Combination method for treating or preventing pediatric atopic diseases

Abstract

The present application describes a method for treating pediatric atopic diseases or reducing their onset or occurrence. In particular, the present application relates to an integrated solution that describes the administration over time and sequentially of three different specific approaches for optimal effectiveness in the treatment of pediatric atopic diseases or in reducing their onset or occurrence.

Description

Technical Field

[0001] This application describes combinations for treating pediatric atopic diseases or reducing their onset or occurrence, and methods of using such combinations. In particular, this application relates to an integrated solution that describes the timed and sequential administration of three different approaches for optimal effectiveness in the treatment of pediatric atopic diseases or the reduction of their onset or occurrence.

Background Art

[0002] The prevalence of pediatric allergic diseases, also known as pediatric atopic diseases, is increasing worldwide. An estimated 20% of children suffer from eczema (atopic dermatitis), and 8% of children report an allergy to at least one food. Atopic diseases represent a failure of immune tolerance and subsequent overreaction to benign inhaled antigens (environmental) or food allergens. There has been considerable research on the potential genetic, metabolomic, environmental, and socioeconomic predictors of atopic diseases, but current clinical guidance for allergic diseases focuses on allergen avoidance and acute treatment of exacerbations and not on prevention.

[0003] The prevention of pediatric atopic diseases requires a multi-modal approach that addresses several underlying causes leading to immune dysregulation and failure to establish or maintain immune tolerance. In early infancy, skin barrier dysfunction, with or without the presence of eczema, and an altered skin microbiome enable food and inhalant antigen allergens to sensitize the infant and result in the generation of immune cells that migrate to the gut or lungs, leading to food allergy or asthma, respectively. Additionally, infants born today in the modernized world lack key keystone gut microbes and thus their functionality due to antibiotic exposure, cesarean delivery, lack of breastfeeding, and / or the transgenerational effects of mothers exposed to the same insults. This enteric dysbiosis microbiome cannot induce a state of immunotolerance and results in a pro-inflammatory environment that mischaracterizes benign antigens. Finally, incorrect historical medical advice and parental anxiety result in a delay in food introduction during infancy, which is required for optimal immune training to specific foods.

[0004] Individual solutions, such as emollients and softeners, probiotics, and food introduction products, have been developed and are commercially available to concerned parents, but an integrated solution that is easy to use and administered by parents and describes the specific temporal and sequential dosing requirements necessary for optimal effectiveness in the prevention of pediatric allergic diseases has not been developed.

Summary of the Invention

Problems to be Solved by the Invention

[0005] Therefore, there is a need to develop such solutions for the prevention of pediatric atopic diseases, such as atopic dermatitis or eczema, food allergy, and asthma.

Means for Solving the Problems

[0006] This application describes a method for treating pediatric atopic diseases or reducing their onset or occurrence. In particular, this application describes a method of integrating individual solutions, such as eczema moisturizers and emollients, probiotics, and food introduction products, in a time-dependent manner.

[0007] In one general aspect, this application is a method of performing it in a subject in need of treatment of a pediatric atopic disease, such as atopic dermatitis, or reduction of its onset or occurrence, the following: (a) Topically administering to a skin area of the subject a first composition comprising a skin barrier function composition, wherein the administration of the first composition starts within about 7 days after the subject's birth, more specifically within about 6 days, 5 days, 4 days, 3 days, 2 days, or 1 day, and continues until at least about 2 months after the subject's birth, topically administering; (b) Orally administering to the subject a second composition comprising an effective amount of probiotics, such as Bifidobacterium cells, wherein the administration of the second composition starts within about 30 days after the subject's birth, more specifically within about 28 days, 21 days, 14 days, or 7 days, and optionally continues until at least before the introduction of solid foods, orally administering; and (c) Orally administering to the subject a pre-measured dose of one or more food allergens, wherein the administration of the one or more food allergens starts within about 1 - 8 months after the subject's birth, more specifically within about 2 - 6 months, orally administering, including performing at least two of the above.

[0008] In another general aspect, this application is a first composition for use in a method of performing it in a subject in need of treatment of a pediatric atopic disease, such as atopic dermatitis, or reduction of its onset or occurrence, the method being the following: (a) Topically administering to the target skin area a first composition comprising a skin barrier function composition, wherein the administration of the first composition starts within about 7 days after birth of the subject, more specifically within about 6 days, 5 days, 4 days, 3 days, 2 days, or 1 day after birth of the subject and continues until at least about 2 months after birth of the subject, the topical administration; (b) Orally administering to the subject a second composition comprising an effective amount of probiotics, such as Bifidobacterium cells, wherein the administration of the second composition starts within about 30 days after birth of the subject, more specifically within about 28 days, 21 days, 14 days, or 7 days after birth of the subject and optionally continues until at least before the introduction of solid foods, the oral administration; and (c) Orally administering to the subject a pre-measured dose of one or more food allergens, wherein the administration of the one or more food allergens starts within about 1 to 8 months after birth of the subject, more specifically within about 2 to 6 months after birth of the subject, the oral administration, including performing at least two of the above. A first composition is described.

[0009] In another general aspect, the present application is for use in a method of treating, or reducing the onset or occurrence of, pediatric atopic diseases, such as atopic dermatitis, in a subject in need thereof, a second composition comprising an effective amount of probiotics, such as Bifidobacterium cells, wherein the method is as follows: (a) Topically administering to the target skin area a first composition comprising a skin barrier function composition, wherein the administration of the first composition starts within about 7 days after birth of the subject, more specifically within about 6 days, 5 days, 4 days, 3 days, 2 days, or 1 day after birth of the subject and continues until at least about 2 months after birth of the subject, the topical administration; (b) Orally administering to the subject a second composition, wherein the administration of the second composition starts within about 30 days after birth of the subject, more specifically within about 28 days, 21 days, 14 days, or 7 days after birth of the subject and optionally continues until at least before the introduction of solid foods, the oral administration; and (c) Administering to the subject one or more food allergens in a pre-measured dose orally, wherein the administration of the one or more food allergens begins within about 1 to 8 months after the subject's birth, more specifically within about 2 to 6 months, and including performing at least two of the following: the oral administration.

[0010] In another general aspect, the present application relates to one or more food allergens in a pre-measured dose for use in a method of treating, or reducing the onset or occurrence of, pediatric atopic diseases, such as atopic dermatitis, in a subject in need thereof, the method comprising (a) Topically administering to a skin area of the subject a first composition comprising a skin barrier function composition, wherein the administration of the first composition begins within about 7 days after the subject's birth, more specifically within about 6 days, 5 days, 4 days, 3 days, 2 days, or 1 day, and continues until at least about 2 months after the subject's birth. (b) Orally administering to the subject a second composition comprising an effective amount of probiotics, such as Bifidobacterium cells, wherein the administration of the second composition begins within about 30 days after the subject's birth, more specifically within about 28 days, 21 days, 14 days, or 7 days, and optionally continues until at least before the introduction of solid foods. (c) Administering to the subject one or more food allergens in a pre-measured dose orally, wherein the administration of the one or more food allergens begins within about 1 to 8 months after the subject's birth, more specifically within about 2 to 6 months, and including performing at least two of the following: the oral administration.

[0011] In some embodiments, the method comprises performing (a) and (b), and preferably, the administration of the first composition begins before the administration of the second composition.

[0012] In some embodiments, the method comprises performing (a) and (c).

[0013] In some embodiments, the method includes performing (b) and (c).

[0014] In some embodiments, the method includes performing (a), (b), and (c), and preferably, the administration of the first composition starts before the administration of the second composition.

[0015] In some embodiments, the first composition includes a softening agent, and more specifically, the first composition further includes colloidal oatmeal, ceramide, and distearyldimonium chloride.

[0016] In some embodiments, the administration of the second composition continues until the desired intestinal microbiota is established.

[0017] In some embodiments, the subject receives 1, 2, 3, 4, 5, or more administrations of the second composition.

[0018] In some embodiments, the administration of the second composition continues for at least 12 weeks.

[0019] In some embodiments, the probiotics include bacterial strains selected from Lactobacillus, Lacticaseibacillus, and Bifidobacterium, and more specifically, include Bifidobacterium cells.

[0020] In some embodiments, the Bifidobacterium cells are B. infantis cells.

[0021] In some embodiments, the second composition includes about 100 million to about 100 billion, more specifically, about 5 billion to about 15 billion, and most particularly, 8 billion colony forming units (CFU) of B. infantis.

[0022] In some embodiments, administration of one or more food allergens comprises: i. administering to the subject a first food allergen at an exposure dose for the first food allergen over one or more days; ii. thereafter, administering to the subject the first food allergen at a maintenance dose for the first food allergen over multiple days; iii. thereafter, administering to the subject the first food allergen at a maintenance dose and a second food allergen at an exposure dose for the second food allergen over one or more days; iv. thereafter, administering both the first food allergen and the second food allergen at a maintenance dose for each food allergen over multiple days.

[0023] In some embodiments, administration of one or more food allergens comprises: v. administering to the subject a third food allergen at an exposure dose for the third food allergen over one or more days; vi. thereafter, further comprising administering to the subject the first food allergen, the second food allergen, and the third food allergen at a maintenance dose for each food allergen over multiple days.

[0024] In some embodiments, the method further comprises continuing the maintenance doses of the first food allergen, the second food allergen, and the third food allergen until a pre-measured dose for each food allergen is consumed.

[0025] In some embodiments, the pre-measured dose for each of the first food allergen, the second food allergen, and the third food allergen is consumed over 12 days.

[0026] In some embodiments, the first food allergen, the second food allergen, and the third food allergen are each independently selected from the group consisting of milk, eggs, peanuts, wheat, soybeans, sesame, fish, crustaceans, and nuts, and preferably are milk, eggs, and peanuts, respectively.

[0027] In another general aspect, the present application describes a kit or combination that houses at least two of a first composition that is a skin barrier function composition for use in the methods described herein, a second composition that contains an effective amount of Bifidobacterium cells, and a pre-measured dose of one or more food allergens.

[0028] Other aspects, features, and advantages of the present invention will become apparent from the following disclosure, including the detailed description of the invention, as well as its preferred embodiments and the appended claims.

Mode for Carrying Out the Invention

[0029] In the background art, various publications, papers, and patents are also cited or described throughout this specification, and the entire content of each of these reference documents is incorporated herein by reference. The consideration of the documents, operations, materials, devices, articles, etc. included in this specification is for the purpose of providing the context of the present invention. Such consideration does not admit that any or all of these things constitute a part of the prior art with respect to any of the inventions disclosed or claimed.

[0030] Unless otherwise specified, all technical and scientific terms used in this specification have the same meaning as commonly understood by those skilled in the technical field to which the present invention pertains. Otherwise, the specific terms used in this specification have the meanings described herein. All patents, published patent applications, and publications cited in this specification are incorporated by reference as if their entireties were described herein.

[0031] As used in this specification and the appended claims, it should be noted that the singular forms "a", "an", and "the" include plural references unless the context clearly dictates otherwise.

[0032] Throughout this specification and the appended claims, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", mean the inclusion of at least one of the recited elements (e.g., integers or steps recited, etc.), but do not mean the exclusion of other unrecited elements, i.e., it is understood that other elements not recited may also be present. As used herein, the term "comprising" can be replaced by the term "containing" or "including", or can sometimes be replaced by the term "having" as used herein.

[0033] When used herein in connection with an aspect or embodiment of the present invention, any of the above terms "comprising", "containing", "including", and "having" can be replaced by the term "consisting of" or "consisting essentially of" to vary the scope of the present disclosure.

[0034] As used herein, the conjunctive term "and / or" between a plurality of recited elements is understood to cover both the individual and combined choices. For example, when two elements are connected by "and / or", the first choice refers to the applicability of the first element without the second element. The second choice refers to the applicability of the second element without the first element. The third choice refers to the applicability of the first and second elements together. Any one of these choices is contemplated, and thus it is understood that when used herein, the term "and / or" meets the requirements of the term. The simultaneous applicability of two or more of the choices is also contemplated, and thus it is understood that the term "and / or" meets the requirements of the term.

[0035] The term "between" as used in phrases such as "between A and B" or "between A~B" refers to the range that includes both A and B.

[0036] As used herein, "essentially free of" or "substantially free of" a component means containing less than 0.1 weight percent of the component. In some embodiments, "essentially free of" or "substantially free of" a component means containing less than 0.01 weight percent of the component or containing no component.

[0037] As used herein, the terms "method" and "procedure" are used interchangeably.

[0038] As used herein, the terms "atopic disease" and "allergic disease" may be used interchangeably. An atopic disease is a class of diseases in which the immune system generates immunoglobulin IgE against common environmental allergens that are generally considered harmless. Examples of atopic diseases include, but are not limited to, atopic dermatitis (AD), allergic rhinitis, asthma, and food allergies. An atopic disease is a class of diseases in which the immune system generates immunoglobulin IgE against common environmental allergens that are generally considered harmless. Examples of atopic diseases include, but are not limited to, atopic dermatitis (AD), allergic rhinitis, asthma, and food allergies.

[0039] As used herein, the terms "atopic dermatitis" or "eczema" refer to a chronic, relapsing inflammatory skin disorder that makes the skin itchy and / or red. Such itchy or pruritic skin is a major symptom of atopic dermatitis, which may also have skin lesions ranging from mild erythema to severe lichenification to erythroderma. This is common in children but can occur at any age. Atopic dermatitis may be accompanied by asthma or hay fever. Currently, there is no cure for atopic dermatitis.

[0040] As used herein, the term "subject" refers to a human. In particular, the subject is an infant. More specifically, the subject is an infant who has an increased risk of developing pediatric atopic diseases, for example, an infant who has one first-degree relative with a history of atopic diseases. The infant may be born via vaginal or cesarean delivery.

[0041] As used herein, the term "effective amount" refers to an amount of a regimen and / or composition sufficient to significantly induce a positive benefit, where the positive benefit includes that which is independent or in combination with other benefits disclosed herein. This means that the content and / or concentration of the active component in the regimen and / or composition is sufficient such that when the regimen and / or composition is applied at normal frequency and normal amount, the regimen and / or composition can effect the treatment of pediatric atopic diseases, or the reduction of their onset or occurrence. The effective amount of a compound, extract, or composition will vary, for example, with the age, health, and environmental exposure of the end user, the duration and nature of the treatment, the specific extract, ingredient, or composition used, the particular pharmaceutically acceptable carrier used, and like factors.

[0042] As used herein, the term "skin barrier function composition" refers to a composition that, when administered to a subject, is capable of enhancing or improving the subject's skin barrier. A skin barrier function composition can include one or more components that promote the skin's ability to provide protection from external threats such as infectious pathogens, chemicals, systemic toxicity, and allergens, protection from enhanced water loss from the body, and / or maintenance of homeostasis within the body. As used herein, the term "emollient" refers to a chemical agent specifically designed to make the outer layer (epidermis) of the skin softer and more pliable. Examples of emollients include, but are not limited to, humectants (e.g., glycerin), butters, oils, esters, lipids, and fatty acids.

[0043] As used herein, a "humectant" is an agent that can maintain or increase the concentration of free water within the epidermis. A humectant can add moisture to the skin, draw water from the dermis into the epidermis, or prevent the desorption of moisture. Humectants include emollients and occlusives. Examples of occlusives include, for example, petroleum jelly (vaseline), mineral oil, silicone, dimethicone, wax, and lanolin.

[0044] As used herein, "infant" refers to a human having an age in the range from birth to approximately 12 months post-birth.

[0045] As used herein, "topical application", "topically", and "topical" mean applying the regimens and / or compositions used according to the present disclosure onto the surface of the skin.

[0046] As used herein, "a second composition comprising an effective amount of a probiotic" refers to a composition containing an effective amount of an isolated or concentrated probiotic. As used herein, "isolated or concentrated probiotic" refers to a probiotic isolated or concentrated from a natural environment. In some embodiments, the second composition is breast milk containing one or more bacterial cells of probiotics, such as Lactobacillus, Lactobacillus casei, and Bifidobacterium, isolated or concentrated from a natural environment. The second composition is not naturally occurring breast milk.

[0047] Method for preventing pediatric atopic diseases This application is a method for treating pediatric atopic diseases, or reducing their onset or occurrence, in a subject in need thereof, comprising the following: (a) Topically administering to a skin area of the subject a first composition comprising a skin barrier function composition, wherein the administration of the first composition starts within about 7 days after the birth of the subject, more specifically within about 6 days, 5 days, 4 days, 3 days, 2 days, or 1 day after the birth of the subject, and continues until at least about 2 months after the birth of the subject; and (b) Orally administering to the subject a second composition comprising an effective amount of a probiotic, such as Bifidobacterium cells, wherein the administration of the second composition starts within about 30 days after the birth of the subject, more specifically within about 28 days, 21 days, 14 days, or 7 days after the birth of the subject, and optionally continues until at least before the introduction of solid foods; and (c) Orally administering to the subject a pre-measured dose of one or more food allergens, wherein the administration of the one or more food allergens starts within about 1 - 8 months after the birth of the subject, more specifically within about 2 - 6 months after the birth of the subject, comprising performing at least two of the above.

[0048] In some embodiments, the method comprises performing (a) and (b).

[0049] In some embodiments, the method comprises performing (a) and (c).

[0050] In some embodiments, the method includes performing (b) and (c).

[0051] In some embodiments, the method includes performing (a), (b), and (c).

[0052] In certain embodiments, the method is (a) topically administering to a target skin region a first composition comprising a skin barrier function composition, wherein the administration of the first composition begins within about 7 days after birth of the target, more specifically within about 6 days, 5 days, 4 days, 3 days, 2 days, or 1 day after birth of the target and continues until at least about 2 months after birth of the target; (b) orally administering to the target one or more food allergens at an exposure dose over one or more days, wherein the administration of the one or more food allergens begins within about 1 - 8 months after birth of the target, more specifically within about 2 - 6 months after birth of the target; (c) after step (b), administering to the target one or more food allergens at a maintenance dose over one or more days.

[0053] In certain embodiments, the method is (a) orally administering to the target a second composition comprising an effective amount of probiotics, such as Bifidobacterium, wherein the administration of the second composition begins within about 30 days after birth of the target, more specifically within about 28 days, 21 days, 14 days, or 7 days after birth of the target and optionally continues until at least before the introduction of solid foods; (b) orally administering to the target one or more food allergens at an exposure dose over one or more days, wherein the administration of the one or more food allergens begins within about 1 - 8 months after birth of the target, more specifically within about 2 - 6 months after birth of the target; (c) after step (b), administering to the target one or more food allergens at a maintenance dose over one or more days.

[0054] In certain embodiments, the method comprises: (a) topically administering to a skin area of a subject a first composition comprising a skin barrier function composition, wherein the administration of the first composition starts within about 7 days after birth of the subject, more specifically within about 6 days, 5 days, 4 days, 3 days, 2 days, or 1 day after birth of the subject and continues until at least about 2 months after birth of the subject; (b) orally administering to the subject a second composition comprising an effective amount of probiotics, such as Bifidobacterium, wherein the administration of the second composition starts within about 30 days after birth of the subject, more specifically within about 28 days, 21 days, 14 days, or 7 days after birth of the subject and optionally continues until at least before the introduction of solid food.

[0055] In certain embodiments, the method comprises: (a) topically administering to a skin area of a subject a first composition comprising a skin barrier function composition, wherein the administration of the first composition starts within about 7 days after birth of the subject, more specifically within about 6 days, 5 days, 4 days, 3 days, 2 days, or 1 day after birth of the subject and continues until at least about 2 months after birth of the subject; (b) orally administering to the subject a second composition comprising an effective amount of probiotics, such as Bifidobacterium, wherein the administration of the second composition starts within about 30 days after birth of the subject, more specifically within about 28 days, 21 days, 14 days, or 7 days after birth of the subject and optionally continues until at least before the introduction of solid food; (c) orally administering to the subject one or more food allergens at an exposure dose over one or more days, wherein the administration of the one or more food allergens starts within about 1 - 8 months after birth of the subject, more specifically within about 2 - 6 months after birth of the subject; (d) after step (c), orally administering to the subject one or more food allergens at a maintenance dose over one or more days.

[0056] In certain embodiments, when both the first composition and the second composition are administered, administration of the first composition begins before administration of the second composition. In certain embodiments, administration of the first composition, the second composition, and / or the allergen begins at different times, but administration of the first composition, the second composition, and / or the allergen can overlap. For example, the first composition can be administered first at about day 1 to about day 7, preferably about day 4, more preferably about day 2 after the subject's birth; the second composition can be administered first at about day 1 to about day 30, preferably about day 1 to day 14 after the subject's birth; and one or more food allergens can be administered first at about month 1 to about month 8, preferably about month 2 to month 6 after the subject's birth.

[0057] With respect to step (a) of the method, the first composition comprises a skin barrier function composition. The skin barrier is important for human life. Physically, the skin barrier protects against external threats such as infectious pathogens, chemicals, systemic toxicity, and allergens. Internally, the skin helps maintain homeostasis and protects against enhanced water loss from the body. See, for example, Kanwar et al., Indian J Med Res. 2018 Jan;147(1):117 - 118 for basic parameters involved in skin barrier function, external factors affecting the skin barrier, and treatments to improve the skin barrier. Also see, for example, Cezmi A. Akdis, Nature Reviews Immunology, 2021(21):739 - 751, and Cezmi A. Akdis, J. Allergy Clin. Immunol., 2022, Volume 149(1):41 - 44. The skin barrier function composition can contain one or more of a humectant, a component that promotes barrier re - construction and inflammation reduction, such as ceramide or avenacin, and a skin protectant that prevents (through surface chemistry) the entry of proteins or other substances into the skin, such as a silicone - based polymer (e.g., dimethicone).

[0058] The first composition is thought to exert its effects, at least in part, by the timing and combination of actions of a single component in the composition, and / or by the timing and combination of actions of a combination of two or more components in the composition, and / or by the timing and combination of actions based on the amount of a single component in the composition, and / or by the timing and combination of actions based on the relative amounts of two or more components in the composition.

[0059] While not wishing to be bound by theory, the inventors believe that the first composition exerts its effects as follows: a. Improving the barrier function; b. Having a probiotic effect on the skin microbiome, thereby stimulating the growth of microorganisms with beneficial properties, i. Some of the components may be thought to achieve this by acting as buffers to achieve an optimal skin pH; stimulating, c. Having an antioxidant effect; d. Having an anti-inflammatory effect; e. Stimulating ceramide production, and f. Stimulating fatty acid production. g. Is thought to be exerted by one or more of forming a surface layer that prevents the penetration of dietary proteins into the skin barrier

[0060] In some embodiments, the first composition is administered at least once a day, preferably at least twice a day.

[0061] In some embodiments, administration of the first composition begins within about 2 days after the subject's birth.

[0062] In some embodiments, the first composition is administered to the subject's entire body skin.

[0063] In some embodiments, the first composition is formulated in a dosage form selected from the group consisting of a balm, a cream, a lotion, an emulsion, a serum, an ointment, and a paste.

[0064] According to an embodiment of the present application, the first composition includes one or more components selected from the group consisting of glycerin, water, cetearyl alcohol, isocetyl alcohol, dimethicone, cetyl alcohol, emblica fruit powder, emblica fruit extract, emblica fruit oil, caprylic / capric triglyceride, ceramide 3, ethylhexylglycerin, p-anisic acid, sodium cetearyl sulfate, palmitic acid, stearic acid, sodium sulfate, sodium chloride, citric acid, dipotassium phosphate, potassium phosphate, sodium hydroxide, tocopherol, benzyl alcohol, benzoic acid, and potassium sorbate, and a carrier.

[0065] In some embodiments, the first composition includes a softening agent. More specifically, the first composition further includes colloidal oatmeal, ceramide, and distearyldimonium chloride.

[0066] In some embodiments, the first composition includes the following components in the amounts described below: a. Caprylic / capric triglyceride, preferably from about 0.0% to about 1.0%, more preferably from about 0.005% to about 1.0%; b. Citric acid, preferably from about 0.0% to about 0.1%, more preferably from about 0.005% to about 0.1%; c. Benzoic acid, preferably from about 0.0% to about 2.0%, more preferably from about 0.1% to about 2.0%; d. Potassium phosphate, preferably from about 0.0% to about 2.0%, more preferably from about 0.05% to about 2.0%; e. Dimethicone, preferably from about 0.0% to about 10.0%, more preferably from about 1.0% to about 10.0%; f. Stearic acid and palmitic acid, preferably from about 0.0% to about 2.0%, more preferably from about 0.1% to about 2.0%; g. Preferably about 0.0% to about 10.0%, more preferably about 1.0% to about 10.0% of isocetyl alcohol, h. Preferably about 0.0% to about 2.0%, more preferably about 0.1% to about 2.0% of Avena sativa (oat) kernel flour, i. Preferably about 0.0% to about 0.1%, more preferably about 0.005% to about 0.1% of ceramide 3, j. Preferably about 0.0% to about 2.0%, more preferably about 0.1% to about 2.0% of ethylhexylglycerin, k. Preferably about 0.0% to about 1.0%, more preferably about 0.005% to about 1.0% of Avena sativa (oat) kernel oil, l. Preferably about 0.0% to about 1.0%, more preferably about 0.005% to about 1.0% of Avena sativa (oat) kernel extract containing glycerin, potassium sorbate, and water, m. Preferably about 15.0% to about 40.0%, more preferably about 20.0% to about 40.0% of water, n. Preferably about 20.0% to about 50.0%, more preferably about 30.0% to about 50.0% of glycerin, o. Preferably about 0.0% to about 2.0%, more preferably about 0.1% to about 2.0% of sodium cetearyl sulfate, p. Preferably about 0.0% to about 2.0%, more preferably about 0.1% to about 2.0% of dipotassium phosphate, q. Preferably about 0.0% to about 1.0%, more preferably about 0.005% to about 1.0% of sodium hydroxide, r. Preferably about 0.0% to about 10.0%, more preferably about 1.0% to about 10.0% of cetyl alcohol, s. Preferably about 0.0% to about 10.0%, more preferably about 1.0% to about 10.0% of cetearyl alcohol, t. Preferably about 0.0% to about 2.0%, more preferably about 0.1% to about 2.0% of benzyl alcohol, and / or u. Preferably about 0.0% to about 2.0%, more preferably about 0.1% to about 2.0% of p-anisic acid, containing one or more of them.

[0067] While not wishing to be bound by theory, the component alone, or in combination with other components, is thought to exert its effects, at least in part, as follows. a. Improving the barrier function. i. Caprylic / capric triglyceride creates a barrier on the surface of the skin, which helps to reduce skin dryness by reducing water loss. ii. Dimethicone acts as a skin protectant. iii. Stearic acid and palmitic acid are fatty acids that create an occlusive barrier that protects the skin from unwanted microorganisms and contaminants while retaining moisture. iv. Hexyldecanol is a fatty alcohol that forms a layer across the skin surface. v. Ceramides, together with saturated fatty acids, create a water-impermeable protective layer to prevent excessive water loss due to evaporation and provide a barrier against microbial invasion. vi. Glycerin, also known as glycerol, is a humectant that can hydrate the outer layer of the skin and improve skin barrier function and skin mechanical properties. b. Having a probiotic effect on the skin microbiome, thereby stimulating the growth of microorganisms with beneficial properties. The application of one or more of the components in the composition is thought to play a role in the balance of the skin microbiota. i. Oatmeal-based products function with the skin to do several things, some of which include creating a protective barrier known as the skin microbiome that defends against opportunistic pathogenic microorganisms on the surface of the skin. 1. Embar (Triticum dicoccum) grain flour 2. Embar (Triticum dicoccum) grain oil 3. Water, glycerin, Embar (Triticum dicoccum) grain extract ii. Buffering the skin pH to facilitate the skin achieving an optimal pH level that can affect the survival and growth rate of microbial species. 1. Citric acid 2. Benzoic acid 3. Potassium phosphate 4. Dipotassium phosphate 5. Sodium hydroxide iii. Glycerin, also known as glycerol, is a humectant that can have an effect on the microbiome. c. Having an antioxidant effect. i. Caprylic / capric triglyceride can act as an antioxidant that functions to neutralize exposed toxins in the environment. ii. Tocopherol d. Having an anti-inflammatory effect. i. One or more components in the composition can correct asymptomatic skin barrier dysfunction and early inflammation in infants with a predisposition, prior to the onset of atopic dermatitis, by improving skin hydration and reducing skin permeability. This skin barrier enhancement prevents skin dryness and cracking and inhibits the penetration of irritants and allergens, which are potential triggers of skin inflammation, into the epidermis. ii. The emmer (Triticum dicoccum) component has anti-inflammatory properties that help reduce itching. 1. Emmer (Triticum dicoccum) grain flour 2. Emmer (Triticum dicoccum) grain oil 3. Water, glycerin, emmer (Triticum dicoccum) grain extract e. Stimulating ceramide production. i. Emmer (Triticum dicoccum) grain flour ii. Emmer (Triticum dicoccum) grain oil iii. Water, glycerin, emmer (Triticum dicoccum) grain extract iv. Glycerin, also known as glycerol f. Stimulating fatty acid production. i. Glycerin, also known as glycerol.

[0068] Ethylhexylglycerin is a glyceryl ether commonly used as part of a preservation system in cosmetic preparations or for skin conditioning properties.

[0069] Sodium cetearyl sulfate is a mixture of stearyl and cetyl sulfates that functions as a surfactant in the composition.

[0070] Cetyl alcohol functions as a thickening and emulsifying agent to promote the non-separation of product components.

[0071] Ceteareth is a mixture of cetyl alcohol and stearyl alcohol, which are fatty alcohols, and is used in personal care products to create a smoother and thicker composition.

[0072] Benzyl alcohol acts as a preservative in skin care products due to its antibacterial and antifungal properties.

[0073] p-Anisic acid acts as a masking agent (which means it helps to mask the odor in the product) and a preservative.

[0074] Dimethicone can also have an anti-foaming effect, which can affect the aesthetics of the product and make the product more desirable for consumer use.

[0075] When used in step (b) of the method, the second composition can contain probiotics that promote the establishment of a healthy microbiota. Examples of probiotics include, but are not limited to, bacterial strains selected from Lactobacillus, Lactobacillus casei, and Bifidobacterium, and more specifically include Bifidobacterium cells. Bifidobacterium is a genus of Gram-positive anaerobic bacteria that are present in the gastrointestinal tract, vagina, and oral cavity of mammals, including humans. Suitable Bifidobacterium can have at least one Human Milk Oligosaccharide (HMO) gene cluster. Bifidobacterium can be similar to Bifidobacterium infantis. Bifidobacterium includes Bifidobacterium longum, Bifidobacterium breve, Bifidobacterium bifidum, Bifidobacterium pseudocatenulatum, Bifidobacterium globosum, Bifidobacterium adolescentis, Bifidobacterium moukalabense, Bifidobacterium reuteri, Bifidobacterium pseudolongum, Bifidobacterium dentium, Bifidobacterium catenulatum, Bifidobacterium sp002742445, Bifidobacterium callitrichos, Bifidobacterium scardovii, Bifidobacterium tissieri, Bifidobacterium subtile, Bifidobacterium gallinarum, Bifidobacterium choerinum, Bifidobacterium angulatum, Bifidobacterium primatum, BifidobacteriumPrimatium), Bifidobacterium myosotis, Bifidobacterium mongoliense, Bifidobacterium merycicum, Bifidobacterium lemurum, Bifidobacterium stellenboschense, Bifidobacterium scaligerum, Bifidobacterium saguini, Bifidobacterium pullorum, Bifidobacterium felsineum, Bifidobacterium eulemuris, Bifidobacterium cuniculi, Bifidobacterium callitrichos_A, Bifidobacterium biavatii, Bifidobacterium anseris, Bifidobacterium vansinderenii, Bifidobacterium sp900551485, Bifidobacterium sp003952945, Bifidobacterium sp003952025, Bifidobacterium sp003952005, Bifidobacterium simiarum, Bifidobacterium pseudolongum_C, Bifidobacterium parmae, Bifidobacterium margollesii, Bifidobacterium kashiwanohense_A, Bifidobacterium italicum, Bifidobacterium imperatoris, Bifidobacterium cricetid, Bifidobacterium catulorum, Bifidobacterium callitrichidarum (B.It may be selected from the group consisting of Callitrichidarum, Bifidobacterium animalis, Bifidobacterium aesculapii, and combinations thereof. The Bifidobacterium may be selected from the group consisting of Bifidobacterium longum, Bifidobacterium breve, Bifidobacterium kashiwanohensis, and combinations thereof. The Bifidobacterium can be Bifidobacterium longum. The Bifidobacterium can be a subspecies of Bifidobacterium longum selected from the group consisting of longum, suis, and infantis.

[0076] In certain embodiments, the Bifidobacterium cells in the second composition are Bifidobacterium infantis cells. As used herein, the term "Bifidobacterium infantis" or "B. infantis" means to refer to the subspecies of Bifidobacterium longum subspecies infantis. Bifidobacterium infantis may include strain EVC001. Bifidobacterium infantis can be isolated and cultured using methods known in the art.

[0077] Bifidobacterium infantis can be co-administered with one or more other probiotics (i.e., other bacteria intended to have health benefits). The other probiotics are It can be a strain selected from Lactobacillus, Lactobacillus casei, and Bifidobacterium. Examples of Bifidobacterium species include Bifidobacterium infantis, Bifidobacterium longum (subspecies other than Bifidobacterium infantis), Bifidobacterium breve, Bifidobacterium catenulatum, Bifidobacterium adolescentis, Bifidobacterium animalis, Bifidobacterium gallicum, Bifidobacterium lactis, Bifidobacterium pseudocatenulatum, and other strains of Bifidobacterium bifidum. Examples of Lactobacillus strains include Lactobacillus paracasei, Lactobacillus acidophilus, Lactobacillus johnsonii, Lactobacillus delbrueckii, Lactobacillus crispatus, Lactobacillus gasseri, Lactobacillus zeae, and combinations thereof. Examples of Lactobacillus casei include Lactobacillus casei, Lactobacillus rhamnosus, and combinations thereof. Other probiotics include Lactiplantibacillus plantarum, Limosilactobacillus fermentum, and Ligilactobacillus salivarius. Alternatively, Bifidobacterium can be administered without any other probiotics. That is, Bifidobacterium can be formulated to be essentially free of any other probiotics.

[0078] The intestinal microbiome profile of interest can be tested and monitored to determine colonization by Bifidobacterium using methods known in the art. Fecal samples can be used in such methods.

[0079] Bifidobacterium can be formulated into compositions that are easy to use and allow for consistent dosing. Fermentation products from Bifidobacterium production can be concentrated and lyophilized to provide a concentrated powder.

[0080] According to an embodiment of the present application, the second composition comprises from about 100 million to about 100 billion, more specifically from about 5 billion to about 15 billion colony forming units (CFU) of Bifidobacterium bifidum, preferably Bifidobacterium infantis, per gram of dry weight. In certain embodiments, the second composition comprises about 8 billion colony forming units (CFU) of Bifidobacterium infantis per gram of dry weight.

[0081] In a preferred embodiment, the second composition is not natural breast milk.

[0082] Bifidobacterium can also be formulated with oligosaccharides.

[0083] As used herein, the term "oligosaccharide" refers to a sugar polymer containing 2 - 20, 2 - 10, 3 - 20, or 3 - 10 monosaccharide units. Oligosaccharides can be those found in mammalian milk (e.g., human or bovine). Oligosaccharides can be synthesized.

[0084] The second composition containing Bifidobacterium can also contain auxiliary components. Such auxiliary components are those commonly used in the art and can be selected from metabolites, fluidizing agents, or combinations thereof. Examples of fluidizing agents include starch, silicon dioxide, cellulose, sodium bicarbonate, calcium silicate, and the like. The auxiliary component may be a milk protein or a constituent. The auxiliary component may contain lactose. That is, in such an example, Bifidobacterium is in powder form mixed with lactose.

[0085] The final form of the second composition can be any of those known in the art. As described above, Bifidobacterium can be in a dry form as a powder (e.g., spray-dried or freeze-dried). The powder can be administered as packets, sachets, tablets, foods, capsules, lozenges, tablets, suspensions, dry forms, and the like.

[0086] In certain embodiments, a second composition containing Bifidobacterium, which is preferred according to one or more embodiments of the present invention, is Evivo® probiotics available from Evolve BioSystems (Davis, CA), which is packaged in a sachet containing 8 billion CFU of Bifidobacterium infantis (EVC001) co-formulated with lactose.

[0087] According to embodiments of the present application, the subject is breastfed or breastfed by nutritional supplements containing one or more human milk oligosaccharides or prebiotics. Human milk oligosaccharides or prebiotics are thought to be able to support the growth of Bifidobacterium (see, for example, Francesca Turroni, et al., Trends in Microbiology, 2018, Volume 26(4):339-350, and Andrea C. Masi and Christopher J. Stewart, iScience, 2022, Volume 25b91):103542). In some embodiments, the prebiotic can be other oligosaccharides, polysaccharides, or fibers. In some embodiments, the nutritional supplement can be an infant formula powder.

[0088] A probiotic, such as a given dose of Bifidobacterium, is provided to a subject as part of a feeding (i.e., it is used as a nutritional supplement). The probiotic, such as Bifidobacterium, can be mixed with any medium that can be consumed by the subject, including breast milk, infant formula powder, water, or food, and then the probiotic, such as Bifidobacterium, is administered to the subject. The probiotic, such as Bifidobacterium, can be mixed in breast milk and then the probiotic, such as Bifidobacterium, is administered to the subject. Alternatively, the probiotic, such as Bifidobacterium, can be mixed in infant formula powder and then Bifidobacterium is administered to the subject. The probiotic, such as Bifidobacterium, is mixed with infant formula powder or breast milk such that the subject can fully incorporate the Bifidobacterium and the subject can still potentially consume the entire dose of Bifidobacterium and there is sufficient infant formula powder or breast milk to consume it. Thus, the probiotic, such as Bifidobacterium, can be mixed with about 3 to about 5 mL of breast milk or infant formula powder and then the probiotic, such as Bifidobacterium, is administered to the subject. The probiotic composition, such as a Bifidobacterium composition, can be mixed by any suitable means, and suitable means include simply stirring the composition in a bowl with the medium (e.g., infant formula powder, breast milk, water) (or any other suitable means for obtaining a mixture). The composition mixed with infant formula powder or breast milk can then be fed to the subject by any suitable means. Suitable means of feeding include the use of a feeding syringe, spoon, or bottle. The probiotic, such as Bifidobacterium, can be administered before feeding the subject when the subject is more likely to be hungry, which is thought to increase the likelihood of consuming the entire dose.

[0089] The dosage and administration frequency can be selected as desired. In some embodiments, a second composition comprising a probiotic, such as Bifidobacterium, is administered once a day, and the once-a-day dosage can contain from about 5 billion to 15 billion or about 8 billion CFU. It is also contemplated to divide the desired total dosage into smaller dosages. Examples can include several smaller dosages throughout the day (e.g., 2, 3, 4, or 5 times a day).

[0090] The total dosage administered per day can range from about 1 million, 500 million, 1 billion, 2 billion, 3 billion, 4 billion, 5 billion, 6 billion, 7 billion, 8 billion, 9 billion, 10 billion, or 12 billion to about 8 billion, 9 billion, 10 billion, 20 billion, 30 billion, 40 billion, 50 billion, 60 billion, 70 billion, 80 billion, 90 billion, 100 billion, 200 billion, 250 billion, or 500 billion colony forming units (CFU) of a probiotic, such as Bifidobacterium. The total dosage administered per day can range from about 5 billion to about 15 billion CFU or about 8 billion CFU. Such total dosage values can be administered in one dosage.

[0091] A second composition comprising a probiotic, such as Bifidobacterium, can be administered starting within about 30 days after the subject's birth, more specifically within about 28 days, 21 days, 14 days, or 7 days. When initiated, the second composition comprising a probiotic, such as Bifidobacterium, can be continuously administered until the 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th week after the subject's birth, or until the 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, or 12th month after the subject's birth, or at least until before the introduction of solid foods. Administration of the second composition can continue until the desired gut microbiota is established. The subject can receive 1, 2, 3, 4, 5, or more administrations of the second composition to facilitate the establishment of the desired microbiota.

[0092] In some embodiments, the second composition is first administered within the first 14 days after the birth of the subject. In some embodiments, the second composition is administered over at least 12 weeks.

[0093] Step (c) of the method described in this application relates to the early introduction of multiple food allergens. Recent randomized controlled trials on the early introduction of highly allergenic foods have shown a reduced correlation in the incidence of food allergies.

[0094] According to embodiments of this application, during the exposure phase, food proteins representing major food allergens are introduced one by one in a stepwise increasing dose. Additional food allergens are added over a period of several days. During the maintenance phase, all maintenance amounts of the relevant food allergens are administered. These continue daily until a typical dietary diversity is achieved from the regular consumption of solid foods. In some embodiments, the administration of one or more food allergens i. administering to the subject a first food allergen at an exposure dose for the first food allergen over one or more days; ii. then administering to the subject the first food allergen at a maintenance dose for the first food allergen over several days; iii. then administering to the subject the first food allergen at a maintenance dose and a second food allergen at an exposure dose for the second food allergen over one or more days; iv. then administering both the first food allergen and the second food allergen at a maintenance dose for each allergen over several days.

[0095] In some embodiments, the exposure dose can optionally be gradually increased.

[0096] In some embodiments, the exposure dose of the first food allergen and the exposure dose of the second food allergen are each lower than the maintenance dose of the first food allergen and the maintenance dose of the second food allergen, respectively.

[0097] The "exposure" phase optionally includes a gradual increase in the amount of food allergen and the sequential introduction of new food allergens. When each maintenance level is achieved, continuation at these levels is done via daily administration during the "maintenance" phase.

[0098] In some embodiments, the method further includes continuing the maintenance dosages of the first food allergen and the second food allergen until the pre-measured dosage for each of the food allergens is completely consumed.

[0099] In some embodiments, the maintenance dosage is continued for several months until the subject regularly consumes as part of the subject's diet a food containing the first food allergen and the second food allergen.

[0100] In some embodiments, the method v. administering to the subject a third food allergen over one or more days at an exposure dosage for the third food allergen, and vi. thereafter, administering to the subject the first food allergen, the second food allergen, and the third food allergen over several days at a maintenance dosage for each of the allergens.

[0101] In certain embodiments, the method further includes continuing the maintenance dosages of the first food allergen, the second food allergen, and the third food allergen until the pre-measured dosage for each of the food allergens is consumed.

[0102] In some embodiments, the pre-measured dosage for each of the first food allergen, the second food allergen, and the third food allergen is consumed over 12 days.

[0103] In certain embodiments, administration of one or more food allergens begins within about 2 to 6 months after the subject's birth, e.g., within 2, 3, 4, 5, or 6 months.

[0104] In some embodiments, the first food allergen, the second food allergen, and the third food allergen are each independently selected from the group consisting of milk, eggs, peanuts, wheat, soybeans, sesame, fish, crustaceans, and nuts, and preferably are milk, eggs, and peanuts, respectively.

[0105] One or more food allergens can be in the form of a powder, a protein powder. The protein powder can be formulated to be easily suspended in breast milk or infant formula, and can have a particle size (e.g., less than about 200 microns) that easily passes through the nipple of a typical baby bottle. One or more food allergens can be provided in the form of a kit, the kit including an outer container (box, bag, pouch, can), the outer container having individually packaged single-use portions that are added by the user to infant formula or breast milk. Alternatively, one or more food allergens can be provided as already mixed with infant formula. For example, the infant formula can be provided in a step kit, the infant formula progressing through different formulations that introduce various allergens and then raise their levels until reaching a final maintenance infant formula, and then this maintenance infant formula can be continuously given to the infant over a period of time. In addition to the step kit, an infant formula containing multiple food allergens at their maintenance levels in their maintenance doses can be provided.

[0106] In some embodiments, a pre-measured dose of a food allergen is mixed into breast milk, a nutritional supplement, or food and then administered to the subject.

[0107] In some embodiments, a pre-measured dose of a food allergen is in the form of a powder.

[0108] In some embodiments, the exposure dose of each food allergen is about 0.01 - 0.3 grams, and the maintenance dose of each food allergen is about 0.05 - 1 gram.

[0109] In some embodiments, the first food allergen comprises milk, the exposure dose of the first food allergen is about 0.2 grams of milk protein, and the maintenance dose of the first food allergen is about 0.4 grams of milk protein.

[0110] In some embodiments, the second food allergen comprises eggs, the exposure dose of the second food allergen is about 0.03 grams of egg protein, and the maintenance dose of the second food allergen is about 0.1 grams of egg protein.

[0111] In some embodiments, the third food allergen comprises peanuts, the exposure dose of the third food allergen is about 0.1 grams of peanut protein, and the maintenance dose of the third food allergen is about 0.4 grams of peanut protein.

[0112] The timing of administration in each of steps (a), (b), and (c) can overlap. For example, ● Administration of the first composition and administration of a second composition comprising probiotics, such as Bifidobacterium, can be carried out in one period, ● Administration of the first composition and administration of one or more food allergens can be carried out in one period, and / or ● Administration of a second composition comprising probiotics, such as Bifidobacterium, and administration of one or more food allergens can be carried out in one period.

[0113] In another general aspect, the present application describes (a) a first composition comprising a skin barrier function composition, (b) a second composition comprising an effective amount of probiotics, such as Bifidobacterium cells, and (c) a kit or combination comprising pre-measured doses of at least two of one or more food allergens.

[0114] In some embodiments, the kit or combination is for use in treating pediatric atopic diseases or reducing their onset or occurrence in a subject in need thereof.

[0115] The first composition, the second composition, and the food allergen in the kit or combination can be those described in the present application, for example, in the above embodiments.

[0116] The above description represents exemplary embodiments of the present invention, but it will be understood that various additional, modifications, and substitutions can be made herein without departing from the spirit and scope of the present invention. In particular, it will be apparent to those skilled in the art that the present invention can be embodied in other specific forms, structures, arrangements, ratios, with other elements, materials, and components without departing from its spirit or essential characteristics. The present invention can be practiced with many modifications to the structure, arrangement, ratio, materials, and components, as well as alternative methods, that are specifically adapted to the particular environment and operating requirements without departing from the principles of the present invention. Accordingly, the embodiments of the present disclosure are to be considered in all respects as illustrative and not restrictive, and the scope of the present invention is indicated by the appended claims and is not limited to the above description. It will be understood that in the claims, the term "comprising / including" does not exclude the presence of other elements or steps. Further, a reference to the singular does not exclude a plurality. Terms such as "a", "an", "first", "second", etc. do not exclude a plurality.

[0117] Embodiments The present application also provides the following non-limiting embodiments.

[0118] Embodiment 1 is a method of treating pediatric atopic diseases or reducing their onset or occurrence in a subject in need thereof, comprising (a) Topically administering to a target skin area a first composition comprising a skin barrier function composition, wherein the administration of the first composition starts within about 7 days after the birth of the target, more specifically, within about 6 days, 5 days, 4 days, 3 days, 2 days, or 1 day after the birth of the target and continues until at least about 2 months after the birth of the target; (b) Orally administering to the target a second composition comprising an effective amount of probiotics, such as Bifidobacterium cells, wherein the administration of the second composition starts within about 30 days after the birth of the target, more specifically, within about 28 days, 21 days, 14 days, or 7 days after the birth of the target and optionally continues until at least before the introduction of solid foods; and (c) Orally administering to the target a pre-measured dose of one or more food allergens, wherein the administration of the one or more food allergens starts within about 1 - 8 months after the birth of the target, more specifically, within about 2 - 6 months after the birth of the target, including performing at least two of the above.

[0119] Embodiment 1a is the method according to Embodiment 1, wherein the method includes performing (a) and (b).

[0120] Embodiment 1a(1) is the method according to Embodiment 1a, wherein the administration of the first composition starts before the administration of the second composition.

[0121] Embodiment 1a(2) is the method according to Embodiment 1a, wherein the administration of the first composition starts after the administration of the second composition.

[0122] Embodiment 1b is the method according to Embodiment 1, wherein the method includes performing (a) and (c).

[0123] Embodiment 1c is the method according to Embodiment 1, wherein the method includes performing (b) and (c).

[0124] Embodiment 1d is the method according to Embodiment 1, wherein the method includes performing (a), (b), and (c).

[0125] Embodiment 1d(1) is the method according to Embodiment 1d, wherein the administration of the first composition starts before the administration of the second composition.

[0126] Embodiment 1d(2) is the method according to Embodiment 1d, wherein the administration of the first composition starts after the administration of the second composition.

[0127] Embodiment 1e is that the method (a) topically administering to a skin region of a subject a first composition comprising a skin barrier function composition, wherein the administration of the first composition starts within about 7 days after the birth of the subject, more specifically, within about 6 days, 5 days, 4 days, 3 days, 2 days, or 1 day after the birth of the subject and continues until at least about 2 months after the birth of the subject; (b) orally administering to the subject one or more food allergens at an exposure dose over one or more days, wherein the administration of the one or more food allergens starts within about 1 to 8 months after the birth of the subject, more specifically, within about 2 to 6 months after the birth of the subject; (c) orally administering to the subject one or more food allergens at a maintenance dose over one or more days after step (b), which is the method according to Embodiment 1.

[0128] Embodiment 1f is that the method (a) orally administering to the subject a second composition comprising an effective amount of probiotics, such as Bifidobacterium cells, wherein the administration of the second composition starts within about 30 days after the birth of the subject, more specifically, within about 28 days, 21 days, 14 days, or 7 days after the birth of the subject and optionally continues until at least before the introduction of solid food; (b) orally administering to the subject one or more food allergens at an exposure dose over one or more days, wherein the administration of the one or more food allergens starts within about 1 to 8 months after the birth of the subject, more specifically, within about 2 to 6 months after the birth of the subject; (c) After step (b), orally administering to the subject one or more food allergens at a maintenance dose over one or more days, the method according to embodiment 1.

[0129] Embodiment 1g is that the method is (a) Topically administering to the skin area of the subject a first composition comprising a skin barrier function composition, wherein the administration of the first composition starts within about 7 days after the birth of the subject, more specifically within about 6 days, 5 days, 4 days, 3 days, 2 days, or 1 day after the birth of the subject, and continues until at least about 2 months after the birth of the subject; (b) Orally administering to the subject a second composition comprising an effective amount of probiotics, such as Bifidobacterium cells, wherein the administration of the second composition starts within about 30 days after the birth of the subject, more specifically within about 28 days, 21 days, 14 days, or 7 days after the birth of the subject, and optionally continues until at least before the introduction of solid foods, the method according to embodiment 1.

[0130] Embodiment 1h is that the method is (a) Topically administering to the skin area of the subject a first composition comprising a skin barrier function composition, wherein the administration of the first composition starts within about 7 days after the birth of the subject, more specifically within about 6 days, 5 days, 4 days, 3 days, 2 days, or 1 day after the birth of the subject, and continues until at least about 2 months after the birth of the subject; (b) Orally administering to the subject a second composition comprising an effective amount of probiotics, such as Bifidobacterium cells, wherein the administration of the second composition starts within about 30 days after the birth of the subject, more specifically within about 28 days, 21 days, 14 days, or 7 days after the birth of the subject, and optionally continues until at least before the introduction of solid foods; (c) Orally administering to the subject one or more food allergens at an exposure dose over one or more days, wherein the administration of the one or more food allergens starts within about 1 - 8 months after the birth of the subject, more specifically within about 2 - 6 months after the birth of the subject; (d) After step (c), orally administering to the subject one or more food allergens at a maintenance dose for one or more days, which is the method according to Embodiment 1.

[0131] Embodiment 2 is the method according to any one of Embodiments 1 to 1b, 1d to 1e, and 1g to 1h, wherein the first composition is administered at least once a day.

[0132] Embodiment 2a is the method according to any one of Embodiments 1 to 1b, 1d to 1e, and 1g to 2, wherein the first composition is administered at least twice a day.

[0133] Embodiment 2b is the method according to any one of Embodiments 1 to 1b, 1d to 1e, and 1g to 2a, wherein the administration of the first composition starts within about 2 days after the birth of the subject.

[0134] Embodiment 3 is the method according to any one of Embodiments 1 to 1b, 1d to 1e, and 1g to 2b, wherein the first composition is administered to the whole body skin of the subject.

[0135] Embodiment 3a is the method according to any one of Embodiments 1 to 1b, 1b to 1e, and 1g to 3, wherein the first composition is formulated in a dosage form selected from the group consisting of balm, cream, lotion, emulsion, serum, ointment, and paste.

[0136] Embodiment 4 is the method according to any one of Embodiments 1 to 1b, 1d to 1e, and 1g to 3a, wherein the first composition comprises one or more components selected from the group consisting of glycerin, water, cetearyl alcohol, isocetyl alcohol, dimethicone, cetyl alcohol, emblica fruit powder, emblica fruit extract, emblica fruit oil, caprylic / capric triglyceride, ceramide 3, ethylhexylglycerin, p-anisic acid, sodium cetearyl sulfate, palmitic acid, stearic acid, sodium sulfate, sodium chloride, citric acid, dipotassium phosphate, potassium phosphate, sodium hydroxide, tocopherol, benzyl alcohol, benzoic acid, and potassium sorbate, and a carrier.

[0137] Embodiment 4a is the method according to any one of Embodiments 1 to 1b, 1d to 1e, and 1d to 3a, wherein the first composition comprises two or more components selected from the group consisting of glycerin, water, cetearyl alcohol, isocetyl alcohol, dimethicone, cetyl alcohol, emblica fruit powder, emblica fruit extract, emblica fruit oil, caprylic / capric triglyceride, ceramide 3, ethylhexylglycerin, p-anisic acid, sodium cetearyl sulfate, palmitic acid, stearic acid, sodium sulfate, sodium chloride, citric acid, dipotassium phosphate, potassium phosphate, sodium hydroxide, tocopherol, benzyl alcohol, benzoic acid, and potassium sorbate, and a carrier.

[0138] Embodiment 4b is the method according to any one of Embodiments 1-1b, 1d-1e, and 1d-3a, wherein the first composition comprises three or more components selected from the group consisting of glycerin, water, cetearyl alcohol, isocetyl alcohol, dimethicone, cetyl alcohol, emu grain powder, emu grain extract, emu grain oil, caprylic / capric triglyceride, ceramide 3, ethylhexylglycerin, p-anisic acid, sodium cetearyl sulfate, palmitic acid, stearic acid, sodium sulfate, sodium chloride, citric acid, dipotassium phosphate, potassium phosphate, sodium hydroxide, tocopherol, benzyl alcohol, benzoic acid, and potassium sorbate, and a carrier.

[0139] Embodiment 4c is the method according to any one of Embodiments 1-1b, 1d-1e, and 1d-3a, wherein the first composition comprises a softening agent, and more specifically, the first composition further comprises colloidal oatmeal, ceramide, and distearyldimonium chloride.

[0140] Embodiment 4d is that the first composition comprises the following components in the amounts described below: a. Caprylic / capric triglyceride, preferably from about 0.0% to about 1.0%, more preferably from about 0.005% to about 1.0%; b. Citric acid, preferably from about 0.0% to about 0.1%, more preferably from about 0.005% to about 0.1%; c. Benzoic acid, preferably from about 0.0% to about 2.0%, more preferably from about 0.1% to about 2.0%; d. Potassium phosphate, preferably from about 0.0% to about 2.0%, more preferably from about 0.05% to about 2.0%; e. Dimethicone, preferably from about 0.0% to about 10.0%, more preferably from about 1.0% to about 10.0%; f. Stearic acid and palmitic acid, preferably from about 0.0% to about 2.0%, more preferably from about 0.1% to about 2.0%; g. Isocetyl alcohol, preferably from about 0.0% to about 10.0%, more preferably from about 1.0% to about 10.0%; h. Preferably about 0.0% to about 2.0%, more preferably about 0.1% to about 2.0% of emmer (Triticum dicoccum) grain flour, i. Preferably about 0.0% to about 0.1%, more preferably about 0.005% to about 0.1% of ceramide 3, j. Preferably about 0.0% to about 2.0%, more preferably about 0.1% to about 2.0% of ethylhexylglycerin, k. Preferably about 0.0% to about 1.0%, more preferably about 0.005% to about 1.0% of emmer (Triticum dicoccum) grain oil, l. Preferably about 0.0% to about 1.0%, more preferably about 0.005% to about 1.0% of an emmer (Triticum dicoccum) grain extract containing glycerin, potassium sorbate, and water, m. Preferably about 15.0% to about 40.0%, more preferably about 20.0% to about 40.0% of water, n. Preferably about 20.0% to about 50.0%, more preferably about 30.0% to about 50.0% of glycerin, o. Preferably about 0.0% to about 2.0%, more preferably about 0.1% to about 2.0% of sodium cetearyl sulfate, p. Preferably about 0.0% to about 2.0%, more preferably about 0.1% to about 2.0% of dipotassium phosphate, q. Preferably about 0.0% to about 1.0%, more preferably about 0.005% to about 1.0% of sodium hydroxide, r. Preferably about 0.0% to about 10.0%, more preferably about 1.0% to about 10.0% of cetyl alcohol, s. Preferably about 0.0% to about 10.0%, more preferably about 1.0% to about 10.0% of cetearyl alcohol, t. Preferably about 0.0% to about 2.0%, more preferably about 0.1% to about 2.0% of benzyl alcohol, and / or u. Preferably about 0.0% to about 2.0%, more preferably about 0.1% to about 2.0% of p - anisic acid, and is a method according to any one of Embodiments 1 - 1b, 1d - 1e, and 1d - 3a, containing one or more of the above.

[0141] Embodiment 5 is the method according to any one of Embodiments 1 to 1a, 1c to 1d, and 1f to 4d, wherein the probiotics include, but are not limited to, bacterial strains selected from the group consisting of Lactobacillus, Lactobacillus casei, and Bifidobacterium.

[0142] In Embodiment 5-1, the Bifidobacterium in the second composition is Bifidobacterium longum, Bifidobacterium breve, Bifidobacterium bifidum, Bifidobacterium pseudocatenulatum, Bifidobacterium globosum, Bifidobacterium adolescentis, Bifidobacterium mucosum, Bifidobacterium longum subsp. infantis, Bifidobacterium pseudolongum, Bifidobacterium dentium, Bifidobacterium catenulatum, Bifidobacterium sp002742445, Bifidobacterium callitrichos, Bifidobacterium scardovii, Bifidobacterium tissieri, Bifidobacterium subtile, Bifidobacterium gallinarum, Bifidobacterium choerinum, Bifidobacterium angulatum, Bifidobacterium primatum, Bifidobacterium myosotis, Bifidobacterium mongoliense, Bifidobacterium merycicum, Bifidobacterium ruminantium, Bifidobacterium stercoricanum, Bifidobacterium scariigerum, Bifidobacterium sagguinii, Bifidobacterium pullorum, Bifidobacterium faecale, Bifidobacterium ermlis, Bifidobacterium kunikii, Bifidobacterium callitrichos_A, Bifidobacterium viavati, Bifidobacterium anseris, Bifidobacterium vansinderenii, Bifidobacterium sp900551485, Bifidobacterium sp003952945, Bifidobacterium sp003952025, B.The method according to embodiment 5, selected from the group consisting of sp003952005, Bifidobacterium simiarum, Bifidobacterium pseudolongum_C, Bifidobacterium parmense, Bifidobacterium margarecisii, Bifidobacterium kashiwanohaensis_A, Bifidobacterium italicum, Bifidobacterium imperatoris, Bifidobacterium chrisetidis, Bifidobacterium caturlarum, Bifidobacterium karitritidarum, Bifidobacterium animalis, Bifidobacterium aesculapii, and combinations thereof.

[0143] Embodiment 5a is the method according to embodiment 5 or 5-1, wherein the Bifidobacterium is selected from the group consisting of Bifidobacterium longum, Bifidobacterium breve, Bifidobacterium kashiwanohaensis, and combinations thereof.

[0144] Embodiment 5b is the method according to any one of embodiments 5 to 5a, wherein the Bifidobacterium is Bifidobacterium longum, preferably a subspecies of Bifidobacterium longum selected from the group consisting of longum, suis, and infantis.

[0145] Embodiment 5c is the method according to any one of embodiments 5 to 5b, wherein the Bifidobacterium cells are Bifidobacterium infantis cells.

[0146] Embodiment 5d is the method according to embodiment 5c, wherein the Bifidobacterium infantis comprises strain EVC001.

[0147] Embodiment 6 is the method according to any one of embodiments 1 to 1a, 1c to 1d, and 1f to 5d, wherein the second composition comprises from about 100 million to about 100 billion, more specifically from about 5 billion to about 15 billion colony forming units (CFU) of Bifidobacterium infantis.

[0148] Embodiment 6a is the method according to any one of Embodiments 1-1a, 1c-1d, and 1f-6, wherein the second composition comprises about 8 billion colony forming units (CFU) of Bifidobacterium infantis.

[0149] Embodiment 7 is the method according to any one of Embodiments 1-1a and 1c-6a, wherein the second composition is administered at least once a day.

[0150] Embodiment 7a is the method according to any one of Embodiments 1-1a, 1c-1d, and 1f-7, wherein administration of the second composition begins within 14 days after birth of the subject.

[0151] Embodiment 7b is the method according to any one of Embodiments 1-1a, 1c-1d, and 1f-7a, wherein administration of the second composition continues for at least 12 weeks.

[0152] Embodiment 7c is the method according to any one of Embodiments 1-1a, 1c-1d, and 1f-7b, wherein administration of the second composition continues until a desired gut microbiota is established.

[0153] Embodiment 7d is the method according to any one of Embodiments 1-1a, 1c-1d, and 1f-7c, wherein the subject receives 1, 2, 3, 4, 5, or more administrations of the second composition.

[0154] Embodiment 8 is the method according to any one of Embodiments 1-7d, wherein the subject is breastfed or is breastfed by a nutritional supplement comprising one or more human milk oligosaccharides or prebiotics.

[0155] Embodiment 8a is the method according to any one of Embodiments 1-8, wherein the subject is breastfed only.

[0156] Embodiment 8b is the method according to any one of Embodiments 1 to 8a, wherein the nutritional supplement comprises powdered milk for infants.

[0157] Embodiment 8c is the method according to Embodiment 8, wherein the prebiotics are other oligosaccharides, polysaccharides, or fibers.

[0158] Embodiment 8d is the method according to Embodiment 8, wherein the nutritional supplement is powdered milk for infants.

[0159] Embodiment 9 is the method according to any one of Embodiments 1 to 1a, 1c to 1d, and 1f to 8d, wherein Bifidobacterium is mixed in breast milk and then a second composition is administered to the subject.

[0160] Embodiment 9a is the method according to any one of Embodiments 1 to 1a, 1c to 1d, and 1f to 8d, wherein Bifidobacterium is mixed in a nutritional supplement, such as powdered milk for infants, and then a second composition is administered to the subject.

[0161] Embodiment 9b is the method according to any one of Embodiments 1 to 1a, 1c to 1d, and 1f to 8d, wherein Bifidobacterium is mixed with about 3 to about 5 mL of breast milk, powdered milk for infants, or water, and then a second composition is administered to the subject.

[0162] Embodiment 10 is the method according to any one of Embodiments 1 to 1a, 1c to 1d, and 1f to 9b, wherein Bifidobacterium is in powder form.

[0163] Embodiment 10a is the method according to Embodiment 10, wherein Bifidobacterium is in powder form mixed with lactose.

[0164] Embodiment 10b is the method according to any one of Embodiments 1 to 1a, 1c to 1d, and 1f to 10a, wherein the second composition is not naturally occurring breast milk.

[0165] Embodiment 11 is that the administration of one or more food allergens i. administering to the subject a first food allergen at an exposure dose for the first food allergen over one or more days; ii. then administering to the subject the first food allergen at a maintenance dose for the first food allergen over several days; iii. then administering to the subject the first food allergen at a maintenance dose and a second food allergen at an exposure dose for the second food allergen over one or more days; iv. then administering both the first food allergen and the second food allergen at a maintenance dose for each food allergen over several days, and includes.

[0166] Embodiment 11a is the method according to Embodiment 11, wherein the exposure dose optionally increases gradually.

[0167] Embodiment 11b is the method according to Embodiment 11 or 11a, wherein the exposure dose of the first food allergen and the exposure dose of the second food allergen are each lower than the maintenance dose of the first food allergen and the maintenance dose of the second food allergen, respectively.

[0168] Embodiment 11c is the method according to any one of Embodiments 11 to 11b, further comprising continuing the maintenance doses of the first food allergen and the second food allergen until the pre-measured doses for each of the food allergens are completely consumed.

[0169] Embodiment 11d is the method according to any one of Embodiments 11 to 11c, wherein the maintenance dose is continued for several months until the subject regularly consumes a food containing the first food allergen and the second food allergen as part of the subject's diet.

[0170] Embodiment 12 is that the method administering to the subject a third food allergen at an exposure dose for the third food allergen over one or more days; vi. further comprising, after that, administering to the subject the first food allergen, the second food allergen, and the third food allergen at a maintenance dose for each of the food allergens over multiple days, the method according to any one of embodiments 11 to 11d.

[0171] Embodiment 12a is the method according to embodiment 12, further comprising continuing the maintenance doses of the first food allergen, the second food allergen, and the third food allergen until the pre-measured dose for each of the food allergens is consumed.

[0172] Embodiment 12b is the method according to embodiment 12 or 12a, wherein the pre-measured dose for each of the first food allergen, the second food allergen, and the third food allergen is consumed over 12 days.

[0173] Embodiment 13 is the method according to any one of embodiments 1, 1b to 1f, and 1h to 12b, wherein the administration of one or more food allergens starts within about 2 to 6 months after the subject's birth.

[0174] Embodiment 14 is the method according to any one of embodiments 1, 1b to 1f, and 1h to 12b, wherein the first food allergen and the second food allergen are each independently selected from the group consisting of milk, eggs, peanuts, wheat, soybeans, sesame, fish, crustaceans, and nuts.

[0175] Embodiment 14a is the method according to embodiment 14, wherein the first food allergen is milk.

[0176] Embodiment 14b is the method according to embodiment 14 or 14a, wherein the second food allergen is eggs.

[0177] Embodiment 15 is the method according to any one of Embodiments 1, 1b to 1f, and 1h to 14b, wherein the third food allergen is selected from the group consisting of milk, eggs, peanuts, wheat, soybeans, sesame seeds, fish, crustaceans, and nuts.

[0178] Embodiment 15a is the method according to Embodiment 15, wherein the third food allergen is peanut.

[0179] Embodiment 16 is the method according to any one of Embodiments 1, 1b to 1f, and 1h to 15a, wherein a pre-measured dose of the food allergen is mixed into breast milk, a nutritional supplement, or food, and then the allergen is administered to the subject.

[0180] Embodiment 17 is the method according to any one of Embodiments 1, 1b to 1f, and 1h to 16, wherein the pre-measured dose of the food allergen is in powder form.

[0181] Embodiment 17a is the method according to Embodiment 17, wherein the allergen consists of particles having a particle size of less than about 200 microns.

[0182] Embodiment 18 is the method according to any one of Embodiments 1, 1b to 1f, and 1h to 17a, wherein the exposure dose of each allergen is about 0.01 to 0.3 grams, and the maintenance dose of each food allergen is about 0.05 to 1 gram.

[0183] Embodiment 18a is the method according to any one of Embodiments 1, 1b to 1f, and 1h to 18, wherein the first food allergen contains milk, the exposure dose of the first food allergen is about 0.2 grams of milk protein, and the maintenance dose of the first food allergen is about 0.4 grams of milk protein.

[0184] Embodiment 18b is the method according to any one of Embodiments 1, 1b - 1f, and 1h - 18a, wherein the second food allergen contains eggs, the exposure dose of the second food allergen is about 0.03 grams of egg protein, and the maintenance dose of the second food allergen is about 0.1 grams of egg protein.

[0185] Embodiment 18c is the method according to any one of Embodiments 1, 1b - 1f, and 1h - 18b, wherein the third food allergen contains peanuts, the exposure dose of the third food allergen is about 0.1 grams of peanut protein, and the maintenance dose of the third food allergen is about 0.4 grams of peanut protein.

[0186] Embodiment 19 is a first composition for use in a method of performing it in a subject in need of treatment of pediatric atopic diseases, such as atopic dermatitis, or reduction of its onset or occurrence, the method comprising (a) topically administering to a skin area of the subject a first composition comprising a skin barrier function composition, wherein the administration of the first composition starts within about 7 days after the subject's birth, more specifically within about 6 days, 5 days, 4 days, 3 days, 2 days, or 1 day after the subject's birth and continues until at least about 2 months after the subject's birth; (b) orally administering to the subject a second composition comprising an effective amount of probiotics, such as Bifidobacterium cells, wherein the administration of the second composition starts within about 30 days after the subject's birth, more specifically within about 28 days, 21 days, 14 days, or 7 days after the subject's birth and optionally continues until at least before the introduction of solid foods; and (c) orally administering to the subject a pre - measured dose of one or more food allergens, wherein the administration of the one or more food allergens starts within about 1 - 8 months after the subject's birth, more specifically within about 2 - 6 months after the subject's birth, and the first composition is described as including performing at least two of the above.

[0187] Embodiment 19a is the first composition for use according to Embodiment 19, wherein the first composition is administered at least once a day.

[0188] Embodiment 19b is the first composition for use according to Embodiment 19 or 19a, wherein the first composition is administered at least twice a day.

[0189] Embodiment 19c is the first composition for use according to any one of Embodiments 19 to 19b, wherein the administration of the first composition starts within about 2 days after the birth of the subject.

[0190] Embodiment 19d is the first composition for use according to any one of Embodiments 19 to 19c, wherein the first composition is administered to the whole body skin of the subject.

[0191] Embodiment 19e is the first composition for use according to any one of Embodiments 19 to 19d, wherein the first composition is formulated in a dosage form selected from the group consisting of a balm, a cream, a lotion, an emulsion, a serum, an ointment, and a paste.

[0192] Embodiment 19f is the first composition for use according to any one of Embodiments 19 to 19e, wherein the first composition comprises one or more components selected from the group consisting of glycerin, water, cetearyl alcohol, isocetyl alcohol, dimethicone, cetyl alcohol, emu grain powder, emu grain extract, emu grain oil, caprylic / capric triglyceride, ceramide 3, ethylhexylglycerin, p-anisic acid, sodium cetearyl sulfate, palmitic acid, stearic acid, sodium sulfate, sodium chloride, citric acid, dipotassium phosphate, potassium phosphate, sodium hydroxide, tocopherol, benzyl alcohol, benzoic acid, and potassium sorbate, and a carrier.

[0193] Embodiment 19g is the first composition for use according to any one of Embodiments 19 to 19f, comprising two or more components selected from the group consisting of glycerin, water, cetearyl alcohol, isocetyl alcohol, dimethicone, cetyl alcohol, embu grain powder, embu grain extract, embu grain oil, caprylic / capric triglyceride, ceramide 3, ethylhexylglycerin, p-anisic acid, sodium cetearyl sulfate, palmitic acid, stearic acid, sodium sulfate, sodium chloride, citric acid, dipotassium phosphate, potassium phosphate, sodium hydroxide, tocopherol, benzyl alcohol, benzoic acid, and potassium sorbate, and a carrier.

[0194] Embodiment 19h is the first composition for use according to any one of Embodiments 19 to 19b, comprising three or more components selected from the group consisting of glycerin, water, cetearyl alcohol, isocetyl alcohol, dimethicone, cetyl alcohol, embu grain powder, embu grain extract, embu grain oil, caprylic / capric triglyceride, ceramide 3, ethylhexylglycerin, p-anisic acid, sodium cetearyl sulfate, palmitic acid, stearic acid, sodium sulfate, sodium chloride, citric acid, dipotassium phosphate, potassium phosphate, sodium hydroxide, tocopherol, benzyl alcohol, benzoic acid, and potassium sorbate, and a carrier.

[0195] Embodiment 19i is the first composition for use according to any one of Embodiments 19 to 19b, wherein the first composition contains a softening agent, and more specifically, the second composition further contains colloidal oatmeal, ceramide, and distearyldimonium chloride.

[0196] Embodiment 19j is such that the first composition contains the following components in the amounts described below: a. Caprylic / capric triglyceride, preferably in an amount of about 0.0% to about 1.0%, more preferably about 0.005% to about 1.0%. b. Preferably about 0.0% to about 0.1%, more preferably about 0.005% to about 0.1% of citric acid, c. Preferably about 0.0% to about 2.0%, more preferably about 0.1% to about 2.0% of benzoic acid, d. Preferably about 0.0% to about 2.0%, more preferably about 0.05% to about 2.0% of potassium phosphate, e. Preferably about 0.0% to about 10.0%, more preferably about 1.0% to about 10.0% of dimethicone, f. Preferably about 0.0% to about 2.0%, more preferably about 0.1% to about 2.0% of stearic acid, palmitic acid, g. Preferably about 0.0% to about 10.0%, more preferably about 1.0% to about 10.0% of isocetyl alcohol, h. Preferably about 0.0% to about 2.0%, more preferably about 0.1% to about 2.0% of emmer (Triticum dicoccum) grain flour, i. Preferably about 0.0% to about 0.1%, more preferably about 0.005% to about 0.1% of ceramide 3, j. Preferably about 0.0% to about 2.0%, more preferably about 0.1% to about 2.0% of ethylhexylglycerin, k. Preferably about 0.0% to about 1.0%, more preferably about 0.005% to about 1.0% of emmer (Triticum dicoccum) grain oil, l. Preferably about 0.0% to about 1.0%, more preferably about 0.005% to about 1.0% of an emmer (Triticum dicoccum) grain extract containing glycerin, potassium sorbate, and water, m. Preferably about 15.0% to about 40.0%, more preferably about 20.0% to about 40.0% of water, n. Preferably about 20.0% to about 50.0%, more preferably about 30.0% to about 50.0% of glycerin, o. Preferably about 0.0% to about 2.0%, more preferably about 0.1% to about 2.0% of sodium cetylesulfate, p. Preferably about 0.0% to about 2.0%, more preferably about 0.1% to about 2.0% of dipotassium phosphate, q. Preferably from about 0.0% to about 1.0%, more preferably from about 0.005% to about 1.0% of sodium hydroxide, r. Preferably from about 0.0% to about 10.0%, more preferably from about 1.0% to about 10.0% of cetyl alcohol, s. Preferably from about 0.0% to about 10.0%, more preferably from about 1.0% to about 10.0% of ceteareth alcohol, t. Preferably from about 0.0% to about 2.0%, more preferably from about 0.1% to about 2.0% of benzyl alcohol, and / or u. Preferably from about 0.0% to about 2.0%, more preferably from about 0.1% to about 2.0% of p-anisic acid, a first composition for use in any one of embodiments 19 to 19b, comprising one or more of the foregoing.

[0197] Embodiment 20 is a second composition comprising an effective amount of probiotics, such as Bifidobacterium cells, for use in a method of treating, or reducing the onset or occurrence of, pediatric atopic diseases, such as atopic dermatitis, in a subject in need thereof, the method comprising: (a) topically administering to a skin area of the subject a first composition comprising a skin barrier function composition, wherein the administration of the first composition begins within about 7 days after birth of the subject, more specifically within about 6 days, 5 days, 4 days, 3 days, 2 days, or 1 day after birth of the subject and continues until at least about 2 months after birth of the subject; (b) orally administering to the subject a second composition, wherein the administration of the second composition begins within about 30 days after birth of the subject, more specifically within about 28 days, 21 days, 14 days, or 7 days after birth of the subject and optionally continues until before the introduction of at least solid foods; and (c) orally administering to the subject a pre-measured dose of one or more food allergens, wherein the administration of the one or more food allergens begins within about 1 to 8 months after birth of the subject, more specifically within about 2 to 6 months after birth of the subject, the second composition comprising performing at least two of the foregoing.

[0198] Embodiment 20a is a second composition for use according to Embodiment 20, wherein the probiotics include, but are not limited to, bacterial strains selected from the genus Lactobacillus, Lactobacillus casei, and Bifidobacterium.

[0199] Embodiment 20a-1 is such that the Bifidobacterium in the second composition is Bifidobacterium longum, Bifidobacterium breve, Bifidobacterium bifidum, Bifidobacterium pseudocatenulatum, Bifidobacterium globosum, Bifidobacterium adolescentis, Bifidobacterium mucosum, Bifidobacterium longum subsp. infantis, Bifidobacterium pseudolongum, Bifidobacterium dentium, Bifidobacterium catenulatum, Bifidobacterium sp002742445, Bifidobacterium caryophyllum, Bifidobacterium scardovii, Bifidobacterium tissieri, Bifidobacterium subtile, Bifidobacterium gallinarum, Bifidobacterium choerinum, Bifidobacterium angularum, Bifidobacterium primatum, Bifidobacterium myosotis, Bifidobacterium mongoliense, Bifidobacterium merycicum, Bifidobacterium ruminantium, Bifidobacterium stellenboschensis, Bifidobacterium scariola, Bifidobacterium saguini, Bifidobacterium pullorum, Bifidobacterium faecale, Bifidobacterium animalis subsp. lactis, Bifidobacterium kunikii, Bifidobacterium caryophyllum_A, Bifidobacterium viaducti, Bifidobacterium anseris, Bifidobacterium vansinderenii, Bifidobacterium sp900551485, Bifidobacterium sp003952945, Bifidobacterium sp003952025, Bifidobacterium sp003952025, Bifidobacterium simiae, Bifidobacterium pseudolongum subsp. globosum, Bifidobacterium palmae, Bifidobacterium margollesii, Bifidobacterium kashiwanohensis_A, Bifidobacterium italicum, Bifidobacterium imperatoris, Bifidobacterium christensenii, Bifidobacterium kashiwanohensis, Bifidobacterium caryolithram, Bifidobacterium animalis, Bifidobacterium aesculapii,The method according to embodiment 20 or 20a, selected from the group consisting of and combinations thereof.

[0200] Embodiment 20b is a second composition for use according to any one of embodiments 20 to 20a-1, wherein the Bifidobacterium is selected from the group consisting of Bifidobacterium longum, Bifidobacterium breve, Bifidobacterium kashiwanohensis, and combinations thereof.

[0201] Embodiment 20c is a second composition for use according to any one of embodiments 20 to 20b, wherein the Bifidobacterium is Bifidobacterium longum, preferably a subspecies of Bifidobacterium longum selected from the group consisting of longum, suis, and infantis.

[0202] Embodiment 20d is a second composition for use according to any one of embodiments 20 to 20c, wherein the Bifidobacterium cells are Bifidobacterium infantis cells.

[0203] Embodiment 20e is a second composition for use according to any one of embodiments 20 to 20d, wherein the Bifidobacterium infantis comprises strain EVC001.

[0204] Embodiment 20f is a second composition for use according to any one of embodiments 20 to 20e, wherein the second composition comprises from about 100 million to about 100 billion, more specifically from about 5 billion to about 15 billion colony forming units (CFU) of Bifidobacterium infantis.

[0205] Embodiment 20g is a second composition for use according to any one of embodiments 20 to 20f, wherein the second composition comprises about 8 billion colony forming units (CFU) of Bifidobacterium infantis.

[0206] Embodiment 20h is the second composition for use according to any one of Embodiments 20 to 20g, wherein the second composition is administered at least once a day.

[0207] Embodiment 20i is the second composition for use according to any one of Embodiments 20 to 20h, wherein administration of the second composition starts within 14 days after birth of the subject.

[0208] Embodiment 20j is the second composition for use according to any one of Embodiments 20 to 20i, wherein administration of the second composition continues for at least 12 weeks.

[0209] Embodiment 20k is the second composition for use according to any one of Embodiments 20 to 20j, wherein the subject is breastfed or is breastfed with a nutritional supplement containing one or more human milk oligosaccharides or prebiotics.

[0210] Embodiment 20k(1) is the second composition for use according to Embodiment 20k, wherein the prebiotic is another oligosaccharide, polysaccharide, or fiber.

[0211] Embodiment 20l is the second composition for use according to any one of Embodiments 20 to 20k, wherein the subject is breastfed only.

[0212] Embodiment 20m is the second composition for use according to any one of Embodiments 20 to 20l, wherein the nutritional supplement contains powdered milk for infants.

[0213] Embodiment 20n is the second composition for use according to any one of Embodiments 20 to 20m, wherein Bifidobacterium is mixed into breast milk and then the second composition is administered to the subject.

[0214] Embodiment 20o is the second composition for use according to any one of Embodiments 20 to 20n, wherein Bifidobacterium is mixed in a nutritional supplement, for example, in a powdered milk formula for infants, and then the second composition is administered to the subject.

[0215] Embodiment 20p is the second composition for use according to any one of Embodiments 20 to 20o, wherein Bifidobacterium is mixed with about 3 to about 5 mL of breast milk, powdered milk formula for infants, or water, and then the second composition is administered to the subject.

[0216] Embodiment 20q is the second composition for use according to any one of Embodiments 20 to 20p, wherein Bifidobacterium is in powder form.

[0217] Embodiment 20r is the second composition for use according to any one of Embodiments 20 to 20q, wherein Bifidobacterium is in powder form mixed with lactose.

[0218] Embodiment 20s is the second composition for use according to any one of Embodiments 20 to 20r, wherein the second composition is not naturally occurring breast milk.

[0219] Embodiment 21 is one or more food allergens in a pre-measured dose for use in a method of treating, reducing the onset or occurrence of, for example, atopic dermatitis in a subject in need thereof, the method comprising: (a) topically administering a first composition comprising a skin barrier function composition to a skin area of the subject, wherein the administration of the first composition starts within about 7 days after the birth of the subject, more specifically within about 6 days, 5 days, 4 days, 3 days, 2 days, or 1 day, and continues until at least about 2 months after the birth of the subject. (b) administering orally to the subject a second composition comprising an effective amount of a probiotic, such as Bifidobacterium cells, wherein the administration of the second composition begins within about 30 days after birth of the subject, more specifically within about 28 days, 21 days, 14 days, or 7 days, and optionally continues until at least before the introduction of solid food, and (c) administering orally to the subject a pre-measured dose of one or more food allergens, wherein the administration of the one or more food allergens begins within about 1 to 8 months after birth of the subject, more specifically within about 2 to 6 months, comprising administering at least two of:

[0220] Embodiment 21a is such that the administration of the one or more food allergens i. administering to the subject a first food allergen at an exposure dose for the first food allergen over one or more days; and ii. thereafter, administering to the subject the first food allergen at a maintenance dose for the first food allergen over multiple days; and iii. thereafter, administering to the subject the first food allergen at a maintenance dose and a second food allergen at an exposure dose for the second food allergen over one or more days; and iv. thereafter, administering both the first food allergen and the second food allergen at a maintenance dose for each food allergen over multiple days.

[0221] Embodiment 21b is one or more food allergens at a pre-measured dose for use according to Embodiment 21a, wherein the exposure dose optionally increases gradually.

[0222] Embodiment 21c is one or more food allergens at a pre-measured dose for use according to Embodiment 21a or 21b, wherein the exposure dose of the first food allergen and the exposure dose of the second food allergen are each lower than the maintenance dose of the first food allergen and the maintenance dose of the second food allergen, respectively.

[0223] Embodiment 21d is one or more food allergens at a pre-measured dose for use according to any one of Embodiments 21-21c, wherein the method further comprises continuing a maintenance dose of the first food allergen and the second food allergen until the pre-measured dose for each of the food allergens is completely consumed.

[0224] Embodiment 21e is one or more food allergens at a pre-measured dose for use according to any one of Embodiments 21-21d, wherein the maintenance dose is continued for several months until the subject regularly consumes a food containing the first food allergen and the second food allergen as part of the subject's diet.

[0225] Embodiment 21f is v. administering to the subject a third food allergen at an exposure dose for one or more days, and vi. thereafter, administering to the subject the first food allergen, the second food allergen, and the third food allergen at a maintenance dose for each of the food allergens for several days, one or more food allergens at a pre-measured dose for use according to any one of Embodiments 21-21e.

[0226] Embodiment 21g is one or more food allergens at a pre-measured dose for use according to any one of Embodiments 21-21f, wherein the method further comprises continuing a maintenance dose of the first food allergen, the second food allergen, and the third food allergen until the pre-measured dose for each of the food allergens is consumed.

[0227] Embodiment 21h is one or more food allergens at a pre-measured dose for use according to any one of Embodiments 21-21g, wherein the pre-measured dose for each of the first food allergen, the second food allergen, and the third food allergen is consumed over 12 days.

[0228] Embodiment 21i is one or more food allergens at a pre-measured dose for use as described in any one of Embodiments 21 to 21h, wherein the administration of one or more food allergens starts within about 2 to 6 months after the birth of the subject.

[0229] Embodiment 21j is one or more food allergens at a pre-measured dose for use as described in any one of Embodiments 21 to 21i, wherein the first food allergen and the second food allergen are each independently selected from the group consisting of milk, eggs, peanuts, wheat, soybeans, sesame, fish, crustaceans, and nuts.

[0230] Embodiment 21k is one or more food allergens at a pre-measured dose for use as described in any one of Embodiments 21 to 21j, wherein the first food allergen is milk.

[0231] Embodiment 21l is one or more food allergens at a pre-measured dose for use as described in any one of Embodiments 21 to 21k, wherein the second food allergen is eggs.

[0232] Embodiment 21m is one or more food allergens at a pre-measured dose for use as described in any one of Embodiments 21 to 21l, wherein the third food allergen is selected from the group consisting of milk, eggs, peanuts, wheat, soybeans, sesame, fish, crustaceans, and nuts.

[0233] Embodiment 21n is one or more food allergens at a pre-measured dose for use as described in any one of Embodiments 21 to 21m, wherein the third food allergen is peanuts.

[0234] Embodiment 21o is one or more food allergens at a pre-measured dose for use according to any one of Embodiments 21 to 21n, wherein the pre-measured dose of food allergen is mixed into breast milk, a nutritional supplement, or food, and then administered to the subject.

[0235] Embodiment 21p is one or more food allergens at a pre-measured dose for use according to any one of Embodiments 21 to 21o, wherein the pre-measured dose of food allergen is in powder form.

[0236] Embodiment 21q is one or more food allergens at a pre-measured dose for use according to any one of Embodiments 21 to 21p, wherein the food allergen consists of particles having a particle size of less than about 200 microns.

[0237] Embodiment 21r is one or more food allergens at a pre-measured dose for use according to any one of Embodiments 21 to 21c, wherein the exposure dose of each food allergen is about 0.01 to 0.3 grams, and the maintenance dose of each food allergen is about 0.05 to 1 gram.

[0238] Embodiment 21s is one or more food allergens at a pre-measured dose for use according to any one of Embodiments 21 to 21r, wherein the first food allergen contains milk, the exposure dose of the first food allergen is about 0.2 grams of milk protein, and the maintenance dose of the first food allergen is about 0.4 grams of milk protein.

[0239] Embodiment 21t is one or more food allergens at a pre-measured dose for use according to any one of Embodiments 21 to 21s, wherein the second food allergen contains eggs, the exposure dose of the second food allergen is about 0.03 grams of egg protein, and the maintenance dose of the second food allergen is about 0.1 grams of egg protein.

[0240] Embodiment 21o is one or more food allergens at a pre-measured dose for use according to any one of Embodiments 21 to 21t, wherein the third food allergen contains peanuts, the exposure dose of the third food allergen is about 0.1 gram of peanut protein, and the maintenance dose of the third food allergen is about 0.4 gram of peanut protein.

[0241] Embodiment 22 describes (a) a first composition comprising a skin barrier function composition, (b) a second composition comprising an effective amount of probiotics, such as Bifidobacterium cells, and (c) a kit or combination comprising at least two of one or more pre-measured doses of food allergens.

[0242] Embodiment 22a is the kit or combination according to Embodiment 22, which is for use in treating pediatric atopic diseases or reducing their onset or occurrence in a subject in need thereof.

[0243] Embodiment 22b is the kit or combination according to Embodiment 22 or 22a, wherein the first combination is the first combination according to any one of Embodiments 2 to 4d.

[0244] Embodiment 22c is the kit or combination according to any one of Embodiments 22 to 22b, wherein the second combination is the second combination according to any one of Embodiments 5 to 10b.

[0245] Embodiment 22d is the kit or combination according to any one of Embodiments 22 to 22c, wherein the food allergen is the food allergen according to any one of Embodiments 11 to 18c.

[0246] Embodiment 23 is any one of Embodiments 1 to 22d, wherein the probiotics include, but are not limited to, bacterial strains selected from the genus Lactobacillus, Lactobacillus casei, and Bifidobacterium.

[0247] Embodiment 23 is any one of Embodiments 1 to 23, wherein the probiotics include, but are not limited to, bacterial strains of Bifidobacterium infantis, Bifidobacterium longum (subspecies other than Bifidobacterium infantis), Bifidobacterium breve, Bifidobacterium catenulatum, Bifidobacterium adolescentis, Bifidobacterium animalis, Bifidobacterium gallicum, Bifidobacterium lactis, Bifidobacterium pseudocatenulatum, Bifidobacterium bifidum, Lactobacillus casei paracasei, Lactobacillus acidophilus, Lactobacillus johnsonii, Lactobacillus delbrueckii, Lactobacillus crispatus, Lactobacillus gasseri, Lactobacillus zeae, Lactobacillus casei, Lactobacillus rhamnosus, Lactiplantibacillus plantarum, Limosilactobacillus fermentum, Ligilactobacillus salivarius, or combinations thereof.

Example

[0248] Example 1: Short-term Topical Application for Prevention of Atopic Dermatitis (STOP AD), a randomized, unblinded, controlled clinical trial. This clinical trial research is designed to investigate the effect of short-term neonatal skin barrier protection using the following skin treatment regimens and compositions for the prevention of atopic dermatitis in high-risk infants. (See https: / / clinicaltrials.gov / ct2 / show / NCT03871998; ucc.ie / en / paediatrics / programmes / postgraduateprogrammes / phd-students / , and https: / / www.infantcentre.ie / research / research-studies / stop-ad / , and https: / / www.authorea.com / doi / full / 10.22541 / au.164940311.12725370 / v1, and Ni Chaoimh, et al., Parental compliance with an infant moisturization protocol in the first 2 months of life, Lad et al., Can more be done to implement translational weaning advise for new mothers, and Lad et al., Neonatal natural moisturizing factor concentrations in a high-risk cohort with parental history of atopy compared to a reference cohort, each presented at European Academy of Allergy and Clinical Immunology (EAACI) 2020).

[0249] High-risk infants were identified using a parental history of atopic disease and randomized to either the following skin treatment regimens and compositions or standard treatment as usual from immediately after recruitment in the hospital after birth (approximately 4 days) to 8 weeks of age. Both the intervention and standard treatment groups were advised to use a standardized bathing schedule over the first 2 months. ● Skin treatment regimens and compositions: Twice-daily whole-body application of AVEENO® Dermexa Fast & Long-Lasting Balm. This contains, in the pack, the following ingredients, glycerin, water, cetearyl alcohol, isocetyl alcohol, dimethicone, cetyl alcohol, oat kernel flour, oat kernel extract, oat kernel oil, caprylic / capric triglyceride, ceramide 3, ethylhexylglycerin, p-anisic acid, sodium cetearyl sulfate, palmitic acid, stearic acid, sodium sulfate, sodium chloride, citric acid, dipotassium phosphate, potassium phosphate, sodium hydroxide, tocopherol, benzyl alcohol, benzoic acid, and potassium sorbate. ● Control: Usual standard treatment without use of a moisturizer for the first two months.

[0250] Both groups received AVEENO® Baby Daily Care Gentle Wash. This contains, in the pack, the following ingredients, water, glycerin, cocamidopropyl betaine, sodium lauroamphoacetate, coconut alkyl glucoside, sodium chloride, hydroxypropyl starch phosphate, oat kernel flour, Aloe barbadensis leaf juice, Olea europaea leaf extract, Chamomilla recutita extract, Helianthus annuus seed oil, sarcosine, magnesium aspartate, potassium aspartate, polyquaternium-7, polysorbate 20, sodium cocooyl amino acids, acrylate / C10-30 alkyl acrylate crosspolymer, propylene glycol, citric acid, sodium hydroxide, tocopherol, tocopheryl acetate, sodium benzoate, potassium sorbate, sodium sulfite, parfum.

[0251] Infants with at least one parent with a positive history of atopic disease (AD, allergic rhinitis or asthma) were eligible for recruitment. Additional inclusion or exclusion criteria are shown below. ● Inclusion criteria: ○ Healthy full-term infants with a gestational age greater than 36 + 6 weeks. ○ At least one parent with self-reported atopic dermatitis, food allergy, allergic rhinitis, or asthma. ○ Do not require hospitalization in the neonatal unit. ● Exclusion criteria: ○ No family history of atopic disease. ○ Require hospitalization in the neonatal unit due to problems other than the establishment of normal breastfeeding. ○ Receiving oral or parenteral antibiotics. ○ Receiving phototherapy for hyperbilirubinemia. ○ Siblings including already recruited twins. ○ Other serious health problems (e.g., abdominal wall defect, congenital heart disease, etc.) or severe extensive skin conditions (e.g., collodion). ○ Any condition that makes the use of skin barrier protectants inappropriate or impossible (e.g., ankle clubfoot or developmental dysplasia of the hip requiring Pavlik harness or cast). ○ Participation in any other clinical trial of investigational medicinal products.

[0252] Within approximately 4 days of birth, the infants were randomized to either treatment with a skin treatment regimen and composition up to 2 months of age or routine standard skin care without a moisturizer. 260 infants participated in the study, including 120 in the intervention group and 140 in the control group.

[0253] The study had 6 visits during the first year of life, at 4 days after birth, and at 2, 4, and 8 weeks, and 6 and 12 months of age, including repeated measurements of weight, transepidermal water loss (TEWL), and Raman-derived natural moisturizing factor (NMF), and evaluated skin barrier function and structure in addition to monitoring skin health and breastfeeding. Questionnaires were filled out regarding infant health, bathing, breastfeeding, and skin care, and skin swabs were taken for microbiome and immune biomarker analysis.

[0254] The primary outcome of the study was the effect of the intervention on the incidence of atopic dermatitis at 12 months. The secondary outcomes included the effect of the intervention on the incidence of atopic dermatitis at 6 months, and the progression of TEWL and NMF values from 0 to 12 months.

[0255] Skin swabs were collected at baseline and again at 8 weeks and 12 months. Healthcare workers blinded to treatment allocation evaluated the presence (yes / no), degree, and severity of atopic dermatitis at 6 and 12 months. DNA samples were collected and tested for filaggrin loss-of-function mutations associated with the risk of atopic dermatitis.

[0256] Insights towards understanding Skin Function in Early Life (I-SEAL) included collecting skin microbiome and immune biomarkers within the larger intervention trial STOP AD to do the following. ● Investigate the longitudinal changes in the skin microbiome from birth to 12 months and its influence on the development of atopic dermatitis. ● Investigate the effect of the use of skin regimens and compositions in the first 2 months of life on the infant skin microbiota. ● Investigate the dynamics of immune biomarkers collected from the surface of infant skin in the first 12 months and their association with atopic dermatitis.

[0257] Results Recruitment / Retention A total of 3059 infants were screened for eligibility from April 2019 to November 2020, and 321 of them were randomized (161 to intervention and 160 to control). Baseline characteristics were balanced across groups (Table 1). There were 61 withdrawals (41 in the intervention and 20 in the control, a 19% decrease), and most (80%) occurred before the second-week visit. The mean (SD) age at randomization was 1.9 (0.9) days.

[0258]

Table 1

[0259] Protocol Adherence In the questionnaire, most parents in the IG reported applying the emollient at least once a day in the first 8 weeks. 2 weeks: 89%, 4 weeks: 91.7%, 8 weeks: 86.6% (Table 2). Application twice a day was reported by 63.3% at 2 weeks, 69.2% at 4 weeks, and 73.1% at 8 weeks. Of those in the IG (n = 114) who had questionnaires at all three time points, 89 (78.1%) reported daily emollient use at all three time points. Less than 20% of the CG reported using the emollient more than 4 days per week at any of the time points. 19% at 2 weeks, 17.5% at 4 weeks, and 13.5% at 8 weeks. Of those in the IG (n = 132) who had questionnaires at all three time points, 90 (68.2%) reported using the emollient less than 4 days per week at all three time points. There was no significant difference in the frequency of bathing between the groups over the intervention period.

[0260]

Table 2

[0261] Diaries for measuring adherence were returned by 95% (114 / 120) of the IG and 82.1% (115 / 140) of the CG. The mean (SD) age at which emollient use was initiated in the IG was 3.5 (1.5) days, and 41.2% (47 / 114) reported applying the emollient at least once on more than 90% (more than 6 days / week) of the recording days. A further 41.2% (47 / 114) reported emollient use for more than 75% (more than 5 days / week) of the recording days. 80 percent (92 / 115) of the CG applied the emollient on 43% or less (3 days / week or less) of the recording days.

[0262] There was no significant difference in the frequency of regular emollient use (more than 4 days a week) between the groups at 6 and 12 months (intervention vs. control at 6 months: 29.6% vs. 29.7%, p = 1.000, and at 12 months: 28.4% vs. 25.8%, p = 0.868).

[0263] Safety No family requested an emergency medical evaluation related to the study intervention. Skin infections reported by parents during the 8-week intervention period occurred in 5% (6 / 120) of the IG and 5.7% (8 / 140) of the CG. One IG infant developed a rash with a potential temporal relationship to the emollient and was advised to stop applying the emollient and withdrew from the study. Two suspected reactions to the study emollient were investigated and confirmed to be unrelated.

[0264] Primary outcome The cumulative incidence of AD at 12 months was 32.8% in the IG vs. 46.4% in the CG, p = 0.036 [Relative Risk (RR) (95% CI): 0.707 (0.516, 0.965)]. The point prevalence of AD at 12 months in children who met the UKWPDC at the time of assessment was 20.5% in the IG vs. 38.2% in the CG, p = 0.003 [RR (95% CI): 0.536 (0.354, 0.813)].

[0265] Secondary AD outcome The cumulative incidence of AD at 6 months was 18.3% in the IG vs. 36.4% in the CG, p = 0.002 [RR (95% CI): 0.503 (0.325, 0.779)]. The point prevalence at 6 months was 18.3% in the IG and 35.0% in the CG, p = 0.004 [RR (95% CI): 0.524 (0.337, 0813)], Table 3.

[0266]

Table 3

[0267] Time-to-event survival analysis using the Kaplan–Meier method demonstrated that IG maintained skin without AD for a longer period than CG in the first 12 months (p = 0.016, log-rank test, Figure 3). Among those with AD outcome data at 6 and 12 months (intervention n = 117, control n = 137), 7.7% of IG infants and 8.0% of CG infants were diagnosed by 6 months but no longer met the criteria at 12 months (p = 1.0). The incidence of AD onset between 6 and 12 months was 13.7% and 9.5% in IG and CG, respectively (p = 0.397), and 10.3% vs 29.2% met the criteria at both 6 and 12 months (p < 0.001) (see Supplementary Figure 1). SCORAD was completed for those who were 6 months or older at diagnosis (n = 55). There was no significant difference in the total SCORAD score at diagnosis between groups [median (IQR) SCORAD: IG 11.3 (8.0, 18.4) vs CG 12.3 (7.4, 16.0), p = 0.888].

[0268] A similar but non-significant relative risk was observed for the primary outcome in the per-protocol analysis [questionnaire per-protocol analysis RR (95%) CI: 0.713 (0.501, 1.014), P = 0.078]. Diary per-protocol analysis RR (95% CI): 0.745 (0.474, 1.173), P = 0.253].

[0269] Food allergen sensitization All infants were introduced to dairy products, and almost all were introduced to egg (99.6%) and peanut (98.0%) by 12 months. Nine infants had a positive SPT to at least one food [intervention; 3.3% (4 / 120), control; 3.6% (5 / 120), p = 1.0].

[0270] TEWL and NMF progression There were no significant differences in TEWL or thumb pulp NMF between the intervention and control groups at birth, 2, 4, 8 weeks, or 6 and 12 months.

[0271] Discussion In this RCT in high-risk infants, daily emollient use starting at 1 week of age and up to 2 months was found to be associated with a significant reduction in the cumulative incidence of AD at 12 months. Daily emollient use was associated with a 50% and 29% reduction in the risk of the cumulative incidence of AD at 6 and 12 months, respectively. Similar risk reductions were observed in the per-protocol analysis, in which participants in the intervention and control groups were included only if they used the emollient at least once a day and less than 4 days a week, respectively. However, these were not significant for the primary outcome. This may be due to conservative adherence criteria being applied, and thus lower numbers being included in the analysis, and thus lower power to detect differences between groups.

[0272] Some cases of AD diagnosed before 6 months resolved by 12 months, but there was no difference in transient cases between the groups. Since the inventors did not collect longer-term data, the inventors cannot rule out the possibility that the intervention may only have delayed the onset of AD beyond 12 months. A recent meta-analysis reported a protective effect of emollients, but only when there was no interval between emollient treatment and AD assessment14. However, there was significant heterogeneity among the four studies included in this analysis. In the inventors' study, the 29% reduction in the risk of cumulative AD at 12 months was maintained 10 months after the intervention.

[0273] The findings are different from the recent findings from two large RCTs, in which no evidence of a protective effect of emollient use from AD was found in the first year (Chalmers JR, Haines RH, Bradshaw LE, et al., "Daily emollient during infancy for prevention of eczema: the BEEP randomised controlled trial," Lancet Lond. Engl., 2020, 395(10228):962-972, Skjerven HO, Rehbinder EM, Vettukattil R, et al., "Skin emollient and early complementary feeding to prevent infant atopic dermatitis (PreventADALL): a factorial, multicentre, cluster-randomised trial," Lancet Lond. Engl., 2020, 395(10228):951-961). Among the most notable differences between these RCTs and ours, there was the timing of the intervention. Treatment in STOP AD was initiated within the first few days of life during the dynamic period of skin maturation and adaptation of the skin to the dramatic environmental changes of extrauterine life. In STOP AD, infants were randomised within 4 days of birth and advised to start emollient treatment immediately in the IG. In BEEP, the median (IQR) age at which emollient use was initiated was 11 days (7, 17) days, and only 89% initiated emollient application 3 weeks earlier. In PreventADALL, the intervention started at 2 weeks of age.

[0274] The emollients used in BEEP and PreventADALL were, respectively, basic petrolatum and paraffin-based formulations. The emollient used in this study consisted of a formulation with added ceramide, specifically developed for very dry itchy skin. Two small studies that similarly used a more complex ceramide-rich emollient reported a non-significant trend towards a protective effect from AD (Lowe AJ, Su JC, Allen KJ, et al. "A randomized trial of a barrier lipid replacement strategy for the prevention of atopic dermatitis and allergic sensitization: the PEBBLES pilot study," Br. J. Dermatol., 2018, 178(1): e19~e21; McClanahan D, Wong A, Kezic S, et al. "A randomized controlled trial of an emollient with ceramide and filaggrin-associated amino acids for the primary prevention of atopic dermatitis in high-risk infants," J. Eur. Acad. Dermatol. Venereol., 2019, 33(11): 2087-2094). Following one of these, the PEBBLES study, a larger RCT including twice-daily application of the same ceramide-based emollient from 0 to 6 months, is ongoing 25. Here, the inventors show a reduced risk of AD at 12 months with a short 2-month intervention period, which may represent a more achievable and family-friendly strategy for AD prevention.

[0275] The high adherence rates of our inventors demonstrate the feasibility of implementing a daily emollient use regimen during the first two months of life. The adherence rate using the diary was lower than that reported in the questionnaire, but 82.4% still reported emollient use on 75% or more of days equal to or exceeding 5 days per week. Infants in this study were closely followed during the intervention period, but similar adherence rates were observed in BEEP, which used a less stringent definition of adherence (emollient use more than 3 days / week) and included limited contact10. In PreventADALL, only 27% of IG had complete adherence to the protocol, which could have influenced the non-existence of a protective effect.

[0276] Our inventors evaluated food allergy outcomes, but this study had no power to detect a reduction in food allergy risk. Unlike BEEP, in which a significant increase in food allergy in IG has not been significantly reported, our inventors found no difference in the prevalence of food allergy between groups. Our inventors did not use SPT to screen for food allergy, but almost all infants had tried milk, egg, and peanut, the most common food allergens, by 12 months, so the reported food sensitization and allergy rates may reflect the true rates in our groups. BEEP reported a higher rate of skin infections in IG, suggesting a greater potential for pathogen exposure with emollient application. Our inventors found no evidence of an increased risk of skin infections with short-term emollient use.

[0277] Despite the reduction in AD risk in IG, there was no difference in TEWL over the first year between groups. Other studies on emollient use during infancy have reported a similar non-existence of an effect of the intervention on TEWL. TEWL measurements are affected by environmental factors and, more critically for infants, by subject-specific parameters including stress and crying26. This could have influenced our ability to detect differences between groups.

[0278] The main strength of this study is the initiation of emollient use within days of birth in the IG. Other strengths include the intensive follow-up of infants, the high adherence rate in the IG, and the low contamination rate in the CG.

[0279] A limitation of this study is that, in response to the COVID-19 pandemic, many AD diagnoses were made remotely. To mitigate this, detailed information and photographs were collected at the time of diagnosis. Also, the SCORAD assessment was completed remotely. This could have affected the assessment of AD severity. Validated diagnostic criteria could not be applied when diagnosing early-onset AD (less than 6 months), and in the diagnosis of early-onset AD, cases were diagnosed based on the presence of AD lesions. However, of the 73 infants diagnosed with AD at less than 6 months, 71 (97.3%) met the UKWPDC at 6 months. The cumulative prevalence of AD in this group was higher than expected based on the rate among infants with a parental atopy history in the Irish birth cohort23. A possible explanation for this is the empirical recruitment of high-risk infants and the intensive monitoring of skin health in this study. Only one-third (32.1%) of the eligible participants in this study were recruited. One of the main reasons for refusal to participate was the requirement of the follow-up schedule, particularly the follow-up schedule included during the intervention period that starts before going home with the newborn, suggesting that more motivated individuals were recruited. The inventors also had a higher dropout rate in the first 2 weeks after birth, particularly in the intervention group, which was mainly due to withdrawal of consent and not due to early onset of AD up to this point. This is a consideration in the assessment of the feasibility of advising daily emollient use in the general population during the early postnatal period.

[0280] The inventors have demonstrated that early initiation of daily use of a special emollient up to 2 months reduces the incidence of AD at 1 year of age in high-risk infants. The mechanism behind this is unclear, but analysis of the microbiota diversity and inflammatory biomarkers in a subgroup of this study is ongoing and may provide further information. Some recent studies do not support the protective effect of emollient use in infancy, but future studies should investigate the use of more complex emollients aimed at enhancing the skin barrier while identifying an effective and parental-acceptable treatment window.

[0281] Example 2: Study on the clinical and immunological effects of a probiotic supplement of Bifidobacterium infantis (EVC001 strain; Evolve BioSystems, Inc., Davis, CA) in the BACH clinical trial This clinical trial study is a randomized placebo-controlled experimental study aimed at reducing or eliminating known confounding effects from factors other than the study intervention (ClinicalTrials.gov identifier: NCT04662619). Therefore, this type of study design is considered rigorous because it can test the causal relationship between the study intervention (in this case, the study probiotic supplement) and the study endpoint.

[0282] Objective The first objective of this study is to evaluate the effect of Bifidobacterium infantis (EVC001) compared to a placebo supplement on the cumulative incidence of AD diagnosed by a physician during the first year of life in healthy breastfed infants at risk of developing AD. The second objective of this study is to evaluate the effect of Bifidobacterium infantis (EVC001) versus a placebo supplement on the following in healthy breastfed infants at risk of developing AD. ● The proportion of infants with adverse events (AE) to evaluate safety and tolerability ● The cumulative incidence of AD at additional time points ● The time to onset of AD ●Bifidobacterium infantis colonization in the infant intestine ●AD severity in subjects with AD The additional objectives of this study are as follows. 1) To evaluate the effect of Bifidobacterium infantis (EVC001) versus placebo nutritional supplement on the following in healthy breastfed infants at risk of developing AD. ●Incidence of atopic diseases other than AD (food allergy, allergic rhinitis, asthma) ●Allergy sensitization ●Intestinal and skin microbiota ●Skin immunological biomarker profile ●Incidence of infantile colic ●Infant sleep ●Infant body measurements ●Relationship between the baseline maternal intestinal microbiota and the development of the infant intestinal microbiota 2) To characterize and compare the microbiota and immunological profiles between infants who did not develop AD and those who developed AD over 1 year in the Bifidobacterium infantis (EVC001) nutritional supplement group and the placebo nutritional supplement group. 3) To determine the immune responder phenotype in the Bifidobacterium infantis (EVC001) nutritional supplement group and the placebo nutritional supplement group. 4) To identify the target gene profile associated with benefiting from nutritional supplement intervention.

[0283] Overview This trial is a randomized, double-blind, placebo-controlled, 2-arm, parallel-group (Groups 1 and 2) trial. The study will enroll approximately 286 infants who have at least one first-degree relative (i.e., biological parent or full sibling with AD, allergic rhinitis, or asthma diagnosed by a physician as reported by the mother) with a history of atopic disease, are currently being breastfed, and whose mothers intend to maintain exclusive breastfeeding for at least 12 weeks (approximately 3 months). Each infant will participate in the study under the supervision of his / her biological mother ("guardian").

[0284] The eligibility assessment of the infants will be conducted within the first 14 days after birth. Eligible infants will be enrolled and randomly assigned (1:1) equally to one of two groups: placebo (group 1) or Bifidobacterium infantis (EVC001) (group 2). Randomization will be stratified by the number of relatives of the infant's first-degree relatives (1 person vs. 2 or more persons) with a history of related atopic diseases (as defined above). All baseline evaluations will be conducted before the first administration of the assigned study nutritional supplement.

[0285] Administration of the assigned study nutritional supplement will start on day 0 and continue for 12 weeks. The caregiver will be instructed to make the best efforts to maintain breastfeeding only for at least these 12 weeks and will be advised to continue breastfeeding for as long as possible during the first year after birth. Following the 12-week nutritional supplement period, the infants will be followed up over 104 weeks (approximately 2 years) via scheduled and unscheduled hospital visits.

[0286] The sub-study is planned to evaluate the possible relationships between the gut microbiota, frequency, and function of specific immune cells in the peripheral circulation, the circulating cytokine profile, and the development of AD using a subset of the main study population (approximately 80 - 100 subjects).

[0287] Subject Selection and Enrollment The eligibility criteria are designed to select subjects for whom the protocol procedures are considered appropriate. The eligibility of the infants will be evaluated within the first 14 days after the birth of the neonate. The initial verification of eligibility may be conducted by individuals without medical qualifications.

[0288] The inclusion criteria for the infants include the following. 1) Male or female neonates less than 14 days old at the time of study enrollment (day 0). 2) Healthy full-term infants. 3) Having at least one first-degree relative (i.e., biological parent or full sibling) with an atopic disease (i.e., AD, allergic rhinitis, or asthma diagnosed by a physician and reported by the mother). 4) Breastfeeding established at the time of study enrollment (day 0), with the intention of the mother to maintain exclusive breastfeeding for 12 weeks or more.

[0289] The exclusion criteria for infants are as follows. 1) Premature birth (gestation period less than 36 weeks [252 days]). 2) Hospitalization in the neonatal unit due to problems other than the establishment of normal feeding. 3) Evidence of baseline disease / condition (e.g., abnormal birth weight) or significant risk of developing a disease / condition (based on the evaluation of maternal / pregnancy information) that, in the opinion of the PI or designee, would pose a significant safety concern or otherwise exclude the infant from study participation if the infant were enrolled in the study. 4) Marked birth defects / complications (e.g., abdominal wall defect, congenital heart disease) that, in the opinion of the PI or designee, would pose a safety concern or otherwise preclude the conduct of the study. 5) Severe extensive skin conditions (e.g., collodion). 6) Medical conditions (in the infant) or maternal medication / supplement use (e.g., daily or routine antibiotics or systemic antifungals) that, in the opinion of the PI or designee, could significantly alter the intestinal or skin microbiome. 7) Consumption of prebiotics or (a) probiotic supplements / milk / powdered milk containing Bifidobacterium longum before enrollment (day 0). 8) Consumption of more than 100 mL of powdered milk per day within 48 hours before enrollment (day 0). 9) Medical conditions (in the infant) or maternal surgery / injury / condition that interfere with breastfeeding. 10) Known infant sensitivity or intolerance to soy or milk protein consumption. 11) Maternal infection with human immunodeficiency virus, tuberculosis, hepatitis C, or hepatitis B. 12) In the opinion of the PI or designee, a condition of the caregiver that would prevent the caregiver and / or infant from complying with the research protocol requirements. 13) Twins or multiple births.

[0290] During the study, the infant's caregiver will be instructed to do their best to ensure that the infant is breastfed only for at least 12 weeks, and to encourage breastfeeding to continue as long as possible during the first year of life. The caregiver will also be required to administer the assigned study nutritional supplement to the infant once a day for 12 weeks according to the provided instructions and training. The caregiver will be instructed to avoid the routine intake of probiotics by the infant during the first 12 weeks of the study (or, if longer, during the breastfeeding period) unless specifically prescribed by the HCP, for example, to prevent or treat antibiotic-related diarrhea or to treat gastroenteritis. The caregiver will also be instructed to ensure that the infant does not consume any prebiotics or any probiotic nutritional supplements / milk / prepared milk formula containing Bifidobacterium during the first 24 weeks of the study.

[0291] Sample size, randomization / nutritional supplement assignment, and blinding Approximately 200 - 400 subjects will be randomly assigned in a 1:1 ratio to receive Bifidobacterium infantis (EVC001) or placebo. Enrolled infants will be randomly assigned equally (1:1) to the active group or the placebo nutritional supplement group according to the randomization schedule. Infants will be stratified by the number of first-degree relatives with a history of atopy (1 vs. 2 or more). The study will be double-blind, and as a result, the caregiver and the PI / designee will not know the assignment of the study nutritional supplement.

[0292] Identification and use of study nutritional supplements Provide the following study nutritional supplements as shown in Table 4 below.

[0293]

Table 4

[0294] The active nutritional supplement is the probiotic powder Bifidobacterium infantis Evivo (registered trademark) available from Evolve BioSystems, Inc., which is in sachets and contains purified lactose and the components of Bifidobacterium longum subsp. infantis EVC001 per dose. Each sachet contains 625 mg of probiotic powder and contains 8 billion CFU of Bifidobacterium infantis (EVC001). The placebo sachets contain 625 mg of lactose.

[0295] Infants will ingest the contents of one sachet of Bifidobacterium infantis (EVC001) or the matching placebo study nutritional supplement once a day for 12 weeks. At the time of nutritional supplementation, the contents of a single sachet are mixed in the provided reservoir with approximately 3 - 5 mL of expressed or pumped breast milk (or infant formula powder if needed). Using the provided syringe, the mixture will be dispensed to the side of the infant's mouth to ensure the infant ingests the full dose.

[0296] Test Period, Procedures, and Assessment Schedule The eligibility assessment of the infants will be conducted within the first 14 days after birth. After enrollment and randomization (day 0), the study nutritional supplement will be administered daily from day 0 to week 12. The caregiver will be instructed to make their best efforts to maintain exclusive breastfeeding for more than 12 weeks. Following the 12 - week nutritional supplementation period, the study subjects will be followed for an additional 92 weeks to complete this 104 - week (2 - year) study.

[0297] Details of the Assessment Tools and Additional Study Procedures Questionnaire on medical, family, medication, and nutritional supplement history: At the time of screening, the investigator will interview the caregiver of each infant to complete a medical, family, medication, and supplement history questionnaire to document the infant's medical history and medication / supplement history, including pregnancy, childbirth, and exposure during / from breastfeeding. The questionnaire will also record information reported by the mother regarding the infant's relatives up to the first-degree relatives who have a history of atopic diseases, such as a current or previous history of AD (including age of onset and details of diagnostic tests), allergic rhinitis / hay fever (including identification of allergens), asthma, food reactions / allergies (such as type of food and reaction, details of any other formal allergy tests), other skin conditions, or immune-mediated diseases.

[0298] Diagnosis of AD: Infants with cases of possible AD identified by the investigator will be evaluated by a physician trained for evaluation and diagnosis. Briefly, AD will be diagnosed if three of the following four criteria are met: 1) pruritus, 2) typical morphology and distribution (involvement of the face and extensor muscles), 3) chronic or chronically relapsing dermatitis, 4) personal or family history of atopic diseases (Rajka G, Langeland T. Grading of the severity of atopic dermatitis. Acta Derm Venereol Suppl (Stockh) 1989;144:13 - 4., Ganemo A, Svensson Å, Svedman C, Gronberg BM, Johansson AC, Wahlgren CF. Usefulness of Rajka & Langeland Eczema Severity Score in clinical practice. Acta Derm Venereol 2016;96:521 - 4.).

[0299] If the infant is diagnosed with AD, its severity will be evaluated at the time of diagnosis and at 12 weeks, 52 weeks, and 104 weeks using the EASI and POEM described below.

[0300] Eczema Area and Severity Index (EASI) for children under 8 years old: EASI is a tool used to measure the extent (area) and severity of atopic eczema / AD (Hanifin JM, Thurston M, Omoto M, Cherill R, Tofte SJ, Graeber M. The eczema area and severity index (EASI): assessment of reliability in atopic dermatitis. EASI Evaluator Group. Exp Dermatol 2001;10:11-8.). This instrument evaluates four body regions, the head and neck (including the face, neck, and scalp), the trunk (including the genital area), the upper extremities (including the hands), and the lower extremities (including the buttocks and feet), which are assigned proportional body surface areas of 20%, 30%, 20%, and 30% respectively. The area score is determined for each of these four body regions based on the percentage of skin affected by AD (defined by the four key signs listed below) within that body region (0 = none, 1 = 1-9%, 2 = 10-29%, 3 = 30-49%, 4 = 50-69%, 5 = 70-89%, 6 = 90-100%). Also, each of the four body regions is evaluated for the severity of the four key signs of AD, erythema, induration / papulation / edema, excoriation, and lichenification, on a scale of 0-3 where 0 = none, 1 = mild, 2 = moderate, and 3 = severe (note: half points are allowed). The total score for each body region is determined by multiplying the sum of the severity scores of the four key signs by the area score and then multiplying the result by the constant body surface area assigned to that body region. The total EASI score is the sum of the body region scores and ranges from 0-72. A designated, trained physician will use EASI to assess the severity of AD at the time of AD diagnosis and, for subjects with AD only, at weeks 12, 52, and 104.

[0301] Patient-Oriented Eczema Measure (POEM): The POEM is a simple, valid, easily interpretable, and reproducible tool for assessing AD and monitoring aspects of the disease that are important to patients (Charman CR, Venn AJ, Williams HC. The Patient-Oriented Eczema Measure: Development and initial validation of a new tool for measuring atopic eczema severity from the patients’ perspective. Arch Dermatol 2004;140:1513-9., Charman CR, Venn AJ, Ravenscroft JC, Williams HC. Translating Patient-Oriented Eczema Measure (POEM) scores into clinical practice by suggesting severity strata derived using anchor-based methods. Br J Dermatol 2013;169:1326-32.). Investigators will interview caregivers at the time of AD diagnosis and, for subjects with AD only, at weeks 12, 52, and 104 to assess seven symptoms (skin itching, sleep disturbance, skin bleeding, skin exudation / capillary bleeding, skin peeling, skin cracking, skin dryness / roughness) using a 5-point scale of frequency of occurrence during the previous week (0 days, 1-2 days, 3-4 days, 5-6 days). The maximum total POEM score is 28.

[0302] Infantile colic The researchers will interview the caregivers to document the signs and symptoms of infantile colic at baseline (day 0), and at 6, 12, and 24 weeks according to the Rome IV criteria (Benninga M, Nurko S, Faure C, Hyman P, St.James-Roberts I, Schechter N. Childhood functional gastrointestinal disorders: neonate / toddler. Gastroenterology 2016;150:1443-55). As defined by the Rome IV criteria, the occurrence of infantile colic will be determined using these caregiver interviews in combination with the daily caregiver entries in the diary. Caregivers will use the diary to document the occurrence and duration of other related symptoms such as crying, fussing, and defecation daily between baseline and 5 - 7, 11 - 13, and 23 - 24 weeks. "Fussing" refers to vocalizations with intermittent distress and is defined as "[behavior] not crying, but also not awake or satisfied" (Benninga, 2016; Zeevenhooven J, Koppen IJ, Benninga MA. The new Rome IV criteria for functional gastrointestinal disorders in infants and toddlers. Pediatr Gastroenterol Hepatol Nutr 2017;20:1-13). As defined by the Rome IV criteria, the occurrence of infantile colic will be determined using the caregiver diary entries in combination with the caregiver interview conducted at the time of the hospital visit.

[0303] Infant physical measurements Infants will have their length / height (using an infant length board), weight, and head circumference measured throughout the study hospitalization. The Body Mass Index (BMI) will be calculated based on the measurements of weight and length / height according to the following formula. BMI (kg / m 2 ) = weight (kg) / ([length or height cm / 100] 2 ).

[0304] Brief Infant Sleep Questionnaire-Revised (BISQ-R) At 12, 24, 52, and 76 weeks, the caregiver will document the infant's sleep habits and patterns over the past two weeks using the BISQ-R. The BISQ-R is an age-based norm-referenced scoring system that provides a comprehensive assessment of infant and toddler sleep patterns (five items related to sleep latency, number and duration of night awakenings, longest period of sleep, and total night sleep), as well as parental perceptions that can affect sleep outcomes (three items related to difficulty at bedtime, overnight sleep, and overall pediatric sleep problems), and parental behaviors (eleven items related to consistency of bedtime routine, bedtime, parental behavior at bedtime and subsequent night awakenings, and sleep position at bedtime and subsequent night awakenings) (Mindell JA, Gould RA, Tikotzy L, Leichman ES, Walters RM. Norm-referenced scoring system for the Brief Infant Sleep Questionnaire-Revised (BISQ-R). Sleep Med 2019;63:106-14). Scores in the range of 0-100 are derived for each subscale, with higher scores indicating better sleep quality, more positive perceptions of sleep quality, and parental habits that promote healthy sleep behaviors and independent infant sleep, respectively. The total score is calculated as the mean of the subscale scores for infant sleep, parental perceptions, and parental behaviors.

[0305] Solid Food Introduction Checklist The caregiver will document the first time the infant consumes a new solid food and include the type and amount of solid food if applicable.

[0306] Record of Use of Infant Food and Research Nutritional Supplements Caregivers will record in a log the details of the mother's breastfeeding, use of infant formula (if applicable), and administration of the study nutritional supplement up to week 12 and, optionally, daily thereafter. Caregivers will also record in the log any missed, incomplete, or extra doses of the study nutritional supplement, and missed supplements will not be made up on subsequent days.

[0307] Blood samples Two (2.0) mL venous whole blood samples will be collected from the infant at 24, 52, and 104 weeks of age. Blood will be processed and stored according to the instructions provided in the Laboratory Reference Manual for future analysis. An allergen-specific serum IgE test will be performed using the venous whole blood samples to assess the development of allergy sensitization. In addition, blood samples may also be used to investigate the phenotypic expression of the infant's immune responders by comparing the serial RNA expression profiles of subjects in the Bifidobacterium infantis (EVC001) nutritional supplement group and the placebo nutritional supplement group. Blood samples may also be used for exome sequencing to determine the presence of mutations in different genes that may be associated with atopic diseases (e.g., AD, asthma, and allergy sensitization) and ichthyosis vulgaris, including the FLG gene.

[0308] Fecal samples If the mother consents to collection (optional), the mother's fecal samples for future microbiome analysis will be collected at 2 - 6 weeks postpartum. Caregivers will collect the infant's feces at the clinic visit within 5 days (preferably within 3 days) before baseline (day 0), and at 6, 12, 24, 52, and 104 weeks of age. The baseline sample should be a sample other than meconium, and if this is not possible before the start of the nutritional supplement, the deviation should be recorded, and a sample other than meconium should be collected as soon as possible (preferably within 24 hours) after the nutritional supplement has been started.

[0309] All fecal samples will be collected using the supplied supplies and frozen and stored in the provided collection tubes and medical waste bags until collected by the investigator during the actual hospital stay. To transport the frozen fecal samples to the research facility, a soft-sided cooler with ice packs will be utilized, and at the test facility, they will be stored at -80 °C for future analysis.

[0310] Feces collected at baseline (day 0), and at 6, 12, 24, 52, and 104 weeks will be analyzed for the overall gut bacterial profile, including the presence of Bifidobacterium infantis, to determine the degree of colonization (percentage of Bifidobacterium infantis colonization within each infant) and incidence (percentage of infants with intestinal Bifidobacterium infantis colonization). An infant's gut will be considered colonized if the fecal concentration of Bifidobacterium infantis determined by shotgun sequencing is 50% or more of all bacteria.

[0311] Skin swab samples Caregivers will be instructed to avoid applying any topical treatments within 3 hours prior to the research hospital visit so as not to interfere with the collection of skin samples. All skin samples collected as detailed below will be frozen and stored at -80 °C at the research facility for future analysis as detailed in the Laboratory Reference Manual.

[0312] Skin Biomarkers: To evaluate the effect of the Bifidobacterium infantis (EVC001) supplement on immune regulation in the skin and to learn about biomarkers associated with the development of AD, the investigators will collect two skin samples using FibroTX skin sample collection swabs at baseline (Day 0), Week 12, and Week 52. If diagnosed with AD, two additional samples will be collected at these time points from the lesion site and adjacent clear non-lesion sites. The FibroTX skin sample collection swab is a sensitive multi-specimen research tool for direct non-invasive biomarker measurement from the skin.

[0313] Skin Microbiome: To evaluate the systemic effect of the investigational supplement on the skin microbiome, the investigators will collect two skin samples using pre-moistened swabs at baseline (Day 0), Week 6, Week 12, and Week 52, one from the antecubital fossa (elbow crease) and the other from a location determined by the investigator or sponsor. If AD is confirmed, two additional samples will be obtained from the lesioned skin and adjacent clean non-lesioned skin at these time points.

[0314] Study Visits and Assessments: An overview of the study procedures and assessment schedule is shown in Table 5 below.

[0315]

Table 5-1

[0316]

Table 5-2

[0317] Study Endpoints and Data Analysis Primary Endpoint: Cumulative incidence of AD up to Week 52. The cumulative incidence of AD up to Week 52 will be compared between the supplement groups.

[0318] Secondary endpoints: ● Compare the distribution of time to onset of AD over 104 weeks between the nutritional supplement groups ● Cumulative incidence of AD over 24 and 104 weeks ● Proportion of infants with Bifidobacterium infantis gut colonization at 12 weeks: Analyze fecal samples collected at 12 weeks for Bifidobacterium infantis colonization and overall bacterial load to determine the proportion of infants with Bifidobacterium infantis gut colonization. The infant gut will be considered colonized as defined above. ● AD severity based on the EASI score at the time of AD onset and at 12, 52, and 104 weeks ● AD severity based on the POEM score at the time of AD onset and at 12, 52, and 104 weeks

[0319] Additional endpoints: ● Cumulative incidence of allergic diseases other than AD over 24, 52, and 104 weeks: The researchers will document the onset of allergic rhinitis, asthma, and food allergies (when confirmed by an expert / pediatric allergist) throughout the study and determine the cumulative incidence of these disorders at 24, 52, and 104 weeks. ● Cumulative incidence of allergy sensitization over 24, 52, and 104 weeks: The researchers will document the occurrence of allergy sensitization to, for example, dietary or inhaled allergens (when confirmed by specific serum IgE testing) and determine the cumulative incidence at 24, 52, and 104 weeks. ● Changes from baseline in the gut and skin microbiome over 104 weeks: Determine changes from baseline in the fecal (at 6, 12, 24, 52, and 104 weeks) and skin (at 6, 12, and 52 weeks) microbiome. ● Proportion of infants with Bifidobacterium infantis gut colonization at 24 weeks: Analyze fecal samples collected in relation to the 24-week visit for Bifidobacterium infantis gut colonization as detailed above. ●Changes from baseline in skin immunological biomarker profiles at 12 and 52 weeks: Determine changes from baseline in skin biomarkers at 12 and 52 weeks. ●Cumulative incidence of infantile colic over 6, 12, and 24 weeks: The diagnosis of infantile colic is based on the Rome IV criteria, which includes data generated by clinic visits and caregiver diaries. ●BISQ-R scores at 12, 24, 52, and 76 weeks: Determine the BISQ-R infant sleep, parental perception, and parental behavior subscale scores, and the total BISQ-R score at 12, 24, 52, and 76 weeks. ●Changes from baseline in infant anthropometry at 6, 12, 24, 52, 76, and 104 weeks: Determine changes from baseline in infant length / height, weight, head circumference, and BMI at 6, 12, 24, 52, 76, and 104 weeks. ●Effect of the maternal gut microbiota on infant gut microbiota development from baseline to 2 years of age: Evaluate the correlation of the gut microbiota of maternal fecal samples collected 2 - 6 weeks after delivery with the development of the infant gut microbiota, including the colonization of Bifidobacterium infantis in the infant at baseline (day 0), and at 6, 12, 24, 52, and 104 weeks. ●Microbiota and immunological profiles in infants with or without AD: Characterize and compare outcome measures related to microbiota and immunological profiles in infants with and without AD who have not developed AD over 1 year and those who have developed AD in the Bifidobacterium infantis (EVC001) supplement group and placebo supplement group. ●Sequential RNA expression analysis at 24, 52, and 104 weeks: Characterize and compare outcome measures related to sequential RNA expression profiles in subjects in the Bifidobacterium infantis (EVC001) supplement group and placebo supplement group at 24, 52, and 104 weeks to investigate the infant immune responder phenotype. ●Target genetic analysis: Characterize outcome measures related to the target genetic profile in infants who did not develop AD over 1 year and those who did develop AD in the Bifidobacterium infantis (EVC001) supplement group, compare them, and identify subjects who may benefit from the intervention.

[0320] Success criteria The success of the study will be primarily determined by a statistically significant effect of the supplement compared to placebo on the cumulative incidence of AD by week 52.

[0321] Overview The above examples constitute a method that includes administering to breastfed infants at increased risk of developing atopic diseases a composition containing Bifidobacterium (Bifidobacterium infantis). Atopic dermatitis, food allergy, allergic rhinitis, and asthma will be monitored and evaluated for signs of prevention, delay, and / or improvement in infants raised on breast milk. Infant colic, infant sleep, and infant body measurements will also be monitored and evaluated.

[0322] Example 3: Learning Early About Peanut (LEAP) and LEAP-On (continuation study) for peanuts: Clinical trial: A clinical trial to investigate how best to prevent peanut allergy.

[0323] These clinical trials investigate whether early introduction and regular consumption of peanuts in infants at high risk for food allergies may prevent peanut allergy and induce long-lasting, sustained tolerance (see, for example, www.leapstudy.co.uk, Elissa M. Abrams, et al., "International Peanut Allergy Prevention, 6 Years After the Learning Early About Peanut Study," J. Allergy Clin. Immunol Pract., January 2022, Volume 10(1):71-77, and George Du Toit, et al., "Randomized Trial of Peanut Consumption in Infants at Risk for Peanut Allergy," N. Engl. J. Med., February 2015, Volume 372(9):803-813).

[0324] Purpose ● How long the effects of early childhood exposure to peanuts persist. ● Whether this therapy affected the risk of peanut allergy developing in siblings. ● Whether parental characteristics affected the development of peanut allergy.

[0325] Results: Of 530 infants in the treatment-intent population who initially had negative results in skin prick tests, the prevalence of peanut allergy at 60 months of age was 13.7% in the avoidance group and 1.9% in the consumption group (P<0.001). Among 98 participants in the treatment-intent population who initially had positive test results, the prevalence of peanut allergy was 35.3% in the avoidance group and 10.6% in the consumption group (P = 0.004). There was no significant between-group difference in the incidence of serious adverse events. The increase in the level of peanut-specific IgG4 antibodies occurred mainly in the consumption group. A larger percentage of participants in the avoidance group had elevated titers of peanut-specific IgE antibodies. Larger wheals in skin prick tests and lower ratios of peanut-specific IgG4:IgE were associated with peanut allergy.

[0326] Example 4: Enquiring About Tolerance (EAT) Trial: Feasibility of an Early Allergenic Food Introduction Regimen The Enquiring About Tolerance (EAT) study was to test the hypothesis that early introduction of multiple allergenic foods starting at 3 months of age in a non-selected population of breastfed-only infants would, as a primary outcome, reduce the prevalence of food allergy and, as a secondary outcome, affect the prevalence of wheezing, eczema, allergic rhinitis, and combined allergic diseases up to 3 years of age. (See, for example, www.ncbi.nlm.nih.gov / pmc / articles / PMC4852987, and Michael R. Perkin, et al., "Randomized Trial of Introduction of Allergenic Foods in Breast-Fed Infants," N. Engl. J. Med., 2016, 374:1733-1743).

[0327] Objective To determine the feasibility of early introduction of multiple allergenic foods to breastfed-only infants starting at 3 months of age and the effect on breastfeeding ability.

[0328] Results: 1303 infants were enrolled. By 5 months of age, the median consumption frequency of all 6 foods was 2 - 3 times per week for each food in the EIG, and there was no consumption for each food in the standard introduction group (P < 0.001 for each comparison). By 6 months of age, non - introduction of allergenic foods in the EIG was less than 5% for each of the 6 foods. Achievement of the strict per - protocol consumption target for the EIG was shown to be more difficult (42% of evaluable EIG participants). The breastfeeding rates in both groups significantly exceeded UK government data for equivalent mothers (P < 0.001 at 6 and 9 months of age).

[0329] It is understood that the examples and embodiments described herein are for illustrative purposes only, and that modifications to the above - described embodiments can be made without departing from the broad inventive concept. Accordingly, the present invention is not limited to the specific embodiments disclosed, but is intended to include modifications within the spirit and scope of the present invention as defined by the appended claims.

[0330] 〔Embodiment〕 (1) A method of performing it in a subject in need of treatment of pediatric atopic diseases, or reduction of their onset or occurrence, comprising: (1) The following: (a) Topically administering a first composition comprising a skin barrier - function composition to a skin area of the subject, wherein the administration of the first composition starts within about 7 days after birth of the subject, more specifically, within about 6 days, 5 days, 4 days, 3 days, 2 days, or 1 day after birth, and continues until at least about 2 months after birth of the subject, and (b) Administering orally to the subject a second composition comprising an effective amount of a probiotic, such as Bifidobacterium cells, wherein the administration of the second composition starts within about 30 days after the birth of the subject, more specifically within about 28 days, 21 days, 14 days, or 7 days, and optionally continues until at least before the introduction of solid food, by oral administration, and performing at least one of the above. (2) Administering orally to the subject one or more food allergens in a pre-measured dose, wherein the administration of the one or more food allergens starts within about 1 to 8 months after the birth of the subject, more specifically within about 2 to 6 months. A method comprising oral administration. (2) The method according to embodiment 1, comprising performing (1)(a) and (2). (3) The method according to embodiment 1, comprising performing (1)(b) and (2). (4) The method according to embodiment 1, comprising performing (1)(a), (1)(b), and (2). (5) The method according to any one of embodiments 1, 2, and 4, wherein the first composition is administered at least once a day.

[0331] (6) The method according to any one of embodiments 1, 2, 4, and 5, wherein the first composition is administered at least twice a day. (7) The method according to any one of embodiments 1, 2, and 4 to 6, wherein the administration of the first composition starts within about 2 days after the birth of the subject. (8) The method according to any one of embodiments 1, 2, and 4 to 7, wherein the first composition is administered to the whole body skin of the subject. (9) The method according to any one of embodiments 1, 2, and 4 to 8, wherein the first composition further comprises colloidal oatmeal, ceramide, and distearyldimonium chloride. (10) The first composition comprises the following components in the amounts described below. a. Caprylic / capric triglyceride, preferably about 0.0% to about 1.0%, more preferably about 0.005% to about 1.0%. b. Preferably about 0.0% to about 0.1%, more preferably about 0.005% to about 0.1% of citric acid, c. Preferably about 0.0% to about 2.0%, more preferably about 0.1% to about 2.0% of benzoic acid, d. Preferably about 0.0% to about 2.0%, more preferably about 0.05% to about 2.0% of potassium phosphate, e. Preferably about 0.0% to about 10.0%, more preferably about 1.0% to about 10.0% of dimethicone, f. Preferably about 0.0% to about 2.0%, more preferably about 0.1% to about 2.0% of stearic acid, palmitic acid, g. Preferably about 0.0% to about 10.0%, more preferably about 1.0% to about 10.0% of isocetyl alcohol, h. Preferably about 0.0% to about 2.0%, more preferably about 0.1% to about 2.0% of emmer (Triticum dicoccum) grain flour, i. Preferably about 0.0% to about 0.1%, more preferably about 0.005% to about 0.1% of ceramide 3, j. Preferably about 0.0% to about 2.0%, more preferably about 0.1% to about 2.0% of ethylhexylglycerin, k. Preferably about 0.0% to about 1.0%, more preferably about 0.005% to about 1.0% of emmer (Triticum dicoccum) grain oil, l. Preferably about 0.0% to about 1.0%, more preferably about 0.005% to about 1.0% of an emmer (Triticum dicoccum) grain extract containing glycerin, potassium sorbate, and water, m. Preferably about 15.0% to about 40.0%, more preferably about 20.0% to about 40.0% of water, n. Preferably about 20.0% to about 50.0%, more preferably about 30.0% to about 50.0% of glycerin, o. Preferably about 0.0% to about 2.0%, more preferably about 0.1% to about 2.0% of sodium ceteareth sulfate, p. Preferably about 0.0% to about 2.0%, more preferably about 0.1% to about 2.0% of dipotassium phosphate, q. Preferably from about 0.0% to about 1.0%, more preferably from about 0.005% to about 1.0% of sodium hydroxide, r. Preferably from about 0.0% to about 10.0%, more preferably from about 1.0% to about 10.0% of cetyl alcohol, s. Preferably from about 0.0% to about 10.0%, more preferably from about 1.0% to about 10.0% of ceteareth alcohol, t. Preferably from about 0.0% to about 2.0%, more preferably from about 0.1% to about 2.0% of benzyl alcohol, and / or u. Preferably from about 0.0% to about 2.0%, more preferably from about 0.1% to about 2.0% of p-anisic acid, a method according to any one of embodiments 1, 2, and 4 to 9, comprising one or more of the foregoing.

[0332] (11) The method according to any one of embodiments 1 and 3 to 10, wherein the second composition is administered at least once a day. (12) The method according to any one of embodiments 1 and 3 to 11, wherein the administration of the second composition continues for at least 12 weeks or the administration of the second composition continues until the establishment of a desired gut microbiota in the subject. (13) The method according to any one of embodiments 1 and 3 to 12, wherein the Bifidobacterium cells are Bifidobacterium infantis cells. (14) The method according to any one of embodiments 1 and 3 to 13, wherein the second composition comprises from about 100 million to about 100 billion, more specifically from about 5 billion to about 15 billion colony forming units (CFU) of Bifidobacterium infantis. (15) The method according to any one of embodiments 1 and 3 to 14, wherein the second composition comprises about 8 billion colony forming units (CFU) of Bifidobacterium infantis.

[0333] (16) The method according to any one of embodiments 1 to 15, wherein the subject is breastfed or is fed with a nutritional supplement containing one or more human milk oligosaccharides, such as infant formula milk. (17) The method according to any one of embodiments 1 to 16, wherein the subject is breastfed only. (18) The method according to any one of embodiments 1 to 17, wherein the nutritional supplement comprises powdered milk for infants. (19) The method according to any one of embodiments 16 to 18, wherein the Bifidobacterium is mixed in breast milk or the nutritional supplement, and then the second composition is administered to the subject. (20) The method according to any one of embodiments 1 and 3 to 19, wherein the Bifidobacterium is in powder form.

[0334] (21) The administration of the one or more food allergens i. administering a first food allergen to the subject at an exposure dose for the first food allergen over one or more days; ii. then administering the first food allergen to the subject at a maintenance dose for the first food allergen over several days; iii. then administering the first food allergen to the subject at the maintenance dose and a second food allergen at an exposure dose for the second food allergen over one or more days; iv. then administering both the first food allergen and the second food allergen at a maintenance dose for each food allergen over several days, the method according to any one of embodiments 1 to 20. (22) The method according to embodiment 21, further comprising continuing the maintenance doses of the first food allergen and the second food allergen until the pre-measured dose for each of the food allergens is completely consumed. (23) The method according to embodiment 21 or 22, wherein the maintenance dose is continued for several months until the subject regularly consumes a food containing the first food allergen and the second food allergen as part of the subject's diet. (24) v. administering a third food allergen to the subject at an exposure dose for the third food allergen over one or more days vi. Then, administering the first food allergen, the second food allergen, and the third food allergen to the subject over several days at a maintenance dose for each of the food allergens, the method according to any one of Embodiments 21 to 23, further comprising. (25) The method according to Embodiment 24, further comprising continuing the maintenance dose of the first food allergen, the second food allergen, and the third food allergen until the pre-measured dose for each of the food allergens is consumed.

[0335] (26) The method according to Embodiment 25, wherein the pre-measured dose for each of the first food allergen, the second food allergen, and the third food allergen is consumed over 12 days. (27) The first food allergen and the second food allergen are each independently selected from the group consisting of milk, eggs, peanuts, wheat, soybeans, sesame, fish, crustaceans, and nuts, and preferably, milk and eggs, respectively, the method according to any one of Embodiments 1 to 26. (28) The third food allergen is selected from the group consisting of milk, eggs, peanuts, wheat, soybeans, sesame, fish, crustaceans, and nuts, and preferably, peanuts, the method according to any one of Embodiments 24 to 27. (29) The pre-measured dose of the food allergen is mixed in breast milk, a nutritional supplement, or food, and then the food allergen is administered to the subject, the method according to any one of Embodiments 1 to 28. (30) The pre-measured dose of the food allergen is in powder form, the method according to any one of Embodiments 1 to 29.

[0336] (31) The exposure dose of each food allergen is about 0.01 to 0.3 grams, and the maintenance dose of each food allergen is about 0.05 to 1 gram, the method according to any one of Embodiments 1 to 30. (32) The method according to any one of embodiments 1 to 31, wherein the first food allergen includes milk, the exposure dose of the first food allergen is about 0.2 grams of milk protein, and the maintenance dose of the first food allergen is about 0.4 grams of milk protein. (33) The method according to any one of embodiments 1 to 32, wherein the second food allergen includes eggs, the exposure dose of the second food allergen is about 0.03 grams of egg protein, and the maintenance dose of the second food allergen is about 0.1 grams of egg protein. (34) The method according to any one of embodiments 1 to 33, wherein the third food allergen includes peanuts, the exposure dose of the third food allergen is about 0.1 grams of peanut protein, and the maintenance dose of the third food allergen is about 0.4 grams of peanut protein. (35) (a) A first composition comprising a skin barrier function composition, (b) A second composition comprising an effective amount of probiotics, such as Bifidobacterium cells, and (c) A kit comprising at least two of a pre-measured dose of one or more food allergens.

[0337] (36) The kit according to embodiment 35, which is for use in treating pediatric atopic diseases or reducing their onset or occurrence in a subject in need thereof. (37) The method or kit according to any one of embodiments 1 to 36, wherein the probiotics include bacterial strains selected from the genus Lactobacillus, Lactobacillus casei, and Bifidobacterium. (38) The method or kit according to embodiment 37, wherein the probiotics comprise a bacterial strain of Bifidobacterium infantis, Bifidobacterium longum (subspecies other than Bifidobacterium infantis), Bifidobacterium breve, Bifidobacterium catenulatum, Bifidobacterium adolescentis, Bifidobacterium animalis, Bifidobacterium gallicum, Bifidobacterium lactis, Bifidobacterium pseudocatenulatum, Bifidobacterium bifidum, Lactobacillus paracasei, Lactobacillus acidophilus, Lactobacillus johnsonii, Lactobacillus delbrueckii, Lactobacillus crispatus, Lactobacillus gasseri, Lactobacillus zeae, Lactobacillus casei, Lactobacillus rhamnosus, Lactiplantibacillus plantarum, Limosilactobacillus fermentum, Ligilactobacillus salivarius, or a combination thereof. (39) A method of performing it in a subject in need of treatment of pediatric atopic diseases or reduction of their onset or occurrence, (1) The following: (a) Topically administering to the skin area of the subject a first composition comprising a skin barrier function composition, wherein the administration of the first composition starts within about 7 days after birth of the subject, more specifically within about 6 days, 5 days, 4 days, 3 days, 2 days, or 1 day, and continues until at least about 2 months after birth of the subject, and (b) Orally administering to the subject a second composition comprising an effective amount of probiotics, such as Bifidobacterium cells, wherein the administration of the second composition starts within about 30 days after birth of the subject, more specifically within about 28 days, 21 days, 14 days, or 7 days, and optionally continues until at least before the introduction of solid food, (2) Optionally, orally administering to the subject one or more food allergens in a pre-measured dose, wherein the administration of the one or more food allergens begins within about 1 to 8 months after the birth of the subject, more specifically, within about 2 to 6 months, the method comprising oral administration. (40) (2) The method according to embodiment 1, further comprising orally administering to the subject one or more food allergens in a pre-measured dose, wherein the administration of the one or more food allergens begins within about 1 to 8 months after the birth of the subject, more specifically, within about 2 to 6 months.

[0338] (41) The method according to embodiment 39 or 40, wherein the first composition is administered at least once a day. (42) The method according to any one of embodiments 39 to 41, wherein the first composition is administered at least twice a day. (43) The method according to any one of embodiments 39 to 42, wherein the administration of the first composition begins within about 2 days after the birth of the subject. (44) The method according to any one of embodiments 39 to 43, wherein the first composition is administered to the entire body skin of the subject. (45) The method according to any one of embodiments 39 to 44, wherein the first composition further comprises colloidal oatmeal, ceramide, and distearyldimonium chloride.

[0339] (46) The first composition comprises the following components in the amounts described below, a. Caprylic / capric triglyceride, preferably from about 0.0% to about 1.0%, more preferably from about 0.005% to about 1.0%, b. Citric acid, preferably from about 0.0% to about 0.1%, more preferably from about 0.005% to about 0.1%, c. Benzoic acid, preferably from about 0.0% to about 2.0%, more preferably from about 0.1% to about 2.0%, d. Potassium phosphate, preferably from about 0.0% to about 2.0%, more preferably from about 0.05% to about 2.0%, e. Preferably from about 0.0% to about 10.0%, more preferably from about 1.0% to about 10.0% of dimethicone, f. Preferably from about 0.0% to about 2.0%, more preferably from about 0.1% to about 2.0% of stearic acid, palmitic acid, g. Preferably from about 0.0% to about 10.0%, more preferably from about 1.0% to about 10.0% of isocetyl alcohol, h. Preferably from about 0.0% to about 2.0%, more preferably from about 0.1% to about 2.0% of emmer (Triticum dicoccum) grain flour, i. Preferably from about 0.0% to about 0.1%, more preferably from about 0.005% to about 0.1% of ceramide 3, j. Preferably from about 0.0% to about 2.0%, more preferably from about 0.1% to about 2.0% of ethylhexylglycerin, k. Preferably from about 0.0% to about 1.0%, more preferably from about 0.005% to about 1.0% of emmer (Triticum dicoccum) grain oil, l. Preferably from about 0.0% to about 1.0%, more preferably from about 0.005% to about 1.0% of emmer (Triticum dicoccum) grain extract containing glycerin, potassium sorbate, and water, m. Preferably from about 15.0% to about 40.0%, more preferably from about 20.0% to about 40.0% of water, n. Preferably from about 20.0% to about 50.0%, more preferably from about 30.0% to about 50.0% of glycerin, o. Preferably from about 0.0% to about 2.0%, more preferably from about 0.1% to about 2.0% of sodium cetearyl sulfate, p. Preferably from about 0.0% to about 2.0%, more preferably from about 0.1% to about 2.0% of dipotassium phosphate, q. Preferably from about 0.0% to about 1.0%, more preferably from about 0.005% to about 1.0% of sodium hydroxide, r. Preferably from about 0.0% to about 10.0%, more preferably from about 1.0% to about 10.0% of cetyl alcohol, s. Preferably from about 0.0% to about 10.0%, more preferably from about 1.0% to about 10.0% of cetearyl alcohol, t. Preferably from about 0.0% to about 2.0%, more preferably from about 0.1% to about 2.0% of benzyl alcohol, and / or u. Preferably from about 0.0% to about 2.0%, more preferably from about 0.1% to about 2.0% of p-anisic acid, the method according to any one of embodiments 39 to 45, comprising one or more of the foregoing. (47) The method according to any one of embodiments 39 to 46, wherein the second composition is administered at least once a day. (48) The method according to any one of embodiments 39 to 47, wherein the administration of the second composition continues for at least 12 weeks, or the administration of the second composition continues until the establishment of the desired intestinal microbiota in the subject. (49) The method according to any one of embodiments 39 to 48, wherein the Bifidobacterium cells are Bifidobacterium infantis cells. (50) The method according to any one of embodiments 39 to 49, wherein the second composition comprises from about 100 million to about 100 billion, more specifically from about 5 billion to about 15 billion colony forming units (CFU) of Bifidobacterium infantis.

[0340] (51) The method according to any one of embodiments 39 to 50, wherein the second composition comprises about 8 billion colony forming units (CFU) of Bifidobacterium infantis. (52) The method according to any one of embodiments 39 to 51, wherein the subject is breastfed or is breastfed with a nutritional supplement containing one or more human milk oligosaccharides, such as infant formula. (53) The method according to any one of embodiments 39 to 52, wherein the subject is breastfed only. (54) The method according to any one of embodiments 39 to 53, wherein the nutritional supplement comprises infant formula. (55) The method according to any one of embodiments 39 to 54, wherein the Bifidobacterium is mixed in breast milk or the nutritional supplement, and then the second composition is administered to the subject.

[0341] (56) The method according to any one of embodiments 39 to 55, wherein the bifidobacterium is in powder form. (57) The administration of the one or more food allergens i. administering to the subject a first food allergen at an exposure dose for the first food allergen over one or more days; ii. then administering to the subject the first food allergen at a maintenance dose for the first food allergen over multiple days; iii. then administering to the subject the first food allergen at the maintenance dose and a second food allergen at an exposure dose for the second food allergen over one or more days; iv. then administering both the first food allergen and the second food allergen at a maintenance dose for each food allergen over multiple days, the method according to any one of embodiments 39 to 56. (58) The method according to any one of embodiments 39 to 57, further comprising continuing the maintenance doses of the first food allergen and the second food allergen until the pre-measured doses for each of the food allergens are completely consumed. (59) The method according to any one of embodiments 39 to 58, wherein the maintenance dose is continued for several months until the subject regularly consumes as part of the subject's diet a food containing the first food allergen and the second food allergen. (60) vii. administering to the subject a third food allergen at an exposure dose for the third food allergen over one or more days; viii. then administering to the subject the first food allergen, the second food allergen, and the third food allergen at a maintenance dose for each food allergen over multiple days, the method according to any one of embodiments 39 to 59.

[0342] (61) The method according to any one of embodiments 39 to 60, further comprising continuing the maintenance dose of the first food allergen, the second food allergen, and the third food allergen until the pre-measured dose for each of the food allergens is consumed. (62) The method according to any one of embodiments 39 to 61, wherein the pre-measured dose for each of the first food allergen, the second food allergen, and the third food allergen is consumed over 12 days. (63) The method according to any one of embodiments 39 to 62, wherein the first food allergen and the second food allergen are each independently selected from the group consisting of milk, eggs, peanuts, wheat, soybeans, sesame seeds, fish, crustaceans, and nuts, and preferably, milk and eggs respectively. (64) The method according to any one of embodiments 39 to 63, wherein the third food allergen is selected from the group consisting of milk, eggs, peanuts, wheat, soybeans, sesame seeds, fish, crustaceans, and nuts, and preferably, peanuts. (65) The method according to any one of embodiments 39 to 64, wherein the pre-measured dose of the food allergen is mixed in breast milk, a nutritional supplement, or food, and then the food allergen is administered to the subject.

[0343] (66) The method according to any one of embodiments 39 to 65, wherein the pre-measured dose of the food allergen is in powder form. (67) The method according to any one of embodiments 39 to 66, wherein the exposure dose of each food allergen is about 0.01 to 0.3 grams, and the maintenance dose of each food allergen is about 0.05 to 1 gram. (68) The method according to any one of embodiments 39 to 67, wherein the first food allergen includes milk, the exposure dose of the first food allergen is about 0.2 grams of milk protein, and the maintenance dose of the first food allergen is about 0.4 grams of milk protein. (69) The method according to any one of embodiments 39 to 68, wherein the second food allergen includes eggs, the exposure dose of the second food allergen is about 0.03 grams of egg protein, and the maintenance dose of the second food allergen is about 0.1 grams of egg protein. (70) The method according to any one of embodiments 39 to 69, wherein the third food allergen includes peanuts, the exposure dose of the third food allergen is about 0.1 grams of peanut protein, and the maintenance dose of the third food allergen is about 0.4 grams of peanut protein.

Claims

1. A kit comprising at least two of: (a) a first composition comprising a skin barrier function composition, (b) a second composition comprising an effective amount of probiotics, such as Bifidobacterium cells, and (c) one or more food allergens in a pre-measured dose.

2. The kit according to claim 1, for use in performing it in a subject in need of treatment of pediatric atopic diseases, or reduction of their onset or occurrence.

3. The kit according to claim 1, wherein the probiotics comprise bacterial strains selected from the genus Lactobacillus, Lactobacillus casei, and Bifidobacterium.

4. The kit according to claim 3, wherein the probiotics comprise bacterial strains of Bifidobacterium infantis, Bifidobacterium longum (subspecies other than Bifidobacterium infantis), Bifidobacterium breve, Bifidobacterium catenulatum, Bifidobacterium adolescentis, Bifidobacterium animalis, Bifidobacterium gallicum, Bifidobacterium lactis, Bifidobacterium pseudocatenulatum, Bifidobacterium bifidum, Lactobacillus casei paracasei, Lactobacillus acidophilus, Lactobacillus johnsonii, Lactobacillus delbrueckii, Lactobacillus crispatus, Lactobacillus gasseri, Lactobacillus zeae, Lactobacillus casei, Lactobacillus rhamnosus, Lactiplantibacillus plantarum, Limosilactobacillus fermentum, Ligilactobacillus salivarius, or combinations thereof.

5. A method of performing it in a subject in need of treatment of pediatric atopic diseases, or reduction of their onset or occurrence, comprising: (1) the following: (a) topically administering to a skin area of the subject a first composition comprising a skin barrier function composition, wherein the administration of the first composition starts within about 7 days after birth of the subject, more specifically within about 6 days, 5 days, 4 days, 3 days, 2 days, or 1 day, and continues until at least about 2 months after birth of the subject, and (b) orally administering to the subject a second composition comprising an effective amount of a probiotic, such as Bifidobacterium cells, wherein the administration of the second composition starts within about 30 days after the birth of the subject, more specifically, within about 28 days, 21 days, 14 days, or 7 days, and optionally continues until at least before the introduction of solid food, and performing at least one of the above oral administrations; (2) orally administering to the subject one or more food allergens in a pre-measured dose, wherein the administration of the one or more food allergens starts within about 1 to 8 months after the birth of the subject, more specifically, within about 2 to 6 months, and a method comprising the above oral administration.

6. The method according to claim 5, comprising performing (1) (a) and (2).

7. The method according to claim 5, comprising performing (1) (b) and (2).

8. The method according to claim 5, comprising performing (1) (a), (1) (b), and (2).

9. The method according to claim 5 or 6, wherein the first composition is administered at least once a day.

10. The method according to claim 5, wherein the first composition is administered at least twice a day.

11. The method according to claim 5, wherein the administration of the first composition starts within about 2 days after the birth of the subject.

12. The method according to claim 5, wherein the first composition is administered to the whole body skin of the subject.

13. The method according to claim 5, wherein the first composition further comprises colloidal oatmeal, ceramide, and distearyldimonium chloride.

14. The first composition comprises the following components in the amounts described below: a. Caprylic / capric triglyceride, preferably about 0.0% to about 1.0%, more preferably about 0.005% to about 1.0%; b. Citric acid, preferably about 0.0% to about 0.1%, more preferably about 0.005% to about 0.1%; c. Benzoic acid, preferably about 0.0% to about 2.0%, more preferably about 0.1% to about 2.0%; d. Potassium phosphate, preferably about 0.0% to about 2.0%, more preferably about 0.05% to about 2.0%; e. Dimethicone, preferably about 0.0% to about 10.0%, more preferably about 1.0% to about 10.0%; f. Preferably from about 0.0% to about 2.0%, more preferably from about 0.1% to about 2.0%, of stearic acid, palmitic acid, g. Preferably from about 0.0% to about 10.0%, more preferably from about 1.0% to about 10.0%, of isocetyl alcohol, h. Preferably from about 0.0% to about 2.0%, more preferably from about 0.1% to about 2.0%, of emmer (Triticum dicoccum) grain flour, i. Preferably from about 0.0% to about 0.1%, more preferably from about 0.005% to about 0.1%, of ceramide 3, j. Preferably from about 0.0% to about 2.0%, more preferably from about 0.1% to about 2.0%, of ethylhexylglycerin, k. Preferably from about 0.0% to about 1.0%, more preferably from about 0.005% to about 1.0%, of emmer (Triticum dicoccum) grain oil, l. Preferably from about 0.0% to about 1.0%, more preferably from about 0.005% to about 1.0%, of an emmer (Triticum dicoccum) grain extract containing glycerin, potassium sorbate, and water, m. Preferably from about 15.0% to about 40.0%, more preferably from about 20.0% to about 40.0%, of water, n. Preferably from about 20.0% to about 50.0%, more preferably from about 30.0% to about 50.0%, of glycerin, o. Preferably from about 0.0% to about 2.0%, more preferably from about 0.1% to about 2.0%, of sodium cetearyl sulfate, p. Preferably from about 0.0% to about 2.0%, more preferably from about 0.1% to about 2.0%, of dipotassium phosphate, q. Preferably from about 0.0% to about 1.0%, more preferably from about 0.005% to about 1.0%, of sodium hydroxide, r. Preferably from about 0.0% to about 10.0%, more preferably from about 1.0% to about 10.0%, of cetyl alcohol, s. Preferably from about 0.0% to about 10.0%, more preferably from about 1.0% to about 10.0%, of cetearyl alcohol, t. Preferably from about 0.0% to about 2.0%, more preferably from about 0.1% to about 2.0%, of benzyl alcohol, and / or u. Preferably from about 0.0% to about 2.0%, more preferably from about 0.1% to about 2.0%, of p-anisic acid, the method according to claim 5 comprising one or more of the foregoing.

15. The method according to claim 5, wherein the second composition is administered at least once a day.

16. The method according to claim 5, wherein the administration of the second composition continues for at least 12 weeks, or the administration of the second composition continues until the establishment of the desired intestinal microbiota in the subject.

17. The method according to claim 5, wherein the Bifidobacterium cells are Bifidobacterium infantis cells.

18. The method according to claim 5, wherein the second composition comprises from about 100 million to about 100 billion, more specifically from about 5 billion to about 15 billion colony forming units (CFU) of Bifidobacterium infantis.

19. The method according to claim 5, wherein the second composition comprises about 8 billion colony forming units (CFU) of Bifidobacterium infantis.

20. The method according to claim 5, wherein the subject is breastfed or is fed by a nutritional supplement comprising one or more human milk oligosaccharides, such as an infant formula.

21. The method according to claim 5, wherein the subject is breastfed only.

22. The method according to claim 5, wherein the nutritional supplement comprises an infant formula.

23. The method according to claim 20, wherein the Bifidobacterium is mixed in breast milk or the nutritional supplement and then the second composition is administered to the subject.

24. The method according to claim 5, wherein the Bifidobacterium is in powder form.

25. The administration of the one or more food allergens is i. administering to the subject a first food allergen at an exposure dose for the first food allergen for one or more days; ii. then administering to the subject the first food allergen at a maintenance dose for the first food allergen for several days; iii. then administering to the subject the first food allergen at the maintenance dose and a second food allergen at an exposure dose for the second food allergen for one or more days; iv. then administering both the first food allergen and the second food allergen at a maintenance dose for each food allergen for several days, the method according to claim 5.

26. The method according to claim 25, further comprising continuing the maintenance dose of the first food allergen and the second food allergen until the pre-measured dose for each of the food allergens is completely consumed.

27. The method according to claim 25 or 26, wherein the maintenance dose is continued for several months until the subject regularly consumes a food containing the first food allergen and the second food allergen as part of the subject's diet.

28. v. Administering to the subject a third food allergen at an exposure dose for the third food allergen for one or more days; vi. Subsequently, administering to the subject the first food allergen, the second food allergen, and the third food allergen at a maintenance dose for each of the food allergens for several days. The method according to claim 25.

29. The method according to claim 28, further comprising continuing the maintenance dose of the first food allergen, the second food allergen, and the third food allergen until the pre-measured dose for each of the food allergens is consumed.

30. The method according to claim 29, wherein the pre-measured dose for each of the first food allergen, the second food allergen, and the third food allergen is consumed over 12 days.

31. The method according to claim 5, wherein the first food allergen and the second food allergen are each independently selected from the group consisting of milk, eggs, peanuts, wheat, soybeans, sesame seeds, fish, crustaceans, and nuts, and preferably are milk and eggs, respectively.

32. The method according to claim 28, wherein the third food allergen is selected from the group consisting of milk, eggs, peanuts, wheat, soybeans, sesame seeds, fish, crustaceans, and nuts, and preferably is peanuts.

33. The method according to claim 5, wherein the pre-measured dose of the food allergen is mixed in breast milk, a nutritional supplement, or food, and then the food allergen is administered to the subject.

34. The method according to claim 5, wherein the pre-measured dose of the food allergen is in powder form.

35. The method according to claim 5, wherein the exposure dose of each food allergen is about 0.01 to 0.3 grams, and the maintenance dose of each food allergen is about 0.05 to 1 gram.

36. The method according to claim 5, wherein the first food allergen includes milk, the exposure dose of the first food allergen is about 0.2 grams of milk protein, and the maintenance dose of the first food allergen is about 0.4 grams of milk protein.

37. The method according to claim 5, wherein the second food allergen includes eggs, the exposure dose of the second food allergen is about 0.03 grams of egg protein, and the maintenance dose of the second food allergen is about 0.1 grams of egg protein.

38. The method according to claim 5, wherein the third food allergen includes peanuts, the exposure dose of the third food allergen is about 0.1 grams of peanut protein, and the maintenance dose of the third food allergen is about 0.4 grams of peanut protein.

39. The method according to claim 5, wherein the probiotics include bacterial strains selected from the group consisting of Lactobacillus, Lactobacillus casei, and Bifidobacterium.

40. The method according to claim 39, wherein the probiotics include bacterial strains of Bifidobacterium infantis, Bifidobacterium longum (subspecies other than Bifidobacterium infantis), Bifidobacterium breve, Bifidobacterium catenulatum, Bifidobacterium adolescentis, Bifidobacterium animalis, Bifidobacterium gallicum, Bifidobacterium lactis, Bifidobacterium pseudocatenulatum, Bifidobacterium bifidum, Lactobacillus casei paracasei, Lactobacillus acidophilus, Lactobacillus johnsonii, Lactobacillus delbrueckii, Lactobacillus crispatus, Lactobacillus gasseri, Lactobacillus zeae, Lactobacillus casei, Lactobacillus rhamnosus, Lactiplantibacillus plantarum, Limosilactobacillus fermentum, Ligilactobacillus salivarius, or combinations thereof.

41. A method of performing it in a subject in need of treatment of pediatric atopic diseases or reduction of their onset or occurrence, (1) The following: (a) Topically administering a first composition containing a skin barrier function composition to a skin area of the subject, wherein the administration of the first composition starts within about 7 days after the birth of the subject, more specifically, within about 6 days, 5 days, 4 days, 3 days, 2 days, or 1 day, and continues until at least about 2 months after the birth of the subject, and (b) Orally administering a second composition containing an effective amount of probiotics, for example, Bifidobacterium cells, to the subject, wherein the administration of the second composition starts within about 30 days after the birth of the subject, more specifically, within about 28 days, 21 days, 14 days, or 7 days, and optionally continues until at least before the introduction of solid foods, and (2) Optionally, orally administering to the subject one or more food allergens in a pre-measured dose, wherein the administration of the one or more food allergens starts within about 1 to 8 months after the birth of the subject, more specifically, within about 2 to 6 months. A method comprising.

42. (2) Further comprising orally administering to the subject one or more food allergens in a pre-measured dose, wherein the administration of the one or more food allergens starts within about 1 to 8 months after the birth of the subject, more specifically, within about 2 to 6 months. The method according to claim 5.

43. The method according to claim 41, wherein the first composition is administered at least once a day.

44. The method according to claim 41, wherein the first composition is administered at least twice a day.

45. The method according to claim 41, wherein the administration of the first composition starts within about 2 days after the birth of the subject.

46. The method according to claim 41, wherein the first composition is administered to the entire body skin of the subject.

47. The method according to claim 41, wherein the first composition further contains colloidal oatmeal, ceramide, and distearyldimonium chloride.

48. The first composition is the following components in the amounts described below, a. Caprylic acid / capric acid triglyceride, preferably about 0.0% to about 1.0%, more preferably about 0.005% to about 1.0%, b. Citric acid, preferably from about 0.0% to about 0.1%, more preferably from about 0.005% to about 0.1%, c. Benzoic acid, preferably from about 0.0% to about 2.0%, more preferably from about 0.1% to about 2.0%, d. Potassium phosphate, preferably from about 0.0% to about 2.0%, more preferably from about 0.05% to about 2.0%, e. Dimethicone, preferably from about 0.0% to about 10.0%, more preferably from about 1.0% to about 10.0%, f. Stearic acid, palmitic acid, preferably from about 0.0% to about 2.0%, more preferably from about 0.1% to about 2.0%, g. Isocetyl alcohol, preferably from about 0.0% to about 10.0%, more preferably from about 1.0% to about 10.0%, h. Embaku (rye) grain powder, preferably from about 0.0% to about 2.0%, more preferably from about 0.1% to about 2.0%, i. Ceramide 3, preferably from about 0.0% to about 0.1%, more preferably from about 0.005% to about 0.1%, j. Ethylhexylglycerin, preferably from about 0.0% to about 2.0%, more preferably from about 0.1% to about 2.0%, k. Embaku (rye) grain oil, preferably from about 0.0% to about 1.0%, more preferably from about 0.005% to about 1.0%, l. Embaku (rye) grain extract containing glycerin, potassium sorbate, and water, preferably from about 0.0% to about 1.0%, more preferably from about 0.005% to about 1.0%, m. Water, preferably from about 15.0% to about 40.0%, more preferably from about 20.0% to about 40.0%, n. Glycerin, preferably from about 20.0% to about 50.0%, more preferably from about 30.0% to about 50.0%, o. Sodium cetylesulfate, preferably from about 0.0% to about 2.0%, more preferably from about 0.1% to about 2.0%, p. Dipotassium phosphate, preferably from about 0.0% to about 2.0%, more preferably from about 0.1% to about 2.0%, q. Sodium hydroxide, preferably from about 0.0% to about 1.0%, more preferably from about 0.005% to about 1.0%, r. Cetyl alcohol, preferably from about 0.0% to about 10.0%, more preferably from about 1.0% to about 10.0%, s. Ceteareth alcohol, preferably from about 0.0% to about 10.0%, more preferably from about 1.0% to about 10.0%, t. Benzyl alcohol, preferably from about 0.0% to about 2.0%, more preferably from about 0.1% to about 2.0%, and / or The method according to claim 41, comprising one or more of p-anisic acid, preferably from about 0.0% to about 2.0%, more preferably from about 0.1% to about 2.0%.

49. The method according to claim 41, wherein the second composition is administered at least once a day.

50. The method according to claim 41, wherein the administration of the second composition continues for at least 12 weeks or until the establishment of the desired gut microbiota in the subject.

51. The method according to claim 41, wherein the Bifidobacterium cells are Bifidobacterium infantis cells.

52. The method according to claim 41, wherein the second composition comprises from about 100 million to about 100 billion, more specifically from about 5 billion to about 15 billion colony forming units (CFU) of Bifidobacterium infantis.

53. The method according to claim 41, wherein the second composition comprises about 8 billion colony forming units (CFU) of Bifidobacterium infantis.

54. The method according to claim 41, wherein the subject is breastfed or fed with a nutritional supplement containing one or more human milk oligosaccharides, such as infant formula milk.

55. The method according to claim 41, wherein the subject is breastfed only.

56. The method according to claim 41, wherein the nutritional supplement comprises infant formula milk.

57. The method according to claim 41, wherein the Bifidobacterium is mixed in breast milk or the nutritional supplement and then the second composition is administered to the subject.

58. The method according to claim 41, wherein the Bifidobacterium is in powder form.

59. The administration of the one or more food allergens is i. administering to the subject a first food allergen at an exposure dose for the first food allergen over one or more days; ii. then administering to the subject the first food allergen at a maintenance dose for the first food allergen over several days; iii. then administering to the subject the first food allergen at the maintenance dose and a second food allergen at an exposure dose for the second food allergen over one or more days; iv. Thereafter, administering both the first food allergen and the second food allergen over several days at a maintenance dose for each food allergen, the method according to claim 41, comprising:

60. The method according to claim 41, further comprising continuing the maintenance doses of the first food allergen and the second food allergen until the pre-measured dose for each of the food allergens is completely consumed.

61. The method according to claim 41, wherein the maintenance dose is continued for several months until the subject regularly consumes as part of the subject's diet a food containing the first food allergen and the second food allergen.

62. vii. Administering to the subject a third food allergen over one or more days at an exposure dose for the third food allergen; viii. Thereafter, administering to the subject the first food allergen, the second food allergen, and the third food allergen over several days at a maintenance dose for each of the food allergens, the method according to claim 41, further comprising:

63. The method according to claim 41, further comprising continuing the maintenance doses of the first food allergen, the second food allergen, and the third food allergen until the pre-measured dose for each of the food allergens is consumed.

64. The method according to claim 41, wherein the pre-measured dose for each of the first food allergen, the second food allergen, and the third food allergen is consumed over 12 days.

65. The method according to claim 41, wherein the first food allergen and the second food allergen are each independently selected from the group consisting of milk, eggs, peanuts, wheat, soybeans, sesame, fish, crustaceans, and nuts, and preferably are milk and eggs, respectively.

66. The method according to claim 41, wherein the third food allergen is selected from the group consisting of milk, eggs, peanuts, wheat, soybeans, sesame, fish, crustaceans, and nuts, and preferably is peanuts.

67. The method according to claim 41, wherein the pre-measured dose of the food allergen is mixed in breast milk, a nutritional supplement, or food, and thereafter, the food allergen is administered to the subject.

68. The method according to claim 41, wherein the pre-measured dose of the food allergen is in powder form.

69. The method according to claim 41, wherein the exposure dose of each food allergen is about 0.01 to 0.3 grams, and the maintenance dose of each food allergen is about 0.05 to 1 gram.

70. The method according to claim 41, wherein the first food allergen comprises milk, the exposure dose of the first food allergen is about 0.2 grams of milk protein, and the maintenance dose of the first food allergen is about 0.4 grams of milk protein.

71. The method according to claim 41, wherein the second food allergen comprises eggs, the exposure dose of the second food allergen is about 0.03 grams of egg protein, and the maintenance dose of the second food allergen is about 0.1 grams of egg protein.

72. The method according to claim 41, wherein the third food allergen comprises peanuts, the exposure dose of the third food allergen is about 0.1 grams of peanut protein, and the maintenance dose of the third food allergen is about 0.4 grams of peanut protein.

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