Milk-based, GOS-comprising compositions and methods employing these compositions for improving bone health in an infant, a young child or a child

Abstract

Methods and compositions for promoting bone growth, enhancing bone growth and / or bone strength in an infant, young child or child in need thereof, the composition comprising a low sugar, low lactose, milk-based composition comprising galactooligosaccharide (GOS).

Description

TITLE COMPOSITIONS AND METHODS FOR IMPROVING BONE HEALTH IN AN INFANT, A YOUNG CHILD OR A CHILDTECHNICAL FIELD

[0001] The present disclosure generally relates to compositions and methods for promoting bone growth, enhancing bone growth and / or bone strength, for example to an infant, young child or a child in need thereof. Some embodiments are directed to a composition comprising milk protein and further comprising a mixture of lactose, glucose, galactose and galactooligosaccharide (GOS).BACKGROUND

[0002] Bone is a tissue that undergoes constant remodelling as a result of the destruction and de novo synthesis of bone tissue in a complex process involving two main types of cells, the osteoblasts which produce new bone tissue and the osteoclasts which destroy bone, respectively. The osteoblasts, the cells responsible for bone formation, differentiate from precursor cells and express and secrete many enzymes and many structural proteins of the bone matrix, including collagen type I, osteocalcin, osteopontin and alkaline phosphatase. The osteoclasts are multinucleated cells which are responsible for bone loss in a process generally designated bone resorption.

[0003] Moreover, at an earlier stage, the growth and development of the human skeleton requires an adequate supply of many different nutritional factors. Classical nutrient deficiencies are associated with stunting (e.g. energy, protein, Zn), rickets (e.g. vitamin D) and other bone abnormalities (e.g. Cu, Zn, vitamin C). There is evidence to suggest that peak bone mass and later fracture risk are influenced by the pattern of growth and nutritional exposures in childhood. However, it is challenging to define dietary reference values using bone health as a criterion, and the question of what type of diet constitutes the best support for optimal bone growth and development remains open (see e.g. Prentice, A., et al., 2006. Proceedings of the Nutrition Society, 65(4), pp.348-360).

[0004] Several approaches may be taken to improve the intake of growth-limiting nutrients, including administration of micronutrient supplements, fortification of food with micronutrients or improved dietary intake. However, particularly in populations where dietary quality is poor, several micronutrient deficiencies can co-occur, in which case growth may be affected by more than one growth-limiting nutrient (see e.g. Rivera, J. A., et al., 2003. The Journal of nutrition, 133(11), pp.4010S-4020S).

[0005] However, there remains a need for providing infant, young child or child nutritional formulae which are more specific to a particular target group and which are more effective in providing a defined intended beneficial effect beyond that of infant, young child or child nutritional formulae known in the art.SUMMARY

[0006] The present invention provides a method of promoting bone growth, enhancing bone growth and / or bone strength, and increasing muscle function and / or muscle mass in an infant, young child or child.

[0007] In particular embodiments, the method for promoting bone growth, enhancing bone growth and / or bone strength includes administering to an infant, young child or child in need thereof a low sugar, low lactose, milk-based composition comprising galactooligosaccharide. In some embodiments, the composition comprises milk protein, preferably at 20-40 % by dry weight of the composition; and a mixture of lactose, glucose, galactose and galactooligosaccharide, the mixture preferably at 35-55% or 32-55%, by dry weight of the composition; preferably, the mixture comprising: 0.1-30% by weight of the lactose, 8-40% by weight of the glucose, 0.1-20% by weight of the galactose and 40-90% by weight of the galactooligosaccharide.

[0008] The promoting bone growth, enhancing bone growth and / or bone strength in an infant, young child or child comprises at least one result selected from the group consisting of: (a) regulating bone turnover b) increasing bone mineral density and microarchitecture; c) increasing bone formation d) maximizing peak bone mass; d) increasing bone mineralization; e) improving bone lengthening and f) combinations thereof.

[0009] Additional features and advantages are described herein and will be apparent from the following Figures and Detailed Description.BRIEF DESCRIPTION OF THE DRAWINGS

[0010] FIG. 1 shows the increase in production of propionate metabolite after 24h fermentation of the active composition (MLG-H) by comparison to GOS alone or negative control (NSC) using batch fermentation.

[0011] FIG. 2 shows the increase in production of valerate metabolite after 24h fermentation of the active composition (MLG-H) by comparison to GOS alone or negative control (NSC) using batch fermentation.

[0012] FIG. 3 shows the increase in production of N,N-Dimethylglycine metabolite after 24h fermentation of the active composition (MLG-H) by comparison to GOS alone or negative control (NSC) using batch fermentation.

[0013] FIG. 4 shows total SCFA production after 24h fermentation of the Active Composition (composition - LM) by comparison to regular milk (regular milk - LM) using batch fermentation with simulated lactose malabsorption.

[0014] FIG. 5 shows plasma 3-indole propionate levels after administration of the composition disclosed herein (IP) compared to administration of a control product (CP) of lactose-free skimmed milk.DETAILED DESCRIPTION

[0015] Definitions

[0016] Some definitions are provided hereafter. Nevertheless, definitions may be located in the “Embodiments” section below, and the above header “Definitions” does not mean that such disclosures in the “Embodiments” section are not definitions.

[0017] All percentages expressed herein are by weight of the total weight of the composition unless expressed otherwise. As used herein, “about,” “approximately” and “substantially” are understood to refer to numbers in a range of numerals, for example the range of -10% to +10% of the referenced number, preferably -5% to +5% of the referenced number, more preferably -1% to +1% of the referenced number, most preferably -0.1% to +0.1% of the referenced number. All numerical ranges herein should be understood to include all integers, whole or fractions, within the range. Moreover, 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 1 to 8, from 3 to 7, from 1 to 9, from 3.6 to 4.6, from 3.5 to 9.9, and so forth.

[0018] As used in this disclosure and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a protein” or “the protein” includes two or more proteins.

[0019] The words “comprise,” “comprises” and “comprising” are to be interpreted inclusively rather than exclusively. Likewise, the terms “include,” “including” and “or” should all be construed to be inclusive, unless such a construction is clearly prohibited from the context. Nevertheless, the compositions and methods disclosed herein may lack any element that is not specifically disclosed herein. Thus, a disclosure of an embodiment using the term “comprising” includes a disclosure of embodiments “consisting essentially of’ and “consisting of’ the components or steps identified.

[0020] The terms “at least one of’ and “and / or” used respectively in the context of “at least one of X and Y” and “X and / or Y” should be interpreted as “X without Y,” or “Y without X,” or “both X and Y.” Where used herein, the terms “example” and “such as,” particularly when followed by a listing of terms, are merely exemplary and illustrative and should not be deemed to be exclusive or comprehensive.

[0021] As used herein, “related to,” “associated with” and “linked with” mean occurring concurrently, preferably mean caused by the same underlying condition, more preferably mean that one of the identified conditions is at least indirectly caused by the other identified condition, and most preferably mean that one of the identified conditions is directly caused by the other identified condition.

[0022] The terms “food”, “food supplement”, “food product” and “food composition” mean a product or composition that is intended for ingestion by an infant, young child or child such as a human and provides at least one nutrient to the infant, young child or child. The compositions of the present disclosure, including the many embodiments described herein, can comprise, consist of, or consist essentially of the elements disclosed herein, as well as any additional or optional ingredients, components, or elements described herein or otherwise useful in a diet supplement.

[0023] “Prevention” includes reduction of risk, incidence and / or severity of a condition or disorder. The terms “treatment” and “treat” include both prophylactic or preventive treatment (that prevent and / or slow the development of a targeted pathologic condition or disorder) and curative, therapeutic or disease-modifying treatment, including therapeutic measures that cure, slow down, lessen symptoms of, and / or halt progression of a diagnosed pathologic condition or disorder; and treatment of patients at risk of contracting a disease or suspected to have contracted a disease, as well as patients who are ill or have beendiagnosed as suffering from a disease or medical condition. The terms “treatment” and “treat” do not necessarily imply that a subject is treated until total recovery. The terms “treatment” and “treat” also refer to the maintenance and / or promotion of health in an infant, young child or child not suffering from a disease but who may be susceptible to the development of an unhealthy condition. The terms “treatment” and “treat” are also intended to include the potentiation or otherwise enhancement of one or more primary prophylactic or therapeutic measures. As non-limiting examples, a treatment can be performed by a patient, a caregiver, a doctor, a nurse, or another healthcare professional.

[0024] As used herein, the term “lactose mal-absorber” refers to an infant, young child or child who has a reduced ability to digest and absorb lactose, which is the sugar found in milk and dairy products. Lactose malabsorption occurs when the body does not produce enough lactase, the enzyme responsible for breaking down lactose into simpler sugars (glucose and galactose) that can be absorbed by the small intestine. Lactose malabsorption can be a result of various factors, including genetic predisposition, certain medical conditions (such as celiac disease or inflammatory bowel disease), or as a temporary condition following an illness or injury to the small intestine.

[0025] As used herein, the term “low lactose” shall refer to a composition with less than or equal to 30% of lactose.

[0026] As used herein, the term “low sugar” shall refer to a composition with less than or equal to 55% of the composition.

[0027] As used herein, a prophylactically or therapeutically “effective amount” is an amount that prevents a deficiency, treats a disease or medical condition in an infant, young child or child, or, more generally, reduces symptoms, manages progression of the disease, or provides a nutritional, physiological, or medical benefit to the infant, young child or child.

[0028] The term “composition” may mean a food, beverage, dietary supplement, complete nutrition or oral nutritional supplement (ONS) or medical food composition, an infant or follow on formulae, or mixture thereof.

[0029] The composition can be in solid form (e.g., powder) or in liquid form. The amount of the various ingredients can be expressed in g / 100 g of the composition on a dry weight basis when it is in a solid form, e.g. a powder, or as a concentration in g / 100 mL of the composition when it refers to a liquid form (this latter also encompasses liquid composition that may be obtained from a powder after reconstitution in a liquid such as water.)

[0030] The term “unit dosage form,” as used herein, refers to physically discrete units suitable as unitary dosages for human and animal subjects, each unit containing apredetermined quantity of the composition disclosed herein in an amount sufficient to produce the desired effect, in association with an acceptable diluent, carrier or vehicle. The specifications for the unit dosage form depend on the particular compounds employed, the effect to be achieved, and the pharmacodynamics associated with each compound in the host.

[0031] The terms infant, young child or child are defined below:

[0032] Infant: according to the Commission Directive 2006 / 141 / EC of 22 December 2006 on infant formulae and follow-on formulae, article 2 (a), the term "infants" means children under the age of 12 months.

[0033] Young Children: according to the Commission Directive 2006 / 141 / EC of 22 December 2006 on infant formulae and follow-on formulae, article 2 (b), the term "young children" or “toddler” means children aged between one and three years. The expression “child” means a between three and seven years of age.

[0034] Infant formulae: according to the Commission Directive 2006 / 141 / EC of 22 December 2006 on infant formulae and follow-on formulae, article 2 (c), the term "infant formulae" means foodstuffs intended for particular nutritional use by infants during the first months of life and satisfying by themselves the nutritional requirements of such infants until the introduction of appropriate complementary feeding. It has to be understood that infants can be fed solely with infant formulas, or that the infant formula can be used by the carer as a complement of human milk. It is synonymous to the widely used expression "starter formula".

[0035] Follow-on formulae: according to the Commission Directive 2006 / 141 / EC of 22 December 2006 on infant formulae and follow-on formulae, article 2 (d), the term "follow-on formulae" means foodstuffs intended for particular nutritional use by infants when appropriate complementary feeding is introduced and constituting the principal liquid element in a progressively diversified diet of such infants.

[0036] “Galactooligosaccharides” (GOS) are oligosaccharides composed of different galactosyl residues (usually from 2 to 9 units) and a terminal glucose linked by P- glycosidic bonds, such as [3-(l— 2), [3-(l— 3), [3-(l— 4), and [3-(l— 6). GOS are normally produced through the enzymatic conversion of lactose.

[0037] EmbodimentsIn an aspect of the present disclosure, a method of promoting bone growth, enhancing bone growth and / or bone strength in an infant, young child or child comprises administering to the infant, young child or child in need thereof or at risk thereof a low sugar, low lactose, milk-based composition comprising galactooligosaccharide.

[0038] In some embodiments, the composition comprises 20-40 % by dry weight of milk protein; and 32-55% by dry weight of a mixture of lactose, glucose, galactose and galactooligosaccharide.

[0039] In some embodiments, the composition comprises 35-55% by dry weight of a mixture of lactose, glucose, galactose and galactooligosaccharide.

[0040] In an embodiment, the mixture of lactose, glucose and galactose and galactooligosaccharide comprises: 0.1-30% by weight of lactose.

[0041] In an embodiment, the mixture of lactose, glucose and galactose and galactooligosaccharide comprises: 8-40% by weight of glucose.

[0042] In an embodiment, the mixture of lactose, glucose and galactose and galactooligosaccharide comprises: 0.1-20% by weight of galactose.

[0043] In an embodiment, the mixture of lactose, glucose and galactose and galactooligosaccharide comprises 40-90% by weight of galactooligosaccharide.In an embodiment, the milk-based composition comprises: milk protein, preferably at 20-40 % by dry weight of the composition; and a mixture of lactose, glucose, galactose and galactooligosaccharide, the mixture preferably at 32-55% by dry weight of the composition; preferably, the mixture comprising: 0.1-30% by weight of the lactose, 8-40% by weight of the glucose, 0.1-20% by weight of the galactose and 40-90% by weight of the galactooligosaccharide.

[0044] In another embodiments, the milk-based composition comprises: milk protein, preferably at 20-40 % by dry weight of the composition; and a mixture of lactose, glucose, galactose and galactooligosaccharide, the mixture preferably at 35-55% by dry weight of the composition; preferably, the mixture comprising: 0.1-30% by weight of the lactose, 8-40% by weight of the glucose, 0.1-20% by weight of the galactose and 40-90% by weight of the galactooligosaccharide.

[0045] Some embodiments provide a contribution from each of the components of the composition individually, in combination, and / or synergistically.

[0046] In particular embodiments, promoting bone growth, enhancing bone growth and / or bone strength in an infant, young child or child comprises at least one result selected from the group consisting of: (a) regulating bone turnover b) increasing bone mineral density and microarchitecture; c) increasing bone formation d) maximizing peak bone mass; d) increasing bone mineralization ; e) improving bone lengthening and f) combinations thereof.

[0047] The infant, young child or child may be diagnosed with such condition(s) or may be suspected of having such condition(s) or may be susceptible to such condition(s). The infant, young child or child may be treated with other therapy or therapies in addition to methods of the disclosure.

[0048] In other embodiment, the infant, young child or child is healthy but may be experiencing unpleasant gastrointestinal manifestation following the consumption of specific food (e.g. lactose containing product, gluten containing product).

[0049] In another embodiment the infant, young child or child is lactose mal- absorber.

[0050] In another embodiment the infant may be preterm infant.

[0051] In specific embodiments, promoting bone growth, enhancing bone growth and / or bone strength is associated with increased and / or decreased levels of certain metabolites, or functional derivatives thereof. In a preferred embodiment, promoting bone growth, enhancing bone growth and / or bone strength is associated with increased levels of short chain fatty acids, propionate, valerate, NN-dimethylglycine, 3 indole propionate and / or 3 -hydroxybutyrate.

[0052] Then, in an embodiment, the infant, young child or child may be susceptible to particular medical conditions or physical states that would benefit from increased metabolite levels, or the infant, young child or child may be suspected of having a medical condition or physical state that would benefit from increased metabolite levels, or increased beneficial fecal bacteria levels. The compositions delivered to the infant, young child or child in such cases include a composition as described above, in particular to facilitate raising or lowering specific metabolite levels in the infant, young child or child. One can measure specific metabolite levels through plasma or fecal samples, for example, in methods well known in the art.

[0053] The method may comprise identifying the infant, young child or child as having a medical condition or physical state or genetic condition that would benefit from increased metabolite levels, or increased beneficial fecal bacteria levels, and / or the method may comprise identifying the infant, young child or child as at risk of a medical condition or physical state that would benefit from increased metabolite levels.

[0054] In specific embodiments, an infant, young child or child is provided effective amounts of compositions as described herein for the explicit purpose of raising intracellular levels of short chain fatty acids e.g. propionate, 3 indole propionate, indoxyl sulfate and / or nicotinamide, because it is determined that the infant, young child or child is afflicted with a condition for which such levels are directly or indirectly related.

[0055] Composition for use

[0056] In some embodiments, the composition comprises 20-40% by dry weight of milk protein. Milk protein includes any protein or combination of proteins derived from milk. The milk proteins may have been derived from milk in any suitable way. In a preferred embodiment, the composition comprises 25-40%, more preferably 30-40% by dry weight of milk protein.

[0057] In some embodiments, the food ingredient further comprises 35-55%, more preferably 32-55%, by dry weight of a mixture of lactose, glucose, galactose and GOS, the mixture comprising: 0.1-30% by weight of lactose, 8-40% by weight of glucose, 0.1-20% by weight of galactose and 40-90% by weight of GOS. In a preferred embodiment, the food ingredient comprises 45-55% by dry weight of the mixture of lactose, glucose, galactose and GOS; in a more preferred embodiment, the food ingredient comprises 50-55% by dry weight of the mixture of lactose, glucose, galactose and GOS. In another preferred embodiment of the invention, the mixture of lactose, glucose, galactose and GOS comprises 60-90% by weight of GOS, more preferred 70-90% by weight of GOS. In yet another preferred embodiment, the mixture of lactose, glucose, galactose and GOS contains: 1-20% by weight of lactose, 15-35% by weight of glucose, 1-10% by weight of galactose and 50-85% by weight of GOS. In a more preferred embodiment of the invention, the mixture of lactose, glucose, galactose and GOS contains: 1-14% by weight of lactose, 15-29% by weight of glucose, 1-8% by weight of galactose and 70-90% by weight of GOS.

[0058] In some embodiments, the mixture of lactose, glucose, galactose and GOS comprises 0.1-30%, such as 0.1-5%, 5-10%, 10-15%, 15-20%, 20-25%, or 25-30% by weight of lactose. In some embodiments, the mixture of lactose, glucose, galactose and GOS comprises 8-40%, such as 8-16%, 16-24%, 24-32%, or 32-40%, by weight of glucose. In some embodiments, the mixture of lactose, glucose, galactose and GOS comprises 0.1-20%, such as 0.1-5%, 5-10%, 10-15%, or 15-20%, by weight of galactose. In some embodiments, the mixture of lactose, glucose, galactose and GOS comprises 40-90%, such as 40-50%, 50-60%, 60-70%, or 70-80% by weight of GOS.

[0059] The composition may further comprise 0.5-30% by dry weight of milk fat and / or minerals derived from milk, preferably 2-20%, more preferably 6-10% by dry weight of milk fat and / or minerals derived from milk. Milk fat includes fat derived from milk in any suitable way. Milk derived minerals include minerals derived from milk in any suitable way, e.g. calcium, sodium, potassium, phosphorus and / or magnesium salts. Milk fat and / or milkderived minerals may originate from liquid milk, such as skim milk, partially skimmed milk and / or whole milk, or from milk powder, such as e.g. skim milk powder and / or whole milk powder.

[0060] The composition may further comprise 0.5-30% by dry weight of at least one of milk fat or mineral derived from milk, preferably a combination thereof. The composition may further comprise 5-20% by dry weight of vegetable oil.

[0061] In a preferred embodiment, the composition further comprises 5-20% by dry weight of vegetable oil, more preferably 8-15% by dry weight of vegetable oil. The vegetable oil may be any suitable vegetable oil, preferably palm oil. In one embodiment, the composition relates to a cocoa, coffee, fruit based and / or malt beverage powder comprising: 10-35% by weight of non-fat milk solids; 0-65% by weight of malt extract solids; 0-15% by weight of cocoa solids; 6-15% by weight of vegetable oil and / or milk fat; 0-25% by weight of sucrose; 1-6% by weight of glucose; 0.1-5% by weight of lactose; and 3-10% by weight of GOS.

[0062] In a preferred embodiment, the invention relates to a cocoa and malt beverage powder comprising 15-35% by weight of non-fat milk solids; 20-50% by weight of malt extract solids; 5-15% by weight of cocoa solids; 6-15% by weight of vegetable oil and / or milk fat; 0-25% by weight of sucrose; 1-6% by weight of glucose; 0.1-5% by weight of lactose; and 3-10% by weight of galactooligosaccharide.

[0063] In one embodiment, the composition relates to a liquid cocoa and / or malt beverage product comprising: 3-10% by weight of non-fat milk solids; 1-6% by weight of malt extract solids; 0-5% by weight of cocoa solids; 0.3-5% by weight of vegetable oil and / or milk fat; 0-5% by weight of sucrose; 0.4-1.5% by weight of glucose; 0.01-1% by weight of lactose; and 0.5-5% by weight of GOS.

[0064] A liquid cocoa and / or malt beverage product is a cocoa and / or malt beverage product in liquid form which is suitable to be consumed without addition of liquid. It may e.g. be packed in a container from which it can be consumed directly upon opening.

[0065] Non-fat milk solids may be derived from any suitable milk source, such as e.g. liquid milk, e.g. skim milk and / or whole milk, and / or milk powder, e.g. skim milk powder and / or whole milk powder. If liquid milk is used, it may be concentrated, e.g. by evaporation or filtration. Malt extract solids may be in any suitable form, e.g. in the form of a powdered or liquid extract of malted barley and / or wheat. Cocoa solids may be from any suitable cocoa source, e.g. in the form of cocoa powder, cocoa mass and / or cocoa butter. Vegetable oil may be any suitable vegetable oil, preferably palm oil. Milk fat may be derived from any suitable milk source, such as e.g. liquid milk or cream, e.g. skim milk, cream, and / or whole milk, and / ormilk powder, e.g. skim milk powder, cream powder, and / or whole milk powder, and / or may be in the form of butter, butter oil and / or anhydrous milk fat. If liquid milk or cream is used, it may be concentrated, e.g. by evaporation or filtration.

[0066] Glucose, lactose and GOS are preferably derived from the composition of the present invention. A liquid cocoa and / or malt beverage product of the invention preferably comprises 10-30% by dry weight of the composition of the invention, more preferably 15-25% by dry weight. In a preferred embodiment, the liquid cocoa and / or malt beverage product comprises 0.5-1% by weight of glucose; 0.01-0.5% by weight of lactose; and 1-4% by weight of GOS.

[0067] A liquid cocoa and / or malt beverage product of the invention may comprise sucrose. Due to the amounts of lactose, glucose and GOS present in the product, the amount of sucrose may be reduced as compared to a conventional cocoa and / or malt beverage powder while retaining an acceptable taste, sweetness and texture. In a preferred embodiment, a cocoa and / or malt beverage product of the invention does not comprise sucrose. In another preferred embodiment, a cocoa and / or malt beverage powder of the invention comprises 0.1-5% by weight of sucrose, more preferably 1-3% by weight of sucrose.

[0068] A liquid cocoa and / or malt beverage product of the invention may comprise any other suitable ingredients known in the art, such as e.g. vitamins, minerals, buffer salts, emulsifiers and stabilizers.

[0069] A liquid cocoa and / or malt beverage product of the invention may be produced in any suitable way known in the art. The ingredients may be in liquid and / or powdered form and may be mixed into an aqueous solution / suspension, e.g. with the addition of water to achieve the desired concentration of ingredients. A food ingredient of the invention is preferably added in liquid form, but may also be added in powdered form.

[0070] In a preferred embodiment, the composition relates to a liquid cocoa and / or malt beverage product comprising: 3-10% by weight of non-fat milk solids; 1-6% by weight of malt extract solids; 1-5% by weight of cocoa solids; 0.3-5% by weight of vegetable oil and / or milk fat; 0-5% by weight of sucrose; 0.4-1.5% by weight of glucose; 0.01-1% by weight of lactose; and 0.5-5% by weight of GOS.

[0071] The composition can be in any oral nutritional form, e.g., as a health drink, as a ready-made drink, optionally as a soft drink, including juices, coffee, tea, milk-shake, yogurt drink, smoothie or soy -based drink; in a food bar; a powder, such as in sachet form; or dispersed in foods of any sort, such as baked products, cereal bars, dairy bars, snack-foods,soups, breakfast cereals, muesli, candies, tabs, cookies, biscuits, crackers (such as rice crackers), and dairy and plant-based products.

[0072] In an embodiment, the nutritional compositions are infant or follow on formulae.

[0073] The nutritional composition according to the invention can be for example an infant formula, a starter infant formula, a follow-on or follow-up formula, a growing-up milk, a baby food, an infant cereal composition, a fortifier such as a human milk fortifier, or a supplement. In some particular embodiments, the composition of the invention is an infant formula, a fortifier or a supplement that may be intended for the first 4 or 6 months of age. In a preferred embodiment the nutritional composition of the invention is an infant formula.

[0074] In some other embodiments the nutritional composition of the present invention is a fortifier. The fortifier can be a breast milk fortifier (e.g. a human milk fortifier) or a formula fortifier such as an infant formula fortifier or a follow-on / follow-up formula fortifier.

[0075] In the present invention, the nutritional compositions can be in a form of a powder to be reconstituted with water. The nutritional compositions can be in a form of a concentrate to be diluted. Upon reconstitution or dilution of the nutritional compositions an end product is preferably a liquid.

[0076] The compositions used typically comprise a fat source, a protein source and a carbohydrate source.

[0077] The fat source in the nutritional compositions may be selected from milk fat and / or vegetable fat. The vegetable fat includes palm olein, high oleic sunflower oil, high oleic safflower oil, canola oil, soy oil, fish oil, coconut oil, cell oils derived from fungi or any mixtures thereof.

[0078] The carbohydrate source includes lactose, saccharose, maltodextrin, glucose syrup, starch and mixtures thereof.

[0079] The compositions may further comprise proteins such as intact or hydrolysed protein, proteins associated with milk fat globule membrane (MFGM), TGF-B (Transforming Growth Factor), casein, whey, soy protein, lactoferrin or any mixtures thereof.

[0080] In addition, the compositions may comprise components selected from vitamins, minerals, trace elements, nucleosides, nucleotides, prebiotics and probiotics

[0081] In some embodiments, the composition relates to a ready to drink beverage. The % weight are based on dry matter of the composition before reconstitution. In an embodiment, the ready to drink beverage comprises 32%-55% of a mixture of Lactose,Glucose, Galactose, and GOS. In an embodiment, the composition comprises 40-45% by dry weight of the mixture of lactose, glucose, galactose and GOS. In an embodiment, the composition comprises 45-50% by dry weight of the mixture of lactose, glucose, galactose and GOS. In an embodiment, the food ingredient comprises 32-37% by dry weight of the mixture of lactose, glucose, galactose and GOS.

[0082] In some embodiments, the mixture of Lactose, Glucose, Galactose and GOS in the composition contains 1-25% by weight of lactose, such as 1-5%, 5-10%, 10-15%, 15- 20%, or 20-25% by weight of lactose. In some embodiments, the mixture of Lactose, Glucose, Galactose and GOS in the composition contains 15-35% by weight of glucose, such as 15-20%, 20-25%, 25-30%, or 30-35% by weight of glucose. In some embodiments, the mixture of Lactose, Glucose, Galactose and GOS in the composition contains 1-10% by weight of galactose, such as 1-2%, 2-4%, 4-6%, 6-8%, or 8-10% by weight of galactose. In some embodiments, the mixture of Lactose, Glucose, Galactose and GOS in the composition contains 50-85% by weight of GOS, such as 50-60%, 60-70%, 70-80%, or 80-85% by weight of GOS.

[0083] In a preferred embodiment, the composition comprises 40-45% of a mixture of Lactose, Glucose, Galactose and GOS. In a preferred embodiment, the mixture of Lactose, Glucose, Galactose and GOS in the composition contains 10-20% by weight of lactose. In a preferred embodiment, the mixture of Lactose, Glucose, Galactose and GOS in the composition contains 15-25% by weight of glucose. In a preferred embodiment, the mixture of Lactose, Glucose, Galactose and GOS in the composition contains 0.1-5% by weight of galactose. In a preferred embodiment, the mixture of Lactose, Glucose, Galactose and GOS in the composition contains 57-70% by weight of GOS.

[0084] In some embodiments, the ready to drink beverage includes milk. In some embodiments, the milk includes full milk, skim milk, and other types of milk. In some embodiments, the ready to drink beverage is optionally fortified with one or more vitamins and minerals.

[0085] The composition can be administered to the infant, young child or child at least two days per week, at least three days per week, all seven days of the week respecting serving size; for at least one week, at least one month, at least two months, at least three months, at least six months, or even longer. In some embodiments, the composition is administered to the infant, young child or child consecutively for a number of days. In an embodiment, the composition can be administered to the infant, young child or child daily for at least 30, 60 or 90 consecutive days.

[0086] In some embodiments, the serving size of the composition is an amount effective to increase certain metabolites or certain bacteria such as Bifidobacteria, for example, about 100 ml, about 200 ml, about 300 ml, about 400 ml or about 300 ml of the composition. In some embodiments, the composition is administered in a unit dosage form that comprises an amount of the composition effective for increasing or decreasing certain metabolites and improving bone health.

[0087] In view of the disclosures herein, an embodiment is a method for promoting bone growth, enhancing bone growth and / or bone strength, the method comprising administering to an infant, young child or child in need thereof a low sugar, low lactose, milkbased composition comprising galactooligosaccharide. In some embodiments, the composition is as described above.

[0088] The promoting bone growth, enhancing bone growth and / or bone strength in an infant, young child or child comprises at least one result selected from the group consisting of: (a) regulating bone turnover b) increasing bone mineral density and microarchitecture; c) increasing bone formation d) maximizing peak bone mass; d) increasing bone mineralization; e) improving bone lengthening and f) combinations thereof.

[0089] Another aspect of the present disclosure is a method for promoting bone growth, enhancing bone growth and / or bone strength, the method comprising administering to an infant, young child or child in need thereof or at risk thereof any of the compositions disclosed herein. The composition may be administered in an amount effective for increasing e.g. SCFAs, propionate, valerate, NN-dimethylglycine, 3 indole propionate and / or 3- hydroxybutyrate. The Research has shown that increasing propionate or valerate levels has been linked to the listed benefits (See Lucas S, et al. Short-chain fatty acids regulate systemic bone mass and protect from pathological bone loss. Nat Commun. 2018 Jan 4;9(1):55). Research has also shown that increasing N,N-Dimethylglycine levels has been linked to the listed benefits (Lawson BR, et al. Immunomodulation of murine collagen-induced arthritis by N,N-dimethylglycine and a preparation of Perna canaliculus. BMC Complement Altern Med. 2007 Jun 11;7:20. doi: 10.1186 / 1472-6882-7-20). Research has shown that increasing levels of 3 Indole propionate have been linked to the listed benefits (see Peng, Renpeng et al. “Gut Clostridium sporogenes-derived indole propionic acid suppresses osteoclast formation by activating pregnane X receptor.” Pharmacological research vol. 202 (2024): 107121); Konopelski, Piotr, and Izabella Mogilnicka. “Biological Effects of Indole-3 -Propionic Acid, a Gut Microbiota-Derived Metabolite, and Its Precursor Tryptophan in Mammals' Health and Disease.” International journal of molecular sciences vol. 23,3 1222. 22 Jan. 2022). Researchhas also shown that increasing levels of 3 -hydroxybutyrate is linked to the listed benefits (see Zhao, Yan et al. “The effect of 3 -hydroxybutyrate on the in vitro differentiation of murine osteoblast MC3T3-E1 and in vivo bone formation in ovariectomized rats.” Biomaterials vol. 28,20 (2007): 3063-73.)

[0090] The composition may be administered to the infant, young child or child in a unit dosage form, wherein the unit dosage form.

[0091] In an embodiment, the composition according to the present invention has been shown to increase production of SCFA by comparison to regular milk in lactose malabsorbers. Moreover, the processus of fermentation was shown to be optimized, with the composition leading to more SCFA production for less gas being produced than regular milk. This phenomenon could improve gut comfort, by minimizing colonic gaz production (responsible for bloating, flatulence and discomfort) while retaining the benefit associated with bacterial fermentation in the colon (SCFA production). In a particular embodiment, the composition according to the present invention, produces less gas for the same amount of SCFA produced as exemplified below. Additionally, our composition was shown to produce similar amount of gaz in lactose malabsorption condition than in regular condition, suggesting that it should not induced gas-associated discomfort in lactose malabsorbers.EXAMPLES

[0092] The following non-limiting example generally illustrates the concepts underlying the embodiments disclosed herein.

[0093] Example 1

[0094] In-vitro batch fermentation experiment was set up to compare the effect of 24h fermentation of GOS or the active composition on the microbial metabolism in healthy individuals (H) or in individuals with lactose malabsorption (LM). For this, the active composition according to Table 1 was subjected to a simulation of upper gastrointestinal tract digestion according to the INFOGEST 2.0 method (Brodkorb et al) to mimic the human upper gastro-intestinal tract digestion before being introduced in the fermenters. This step removed small sugars such as lactose, glucose and galactose. The in vitro digestion process also removed some of the GOS (which is contrary to what is observed in vivo in human where GOS remains undigested in the upper gastrointestinal tract). For these reasons, some GOS was directly added in the fermenters to mimic human digestion; final concentrations of GOS are presented in Table 2. In other experiments, lactose (+ / - GOS) was added to the fermenters to mimic human lactosemalabsorption (LM); final concentrations of lactose are presented in Table 2. A negative control was also introduced to evaluate the basal microbial metabolism after 24h without any substrate addition (NSC). Each condition was tested using fecal inoculum of 12 healthy donors. Microbial metabolites (including short chain fatty acids) were measured using a combination of targeted and untargeted metabolomics approaches by ultra-high performance liquid chromatography mass spectrometry (UPLC-MS). Significant differences in microbial metabolite production between conditions were calculated using paired-t test (*<pvalue=0.05; * *<p-value=0.01 ; * * *<p-value=0.001 ).

[0095] Table 1 : Active composition

[0096] Table 2: Final concentrations of Lactose and GOS before in-vitro batch fermentation.

[0097] Results

[0098] FIGS. 1-3 include box plots showing significant increase in production of propionate, valerate and N,N-Dimethylglycine metabolites after 24h fermentation of thecomposition disclosed herein by comparison to GOS alone or negative control (NSC) using batch fermentation.

[0099] The box plots displayed the median, the 25thand 75thpercentile and the distribution of the metabolite level for each donor (n=12) after 24h fermentation in mM for propionate and valerate or in arbitrary unit (A.U) for NN-dimethylglycine. A significant increase in propionate, valerate and NN-dimethylglycine was found after 24h fermentation of the active composition by comparison to GOS alone or in the NSC highlighting a boost in the production of microbial metabolites with known gut-related benefits. Indeed, Research has shown that increasing propionate or valerate levels has been linked to the listed benefits (See Lucas S, et al. Short-chain fatty acids regulate systemic bone mass and protect from pathological bone loss. Nat Commun. 2018 Jan 4;9(1):55. doi: 10.1038 / s41467-017-02490-4.). Research has also shown that increasing N,N-Dimethylglycine levels has been linked to the listed benefits (Lawson BR, et al. Immunomodulation of murine collagen-induced arthritis by N,N-dimethylglycine and a preparation of Perna canaliculus. BMC Complement Altern Med. 2007 Jun 1 I;7:2O. doi: 10.1186 / 1472-6882-7-20).

[0100] FIG. 4 shows the slight increase in SCFA production (+8%) after 24h fermentation of the composition disclosed herein by comparison to regular milk using batch fermentation with simulated lactose malabsorption (LM). This indicates that despite producing less gas, the Active Composition leads to more production of SCFA with the associated health benefit as described herein. The processus of fermentation is optimized with the Active Composition leading to more SCFA production for less gas being produced, potentially improving gut comfort while retaining the benefit associated with bacterial fermentation in the colon.

[0101] Example 2

[0102] The inventors examined the effect of administering the composition disclosed herein, versus lactose-free milk, in 26 healthy individuals. Table 3 shows the composition administered versus the control.Table 3: Active composition versus control composition administered to individuals

[0103] Specifically, the inventors employed targeted and untargeted metabolomics for plasma samples and metagenomics for fecal samples. The composition disclosed herein was administered once daily for 2 weeks in a 200 ml drink portion.

[0104] 92 plasma and fecal samples were analyzed using liquid chromatography high resolution mass spectrometer. The features (characterized by their retention time and accurate m / z) were linearized and normalized. The features were annotated by their exact mass (m z) according to the Human Metabolome database (HMDB). Different statistical approaches were tested to study the effect of the administration of the composition. A statistical analysis was performed with linear models (after log transformation of the data) considering the period and the treatment to study the effect of the administration of the composition. Statistical significance was analyzed with a type 2 analysis of covariance and a false discovery rate estimate was performed. p<0.05 was considered as a significant change.

[0105] Among the significantly annotated features reported in plasma, the inventors found an increase for 3-indole propionic acid (FC of 0.77, p=0.01, with its identity confirmed by injecting a pure standard) as shown in Figure 5.

Claims

CLAIMSClaim 1 : A method for promoting bone growth, enhancing bone growth and / or bone strength, the method comprising administering to an infant, young child or child in need thereof a low sugar, low lactose, milk-based composition comprising galactooligosaccharide.Claim 2: The method of claim 1, wherein the composition comprises 35-55% by dry weight of a mixture of lactose, glucose, galactose and galactooligosaccharide.Claim 3: The method of claim 1 or 2, wherein the composition comprises 20-40 % by dry weight of milk protein; and 32-55% by dry weight of a mixture of lactose, glucose, galactose and galactooligosaccharide.Claim 4: The method of any of claims 2 to 3, wherein the mixture of lactose, glucose and galactose and galactooligosaccharide comprises 0.1-30% by weight of lactose.Claim 5: The method of any of claims 2 to 4, wherein the mixture of lactose, glucose and galactose and galactooligosaccharide comprises: 8-40% by weight of glucose.Claim 6: The method of any of claims 2 to 5, wherein the mixture of lactose, glucose and galactose and galactooligosaccharide comprises: 0.1-20% by weight of galactose.Claim 7: The method of any of claims 2 to 6, wherein the mixture of lactose, glucose and galactose and galactooligosaccharide comprises 40-90% by weight of galactooligosaccharide.Claim 8: The method of any of preceding claims, wherein the milk-based composition comprises: milk protein, preferably at 20-40 % by dry weight of the composition; and a mixture of lactose, glucose, galactose and galactooligosaccharide, the mixture preferably at 32-55% by dry weight of the composition;preferably, the mixture comprising: 0.1-30% by weight of the lactose, 8-40% by weight of the glucose, 0.1-20% by weight of the galactose and 40-90% by weight of the galactooligosaccharide.Claim 9: The method of any preceding claims, wherein the promoting bone growth, enhancing bone growth and / or bone strength in an infant, young child or child comprises at least one result selected from the group consisting of: (a) regulating bone turnover b) increasing bone mineral density and microarchitecture; c) increasing bone formation d) maximizing peak bone mass; d) increasing bone mineralization; e) improving bone lengthening and f) combinations thereof.Claim 10: The method according to claim 9, wherein the composition is administered in an amount effective for increasing levels of SCFAs, propionate, 3 indole propionate, indoxyl sulfate and / or nicotinamide.Claim 11 : The method of any preceding claim, wherein the composition is administered to the infant, young child or child in a unit dosage form.Claim 12: The method according to any preceding claim, wherein the infant, young child or child is lactose mal-absorber.

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