Low lactose, low sugar, milk-based composition comprising GOS for use in improving metabolic health, immune health, brain health and / or preventing and / or treating GI-disorders or improving digestive comfort in an infant, young child or child

Abstract

Methods and compositions for improving metabolic health, immune health, brain health, and / or treating and / or preventing gastrointestinal disorders and / or improving digestive comfort in an infant, a young child or a 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 HEALTH IN AN INFANT, A YOUNG CHILD OR A CHILDTECHNICAL FIELD

[0001] The present disclosure generally relates to compositions and methods treating and / or preventing metabolic, immune, brain health and / or gastrointestinal disorders and / or improving digestive comfort in an infant, a young child or a child. Some embodiments are directed to a composition comprising milk protein and further comprising a mixture of lactose, glucose, galactose and galactooligosaccharide (GOS).BACKGROUND

[0002] Gut microbiota metabolites play an important role in host health and nutrient metabolism. More and more scientific evidence suggests that metabolites produced by gut microbiota are important mediators of benefits for the host. Supplementation with galactooligosaccharides (GOS) has been previously linked to several health benefits, predominantly via gut microbiome modulation. While many studies are focused on beneficial metabolites originating from gut carbohydrate fermentation, it appears that bacterial metabolites from protein metabolisms also play an important role in host physiology.

[0003] Moreover, lactose malabsorption is a condition in which the body is unable to fully digest lactose, a sugar found in milk and dairy products. This occurs due to a deficiency or absence of lactase, an enzyme produced in the small intestine that breaks down lactose into simpler sugars for absorption into the bloodstream. As a result, undigested lactose passes into the large intestine, where it is fermented by bacteria, leading to symptoms such as bloating, gas, diarrhea, and abdominal discomfort. Lactose malabsorption is different from lactose intolerance, which refers to the development of symptoms after consuming lactose-containing foods.

[0004] It is important for lactose malabsorbers to manage their condition by adjusting their diet to limit or avoid lactose-containing foods and beverages. Lactose-free or low lactose alternatives or non-dairy sources of calcium exist that are suitable for infant, a young child or a child with lactose malabsorption, however, there remains a need for a composition for easy and convenient administration to any infant, a young child or a child resulting in an increase in beneficial microbial metabolites.

[0005] There remains a need for a composition for easy and convenient administration to an infant or young child resulting in an increase in beneficial microbial metabolites.SUMMARY

[0006] Embodiments of the disclosure concern methods and / or compositions for improving metabolic, immune, brain health and / or gastrointestinal health and / or digestive comfort.

[0007] In particular embodiments, a method for treating and / or preventing gastrointestinal disorders and / or improving digestive comfort 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 improving of the metabolic health can comprise at least one result selected from the group consisting of: (a) appetite or food intake control or regulation; (b) managing glucose levels; (c) preventing and / or treating overweight or obesity, in particular reduction of risk of obesity later in life; (d) normalizing blood lipid profiles; (e) skin health; (f) reducing inflammation; (g) preventing and / or attenuating oxidative stress; (h) improved lipid metabolism; (i) improving intestinal barrier; (j) reducing intestinal permeability; (k) modulation of glucose metabolism; (1) protection from fatty liver; (m) promoting timely growth of Faecalibacterium prausnitzii, (o) promoting growth of Bifidobacterium; (p) increasing Bifidobacterium shunt pathway; (q) increasing NAD salvage pathway; (r) preservation of P- cell function; (s) preventing diabetes, in particular reduction of diabetes later in life; (t) improve and / or maintain insulin sensitivity; (u) preventing high blood pressure; (v) maintaining insulin response; (w) maintaining beta-cell function to maintain insulin secretion and (x) combinations thereof.

[0009] The improving brain health can comprise at least one result selected from the group consisting of: (a) improve brain maturation; b) preventing mental fatigue, maintain focus & concentration ; c) support optimal cognitive and / or neuronal function; d) support optimal brain metabolism; e) improving brain function; f) supporting cognitive and / or socialdevelopment; g) support optimal learning and memory; h) support language development; i) supporting emotional regulation; j) supporting motor and / or coordination skills; k) support optimal myelination; 1) reducing inflammation; m) preventing and / or attenuating oxidative stress; (n) support blood brain barrier integrity protection; (o) promote axon growth; p) support optimal brain and / or neuronal connectivity; q) support neurogenesis and synaptic connectivity; r) managing stress; s) helping manage anxiety and / or mood related disorders; (t) coping with pain; (u) improve sleep, in particular sleep quality for brain recovery and (v) combinations thereof.

[0010] The improving of the immune health can comprise at least one result selected from the group consisting of: (a) protection and / or reducing the risk of infections such as gastrointestinal and respiratory infections; (b) protection against pathogens such as viral, bacterial or fungal pathogens; (c) reducing inflammation; (d) preventing and / or attenuating oxidative stress; (e) promoting adequate gut barrier function; (f) promoting growth of Bifidobacterium; (g) increasing Bifidobacterium shunt pathway; (i) increasing NAD salvage pathway; (j) preventing and / or treating allergic asthma, (k) preventing allergic march; (1) promoting immune homeostasis; (m) supporting immune resilience at weaning period; (1) preventing and / or treating clostridioides difficile infection; (m) preventing and / or treating autoimmune diseases such as celiac disease and (n) combinations thereof.

[0011] The prevention and / or treatment of gastrointestinal disorders and / or improvement of digestive comfort comprises at least one result selected from the group consisting of: (a) preventing and / or attenuating stomach related disorders such as belching, stomach discomfort, fullness, nausea, heartburn, acid reflux and / or gastric ulcers; (b)preventing and / or attenuating intestine related disorders such as rumbling, abdominal discomfort, cramps and / or fullness; (c) reducing and / or preventing colon related digestive disorders such as bloating, gas / flatulence, diarrhea and / or constipation; (d) reducing and / or preventing intestinal inflammation such as colitis, ulcerative colitis, inflammatory bowel disease and / or gastritis; (e) prevent gastrointestinal motility related disorder and / or transit related disorder selected from constipation, vomiting or regurgitation, bloating, diarrhea, nausea, weight loss, pain or swallowing problems, heartburn or GERD and / or urgent need to have bowel movement; (f) reducing gastric distension; (g) reducing small bowel water content; (h) decreasing small bowel transit; (i) improving colonic fermentation; (j) reducing colonic fermentation; (k) reducing colonic gas; (1) reducing colonic water content; (m) reducing colic symptoms; (n) reducing fussing / crying time; (o) improvement of stool consistency; (p) enhance nutrient absorption; (q) improved digestion; (r) improved tolerance to food; (s) preventing disorders of gut-braininteractions (DGBIs), like regurgitation, infantile colic, functional abdominal pain, functional constipation, functional diarrhea, functional dyspepsia, irritable bowel syndrome; (t) preventing the discomfort march / promote comfort march and (u) combinations thereof.

[0012] Additional features and advantages are described herein and will be apparent from the following Figures and Detailed Description.BRIEF DESCRIPTION OF THE DRAWINGS

[0013] FIG. 1 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.

[0014] FIG. 2 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.

[0015] 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.

[0016] FIG. 4 shows the decrease in gas 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.

[0017] FIG. 5 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.

[0018] FIG. 6 shows ratio gas production to 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.

[0019] FIG. 7 represents gas production after 24 h fermentation of the Active composition using batch fermentation with (composition - LM) or without simulated lactose malabsorption (composition).

[0020] FIG. 8 shows fecal cadaverine concentration in 24 healthy individuals in control and intervention groups. Data reported are mean and SD. LMS stands for Least Mean Square analysis based on a linear mixed effects model with product, sequence and period as fixed effects.

[0021] FIG. 9 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.

[0022] FIG. 10 shows plasma 3 -hydroxydecanoic acid levels after administration of the composition disclosed herein (IP) compared to administration of a control product (CP) of lactose-free skimmed milk.

[0023] FIG. 11 shows plasma 12,13-DiHODE levels after administration of the composition disclosed herein (IP) compared to administration of a control product (CP) of lactose-free skimmed milk.

[0024] FIG. 12 shows plasma indoxyl sulfate levels after administration of the composition disclosed herein (IP) compared to administration of a control product (CP) of lactose-free skimmed milk.

[0025] FIG. 13 shows plasma p-cresol sulfate levels after administration of the composition disclosed herein (IP) compared to administration of a control product (CP) of lactose-free skimmed milk.

[0026] FIG. 14 shows plasma acetate levels after administration of the composition disclosed herein (IP) compared to administration of a control product (CP) of lactose-free skimmed milk.

[0027] FIG. 15 shows plasma caprylic acid levels after administration of the composition disclosed herein (IP) compared to administration of a control product (CP) of lactose-free skimmed milk.

[0028] FIG. 16 shows plasma nicotinamide levels after administration of the composition disclosed herein (IP) compared to administration of a control product (CP) of lactose-free skimmed milk.

[0029] FIG. 17 shows plasma beta-alanine levels after administration of the composition disclosed herein (IP) compared to administration of a control product (CP) of lactose-free skimmed milk.

[0030] FIG. 18 shows plasma ketone body levels after administration of the composition disclosed herein (IP) compared to administration of a control product (CP) of lactose-free skimmed milk.

[0031] FIG. 19 shows fecal Bifidobacterium levels after administration of the composition disclosed herein (IP) compared to administration of a control product (CP) of lactose-free skimmed milk.

[0032] FIG. 20 shows fecal B. longum levels after administration of the composition disclosed herein (IP) compared to administration of a control product (CP) of lactose-free skimmed milk.

[0033] FIG. 21 shows fecal B. adolescentis levels after administration of the composition disclosed herein (IP) compared to administration of a control product (CP) of lactose-free skimmed milk.

[0034] FIG. 22 shows fecal B. bifidum levels after administration of the composition disclosed herein (IP) compared to administration of a control product (CP) of lactose-free skimmed milk.

[0035] FIG. 23 shows the Bifidobacterium shunt pathway abundance after administration of the composition disclosed herein (IP) compared to administration of a control product (CP) of lactose-free skimmed milk.

[0036] FIG. 24 shows the NAD salvage pathway abundance after administration of the composition disclosed herein (IP) compared to administration of a control product (CP) of lactose-free skimmed milk.

[0037] FIG. 25-30 show the increase of certain metabolites during fermentation of the composition of the present invention compared to GOS alone and a control.DETAILED DESCRIPTION

[0038] Definitions

[0039] 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.

[0040] 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.

[0041] 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.

[0042] 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.

[0043] 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.

[0044] 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.

[0045] 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.

[0046] 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" means children aged between one and three years.

[0047] 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".

[0048] 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.

[0049] As used herein, the term “metabolic health” shall refer to the ability for your body to digest and absorb nutrients from food without abnormal or unhealthy spikes in blood sugar, blood lipid, inflammation, and / or insulin. “Improving metabolic health” shall refer to mechanisms for directly or indirectly reducing the incidence of spikes in blood sugar, inflammation, insulin, and / or blood fat.

[0050] As used herein, the term “oxidative stress” refers to the state in an infant / young child, or cell or tissue of an infant / young child, of an imbalance between the production of reactive oxygen and the ability to detoxify the reactive intermediates or easily repair the resulting damage in a biological system. The natural reducing environment within cells is maintained by processes using a constant input of metabolic energy, and disturbances in this normal redox state can result in toxic effects through the production of, for example, free radicals and peroxides that damage cellular components, such as proteins, lipids, and / or DNA, for example.

[0051] 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 and provides at least one nutrient to the infant / young 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.

[0052] “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 been diagnosed 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 childnot 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 nonlimiting examples, a treatment can be performed by a patient, a caregiver, a doctor, a nurse, or another healthcare professional.

[0053] As used herein, the term “lactose mal-absorber” refers to an infant / young 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.

[0054] As used herein, the term “low lactose” shall refer to a composition with less than or equal to 30% of lactose.

[0055] As used herein, the term “low sugar” shall refer to a composition with less than or equal to 55% of the composition.

[0056] 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, more generally, reduces symptoms, manages progression of the disease, or provides a nutritional, physiological, or medical benefit to the infant / young child.

[0057] 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.

[0058] 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.)

[0059] 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 a predetermined quantity of the composition disclosed herein in an amount sufficient to produce the desired effect, in association with an acceptable diluent, carrier or vehicle. Thespecifications 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.

[0060] “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 -(l- 6). GOS are normally produced through the enzymatic conversion of lactose.

[0061] EmbodimentsIn an aspect of the present disclosure, a method of improving metabolic, immune, brain health and / or treating and / or preventing gastrointestinal disorders and / or improving digestive comfort comprises administering to an infant / young child in need thereof or at risk thereof a low sugar, low lactose, milk-based composition comprising galactooligosaccharide. In certain embodiments of the invention, there are methods and compositions for improving metabolic, immune, and / or brain health, the improvement of metabolic, immune, and / or brain health caused directly or indirectly by increasing or decreasing levels of certain metabolites or certain bacteria such as Bifidobacteria in the infant / young child. The infant / young child may be of any age or state of health, although in particular embodiments the infant / young child may be susceptible to particular medical conditions or physical states that are treated or prevented directly or indirectly with increased or decreased metabolite levels, or has a medical condition or physical state that are treated or prevented directly or indirectly with increased metabolite levels.

[0062] The infant / young 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, a young child or a child may be treated with other therapy or therapies in addition to methods of the disclosure.

[0063] In other embodiment, the infant, a young child or a child is healthy but may be experiencing unpleasant gastrointestinal manifestation following the consumption of specific food (e.g. lactose containing product, gluten containing product).

[0064] In another embodiment the infant, a young child or a child is lactose mal- absorber.

[0065] In other embodiment, the infant, a young child or a child may be of any age or state of health, although in particular embodiments the infant, a young child or a child may be susceptible to particular medical conditions or physical states or genetic traits (e.g. lactase deficiency).

[0066] 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.

[0067] In some embodiments, the composition comprises 35-55% by dry weight of a mixture of lactose, glucose, galactose and galactooligosaccharide.

[0068] In an embodiment, the mixture of lactose, glucose and galactose and galactooligosaccharide comprises: 0.1-30% by weight of lactose.

[0069] In an embodiment, the mixture of lactose, glucose and galactose and galactooligosaccharide comprises: 8-40% by weight of glucose.

[0070] In an embodiment, the mixture of lactose, glucose and galactose and galactooligosaccharide comprises: 0.1-20% by weight of galactose.

[0071] 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.

[0072] 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.

[0073] Some embodiments provide a contribution from each of the components of the composition individually, in combination, and / or synergistically.

[0074] Composition for use

[0075] 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 preferredembodiment, the composition comprises 25-40%, more preferably 30-40% by dry weight of milk protein.

[0076] 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.

[0077] 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.

[0078] 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 milk derived 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.

[0079] 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.

[0080] 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.

[0081] 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.

[0082] 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.

[0083] 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.

[0084] 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 / or milk 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.

[0085] 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.

[0086] 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.

[0087] 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.

[0088] 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.

[0089] 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.

[0090] 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.

[0091] In an embodiment, the nutritional compositions are infant or follow on formulae.

[0092] 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.

[0093] The compositions used typically comprise a fat source, a protein source and a carbohydrate source.

[0094] 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.

[0095] The carbohydrate source includes lactose, saccharose, maltodextrin, glucose syrup, starch and mixtures thereof.

[0096] 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.

[0097] The compositions used may comprise milk fat globule membranes (MFGM).

[0098] In addition, the compositions may comprise components selected from vitamins, minerals, trace elements, nucleosides, nucleotides, prebiotics and probiotics

[0099] 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.

[0100] 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 someembodiments, 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.

[0101] 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.

[0102] 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. In a preferred embodiment, the one or more vitamins include vitamins for providing a health benefit as disclosed herein.

[0103] The composition can be administered to the infant, a young child or a 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, a young child or a child consecutively for a number of days. In an embodiment, the composition can be administered to the infant, a young child or a child daily for at least 30, 60 or 90 consecutive days.

[0104] 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, 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 health benefits as disclosed herein.

[0105] Metabolic health

[0106] In certain embodiments of the invention, there are methods and compositions for improving metabolic health, the improvement of metabolic health caused directly or indirectly by increasing or decreasing levels of certain metabolites or certain bacteria such as Bifidobacteria in the infant, a young child or a child. The compositions delivered to the infant, a young child or a child in such cases include at least a mixture of lactose, glucose, galactoseand galactooligosaccharide, 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 galactooligosaccharide, in particular to facilitate raising or lowering specific metabolite levels in the infant, a young child or a child. One can measure specific metabolite levels through plasma or fecal samples, for example, in methods well known in the art.

[0107] In specific embodiments, improvement of metabolic health is associated with increased and / or decreased levels of certain metabolites, certain bacteria such as Bifidobacteria, or functional derivatives thereof. In particular embodiments, improving metabolic health comprises one or more of the following: (a) appetite or food intake control or regulation; (b) managing glucose levels; (c) preventing and / or treating overweight or obesity, in particular reduction of risk of obesity later in life; (d) normalizing blood lipid profiles; (e) skin health; (f) reducing inflammation; (g) preventing and / or attenuating oxidative stress; (h) improved lipid metabolism; (i) improving intestinal barrier; (j) reducing intestinal permeability; (k) modulation of glucose metabolism; (1) protection from fatty liver; (m) promoting timely growth of Faecalibacterium prausnitzii, (o) promoting growth of Bifidobacterium; (p) increasing Bifidobacterium shunt pathway; (q) increasing NAD salvage pathway; (r) preservation of P- cell function; (s) preventing diabetes, in particular reduction of diabetes later in life; (t) improve and / or maintain insulin sensitivity; (u) preventing high blood pressure; (v) maintaining insulin response; maintaining beta-cell function to maintain insulin secretion and (z) combinations thereof.

[0108] The infant, a young child or a 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, a young child or a child may be treated with other therapy or therapies in addition to methods of the disclosure.

[0109] In one embodiment of the disclosure, there is a method of producing increased blood levels of certain metabolites, including 3-indole propionate, propionate, indoxyl-3 -carboxylate, valerate, tricarballylic acid, imidazole acetate, acetate, N,N,- dimethylglycine, caprylic acid, nicotinamide, beta-alanine, ketone bodies, 3 -hydroxybutyrate, 12,13-diHODE, and / or 3 -hydroxy decanoic acid. Preferably, the composition is administered in an effective amount to increase one or more Bifidobacterium, including but not limited to B. longum, B. adolescentis, B. bifidum, in an infant, a young child or a child in need thereof by administering the composition disclosed herein. The infant, a young child or a child may be known to have a medical condition or physical state that would benefit from increased metabolite levels, or the infant, a young child or a child may be suspected of having a medicalcondition or physical state that would benefit from increased metabolite levels, or increased beneficial fecal bacteria levels.

[0110] The method may comprise identifying the infant, a young child or a child as having a medical condition or physical state that would benefit from increased metabolite levels, or increased beneficial fecal bacteria levels, and / or the method may comprise identifying the infant, a young child or a child as at risk of a medical condition or physical state that would benefit from increased metabolite levels, or increased beneficial fecal bacteria levels. In particular embodiments, the infant, a young child or a child subjected with methods and / or compositions of the invention is desiring prevention of one or more undesirable physical states (or the effects thereof, such as with aging) or medical conditions.

[0111] Preferably the composition is administered in an amount effective to increase one or more metabolite levels selected from the group consisting of 3-indole propionate, propionate, indole-3 -carboxylate, valerate, tricarballylic acid, imidazole acetate, N,N,- dimethylglycine, caprylic acid, nicotinamide, beta-alanine, ketone bodies, 3 -hydroxybutyrate, 12,13-diHODE, and / or 3 -hydroxy decanoic acid. Preferably, the composition is administered in an effective amount to increase one or more Bifidobacterium, including but not limited to B. longum, B. adolescentis, B. bifidum. Preferably, the compostion is administered in an effective amount to increase one or more Bifidobacterium, including but not limited to B. longum, B. adolescentis, B. bifidum.

[0112] In some embodiments, there is a method for one or more of preventing oxidative stress, reducing inflammation, improving the intestinal barrier, reducing intestinal permeability, modulating glucose metabolism, improve and / or maintain insulin sensitivity;, preventing and / or treating overweight or obesity, appetite or food intake control or regulation, and / or protecting against fatty liver, the method comprising administering to an individual in need thereof or at risk thereof any of the compositions disclosed herein. The composition may be administered in an amount effective for increasing levels of 3-indole propionate or propionate in the individual. The composition may be administered to the individual in a unit dosage form, wherein the unit dosage form comprises an amount of the composition effective for increasing levels of 3-indole propionate or propionate in an individual. Research has shown the increasing propionate levels has been linked to the listed benefits (See Vinolo MA, Rodrigues HG, Nachbar RT, Curi R. Regulation of inflammation by short chain fatty acids. Nutrients. 2011;3:858-76; De Vadder, F. et al. Microbiota-generated metabolites promote metabolic benefits via gut-brain neural circuits. Cell 156, 84-96 (2014); Chambers, E. S. et al. Effects of targeted delivery of propionate to the human colon on appetite regulation, bodyweight maintenance and adiposity in overweight adults. Gut 64, 1744-1754 (2015).; Xiong, Y. et al. Short-chain fatty acids stimulate leptin production in adipocytes through the G protein coupled receptor GPR41. Proc. Natl Acad. Sci. USA 101, 1045-1050 (2004).; Goswami, C., Iwasaki, Y. & Yada, T. Short-chain fatty acids suppress food intake by activating vagal afferent neurons. J. Nutr. Biochem. 57, 130-135 (2018).; Mills, S. W., Montgomery, S. H., & Morck, D. W. (2006). Evaluation of the effects of short-chain fatty acids and extracellular pH on bovine neutrophil function in vitro. American Journal of Veterinary Research, 67(11), 1901-1907.; Pingitore A, Chambers ES, Hill T, Maldonado IR, Liu B, Bewick G, Morrison DJ, Preston T, Wallis GA, Tedford C, Castanera Gonzalez R, Huang GC, Choudhary P, Frost G and Persaud SJ. The diet-derived short chain fatty acid propionate improves beta-cell function in humans and stimulates insulin secretion from human islets in vitro, Diabetes, Obesity and Metabolism 2017; 19(2): 257-265.; Chambers ES, Byrne CS, Aspey K, Chen Y, Khan S, Morrison DJ, Frost G. Acute oral sodium propionate supplementation raises resting energy expenditure and lipid oxidation in fasted humans. Diabetes Obes Metab. 2018 Apr;20(4): 1034-1039. doi: 10.1111 / dom. l3159. Epub 2017 Dec 17. PMID: 29134744; PMCID: PMC5873405.; Chambers ES, Viardot A, Psichas A, Morrison DJ, Murphy KG, Zac-Varghese SE, MacDougall K, Preston T, Tedford C, Finlayson GS, Blundell JE, Bell JD, Thomas EL, Mt- Isa S, Ashby D, Gibson GR, Kolida S, Dhillo WS, Bloom SR, Morley W, Clegg S, Frost G. Effects of targeted delivery of propionate to the human colon on appetite regulation, body weight maintenance and adiposity in overweight adults. Gut. 2015 Nov;64(l l): 1744-54. doi: 10.1136 / gutjnl-2014-307913. Epub 2014 Dec 10. PMID: 25500202; PMCID: PMC468017L; Chambers ES, Viardot A, Psichas A, Morrison DJ, Murphy KG, Zac-Varghese SE, MacDougall K, Preston T, Tedford C, Finlayson GS, Blundell JE, Bell JD, Thomas EL, Mt- Isa S, Ashby D, Gibson GR, Kolida S, Dhillo WS, Bloom SR, Morley W, Clegg S, Frost G. Effects of targeted delivery of propionate to the human colon on appetite regulation, body weight maintenance and adiposity in overweight adults. Gut. 2015 Nov;64(l l): 1744-54. doi: 10.1136 / gutjnl-2014-307913. Epub 2014 Dec 10. PMID: 25500202; PMCID: PMC468017L, the entireties of each of which are incorporated herein by reference.)

[0113] In some embodiments, there is a method for one or more of improving skin health, and / or normalizing blood lipid profiles, the method comprising administering to an individual in need thereof or at risk thereof any of the compositions disclosed herein. The composition may be administered in an amount effective for increasing levels of nicotinamide in the individual. The composition may be administered to the individual in a unit dosage form,wherein the unit dosage form comprises an amount of the composition effective for increasing levels of nicotinamide in an individual.

[0114] In some embodiments, there is a method for one or more of preventing and / or treating overweight or obesity, and / or appetite or food intake control or regulation, the method comprising administering to an individual in need thereof or at risk thereof any of the compositions disclosed herein. The composition may be administered in an amount effective for increasing levels of acetate in the individual. The composition may be administered to the individual in a unit dosage form, wherein the unit dosage form comprises an amount of the composition effective for increasing levels of acetate in an individual.

[0115] In some embodiments, there is a method for one or more of preventing and / or treating obesity, appetite or food intake control or regulation, and / or managing weight, the method comprising administering to an individual in need thereof or at risk thereof any of the compositions disclosed herein. The composition may be administered in an amount effective for increasing levels of Bifidobacterium in the individual. The composition may be administered to the individual in a unit dosage form, wherein the unit dosage form comprises an amount of the composition effective for increasing levels of Bifidobacterium in an individual.

[0116] In some embodiments, there is a method for one or more of reducing and / or preventing oxidative stress, the method comprising administering to an individual in need thereof or at risk thereof any of the compositions disclosed herein. The composition may be administered in an amount effective for increasing levels of 3 -hydroxybutyrate in the individual. The composition may be administered to the individual in a unit dosage form, wherein the unit dosage form comprises an amount of the composition effective for increasing levels of 3 -hydroxybutyrate in an individual.

[0117] In some embodiments, there is a method for improving lipid metabolism, the method comprising administering to an individual in need thereof or at risk thereof any of the compositions disclosed herein. The composition may be administered in an amount effective for increasing levels of 12,13-diHODE in the individual. The composition may be administered to the individual in a unit dosage form, wherein the unit dosage form comprises an amount of the composition effective for increasing levels of 12, 13-diHODE in an individual.

[0118] In some embodiments, there is a method for reducing inflammation, and modulating glucose levels, the method comprising administering to an individual in need thereof or at risk thereof any of the compositions disclosed herein. The composition may be administered in an amount effective for increasing levels of valerate in the individual. Thecomposition may be administered to the individual in a unit dosage form, wherein the unit dosage form comprises an amount of the composition effective for increasing levels of valerate in an individual. Research has shown increasing levels of valerate has been linked to the listed benefits (See Zhu L, et al. Microbiota-assisted iron uptake promotes immune tolerance in the intestine. Nat Commun. 2023 May 15;14(l):2790.; Luu M., et al. The Short-Chain Fatty Acid Pentanoate Suppresses Autoimmunity by Modulating the Metabolic-Epigenetic Crosstalk in Lymphocytes. Nat. Commun. 2019; 10:760.; Gao, G., et al. Effects of valerate on intestinal barrier function in cultured Caco-2 epithelial cell monolayers. Mol Biol Rep 49, 1817-1825 (2022); Han J-H, et al. (2014) The Effects of Propionate and Valerate on Insulin Responsiveness for Glucose Uptake in 3T3-L1 Adipocytes and C2C12 Myotubes via G Protein-Coupled Receptor 41. PLoS ONE 9(4): e95268.; McDonald JAK et al. Inhibiting Growth of Clostridioides difficile by Restoring Valerate, Produced by the Intestinal Microbiota. Gastroenterology 2018; 155; Issue 5, 1495-1507. el5 the entireties of each of which are incorporated herein by reference.)

[0119] In some embodiments, there is a method for reducing inflammation, the method comprising administering to an individual in need thereof or at risk thereof any of the compositions disclosed herein. The composition may be administered in an amount effective for increasing levels of Tricarballylic acid in the individual. The composition may be administered to the individual in a unit dosage form, wherein the unit dosage form comprises an amount of the composition effective for increasing levels of Tricarballylic acid in an individual. Research has shown increasing levels of Tricarballylic acid has been linked to the listed benefits (See Ashbrook MJ, McDonough KL, Pituch JJ, Christopherson PL, Cornell TT, Selewski DT, Shanley TP, Blatt NB. Citrate modulates lipopolysaccharide-induced monocyte inflammatory responses. Clin Exp Immunol. 2015 Jun;180(3):520-30. doi: 10.1111 / cei., the entirety of which is incorporated herein by reference.)

[0120] In some embodiments, there is a method for preventing high blood pressure, the method comprising administering to an individual in need thereof or at risk thereof any of the compositions disclosed herein. The composition may be administered in an amount effective for increasing levels of imidazole acetate in the individual. The composition may be administered to the individual in a unit dosage form, wherein the unit dosage form comprises an amount of the composition effective for increasing levels of imidazole acetate in an individual. Research has shown increasing levels of imidazole acetate has been linked to the listed benefits (See Tunnicliff 1998, Pharmacology and Function of Imidazole 4-Acetic Acidin Brain. Gen Pharmacol. 1998 Oct;31(4):503-9. doi: 10.1016 / s0306-3623(98)00079-2., the entirety of which is incorporated herein by reference.)

[0121] In some embodiments, there is a method for improving the intestinal barrier, maintaining normal insulin response, and reducing oxidative stress, the method comprising administering to an individual in need thereof or at risk thereof any of the compositions disclosed herein. The composition may be administered in an amount effective for increasing levels of N,N-Dimethylglycine in the individual. The composition may be administered to the individual in a unit dosage form, wherein the unit dosage form comprises an amount of the composition effective for increasing levels of N,N-Dimethylglycine in an individual. Research has shown increasing levels of N,N-Dimethylglycine has been linked to the listed benefits (See Wang et al. 2022. Heat stress-induced intestinal barrier damage and dimethylglycine alleviates via improving the metabolism function of microbiota gut brain axis. Ecotoxicology and Environmental Safety Volume 244, 1 October 2022, 114053. https: / / www.sciencedirect.com / science / article / pii / S0147651322008934; Magnusson et al. 2015. Dimethylglycine Deficiency and the Development of Diabetes. Diabetes. 2015 Aug;64(8):3010-6. doi: 10.2337 / dbl4-1863. Epub 2015 Mar 20.; Takahashi et al. 2016. N, N- Dimethylglycine decreases oxidative stress and improves in vitro development of bovine embryos. J Reprod Dev. 2016 Apr; 62(2): 209-212. doi: 10.1262 / jrd.2015-149, the entireties of each of which are incorporated herein by reference.)

[0122] Immune health

[0123] In specific embodiments, improvement of immune health is associated with increased and / or decreased levels of certain metabolites, certain bacteria such as Bifidobacteria, or functional derivatives thereof. In particular embodiments, improving immune health comprises one or more of the following: (a) protection and / or reducing the risk of infections such as gastrointestinal and respiratory infections; (b) protection against pathogens such as viral, bacterial or fungal pathogens; (c) reducing inflammation; (d) preventing and / or attenuating oxidative stress; (e) promoting adequate gut barrier function; (f) promoting growth of Bifidobacterium; (g) increasing Bifidobacterium shunt pathway; (i) increasing NAD salvage pathway; (j) preventing and / or treating allergic asthma, (k) preventing allergic march; (1) promoting immune homeostasis; (m) supporting immune resilience at weaning period; (1) preventing and / or treating clostridioides difficile infection; (m) preventing and / or treating autoimmune diseases such as celiac disease and (n) combinations thereof.

[0124] The infant, a young child or a 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, a young child or a child may be treated with other therapy or therapies in addition to methods of the disclosure.

[0125] In one embodiment of the disclosure, there is a method of producing increased blood levels of certain metabolites, including 3-indole propionate, acetate, caprylic acid, nicotinamide, beta-alanine, ketone bodies, 3 -hydroxybutyrate, 12,13-diHODE, propionate, indole-3 -carboxylate, valerate, N,N-Dimethylglycine, tricarballylic acid, propionate, and / or 3 -hydroxy decanoic acid (or functional derivatives thereof) or increased fecal levels of Bifidobacterium, including but not limited to B. adolescentis, bifidum, longum, in an infant, a young child or a child in need thereof by administering the composition disclosed herein. The infant, a young child or a child may be known to have a medical condition or physical state that would benefit from increased metabolite levels, or the infant, a young child or a 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.

[0126] The method may comprise identifying the infant, a young child or a child as having a medical condition or physical state that would benefit from increased metabolite levels, or increased beneficial fecal bacteria levels, and / or the method may comprise identifying the infant, a young child or a child as at risk of a medical condition or physical state that would benefit from increased metabolite levels, or increased beneficial fecal bacteria levels. In particular embodiments, the infant, a young child or a child subjected with methods and / or compositions of the invention is desiring prevention of one or more undesirable physical states (or the effects thereof, such as with aging) or medical conditions.

[0127] In specific embodiments, an infant, a young child or a child is provided effective amounts of compositions as described herein for the explicit purpose of raising intracellular levels of 3-indole propionate, acetate, caprylic acid, nicotinamide, beta-alanine, ketone bodies, 3 -hydroxybutyrate, 12,13-diHODE, propionate, indole-3 -carboxylate, valerate, N,N-Dimethylglycine, tricarballylic acid, propionate, and / or 3 -hydroxy decanoic acid or increasing fecal levels of Bifidobacterium, including but not limited to B. adolescentis, bifidum, longum, because it is determined that the infant, a young child or a child is afflicted with a condition for which such levels are directly or indirectly related. Additionally, an infant, a young child or a child is provided effective amounts of compositions as described herein for the explicit purpose of decreasing levels of indoxyl sulfate and / or p-cresol sulfate because it is determined that the infant, a young child or a child is afflicted with a condition for which such levels are directly or indirectly related.

[0128] Preferably the composition is administered in an amount effective to increase one or more metabolite levels selected from the group consisting of: 3-indole propionate, acetate, caprylic acid, nicotinamide, beta-alanine, ketone bodies, 3 -hydroxybutyrate, 12,13- diHODE, indole-3 -carboxylate, propionate, valerate, N,N-Dimethylglycine, tricarballylic acid, and / or 3 -hydroxy decanoic acid. Preferably, the composition is administered in an effective amount to increase one or more Bifidobacterium, including but not limited to B. longum, B. adolescentis, B. bifidum.

[0129] In another embodiment, the present disclosure is a method for preventing and / or treating allergic asthma, preventing and / or treating autoimmune diseases, promoting immune homeostasis, reducing inflammation; preventing and / or attenuating oxidative stress; improving the intestinal barrier, and / or reducing intestinal permeability, the method comprising administering to an individual in need thereof or at risk thereof any of the compositions disclosed herein. The composition may be administered in an amount effective for increasing levels of 3-indole propionate or proprionate in the individual. The composition may be administered to the individual in a unit dosage form, wherein the unit dosage form comprises an amount of the composition effective for increasing levels of 3-indole propionate or propionate in an individual. Research has shown that increasing propionate levels has been linked to the listed benefits (See Trompette A, Gollwitzer ES, Yadava K, Sichelstiel AK, Sprenger N, Ngom-Bru C, et al. Gut microbiota metabolism of dietary fiber influences allergic airway disease and hematopoiesis. Nat Med (2014) 20(2): 159-66. doi: 10.1038 / nm.3444; Zaiatz-Bittencourt V, Jones F, Tosetto M, Scaife C, Cagney G, Jones E, Doherty GA, Ryan EJ. Butyrate limits human natural killer cell effector function. Sci Rep. 2023 Feb 15; 13(1):2715. doi: 10.1038 / s41598-023-29731-5. PMID: 36792800; PMCID: PMC9932090.; Duscha A, Gisevius B, Hirschberg S, Yissachar N, Stangl GI, Dawin E, Bader V, Haase S, Kaisler J, David C, Schneider R, Troisi R, Zent D, Hegelmaier T, Dokalis N, Gerstein S, Del Mare-Roumani S, Amidror S, Staszewski O, Poschmann G, Stiihler K, Hirche F, Balogh A, Kempa S, Trager P, Zaiss MM, Holm JB, Massa MG, Nielsen HB, Faissner A, Lukas C, Gatermann SG, Scholz M, Przuntek H, Prinz M, Forslund SK, Winklhofer KF, Muller DN, Linker RA, Gold R, Haghikia A. Propionic Acid Shapes the Multiple Sclerosis Disease Course by an Immunomodulatory Mechanism. Cell. 2020 Mar 19;180(6): 1067-1080.el6. doi: 10.1016 / j.cell.2020.02.035. Epub 2020 Mar 10. PMID: 32160527.; Vinolo MA, Rodrigues HG, Nachbar RT, Curi R. Regulation of inflammation by short chain fatty acids. Nutrients. 2011;3:858-76: https: / / www.mdpi.eom / 2072-6643 / 3 / 10 / 858; Mills, S. W ., Montgomery, S. H., & Morck, D. W. (2006). Evaluation of the effects of short-chain fatty acids and extracellular pH on bovineneutrophil function in vitro. American Journal of Veterinary Research, 67(11), 1901-1907.; Sina, C.; Gavrilova, O.; Forster, M.; Till, A.; Derer, S.; Hildebrand, F.; Raabe, B.; Chalaris, A.; Scheller, J.; Rehmann, A.; et al. G protein-coupled receptor 43 is essential for neutrophil recruitment during intestinal inflammation. J. Immunol. 2009, 183, 7514-7522.; Arpaia, N. et al. Metabolites produced by commensal bacteria promote peripheral regulatory T cell generation. Nature 504, 451-455 (2013)., the entireties of each of which are incorporated herein by reference.)

[0130] In another embodiment, the present disclosure is a method for treating viral respiratory infections, the method comprising administering to an individual in need thereof or at risk thereof any of the compositions disclosed herein. The composition may be administered in an amount effective for increasing levels of acetate in the individual. The composition may be administered to the individual in a unit dosage form, wherein the unit dosage form comprises an amount of the composition effective for increasing levels of acetate in an individual.

[0131] In another embodiment, the present disclosure is a method for one or more of preventing and / or treating infections such as viral respiratory infections and / or protecting an individual against pathogens, the method comprising administering to an individual in need thereof or at risk thereof any of the compositions disclosed herein. The composition may be administered in an amount effective for increasing levels of Bifidobacterium in the individual. The composition may be administered to the individual in a unit dosage form, wherein the unit dosage form comprises an amount of the composition effective for increasing levels of Bifidobacterium in an individual.

[0132] In another embodiment, the present disclosure is a method for reducing and / or preventing oxidative stress, the method comprising administering to an individual in need thereof or at risk thereof any of the compositions disclosed herein. The composition may be administered in an amount effective for increasing levels of 3 -hydroxybutyrate in the individual. The composition may be administered to the individual in a unit dosage form, wherein the unit dosage form comprises an amount of the composition effective for increasing levels of 3 -hydroxybutyrate in an individual.

[0133] In another embodiment, the present disclosure is a method for promoting immune homeostasis, preventing and / or treating Clostridium difficile infection, cancer immunotherapy; preventing and / or treating intestinal inflammation; preventing and / or treating autoimmune diseases, and reducing inflammation, the method comprising administering to an individual in need thereof or at risk thereof any of the compositions disclosed herein. The composition may be administered in an amount effective for increasing levels of valerate in theindividual. The composition may be administered to the individual in a unit dosage form, wherein the unit dosage form comprises an amount of the composition effective for increasing levels of valerate in an individual. Research has shown that increasing valerate levels has been linked to the listed benefits (See Smith PM, Howitt MR, Panikov N, Michaud M, Gallini CA, Bohlooly YM, et al. The microbial metabolites, short-chain fatty acids, regulate colonic treg cell homeostasis. Sci (New York NY) (2013) 341(6145):569-73. doi:10.1126 / science.l241165, McDonald, J. A. K., Mullish, B. H., Pechlivanis, A., Liu, Z. G., Brignardello, J., Kao, D., et al. (2018). Inhibiting growth of Clostridioides difficile by restoring valerate, produced by the intestinal microbiota. Gastroenterology. 155, 1495-1507. doi: 10.1053 / j.gastro.2018.07.014, Luu, M., Pautz, S., Kohl, V. et al. The short-chain fatty acid pentanoate suppresses autoimmunity by modulating the metabolic-epigenetic crosstalk in lymphocytes. Nat Commun 10, 760 (2019). https: / / doi.org / 10.1038 / s41467-019-08711-2; Luu et al., 2021 https: / / pubmed.ncbi.nlm.nih.gov / 34210970 / ; Luu M., Pautz S., Kohl V., Singh R., Romero R., Lucas S., Hofmann J., Raifer H., Vachharajani N., Carrascosa L.C., et al. The Short-Chain Fatty Acid Pentanoate Suppresses Autoimmunity by Modulating the Metabolic- Epigenetic Crosstalk in Lymphocytes. Nat. Commun. 2019;10:760. doi: 10.1038 / s41467-019- 08711-2; Gao, G., Zhou, J., Wang, H. et al. Effects of valerate on intestinal barrier function in cultured Caco-2 epithelial cell monolayers. Mol Biol Rep 49, 1817-1825 (2022). https: / / doi.Org / 10.1007 / sl l033-021-06991-w; Luu M., Pautz S., Kohl V., Singh R., Romero R., Lucas S., Hofmann J., Raifer H., Vachharajani N., Carrascosa L.C., et al. The Short-Chain Fatty Acid Pentanoate Suppresses Autoimmunity by Modulating the Metabolic-Epigenetic Crosstalk in Lymphocytes. Nat. Commun. 2019;10:760. doi: 10.1038 / s41467-019-08711-2, the entireties of each of which are incorporated herein by reference.)

[0134] In another embodiment, the present disclosure is a method for reducing oxidative stress, strengthening the intestinal barrier, improving immunity, reducing inflammation, improving intestinal barrier, the method comprising administering to an individual in need thereof or at risk thereof any of the compositions disclosed herein. The composition may be administered in an amount effective for increasing levels of N,N- Dimethylglycine in the individual. The composition may be administered to the individual in a unit dosage form, wherein the unit dosage form comprises an amount of the composition effective for increasing levels of N,N-Dimethylglycine in an individual. Research has shown that increasing N,N-Dimethylglycine levels has been linked to the listed benefits (See Cools A. et al. Effect of N,N-dimethylglycine supplementation in parturition feed for sows on metabolism, nutrient digestibility and reproductive performance. Animal. 2010;4(12):2004-2011; Bai K. et al. Dietary dimethylglycine sodium salt supplementation improves growth performance, redox status, and skeletal muscle function of intrauterine growth-restricted weaned piglets. J Anim Sci. 2021;99(7) skabl86; Graber C.D., Goust J.M., Glassman A.D., Kendall R., Loadholt C.B. Immunomodulating Properties of Dimethylglycine in Humans. J. Infect. Dis. 1981;143: 101-105. doi: 10.1093 / infdis / 143.1.101; Wang et al. 2022. Heat stress- induced intestinal barrier damage and dimethylglycine alleviates via improving the metabolism function of microbiota gut brain axis. Ecotoxicology and Environmental Safety Volume 244, 1 October 2022, 114053. https: / / www.sciencedirect.com / science / artide / pii / S0147651322008934; Takahashi et al. 2016. N, N-Dimethylglycine decreases oxidative stress and improves in vitro development of bovine embryos. J Reprod Dev. 2016 Apr; 62(2): 209-212. doi: 10.1262 / jrd.2015-149, the entireties of each of which are herein incorporated by reference.)

[0135] In another embodiment, the present disclosure is a method for reducing inflammation, the method comprising administering to an individual in need thereof or at risk thereof any of the compositions disclosed herein. The composition may be administered in an amount effective for increasing levels of Tricarballylic acid in the individual. The composition may be administered to the individual in a unit dosage form, wherein the unit dosage form comprises an amount of the composition effective for increasing levels of Tricarballylic acid in an individual. Research has shown that increasing Tricarballylic acid levels has been linked to the listed benefits (See Ashbrook MJ, McDonough KL, Pituch JJ, Christopherson PL, Cornell TT, Selewski DT, Shanley TP, Blatt NB. Citrate modulates lipopolysaccharide- induced monocyte inflammatory responses. Clin Exp Immunol. 2015 Jun;180(3):520-30. doi: 10.1111 / cei ., the entirety of which is herein incorporated by reference.)Brain health

[0136] The improving brain health can comprise at least one result selected from the group consisting of: (a) improve brain maturation; b) preventing mental fatigue, maintain focus & concentration ; c) support optimal cognitive and / or neuronal function; d) support optimal brain metabolism; e) improving brain function; f) supporting cognitive and / or social development; g) support optimal learning and memory; h) support language development; i) supporting emotional regulation; j) supporting motor and / or coordination skills; k) support optimal myelination; 1) reducing inflammation; m) preventing and / or attenuating oxidative stress; (n) support blood brain barrier integrity protection; (o) promote axon growth; p) support optimal brain and / or neuronal connectivity; q) support neurogenesis and synaptic connectivity; r) managing stress; s) helping manage anxiety and / or mood related disorders; (t) coping withpain; (u) improve sleep, in particular sleep quality for brain recovery and (v) combinations thereof.

[0137] Preferably the composition is administered in an amount effective to increase at least one metabolite level selected from the group consisting of: 3-indole propionate, valerate, N,N-Dimethylglycine, Imidazole acetate, tricarballylic acid, acetate, caprylic acid, nicotinamide, beta-alanine, ketone bodies, 3 -hydroxybutyrate, 12,13-diHODE, and / or 3- hydroxydecanoic acid. Preferably, the composition is administered in an effective amount to increase one or more Bifidobacterium, including but not limited to B. longum, B. adolescentis, B. bifidum.

[0138] In an embodiment, the present disclosure is a method for one or more of cognitive and / or brain function, managing stress, improve sleep, preventing and / or attenuating oxidative stress, reducing inflammation, improving brain function, supporting blood brain barrier integrity protection, the method comprising administering to an infant, a young child or a 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 levels of 3-indole propionate or propionate in the infant, a young child or a child. The composition may be administered to the infant, a young child or a child in a unit dosage form, wherein the unit dosage form comprises an amount of the composition effective for increasing levels of 3-indole propionate or propionate in an infant, a young child or a child. Research has shown that increased propionate levels have been linked to the listed benefits (See Zaiatz-Bittencourt V, Jones F, Tosetto M, Scaife C, Cagney G, Jones E, Doherty GA, Ryan EJ. Butyrate limits human natural killer cell effector function. Sci Rep. 2023 Feb 15; 13(1):2715. ; Vinolo MA, Rodrigues HG, Nachbar RT, Curi R. Regulation of inflammation by short chain fatty acids. Nutrients. 2011;3:858-76:; Waldecker, M., Kautenburger, T., Daumann, H., Busch, C. & Schrenk, D. Inhibition of histonedeacetylase activity by short-chain fatty acids and some polyphenol metabolites formed in the colon. J. Nutr. Biochem. 19, 587-593 (2008).; Byrne, C. S. et al. Increased colonic propionate reduces anticipatory reward responses in the human striatum to high-energy foods. Am. J. Clin. Nutr. 104, 5-14 (2016).; Hoyles, L. et al. Microbiome-host systems interactions: protective effects of propionate upon the blood-brain barrier. Microbiome 6, 55 (2018)., Health AL, et al. Association between the faecal short-chain fatty acid propionate and infant sleep, EJCN 2020; 74, 1362-1365 the entireties of each of which are herein incorporated by reference.)

[0139] Yet another embodiment of the present disclosure is a method for improving cognition, the method comprising administering to an infant, a young child or a child in needthereof or at risk thereof any of the compositions disclosed herein. The composition may be administered in an amount effective for increasing levels of nicotinamide in the infant, a young child or a child. The composition may be administered to the infant, a young child or a child in a unit dosage form, wherein the unit dosage form comprises an amount of the composition effective for increasing levels of nicotinamide in an infant, a young child or a child.

[0140] Yet another embodiment of the present disclosure is a method for one or more of reducing and / or preventing oxidative stress, the method comprising administering to an infant, a young child or a 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 levels of 3 -hydroxybutyrate in the infant, a young child or a child. The composition may be administered to the infant, a young child or a child in a unit dosage form, wherein the unit dosage form comprises an amount of the composition effective for increasing levels of 3- hydroxybutyrate in an infant, a young child or a child.

[0141] Yet another embodiment of the present disclosure is a method for one or more of reducing inflammation, the method comprising administering to an infant, a young child or a 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 levels of valerate in the infant, a young child or a child. The composition may be administered to the infant, a young child or a child in a unit dosage form, wherein the unit dosage form comprises an amount of the composition effective for increasing levels of valerate in an infant, a young child or a child. Research has shown that increased valerate levels have been linked to the listed benefits (See Tyler J. Wenzel, Ellen J. Gates, Athena L. Ranger, Andis Klegeris, Short-chain fatty acids (SCFAs) alone or in combination regulate select immune functions of microglia-like cells, Molecular and Cellular Neuroscience, Volume 105, 2020, 103493, ISSN 1044-7431, https: / / doi.Org / 10.1016 / j.mcn.2020.103493; Luu M., Pautz S., Kohl V., Singh R., Romero R., Lucas S., Hofmann J., Raifer H., Vachharajani N., Carrascosa L.C., et al. The Short-Chain Fatty Acid Pentanoate Suppresses Autoimmunity by Modulating the Metabolic-Epigenetic Crosstalk in Lymphocytes. Nat. Commun. 2019;10:760. doi: 10.1038 / s41467-019-08711-2, the entireties of each of which are herein incorporated by reference.)

[0142] Yet another embodiment of the present disclosure is a method for reducing oxidative stress, helping manage helping manage mood related disorders, support optimal memory, and / or promote axon growth, the method comprising administering to an infant, a young child or a 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 levels ofN,N-Dimethylglycine in the infant, a young child or a child. The composition may be administered to the infant, a young child or a child in a unit dosage form, wherein the unit dosage form comprises an amount of the composition effective for increasing levels of N,N- Dimethylglycine in an infant, a young child or a child. Research has shown that increased N,N- Dimethylglycine levels have been linked to the listed benefits (See Cools A. et al. Effect of N,N-dimethylglycine supplementation in parturition feed for sows on metabolism, nutrient digestibility and reproductive performance. Animal. 2010;4(12):2004-2011; Lin et al. 2016. N,N-dimethylglycine differentially modulates psychotomimetic and antidepressant-like effects of ketamine in mice. Prog Neuropsychopharmacol Biol Psychiatry. 2016 Nov 3:71 :7-13. doi: 10.1016 / j.pnpbp.2016.06.002. Epub 2016 Jun 10.; Hsieh et al. 2020. N,N-dimethylglycine prevents toluene-induced impairment in recognition memory and synaptic plasticity in mice. Toxicology Volume 446, 15 December 2020, 152613. https: / / www.sciencedirect.eom / science / article / pii / S0300483X20302523#abs0010; Takahashi et al. 2016. N, N-Dimethylglycine decreases oxidative stress and improves in vitro development of bovine embryos. J Reprod Dev. 2016 Apr; 62(2): 209-212. doi: 10.1262 / jrd.2015-149; Zhang J, Jiang C, Liu X, et al. The metabolomic profiling identifies N, N-dimethylglycine as a facilitator of dorsal root ganglia neuron axon regeneration after injury. FASEB J. 2022; 36:e22305., the entireties of each of which are herein incorporated by reference.)

[0143] Yet another embodiment of the present disclosure is a method for reducing inflammation, the method comprising administering to an infant, a young child or a 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 levels of Tricarballylic acid in the infant, a young child or a child. The composition may be administered to the infant, a young child or a child in a unit dosage form, wherein the unit dosage form comprises an amount of the composition effective for increasing levels of Tricarballylic acid in an infant, a young child or a child. Research has shown that increased Tricarballylic acid levels have been linked to the listed benefits (See Ashbrook MJ, McDonough KL, Pituch JJ, Christopherson PL, Cornell TT, Selewski DT, Shanley TP, Blatt NB. Citrate modulates lipopolysaccharide-induced monocyte inflammatory responses. Clin Exp Immunol. 2015 Jun;180(3):520-30. doi: 10.1111 / cei., the entirety of which is herein incorporated by reference.)

[0144] Yet another embodiment of the present disclosure is a method for one or more of reducing and / or attenuating anxiety, promoting and / or improving sleep, and preventing pain, the method comprising administering to an infant, a young child or a child in need thereofor at risk thereof any of the compositions disclosed herein. The composition may be administered in an amount effective for increasing levels of Imidazole acetate in the infant, a young child or a child. The composition may be administered to the infant, a young child or a child in a unit dosage form, wherein the unit dosage form comprises an amount of the composition effective for increasing levels of Imidazole acetate in an infant, a young child or a child. Research has shown that increased Imidazole acetate levels have been linked to the listed benefits (See You, Z., et al. (2024). The contribution of polyamine pathway to determinations of diagnosis for treatment-resistant depression: A metabolomic analysis. Prog Neuropsychopharmacol Biol Psychiatry, 128, 110849. doi: 10.1016 / j.pnpbp.2023.110849; E. Roberts, D.G. Simonsen. A hypnotic and possible analgesic effect of imidazoleacetic acid in mice. Biochem. Pharmac., 15 (1966), pp. 1875-1877; Tunnicliff 1998, Pharmacology and Function of Imidazole 4-Acetic Acid in Brain. Gen Pharmacol. 1998 Oct;31(4):503-9. doi: 10.1016 / s0306-3623(98)00079-2.; E. Roberts, D.G. Simonsen. A hypnotic and possible analgesic effect of imidazoleacetic acid in mice. Biochem. Pharmac., 15 (1966), pp. 1875-1877, the entireties of each of which are herein incorporated by reference.)

[0145] Gastrointestinal disorder and digestive comfort

[0146] In specific embodiments, treatment and / or prevention of gastrointestinal disorders and / or improvement of digestive comfort is associated with increased and / or decreased levels of certain metabolites, or functional derivatives thereof. In a preferred embodiment, treatment and / or prevention of gastrointestinal disorders and / or improvement of digestive comfort is associated with increased levels of short chain fatty acids e.g. propionate, valerate and / or N,N-Dimethylglycine and / or decreased levels of cadaverine.

[0147] Then, in an embodiment, the infant, a young child or a child may be susceptible to particular medical conditions or physical states that would benefit from increased metabolite levels, or the infant, a young child or a 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, a young child or a child in such cases include a composition as described above, in particular to facilitate raising or lowering specific metabolite levels in the infant, a young child or a child. One can measure specific metabolite levels through plasma or fecal samples, for example, in methods well known in the art.

[0148] The method may comprise identifying the infant, a young child or a 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 maycomprise identifying the infant, a young child or a child as at risk of a medical condition or physical state that would benefit from increased metabolite levels.

[0149] In specific embodiments, an infant, a young child or a child is provided effective amounts of compositions as described herein for the explicit purpose of raising intracellular levels of propionate, valerate, N,N-Dimethylglycine, because it is determined that the infant, a young child or a child is afflicted with a condition for which such levels are directly or indirectly related. Additionally, an infant, a young child or a child is provided effective amounts of compositions as described herein for the explicit purpose of decreasing levels of cadaverine because it is determined that the infant, a young child or a child is afflicted with a condition for which such levels are directly or indirectly related.

[0150] In view of the disclosures herein, an embodiment is a method for treating and / or preventing gastrointestinal disorders and / or improving digestive comfort, the method comprising administering to an infant, a young child or a child in need thereof a low sugar, low lactose, milk-based composition comprising galactooligosaccharide. In some embodiments, the composition is as described above.

[0151] The preventing and / or treating of the gastrointestinal health and / or improving digestive comfort can comprise at least one result selected from the group consisting of: (a) preventing and / or attenuating stomach related disorders such as belching, stomach discomfort, fullness, nausea, heartburn, acid reflux and / or gastric ulcers; (b)preventing and / or attenuating intestine related disorders such as rumbling, abdominal discomfort, cramps and / or fullness; (c) reducing and / or preventing colon related digestive disorders such as bloating, gas / flatulence, diarrhea and / or constipation; (d) reducing and / or preventing intestinal inflammation such as colitis, ulcerative colitis, inflammatory bowel disease and / or gastritis; (e) prevent gastrointestinal motility related disorder and / or transit related disorder selected from constipation, vomiting or regurgitation, bloating, diarrhea, nausea, weight loss, pain or swallowing problems, heartburn or GERD and / or urgent need to have bowel movement; (f) reducing gastric distension; (g) reducing small bowel water content; (h) decreasing small bowel transit; (i) improving colonic fermentation; (j) reducing colonic fermentation; (k) reducing colonic gas; (1) reducing colonic water content; (m) reducing colic symptoms; (n) reducing fussing / crying time; (o) improvement of stool consistency; (p) enhance nutrient absorption; (q) improved digestion; (r) improved tolerance to food; (s) preventing disorders of gut-brain interactions (DGBIs), like regurgitation, infantile colic, functional abdominal pain, functional constipation, functional diarrhea, functional dyspepsia, irritable bowel syndrome; (t) preventing the discomfort march / promote comfort march and (u) combinations thereof.

[0152] In an embodiment, the gastrointestinal motility related disorder and / or transit related disorder is selected from severe constipation, vomititng or regurgitation, bloating, diarrhea, nausea, weight loss, pain or swallowing problems, heartburn or GERD and / or urgent need to have bowel movement.

[0153] In an embodiment the composition is administered in an amount effective for reducing the levels of cadaverine. Research has shown that decreasing cadaverine levels has been linked to the listed benefits (see Galie etal., Mol. Nut. Food Res., 2021). Moreover, high cadaverine concentrations were reported to be cytotoxic (del Rio etal., Scient. Reports., 2019) and detrimental for gut homeostasis by inhibiting epithelial growth and adherence, which might relate to Crohn’s disease pathogenesis (Diederen et al. Scient Report, 2020). This is further supported by the notion that cadaverine might compromise histamine degradation (Sanchez- Perez et al., Frontier Nut, 2022; Khalid Omer et al., Journal of Food Protection, 2021) and thereby could support these adverse effects.

[0154] Another aspect of the present disclosure is a method for preventing and / or attenuating stomach related disorders such as belching, stomach discomfort, fullness, nausea, heartbum, acid reflux and / or gastric ulcers, the method comprising administering to an infant, a young child or a child in need thereof or at risk thereof any of the compositions disclosed herein. The composition may be administered in an amount effective for reducing gastric distension, gastric volume and / or for increasing levels of NN dimethylglycine. The Research has shown that increasing NN dimethylglycine levels has been linked to the listed benefits (See Hariganesh K, Prathiba J. Effect of dimethylglycine on gastric ulcers in rats. J Pharm Pharmacol. 2000; 52.

[0155] The composition may be administered to the infant, a young child or a child in a unit dosage form, wherein the unit dosage form.

[0156] Yet another aspect of the present disclosure is a method for preventing and / or attenuating abdominal related disorders such as rumbling, abdominal discomfort, cramps and / or fullness, the method comprising administering to an infant, a young child or a child in need thereof or at risk thereof any of the compositions disclosed herein. The composition may be administered in an amount effective for decreasing small bowel transit and / or decrease small bowel water content. The composition may be administered to the infant, a young child or a child in a unit dosage form.

[0157] Yet another aspect of the present disclosure is a method for reducing and / or preventing colon related digestive disorders such as bloating, gas / flatulence, diarrhea and / or constipation, the method comprising administering to an infant, a young child or a child in needthereof or at risk thereof any of the compositions disclosed herein. The composition may be administered in an amount effective to improve colonic fermentation in order e.g. to reduce colonic gas, colonic water content, colonic distention and / or small bowel water content. The composition may be administered to the infant, a young child or a child in a unit dosage form.

[0158] Yet another aspect of the present disclosure is a method for reducing and / or preventing intestinal inflammation such as colitis, ulcerative colitis, inflammatory bowel disease and / or gastritis, the method comprising administering to an infant, a young child or a 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 levels of valerate in the subject. Research has shown that increasing NN dimethylglycine levels has been linked to the listed benefits (See Zhu L, Li G, Liang Z, Qi T, Deng K, Yu J, Peng Y, Zheng J, Song Y, Chang X. Microbiota-assisted iron uptake promotes immune tolerance in the intestine. Nat Commun. 2023 May 15 ; 14(l):2790. The composition may be administered to the infant, a young child or a child in a unit dosage form.

[0159] Yet another aspect of the present disclosure is a method for preventing gastrointestinal motility related disorders and / or transit related disorders, the method comprising administering to an infant, a young child or a 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 levels of propionate in the infant, a young child or a child. Research has shown that increasing propionate levels has been linked to the listed benefits (SeeYano, J. M. et al. Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis. Cell 161, 264-276 (2015). The composition may be administered to the infant, a young child or a child in a unit dosage form.

[0160] 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

[0161] The following non-limiting example generally illustrates the concepts underlying the embodiments disclosed herein.

[0162] Example 1

[0163] 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 adults (H) or in adults 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 gastrointestinal 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 lactose malabsorption (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 adult 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 ).

[0164] Additionally, gas production was measured in each fermenter (in mbar) and normalized to the total amount of substrate (GOS and lactose) added to the fermenters (expressed in mbar / g of added substrate). This data was also used to calculate the ratio of gas production to SCFA (expressed in mbar / mM of SCFA produced). A low gas production in relation to the amount of added substrate or the amount of SCFA produced are indicative of an optimized colonic fermentation.

[0165]

[0166] Table 1 : Active composition

[0167] Table 2: Final concentrations of Lactose and GOS before in-vitro batch fermentation.

[0168] Results

[0169] FIGS. 1-3 include box plots showing significant increase in production of valerate, propionate and N,N-Dimethylglycine metabolites after 24h fermentation of the composition disclosed herein by comparison to GOS alone or negative control (NSC) using batch fermentation.

[0170] 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 valerate levels has been linked to the listed benefits (Zhu L et al. Microbiota-assisted iron uptake promotes immune tolerance in the intestine. Nat Commun.2023 May 15;14(l):2790. Also, Research has shown that propionate levels have been linked to gut motility (Yano, J.M. et al. Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis. Cell 161, 264-276 (2015). Additionally, NN dimethyl glycine has been linked to gastric ulcers (Hariganesh K, et al. Effect of dimethylglycine on gastric ulcers in rats. J Pharm Pharmacol. 2000;52: 1519-1522).

[0171] FIG. 4 shows the decrease in gas production (-16%) after 24h fermentation of the Active Composition by comparison to regular milk using batch fermentation with simulated lactose malabsorption (LM). Decrease in gas production is associated with less bloating, less flatulence, potentially leading to an improved gut comfort.

[0172] FIG. 5 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.

[0173] FIG. 6 shows decrease in the ratio of gas production to total SCFA production of 22% after 24h fermentation of the Active Composition by comparison to regular milk using batch fermentation with simulated lactose malabsorption (LM). The Active Composition produces less gas for a similar quantity of SCFA produced.

[0174] FIG. 7 represents gas production after 24 h fermentation of the Active Composition using batch fermentation with (LM) or without simulated lactose malabsorption. In lactose malabsorber, the Active Composition does not result in more gas production than in individuals that can digest lactose. It should thus not trigger any gas related inconvenience (bloating, less flatulence), similarly as what would be observed in individuals which can digest lactose.

[0175] Example 2

[0176] The inventors examined the effect of administering the composition disclosed herein, versus lactose-free milk, in 26 healthy adults. Table 1 shows the composition administered versus the control.

[0177] Table 3: Active composition versus control composition

[0178] Specifically, the inventors employed targeted metabolomics for fecal samples. The composition disclosed herein was administered once daily for 2 weeks in a 200 ml drink portion.

[0179] 92 plasma and fecal samples were analyzed using liquid chromatography tandem mass spectrometer. 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.

[0180] Polyamines are compounds such as putrescine, spermidine, spermine and cadaverine. Their presence in feces samples is associated to diet composition since there are derived from meal and absorbed in the upper part of the intestine. Fecal analysis of polyamines can be performed using various analytical approaches. Pre-column derivatization with dansylchloride and 9-fluorenylmethylchloroformate with fluorescence detection is one of the most deployed analytical method for the determination of polyamines in feces (Fiori et al., Assessment of gut microbiota fecal metabolites by chromatographic targeted approaches, J. Pharm and Biomedical Analysis., 2020). Different chromatographic conditions can be also used for polyamines analysis such as ion exchange chromatography or with Hydrophilic Interaction Liquid Chromatography coupled to tandem mass spectrometry (HILIC - MS / MS). Briefly, in our study, dried fecal samples were resuspended in milli-Q water, sonicated and centrifuged at 4°C for 15min. An aliquot of the supernatant was then extracted with an organic solvent containing appropriate internal standards, then the mixture was vortexed and centrifuged and transferred into a vial before analysis. A targeted LC-MSMS was then used to determine the absolute concentration of fecal polyamines. The chromatographic separation wasconducted in HILIC conditions in positive mode and following specific transitions in MRM mode. External calibration curved were processed in the same conditions and the labeled internal standards were used to establish response factor for each metabolite.

[0181] Results.

[0182] In fecal samples, cadaverine concentrations only increased in the control group but decreased in the intervention group (p=0.018) (Fig. 8).

[0183] The differential effect on cadaverine concentrations is beneficial for improving gut health and reducing digestive symptoms: Indeed, a diet that helps reducing fecal cadaverine levels promotes a healthier gut environment and improved digestion (Galie et al., Mol. Nut. Food Res., 2021). Moreover, high cadaverine concentrations were reported to be cytotoxic (del Rio et al., Scient. Reports., 2019) and detrimental for gut homeostasis by inhibiting epithelial growth and adherence, which might relate to Crohn’s disease pathogenesis (Diederen et al. Scient Report, 2020). This is further supported by the notion that cadaverine might compromise histamine degradation (Sanchez-Perez et al., Frontier Nut, 2022; Khalid Omer etal., Journal of Food Protection, 2021) and thereby could support these adverse effects.Example 3

[0184] The following non-limiting example generally illustrates the concepts underlying the embodiments disclosed herein.

[0185] The inventors examined the effect of administering the composition disclosed herein, versus lactose-free milk, in 26 healthy adults. Table 1 shows the composition administered versus the control.Table 1 : Active composition versus control composition administered to individuals

[0186] 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.

[0187] 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.

[0188] 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 1. Two additional features, which were putatively annotated as 3 -hydroxy decanoic acid and 12,13-DiHODE (a lineolic acid derivative), were also significantly increased with the intervention of the current composition (FC < 0.5). Figure 2 and Figure 3 show the increases levels of 3 -hydroxy decanoic acid and 12,13-DiHODE, respectively, of the intervention group compared to the control group. As seen in Figures 4 and 5, the two uremic toxins indoxyl-sulfate and p-cresol sulfate were significantly (p<0.05) reduced in the intervention group with a FC of -0.52 and -0.83, respectively.

[0189] The results of the targeted metabolomics for plasma samples are shown in Figures 6 through 10. Plasma levels of acetate, caprylic acid, nicotinamide, and beta-alanine were significantly increased in the intervention group as shown in Figures 6, 7, 8, and 9, respectively. Additionally, the level of ketone bodies showed an increase in the intervention group as shown in Figure 10, but no dietary intake information was obtained on the study.

[0190] The results of the metagenomics for fecal samples are shown in Figures 11 through 14. Bifidobacterium levels significantly increased in the intervention group as shown in Figure 11. Specifically, fecal levels of B. longum, B. adolescentis, and B. bifidum significantly increased in the intervention group as seen in Figures 12, 13, and 14, respectively.

[0191] Figures 15 and 16 show the effect of administration on the Bifidobacterium shunt pathways and NAD salvage pathways.

[0192] An overview of targeted and untargeted metabolomics and metagenomics results is shown in the Table 2.Table 2: Metabolite levels after administration of the composition of the present disclosure.

[0193] Example 4

[0194] 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 adults. For this, the active composition according to Table 3 was subjected to a simulation of upper gastrointestinal tract 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. On the other hand, GOS which is not digested by human gut was directly introduced in the fermenters. The total amount of GOS in the fermenters was the same between the two conditions (see Table 4). 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 adult 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).

[0195] Table 3: Active composition

[0196] Table 4: Lactose and GOS levels of compositions after INFOGEST

[0197] FIGS. 17-22 include box plots showing significant increase in production of beneficial metabolites after 24h fermentation of the composition disclosed herein by comparison to GOS alone or negative control (NSC) using batch fermentation.

Claims

CLAIMSClaim 1 : A method for improving metabolic health, immune health, brain health and / or preventing and / or treating gastrointestinal disorders and / or improving digestive comfort, the method comprising administering to an infant, a young child or a 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 claim, wherein the improving of immune health comprises at least one result selected from the group consisting of: (a) protection and / or reducing the risk of infections such as gastrointestinal and respiratory infections; (b) protection against pathogens such as viral, bacterial or fungal pathogens; (c) reducing inflammation; (d) preventing and / or attenuating oxidative stress; (e) promoting adequate gut barrier function; (f) promoting growth of Bifidobacterium; (g) increasing Bifidobacterium shunt pathway; (i) increasing NAD salvage pathway; (j) preventing and / or treating allergic asthma, (k) preventing allergic march; (1) promoting immune homeostasis; (m) supporting immune resilience at weaning period; (1) preventing and / or treating clostridioides difficile infection; (m) preventing and / or treating autoimmune diseases such as celiac disease and (n) combinations thereof.Claim 10: The method of any of claims 1 to 9, wherein the composition is administered in an amount effective to increase at least one metabolite selected from the group consisting of: 3 -indole propionate, acetate, caprylic acid, nicotinamide, beta-alanine, ketone bodies, 3- hydroxybutyrate, 12,13-diHODE, propionate, indole-3 -carboxylate, valerate, N,N- Dimethylglycine, tricarballylic acid and / or 3 -hydroxy decanoic acid.Claim 11 : The method of any of claims 1 to 10, wherein the composition is administered in an amount effective to increase one or more Bifidobacterium, including but not limited to B. longum, B. adolescentis, B. bifidum.Claim 12: A method according to claim 9, for one or more of preventing oxidative stress, reducing inflammation, improving the intestinal barrier, and / or reducing intestinal permeability, the method comprising administering to an infant, a young child or a child in need thereof or at risk thereof a composition comprising: 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 13: The method of claim 12, wherein the composition is administered in an amount effective for increasing levels of 3-indole propionate in the infant, a young child or a child.Claim 14: The method of any of claims 12 and 13, wherein the composition is administered to the infant, a young child or a child in a unit dosage form, wherein the unit dosage form comprises an amount of the composition effective for increasing levels of 3-indole propionate in an infant, a young child or a child.Claim 15: A method according to claim 9, for one or more of preventing and / or treating infections such as viral respiratory infections, the method comprising administering to an infant, a young child or a child in need thereof or at risk thereof a composition comprising: 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 16: The method of claim 15, wherein the composition is administered in an amount effective for increasing levels of acetate in the infant, a young child or a child.Claim 17: The method of any of claims 15 and 16, wherein the composition is administered to the infant, a young child or a child in a unit dosage form, wherein the unit dosage form comprises an amount of the composition effective for increasing levels of acetate in an infant, a young child or a child.Claim 18: A method according to claim 9, for one or more of preventing and / or treating infections such as viral respiratory infections, and / or protecting an infant, a young child or achild against pathogens, the method comprising administering to an infant, a young child or a child in need thereof or at risk thereof a composition comprising: 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 19: The method of claim 18, wherein the composition is administered in an amount effective for increasing levels of Bifidobacterium in the infant, a young child or a child.Claim 20: The method of any of claims 18 and 19, wherein the composition is administered to the infant, a young child or a child in a unit dosage form, wherein the unit dosage form comprises an amount of the composition effective for increasing levels of Bifidobacterium in an infant, a young child or a child.Claim 21 : A method according to claim 9, for one or more of reducing and / or preventing oxidative stress, the method comprising administering to an infant, a young child or a child in need thereof or at risk thereof a composition comprising: 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 22: The method of claim 21, wherein the composition is administered in an amount effective for increasing levels of 3 -hydroxybutyrate in the infant, a young child or a child.Claim 23: The method of any of claims 21 and 22, wherein the composition is administered to the infant, a young child or a child in a unit dosage form, wherein the unit dosage form comprises an amount of the composition effective for increasing levels of 3-hydroxybutyrate in an infant, a young child or a child.Claim 24: The method of any of claims 1 to 8, wherein the improving of metabolic health comprises at least one result selected from the group consisting of: (a) appetite or food intake control or regulation; (b) managing glucose levels; (c) preventing and / or treating overweight or obesity, in particular reduction of risk of obesity later in life; (d) normalizing blood lipid profiles; (e) skin health; (f) reducing inflammation; (g) preventing and / or attenuating oxidative stress; (h) improved lipid metabolism; (i) improving intestinal barrier; (j) reducing intestinal permeability; (k) modulation of glucose metabolism; (1) protection from fatty liver; (m) promoting timely growth of Faecalibacterium prausnitzii, (o) promoting growth of Bifidobacterium; (p) increasing Bifidobacterium shunt pathway; (q) increasing NAD salvage pathway; (r) preservation of P-cell function; (s) preventing diabetes, in particular reduction of diabetes later in life; (t) improve and / or maintain insulin sensitivity; (u) preventing high blood pressure; (v) maintaining insulin response; (w) maintaining beta-cell function to maintain insulin secretion and (x) combinations thereof.Claim 25: The method of claim 24, wherein the composition is administered in an amount effective to increase at least one metabolite selected from the group consisting of: 3- indole propionate, propionate valerate, tricarballylic acid, imidazole acetate, N,N,- dimethylglycine, indole-3 -carboxylate, caprylic acid, nicotinamide, beta-alanine, ketone bodies, 3 -hydroxybutyrate, 12,13-diHODE, and / or 3 -hydroxy decanoic acid. Preferably, the composition is administered in an effective amount to increase one or more Bifidobacterium, including but not limited to B. longum, B. adolescentis, B. bifidum.Claim 26: The method of any of claims 24 to 25, wherein the composition is administered in an amount effective to increase one or more Bifidobacterium, including but not limited to B. longum, B. adolescentis, B. bifidum.Claim 27: A method according to claim 24, for one or more of preventing oxidative stress, reducing inflammation, improving the intestinal barrier, reducing intestinal permeability, modulating glucose metabolism, improve and / or maintain insulin sensitivity;, preventing and / or treating overweight or obesity, appetite or food intake control or regulation, and / or protecting against fatty liver, the method comprising administering to an infant, a young child or a child in need thereof or at risk thereof a composition comprising: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 28: The method of claim 27, wherein the composition is administered in an amount effective for increasing levels of 3-indole propionate in the infant, a young child or a child.Claim 29: The method of any of claims 27 and 28, wherein the composition is administered to the infant, a young child or a child in a unit dosage form, wherein the unit dosage form comprises an amount of the composition effective for increasing levels of 3-indole propionate in an infant, a young child or a child.Claim 30: A method according to claim 24, for one or more of improving skin health, and / or normalizing blood lipid profiles, the method comprising administering to an infant, a young child or a child in need thereof or at risk thereof a composition comprising: 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 31 : The method of claim 30, wherein the composition is administered in an amount effective for increasing levels of nicotinamide in the infant, a young child or a child.Claim 32: The method of any of claims 30 and 31, wherein the composition is administered to the infant, a young child or a child in a unit dosage form, wherein the unit dosage form comprises an amount of the composition effective for increasing levels of nicotinamide in an infant, a young child or a child.Claim 33: A method according to claim 24, for one or more of preventing and / or treating obesity, appetite or food intake control or regulation, and / or managing weight, the method comprising administering to an infant, a young child or a child in need thereof or at risk thereof a composition comprising: 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 34: The method of claim 33, wherein the composition is administered in an amount effective for increasing levels of acetate in the infant, a young child or a child.Claim 35: The method of any of claims 33 and 34, wherein the composition is administered to the infant, a young child or a child in a unit dosage form, wherein the unit dosage form comprises an amount of the composition effective for increasing levels of acetate in an infant, a young child or a childClaim 36: A method according to claim 24, for one or more of preventing and / or treating obesity, appetite or food intake control or regulation, and / or managing weight, the method comprising administering to an infant, a young child or a child in need thereof or at risk thereof a composition comprising: 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 37: The method of claim 36, wherein the composition is administered in an amount effective for increasing levels of Bifidobacterium in the infant, a young child or a child.Claim 38: The method of any of claims 36 and 37, wherein the composition is administered to the infant, a young child or a child in a unit dosage form, wherein the unit dosage form comprises an amount of the composition effective for increasing levels of Bifidobacterium in an infant, a young child or a child.Claim 39: A method according to claim 24, for one or more of reducing and / or preventing oxidative stress, the method comprising administering to an infant, a young child or a child in need thereof or at risk thereof a composition comprising: 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 40: The method of claim 39, wherein the composition is administered in an amount effective for increasing levels of 3 -hydroxybutyrate in the infant, a young child or a child.Claim 41 : The method of any of claims 39 and 40, wherein the composition is administered to the infant, a young child or a child in a unit dosage form, wherein the unit dosage form comprises an amount of the composition effective for increasing levels of 3- hydroxybutyrate in an infant, a young child or a child.Claim 42: A method according to claim 24, for improving lipid metabolism, the method comprising administering to an infant, a young child or a child in need thereof or at risk thereof a composition comprising: 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 43: The method of claim 42, wherein the composition is administered in an amount effective for increasing levels of 12,13-diHODE in the infant, a young child or a child.Claim 44: The method of any of claims 42 and 43, wherein the composition is administered to the infant, a young child or a child in a unit dosage form, wherein the unit dosage form comprises an amount of the composition effective for increasing levels of 12,13- diHODE in an infant, a young child or a child.Claim 45: The method of any of claim 1 to 8, wherein the improving of brain health comprises at least one result selected from the group consisting of: a) improve brain maturation ; b) preventing mental fatigue, maintain focus & concentration ; c) support optimal cognitive and / or neuronal function; d) support optimal brain metabolism; e) improving brain function; f) supporting cognitive and / or social development; g) support optimal learning and memory; h) support language development; i) supporting emotional regulation; j) supporting motor and / or coordination skills; k) support optimal myelination; 1) reducing inflammation; m) preventing and / or attenuating oxidative stress; (n) support blood brain barrier integrity protection; (o) promote axon growth; p) support optimal brain and / or neuronal connectivity; q) support neurogenesis and synaptic connectivity; r) managing stress; s) helping manage anxiety and / or mood related disorders; (t) coping with pain; (u) improve sleep, in particular sleep quality for brain recovery and (v) combinations thereof.Claim 46: The method of any of claim 45, wherein the composition is administered in an amount effective to increase at least one metabolite selected from the group consisting of: 3 -indole propionate, propionate, valerate, N,N-Dimethylglycine, Imidazole acetate, tricarballylic acid, acetate, caprylic acid, nicotinamide, beta-alanine, ketone bodies, 3- hydroxybutyrate, 12,13-diHODE, and / or 3 -hydroxy decanoic acid.Claim 47: The method of claims 45 and 46, wherein the composition is administered in an amount effective to increase one or more Bifidobacterium, including but not limited to B. longum, B. adolescentis, B. bifidum.Claim 48: A method according to claim 45, for one or more of cognitive and / or brain function, managing stress, preventing and / or attenuating oxidative stress, reducing inflammation, improving brain function, improving sleep, supporting blood brain barrier integrity protection, the method comprising administering to an, the method comprisingadministering to an infant, a young child or a child in need thereof or at risk thereof a composition comprising: 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 49: The method of claim 48, wherein the composition is administered in an amount effective for increasing levels of 3-indole propionate or propionate in the infant, a young child or a child.Claim 50: The method of any of claims 48 and 49, wherein the composition is administered to the infant, a young child or a child in a unit dosage form, wherein the unit dosage form comprises an amount of the composition effective for increasing levels of 3-indole propionate in an infant, a young child or a child.Claim 51 : A method according to claim 45, for one or more of improving cognition, the method comprising administering to an infant, a young child or a child in need thereof or at risk thereof a composition comprising: 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 52: The method of claim 51, wherein the composition is administered in an amount effective for increasing levels of nicotinamide in the infant, a young child or a child.Claim 53: The method of any of claims 51 and 52, wherein the composition is administered to the infant, a young child or a child in a unit dosage form, wherein the unit dosage form comprises an amount of the composition effective for increasing levels ofnicotinamide in an infant, a young child or a child.Claim 54: A method according to claim 45, for one or more of reducing and / or preventing oxidative stress, the method comprising administering to an infant, a young child or a child in need thereof or at risk thereof a composition comprising: 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 55: The method of claim 54, wherein the composition is administered in an amount effective for increasing levels of 3 -hydroxybutyrate in the infant, a young child or a child.Claim 56: The method of any of claims 54 and 55, wherein the composition is administered to the infant, a young child or a child in a unit dosage form, wherein the unit dosage form comprises an amount of the composition effective for increasing levels of 3- hydroxybutyrate in an infant, a young child or a child.Claim 57: The method of any of claims 1 to 8, wherein the treating and / or preventing gastrointestinal disorders health and / or improving digestive comfort comprises at least one result selected from the group consisting of: (a) preventing and / or attenuating stomach related disorders such as belching, stomach discomfort, fullness, nausea, heartburn, acid reflux and / or gastric ulcers; (b) preventing and / or attenuating intestine related disorders such as rumbling, abdominal discomfort, cramps and / or fullness; (c) reducing and / or preventing colon related digestive disorders such as bloating, gas / flatulence, diarrhea and / or constipation; (d) reducing and / or preventing intestinal inflammation such as colitis, ulcerative colitis, inflammatory bowel disease and / or gastritis; (e) prevent gastrointestinal motility related disorder and / or transit related disorder selected from constipation, vomiting or regurgitation, bloating, diarrhoea, nausea, weight loss, pain or swallowing problems, heartbum or GERD and / or urgent need to have bowel movement; (f) reducing gastric distension; (g) reducing small bowel water content; (h) decreasing small bowel transit; (i) improving colonic fermentation; (j) reducingcolonic fermentation; (k) reducing colonic gas; (1) reducing colonic water content; (m) reducing colic symptoms; (n) reducing fussing / crying time; (o) improvement of stool consistency; (p) enhance nutrient absorption; (q) improved digestion; (r) improved tolerance to food; (s) preventing disorders of gut-brain interactions (DGBIs), like regurgitation, infantile colic, functional abdominal pain, functional constipation, functional diarrhoea, functional dyspepsia, irritable bowel syndrome; (t) preventing the discomfort march / promote comfort march and (u) combinations thereofClaim 58: The method according to claim 57, wherein the gastrointestinal motility related disorder and / or transit related disorder is selected from constipation, vomititng or regurgitation, bloating, diarrhea, nausea, weight loss, pain or swallowing problems, heartburn or GERD and / or urgent need to have bowel movement.Claim 59: The method according to any of claims 57 to 58, wherein the composition is administered in an amount effective for reducing the levels of cadaverine.Claim 60: A method according to claim 57, for preventing and / or attenuating stomach related disorders such as belching, stomach discomfort, fullness, nausea, heartburn, acid reflux and / or gastric ulcers the method comprising administering to an infant, a young child or a child in need thereof or at risk thereof a composition comprising: 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 61 : The method of claim 60, wherein the composition is administered in an amount effective for reducing gastric distension, gastric volume and / or for increasing levels of NN dimethylglycine.Claim 62: A method according to claim 57, for preventing and / or attenuating abdominal related disorders such as rumbling, abdominal discomfort, cramps and / or fullness,the method comprising administering to an infant, a young child or a child in need thereof or at risk thereof a composition comprising: 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 63: The method of claim 62, wherein the composition is administered in an amount effective to decrease small bowel transit and / or decrease small bowel water content.Claim 64: A method according to claim 57, for reducing and / or preventing colon related digestive disorders such as bloating, gas / flatulence, diarrhea and / or constipation, the method comprising administering to an infant, a young child or a child in need thereof or at risk thereof a composition comprising: 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 65: The method of claim 64, wherein the composition is administered in an amount effective to improve colonic fermentation, reduce colonic fermentation, colonic gas, colonic water content and / or small bowel water content.Claim 66: A method according to claim 57, for reducing and / or preventing intestinal inflammation such as colitis, ulcerative colitis, inflammatory bowel disease and / or gastritis, the method comprising administering to an infant, a young child or a child in need thereof or at risk thereof a composition comprising: 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 67: the method according to claim 66, wherein the composition is administered in an amount effective for increasing levels of valerate in the subject.Claim 68: A method according to claim 57, for preventing gastrointestinal motility related disorders and / or transit related disorders, the method comprising administering to an infant, a young child or a child in need thereof or at risk thereof a composition comprising: 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 69: The method of claim 68, wherein the composition is administered in an amount effective for increasing levels of propionate in the infant, a young child or a child.Claim 70: The method of any preceding claim, wherein the composition is administered to the infant, a young child or a child in a unit dosage form.Claim 71 : The method according to any preceding claim, wherein the infant, a young child or a child is lactose mal-absorber.

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