Compositions and methods for improving brain health

Abstract

A method for improving brain health comprises administering to an individual in need a composition comprising, preferably by dry weight, 20-40% milk protein; and preferably by dry weight, 32-55% of a mixture of lactose, glucose, galactose, and galactooligosaccharides. The mixture of lactose, glucose, galactose, and galactooligosaccharides may contain 0.1-30% by weight lactose, 8-40% by weight glucose at 32-55% by dry weight, 0.1-20% by weight galactose, and 40-90% by weight galactooligosaccharides.

Description

Technical Field

[0001]

[0001] The present disclosure generally relates to compositions and methods for improving brain health. Some embodiments relate to compositions comprising milk protein, and further comprising a mixture of lactose, glucose, galactose, and galactooligosaccharide (GOS).

Background Art

[0002]

[0002] Gut microbiota metabolites play an important role in host health and nutrient metabolism. There is increasing scientific evidence suggesting that metabolites produced by the gut microbiota are important mediators of host benefits. Supplementation with galactooligosaccharide (GOS) has previously been associated with several health benefits mainly through modulation of the gut microbiome. While many studies have focused on beneficial metabolites derived from intestinal carbohydrate fermentation, metabolites from bacterial protein metabolism also appear to play an important role in host physiology.

[0003]

[0003] There is still a need for compositions for easy and convenient administration to an individual that result in an increase in beneficial microbial metabolites.

Summary of the Invention

[0004]

[0004] Embodiments of the present disclosure relate to methods and / or compositions for improving brain health, wherein in the brain health, the decrease in the blood or intracellular levels of specific metabolites, and the fecal levels of specific bacteria are directly or indirectly affected. In certain embodiments, the levels of specific metabolites in an individual, and the levels of corresponding specific bacteria, such as Bifidobacteria, increase when a medical condition or physical condition is treated, prevented, or the onset is delayed. In certain embodiments, the levels of specific metabolites in an individual decrease when a medical condition or physical condition is treated, prevented, or the onset is delayed.

[0005]

[0005] In certain embodiments, a method for improving brain health comprises the step of administering a low-sugar, low-lactose milk composition containing galactooligosaccharides to an individual in need thereof. In some embodiments, the composition comprises milk protein, preferably 20-40% by dry weight of the composition; and a mixture of lactose, glucose, galactose, and galactooligosaccharides, preferably 35-55% or 32-55% by dry weight of the mixture; preferably, the mixture comprises 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 galactooligosaccharides.

[0006]

[0006] Improvements in brain health may include at least one outcome selected from the group consisting of (a) improved cognition; (b) reduced inflammation; (c) prevention and / or reduction of oxidative stress; (d) reduction of nerve damage after stroke; (e) stress management; (f) protection from neurodegenerative diseases, including but not limited to Alzheimer's disease; (g) protection from nerve damage; and (h) reduced neuroinflammation; (i) improved brain function; (j) improved protection of blood-brain barrier integrity; (k) reduced and / or prevention of anxiety; (l) improved sleep; (m) reduced pain; (n) prevention or reduction of depression and / or mood-related disorders; (o) prevention of memory impairment; (p) promotion of axonal regeneration; and (q) combinations thereof.

[0007]

[0007] The composition may further contain at least one of milk fat or milk-derived minerals, preferably a combination thereof, in a dry weight of 0.5 to 30%. The composition may further contain 5 to 20% vegetable oil, in a dry weight.

[0008]

[0008] Preferably, the composition is administered in an amount effective to increase the level of one or more metabolites selected from the group consisting of 3-indolepropionate, valerate, N,N-dimethylglycine, imidazole acetate, tricarbaryl acid, acetate, caprylic acid, nicotinamide, β-alanine, ketone bodies, 3-hydroxybutyrate, 12,13-diHODE, and / or 3-hydroxydecanoic acid. Preferably, the composition is administered in an amount effective to increase one or more Bifidobacterium species, including but not limited to B. longum, B. adolescentis, and B. bifidum.

[0009]

[0009] Another aspect of the present disclosure is a method for improving cognitive function, managing stress, preventing oxidative stress, reducing inflammation, and / or neuroprotection, comprising the step of administering one of the compositions disclosed herein to an individual who needs or is at risk thereof. The compositions may be administered in an amount effective to increase the level of 3-indolepropionate in the individual. The compositions may be administered to the individual in unit dosage forms, each unit dosage form containing an amount of the composition effective to increase the level of 3-indolepropionate in the individual.

[0010]

[0010] Another aspect of the present disclosure is a method for improving cognition, comprising the step of administering one of the compositions disclosed herein to an individual who needs or is at risk of having such improvement. The compositions may be administered in an amount effective to increase the level of nicotinamide in the individual. The compositions may be administered to the individual in unit dosage forms, each unit dosage form containing an amount of the composition effective to increase the level of nicotinamide in the individual.

[0011]

[0011] A further aspect of the present disclosure is a method for the prevention and / or treatment of cognitive decline, comprising the step of administering one of the compositions disclosed herein to an individual who needs or is at risk thereof. The compositions may be administered in an amount effective to increase the level of acetate in the individual. The compositions may be administered to the individual in unit dosage forms, each unit dosage form containing an amount of the composition effective to increase the level of acetate in the individual.

[0012]

[0012] A further aspect of the present disclosure is a method for the prevention and / or treatment of cognitive decline, comprising the step of administering one of the compositions disclosed herein to an individual who needs or is at risk thereof. The compositions may be administered in an amount effective to increase the level of bifidobacterium in the individual. The compositions may be administered to the individual in unit dosage forms, each unit dosage form comprising an amount effective to increase the level of bifidobacterium in the individual.

[0013]

[0013] A further aspect of the present disclosure is a method for reducing and / or preventing oxidative stress and / or treating and / or preventing age-related diseases, comprising the step of administering one of the compositions disclosed herein to an individual who needs or is at risk thereof. The compositions may be administered in an amount effective to increase the level of 3-hydroxybutyrate in the individual. The compositions may be administered to the individual in unit dosage forms, each unit dosage form containing an amount of the composition effective to increase the level of 3-hydroxybutyrate in the individual.

[0014]

[0014] The embodiments disclosed herein are, respectively, "Methods of Use of Oligosaccharide Compositions For Modulating Microbiota And Their Metabolic Products, And As Therapeutics For Health Application" by Amicucci et al., International Publication No. 2022241163; "Process For Preparing Enzymatically-Treated Food Compositions With Gos And Low Lactose Content And Food Compositions Thereof" by Sabine et al., International Publication No. 2023057540; "Milk Oligosaccharide Galactooligosaccharide Composition For Infant Formula Containing The Soluble Oligosaccharide Fraction Present In Milk, And Having A Low Level Of Monosaccharides, And A Process To Produce The Composition" by Berrocal Rafael et al., U.S. Patent Application Publication No. 20140087021; and "Synthetic composition for treating metabolic" by Elison et al. "Immune system stimulating nutrition" by Potappel-Van'T Land Belinda et al., U.S. Patent No. 11,529,364; Tams JWIt possesses one or more advantageous features not provided in the compositions and methods of "Milk products comprising high amount of galactooligosaccharides(gos) and their production" by [author's name], European Patent No. 3624594; and "Enzymatic conversion of milk lactose to prebiotic galactooligosaccharides to produce low lactose yogurt" by Raza, Iqbal, Ullah, Khan, and Imran, J Food Process Preserv. 2018;42:e13586. https: / / doi.org / 10.1111 / jfpp.13586.

[0015]

[0015] Further features and advantages are described herein and will become apparent from the following drawings and embodiments for carrying out the invention. [Brief explanation of the drawing]

[0016] [Figure 1] The plasma 3-indolepropionate levels after administration of the compositions (IP) disclosed herein are shown in comparison to those after administration of a control product (CP) of lactose-free skim milk. [Figure 2] The plasma 3-hydroxydecanoic acid levels after administration of the compositions (IP) disclosed herein are shown in comparison to those after administration of a control product (CP) of lactose-free skim milk. [Figure 3] The plasma 12,13-DiHODE levels after administration of the compositions (IP) disclosed herein are shown in comparison to those after administration of a control product (CP) of lactose-free skim milk. [Figure 4] The plasma indoxyl sulfate levels after administration of the compositions (IP) disclosed herein are shown in comparison to those after administration of a control product (CP) of lactose-free skim milk. [Figure 5]The plasma p-cresol sulfate levels after administration of the compositions (IP) disclosed herein are shown in comparison to those after administration of a control product (CP) of lactose-free skim milk. [Figure 6] The plasma acetate levels after administration of the compositions (IP) disclosed herein are shown in comparison to those after administration of a control product (CP) of lactose-free skim milk. [Figure 7] The plasma caprylic acid levels after administration of the compositions (IP) disclosed herein are shown in comparison to those after administration of a control product (CP) of lactose-free skim milk. [Figure 8] The plasma nicotinamide levels after administration of the compositions (IP) disclosed herein are shown in comparison to those after administration of a control product (CP) of lactose-free skim milk. [Figure 9] The plasma β-alanine levels after administration of the compositions (IP) disclosed herein are shown in comparison to those after administration of a control product (CP) of lactose-free skim milk. [Figure 10] The plasma ketone levels after administration of the compositions (IP) disclosed herein are shown in comparison to those after administration of a control product (CP) of lactose-free skim milk. [Figure 11] The fecal bifidobacterium levels after administration of the compositions (IP) disclosed herein are shown in comparison to those after administration of a control product (CP) of lactose-free skim milk. [Figure 12] The fecal B. longum levels after administration of the compositions (IP) disclosed herein are shown in comparison to those after administration of a control product (CP) of lactose-free skim milk. [Figure 13] The fecal B. adolescentis levels after administration of the compositions (IP) disclosed herein are shown in comparison to those after administration of a control product (CP) of lactose-free skim milk. [Figure 14] The fecal B. bifidum levels after administration of the compositions (IP) disclosed herein are shown in comparison to those after administration of a control product (CP) of lactose-free skim milk. [Figure 15]The abundance of the Bifidobacterium shunt pathway after administration of the composition (IP) disclosed herein is shown in comparison to the administration of a control product (CP) of lactose-free skim milk. [Figure 16] The abundance of the NAD salvage pathway after administration of the composition (IP) disclosed herein is shown in comparison to the administration of a control product (CP) of lactose-free skim milk. [Figure 17] The increase in specific metabolites during fermentation of the composition of the present invention is shown in comparison to GOS alone and a control. [Figure 18] The increase in specific metabolites during fermentation of the composition of the present invention is shown in comparison to GOS alone and a control. [Figure 19] The increase in specific metabolites during fermentation of the composition of the present invention is shown in comparison to GOS alone and a control. [Figure 20] The increase in specific metabolites during fermentation of the composition of the present invention is shown in comparison to GOS alone and a control. [Figure 21] The increase in specific metabolites during fermentation of the composition of the present invention is shown in comparison to GOS alone and a control.

Mode for Carrying Out the Invention

[0017]

[0033] Definitions

[0034] Several definitions are shown below. However, there may be cases where the definitions are in the section "Embodiments" below, and the above heading "Definitions" does not mean that such disclosure in the "Embodiments" section is not a definition.

[0018]

[0035] All percentages expressed herein are by total weight of the composition unless otherwise stated. As used herein, “about,” “approximately,” and “substantially” are understood to refer to a range of numbers, for example, within -10% to +10% of the reference number, preferably within -5% to +5%, more preferably within -1% to +1%, and most preferably within -0.1% to +0.1%. All numerical ranges herein should be understood to include all integers, whole numbers, or fractions within that range. Furthermore, these numerical ranges should be interpreted as supporting claims that cover any number or subset of a number within that range. For example, a disclosure of 1 to 10 should be interpreted as corresponding to ranges such as 1 to 8, 3 to 7, 1 to 9, 3.6 to 4.6, 3.5 to 9.9, etc.

[0019]

[0036] When used in this disclosure and the attached claims, the singular forms "a," "an," and "the" also refer to multiple objects unless otherwise indicated by the context. Thus, for example, a reference to "a protein" or "the protein" includes two or more proteins.

[0020]

[0037] The terms “comprise,” “comprises,” and “comprising” should be interpreted as not being exclusive but potentially encompassing others. Similarly, the terms “include,” “including,” and “or” should all be interpreted as potentially encompassing others unless such interpretation is clearly prevented by the context. However, compositions and methods disclosed herein may lack any elements not specifically disclosed herein. Therefore, disclosures of embodiments using the term “comprising” include disclosures of embodiments that “essentially include / consistently consist of” a specified component or process, and disclosures of embodiments that “consist of” a specified component or process.

[0021]

[0038] The terms "at least one of X and Y" and "and / or Y," as used in the context of "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 list of terms, are for illustrative and illustrative purposes only and should not be considered exclusive or inclusive.

[0022]

[0039] As used herein, “related to,” “associated with,” and “linked with” mean that they occur simultaneously, preferably resulting from the same underlying state, more preferably that one of the specified states is at least indirectly resulting from another specified state, and most preferably that one of the specified states is directly resulting from another specified state.

[0023]

[0040] The term "chronic kidney disease" refers to the progressive loss of kidney function. The kidneys filter waste products and excess fluids from the blood, which are then excreted in the urine. As chronic kidney disease progresses, fluids, electrolytes, and waste products can accumulate in the body at dangerous levels. Chronic kidney disease occurs when a disease or condition impairs kidney function and worsens kidney damage over months or years. Diabetes and hypertension are two major risk factors.

[0024]

[0041] The term "diabetes" refers to a disease that results in high glucose levels in the bloodstream.

[0025]

[0042] Cognitive function can be defined as the mental process of knowing, including, but not limited to, aspects such as awareness, perception, reasoning, and judgment, but which become known through perception, reasoning, or intuition; including knowledge. In certain embodiments, compositions such as those contemplated herein are provided to an individual to improve memory, including in the case of a normal individual or an individual with memory impairment.

[0026]

[0043] The terms “food,” “nutritional supplement,” “food product,” and “food composition” mean products or compositions intended for consumption by an individual, such as a human, and providing to such individual at least one nutrient. The compositions of this disclosure, including many embodiments described herein, may include, consist of, or essentially include the elements disclosed herein, as well as any additional or optional raw materials, components, or elements described herein or not described herein that are useful in a dietary supplement.

[0027]

[0044] "Prevention" includes reducing the risk, incidence, and / or severity of a condition or disorder. The terms "treatment / therapy" and "to treat / medicate" include both preventive or deterrent treatments (treatments that prevent and / or delay the onset of a diseased condition or disorder) and curative, therapeutic, or disease-modifying treatments, such as therapeutic measures for the cure, delay, reduction of symptoms, and / or cessation of progression of a diagnosed diseased condition or disorder, as well as treatment for patients at risk of developing a disease, suspected of having a disease, and patients who are unwell or diagnosed with a disease or medical condition. The terms "treatment / therapy" and "to treat / medicate" do not necessarily mean treating until the subject is fully recovered. The terms "treatment / therapy" and "to treat / medicate" also refer to maintaining and / or promoting the health of individuals who are not diseased but are susceptible to unhealthy conditions. The terms “treatment / therapy” and “to treat / therapy” are also intended to include the synergistic effect, or otherwise enhancement, of one or more primary preventive or therapeutic measures. In non-exclusive examples, treatment / therapy may be performed by a patient, caregiver, physician, nurse, or other healthcare professional.

[0028]

[0045] As used herein, the term "low lactose" refers to a composition containing 30% or less lactose.

[0029]

[0046] As used herein, the term "low sugar" refers to a composition containing 55% or less sugar.

[0030]

[0047] As used herein, a preventive or therapeutic “effective dose” is an amount that prevents a deficiency in an individual, treats a disease or medical condition, or, more generally, an amount that reduces symptoms in an individual, controls the progression of a disease, or provides a nutritional, physiological, or medical benefit.

[0031]

[0048] As used herein, the term “metabolic health” refers to the body’s ability to digest and absorb nutrients from food without abnormal or unhealthy spikes in blood glucose, blood lipids, inflammation, and / or insulin. “Improving metabolic health” refers to mechanisms for directly or indirectly reducing the incidence of spikes in blood glucose, inflammation, insulin, and / or blood lipids. Furthermore, “improving metabolic health” may refer to preventing and / or treating obesity, type II diabetes, heart disease, cognitive impairment, stroke, kidney disease, and / or fatty liver disease.

[0032]

[0049] As used herein, “brain health” refers to the health of an individual relating to the cognitive, sensory, social-emotional, behavioral, and motor domains. “Improving brain health” refers to mechanisms for directly or indirectly maintaining optimal brain integrity and mental and cognitive functions. Furthermore, “improving brain health” may refer to preventing and / or treating stroke, migraines, dementia, cognitive decline, epilepsy, neurodegenerative diseases such as Alzheimer’s disease and / or Parkinson’s disease.

[0033]

[0050] As used herein, the term “oxidative stress” refers to an individual, or a state in the cells or tissues of an individual, in which there is an imbalance between the production of reactive oxygen species and the ability to readily detoxify reactive intermediates or repair the resulting damage in the biological system. The normal reducing environment within cells is maintained by processes using a constant influx of metabolic energy, and a disruption in this normal redox state can lead to toxic effects, for example, by the production of free radicals and peroxides that damage cellular components such as proteins, lipids, and / or DNA.

[0034]

[0051] The term "composition" may mean a food, beverage, dietary supplement, complete nutrition or oral nutritional supplement (ONS), or medical food composition, or a mixture thereof.

[0035]

[0052] The composition may be in solid form (e.g., powder) or liquid form. The amount of various raw materials can be expressed in grams per 100g of composition (g / 100g) on ​​a dry weight basis if it is in solid form, e.g., powder, or as a concentration in grams per 100mL of composition (g / 100mL) if it refers to liquid form (liquid form also includes liquid compositions that can be obtained after powder reconstitution with a liquid, e.g., water).

[0036]

[0053] As used herein, the term "unit dosage form" refers to a physically divided unit suitable as a dosage unit for human and animal subjects, each unit containing a predetermined amount of the composition disclosed herein in an amount sufficient to produce the desired effect, together with an acceptable diluent, carrier, or vehicle. The specifications of the unit dosage form depend on the specific compound used, the effect to be achieved, and the pharmacodynamics of each compound in the host body.

[0037]

[0054] Embodiment In one aspect of the present disclosure, a method for improving brain health includes administering a low-sugar, low-lactose dairy composition containing galactooligosaccharides to an individual who needs or is at risk of having such health.

[0038]

[0055] 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 galactooligosaccharides.

[0039]

[0056] In some embodiments, the composition comprises a mixture of lactose, glucose, galactose, and galactooligosaccharides, comprising 35-55% by dry weight.

[0040]

[0057] In one embodiment, the mixture of lactose, glucose, galactose, and galactooligosaccharide contains 0.1 to 30% by weight of lactose.

[0041]

[0058] In one embodiment, the mixture of lactose, glucose, galactose, and galactooligosaccharide contains 8-40% by weight of glucose.

[0042]

[0059] In one embodiment, the mixture of lactose, glucose, galactose, and galactooligosaccharide contains 0.1 to 20% by weight of galactose.

[0043]

[0060] In one embodiment, the mixture of lactose, glucose, galactose, and galactooligosaccharides contains 40-90% by weight of galactooligosaccharides. In one embodiment, a milky composition, Milk protein, preferably 20-40% of the composition by dry weight; and A mixture of lactose, glucose, galactose, and galactooligosaccharides, preferably such mixture making up 32-55% of the composition by dry weight; Includes, Preferably, the mixture contains 0.1 to 30% by weight of lactose, 8 to 40% by weight of glucose, 0.1 to 20% by weight of galactose, and 40 to 90% by weight of galactooligosaccharides.

[0044] In another embodiment, a milky composition, Milk protein, preferably 20-40% of the composition by dry weight; and A mixture of lactose, glucose, galactose, and galactooligosaccharides, preferably 35-55% of the composition by dry weight; Includes, Preferably, the mixture contains 0.1 to 30% by weight of lactose, 8 to 40% by weight of glucose, 0.1 to 20% by weight of galactose, and 40 to 90% by weight of galactooligosaccharides.

[0045]

[0061] Some embodiments provide contributions from each component of the composition individually, in combination, and / or synergistically.

[0046]

[0062] In certain embodiments of the present invention, there exist methods and compositions for improving brain health, the improvement of brain health being brought about directly or indirectly by increasing or decreasing the levels of specific metabolites or specific bacteria, such as Bifidobacterium, in an individual. The individual may be of any age or health condition, but in certain embodiments, the individual is susceptible to or has a medical or physical condition that is directly or indirectly associated with an increase or decrease in metabolite levels, or that is directly or indirectly treated or prevented by an increase in metabolite levels. The composition provided to the individual in such cases comprises a mixture of at least lactose, glucose, galactose, and galactooligosaccharides, the mixture comprising 0.1 to 30% by weight of lactose, 8 to 40% by weight of glucose, 0.1 to 20% by weight of galactose, and 40 to 90% by weight of galactooligosaccharides, in particular to promote an increase or decrease in the level of a specific metabolite in the individual. For example, the level of a specific metabolite can be measured from a plasma sample or a fecal sample by methods well known in the art.

[0047]

[0063] In certain embodiments, improved brain health is associated with increased and / or decreased levels of specific metabolites, specific bacteria, e.g., Bifidobacterium species, or their functional derivatives. In certain embodiments, improved brain health is associated with (a) control of appetite or food intake; (b) management of glucose levels; (c) weight management; (d) protection from viral respiratory infections; (e) normalization of blood lipid profiles; (f) skin health; (g) protection from pathogens; (h) improved cognition; (i) reduction of inflammation; (j) prevention and / or reduction of oxidative stress; (k) reduction of nerve damage after stroke; (l) stress management; (m) improved lipid metabolism; (n) improved intestinal barrier; (o) reduced intestinal permeability; (p) regulation of glucose metabolism; (q) protection from fatty liver; (r) protection from neurodegenerative diseases, including but not limited to Alzheimer's disease; (s) protection from nerve damage; (t) Faecalibacterium prausnitzii (u) promoting the growth of Bifidobacterium prausnitzii; (v) protecting the kidney, especially in chronic kidney disease; (w) enhancing the Bifidobacterium shunt pathway; (x) enhancing the NAD salvage pathway; and (y) one or more combinations thereof. Individuals may be diagnosed with such a condition, suspected to have such a condition, or susceptible to such a condition. Individuals may be treated with one or more other therapies in addition to the methods of this disclosure.

[0048]

[0064] In certain embodiments, the composition is administered in an amount effective to improve cognitive function in an individual, including to individuals without detectable cognitive impairment or to individuals with detectable cognitive impairment, including impairment for any reason. In certain embodiments, the method delays the onset of cognitive impairment and / or enhances normal cognitive function.

[0049]

[0065] In one embodiment of the present disclosure, there exists a method for causing elevated blood levels of specific metabolites, such as 3-indolepropionate, acetate, caprylic acid, nicotinamide, β-alanine, ketone bodies, 3-hydroxybutyrate, 12,13-diHODE, and / or 3-hydroxydecanoic acid (or functional derivatives thereof), or elevated fecal levels of Bifidobacterium, including but not limited to B. adolescentis, B. bifidum, and B. longum, by administering the compositions disclosed herein to an individual in need thereof. The individual may be found to have a medical or physical condition in which an elevated metabolite level could be beneficial, or there may be suspicion that the individual has a medical or physical condition in which an elevated metabolite level or elevated fecal bacteria level could be beneficial.

[0050]

[0066] The method may include a step of identifying an individual as having a medical or physical condition for which an increase in elevated metabolite levels or elevated levels of beneficial fecal bacteria could be beneficial, and / or the method may include a step of identifying an individual as being at risk of a medical or physical condition for which an increase in elevated metabolite levels or elevated levels of beneficial fecal bacteria could be beneficial. In certain embodiments, an individual subjected to the method and / or composition of the present invention desires the prevention of one or more undesirable physical conditions (or the effects of physical conditions such as those associated with aging) or medical conditions.

[0051]

[0067] In certain embodiments, an effective amount of the composition described herein is provided to an individual for the explicit purpose of increasing intracellular levels of 3-indolepropionate, acetate, caprylic acid, nicotinamide, β-alanine, ketone bodies, 3-hydroxybutyrate, 12,13-diHODE, and / or 3-hydroxydecanoic acid, or for increasing fecal levels of Bifidobacterium, including but not limited to B. adolescentis, B. bifidum, and B. longum, because the individual is assessed to be suffering from a condition in which such levels are directly or indirectly related. Furthermore, in certain embodiments, an individual is provided with an effective amount of the composition described herein for the explicit purpose of decreasing levels of indoxyl sulfate and / or p-cresol sulfate, because the individual is assessed to be suffering from a condition in which such levels are directly or indirectly related.

[0052]

[0068] In some embodiments, there are methods for improving cognitive function, e.g., improvement in individuals with diabetes-induced cognitive impairment, stress management, prevention of oxidative stress, prevention and / or treatment of type II diabetes, reduction of inflammation, improvement of the intestinal barrier, reduction of intestinal permeability, regulation of glucose metabolism, protection from fatty liver, and / or neuroprotection, e.g., protection of neurons from oxidative damage in individuals. In certain embodiments, administration of the compositions intended herein increases the levels of 3-indolepropionate that are directly or indirectly related to cognitive function, stress management, oxidative stress, inflammation, intestinal permeability, glucose metabolism, fatty liver, and / or neuroprotection.

[0053]

[0069] In some embodiments, there are methods for reducing and / or preventing oxidative stress in individuals. In a particular embodiment, the method is useful for treating and / or preventing medical conditions associated with oxidative stress. In certain cases, the present invention provides methods and compositions useful for aging. In certain embodiments, administration of the compositions intended herein increases the levels of 3-hydroxybutyrate, which is directly or indirectly associated with oxidative stress and age-related diseases.

[0054]

[0070] In some embodiments, there are methods for treating or preventing cognitive impairment in an individual, reducing oxidative stress, and / or increasing levels of Faecalibacterium prausnitzii in the gut microbiome. In certain embodiments, administration of the compositions intended herein reduces levels of p-cresol sulfate, which is directly or indirectly associated with cognitive impairment, oxidative stress, and / or levels of Faecalibacterium prausnitzii.

[0055]

[0071] In some embodiments, the composition contains 20-40% milk protein by dry weight. The milk protein includes proteins or combinations of proteins derived from milk. The milk protein may be derived from milk by any preferred method. In preferred embodiments, the composition contains 25-40%, more preferably 30-40%, milk protein by dry weight.

[0056]

[0072] In some embodiments, the food ingredient further comprises 35-55% or 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 preferred embodiments, the food ingredient comprises 45-55% by dry weight of a mixture of lactose, glucose, galactose, and GOS; in more preferred embodiments, the food ingredient comprises 50-55% by dry weight of a mixture of lactose, glucose, galactose, and GOS. In another preferred embodiment of the present invention, the mixture of lactose, glucose, galactose, and GOS comprises 60-90% by weight of GOS, more preferably 70-90% by weight of GOS. In yet another preferred embodiment, the mixture of lactose, glucose, galactose, and GOS contains 1 to 20% by weight of lactose, 15 to 35% by weight of glucose, 1 to 10% by weight of galactose, and 50 to 85% by weight of GOS. In a more preferred embodiment of the present invention, the mixture of lactose, glucose, galactose, and GOS contains 1 to 14% by weight of lactose, 15 to 29% by weight of glucose, 1 to 8% by weight of galactose, and 70 to 90% by weight of GOS.

[0057]

[0073] In some embodiments, the mixture of lactose, glucose, galactose, and GOS contains 0.1 to 30% by weight, for example, 0.1 to 5%, 5 to 10%, 10 to 15%, 15 to 20%, 20 to 25%, or 25 to 30% by weight of lactose. In some embodiments, the mixture of lactose, glucose, galactose, and GOS contains 8 to 40% by weight, for example, 8 to 16%, 16 to 24%, 24 to 32%, or 32 to 40% by weight of glucose. In some embodiments, the mixture of lactose, glucose, galactose, and GOS contains 0.1 to 20% by weight, for example, 0.1 to 5%, 5 to 10%, 10 to 15%, or 15 to 20% by weight of galactose. In some embodiments, the mixture of lactose, glucose, galactose, and GOS contains 40-90% by weight of GOS, for example, 40-50% by weight, 50-60% by weight, 60-70% by weight, or 70-80% by weight.

[0058]

[0074] The composition may further contain 0.5 to 30% by dry weight of milk fat and / or milk-derived minerals, preferably 2 to 20%, more preferably 6 to 10% by dry weight of milk fat and / or milk-derived minerals. The milk fat includes fats derived from milk in any preferred manner. The milk-derived minerals include minerals derived from milk in any preferred manner, such as salts of calcium, sodium, potassium, phosphorus, and / or magnesium. The milk fat and / or milk-derived minerals may be derived from liquid milk, such as skim milk, partially skim milk, and / or whole milk, or from powdered milk, such as skim milk powder and / or whole milk powder.

[0059]

[0075] In a preferred embodiment, the composition further comprises 5-20% vegetable oil by dry weight, more preferably 8-15% vegetable oil by dry weight. 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 nonfat 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.

[0060]

[0076] Non-fat milk solids may be derived from any suitable milk raw material, such as liquid milk, such as skim milk and / or whole milk, and / or powdered milk, such as skim milk powder and / or whole milk powder. If liquid milk is used, it may be concentrated by evaporation or filtration, for example. Malt extract solids may be in any suitable form, such as barley malt and / or wheat malt powder or liquid extract. Cocoa solids may be derived from any suitable cocoa raw material, such as 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 raw material, such as liquid milk or cream, such as skim milk, cream and / or whole milk, and / or powdered milk, such as skim milk powder, cream powder and / or whole milk powder, and / or butter, butter oil and / or anhydrous milk fat. If liquid milk or cream is used, it may be concentrated by evaporation or filtration, for example.

[0061]

[0077] Glucose, lactose, and GOS are preferably derived from the composition of the present invention. The cocoa and / or malt beverage powder of the present invention preferably contains 10 to 30% by dry weight of the composition of the present invention, more preferably 15 to 25% by dry weight of the composition of the present invention. In a preferred embodiment of the present invention, the cocoa and / or malt beverage powder contains 2 to 4% by weight of glucose, 0.1 to 2% by weight of lactose, and 5 to 10% by weight of GOS.

[0062]

[0078] The cocoa and / or malt beverage powder of the present invention may contain sucrose. Depending on the amount of lactose, glucose, and GOS present in the product, the amount of sucrose can be reduced compared to conventional cocoa and / or malt beverage powders while maintaining an acceptable taste, sweetness, and texture. In a preferred embodiment, the cocoa and / or malt beverage product of the present invention does not contain sucrose. In another preferred embodiment, the cocoa and / or malt beverage powder of the present invention contains 1 to 25% by weight of sucrose, more preferably 5 to 20% by weight of sucrose.

[0063]

[0079] The cocoa and / or malt beverage powder of the present invention may also contain any other suitable raw materials known in the art, such as vitamins, minerals, buffer salts, emulsifiers, and stabilizers.

[0064]

[0080] The cocoa and / or malt beverage powder of the present invention may be produced by any preferred method known in the art. The raw materials may be, for example, in powder form, mixed in a dry state, some or all of the raw materials may be mixed in an aqueous solution / suspension and then dried to make a powder, or some or all of the powdered raw materials may be co-aggregated, for example, to produce a powder with improved solubility.

[0065]

[0081] In a preferred embodiment, the present 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 galactooligosaccharides.

[0066]

[0082] In one embodiment, the composition relates to a liquid cocoa and / or malt beverage product comprising 3 to 10% by weight of non-fat milk solids, 1 to 6% by weight of malt extract solids, 0 to 5% by weight of cocoa solids, 0.3 to 5% by weight of vegetable oil and / or milk fat, 0 to 5% by weight of sucrose, 0.4 to 1.5% by weight of glucose, 0.01 to 1% by weight of lactose, and 0.5 to 5% by weight of GOS.

[0067]

[0083] Liquid cocoa and / or malt beverage products are cocoa and / or malt beverage products in liquid form that are suitable for consumption without the addition of liquid. The product may be packaged, for example, in a container that can be opened and consumed directly.

[0068]

[0084] Non-fat milk solids may be derived from any suitable milk raw material, such as liquid milk, such as skim milk and / or whole milk, and / or powdered milk, such as skim milk powder and / or whole milk powder. If liquid milk is used, it may be concentrated, for example, by evaporation or filtration. Malt extract solids may be in any suitable form, such as powder or liquid extract of barley malt and / or wheat malt. Cocoa solids may be derived from any suitable cocoa raw material, such as 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 raw material, such as liquid milk or cream, such as skim milk, cream and / or whole milk, and / or powdered milk, such as skim milk powder, cream powder and / or whole milk powder, and / or butter, butter oil and / or anhydrous milk fat. If liquid milk or cream is used, it may be concentrated, for example, by evaporation or filtration.

[0069]

[0085] Glucose, lactose, and GOS are preferably derived from the composition of the present invention. The liquid cocoa and / or malt beverage product of the present invention preferably contains 10-30% by dry weight, more preferably 15-25% by dry weight, of the composition of the present invention. In a preferred embodiment, the liquid cocoa and / or malt beverage product contains 0.5-1% by weight of glucose, 0.01-0.5% by weight of lactose, and 1-4% by weight of GOS.

[0070]

[0086] The liquid cocoa and / or malt beverage product of the present invention may contain sucrose. Depending on the amount of lactose, glucose, and GOS present in the product, the amount of sucrose can be reduced compared to conventional cocoa and / or malt beverage powders while maintaining an acceptable taste, sweetness, and texture. In a preferred embodiment, the cocoa and / or malt beverage product of the present invention does not contain sucrose. In another preferred embodiment, the cocoa and / or malt beverage powder of the present invention contains 0.1 to 5% by weight of sucrose, more preferably 1 to 3% by weight of sucrose.

[0071]

[0087] The liquid cocoa and / or malt beverage product of the present invention may also contain any other suitable raw materials known in the art, such as vitamins, minerals, buffer salts, emulsifiers, and stabilizers.

[0072]

[0088] The liquid cocoa and / or malt beverage product of the present invention may be manufactured by any preferred method known in the art. The raw materials may be in liquid and / or powder form and may be mixed into an aqueous solution / aqueous suspension, for example by adding water, to achieve the desired concentration of the raw materials. The food raw materials of the present invention are preferably added in liquid form, but may also be added in powder form.

[0073]

[0089] In a preferred embodiment, the composition relates to a liquid cocoa and / or malt beverage product comprising 3 to 10% by weight of non-fat milk solids, 1 to 6% by weight of malt extract solids, 1 to 5% by weight of cocoa solids, 0.3 to 5% by weight of vegetable oil and / or milk fat, 0 to 5% by weight of sucrose, 0.4 to 1.5% by weight of glucose, 0.01 to 1% by weight of lactose, and 0.5 to 5% by weight of GOS.

[0074]

[0090] The composition may be in any oral nutritional form, for example, as a health drink, as a ready-made beverage, or optionally as a soft drink such as juice, coffee, tea, milkshake, yogurt drink, smoothie, or soy-based beverage; in the form of a food bar; in the form of a powder, such as a sachet; or dispersed in any type of food, such as baked products, cereal bars, dairy bars, snack foods, soups, breakfast cereals, muesli, candies, tabs, cookies, biscuits, crackers (such as rice crackers), and dispersed in dairy and plant-based products.

[0075]

[0091] In some embodiments, the composition relates to a ready-to-drink beverage. Weight percent is based on the dry weight of the composition before reconstitution. In one embodiment, the ready-to-drink beverage contains 32% to 55% of a mixture of lactose, glucose, galactose, and GOS by dry weight. In one embodiment, the composition contains 40% to 45% of a mixture of lactose, glucose, galactose, and GOS by dry weight. In one embodiment, the composition contains 45% to 50% of a mixture of lactose, glucose, galactose, and GOS by dry weight. In one embodiment, the food ingredient contains 32% to 37% of a mixture of lactose, glucose, galactose, and GOS by dry weight.

[0076]

[0092] In some other embodiments, the mixture of lactose, glucose, galactose, and GOS in the composition contains 1 to 25% by weight of lactose, for example 1 to 5%, 5 to 10%, 10 to 15%, 15 to 20%, or 20 to 25% by weight of lactose. In some embodiments, the mixture of lactose, glucose, galactose, and GOS in the composition contains 15 to 35% by weight of glucose, for example 15 to 20%, 20 to 25%, 25 to 30%, or 30 to 35% by weight of glucose. In some embodiments, the mixture of lactose, glucose, galactose, and GOS in the composition contains 1 to 10% by weight of galactose, for example 1 to 2%, 2 to 4%, 4 to 6%, 6 to 8%, or 8 to 10% by weight of galactose. In some embodiments, the mixture of lactose, glucose, galactose, and GOS in the composition contains 50-85% by weight of GOS, for example, 50-60% by weight, 60-70% by weight, 70-80% by weight, or 80-85% by weight of GOS.

[0077]

[0093] In a preferred embodiment, the composition contains 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.

[0078]

[0094] In some embodiments, the ready-to-drink beverage contains milk. In some embodiments, the milk includes full-cream 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 preferred embodiments, the one or more vitamins include vitamins that provide benefits, such as improved brain health.

[0079]

[0095] The composition can be administered to an individual in single servings on at least two days, at least three days, or all seven days of the week; for at least one week, at least one month, at least two months, at least three months, at least six months, or for a longer period. In some embodiments, the composition is administered to the individual over several consecutive days. In one embodiment, the composition of the present invention can be administered to an individual daily for at least 30, 60, or 90 consecutive days.

[0080]

[0096] In some embodiments, one serving of the composition is an amount effective in increasing a specific metabolite or a specific bacterium, such as Bifidobacterium, 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 containing an amount effective in increasing or decreasing a specific metabolite and improving metabolic health.

[0081]

[0097] In consideration of the disclosure herein, one embodiment is a method for improving brain health, the method comprising the step of administering a low-sugar, low-lactose milk composition containing galactooligosaccharides to an individual in need thereof. In some embodiments, the composition preferably comprises 20-40% by dry weight of milk protein; and a mixture of lactose, glucose, galactose, and galactooligosaccharides, preferably comprising 35-55% or 32-55% by dry weight of the composition; preferably, the mixture comprises 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 galactooligosaccharides.

[0082]

[0098] Improvements in brain health may include at least one outcome selected from the group consisting of (a) improved cognition; (b) reduced inflammation; (c) prevention and / or reduction of oxidative stress; (d) reduced nerve damage after stroke; (e) stress management; (f) protection from neurodegenerative diseases, including but not limited to Alzheimer's disease; (g) protection from nerve damage; and (h) reduced neuroinflammation; (i) improved brain function; (j) improved protection of blood-brain barrier integrity; (k) reduced and / or prevention of anxiety; (l) improved sleep; (m) reduced pain; (n) prevention of memory impairment; (o) promotion of axonal regeneration; and (p) combinations thereof.

[0083]

[0099] The composition may further contain at least one of milk fat or milk-derived minerals, preferably a combination thereof, in a dry weight of 0.5 to 30%. The composition may further contain 5 to 20% vegetable oil, in a dry weight.

[0084]

[0100] Preferably, the composition is administered in an amount effective to increase the level of one or more metabolites selected from the group consisting of 3-indolepropionate, valerate, N,N-dimethylglycine, imidazole acetate, tricarbaryl acid, acetate, caprylic acid, nicotinamide, β-alanine, ketone bodies, 3-hydroxybutyrate, 12,13-diHODE, and / or 3-hydroxydecanoic acid. Preferably, the composition is administered in an amount effective to increase one or more Bifidobacterium species, including but not limited to B. longum, B. adolescentis, and B. bifidum.

[0085]

[0101] Another aspect of this disclosure is a method for one or more of the following: cognitive function, stress management, prevention of oxidative stress, reduction of inflammation, improvement of brain function, reduction of predictive reward response, improvement of blood-brain barrier integrity, and / or neuroprotection, comprising the step of administering one of the compositions disclosed herein to an individual who needs or is at risk thereof. The compositions may be administered in an amount effective to increase the level of 3-indolepropionate or propionate in the individual. The compositions may also be administered to the individual in unit dosage forms, each unit dosage form comprising an amount effective to increase the level of 3-indolepropionate or propionate in the individual.Studies have shown that elevated propionate levels are associated with the listed benefits (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.;Vinolo MA, Rodrigues HG, Nachbar RT, Curi R. Regulation of inflammation by short chain fatty acids.Nutrients.2011;3:858-76:https: / / www.mdpi.com / 2072-6643 / 3 / 10 / 858;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,CSet 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 See 6,55 (2018). Each of these in whole is incorporated herein by reference.

[0086]

[0102] A further aspect of this disclosure is a method for improving cognition, comprising the step of administering one of the compositions disclosed herein to an individual who needs or is at risk of having such cognition. The compositions may be administered in an amount effective to increase the level of nicotinamide in the individual. The compositions may also be administered to the individual in unit dosage forms, each unit dosage form containing an amount of the composition effective to increase the level of nicotinamide in the individual.

[0087]

[0103] A further aspect of this disclosure is a method for the prevention and / or treatment of cognitive decline, comprising the step of administering one of the compositions disclosed herein to an individual who needs or is at risk thereof. The compositions may be administered in an amount effective to increase the level of acetate in the individual. The compositions may also be administered to the individual in unit dosage forms, each unit dosage form containing an amount of the composition effective to increase the level of acetate in the individual.

[0088]

[0104] A further aspect of this disclosure is a method for the prevention and / or treatment of cognitive decline, comprising the step of administering one of the compositions disclosed herein to an individual who needs or is at risk thereof. The compositions may be administered in an amount effective to increase the level of bifidobacterium in the individual. The compositions may also be administered to the individual in unit dosage forms, each unit dosage form containing an amount of the composition effective to increase the level of bifidobacterium in the individual.

[0089]

[0105] A further aspect of this disclosure is a method for reducing and / or preventing oxidative stress and / or treating and / or preventing age-related diseases, comprising the step of administering one of the compositions disclosed herein to an individual in need of or at risk thereof. The compositions may be administered in an amount effective to increase the level of 3-hydroxybutyrate in the individual. The compositions may also be administered to the individual in unit dosage forms, each unit dosage form comprising an amount effective to increase the level of 3-hydroxybutyrate in the individual.

[0090]

[0106] A further aspect of this disclosure is a method for reducing neuroinflammation and / or inflammation, comprising the step of administering one of the compositions disclosed herein to an individual in need of or at risk of such reduction. The compositions may be administered in an amount effective to increase the level of valerate in the individual. The compositions may also be administered to the individual in unit dosage forms, each unit dosage form containing an amount of the composition effective to increase the level of valerate in the individual. Studies have shown that elevated valerate levels are associated with the listed benefits (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 LC, et al. The Short-Chain Fatty Acid Pentanoate Suppresses Autoimmunity by Modulating the Metabolic-Epigenetic See Crosstalk in Lymphocytes. Nat.Commun. 2019;10:760.doi:10.1038 / s41467-019-08711-2. Each of these in whole is incorporated herein by reference.

[0091]

[0107] A further aspect of this disclosure is a method for reducing oxidative stress, preventing or alleviating depression and / or mood-related disorders, preventing memory impairment, and promoting axonal regeneration, comprising the step of administering one of the compositions disclosed herein to an individual in need of or at risk thereof. The compositions may be administered in an amount effective to increase the level of N,N-dimethylglycine in the individual. The compositions may also be administered to the individual in unit dosage forms, each unit dosage form containing an amount of the composition effective to increase the level of N,N-dimethylglycine in the individual. Studies have shown that elevated N,N-dimethylglycine levels are associated with the listed benefits (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.com / science / article / pii / S0300483X20302523#abs0010;Takahashi et al.2016.See also: 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. (Each of these is incorporated herein by reference).

[0092]

[0108] A further aspect of this disclosure is a method for reducing inflammation, comprising the step of administering one of the compositions disclosed herein to an individual in need of or at risk of such inflammation. The compositions may be administered in an amount effective to increase the level of tricarbaryl acid in the individual. The compositions may also be administered to the individual in unit dosage forms, each containing an amount of the composition effective to increase the level of tricarbaryl acid in the individual. Studies have shown that increased tricarbaryl acid levels are associated with the enumerated 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 entire work incorporated herein by reference).

[0093]

[0109] A further aspect of this disclosure is a method for reducing and / or alleviating anxiety, promoting and / or improving sleep, and preventing pain, comprising the step of administering one of the compositions disclosed herein to an individual who needs or is at risk of having such pain. The compositions may be administered in an amount effective to increase the level of imidazole acetate in the individual. The compositions may also be administered to the individual in unit dosage forms, each unit dosage form containing an amount of the composition effective to increase the level of imidazole acetate in the individual. Studies have shown that elevated imidazole acetate levels are associated with the listed benefits (You, Z., Wang, C., Lan, X., Li, W., Shang, D., Zhang, F...Ning, Y. (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, DGSimonsen. 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 See Pharmacol. 1998 Oct;31(4):503-9.doi:10.1016 / s0306-3623(98)00079-2.;E. Roberts, DGSimonsen. A hypnotic and possible analgesic effect of imidazoleacetic acid in mice. Biochem. Pharmac., 15 (1966), pp.1875-1877.Each of these in its entirety is incorporated herein by reference. [Examples]

[0094]

[0110] Example 1

[0111] The following non-limiting examples generally illustrate the concepts underlying the embodiments disclosed herein.

[0095]

[0112] The inventors investigated the effects of administering the compositions disclosed herein to 26 healthy adults compared to lactose-free milk. Table 1 shows a comparison between the administered compositions and the control.

[0096] [Table 1]

[0097]

[0113] Specifically, the inventors used targeted metabolomics and untargeted metabolomics for plasma samples, and metagenomics for fecal samples. The compositions disclosed herein were administered once daily for two weeks in 200 mL beverage portions.

[0098]

[0114] Ninety-two plasma and fecal samples were analyzed using a liquid chromatography-high-resolution mass spectrometer. Feature characteristics (evaluated by retention time and accurate m / z) were linearized and normalized. Feature characteristics were annotated by their accurate mass (m / z) according to the Human Metabolome Database (HMDB). Different statistical approaches were tested to study the effects of composition administration. Statistical analysis was performed using a linear model (after log-transformation of data), considering duration and treatment, to study the effects of composition administration. Statistical significance was analyzed using type 2 covariance analysis, and false detection rate estimation was performed. A p < 0.05 was considered a significant change.

[0099]

[0115] Among the significantly annotated features reported in plasma, we found an increase in 3-indolepropionic acid (FC of 0.77, p=0.01, its identity confirmed by injecting a pure standard substance), as shown in Figure 1. Two further features, estimated to be 3-hydroxydecanoic acid and 12,13-DiHODE (a linoleic acid derivative), also significantly increased with intervention in the composition (FC<0.5). Figures 2 and 3 show the increased levels of 3-hydroxydecanoic acid and 12,13-DiHODE in the intervention group compared to the control group, respectively. As seen in Figures 4 and 5, two uremic toxins, indoxyl sulfate and p-cresol sulfate, were significantly decreased (p<0.05) in the intervention group, with FCs of -0.52 and -0.83, respectively.

[0100]

[0116] The results of targeted metabolomics on plasma samples are shown in Figures 6 to 10. Plasma levels of acetate, caprylic acid, nicotinamide, and β-alanine were significantly elevated in the intervention group, as shown in Figures 6, 7, 8, and 9, respectively. Furthermore, ketone body levels were elevated in the intervention group, as shown in Figure 10, although dietary intake information was not available in this study.

[0101]

[0117] The results of metagenomics analysis of fecal samples are shown in Figures 11-14. Bifidobacterium levels were significantly elevated in the intervention group, as shown in Figure 11. Specifically, the fecal levels of B. longum, B. adolescentis, and B. bifidum were significantly elevated in the intervention group, as seen in Figures 12, 13, and 14, respectively.

[0102]

[0118] Figures 15 and 16 show the effects of administration on the Bifidobacterium shunt pathway and the NAD salvage pathway.

[0103]

[0119] Table 2 summarizes the results of targeted metabolomics, untargeted metabolomics, and metagenomics.

[0104] [Table 2]

[0105]

[0120] Example 2

[0121] To compare the effects of 24-hour fermentation of GOS or active compositions on microbial metabolism in healthy adults, in vitro batch fermentation experiments were set up. For these experiments, the active compositions listed in Table 3 were subjected to upper gastrointestinal tract simulation using the INFOGEST 2.0 method (Brodkorb et al.), which mimics human upper gastrointestinal digestion, before being introduced into the fermenter. This process removed small sugars such as lactose. On the other hand, GOS, which is not digested in the human gastrointestinal tract, was introduced directly into the fermenter. The total amount of GOS in the fermenter was the same between the two conditions (see Table 4). A negative control was also introduced to evaluate the baseline microbial metabolism after 24 hours without substrate addition (NSC). Each condition was tested using fecal inoculum from 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).

[0106]

[0122] [Table 3]

[0107]

[0123] [Table 4]

[0108]

[0124] Figures 17–21 include box plots showing a significant increase in the production of beneficial metabolites after 24 hours of fermentation of the compositions disclosed herein, compared to GOS alone or a negative control (NSC), using batch fermentation.

[0109]

[0125] Embodiment

[0126] 1. A method for improving brain health, comprising the step of administering a low-sugar, low-lactose dairy composition containing galactooligosaccharides to an individual in need thereof.

[0110]

[0127] 2- The milk-based composition is Milk protein, preferably 20-40% of the composition by dry weight; and A mixture of lactose, glucose, galactose, and galactooligosaccharides, preferably 35-55% of the composition by dry weight; Includes, Preferably, the method according to claim 1, wherein the mixture comprises 0.1 to 30% by weight of lactose, 8 to 40% by weight of glucose, 0.1 to 20% by weight of galactose, and 40 to 90% by weight of galactooligosaccharides.

[0111]

[0128] 3: The method according to any one of claims 1 or 2, wherein the improvement in brain health includes at least one result selected from the group consisting of (a) improved cognition; (b) reduced inflammation; (c) prevention and / or reduction of oxidative stress; (d) reduced nerve damage after stroke; (e) stress management; (f) protection from neurodegenerative diseases, including but not limited to Alzheimer's disease; (g) protection from nerve damage; and (h) a combination thereof.

[0112]

[0129] 4: The method according to any one of claims 1 to 3, wherein the composition is administered in an amount effective in increasing at least one metabolite selected from the group consisting of 3-indolepropionate, acetate, caprylic acid, nicotinamide, β-alanine, ketone bodies, 3-hydroxybutyrate, 12,13-diHODE, and / or 3-hydroxydecanoic acid.

[0113]

[0130] 5: The method according to any one of claims 1 to 4, wherein the composition is administered in an amount effective to increase one or more Bifidobacterium species, including but not limited to B. longum, B. adolescentis, and B. bifidum.

[0114]

[0131] 6: A method for one or more of the following: improvement of cognitive function, stress management, prevention of oxidative stress, reduction of inflammation, and / or neuroprotection, wherein the method comprises the step of administering a composition to an individual who needs or is at risk thereof, Milk protein, preferably 20-40% of the composition by dry weight; and A mixture of lactose, glucose, galactose, and galactooligosaccharides, preferably 35-55% of the composition by dry weight; Includes, Preferably, the mixture comprises 0.1 to 30% by weight of lactose, 8 to 40% by weight of glucose, 0.1 to 20% by weight of galactose, and 40 to 90% by weight of galactooligosaccharides.

[0115]

[0132] 7: The method according to 6, wherein the composition is administered in an amount effective to increase the level of 3-indolepropionate in the individual.

[0116]

[0133] 8. The method according to any one of claims 6 and 7, wherein the composition is administered to the individual in a unit dosage form, and the unit dosage form comprises an amount of the composition effective in increasing the level of 3-indolepropionate in the individual.

[0117] 9: A method for improving one or more cognitive functions, the method comprising the step of administering a composition to an individual who needs or is at risk of needing such function, Milk protein, preferably 20-40% of the composition by dry weight; and A mixture of lactose, glucose, galactose, and galactooligosaccharides, preferably 35-55% of the composition by dry weight; Includes, Preferably, the mixture comprises 0.1 to 30% by weight of lactose, 8 to 40% by weight of glucose, 0.1 to 20% by weight of galactose, and 40 to 90% by weight of galactooligosaccharides.

[0118]

[0134] 10: The method according to 9, wherein the composition is administered in an amount effective to increase the level of nicotinamide in the individual.

[0119]

[0135] 11: The method according to any one of claims 9 and 10, wherein the composition is administered to the individual in a unit dosage form, and the unit dosage form comprises an amount of the composition effective in increasing the level of nicotinamide in the individual.

[0120]

[0136] 12: A method for one or more of the prevention and / or treatment of cognitive decline, wherein the method comprises the step of administering a composition to an individual who needs or is at risk thereof, Milk protein, preferably 20-40% of the composition by dry weight; and A mixture of lactose, glucose, galactose, and galactooligosaccharides, preferably 35-55% of the composition by dry weight; Includes, Preferably, the mixture comprises 0.1 to 30% by weight of lactose, 8 to 40% by weight of glucose, 0.1 to 20% by weight of galactose, and 40 to 90% by weight of galactooligosaccharides.

[0121]

[0137] 13: The method according to 12, wherein the composition is administered in an amount effective in increasing the level of acetate in the solid.

[0122]

[0138] 14: The method according to any one of claims 12 and 13, wherein the composition is administered to the individual in a unit dosage form, and the unit dosage form comprises an amount of the composition effective in increasing the level of acetate in the individual.

[0123]

[0139] 15: A method for one or more of the prevention and / or treatment of cognitive decline, wherein the method comprises the step of administering a composition to an individual who needs or is at risk thereof, the composition is Milk protein, preferably 20-40% of the composition by dry weight; and A mixture of lactose, glucose, galactose, and galactooligosaccharides, preferably 35-55% of the composition by dry weight; Includes, Preferably, the mixture comprises 0.1 to 30% by weight of lactose, 8 to 40% by weight of glucose, 0.1 to 20% by weight of galactose, and 40 to 90% by weight of galactooligosaccharides.

[0124]

[0140] 16: The method according to 15, wherein the composition is administered in an amount effective in increasing the level of Bifidobacterium in the individual.

[0125]

[0141] 17: The method according to any one of claims 15 and 16, wherein the composition is administered to the individual in a unit dosage form, the unit dosage form comprising an amount of the composition effective in increasing the level of bifidobacterium in the individual.

[0126]

[0142] 18: A method for reducing and / or preventing oxidative stress, and / or treating and / or preventing age-related diseases, wherein the method comprises the step of administering a composition to an individual that needs or is at risk thereof, Milk protein, preferably 20-40% of the composition by dry weight; and A mixture of lactose, glucose, galactose, and galactooligosaccharides, preferably 35-55% of the composition by dry weight; Includes, Preferably, the mixture comprises 0.1 to 30% by weight of lactose, 8 to 40% by weight of glucose, 0.1 to 20% by weight of galactose, and 40 to 90% by weight of galactooligosaccharides.

[0127]

[0143] 19: The method according to 18, wherein the composition is administered in an amount effective in increasing the level of 3-hydroxybutyrate in the solid.

[0128]

[0144] 20: The method according to any one of claims 18 and 19, wherein the composition is administered to the individual in a unit dosage form, the unit dosage form comprising an amount of the composition effective in increasing the level of 3-hydroxybutyrate in the individual.

Claims

1. A method for improving brain health, comprising the step of administering a low-sugar, low-lactose dairy composition containing galactooligosaccharides to an individual in need thereof.

2. The milk-based composition is Milk protein, preferably 20-40% of the composition by dry weight of milk protein, and A mixture of lactose, glucose, galactose, and galactooligosaccharide, preferably 32 to 55% of the composition by dry weight of the mixture. Includes, Preferably, the mixture contains 0.1 to 30% by weight of lactose, 8 to 40% by weight of glucose, 0.1 to 20% by weight of galactose, and 40 to 90% by weight of galactooligosaccharides. The method according to claim 1.

3. The method according to claim 1 or 2, wherein the improvement in brain health includes at least one result selected from the group consisting of: (a) improved cognition, (b) reduced inflammation, (c) prevention and / or reduction of oxidative stress, (d) reduction of nerve damage after stroke, (e) stress management, (f) protection from neurodegenerative diseases including but not limited to Alzheimer's disease, (g) protection from nerve damage, and (h) reduced neuroinflammation, (i) improved brain function, (j) improved protection of blood-brain barrier integrity, (k) reduced and / or prevention of anxiety, (l) improved sleep, (m) reduced pain, (n) prevention or reduction of depression and / or mood-related disorders, (o) prevention of memory impairment, (p) promotion of axonal regeneration, and (q) a combination thereof.

4. The method according to any one of claims 1 to 3, wherein the composition is administered in an amount effective in increasing at least one metabolite selected from the group consisting of 3-indolepropionate, propionate, valerate, N,N-dimethylglycine, imidazole acetate, tricarbaryl acid, acetate, caprylic acid, nicotinamide, β-alanine, ketone bodies, 3-hydroxybutyrate, 12,13-diHODE, and / or 3-hydroxydecanoic acid.

5. The method according to any one of claims 1 to 4, wherein the composition is administered in an amount effective in increasing one or more Bifidobacterium species, including but not limited to B. longum, B. adolescentis, and B. bifidum.

6. A method for improving cognitive function, managing stress, preventing oxidative stress, reducing inflammation, and / or neuroprotection, wherein the method comprises the step of administering a composition to an individual who needs or is at risk thereof, Milk protein, preferably 20-40% of the composition by dry weight of milk protein, and A mixture of lactose, glucose, galactose, and galactooligosaccharide, preferably 32 to 55% of the composition by dry weight of the mixture. Includes, Preferably, the mixture contains 0.1 to 30% by weight of lactose, 8 to 40% by weight of glucose, 0.1 to 20% by weight of galactose, and 40 to 90% by weight of galactooligosaccharides. method.

7. The method according to claim 6, wherein the composition is administered in an amount effective in increasing the level of 3-indolepropionate in the individual.

8. The method according to any one of claims 6 and 7, wherein the composition is administered to the individual in a unit dosage form, and the unit dosage form comprises an amount of the composition effective in increasing the level of 3-indolepropionate in the individual.

9. A method for improving one or more cognitive functions, the method comprising the step of administering a composition to an individual who needs or is at risk of needing such function, Milk protein, preferably 20-40% of the composition by dry weight of milk protein, and A mixture of lactose, glucose, galactose, and galactooligosaccharide, preferably 32 to 55% of the composition by dry weight of the mixture. Includes, Preferably, the mixture comprises 0.1 to 30% by weight of lactose, 8 to 40% by weight of glucose, 0.1 to 20% by weight of galactose, and 40 to 90% by weight of galactooligosaccharides.

10. The method according to claim 9, wherein the composition is administered in an amount effective in increasing the level of nicotinamide in the individual.

11. The method according to any one of claims 9 and 10, wherein the composition is administered to the individual in a unit dosage form, and the unit dosage form comprises an amount of the composition effective in increasing the level of nicotinamide in the individual.

12. A method for one or more of the prevention and / or treatment of cognitive decline, wherein the method comprises the step of administering a composition to an individual who needs or is at risk thereof, Milk protein, preferably 20-40% of the composition by dry weight of milk protein, and A mixture of lactose, glucose, galactose, and galactooligosaccharide, preferably 32 to 55% of the composition by dry weight of the mixture. Includes, Preferably, the mixture comprises 0.1 to 30% by weight of lactose, 8 to 40% by weight of glucose, 0.1 to 20% by weight of galactose, and 40 to 90% by weight of galactooligosaccharides.

13. The method according to claim 12, wherein the composition is administered in an amount effective in increasing the level of acetate in the solid.

14. The method according to any one of claims 12 and 13, wherein the composition is administered to the individual in a unit dosage form, and the unit dosage form comprises an amount of the composition effective in increasing the level of acetate in the individual.

15. A method for one or more of the prevention and / or treatment of cognitive decline, wherein the method comprises the step of administering a composition to an individual who needs or is at risk thereof, Milk protein, preferably 20-40% of the composition by dry weight of milk protein, and A mixture of lactose, glucose, galactose, and galactooligosaccharide, preferably 32 to 55% of the composition by dry weight of the mixture. Includes, Preferably, the mixture comprises 0.1 to 30% by weight of lactose, 8 to 40% by weight of glucose, 0.1 to 20% by weight of galactose, and 40 to 90% by weight of galactooligosaccharides.

16. The method according to claim 15, wherein the composition is administered in an amount effective in increasing the level of Bifidobacterium in the individual.

17. The method according to any one of claims 15 and 16, wherein the composition is administered to the individual in a unit dosage form, and the unit dosage form comprises an amount of the composition effective in increasing the level of Bifidobacterium in the individual.

18. A method for reducing and / or preventing oxidative stress, and / or treating and / or preventing age-related diseases, wherein the method comprises the step of administering a composition to an individual that needs or is at risk thereof, Milk protein, preferably 20-40% of the composition by dry weight of milk protein, and A mixture of lactose, glucose, galactose, and galactooligosaccharide, preferably 32 to 55% of the composition by dry weight of the mixture. Includes, Preferably, the mixture comprises 0.1 to 30% by weight of lactose, 8 to 40% by weight of glucose, 0.1 to 20% by weight of galactose, and 40 to 90% by weight of galactooligosaccharides.

19. The method according to claim 18, wherein the composition is administered in an amount effective in increasing the level of 3-hydroxybutyrate in the solid.

20. The method according to any one of claims 18 and 19, wherein the composition is administered to the individual in a unit dosage form, and the unit dosage form comprises an amount of the composition effective in increasing the level of 3-hydroxybutyrate in the individual.

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