increasing one or more lung surfactants in an individual; and reducing or ameliorating symptoms of lung injury in an individual.

[0007] In certain exemplary aspects, the general inventive concepts relate to a method of improving lung function in an individual in need thereof. The method comprises identifying an individual in need of improved lung function; and administering to the individual a nutritional composition comprising: a) a neutral human milk oligosaccharide; b) an acidic human milk oligosaccharide; and c) a designed lipid component.

[0008] In certain exemplary aspects, the general inventive concepts relate to a method of improving lung elasticity in an individual in need thereof, the method comprises identifying an individual in need of improved lung elasticity; and administering to the individual a nutritional composition comprising: a) a neutral human milk oligosaccharide; b) an acidic human milk oligosaccharide; and c) a designed lipid component.

[0009] In certain exemplary aspects, the general inventive concepts relate to a method of increasing at least one lung surfactant in an individual in need thereof, the method comprises administering to the individual a nutritional composition comprising: a) a neutral human milk oligosaccharide; b) an acidic human milk oligosaccharide; and c) a designed lipid component.

[0010] In certain exemplary aspects, the general inventive concepts relate to a nutritional composition for use in treating insufficient lung function. The nutritional composition comprising: a) a neutral human milk oligosaccharide; b) an acidic human milk oligosaccharide; and c) a designed lipid component.

[0011] In certain exemplary aspects, the general inventive concepts relate to a nutritional composition for use in increasing at least one lung surfactant protein. The nutritional composition comprising: a) a neutral human milk oligosaccharide; b) an acidic human milk oligosaccharide; and c) a designed lipid component.

[0012] In certain exemplary aspects, the general inventive concepts relate to a nutritional composition for improving lung function in an individual in need thereof. The nutritional composition comprising: a) a neutral human milk oligosaccharide; b) an acidic human milk oligosaccharide; and c) a designed lipid component.

[0013] In certain exemplary aspects, the general inventive concepts relate to a nutritional composition for improving lung elasticity in an individual in need thereof, the nutritional composition comprising: a) a neutral human milk oligosaccharide; b) an acidic human milk oligosaccharide; and c) a designed lipid component.

BRIEF DESCRIPTION OF THE DRAWINGS

[0014] Figure 1 is a bar graph showing increases in lung surfactant A (SP-A) after administration of various test formulations using a designed lipid component (PDF) and HMOs. [0015] Figure 2 is a graph showing increases in SP-A after administration of various test formulations using a designed lipid component (PDF) and HMOs.

[0016] Figure 3 is a bar graph showing change in viral titer (RSV) after exposure to various test formulations using a designed lipid component (PDF) and HMOs.

DETAILED DESCRIPTION

[0017] The nutritional compositions and methods described herein utilize a mixture of HMOs and a designed lipid component alone or in combination with other functional ingredients, for controlling, preventing, and/or treating a number of diseases and conditions as described in greater detail herein. These and other features of the nutritional compositions and methods, as well as some of the many optional variations and additions, are described in detail hereafter.

[0018] The term “human milk oligosaccharide” or “HMO”, as used herein, unless otherwise specified, refers generally to a number of complex carbohydrates found in human breast milk that can be in acidic or neutral form, and, in certain instances, to precursors thereof. Exemplary non-limiting human milk oligosaccharides include fucosylated, sialylated, and N- acetylated oligosaccharides. Specific non-limiting embodiments include: 2'-fucosyllactose (2’- FL), 3-fucosyllactose (3-FL), 3'-sialyllactose (3’-SL), 6'-sialyllactose (6’-SL), lacto-N-tetraose (LNT), and lacto-N-neotetraose (LNnT). The term “HMO blend,” unless specified otherwise, refers to a combination of fucosylated, sialylated, and N-acetylated oligosaccharides, which may comprise at least two of 2’-FL, 3-FL, 3’-SL, 6’-SL, and LNT.

[0019] The term “designed lipid component” refers to a source of lipids and/or lipid like components according to the general inventive concepts. In certain exemplary embodiments, a designed lipid component will be comprised of phospholipids alone or in combination with other lipid sources, including those derived from animal, microbial, or vegetable sources. In certain exemplary embodiments, a designed lipid component comprises a source of mono/di glycerides alone or in combination with other lipid sources. In certain exemplary embodiments, a designed lipid component comprises a source of free fatty acids alone or in combination with other lipid sources. In certain exemplary embodiments, a designed lipid component comprises combinations of two or more of the above-listed components. One specific, non-limiting example of a designed lipid component (as a percentage of the total fat in a nutritional composition) comprises a mixture of phospholipids, mono/di-glycerides, and free fatty acids is composed of a mixture of soy free fatty acids (17.5 %), monoglycerides (20 %) and lecithin (10.3 %).

[0020] The terms “fat” and “oil” as used herein, unless otherwise specified, are used interchangeably to refer to lipid materials derived or processed from plants or animals. These terms also include synthetic lipid materials so long as such synthetic materials are suitable for oral administration to humans.

[0021] The term “shelf stable” as used herein, unless otherwise specified, refers to a nutritional composition that remains commercially stable after being packaged and then stored at 18-24° C for at least 3 months, including from about 3 months to about 36 months, including from about 3 months to about 24 months, and also including from about 3 months to about 18 months.

[0022] The terms “nutritional formulation” or “nutritional composition” as used herein, are used interchangeably and, unless otherwise specified, refer to synthetic formulas including nutritional liquids, nutritional powders, nutritional solids, nutritional semi-solids, nutritional semi-liquids, nutritional supplements, and any other nutritional food product as known in the art. The nutritional powders may be reconstituted to form a nutritional liquid, all of which comprise one or more of fat, protein and carbohydrate and are suitable for oral consumption by a human. The terms “nutritional formulation” or “nutritional composition” do not include human breast milk and do not refer to supplemented milk, whether of human origin or otherwise.

[0023] The term “nutritional liquid” as used herein, unless otherwise specified, refers to nutritional compositions in ready -to-drink liquid form, concentrated form, and nutritional liquids made by reconstituting the nutritional powders described herein prior to use.

[0024] The term “nutritional powder” as used herein, unless otherwise specified, refers to nutritional compositions in flowable or scoopable form that can be reconstituted with water or another aqueous liquid prior to consumption and includes both spray dried and dry-mixed/dry- blended powders.

[0025] The term “nutritional semi-solid,” as used herein, unless otherwise specified, refers to nutritional compositions that are intermediate in properties, such as rigidity, between solids and liquids. Some semi-solids examples include puddings, gelatins, and doughs.

[0026] The term “nutritional semi-liquid,” as used herein, unless otherwise specified, refers to nutritional compositions that are intermediate in properties, such as flow properties, between liquids and solids. Some semi-liquids examples include thick shakes and liquid gels.

[0027] The term “individual” as used herein, refers generally to a preterm infant, infant, toddler, child, or adult, including elderly adults.

[0028] The term “infant” as used herein, refers generally to individuals up to age 36 months of age, actual or corrected and in certain instances may include toddlers. In certain aspects, the term infant refers to individuals up to 12 months of age, actual or corrected.

[0029] The term “preterm infant” as used herein refers to those infants born at less than 37 weeks gestation, have a birth weight of less than 2500 gm, or both.

[0030] The term “toddler” as used herein, unless otherwise specified, refers to an individual greater than one year of age up to three years of age.

[0031] The term “child” as used herein, unless otherwise specified, refers to an individual greater than three years of age up to twelve years of age.

[0032] The term “synthetic child formula” as used herein, unless otherwise specified, refers to liquid, semi-liquid, solid, and semi-solid human milk replacements or substitutes that are suitable for consumption by a child up to twelve years of age. The term “synthetic child formula” does not include human breast milk.

[0033] The term “preterm infant formula” as used herein, unless otherwise specified, refers to liquid and solid nutritional products suitable for consumption by a preterm infant. The term “preterm infant formula” does not include human breast milk. [0034] The term “human milk fortifier” as used herein, unless otherwise specified, refers to liquid and solid nutritional products suitable for mixing with breast milk or preterm infant formula or infant formula for consumption by a preterm infant or term infant. A human milk fortifier alone (i.e., when not mixed with breast milk or an infant formula) is not a sole source of nutrition suitable for an infant.

[0035] As used herein, all concentrations expressed as either “pg/liter,” “mg/liter,” “mg/L,” “mcg/L,” “mg/mL” etc., refer to ingredient concentrations within the described nutritional compositions as calculated on an as-fed basis (e.g., reconstituted for consumption in the case of nutritional powders), unless otherwise specified.

[0036] The term “reconstitute” or various other forms such as “reconstituted” or “reconstituting” all refer to the general act of adding a suitable amount of liquid, typically water, to a form of nutritional formulation that is not in its ready-to-drink liquid form, such as nutritional powder or a concentrated form of a nutritional liquid, thereby making the nutritional composition ready-to-drink.

[0037] The terms “susceptible” and “at risk” as used herein, unless otherwise specified, mean having little resistance to a certain condition or disease relative to the general population, including being genetically predisposed, having a family history of, and/or having symptoms of the condition or disease. The term refers to those having a vulnerability higher than the general population.

[0038] The terms “modulating” or “modulation” or “modulate” as used herein, unless otherwise specified, refer to the targeted movement of a selected characteristic. In certain embodiments, the term refers to balancing or “right sizing” or “shaping” a biological response or expression level. In certain embodiments, balancing a biological response refers to increasing or decreasing select members of a biological response profile (e.g., an immune response) to avoid unwanted over expression (e.g., auto-immune responses) or under expression (e.g., immune suppression). Modulation also refers to attenuation of the duration of immune response and resolution, with an appropriate immune response persisting for an amount of time necessary to prevent infection or tissue damage but resolving prior to the onset of unwanted auto-immune damage. [0039] The term “ameliorate” as used herein, unless otherwise specified, means to eliminate, delay, or reduce the prevalence or severity of symptoms associated with a condition or disease.

[0040] The term “an effective amount” or “therapeutically effective amount” is intended to qualify the amount of an active ingredient (e.g., HMO and/or a designed lipid component) which will achieve the goal of preventing or treating a disease or condition or that which will achieve the goal of decreasing the risk that the patient will suffer an adverse health event, including reducing or preventing one or more symptoms, while avoiding adverse side effects such as those typically associated with alternative therapies. The effective amount may be administered in one or more doses.

[0041] The terms “treating” and “treatment” as used herein, unless otherwise specified, includes delaying the onset of a condition, reducing the severity of symptoms of a condition, or eliminating some or all of the symptoms of a condition.

[0042] The term “food products” as used herein refer to delivery vehicles that contain one or more of fats, amino nitrogen and carbohydrates and provides some or all of the nutritional support for a patient in the recommended daily amounts. Frequently a food product will contain vitamins, minerals, trace minerals and the like to provide balanced nutrition to meal replacements, medical foods, supplements. The food products may be in any typical form such as beverages, powders, bars, juices, carbonated beverages, bottled water, etc.

[0043] All percentages, parts and ratios as used herein, are by weight of the total composition, unless otherwise specified. All such weights, as they pertain to listed ingredients, are based on the active level and, therefore, do not include solvents or by-products that may be included in commercially available materials, unless otherwise specified.

[0044] Numerical ranges as used herein are intended to include every number and subset of numbers within that range, whether specifically disclosed or not. Further, these numerical ranges should be construed as providing support for a claim directed to any number or subset of numbers in that range. For example, a disclosure of from 1 to 10 should be construed as supporting a range of from 2 to 8, from 3 to 7, from 5 to 6, from 1 to 9, from 3.6 to 4.6, from 3.5 to 9.9, and so forth.

[0045] All references to singular characteristics or limitations of the general inventive concepts shall include the corresponding plural characteristic or limitation, and vice versa, unless otherwise specified or clearly implied to the contrary by the context in which the reference is made.

[0046] All combinations of method or process steps as used herein can be performed in any order, unless otherwise specified or clearly implied to the contrary by the context in which the referenced combination is made.

[0047] The HMOs and designed lipids can be formulated in suitable compositions and then, in accordance with the methods of the invention, administered to an individual in a form adapted to the chosen route of administration. The formulations include, but are not limited to, those suitable for oral or parental (including subcutaneous, intramuscular, intraperitoneal, intratumoral, and intravenous) administration. Oral administration, as defined herein, includes any form of administration in which the HMOs and a designed lipid component pass through the esophagus of the patient. For example, oral administration includes nasogastric intubation, in which a tube is run from through the nose to the stomach of the patient to administer food or drugs.

[0048] Oral formulations include any solid, liquid, or powder formulation suitable for use herein, provided that such a formulation allows for the safe and effective oral delivery of the HMOs and optional nutritive components. In preferred aspects, the oral formulation is a liquid nutritional composition. Formulations of the present invention suitable for oral administration may be presented as discrete units such as tablets, troches, capsules, lozenges, wafers, or cachets, each containing a predetermined amount of the HMO and/or a designed lipid component as a powder or granules or as a solution or suspension in an aqueous liquor or non-aqueous liquid such as a syrup, an elixir, an emulsion, or a draught.

[0049] The nutritional compositions and methods may comprise, consist of, or consist essentially of the essential elements of the compositions and methods as described herein, as well as any additional or optional element described herein or otherwise useful in nutritional composition applications.

[0050] As previously mentioned, the general inventive concepts are directed to nutritional compositions including at least one HMO, in combination with a designed lipid component, for use in modulating or treating the conditions or diseases described herein, including but not limited to: improving lung function in an individual; improving lung elasticity in an individual; (or treating a lack of lung elasticity or conditions characterized by hampered lung elasticity) in an individual; increasing one or more lung surfactants in an individual; and reducing or ameliorating symptoms of lung injury in an individual. The concepts are based on the discovery that HMOs and a designed lipid component act in concert to interact with the individual’s own systems to improve at least one marker of lung health.

[0051] In certain exemplary aspects, the general inventive concepts relate to a method of improving lung function in an individual in need thereof. The method comprises identifying an individual in need of improved lung function; and administering to the individual a nutritional composition comprising: a) a neutral human milk oligosaccharide; b) an acidic human milk oligosaccharide; and c) a designed lipid component. In certain exemplary aspects, improving lung function comprises increasing at least one lung surfactant. In certain exemplary aspects the lung surfactant is lung surfactant A. In certain exemplary aspects the lung surfactant is increased in an amount of at least 10%, including 10% to 150%, or more. In certain exemplary aspects, the at least one lung surfactant is increased by 20% to 150%. In certain exemplary aspects, the at least one lung surfactant is increased by 30% to 150%. In certain exemplary aspects, the at least one lung surfactant is increased by 40% to 150%. In certain exemplary aspects, the at least one lung surfactant is increased by 50% to 150%. In certain exemplary aspects, the at least one lung surfactant is increased by 60% to 150%. In certain exemplary aspects, the at least one lung surfactant is increased by 70% to 150%. In certain exemplary aspects, the at least one lung surfactant is increased by 80% to 150%. In certain exemplary aspects, the at least one lung surfactant is increased by 90% to 150%. In certain exemplary aspects, the at least one lung surfactant is increased by 100% to 150%. In certain exemplary aspects, the at least one lung surfactant is increased by 110% to 150%. In certain exemplary aspects, the at least one lung surfactant is increased by 120% to 150%. In certain exemplary aspects, the at least one lung surfactant is increased by 130% to 150%. In certain exemplary aspects, the at least one lung surfactant is increased by 140% to 150%. In certain exemplary aspects, the at least one lung surfactant is increased by 10% to 100%. In certain exemplary aspects, the at least one lung surfactant is increased by 10% to 90%. In certain exemplary aspects, the at least one lung surfactant is increased by 10% to 80%. In certain exemplary aspects, the at least one lung surfactant is increased by 10% to 70%. In certain exemplary aspects, the at least one lung surfactant is increased by 10% to 60%. In certain exemplary aspects, the at least one lung surfactant is increased by 10% to 50%. In certain exemplary aspects, the at least one lung surfactant is increased by 10% to 40%. In certain exemplary aspects, the at least one lung surfactant is increased by 10% to 30%. In certain exemplary aspects, the at least one lung surfactant is increased by 10% to 20%.

[0052] In certain exemplary aspects, the general inventive concepts relate to a method of improving lung elasticity in an individual in need thereof, the method comprises identifying an individual in need of improved lung elasticity; and administering to the individual a nutritional composition comprising: a) a neutral human milk oligosaccharide; b) an acidic human milk oligosaccharide; and c) a designed lipid component. In certain exemplary embodiments, a neutral human milk oligosaccharide; an acidic human milk oligosaccharide; and a designed lipid component are provided in therapeutically effective amounts. In certain exemplary embodiments, the individual’s lung elasticity is improved by an increase in at least one lung surfactant.

[0053] In certain exemplary aspects, the general inventive concepts relate to a method of increasing at least one lung surfactant in an individual in need thereof, the method comprises administering to the individual a nutritional composition comprising: a) a neutral human milk oligosaccharide; b) an acidic human milk oligosaccharide; and c) a designed lipid component. In certain exemplary embodiments, a neutral human milk oligosaccharide; an acidic human milk oligosaccharide; and a designed lipid component are provided in therapeutically effective amounts.

[0054] In certain exemplary aspects, the general inventive concepts relate to a nutritional composition for use in treating insufficient lung function. In certain exemplary aspects, the nutritional composition comprises: a) a neutral human milk oligosaccharide; b) an acidic human milk oligosaccharide; and c) a designed lipid component.

[0055] In certain exemplary aspects, the general inventive concepts relate to a nutritional composition for use in modulating lung immune function, including treating insufficient lung immune function. In certain exemplary aspects, the nutritional composition comprises: a) a neutral human milk oligosaccharide; b) an acidic human milk oligosaccharide; and c) a designed lipid component. In certain exemplary aspects the lung immune function is viral immunity.

[0056] In certain exemplary aspects, the general inventive concepts relate to a nutritional composition for use in increasing at least one lung surfactant including surfactant protein A (SP-A). In certain exemplary aspects, the nutritional composition comprises: a) a neutral human milk oligosaccharide; b) an acidic human milk oligosaccharide; and c) a designed lipid component.

In certain exemplary aspects, the general inventive concepts relate to a nutritional composition for use in increasing at least one lung surfactant. In certain exemplary embodiments, the lung surfactant is increased following the administration of HMO and/or a designed lipid component to cultured A549 lung epithelial cells.

Human Milk Oligosaccharides

[0057] The nutritional compositions according to the general inventive concepts include an HMO component comprising at least one HMO, and in many embodiments, a combination of two or more HMOs, including neutral and acidic HMOs. The composition of human milk oligosaccharides is very complex and more than 200 different oligosaccharide structures are known.

[0058] The HMOs may be included in the nutritional compositions with a designed lipid component alone, or in some embodiments, in combination with other functional components to aid in ameliorating symptoms of the particular condition or disease (LCPUFAs, probiotics, antioxidants, nucleotides, etc.) as described herein. The HMO or HMOs may be isolated or enriched from milk(s) secreted by mammals including, but not limited to: human, bovine, ovine, porcine, or caprine species. The HMOs may also be produced via microbial fermentation, enzymatic processes, chemical synthesis, or combinations thereof.

[0059] Suitable HMOs for use in the nutritional compositions may include neutral oligosaccharides, n-acetyl glucosylated oligosaccharides, acidic HMOs, and HMO precursors. Specific non-limiting examples of HMOs that may be included individually or in combination in the compositions according to the general inventive concepts include: 2’-FL, 3-FL, 3’-SL, 6'-SL, LNnT, and LNT.

[0060] Other HMOs that may be included in certain embodiments include: N- acetylglucosamine (GlcNAc); L-fucose (L-Fuc); D-fucose (D-Fuc); fucosyl oligosaccharides (i.e., Lacto-N-fucopentaose I; Lacto-N-fucopentaose II; Lacto-N-fucopentaose III; Lacto-N- difucohexaose I; and Lactodifucotetraose); non-fucosylated, non-sialylated oligosaccharides (i.e., Lacto-N-neotetraose); sialyl fucosyl oligosaccharides (i.e., 3'-Sialyl-3-fucosyllactose; Disialomonofucosyllacto-N-neohexaose; Monofucosylmonosialyllacto-N-octaose (sialyl Lea); Sialyllacto-N-fucohexaose II; Disialyllacto-N-fucopentaose II; Monofucosyldisialyllacto-N- tetraose); and sialyl oligosaccharides (i.e., 3'-Sialyllactose; 3-Sialyllactosamine; 6'-Sialyllactose; 6'-Sialyllactosamine; Sialyllacto-N-neotetraose c; Monosialyllacto-N-hexaose; Disialyllacto-N- hexaose I; Monosialyllacto-N-neohexaose I; Monosialyllacto-N-neohexaose II; Disialyllacto-N- neohexaose; Disialyllacto-N-tetraose; Disialyllacto-N-hexaose II; Sialyllacto-N-tetraose a; Disialyllacto-N-hexaose I; and Sialyllacto-N-tetraose b). Also useful are variants in which the glucose (Glc at the reducing end is replaced by N-acetylglucosamine (e.g., 2'-fucosyl-N- acetylglucosamine (2'-FLNac) is such a variant to 2'-fucosyllactose). These HMOs are described more fully in U.S. Patent Application No. 2009/0098240, which is herein incorporated by reference in its entirety. Other suitable examples of HMOs that may be included in the compositions according to the general inventive concepts include lacto-N-fucopentaose V, lacto- N-hexaose, para-lacto-N-hexaose, lacto-N-neohexaose, para-lacto-N-neohexaose, monofucosyllacto-N-hexaose II, isomeric fucosylated lacto-N-hexaose (1), isomeric fucosylated lacto-N-hexaose (3), isomeric fucosylated lacto-N-hexaose (2), difucosyl-para-lacto-N- neohexaose, difucosyl-para-lacto-N-hexaose, difucosyllacto-N-hexaose, lacto-N-neoocataose, para-lacto-N-octanose, iso-lacto-N-octaose, lacto-N-octaose, monofucosyllacto-neoocataose, monofucosyllacto-N-ocataose, difucosyllacto-N-octaose I, difucosyllacto-N-octaose II, difucosyllacto-N-neoocataose II, difucosyllacto-N-neoocataose I, lacto-N-decaose, trifucosyllacto-N-neooctaose, trifucosyllacto-N-octaose, trifucosyl-iso-lacto-N-octaose, lacto-N- difuco-hexaose II, sialyl-lacto-N-tetraose a, sialyl-lacto-N-tetraose b, sialyl-lacto-N-tetraose c, sialyl-fucosyl-lacto-N-tetraose I, sialyl-fucosyl-lacto-N-tetraose II, and disialyl-lacto-N-tetraose, and combinations thereof.

[0061] The HMOs are present in the nutritional compositions in total amounts of HMO in the composition (mg of HMO per mL of composition) of at least about 0.001 mg/mL to about 20 mg/mL, including about 0.001 mg/mL to about 20 mg/mL, 1 mg/mL to about 10 mg/mL, 2 mg/mL to about 10 mg/mL, and including from about 2.5 mg/mL to about 8.5 mg/mL. Typically, the amount of HMO in the nutritional composition will depend on the specific HMO or HMOs present and the amounts of other components in the nutritional compositions.

[0062] In certain exemplary aspects of the present disclosure, the nutritional composition includes a neutral HMO and an acidic HMO (e.g., at least one of 2’-FL, 3-FL, 3’- SL, 6'-SL, and LNT) in a total amount of HMO of from about 0.001 mg/mL to about 20 mg/mL, including from about 0.01 mg/mL to about 20 mg/mL, including from about 0.1 mg/mL to about 20 mg/mL, about 0.5 mg/mL to about 20 mg/mL, about 1 mg/mL to about 20 mg/mL, about 2 mg/mL to about 20 mg/mL. about 3 mg/mL to about 20 mg/mL, and about 5 mg/mL to about 20 mg/mL. In certain exemplary aspects of the present disclosure, the nutritional composition includes at least one of 2’-FL, 3-FL, 3’-SL, 6'-SL, and LNT in a total amount of HMO of from about 0.1 g/L to about 20 mg/mL, including from about 0.1 g/L to about 15 mg/mL, including from about 0.1 g/L to about 10 g/L, including from about 0.1 g/L to about 9 g/L, including from about 0.1 g/L to about 8 g/L, including from about 0.1 g/L to about 7 g/L, including from about 0.1 g/L to about 6 g/L, including from about 0.1 g/L to about 5 g/L, including from about 0.1 g/L to about 4 g/L, including from about 0.1 g/L to about 3 g/L, including from about 0.1 g/L to about 2 g/L, including from about 0.5 g/L to about 4 g/L, including from about 0.5 g/L to about 3 g/L, including from about 1 g/L to about 2.5 g/L; and including from about 3.1 g/L to about 8.2 g/L.

[0063] In certain exemplary aspects of the present disclosure, the nutritional composition comprises at least one of a (neutral) fucosylated HMO and a (acidic) sialylated HMO. In certain exemplary aspects of the present disclosure, the nutritional composition also comprises at least one N-acetylated HMO (often these also fall under the term “neutral”). In certain exemplary aspects of the present disclosure, the nutritional composition comprises a combination of a fucosylated HMO, a sialylated HMO, and an N-acetylated HMO. Specific non limiting examples of suitable HMOs for use according to the general inventive concepts include 2’-FL, 3-FL, 3’-FL, 6’-SL, and LNT.

[0064] In certain exemplary aspects of the present disclosure, the nutritional composition comprises a combination of 2’-FL, 3-FL, LNT, 3’-SL, and 6’-SL. In certain exemplary aspects of the present disclosure, the nutritional composition comprises 2’-FL in an amount up to 4.15 g/L, LNT in an amount up to 2.11 g/L, 3-FL in an amount up to 1.17 g/L, 3’- SL in an amount up to 0.36 g/L, and 6’-SL in an amount up to 0.44 g/L.

[0065] In certain aspects of the present disclosure, the nutritional composition includes at least one HMO and one or more additional components as described herein such that the composition provides a synergistic benefit to the end user, such as a synergistic benefit in modulating or treating one or more of the conditions or diseases described herein.

Designed Lipid Component

[0066] The nutritional compositions according to the general inventive concepts include a designed lipid component comprising at least one lipid ingredient, and in many embodiments, a combination of two or more lipids or types of lipids (including phospholipids) alone or in combination with mono/di-glycerides mixtures and/or free fatty acids. Suitable phospholipids (PL) for use in the designed lipid component according to the general inventive concepts include those derived from vegetable (such as soybean, sunflower, rapeseed, canola, com, olive, cotton seeds and oils, etc.), animal (egg yolk, mammalian milk fat, etc.), marine animal sources (salmon, krill oils, etc.), single cell organisms (algal oils), those produced from microbial fermentation, including sphingophospholipids and glycerophospholipids (GPLs) and all know PL species (phosphatidic acid, phosphatidylethanolamine, phosphatidylserine, phosphoinositide, lyso-phosphatidylcholines, diacyl-phosphatidylcholines), ether-linked phosphatidylcholines, sphingomyelines (including ceramides, glucosyl ceramides, lactosyl ceramides, etc.) An example of a suitable phospholipid is lecithin. [0067] In certain embodiments, the designed lipid component comprises fatty acid- containing mono- and/or di-glycerides, alone or in combination with a phospholipid and/or a free fatty acid component as described below. Mono- and/or di-glycerides are normal metabolites in the body formed during the breakdown of triglycerides. As noted, the fatty acid-containing monoglycerides may be included in the nutritional products in combination with a phospholipid and/or a free fatty acid component, such as fatty acids and/or fatty acid salts as described below.

[0068] Suitable mono/di-glyceride constituent fatty acids for use in the nutritional products include fatty acids having a chain length of from 4 to 22 carbon atoms, including fatty acids having a chain length of from 14 to 20 carbon atoms, one non-limiting example is palmitic acid (16 carbon atoms). In certain exemplary embodiments the mono/di -glycerides comprise fats or oils from any oil source. In certain exemplary embodiments, the mono/di glycerides are present in a ratio of mono:di of 10:1 to 0.5:1 by weight.

[0069] In one specific embodiment, the mono/di-glycerides (and optionally the fatty acid component as discussed below) in the nutritional composition are partially or totally provided to the composition through the use of hydrolyzed lard or hydrolyzed tallow.

[0070] In another embodiment, the mono/di-glycerides in the nutritional composition are partially or totally derived from oils such as vegetable oils, marine oils, fish oils, algae oil, fungal oils, tree resin, and combinations thereof. Suitable vegetable oils include, for example, olive oil, canola oil, corn oil, palm oil, soybean oil, and combinations thereof.

[0071] In embodiments wherein the mono/di-glycerides are present in the designed lipid component, they may be present in amounts of at least about 1% by weight of the total fat included in the nutritional composition, including at least about 5% by weight of the total fat included in the nutritional composition, including at least about 10% by weight of the total fat included in the nutritional composition, including at least about 15% by weight of the fat included in the nutritional composition, including at least about 20% by weight of the fat component included in the nutritional composition, including from 1% to 45%, including from 5% to 45%, including from 10% to 45%, including from 12% to 45%, including from

15% to 25%, and including about 10%, including about 15%, including about 20%, including about 25%, including about 30%, and further including about 35%, or even about 40%, or even about 50%, or even about 60%, or even about 70%, or even about 80%, or even about 90%, or even about 100% by weight of the fat included in the nutritional composition.

[0072] In addition to, or in place of, the fatty acid-containing mono/di-glycerides described above, the designed lipid component of the present disclosure may include a fatty acid component comprising fatty acids (also called free fatty acids). Fatty acids are normal metabolites in the body notably formed during the breakdown of fat (triglycerides, diglycerides, cholesterol esters, and certain phospholipids). This fatty acid component is separate and distinct from the fatty acid-containing mono/di-glycerides discussed above.

[0073] Any fatty acid beneficial in a nutritional composition can be included in the nutritional compositions as part of the designed lipid component. In one embodiment, the fatty acid is an unsaturated free fatty acid. In certain exemplary embodiments the fatty acid may be a medium chain fatty acid. Exemplary fatty acids suitable for inclusion in the nutritional compositions described herein include, but are not limited to, arachidonic acid, linolenic acid, linoleic acid, alpha-linolenic acid, palmitic acid, docosahexaenoic acid, stearidonic acid, oleic acid, eicosenoic acid, mead acid, erucic acid, nervonic acid, and mixtures and combinations thereof. Examples of preferred fatty acids include arachidonic acid, linoleic acid, linolenic acid, docosahexaenoic acid, and oleic acid.

[0074] The fatty acid component for inclusion in the designed lipid component include those derived from oils such as vegetable oils, marine oils, fish oils, algae oil, fungal oils, animal fats, those derived from microbial fermentation, fractionated animal fats and combinations thereof. Suitable vegetable oils include, for example, olive oil, canola oil, com oil, soybean oil, and combinations thereof. In one embodiment, when animal fat is used, the fatty acids are derived by enzymatic hydrolysis of lard or tallow. In certain embodiments, at least some of the fatty acids are derived from soybean oil or tree resin. Once derived from the oil source, the fatty acids are substantially free of monoglycerides, diglycerides and triglycerides.

[0075] The individual constituents of the designed lipid component can be present in the nutritional compositions in a variety of concentrations depending on the nutritional needs of the consumer and the intended therapeutic target. In certain embodiments, phospholipids are present in the nutritional composition in amounts from about 0.003g/L to about 5 g/L. In certain embodiments, phospholipids are present in the nutritional composition in amounts from about 0.004g/L to about 5 g/L. In certain embodiments, phospholipids are present in the nutritional composition in amounts from about 0.005g/L to about 5 g/L. In certain embodiments, phospholipids are present in the nutritional composition in amounts from about 0.006g/L to about 5 g/L. In certain embodiments, phospholipids are present in the nutritional composition in amounts from about 0.007g/L to about 5 g/L. In certain embodiments, phospholipids are present in the nutritional composition in amounts from about 0.008g/L to about 5 g/L. In certain embodiments, phospholipids are present in the nutritional composition in amounts from about 0.009g/L to about 5 g/L. In certain embodiments, phospholipids are present in the nutritional composition in amounts from about O.OlOg/L to about 5 g/L. In certain embodiments, phospholipids are present in the nutritional composition in amounts from about 0.01 lg/L to about 5 g/L. In certain embodiments, phospholipids are present in the nutritional composition in amounts from about 0.012g/L to about 5 g/L. In certain embodiments, phospholipids are present in the nutritional composition in amounts from about 0.013g/L to about 5 g/L. In certain embodiments, phospholipids are present in the nutritional composition in amounts from about 0.014g/L to about 5 g/L. In certain embodiments, phospholipids are present in the nutritional composition in amounts from about 0.015g/L to about 4 g/L. In certain embodiments, phospholipids are present in the nutritional composition in amounts from about 0.015g/L to about 3 g/L. In certain embodiments, phospholipids are present in the nutritional composition in amounts from about 0.015g/L to about 2 g/L. In certain embodiments, phospholipids are present in the nutritional composition in amounts from about 0.015g/L to about 1 g/L. In certain embodiments, phospholipids are present in the nutritional composition in amounts from about 0.015g/L to about 5 g/L. In certain embodiments, phospholipids are present in the nutritional composition in amounts from about 0.02g/L to about 5 g/L. In certain embodiments, phospholipids are present in the nutritional composition in amounts from about 0.03g/L to about 5 g/L. In certain embodiments, phospholipids are present in the nutritional composition in amounts from about 0.04g/L to about 5 g/L. In certain embodiments, phospholipids are present in the nutritional composition in amounts from about 0.05g/L to about 5 g/L. In certain embodiments, phospholipids are present in the nutritional composition in amounts from about O.lg/L to about 5 g/L. In certain embodiments, phospholipids are present in the nutritional composition in amounts from about 0.2g/L to about 5 g/L. In certain embodiments, phospholipids are present in the nutritional composition in amounts from about 0.3g/L to about 5 g/L. In certain embodiments, phospholipids are present in the nutritional composition in amounts from about 0.4g/L to about 5 g/L. In certain embodiments, phospholipids are present in the nutritional composition in amounts from about 0.5g/L to about 5 g/L. In certain embodiments, phospholipids are present in the nutritional composition in amounts from about 1 g/L to about 5 g/L.

[0076] In certain embodiments, mono and di glycerides are present in the nutritional composition in amounts from about 0.01 g/L to about 10 g/L. In certain embodiments, mono and di glycerides are present in the nutritional composition in amounts from about 0.02 g/L to about 10 g/L. In certain embodiments, mono and di glycerides are present in the nutritional composition in amounts from about 0.03 g/L to about 10 g/L. In certain embodiments, mono and di glycerides are present in the nutritional composition in amounts from about 0.04 g/L to about 10 g/L. In certain embodiments, mono and di glycerides are present in the nutritional composition in amounts from about 0.5 g/L to about 10 g/L. In certain embodiments, mono and di glycerides are present in the nutritional composition in amounts from about 0.06 g/L to about 10 g/L. In certain embodiments, mono and di glycerides are present in the nutritional composition in amounts from about 0.07 g/L to about 10 g/L. In certain embodiments, mono and di glycerides are present in the nutritional composition in amounts from about 0.08 g/L to about 10 g/L. In certain embodiments, mono and di glycerides are present in the nutritional composition in amounts from about 0.09 g/L to about 10 g/L. In certain embodiments, mono and di glycerides are present in the nutritional composition in amounts from about 0.1 g/L to about 10 g/L. In certain embodiments, mono and di glycerides are present in the nutritional composition in amounts from about O.lg/L to about 9 g/L. In certain embodiments, mono and di glycerides are present in the nutritional composition in amounts from about 0.1 g/L to about 8 g/L. In certain embodiments, mono and di glycerides are present in the nutritional composition in amounts from about 0.1 g/L to about 7 g/L. In certain embodiments, mono and di glycerides are present in the nutritional composition in amounts from about 0.2 g/L to about 7 g/L. In certain embodiments, mono and di glycerides are present in the nutritional composition in amounts from about 0.3 g/L to about 7 g/L. In certain embodiments, mono and di glycerides are present in the nutritional composition in amounts from about 0.4 g/L to about 7 g/L. In certain embodiments, mono and di glycerides are present in the nutritional composition in amounts from about 0.5 g/L to about 7 g/L. In certain embodiments, mono and di glycerides are present in the nutritional composition in amounts from about 1 g/L to about 7 g/L. In certain embodiments, mono and di glycerides are present in the nutritional composition in amounts from about 2 g/L to about 7 g/L. In certain embodiments, mono and di glycerides are present in the nutritional composition in amounts from about 3 g/L to about 7 g/L. In certain embodiments, mono and di glycerides are present in the nutritional composition in amounts from about 4 g/L to about 7 g/L. In certain embodiments, mono and di glycerides are present in the nutritional composition in amounts from about 5 g/L to about 7 g/L.

[0077] In certain embodiments, free fatty acids are present in the nutritional composition in amounts from about 0.005 g/L to about 10 g/L. In certain embodiments, free fatty acids are present in the nutritional composition in amounts from about 0.009 g/L to about 10 g/L. In certain embodiments, free fatty acids are present in the nutritional composition in amounts from about 0.01 g/L to about 10 g/L. In certain embodiments, free fatty acids are present in the nutritional composition in amounts from about 0.02 g/L to about 10 g/L. In certain embodiments, free fatty acids are present in the nutritional composition in amounts from about 0.03 g/L to about 10 g/L. In certain embodiments, free fatty acids are present in the nutritional composition in amounts from about 0.04 g/L to about 10 g/L. In certain embodiments, free fatty acids are present in the nutritional composition in amounts from about 0.05 g/L to about 10 g/L. In certain embodiments, free fatty acids are present in the nutritional composition in amounts from about 0.06 g/L to about 10 g/L. In certain embodiments, free fatty acids are present in the nutritional composition in amounts from about 0.07 g/L to about 10 g/L. In certain embodiments, free fatty acids are present in the nutritional composition in amounts from about 0.08 g/L to about 10 g/L. In certain embodiments, free fatty acids are present in the nutritional composition in amounts from about 0.09 g/L to about 10 g/L. In certain embodiments, free fatty acids are present in the nutritional composition in amounts from about 0.1 g/L to about 10 g/L.

In certain embodiments, free fatty acids are present in the nutritional composition in amounts from about O.lg/L to about 9 g/L. In certain embodiments, free fatty acids are present in the nutritional composition in amounts from about 0.1 g/L to about 8 g/L. In certain embodiments, free fatty acids are present in the nutritional composition in amounts from about 0.1 g/L to about 7 g/L. In certain embodiments, free fatty acids are present in the nutritional composition in amounts from about 0.2 g/L to about 7 g/L. In certain embodiments, free fatty acids are present in the nutritional composition in amounts from about 0.3 g/L to about 7 g/L. In certain embodiments, free fatty acids are present in the nutritional composition in amounts from about 0.4 g/L to about 7 g/L. In certain embodiments, free fatty acids are present in the nutritional composition in amounts from about 0.5 g/L to about 7 g/L. In certain embodiments, free fatty acids are present in the nutritional composition in amounts from about 1 g/L to about 7 g/L. In certain embodiments, free fatty acids are present in the nutritional composition in amounts from about 2 g/L to about 7 g/L. In certain embodiments, free fatty acids are present in the nutritional composition in amounts from about 3 g/L to about 7 g/L. In certain embodiments, free fatty acids are present in the nutritional composition in amounts from about 4 g/L to about 7 g/L. In certain embodiments, free fatty acids are present in the nutritional composition in amounts from about 5 g/L to about 7 g/L. In certain exemplary embodiments, the free fatty acids are optional in the designed lipid component (excluding inherent amounts).

Probiotics

[0078] In certain exemplary aspects, the nutritional composition comprises up to 10⁹ cfu/g (e.g., when a powdered or reconstitutable composition) of a probiotic or combination of probiotics as described herein, including in a range from about 10 cfu/g to about 10⁹ cfu/g, or from about 10² cfu/g to about 10⁷ cfu/g, or from about 10³cfu/g to about 10⁶ cfu/g, or from about 10⁴ cfu/g to about 10⁶ cfu/g. For example, in specific embodiments, the powdered nutritional composition comprises up to 10⁹ cfu/g of probiotic, including in a range from about 10 cfu/g to about 10⁹ cfu/g, or from about 10² cfu/g to about 10⁷ cfu/g, or from about 10³cfu/g to about 10⁶ cfu/g, or from about 10⁴ cfu/g to about 10⁶ cfu/g.

[0079] In certain exemplary aspects, the probiotic comprises a probiotic blend in a total cell count amount of at least 1 billion colony forming unit (CFU) per serving. In certain exemplary aspects, the probiotic blend comprises 10 million colony forming units (CFU) to 10 billion CFU of Bifidobacterium lactis , 10 million CFU to 10 billion CFU of Bifidobacterium infantis , and 10 million CFU to 10 billion CFU of Streptococcus thermophilus. [0080] In addition to the HMOs, designed lipid component and probiotics described above, the nutritional compositions according to the general inventive concepts may include Long Chain Polyunsaturated Fatty Acids (LCPUFAs). LCPUFAs are included in the nutritional compositions to provide nutritional support, as well as to modulate or treat the conditions or diseases described herein. In certain aspects of the present disclosure, the nutritional composition includes a combination of the HMOs and a designed lipid component and one or more LCPUFAs such that the composition provides a synergistic benefit to the end user, such as a synergistic benefit in modulating or treating one or more of the conditions or diseases described herein.

[0081] Exemplary LCPUFAs for use in the nutritional compositions include, for example, w-3 LCPUFAs and w-6 LCPUFAs. Specific LCPUFAs include docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), docosapentaenoic acid (DP A), arachidonic acid (ARA), linoleic acid, linolenic acid (alpha linolenic acid) and gamma-linolenic acid derived from oil sources such as plant oils, marine plankton, fungal oils, krill oil, microbial fermentation, and fish oils. In one particular aspect, the LCPUFAs are derived from fish oils such as menhaden, salmon, anchovy, cod, halibut, tuna, or herring oil. Particularly preferred LCPUFAs for use in the nutritional compositions include DHA, ARA, EPA, DP A, and combinations thereof.

[0082] In order to reduce potential side effects of high dosages of LCPUFAs including DHA, ARA, EPA, DP A, in the nutritional compositions, the content of DHA, ARA, EPA, DP A, preferably does not exceed 5% by weight of the total fat content, including below 2% by weight of the total fat content, and including below 1% by weight of the total fat content in the nutritional composition.

[0083] The LCPUFA may be provided as free fatty acids, in triglyceride form, in diglyceride form, in monoglyceride form, in phospholipid form, in esterified form or as a mixture of one or more of the above, preferably in triglyceride form.

[0084] The nutritional compositions as described herein will typically comprise total concentrations of ARA, DHA, EPA, and DPA of from about 0.001 g/L to about 1 g/L, including from about 0.01 g/L to about 1 g/L, and about 0.1 g/L to about 1 g/L. [0085] In an exemplary embodiment, the nutritional compositions include a long chain polyunsaturated fatty acid component comprising DHA and ARA in a concentration of from about 0.17 mg/mL to about 0.33 mg/mL, including from about 0.17 mg/mL to about 0.26 mg/mL of ARA and DHA. In an exemplary embodiment, the nutritional compositions include DHA in a concentration of from about 0.025 mg/mL to about 0.130 mg/mL. In another embodiment, the nutritional compositions include ARA in a concentration of from about 0.080 mg/mL to about 0.350 mg/mL. In yet another embodiment, the nutritional compositions include combinations of DHA and ARA such that the ratio of DHA to ARA ranges from about 1 :4 to about 1 :2.

[0086] In addition to the specific functional ingredients described herein, the nutritional composition includes one or more ingredients that help satisfy the individual’s nutritional requirements. The optional nutrients can provide up to about 1000 kcal of energy per serving or dose, including from about 25 to about 900 kcal, from about 75 to about 700 kcal, from about 150 to about 500 kcal, from about 350 to about 500 kcal, or from about 200 to about 300 kcal.

[0087] The nutritional compositions may be formulated with sufficient kinds and amounts of nutrients to provide a sole, primary, or supplemental source of nutrition, or to provide a specialized nutritional composition for use in individuals afflicted with specific diseases or conditions or with a targeted nutritional benefit as described below.

[0088] The nutritional compositions including the HMO or HMOs and designed lipid component may be formulated to include at least one of protein, fat, and carbohydrate. In many embodiments, the nutritional compositions will include the HMO or HMOs and designed lipid component with protein, carbohydrate and fat (in addition to or including the designed lipid component). Although total concentrations or amounts of the fat, protein, and carbohydrates may vary depending upon the product type (i.e., nutritional formula), product form (i.e., nutritional solid, powder, ready-to-feed liquid, or concentrated liquid) and targeted dietary needs of the intended user, such concentrations or amounts most typically fall within one of the following embodied ranges, inclusive of any other essential fat, protein, and/or carbohydrate ingredients as described herein. Macronutrients

[0089] In certain aspects, the nutritional composition will include at least one of protein, fat, and carbohydrate. In many aspects, the nutritional composition will include protein, fat (in addition to or including the designed lipid component), and carbohydrate.

[0090] Where present, carbohydrate concentrations most typically will range from about 5% to about 40%, including from about 7% to about 30%, including from about 10% to about 25%, by weight of the nutritional composition. Where present, fat concentrations most typically range from about 1% to about 30%, including from about 2% to about 15%, and also including from about 3% to about 10%, by weight of the nutritional composition. Where present, protein concentrations most typically range from about 0.5% to about 30%, including from about 1% to about 15%, and also including from about 2% to about 10%, by weight of the nutritional composition.

[0091] The amount of any or all of the carbohydrates, fats, and proteins in any of the nutritional compositions (e.g., infant formula) described herein may also be characterized as a percentage of total calories in the nutritional composition as set forth in the following table. These macronutrients for nutritional compositions according to the general inventive concepts are most typically formulated within any of the caloric ranges (embodiments A-F) described in the following table (each numerical value is preceded by the term “about”).

Table 2. Exemplary macronutrient profiles of nutritional compositions

Fat

[0092] The nutritional compositions according to the general inventive concepts may, in addition to or including the designed lipid component and LCPUFA’s, comprise an additional source or sources of fat. Suitable additional sources of fat for use herein include any fat or fat source that is suitable for use in an oral nutritional composition and is compatible with the essential elements and features of such compositions. Most typically the fat may be an emulsified fat, concentrations of which may range from about 1% to about 30%, including from about 2% to about 15%, and also including from about 3% to about 10%, by weight. In an exemplary aspect of the present disclosure, the additional fat is derived from short chain fatty acids.

[0093] Additional non-limiting examples of suitable fats or sources thereof for use in the nutritional compositions described herein include coconut oil, fractionated coconut oil, soybean oil, com oil, olive oil, safflower oil, high oleic safflower oil, oleic acids (EMERSOL 6313 OLEIC ACID, Cognis Oleochemicals, Malaysia), MCT oil (medium chain triglycerides), sunflower oil, high oleic sunflower oil, palm and palm kernel oils, palm olein, canola oil, marine oils, fish oils, fungal oils, algae oils, cottonseed oils, and combinations thereof. Lipid sources of arachidonic acid and docosahexaenoic acid include, but are not limited to, marine oil, egg yolk oil, and fungal or algal oil. [0094] Numerous commercial sources for these fats are readily available and known to one practicing the art. For example, soy and canola oils are available from Archer Daniels Midland of Decatur, Ill. Corn, coconut, palm and palm kernel oils are available from Premier Edible Oils Corporation of Portland, Organ. Fractionated coconut oil is available from Henkel Corporation of LaGrange, Ill. High oleic safflower and high oleic sunflower oils are available from SVO Specialty Products of Eastlake, Ohio. Marine oil is available from Mochida International of Tokyo, Japan. Olive oil is available from Anglia Oils of North Humberside, United Kingdom. Sunflower and cottonseed oils are available from Cargill of Minneapolis,

Minn. Safflower oil is available from California Oils Corporation of Richmond, Calif.

[0095] In addition to these food grade oils, structured lipids may be incorporated into the food product if desired. Structured lipids are known in the art. A concise description of structured lipids can be found in INFORM, Vol. 8, No. 10, page 1004; entitled Structured lipids allow fat tailoring (October 1997). Also see U.S. Pat. No. 4,871,768. Structured lipids are predominantly triacylglycerols containing mixtures of medium and long chain fatty acids on the same glycerol nucleus. Structured lipids and their use in enteral formula are also described in U.S. Pat. Nos. 6,194,379 and 6,160,007.

[0096] Optionally, w-3 fatty acids may comprise up to approximately 5% of the oil blend, preferably the w-3 fatty acids largely consist of the longer chain forms, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Dietary oils used in the preparation of the nutritional composition generally contain w-3 fatty acids in the triglyceride form and include, but are not limited to canola, medium chain triglycerides, fish, soybean, soy lecithin, corn, safflower, sunflower, high-oleic sunflower, high-oleic safflower, olive, borage, black currant, evening primrose and flaxseed oil.

Protein

[0097] The nutritional compositions according to the general inventive concepts may include protein. As mentioned above, when present, protein concentrations most typically range from about 0.5% to about 30%, including from about 1% to about 15%, and also including from about 2% to about 10%, by weight of the nutritional composition. Any protein source that is suitable for use in oral nutritional composition and is compatible with the essential elements and features of such formulas is suitable for use in the nutritional compositions.

[0098] Non-limiting examples of suitable proteins or sources thereof for use in the nutritional compositions include hydrolyzed, partially hydrolyzed or non-hydrolyzed proteins or protein sources, which may be derived from any known or otherwise suitable source such as milk ( e.g ., casein, whey), animal (e.g, meat, fish), cereal (e.g. , rice, com), vegetable (e.g, soy) or combinations thereof. Non-limiting examples of such proteins include milk protein isolates, milk protein concentrates as described herein, casein protein isolates, extensively hydrolyzed casein, whey protein, sodium or calcium caseinates, whole cow milk, partially or completely defatted milk, soy protein isolates, and soy protein concentrates. In an aspect, the nutritional compositions include a protein source derived from milk proteins of human and/or bovine origin.

[0099] Those of ordinary skill in the art will recognize that total protein content will vary depending on the target consumer and depending on nutritional needs. In certain exemplary aspects of the present disclosure, an infant formula is contemplated having up to about 21 grams of protein per liter. In certain exemplary aspects of the present disclosure, an adult nutritional composition is contemplated having up to about 90 grams of protein per liter.

[00100] In an exemplary aspect of the present disclosure, the protein source is a hydrolyzed protein, i.e ., a protein hydrolysate. In this context, the terms “hydrolyzed protein” or “protein hydrolysates” are used interchangeably herein and include extensively hydrolyzed proteins, wherein the degree of hydrolysis is most often at least about 20%, including from about 20% to about 80%, and also including from about 30% to about 80%, even more preferably from about 40% to about 60%. The degree of hydrolysis is the extent to which peptide bonds are broken by a hydrolysis method. The degree of protein hydrolysis for purposes of characterizing the extensively hydrolyzed protein component of these embodiments is easily determined by one of ordinary skill in the formulation arts by quantifying the amino nitrogen to total nitrogen ratio (AN/TN) of the protein component of the selected liquid formulation. The amino nitrogen component is quantified by USP titration methods for determining amino nitrogen content, while the total nitrogen component is determined by the Tecator Kjeldahl method, all of which are well known methods to one of ordinary skill in the analytical chemistry art. [00101] Suitable hydrolyzed proteins include soy protein hydrolysate, casein protein hydrolysate, whey protein hydrolysate, rice protein hydrolysate, potato protein hydrolysate, fish protein hydrolysate, egg albumen hydrolysate, gelatin protein hydrolysate, combinations of animal and vegetable protein hydrolysates, and combinations thereof. Particularly preferred protein hydrolysates include whey protein hydrolysate and hydrolyzed sodium caseinate.

[00102] When used in the nutritional compositions, the protein source may include at least about 1% (by weight total protein) protein hydrolysate, including from about 2% to 100% (by weight total protein) protein hydrolysate, including from about 2% to 10% (by weight total protein) protein hydrolysate, including from about 5% to 100% (by weight total protein) protein hydrolysate, including from about 10% to 100% (by weight total protein) protein hydrolysate, and including from about 20% to about 80% (by weight total protein) protein hydrolysate, and including about 50% (by weight total protein) protein hydrolysate. In an aspect, the nutritional composition includes 100% (by weight total protein) protein hydrolysate.

Carbohydrate

[00103] The nutritional compositions according to the general inventive concepts may, in addition to the HMOs, include carbohydrates that are suitable for use in an oral nutritional composition and are compatible with the essential elements and features of such compositions. Where present, carbohydrate concentrations most typically will range from about 5% to about 40%, including from about 7% to about 30%, including from about 10% to about 25%, by weight of the nutritional composition.

[00104] Non-limiting examples of suitable carbohydrates or sources thereof for use in the nutritional compositions described herein include maltodextrin, hydrolyzed or modified starch or cornstarch, glucose polymers, com syrup, corn syrup solids, rice-derived carbohydrates, pea-derived carbohydrates, potato-derived carbohydrates, tapioca, sucrose, glucose, fructose, lactose, high fructose corn syrup, honey, sugar alcohols (e.g. , maltitol, erythritol, sorbitol), artificial sweeteners (e.g., sucralose, acesulfame potassium, stevia) and combinations thereof. A particularly desirable carbohydrate is a low dextrose equivalent (DE) maltodextrin.

Optional Ingredients [00105] The nutritional compositions according to the general inventive concepts may further comprise other optional components that may modify the physical, chemical, aesthetic or processing characteristics of the products or serve as pharmaceutical or additional nutritional components when used in the targeted population. Many such optional ingredients are known or otherwise suitable for use in medical food or other nutritional compositions or pharmaceutical dosage forms and may also be used in the compositions herein, provided that such optional ingredients are safe for oral administration and are compatible with the essential and other ingredients in the selected product form.

[00106] Non-limiting examples of such optional ingredients include preservatives, emulsifying agents, buffers, fructooligosaccharides, fiber, galactooligosaccharides, polydextrose, and other prebiotics, pharmaceutical actives, anti-inflammatory agents, additional nutrients as described herein, colorants, flavors, thickening agents and stabilizers, lubricants, and so forth.

[00107] The nutritional compositions may further comprise a sweetening agent, preferably including at least one sugar alcohol such as maltitol, erythritol, sorbitol, xylitol, mannitol, isomalt, and lactitol, and also preferably including at least one artificial or high potency sweetener such as acesulfame K, aspartame, sucralose, saccharin, stevia, and tagatose. These sweetening agents, especially as a combination of a sugar alcohol and an artificial sweetener, are especially useful in formulating liquid beverage embodiments according to the general inventive concepts having a desirable favor profile. These sweetener combinations are especially effective in masking undesirable flavors sometimes associated with the addition of vegetable proteins to a liquid beverage. Optional sugar alcohol concentrations in the nutritional compositions may range from at least 0.01%, including from about 0.1% to about 10%, and also including from about 1% to about 6%, by weight of the nutritional compositions. Optional artificial sweetener concentrations may range from about 0.01%, including from about 0.05% to about 5%, also including from about 0.1% to about 1.0%, by weight of the nutritional compositions.

[00108] A flowing agent or anti-caking agent may be included in the nutritional compositions as described herein to retard clumping or caking of the powder over time and to make a powder composition flow easily from its container. Any known flowing or anti-caking agents that are known or otherwise suitable for use in a nutritional powder or product form are suitable for use herein, non-limiting examples of which include tricalcium phosphate, silicates, and combinations thereof. The concentration of the flowing agent or anti-caking agent in the nutritional composition varies depending upon the product form, the other selected ingredients, the desired flow properties, and so forth, but most typically range from about 0.1% to about 4%, including from about 0.5% to about 2%, by weight of the nutritional composition.

[00109] A stabilizer may also be included in the nutritional compositions. Any stabilizer that is known or otherwise suitable for use in a nutritional composition is also suitable for use herein, some non-limiting examples of which include gums such as xanthan gum. The stabilizer may represent from about 0.1% to about 5.0%, including from about 0.5% to about 3%, including from about 0.7% to about 1.5%, by weight of the nutritional composition.

[00110] The nutritional compositions may further comprise any of a variety of other vitamins or related nutrients, non-limiting examples of which include vitamin A, vitamin D, vitamin E, vitamin K, thiamine, riboflavin, pyridoxine, vitamin Bo, niacin, folic acid, pantothenic acid, biotin, vitamin C, choline, inositol, salts and derivatives thereof, and combinations thereof. The food products preferably include, but are not limited to, the following vitamins and minerals: calcium, phosphorus, sodium, chloride, magnesium, manganese, iron, copper, zinc, selenium, iodine, chromium, molybdenum, conditionally essential nutrients m- inositol, carnitine and taurine, and Vitamins A, C, D, E, K and the B complex, and mixtures thereof.

[00111] The nutritional compositions may further comprise any of a variety of other additional minerals, non-limiting examples of which include calcium, phosphorus, magnesium, iron, zinc, manganese, copper, sodium, potassium, molybdenum, chromium, chloride, and combinations thereof.

[00112] The nutritional compositions also may contain fiber and stabilizers. Suitable sources of fiber and/or stabilizers include, but are not limited to, xanthan gum, guar gum, gum arabic, gum ghatti, gum karaya, gum tracacanth, agar, furcellaran, gellan gum, locust bean gum, pectin, low and high methoxy pectin, oat and barley glucans, carrageenans, psyllium, gelatin, microcrystalline cellulose, CMC (sodium carboxymethylcellulose), methylcellulose hydroxypropyl methyl cellulose, hydroxypropyl cellulose, DATEM (diacetyl tartaric acid esters of mono- and diglycerides), dextran, FOS (fructooligosaccharides), and mixtures thereof. Numerous commercial sources of soluble dietary fibers are available. For example, gum arabic, hydrolyzed carboxymethylcellulose, guar gum, pectin and the low and high methoxy pectins are available from TIC Gums, Inc. of Belcamp, Md. The oat and barley glucans are available from Mountain Lake Specialty Ingredients, Inc. of Omaha, Nebr. Psyllium is available from the Meer Corporation of North Bergen, N.J. while the carrageenan is available from FMC Corporation of Philadelphia, Pa.

[00113] In addition to fiber, the nutritional compositions may also contain oligosaccharides such as fructooligosaccharides (FOS) or galactooligosaccharides (GOS). Oligosaccharides are rapidly and extensively fermented to short chain fatty acids by anaerobic microorganisms that inhabit the large bowel. These oligosaccharides are preferential energy sources for most Bifidobacterium species, but are not utilized by potentially pathogenic organisms such as Clostridium perfingens, C. difficile , or Eschericia coli.

[00114] The nutritional compositions may additionally comprise one or more thickeners (i.e., thickening agents). The addition of thickeners reduces the incidences of paresthesia by inducing the feeling of satiety, which prolongs gastric transit time as discussed above.

Nutritional Composition Forms

[00115] The nutritional compositions according to the general inventive concepts may be formulated and administered in any known or otherwise suitable oral product form. Any solid, liquid, semi-solid, and semi-liquid, or powder product form, including combinations or variations thereof, are suitable for use herein, provided that such forms allow for safe and effective oral delivery to the individual of the essential ingredients as also defined herein.

[00116] The nutritional compositions according to the general inventive concepts include an HMO blend as described herein. The compositions may include an HMO mixture with the designed lipid component alone or in combination with other functional ingredients, such as LCPUFAs, nucleotides, and antioxidants, such as carotenoids and vitamins, as discussed herein.

[00117] The nutritional compositions may be in any product form comprising the ingredients described herein, and which is safe and effective for oral administration. The nutritional compositions may be formulated to include only the ingredients described herein, or may be modified with optional ingredients to form a number of different product forms.

[00118] The nutritional compositions according to the general inventive concepts are desirably formulated as dietary product forms, which are defined herein as those embodiments comprising the ingredients according to the general inventive concepts in a product form that then contains at least one of fat, protein, and carbohydrate, and preferably also contains vitamins, minerals, or combinations thereof. The nutritional compositions will comprise at least HMOs and a designed lipid component, desirably in combination with at least one of protein, fat, vitamins, and minerals, to produce a nutritional composition.

Nutritional Liquids

[00119] Liquid nutritional compositions include both concentrated and ready -to-feed nutritional liquids. These nutritional liquids are most typically formulated as suspensions or emulsions, although other liquid forms are within the scope of the general inventive concepts. Nutritional compositions in the form of emulsions suitable for use may be aqueous emulsions comprising proteins, fats, and carbohydrates. These emulsions are generally flowable or drinkable liquids at from about 1° C. to about 25° C. and are typically in the form of oil-in-water, water-in-oil, or complex aqueous emulsions, although such emulsions are most typically in the form of oil-in-water emulsions having a continuous aqueous phase and a discontinuous oil phase.

[00120] The nutritional liquids may be and typically are shelf stable. The nutritional emulsions typically contain up to about 95% by weight of water, including from about 50% to about 95%, also including from about 60% to about 90%, and also including from about 70% to about 85%, of water by weight of the nutritional emulsions. The nutritional emulsions may have a variety of product densities, but most typically have a density greater than about 1.03 g/mL, including greater than about 1.04 g/mL, including greater than about 1.055 g/mL, including from about 1.06 g/mL to about 1.12 g/mL, and also including from about 1.085 g/mL to about 1.10 g/mL.

[00121] The nutritional liquid compositions may have a caloric density tailored to the nutritional needs of the ultimate user, although in most instances the emulsions comprise generally at least 19 kcal/fl oz (660 kcal/liter), more typically from about 20 kcal/fl oz (675-680 kcal/liter) to about 25 kcal/fl oz (820 kcal/liter), even more typically from about 20 kcal/fl oz (675-680 kcal/liter) to about 24 kcal/fl oz (800-810 kcal/liter). Generally, the 22-24 kcal/fl oz formulas are more commonly used in preterm or low birth weight infants, and the 20-21 kcal/fl oz (675-680 to 700 kcal/liter) formulas are more often used in term infants. In some aspects of the present disclosure, the emulsion may have a caloric density of from about 50-100 kcal/liter to about 660 kcal/liter, including from about 150 kcal/liter to about 500 kcal/liter. In an exemplary aspect of the present disclosure, the emulsion may have a caloric density of 25, or 50, or 75, or 100 kcal/liter.

[00122] The nutritional emulsion may have a pH ranging from about 2.5 to about 8, but are most advantageously in a range of from about 4.5 to about 7.5, including from about 5.5 to about 7.3, including from about 6.2 to about 7.2.

[00123] Although the serving size for the nutritional liquid can vary depending upon a number of variables, a typical serving size is generally at least about 1 mL, or even at least about 2 mL, or even at least about 5 mL, or even at least about 10 mL, or even at least about 25 mL, including ranges from about 1 mL to about 360 mL, including from about 30 mL to about 250 mL, and including from about 60 mL to about 240 mL.

Nutritional Solids

[00124] The nutritional compositions in the form of nutritional solids may be in any solid form but are typically in the form of flowable or substantially flowable particulate compositions, or at least particulate compositions. Particularly suitable nutritional solid product forms include spray dried, agglomerated and/or dry-blended powder compositions. The compositions can easily be scooped and measured with a spoon or similar other device, and can easily be reconstituted by the intended user with a suitable aqueous liquid, typically water, to form a nutritional composition for immediate oral or enteral use. In this context, “immediate” use generally means within about 48 hours, most typically within about 24 hours, preferably right after reconstitution.

[00125] The nutritional powders may be reconstituted with water prior to use to a caloric density tailored to the nutritional needs of the ultimate user, similar to that described above for liquid nutritional compositions.

Methods of Manufacture

[00126] The nutritional compositions according to the general inventive concepts may be prepared by any known or otherwise effective manufacturing technique for preparing the nutritional compositions. Many such techniques are known for any given product form such as nutritional liquids or powders and can easily be applied by one of ordinary skill in the art to the nutritional compositions described herein.

[00127] The nutritional compositions (e.g., infant formulas) according to the general inventive concepts can therefore be prepared by any of a variety of known or otherwise effective formulation or manufacturing methods. In one suitable manufacturing process, for example, at least three separate slurries are prepared, including a protein-in-fat (PIF) slurry, a carbohydrate- mineral (CHO-MIN) slurry, and a protein-in-water (PIW) slurry. The PIF slurry is formed by heating and mixing the oil (e.g., canola oil, com oil, etc.) and then adding an emulsifier (e.g. , lecithin), fat soluble vitamins, and a portion of the total protein (e.g, milk protein concentrate, etc.) with continued heat and agitation. The CHO-MIN slurry is formed by adding with heated agitation to water: minerals (e.g, potassium citrate, dipotassium phosphate, sodium citrate, etc.), trace and ultra-trace minerals (TM/UTM premix), thickening or suspending agents (e.g, avicel, gellan, and carrageenan). The resulting CHO-MIN slurry is held for 10 minutes with continued heat and agitation before adding additional minerals (e.g, potassium chloride, magnesium carbonate, potassium iodide, etc.), and/or carbohydrates (e.g, HMOs, fructooligosaccharide, sucrose, corn syrup, etc.). The PIW slurry is then formed by mixing with heat and agitation the remaining protein, if any. [00128] The resulting slurries are then blended together with agitation and the pH adjusted to 6.6-7.0, after which the composition is subjected to processing during which the composition is emulsified and homogenized. Water soluble vitamins and ascorbic acid are added, the pH is adjusted to the desired range if necessary, flavors are added, and water is added to achieve the desired total solid level. This emulsion can then be further diluted, heat-treated, and packaged to form a ready-to-feed or concentrated liquid, or it can be heat-treated and subsequently processed and packaged as a reconstitutable powder, e.g ., spray dried, drymixed, agglomerated.

[00129] The nutritional solid, such as a spray dried nutritional powder or drymixed nutritional powder, may be prepared by any collection of known or otherwise effective techniques, suitable for making and formulating a nutritional powder.

[00130] For example, when the nutritional powder is a spray dried nutritional powder, the spray drying step may likewise include any spray drying technique that is known for or otherwise suitable for use in the production of nutritional powders. Many different spray drying methods and techniques are known for use in the nutrition field, all of which are suitable for use in the manufacture of the spray dried nutritional powders herein.

[00131] One method of preparing the spray dried nutritional powder comprises forming and homogenizing an aqueous slurry or liquid comprising predigested fat, and optionally protein, carbohydrate, and other sources of fat as described above, and then spray drying the slurry or liquid to produce a spray dried nutritional powder. The method may further comprise the step of spray drying, drymixing, or otherwise adding additional nutritional ingredients, including any one or more of the ingredients described herein, to the spray dried nutritional powder.

[00132] Other suitable methods for making nutritional compositions are described, for example, in U.S. Pat. No. 6,365,218 (Borschel, et al.), U.S. Patent No. 6,589,576 (Borschel, et al .), U.S. Pat. No. 6,306,908 (Carlson, et al.), U.S. Patent Application No. 20030118703 A1 (Nguyen, et al.), which descriptions are incorporated herein by reference to the extent that they are consistent herewith.

Methods of Use [00133] The methods of use according to the general inventive concepts include the oral administration of the nutritional compositions (e.g., infant formulas including preterm infant formulas, pediatric formulas, and adult formulas) that include HMOs (e.g., combinations of neutral and acidic HMOs), a designed lipid component containing (e.g., free fatty acids and mono- and di-glycerides) and, in certain aspects of the present disclosure, combined with PUFAs, probiotics, nucleotides, and carotenoids to improve or modulate at least one of the conditions or diseases discussed herein, including but not limited to improving lung function, increasing lung surfactant, and modulating lung immunity, or symptoms thereof.

[00134] The nutritional compositions as described herein can be administered to individuals including preterm and term infants, toddlers, children, adults, and elderly individuals generally, or may, in certain aspects of the present disclosure, be administered to a specific subclass of individuals that are “in need thereof;” that is, to specific infants that would particularly benefit by administration of the nutritional composition. For example, a specific infant may be “in need of’ the nutritional compositions as described herein if they are susceptible to (i.e., have one or more of a genetic predisposition, a family history of, and symptoms of the disease or condition) diseases and conditions that can impair/reduce function in one or more of the areas discussed herein, including but not limited to susceptibility to impaired lung function (i.e., the compositions treat impaired lung function and/or undesirable or insufficient lung immunity) or sub-optimal lung development or function. Likewise, in another aspect, an adult or elderly individual may be in need of a nutritional composition according to the general inventive concepts for similar reasons.

[00135] Certain specific populations with need include those having substandard or abnormal maturation and/or development and/or function (e.g., elasticity or surfactant amount) of the lung; individuals having abnormal lung immunity (including either or both of overactive immunity and underactive immunity); individuals having insufficient lung function; individuals having insufficient lung surfactant; and individuals having impaired lung function. In certain aspects according to the general inventive concepts, the individual has been diagnosed with impaired lung function. [00136] Based on the foregoing, because some of the method embodiments according to the general inventive concepts are directed to specific subsets or subclasses of identified individuals (that is, the subset or subclass of individuals “in need” of assistance in addressing one or more specific diseases or specific conditions noted herein), not all individuals will fall within the subset or subclass of individuals as described herein for certain diseases or conditions.

[00137] When administered to the individual in need thereof, the individual desirably consumes at least one serving of the nutritional composition daily, and in some embodiments, may consume two, three, or even more servings per day. Each serving is desirably administered as a single, undivided dose, although the serving may also be divided into two or more partial or divided servings to be taken at two or more times during the day. The methods according to the general inventive concepts include continuous day after day administration, as well as periodic or limited administration, although continuous day after day administration is generally desirable. The methods according to the general inventive concepts are preferably applied on a daily basis, wherein the daily administration is maintained continuously for at least 3 days, including at least 5 days, including at least 1 month, including at least 6 weeks, including at least 8 weeks, including at least 2 months, including at least 6 months, desirably for at least about 18-24 months, desirably as a long term, continuous, daily, dietary source or supplement.

Examples

[00138] The following examples illustrate exemplary embodiments and/or features of the methods and nutritional compositions according to the general inventive concepts. The examples are given solely for the purpose of illustration and are not to be construed as limitations of the general inventive concepts, as many variations thereof are possible without departing from the spirit and scope of the general inventive concepts. All exemplified amounts are weight percentages based upon the total weight of the composition, unless otherwise specified.

[00139] A nutritional composition comprising an HMO (e.g., a fucosylated, sialylated, or N-acetylated oligosaccharide) and a designed lipid component, alone or in combination with another HMO and/or one or more probiotics, LCPUFAs is administered to an individual. The nutritional composition promotes lung function, including but not limited to treating insufficient lung function or lung immunity.

[00140] Example 1: The following is an exemplary powdered nutritional composition (infant formula) according to the general inventive concepts.

[00141] Example 2: The following is an exemplary liquid nutritional composition (infant formula) according to the general inventive concepts.

[00142] Example 3: The following is an exemplary liquid nutritional composition according to the general inventive concepts.

[00143] Example 4: Pulmonary surfactant is a complex mixture of lipid and protein secreted by the alveolar epithelium. It serves an essential function of reducing the surface tension at the air-liquid interface, thereby facilitating gas exchange. A549 cells can be utilized to measure the expression of surfactant proteins. A commercially available ELISA kit manufactured by R&D Systems (Product number NBP2-76692) is used to quantify the secretion of surfactant protein A (SP-A) in cultured A549 cells treated with a designed lipid component and/or HMO(s). Cells are cultured to confluence in 24 well sterile plastic cell culture plates at 37 °C and 5% CO2. These cultures are treated with an HMO blend (2.99 g/L 2'-FL, 0.75 g/L 3-FL, 1.5 g/L LNT, 0.23 g/L 3'- SL, and 0.28 g/L 6'-SL) and or designed lipid component or control preparations. The designed lipid component contained 0.009-0.3 g/L free fatty acid, 0.01-0.32 g/L monoglyceride, 0.0035- 0.11 g/L lecithin, and 0.1-3.5 g/L whey protein. Treatments were suspended in cell culture media (DMEM:F12 containing 10% fetal bovine serum) and added to cell cultures for 24 hours prior to the collection of cell culture supernatant and the measurement of secreted surfactant concentration according to the ELISA kit manufacturer’s instructions. These experiments demonstrate that one or more combinations of HMO(s) and a designed lipid component promote higher levels of surfactant secretion than can be achieved with matched concentrations of either alone.

[00144] Example 5: Previous studies have established the Respiratory Syncytial Virus (RSV) NM232 model system as an effective means of screening bioactive compounds against a respiratory virus in a cell culture system. These assays rely primarily on the Hep2 cell line, a publicly available immortalized human cell line derived from human larynx carcinoma and HeLa coculture.

[00145] Briefly, HMOs and a designed lipid component are added 24 hours prior to infection and maintained in the culture medium during and after infection. All infected monolayers are incubated in medium containing the investigational components. Infected cultures are frozen and then thawed and processed for titration of infectious virus yields. Infectious virus yields are determined for each culture by plaque assay. For each condition, three experimental replicates are run. RSV infections and infectious virus yield titrations will be carried out in Hep2 human lung epithelial cells. These assays evaluated 2 doses of designed lipid component with and without HMOs and appropriate control conditions.

[00146] Viral tiers and CPE will be measured to determine whether investigational designed lipid components alone or in combination with HMOs can attenuate viral infection of epithelial cells in vitro. These experiments demonstrate that combinations of HMO(s) and designed lipid components are more effective in limiting viral replication than the application of either HMO(s) or designed lipid components alone.

[00147] Unless otherwise indicated herein, all sub-embodiments and optional embodiments are respective sub-embodiments and optional embodiments to all embodiments described herein. While the present application has been illustrated by the description of embodiments thereof, and while the embodiments have been described in considerable detail, it is not the intention of the applicants to restrict or in any way limit the scope of the appended claims to such detail. Additional advantages and modifications will readily appear to those skilled in the art. Therefore, the application, in its broader aspects, is not limited to the specific details, the representative compositions or formulations, and illustrative examples shown and described. Accordingly, departures may be made from such details without departing from the spirit or scope of the applicant’s general disclosure herein.

Claims

WHAT IS CLAIMED IS:

1. A method of improving lung function in an individual in need thereof, the method comprising: identifying an individual in need of improved lung function; and administering to the individual a nutritional composition comprising: a) a neutral human milk oligosaccharide; b) an acidic human milk oligosaccharide; and c) a designed lipid component.

2. The method of claim 1, wherein the nutritional composition further comprises a probiotic blend comprising at least two strains of bacteria.

3. The method of any preceding claim, wherein the neutral human milk oligosaccharide is selected from 2’-fucosyllactose, 3-fucosyllactoise, and lacto-N-tetraose and the acidic human milk oligosaccharide is selected from 3’-sialylactose and 6’-sialyllactose.

4. The method of any one of claims 1-3, wherein the neutral human milk oligosaccharide includes at least one of 2’-fucosyllactose, 3-fucosyllactose, and combinations thereof.

5. The method of any one of claims 1-4, wherein the acidic human milk oligosaccharide includes at least one of 3’-sialyllactose, 6’-sialyllactose, and combinations thereof.

6. The method of any preceding claim, wherein the nutritional composition further comprises lacto-N-tetraose.

7. The method of any preceding claim, wherein the composition is a liquid comprising 0.1 g/L to 10 g/L of a combination of 2’-fucosyllactose, 3-fucosyllactose, 3’-sialyllactose, 6’- sialyllactose, and lacto-N-tetraose.

8. The method of claim 7, wherein the composition is a liquid or reconstitutable powder comprising 2’-fucosyllactose in an amount up to 4.15 g/L, lacto-N-tetraose in an amount up to

2.11 g/L, 3-fucosyllactose in an amount up to 1.17 g/L, 3’-sialyllactose in an amount up to 0.36 g/L, and 6’-sialyllactose in an amount up to 0.44 g/L.

9. The method of any preceding claim, wherein the designed lipid component comprises fatty acids derived from a vegetable oil, mono/di-glycerides derived from vegetable oils, and phospholipids derived from at least one of soy, sunflower lecithin, egg, marine sources, single cells, microbial fermentation, and dairy fat.

10. The method of claim 9, wherein the nutritional composition comprises at least 0.2% of free fatty acids, mono/di-glycerides, or phospholipids by weight.

11. The method of any one of claims 1 to 10, wherein the individual is an infant.

12. The method of any one of claims 1 to 10, wherein the individual is an adult.

13. A method of improving lung elasticity in an individual in need thereof, the method comprising: identifying an individual in need of improved lung elasticity; and administering to the individual a nutritional composition comprising: a) a neutral human milk oligosaccharide; b) an acidic human milk oligosaccharide; and c) a designed lipid component.

14. The method of claim 13, wherein the nutritional composition further comprises a probiotic blend comprising at least two strains of bacteria.

15. The method of claim 14, wherein the neutral human milk oligosaccharide is selected from 2’-fucosyllactose, 3-fucosyllactoise, and lacto-N-tetraose and the acidic human milk oligosaccharide is selected from 3’-sialylactose and 6’-sialyllactose.

16. The method of any one of claims 13-15, wherein the neutral human milk oligosaccharide is 2’-fucosyllactose, and the acidic human milk oligosaccharide is 6’-sialyllactose.

17. A method of modulating lung immunity in an individual in need thereof, the method comprising: identifying an individual in need of improved lung immune response; and administering to the individual a nutritional composition comprising: a) a neutral human milk oligosaccharide; b) an acidic human milk oligosaccharide; and c) a designed lipid component.

18. The method of claim 17, wherein the nutritional composition further comprises a probiotic blend comprising at least two strains of bacteria.

19. The method of claim 17, wherein the neutral human milk oligosaccharide is selected from 2’-fucosyllactose, 3-fucosyllactoise, and lacto-N-tetraose and the acidic human milk oligosaccharide is selected from 3’-sialylactose and 6’-sialyllactose.

20. The method of any one of claims 17-19, wherein the neutral human milk oligosaccharide is 2’-fucosyllactose, and the acidic human milk oligosaccharide is 6’-sialyllactose.

21. A method of increasing at least one lung surfactant in an individual in need thereof, the method comprising: administering to the individual a nutritional composition comprising: a) a neutral human milk oligosaccharide; b) an acidic human milk oligosaccharide; and c) a designed lipid component.

22. The method of claim 21, wherein the nutritional composition further comprises a probiotic blend comprising at least two strains of bacteria.

23. The method of claim 21, wherein the neutral human milk oligosaccharide is selected from 2’-fucosyllactose, 3-fucosyllactoise, and lacto-N-tetraose and the acidic human milk oligosaccharide is selected from 3’-sialylactose and 6’-sialyllactose.

24. The method of any one of claims 21-23, wherein the neutral human milk oligosaccharide is 2’-fucosyllactose, and the acidic human milk oligosaccharide is 6’-sialyllactose.

25. A nutritional composition for improving lung function in an individual in need thereof, the nutritional composition comprising: a) a neutral human milk oligosaccharide; b) an acidic human milk oligosaccharide; and c) a designed lipid component.

26. The nutritional composition of claim 25, wherein the neutral human milk oligosaccharide is selected from 2’-fucosyllactose, 3-fucosyllactoise, and lacto-N-tetraose and the acidic human milk oligosaccharide is selected from 3’-sialylactose and 6’-sialyllactose.

27. A nutritional composition for improving lung elasticity in an individual in need thereof, the nutritional composition comprising: a) a neutral human milk oligosaccharide; b) an acidic human milk oligosaccharide; and c) a designed lipid component.

28. The nutritional composition of claim 27, wherein the neutral human milk oligosaccharide is selected from 2’-fucosyllactose, 3-fucosyllactoise, and lacto-N-tetraose and the acidic human milk oligosaccharide is selected from 3’-sialylactose and 6’-sialyllactose.

29. A nutritional composition for modulating lung immunity in an individual in need thereof, the nutritional composition comprising: a) a neutral human milk oligosaccharide; b) an acidic human milk oligosaccharide; and c) a designed lipid component.

30. The nutritional composition of claim 29, wherein the neutral human milk oligosaccharide is selected from 2’-fucosyllactose, 3-fucosyllactoise, and lacto-N-tetraose and the acidic human milk oligosaccharide is selected from 3’-sialylactose and 6’-sialyllactose.

31. A nutritional composition for increasing at least one lung surfactant in an individual in need thereof, the nutritional composition comprising: a) a neutral human milk oligosaccharide; b) an acidic human milk oligosaccharide; and c) a designed lipid component.

32. The nutritional composition of claim 31, wherein the neutral human milk oligosaccharide is selected from 2’-fucosyllactose, 3-fucosyllactoise, and lacto-N-tetraose and the acidic human milk oligosaccharide is selected from 3’-sialylactose and 6’-sialyllactose.

33. A nutritional composition for treating insufficient lung function in an individual in need thereof, the nutritional composition comprising: a) a neutral human milk oligosaccharide; b) an acidic human milk oligosaccharide; and c) a designed lipid component.

34. The nutritional composition of claim 33, wherein the neutral human milk oligosaccharide is selected from 2’-fucosyllactose, 3-fucosyllactoise, and lacto-N-tetraose and the acidic human milk oligosaccharide is selected from 3’-sialylactose and 6’-sialyllactose.