Combination methods for treating or preventing atopic diseases in children

Abstract

Methods of treating or reducing onset or occurrence of atopic diseases in children are described. Specifically, the present application relates to an integrated solution that takes into account the temporal and sequential administration of three different specific methods to achieve the optimal effect of treating or reducing the onset or occurrence of atopic diseases in children.

Description

Technical Field

[0001] The present application describes a combination for treating atopic diseases in children or reducing their onset or occurrence and a method of using the combination. Specifically, the present application relates to an integrated solution that takes into account the time and sequential application of three different methods to obtain the best effect of treating atopic diseases in children or reducing their onset or occurrence. Background Art

[0002] The prevalence of pediatric allergic disease (also known as childhood atopy) is increasing worldwide. An estimated 20% of children suffer from eczema (atopic dermatitis) and 8% report an allergy to at least one food. Atopic disease represents a failure of immune tolerance and subsequent overreaction to benign inhalant (environmental) or food allergens. Although there has been extensive research into the potential genetic, metabolomic, environmental, and socioeconomic predictors of atopic disease, current clinical guidance for allergic disease focuses on avoidance of allergens and acute treatment of exacerbations rather than prevention.

[0003] Prevention of atopic diseases in children requires a multimodal approach that addresses several underlying causes that lead to dysregulation of the immune system and failure to establish or maintain immune tolerance. In early infancy, skin barrier disorders and altered skin microbiota in the presence or absence of eczema allow food and inhalant allergens to sensitize infants and produce immune cells that migrate to the intestine or lungs, leading to food allergies or asthma, respectively. In addition, infants born in the modern world today lack important key intestinal microorganisms and therefore lack their functions due to cross-generational effects caused by exposure to antibiotics, cesarean sections, lack of breastfeeding, and / or their mothers suffering the same damage. This intestinal dysbiotic microbiome cannot induce a tolerant state and leads to a pro-inflammatory environment that mischaracterizes benign antigens. Finally, incorrect historical medical advice and parental anxiety lead to delayed introduction of food in infancy, which is required for optimal immune training of specific foods.

[0004] While individual solutions, such as moisturizers and emollients, probiotics, and food introduction products have been developed and marketed to concerned parents, an easy-to-use, parent-administered integrated solution has not been developed that takes into account the specific timing and sequence of application requirements needed to achieve optimal results in preventing childhood allergic diseases. Therefore, there is a need to develop such a solution to prevent childhood atopic diseases, such as atopic dermatitis or eczema, food allergies, and asthma. Summary of the invention

[0005] The present application describes methods of treating or reducing the onset or occurrence of atopic diseases in children. Specifically, the present application describes methods of integrating individual solutions such as eczema moisturizers and emollients, probiotics, and food-introduced products in a temporal manner.

[0006] In one general aspect, the present application describes a method of treating a pediatric atopic disease (such as atopic dermatitis) in a subject in need thereof or reducing the onset or occurrence thereof, the method comprising performing at least two of the following:

[0007] (a) topically applying a first composition to a skin area of ​​a subject, wherein the first composition comprises a skin barrier function composition, and the application of the first composition begins within about seven days after birth of the subject, more specifically within about six days, five days, four days, three days, two days or one day after birth of the subject, and continues until at least about two months after birth of the subject;

[0008] (b) orally administering to the subject a second composition comprising an effective amount of probiotics such as Bifidobacterium cells, wherein 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 at least until the introduction of solid food; and

[0009] (c) orally administering a pre-measured dose of one or more food allergens to the subject, wherein administration of the one or more food allergens begins within about 1-8 months after birth of the subject, more specifically, within about 2-6 months after birth of the subject.

[0010] In another general aspect, the present application describes a first composition for use in a method of treating a pediatric atopic disease (such as atopic dermatitis) in a subject in need thereof or reducing the onset or occurrence thereof, the method comprising performing at least two of the following:

[0011] (a) topically applying a first composition to a skin area of ​​a subject, wherein the first composition comprises a skin barrier function composition, and the application of the first composition begins within about seven days after birth of the subject, more specifically within about six days, five days, four days, three days, two days or one day after birth of the subject, and continues until at least about two months after birth of the subject;

[0012] (b) orally administering to the subject a second composition comprising an effective amount of probiotics such as bifidobacterium cells, wherein 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 at least until the introduction of solid food; and

[0013] (c) orally administering a pre-measured dose of one or more food allergens to the subject, wherein administration of the one or more food allergens begins within about 1-8 months after birth of the subject, more specifically, within about 2-6 months after birth of the subject.

[0014] In another general aspect, the present application describes a second composition for use in a method of treating a pediatric atopic disease (such as atopic dermatitis) in a subject in need thereof or reducing the onset or occurrence thereof, the second composition comprising an effective amount of a probiotic, such as a Bifidobacterium cell, the method comprising performing at least two of the following:

[0015] (a) topically applying a first composition to a skin area of ​​a subject, wherein the first composition comprises a skin barrier function composition, and the application of the first composition begins within about seven days after birth of the subject, more specifically within about six days, five days, four days, three days, two days or one day after birth of the subject, and continues until at least about two months after birth of the subject;

[0016] (b) orally administering the second composition to the subject, wherein administration of the second composition begins within about 30 days after birth of the subject, more specifically, from about 28 days, 21 days,

[0017] Beginning within 14 days or 7 days and optionally continuing at least until solid foods are introduced;

[0018] as well as

[0019] (c) orally administering a pre-measured dose of one or more food allergens to the subject, wherein administration of the one or more food allergens begins within about 1-8 months after birth of the subject, more specifically, within about 2-6 months after birth of the subject.

[0020] In another general aspect, the present application describes a pre-measured dose of one or more food allergens for use in a method of treating a pediatric atopic disease (such as atopic dermatitis) in a subject in need thereof or reducing the onset or occurrence thereof, the method comprising performing at least two of the following:

[0021] (a) topically applying a first composition to a skin area of ​​a subject, wherein the first composition comprises a skin barrier function composition, and the application of the first composition begins within about seven days after birth of the subject, more specifically within about six days, five days, four days, three days, two days or one day after birth of the subject, and continues until at least about two months after birth of the subject;

[0022] (b) orally administering to the subject a second composition comprising an effective amount of probiotics such as bifidobacterium cells, wherein 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 at least until the introduction of solid food; and

[0023] (c) orally administering a pre-measured dose of one or more food allergens to the subject, wherein administration of the one or more food allergens begins within about 1-8 months after birth of the subject, more specifically, within about 2-6 months after birth of the subject.

[0024] In some embodiments, the method comprises performing (a) and (b), preferably beginning administration of the first composition prior to administration of the second composition.

[0025] In some embodiments, the method comprises performing (a) and (c).

[0026] In some embodiments, the method comprises performing (b) and (c).

[0027] In some embodiments, the method comprises performing (a), (b), and (c), preferably beginning administration of the first composition prior to administration of the second composition.

[0028] In some embodiments, the first composition comprises an emollient, more specifically, the first composition further comprises colloidal oatmeal, ceramide, and distearyldimonium chloride.

[0029] In some embodiments, administration of the second composition continues until the desired intestinal microbiota is established.

[0030] In some embodiments, the subject receives one, two, three, four, five, or more administrations of the second composition.

[0031] In some embodiments, administration of the second composition continues for at least 12 weeks.

[0032] In some embodiments, the probiotic comprises a bacterial strain selected from the genera Lactobacillus, Lacticaseibacillus and Bifidobacterium, and more specifically comprises Bifidobacterium cells.

[0033] In some embodiments, the Bifidobacterium cell is a Bifidobacterium infantis (B. infantis) cell.

[0034] In some embodiments, the second composition comprises from about 100 million to about 100 billion, more specifically from about 5 billion to about 15 billion, most specifically 8 billion colony forming units (CFU) of Bifidobacterium infantis.

[0035] In some embodiments, administration of one or more food allergens comprises:

[0036] i. administering a first food allergen to the subject at an exposure dose of the first food allergen for one or more days;

[0037] ii. subsequently administering the first food allergen to the subject at a maintenance dose of the first food allergen for a plurality of days;

[0038] iii. subsequently administering the first food allergen to the subject at a maintenance dose and administering the second food allergen to the subject at an exposure dose of the second food allergen for one or more days; and

[0039] iv. Subsequently administering both the first food allergen and the second food allergen at a maintenance dose of each food allergen for multiple days.

[0040] In some embodiments, administration of one or more food allergens further comprises:

[0041] v. administering a third food allergen to the subject at an exposure dose of the third food allergen for one or more days,

[0042] vi. subsequently administering the first food allergen, the second food allergen, and the third food allergen to the subject at a maintenance dose of each food allergen for a number of days.

[0043] In some embodiments, the method further comprises continuing the maintenance dose of the first food allergen, the second food allergen, and the third food allergen until the pre-measured dose of each food allergen is consumed.

[0044] In some embodiments, the pre-measured doses of each of the first food allergen, the second food allergen, and the third food allergen are consumed over 12 days.

[0045] 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, soy, sesame, fish, shellfish, and tree nuts, preferably milk, eggs, and peanuts, respectively.

[0046] In another general aspect, the present application describes a kit or combination for use in the methods described herein, the kit or combination containing a first composition that is a skin barrier function composition, a second composition comprising an effective amount of bifidobacterium cells, and at least two of a pre-measured dose of one or more food allergens.

[0047] Other aspects, features, and advantages of the invention will be apparent from the following disclosure, including the detailed description of the invention and preferred embodiments thereof, and the appended claims. DETAILED DESCRIPTION

[0048] Various publications, articles, and patents are cited or described in the background and throughout the specification; each of these references is incorporated herein by reference in its entirety. The discussion of documents, acts, materials, devices, articles, etc. included in this specification is intended to provide context for the present invention. Such discussion is not an admission that any or all of these matters form part of the prior art with respect to any invention disclosed or claimed.

[0049] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention belongs. Otherwise, certain terms used herein have the meanings described in this specification. All patents, published patent applications, and publications cited herein are incorporated herein by reference as if fully set forth herein.

[0050] It is noted that as used herein and in the appended claims, the singular forms "a," "an," "the," and "said" include plural referents unless the context clearly dictates otherwise.

[0051] Throughout this specification and the claims that follow, unless the context requires otherwise, the word "comprise" and variations such as "include" and "contain" will be understood to imply the inclusion of at least one or more listed elements (e.g., stated integers or steps, etc.), but not to exclude other unlisted elements, i.e., other elements not mentioned may also be present. When used herein, the term "comprise" may be replaced with the term "contain" or "includes", or sometimes with the term "have" when used herein.

[0052] Whenever used herein in the context of one aspect or embodiment of the present invention, any of the foregoing terms "comprising," "containing," "including," and "having" may be replaced with the terms "consisting of" or "consisting essentially of to alter the scope of the present disclosure.

[0053] As used herein, the connection term "and / or" between multiple listed elements is understood to include both single options and combined options. For example, where two elements are connected by "and / or", the first option refers to the application of the first element without the second element. The second option refers to the application of the second element without the first element. The third option refers to the application of the first element and the second element together. Any of these options is understood to fall within the meaning and therefore meets the requirements of the term "and / or" as used herein. The parallel applicability of more than one option is also understood to fall within the meaning and therefore meets the requirements of the term "and / or".

[0054] The term “between” as used in phrases such as “between A and B” or “between AB” refers to a range that includes both A and B.

[0055] As used herein, "substantially free" or "essentially free" of a certain component means containing less than 0.1 weight percent of the component. In some embodiments, "essentially free" or "essentially free" of a certain component means containing less than 0.01 weight percent of the component or not containing the component.

[0056] As used herein, the terms "method" and "procedure" are used interchangeably.

[0057] As used herein, the terms "atopic disease" and "allergic disease" are used interchangeably. Atopic disease is a disease in which the immune system responds to common environmental allergens that are generally considered harmless.

[0058] A class of diseases that produce the immunoglobulin IgE. Examples of atopic diseases include, but are not limited to, atopic dermatitis (AD), allergic rhinitis, asthma, and food allergies.

[0059] As used herein, the term "atopic dermatitis" or "eczema" refers to a chronic, recurring inflammatory skin disorder that causes itching and / or redness of the skin. Pruritus, or itchy skin, is the main symptom of atopic dermatitis, which can also have skin lesions ranging from mild erythema to severe lichenification to erythroderma. It is common in children but can occur at any age. Atopic dermatitis can be accompanied by asthma or hay fever. There is currently no cure for atopic dermatitis.

[0060] As used herein, the term "subject" refers to a human. Specifically, the subject is an infant. More specifically, the subject is an infant at increased risk of developing a childhood atopic disease, for example, an infant with a first-degree relative with a history of atopic disease. The infant may be born vaginally or by caesarean section.

[0061] As used herein, the term "effective amount" refers to an amount of a regimen and / or composition sufficient to significantly induce a positive benefit, including independently or in combination with other benefits disclosed herein. This means that the amount and / or concentration of the active ingredient in the regimen and / or composition is sufficient to treat atopic disease in a child or reduce the onset or occurrence of the disease when the regimen and / or composition is applied at normal frequency and in normal amounts. The effective amount of the compound, extract or composition will vary with factors such as the age, health and environmental exposure status of the end user, the duration and nature of the treatment, the specific extract, ingredient or composition employed, and the specific pharmaceutically acceptable carrier used.

[0062] As used herein, the term "skin barrier function composition" refers to a composition that can enhance or improve the skin barrier of a subject when applied to a subject. The skin barrier function composition may include one or more ingredients that help the skin provide protection against external threats such as infectious agents, chemicals, systemic toxicity and allergens, protection against increased water loss in the body, and / or maintain homeostasis in the body. As used herein, the term "emollient" refers to a chemical agent specifically designed to make the outer layer of the skin (epidermis) softer and more flexible. Examples of emollients include, but are not limited to, humectants (e.g., glycerol), butter, oil, esters, lipids and fatty acids.

[0063] As used herein, "humectants" are those agents that maintain or increase the free water concentration in the epidermis. It can add moisture to the skin, draw water from the dermis into the epidermis, or prevent water loss. Humectants include emollients and occlusives. Examples of occlusives include, for example, petroleum jelly (petrolatum), mineral oil, silicones, polydimethylsiloxanes, waxes, and lanolin.

[0064] As used herein, "infant" refers to a human ranging in age from birth to about twelve months.

[0065] As used herein, "topical application," "topically," and "topical" refer to applying the regimens and / or compositions for use in accordance with the present disclosure to the surface of the skin.

[0066] As used herein, "a second composition comprising an effective amount of probiotics" refers to a composition containing an effective amount of isolated or enriched probiotics. As used herein, "isolated or enriched probiotics" refers to probiotics isolated or enriched from their natural environment. In some embodiments, the second composition is breast milk containing probiotics, such as one or more bacterial cells of the genera Lactobacillus, Lactobacillus, and Bifidobacterium that are isolated or enriched from their natural environment. The second composition is not naturally occurring breast milk.

[0067] Ways to prevent atopic diseases in children

[0068] The present application describes a method of treating a pediatric atopic disease or reducing its onset or occurrence in a subject in need thereof, the method comprising performing at least two of the following:

[0069] (a) topically applying a first composition to a skin area of ​​a subject, wherein the first composition comprises a skin barrier function composition, and the application of the first composition begins within about seven days after birth of the subject, more specifically within about six days, five days, four days, three days, two days or one day after birth of the subject, and continues until at least about two months after birth of the subject; and

[0070] (b) orally administering to the subject a second composition comprising an effective amount of probiotics such as bifidobacterium cells, wherein 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 at least until the introduction of solid food; and

[0071] (c) orally administering a pre-measured dose of one or more food allergens to the subject, wherein administration of the one or more food allergens begins within about 1-8 months after birth of the subject, more specifically, within about 2-6 months after birth of the subject.

[0072] In some embodiments, the method comprises performing (a) and (b).

[0073] In some embodiments, the method comprises performing (a) and (c).

[0074] In some embodiments, the method comprises performing (b) and (c).

[0075] In some embodiments, the method comprises performing (a), (b), and (c).

[0076] In certain embodiments, the method comprises:

[0077] (a) topically applying a first composition to a skin area of ​​a subject, wherein the first composition comprises a skin barrier function composition, and the application of the first composition begins within about seven days after birth of the subject, more specifically within about six days, five days, four days, three days, two days or one day after birth of the subject, and continues until at least about two months after birth of the subject;

[0078] (b) orally administering one or more food allergens to the subject at an exposing dose for one or more days, wherein administration of the one or more food allergens begins within about 1-8 months after birth of the subject, more specifically, within about 2-6 months after birth of the subject; and

[0079] (c) administering the one or more food allergens to the subject at a maintenance dose for one or more days after step (b).

[0080] In certain embodiments, the method comprises:

[0081] (a) orally administering to a subject a second composition comprising an effective amount of probiotics such as bifidobacteria, wherein 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 at least until the introduction of solid food;

[0082] (b) orally administering one or more food allergens to the subject at an exposing dose for one or more days, wherein administration of the one or more food allergens begins within about 1-8 months after birth of the subject, more specifically, within about 2-6 months after birth of the subject; and

[0083] (c) orally administering one or more food allergens to the subject at a maintenance dose for one or more days after step (b).

[0084] In certain embodiments, the method comprises:

[0085] (a) topically applying a first composition to a skin area of ​​a subject, wherein the first composition comprises a skin barrier function composition, and the application of the first composition begins within about seven days after birth of the subject, more specifically within about six days, five days, four days, three days, two days or one day after birth of the subject, and continues until at least about two months after birth of the subject; and

[0086] (b) orally administering to the subject a second composition comprising an effective amount of a probiotic such as Bifidobacterium, wherein 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 at least until the introduction of solid food.

[0087] In certain embodiments, the method comprises:

[0088] (a) topically applying a first composition to a skin area of ​​a subject, wherein the first composition comprises a skin barrier function composition, and the application of the first composition begins within about seven days after birth of the subject, more specifically within about six days, five days, four days, three days, two days or one day after birth of the subject, and continues until at least about two months after birth of the subject;

[0089] (b) orally administering to the subject a second composition comprising an effective amount of a probiotic such as a bifidobacterium, wherein 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 at least until the introduction of solid food;

[0090] (c) orally administering one or more food allergens to the subject at an exposing dose for one or more days, wherein administration of the one or more food allergens begins within about 1-8 months after birth of the subject, more specifically, within about 2-6 months after birth of the subject; and

[0091] (d) after step (c), orally administering to the subject one or more food allergens at a maintenance dose for one or more days.

[0092] In certain embodiments, when both the first composition and the second composition are to be administered, administration of the first composition is initiated before administration of the second composition. In certain embodiments, when administration of the first composition, the second composition, and / or the allergen is initiated at different times, administration of the first composition, the second composition, and / or the allergen may overlap. For example, the first composition may be first administered from about one day to about seven days after birth of the subject, preferably from about four days, more preferably from about two days; and the second composition may be first administered from about one day to about 30 days after birth of the subject, preferably from about one day to 14 days, and one or more food allergens may be first administered from about one month to about eight months, preferably from about two months to six months after birth of the subject.

[0093] Regarding step (a) of the method, the first composition comprises a skin barrier function composition. The skin barrier is very important for human life. Physically, it protects against external threats such as infectious agents, chemicals, systemic toxicity, and allergens. Internally, the skin helps maintain homeostasis and prevents increased water loss in the body. For basic parameters related to skin barrier function, external factors affecting the skin barrier, and treatments for improving the skin barrier, see, e.g., Kanwar et al., Indian J Med Res. January 2018; 147 (1): 117-118. See also, e.g., Cezmi A. Akdis, Nature Reviews Immunology, 2021 (21): 739-751 and Cezmi A. Akdis, J. Allergy Clin. Immunol., 2022, Vol. 149 (1): 41-44. The skin barrier function composition may contain one or more of a moisturizer, ingredients that help rebuild the barrier and reduce inflammation (such as ceramide or oatmeal), and a skin protectant that prevents proteins or other substances from entering the skin (through surface chemistry), such as silicone-based polymers (e.g., polydimethylsiloxane).

[0094] It is believed that the first composition exerts its effect at least in part through a combination of the timing of administration and the effect of a single ingredient in the composition; and / or through a combination of the timing of administration and the effect of a combination of two or more ingredients in the composition; and / or through a combination of the timing of administration and an effect based on the amount of a single ingredient in the composition; and / or through a combination of the timing of administration and an effect based on the relative amounts of two or more ingredients in the composition.

[0095] Without being bound by theory, the inventors believe that the first composition exerts its effect by one or more of the following means:

[0096] a. Improve barrier function;

[0097] b. have a probiotic effect on the skin microbiome, thereby stimulating the growth of microorganisms with beneficial properties;

[0098] i. Some ingredients are believed to achieve this by acting as buffers to achieve optimal skin pH;

[0099] c. Has antioxidant effect;

[0100] d. Has anti-inflammatory effects;

[0101] e. Stimulate ceramide production; and

[0102] f. Stimulate fatty acid production.

[0103] g. Forms a surface layer that prevents food proteins from penetrating the skin barrier

[0104] In some embodiments, the first composition is administered at least once a day, preferably at least twice a day.

[0105] In some embodiments, administration of the first composition begins within about two days after birth of the subject.

[0106] In some embodiments, the first composition is applied to the skin of the subject all over the body.

[0107] In some embodiments, the first composition is formulated into a dosage form selected from the group consisting of a balm, a cream, a lotion, an emulsion, a serum, an ointment, and a paste.

[0108] According to an embodiment of the present application, the first composition comprises one or more ingredients selected from the group consisting of 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-methoxybenzoic acid, sodium cetearyl sulfate, palmitic acid, stearic acid, sodium sulfate, sodium chloride, citric acid, dipotassium hydrogen phosphate, potassium phosphate, sodium hydroxide, tocopherol, benzyl alcohol, benzoic acid and potassium sorbate and a carrier.

[0109] In some embodiments, the first composition comprises an emollient, more specifically, the first composition further comprises colloidal oatmeal, ceramide, and distearyldimonium chloride.

[0110] In some embodiments, the first composition comprises one or more of the following ingredients in the amounts indicated below:

[0111] a. caprylic / capric triglyceride, preferably from about 0.0% to about 1.0%, more preferably from about 0.005% to about 1.0%;

[0112] b. citric acid, preferably from about 0.0% to about 0.1%, more preferably from about 0.005% to about 0.1%;

[0113] c. benzoic acid, preferably from about 0.0% to about 2.0%, more preferably from about 0.1% to about 2.0%;

[0114] d. potassium phosphate, preferably from about 0.0% to about 2.0%, more preferably from about 0.05% to about 2.0%;

[0115] e. polydimethylsiloxane, preferably from about 0.0% to about 10.0%, more preferably from about 1.0% to about 10.0%;

[0116] f. stearic acid; palmitic acid, preferably from about 0.0% to about 2.0%, more preferably from about 0.1% to about 2.0%;

[0117] g. isocetyl alcohol, preferably from about 0.0% to about 10.0%, more preferably from about 1.0% to about 10.0%;

[0118] h. oat kernel flour, preferably from about 0.0% to about 2.0%, more preferably from about 0.1% to about 2.0%;

[0119] i. Ceramide 3, preferably from about 0.0% to about 0.1%, more preferably from about 0.005% to about 0.1%;

[0120] j. ethylhexylglycerin, preferably from about 0.0% to about 2.0%, more preferably from about 0.1% to about 2.0%;

[0121] k. oat kernel oil, preferably from about 0.0% to about 1.0%, more preferably from about 0.005% to about 1.0%;

[0122] l. an oat kernel extract comprising glycerin, potassium sorbate and water, preferably from about 0.0% to about 1.0%, more preferably from about 0.005% to about 1.0%;

[0123] m. water, preferably from about 15.0% to about 40.0%, more preferably from about 20.0% to about 40.0%;

[0124] n. glycerol, preferably from about 20.0% to about 50.0%, more preferably from about 30.0% to about 50.0%;

[0125] o. Sodium cetearyl sulfate, preferably from about 0.0% to about 2.0%, more preferably from about 0.1% to about 2.0%;

[0126] p. dipotassium hydrogen phosphate, preferably from about 0.0% to about 2.0%, more preferably from about 0.1% to about 2.0%;

[0127] q. sodium hydroxide, preferably from about 0.0% to about 1.0%, more preferably from about 0.005% to about 1.0%;

[0128] r. cetyl alcohol, preferably from about 0.0% to about 10.0%, more preferably from about 1.0% to about 10.0%;

[0129] s. Cetearyl alcohol, preferably from about 0.0% to about 10.0%, more preferably from about 1.0% to about 10.0%;

[0130] t. benzyl alcohol, preferably from about 0.0% to about 2.0%, more preferably from about 0.1% to about 2.0%; and / or

[0131] u. p-Anisic acid, preferably from about 0.0% to about 2.0%, more preferably from about 0.1% to about 2.0%.

[0132] Without being bound by theory, it is believed that these ingredients, alone or in combination with other ingredients, function at least in part as follows:

[0133] a. Improve barrier function;

[0134] i. Caprylic / capric triglyceride forms a barrier on the skin's surface, which helps reduce skin dryness by reducing moisture loss.

[0135] ii. Dimethicone acts as a skin protectant.

[0136] iii. Stearic acid and palmitic acid are fatty acids that form an occlusive barrier that protects the skin from undesirable microorganisms and pollutants while retaining moisture.

[0137] iv. Hexyldecanol is a fatty alcohol that forms a layer on the surface of the skin.

[0138] v. Ceramides together with saturated fatty acids form a water-impermeable protective layer to prevent excessive water loss due to evaporation and provide a barrier against the entry of microorganisms.

[0139] vi. Glycerin, also known as glycerol, is a humectant that hydrates the outer layer of the skin and improves skin barrier function and skin mechanical properties.

[0140] b. Has a probiotic effect on the skin microbiome, thereby stimulating the growth of microorganisms with beneficial properties. It is believed that one or more of the ingredients in the applied composition may play a role in the balance of the skin microbiome.

[0141] i. Oat-based products work in concert with the skin to perform multiple functions, including forming a protective barrier on the surface of the skin (called the skin microbiome) that protects against invasion by opportunistic pathogenic microorganisms.

[0142] 1. Oat Kernel Flour

[0143] 2. Oat Kernel Oil

[0144] 3. Water; Glycerin; Oat Kernel Extract

[0145] ii. Buffering skin pH to help the skin reach an optimal pH level that can affect the survival and growth rate of microbial species:

[0146] 1. Citric Acid

[0147] 2. Benzoic acid

[0148] 3. Potassium phosphate

[0149] 4. Potassium hydrogen phosphate

[0150] 5. Sodium hydroxide

[0151] iii. Glycerol, also known as propylene glycol, is a humectant that can have an impact on the microbiome.

[0152] c. Has antioxidant effect;

[0153] i. Caprylic / capric triglycerides can act as an antioxidant, which serves to neutralize toxins from exposure to the environment.

[0154] ii. Tocopherol

[0155] d. Has anti-inflammatory effects;

[0156] i. One or more ingredients in the composition can correct subclinical skin barrier dysfunction and early inflammation in susceptible infants before atopic dermatitis develops 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 into the epidermis, which are potential triggers of skin inflammation.

[0157] ii. The oatmeal component has anti-inflammatory properties which helps reduce itching.

[0158] 1. Oat Kernel Flour

[0159] 2. Oat Kernel Oil

[0160] 3. Water; Glycerin; Oat Kernel Extract

[0161] e. Stimulate ceramide production;

[0162] i. Oat Kernel Flour

[0163] ii. Oat Kernel Oil

[0164] iii. Water; Glycerin; Oat Kernel Extract

[0165] iv. Glycerol, also known as propylene glycol

[0166] f. Stimulate fatty acid production.

[0167] i. Glycerin, also known as propylene glycol.

[0168] Ethylhexylglycerin is a glyceryl ether that is often used as a part of the preservative system in cosmetic formulations or for their skin conditioning properties.

[0169] Sodium cetearyl sulfate is a mixture of stearyl and cetyl sulfates which acts as a surfactant in the composition.

[0170] Cetyl alcohol acts as a thickener and emulsifier, helping to prevent product ingredients from separating.

[0171] Cetearyl alcohol is a mixture of two fatty alcohols, cetyl alcohol and stearyl alcohol, and is used in personal care products to create a smoother, thicker composition.

[0172] Benzyl alcohol is used as a preservative in skin care products due to its antibacterial and antifungal properties.

[0173] Para-methoxybenzoic acid is used as a masking agent (meaning it helps mask the smell in a product) and a preservative.

[0174] Polydimethylsiloxanes may also have a defoaming effect, which may affect the aesthetics of the product to make it more desirable for consumer use.

[0175] As used in step (b) of the method, the second composition may contain probiotics that help establish a healthy microbiome. Examples of probiotics include, but are not limited to, bacterial strains selected from the genera Lactobacillus, Lactobacillus and Bifidobacterium, more specifically including bifidobacterial cells. Bifidobacterium is a genus of Gram-positive anaerobic bacteria that resides in the gastrointestinal tract, vagina and oral passages of mammals (including humans). Suitable bifidobacteria may be those having at least one human milk oligosaccharide (HMO) gene cluster. The bifidobacterium may be a bifidobacterium similar to infantis. The bifidobacterium may be selected from the group consisting of: Bifidobacterium longum, Bifidobacterium breve, Bifidobacterium bifidum, Bifidobacterium pseudocatenulatum, Bifidobacterium globosum, Bifidobacterium adolescentis, Bifidobacterium moukalabense, Bifidobacterium reuteri, Bifidobacterium pseudolongum, Bifidobacterium dentata B.dentium, B.catenulatum, B.sp002742445, B.callitrichos, B.scardovii, B.tissieri, B.subtile, B.gallinarum, B.choerinum, B.angulatum, B.pr imatium), Bifidobacterium myosotis, Bifidobacterium mongoliense, Bifidobacterium merycicum, Bifidobacterium lemurum, Bifidobacterium stellenboschense, Bifidobacterium scaligerum, Bifidobacterium saguini, Bifidobacterium pullorum, Bifidobacterium felsineum, Bifidobacterium eu B.eulemuris), rabbit Bifidobacterium (B.cuniculi), fine hair Bifidobacterium _A (B.callitrichos_A), Bifidobacterium bivatii, goose Bifidobacterium (B.anSeris), Vansinderenii Bifidobacterium (B.vansinderenii), B.sp900551485, B.sp003952945, B.sp003952025, B.sp003952005, simian Bifidobacterium (B.simiarum), pseudo long Bifidobacterium _C (B.pseudolongum_C), Bifidobacterium parmae ​​(B.parmae), Bifidobacterium margollesii (B.margollesii), Bifidobacterium kashiwanohense_A (B.kashiwanohense_A), Bifidobacterium italicum (B.italicum), Bifidobacterium imperatoris (B.imperatoris), Bifidobacterium cricetid (B.catulorum), Bifidobacterium callitrichidarum (B.callitrichidarum), Bifidobacterium animalis (B.animalis), Bifidobacterium aesculapii (B.aesculapii) and combinations thereof. The bifidobacterium may be selected from the group consisting of Bifidobacterium longum, Bifidobacterium breve, Bifidobacterium kashiwanohense and combinations thereof. The bifidobacterium may be Bifidobacterium longum. The bifidobacterium may be a subspecies of Bifidobacterium longum selected from the group consisting of Bifidobacterium longum, Bifidobacterium breve, Bifidobacterium kashiwanohense and combinations thereof.

[0176] In certain embodiments, the bifidobacterium cells in the second composition are Bifidobacterium infantis cells. As used herein, the term "Bifidobacterium infantis" or "B. infantis" is intended to refer to the subspecies infantis of Bifidobacterium longum. Bifidobacterium infantis may include strain EVC001. Bifidobacterium infantis may be isolated and cultured using methods known in the art.

[0177] Bifidobacterium infantis can be co-administered with one or more other probiotics (i.e., other bacteria intended to have health benefits). Other probiotics can be strains selected from the genus Lactobacillus, the genus Lactobacillus and the genus Bifidobacterium. The example of Bifidobacterium species includes Bifidobacterium infantis, Bifidobacterium longum (subspecies except Bifidobacterium infantis), Bifidobacterium breve, Bifidobacterium chain, Bifidobacterium adolescentis, Bifidobacterium animalis, Bifidobacterium gallicum (B. gallicum), Bifidobacterium lactis (B. lactis), Bifidobacterium pseudochain and other strains of Bifidobacterium bifidum. The example of Lactobacillus strains includes Lactobacillus paracasei (L. paracasei), Lactobacillus acidophilus (L. acidophilus), Lactobacillus johnsonii (L. johnsonii), Lactobacillus delbrueckii (L. delbrueckii), Lactobacillus crispatus (L. crispus), Lactobacillus gasser (L. gasser), Lactobacillus zeae (L. zeae) and combinations thereof. Examples of lactobacillus include L. casei, L. rhamnosus, and combinations thereof. Other probiotics include Lactiplantibacillus plantarum, Limosilactobacillus fermentum, and Ligilactobacillus salivarius. Alternatively, bifidobacteria may be administered without any other probiotics. That is, bifidobacteria may be formulated to be substantially free of any other probiotics.

[0178] The intestinal microbiome profile of a subject can be tested and monitored using methods known in the art to determine colonization with bifidobacteria. Stool samples can be used in such methods.

[0179] Bifidobacteria can be formulated into compositions that are easy to use and allow for consistent dosing. Fermentation products produced from Bifidobacteria can be concentrated and freeze-dried to provide concentrated powders.

[0180] According to an embodiment of the present application, the second composition comprises about 100 million to about 100 billion, more specifically about 5 billion to about 15 billion colony forming units (CFU) of Bifidobacterium per gram of dry weight, preferably Bifidobacterium infantis. In certain embodiments, the second composition comprises about 8 billion colony forming units (CFU) of Bifidobacterium infantis per gram of dry weight.

[0181] In a preferred embodiment, the second composition is not naturally occurring breast milk.

[0182] Bifidobacterium can also be formulated with oligosaccharides. As used herein, the term "oligosaccharide" refers to a sugar polymer containing 2 to 20, 2 to 10, 3 to 20 or 3 to 10 monosaccharide units. Oligosaccharides can be those found in mammalian milk (e.g., humans or cows). Oligosaccharides can be synthesized.

[0183] The second composition containing bifidobacteria may also contain auxiliary components. Such auxiliary components are those commonly used in the art and may be selected from metabolites, leveling agents or combinations thereof. Examples of leveling agents include starch, silicon dioxide, cellulose, sodium bicarbonate, calcium silicate, etc. The auxiliary component may also be a milk protein or ingredient. The auxiliary component may include lactose. That is, in such examples, the bifidobacteria are in powder form mixed with lactose.

[0184] The final form of the second composition can be any form known in the art. As described above, the bifidobacteria can be in a dry form (e.g., spray-dried or freeze-dried) as a powder. The powder can be administered in a sachet, pouch, tablet, food, capsule, lozenge, tablet, suspension, dry form, etc.

[0185] In certain embodiments, a suitable second composition containing Bifidobacterium according to one or more embodiments of the present invention is available from Evolve BioSystems (Davis, CA). Probiotics packaged in sachets containing 8 billion CFU of Bifidobacterium infantis (EVC001) co-formulated with lactose.

[0186] According to an embodiment of the present application, the subject is breastfed or fed with a supplement comprising one or more human breast milk oligosaccharides or prebiotics. It is believed that human breast milk oligosaccharides or prebiotics can support the growth of bifidobacteria (see, e.g., Francesca Turroni et al., Trends in Microbiology, 2018, Vol. 26 (4): 339-350 and Andrea C. Masi and Christopher J. Stewart, iScience, 2022, Vol. 25b91): 103542). In some embodiments, prebiotics can be other oligosaccharides, polysaccharides or fibers. In some embodiments, the supplement can be infant formula.

[0187] A given dose of probiotics such as bifidobacterium is provided to the subject as a part of feeding (i.e., it is used as a food supplement). Before probiotics such as bifidobacterium are applied to the subject, probiotics such as bifidobacterium can be mixed with any medium edible to the subject, including breast milk, infant formula, water or food. Probiotics such as bifidobacterium can be mixed into breast milk before probiotics such as bifidobacterium are applied to the subject. Alternatively, probiotics such as bifidobacterium can be mixed into infant formula before bifidobacterium is applied to the subject. Probiotics such as bifidobacterium are mixed with enough infant formula or breast milk so that the subject can fully absorb bifidobacterium and the subject can still possibly and can eat the bifidobacterium of the whole dose. Therefore, probiotics such as bifidobacterium can be mixed with breast milk or infant formula of about 3mL to about 5mL before probiotics such as bifidobacterium are applied to the subject. The probiotic (such as Bifidobacterium) composition can be mixed by any suitable means, including simply stirring the composition with a medium (e.g., infant formula, breast milk, water) in a bowl (or any other suitable means to obtain a mixture). The composition mixed with infant formula or breast milk can then be fed to the subject by any suitable means. Suitable feeding methods include using a feeding syringe, spoon or bottle. When the subject is more likely to be hungry, the probiotic, such as Bifidobacterium, can be administered before feeding the subject, which is believed to increase the likelihood of consuming the entire dose.

[0188] The dosage and dosing frequency can be selected as needed. In some embodiments, the second composition comprising probiotics (such as bifidobacteria) is administered once daily, and the once daily dose may contain about 5-15 billion or about 8 billion CFU. It is also contemplated that the total desired dose will be divided into smaller doses. Examples may include smaller doses several times throughout the day (e.g., 2, 3, 4, or 5 times a day).

[0189] The total dose administered daily may be in the range of 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 probiotics such as bifidobacteria. The total dose administered daily may be in the range of about 5 billion to about 15 billion CFU, or about 8 billion CFU. Such total dose values ​​may be given in one dose.

[0190] The second composition comprising probiotics such as bifidobacteria can be used after the birth of the experimenter in about 30 days, more specifically in about 28 days, 21 days, 14 days or 7 days after the birth of the experimenter. Once started, the second composition comprising probiotics such as bifidobacteria can be used continuously until the experimenter is born in the 4th week, the 5th week, the 6th week, the 7th week, the 8th week, the 9th week, the 10th week, the 11th week, the 12th week, or until the experimenter is born in the 3rd month, the 4th month, the 5th month, the 6th month, the 7th month, the 8th month, the 9th month, the 10th month, the 11th month or the 12th month, or at least before the introduction of solid food. The use of the second composition can be sustainable until the desired intestinal microbial community is established. The experimenter can accept one, two, three, four, five or more applications of the second composition to help establish the desired microbial community.

[0191] In some embodiments, the second composition is first administered within the first 14 days after birth of the subject. In some embodiments, the second composition is administered for at least 12 weeks.

[0192] Step (c) of the method described herein involves early introduction of multiple food allergens. Recent randomized controlled trials of early introduction of highly allergenic foods have shown an associated reduction in the incidence of food allergies.

[0193] According to an embodiment of the present application, during the exposure phase, food proteins representing major food allergens are introduced one by one and the doses are increased stepwise. Additional food allergens are added over the course of multiple days. During the maintenance phase, sustained amounts of all relevant food allergens are administered. This is continued daily until daily dietary diversity is achieved by regular consumption of solid foods. In some embodiments, the administration of one or more food allergens includes:

[0194] i. administering a first food allergen to the subject at an exposure dose of the first food allergen for one or more days;

[0195] ii. subsequently administering the first food allergen to the subject at a maintenance dose of the first food allergen for a plurality of days;

[0196] iii. subsequently administering the first food allergen to the subject at a maintenance dose and administering the second food allergen to the subject at an exposure dose of the second food allergen for one or more days; and

[0197] iv. Subsequently administering both the first food allergen and the second food allergen at a maintenance dose of each allergen for multiple days.

[0198] In some embodiments, the exposure dose may optionally be increased gradually.

[0199] In some embodiments, the exposure dose to the first food allergen and the exposure dose to the second food allergen are lower than the maintenance dose of the first food allergen and the maintenance dose of the second food allergen, respectively.

[0200] The "exposure" phase includes the optional stepwise increase in the amount of food allergens and the sequential introduction of new food allergens. Once the respective maintenance levels are reached, these levels are continued by daily administration during the "maintenance" phase.

[0201] In some embodiments, the method further comprises continuing the maintenance dose of the first food allergen and the second food allergen until the pre-measured dose of each food allergen is completely consumed.

[0202] In some embodiments, the maintenance dose is continued for several months until the subject regularly consumes foods containing the first food allergen and the second food allergen as part of the subject's diet.

[0203] In some embodiments, the method further comprises:

[0204] v. administering a third food allergen to the subject at an exposure dose of the third food allergen for one or more days, and

[0205] vi. subsequently administering the first food allergen, the second food allergen, and the third food allergen to the subject at a maintenance dose of each allergen for a number of days.

[0206] In certain embodiments, the method further comprises continuing the maintenance dose of the first food allergen, the second food allergen, and the third food allergen until the pre-measured dose of each food allergen is consumed.

[0207] In some embodiments, the pre-measured doses of each of the first food allergen, the second food allergen, and the third food allergen are consumed over 12 days.

[0208] In certain embodiments, administration of one or more food allergens begins within about 2-6 months of birth of the subject, such as within 2, 3, 4, 5, or 6 months.

[0209] 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, soy, sesame, fish, shellfish, and tree nuts, preferably milk, eggs, and peanuts, respectively.

[0210] One or more food allergens can be in powder form, such as protein powder. Protein powder can be formulated to be easily suspended in breast milk or infant formula, and can have a particle size (such as less than about 200 microns) that is easy to pass through the nipple of an ordinary baby bottle. One or more food allergens can be provided in the form of a kit, which includes an outer container (box, bag, bag, can) with a disposable part that is individually packaged, and the disposable part is added to the infant formula or breast milk by the user. Alternatively, one or more food allergens can be provided in the form of already mixed with infant formula. For example, infant formula can be provided in the form of a segmented kit, wherein the infant formula is upgraded by different formulas, and the formula introduces and then increases the level of various allergens until the final maintenance infant formula is reached, and then the maintenance infant formula can continue to be given to the infant for a period of time. In addition to the segmented kit, infant formula containing a maintenance level of a plurality of food allergens at a maintenance dose can also be provided.

[0211] In some embodiments, a pre-measured dose of a food allergen is mixed into breast milk, a supplement, or a food prior to administration of the allergen to a subject.

[0212] In some embodiments, the pre-measured dose of the food allergen is in the form of a powder.

[0213] In some embodiments, the exposure dose of each food allergen is between about 0.01 grams and 0.3 grams, and the maintenance dose of each food allergen is between about 0.05 grams and 1 gram.

[0214] In some embodiments, the first food allergen comprises milk, and the exposure dose of the first food allergen is about 0.2 grams of milk protein, wherein the maintenance dose of the first food allergen is about 0.4 grams of milk protein.

[0215] In some embodiments, the second food allergen comprises egg, and the exposure dose of the second food allergen is about 0.03 grams of egg protein, wherein the maintenance dose of the second food allergen is about 0.1 grams of egg protein.

[0216] In some embodiments, the third food allergen comprises peanut, and the exposure dose of the third food allergen is about 0.1 grams of peanut protein, and wherein the maintenance dose of the third food allergen is about 0.4 grams of peanut protein.

[0217] The timing of administration in each of steps (a), (b) and (c) may overlap. For example,

[0218] The administration of the first composition and the administration of the second composition comprising probiotics such as bifidobacteria may be performed within one period of time;

[0219] The administration of the first composition and the administration of the one or more food allergens may be performed within a time period; and / or

[0220] • The administration of the second composition comprising probiotics such as bifidobacteria and the administration of the one or more food allergens may be performed within one period of time.

[0221] In another general aspect, the present application describes a kit or combination comprising at least two of the following:

[0222] (a) a first composition comprising a skin barrier function composition;

[0223] (b) a second composition comprising an effective amount of probiotics, such as Bifidobacterium cells; and

[0224] (c) a pre-measured dose of one or more food allergens.

[0225] In some embodiments, the kit or combination is used to treat or reduce the onset or occurrence of a pediatric atopic disease in a subject in need thereof.

[0226] The first composition, the second composition and the food allergen in the kit or combination may be those described in the present application such as in the above embodiments.

[0227] Although the foregoing description represents an exemplary embodiment of the present invention, it should be understood that various additions, modifications and substitutions may be made herein without departing from the spirit and scope of the present invention. Specifically, it should be clear to those skilled in the art that the present invention may be implemented in other specific forms, structures, arrangements, proportions, and with other elements, materials and components without departing from the spirit or essential features of the present invention. It should be understood by those skilled in the art that the present invention may be used together with many modifications of the structures, arrangements, proportions, materials and components used in the practice of the present invention, which are particularly suitable for specific environments and operating requirements without departing from the principles of the present invention. Therefore, the embodiments disclosed herein are considered to be illustrative and non-restrictive in all respects, and the scope of the present invention is indicated by the appended claims and is not limited by the foregoing description. It should be understood that in the claims, the term "including / comprising" does not exclude other elements or steps. In addition, references in the singular form do not exclude plural numbers. The terms "one", "a", "first", "second", etc. do not exclude plural numbers.

[0228] Implementation

[0229] The present application also provides the following non-limiting embodiments.

[0230] Embodiment 1 is a method of treating a pediatric atopic disease or reducing the onset or occurrence thereof in a subject in need thereof, the method comprising performing at least two of the following:

[0231] (a) topically applying a first composition to the skin area of ​​the subject, wherein the first composition comprises a skin barrier function composition, and the application of the first composition starts within about seven days after the birth of the subject, more specifically, starts within about six days, five days, four days, three days, two days or one day after the birth of the subject, and continues until at least about two months after the birth of the subject; and

[0232] (b) orally administering to the subject a second composition comprising an effective amount of probiotics such as Bifidobacterium cells, wherein 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 at least until the introduction of solid food; and

[0233] (c) orally administering a pre-measured dose of one or more food allergens to the subject, wherein administration of the one or more food allergens begins within about 1-8 months after birth of the subject, more specifically, within about 2-6 months after birth of the subject.

[0234] Embodiment 1a is a method according to embodiment 1, wherein the method comprises performing (a) and (b).

[0235] Embodiment 1a(1) is a method according to embodiment 1a, wherein administration of the first composition begins before administration of the second composition.

[0236] Embodiment 1a(2) is a method according to embodiment 1a, wherein administration of the first composition is initiated after administration of the second composition.

[0237] Embodiment 1b is a method according to embodiment 1, wherein the method comprises performing (a) and (c).

[0238] Embodiment 1c is a method according to embodiment 1, wherein the method comprises performing (b) and (c).

[0239] Embodiment 1d is a method according to embodiment 1, wherein the method comprises performing (a), (b) and (c).

[0240] Embodiment 1d(1) is a method according to embodiment 1d, wherein administration of the first composition begins before administration of the second composition.

[0241] Embodiment 1d(2) is a method according to embodiment 1d, wherein administration of the first composition is initiated after administration of the second composition.

[0242] Embodiment 1e is a method according to embodiment 1, wherein the method comprises:

[0243] (a) topically applying a first composition to the skin area of ​​the subject, wherein the first composition comprises a skin barrier function composition, and the application of the first composition starts within about seven days after the birth of the subject, more specifically, starts within about six days, five days, four days, three days, two days or one day after the birth of the subject, and continues until at least about two months after the birth of the subject;

[0244] (b) orally administering one or more food allergens to the subject at an exposing dose for one or more days, wherein the administration of the one or more food allergens begins within about 1-8 months after birth of the subject, more specifically, within about 2-6 months after birth of the subject; and

[0245] (c) after step (b), orally administering the one or more food allergens to the subject at a maintenance dose for one or more days.

[0246] Embodiment 1f is a method according to embodiment 1, wherein the method comprises:

[0247] (a) orally administering to the subject a second composition comprising an effective amount of probiotics such as bifidobacterium cells, wherein 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 at least until the introduction of solid food;

[0248] (b) orally administering one or more food allergens to the subject at an exposing dose for one or more days, wherein the administration of the one or more food allergens begins within about 1-8 months after birth of the subject, more specifically, within about 2-6 months after birth of the subject; and

[0249] (c) after step (b), orally administering the one or more food allergens to the subject at a maintenance dose for one or more days.

[0250] Embodiment 1g is a method according to embodiment 1, wherein the method comprises:

[0251] (a) topically applying a first composition to the skin area of ​​the subject, wherein the first composition comprises a skin barrier function composition, and the application of the first composition starts within about seven days after the birth of the subject, more specifically, starts within about six days, five days, four days, three days, two days or one day after the birth of the subject, and continues until at least about two months after the birth of the subject; and

[0252] (b) orally administering to the subject a second composition comprising an effective amount of probiotics such as Bifidobacterium cells, wherein 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 at least until the introduction of solid food.

[0253] Embodiment 1h is a method according to embodiment 1, wherein the method comprises:

[0254] (a) topically applying a first composition to the skin area of ​​the subject, wherein the first composition comprises a skin barrier function composition, and the application of the first composition starts within about seven days after the birth of the subject, more specifically, starts within about six days, five days, four days, three days, two days or one day after the birth of the subject, and continues until at least about two months after the birth of the subject;

[0255] (b) orally administering to the subject a second composition comprising an effective amount of probiotics such as Bifidobacterium cells, wherein 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 at least until the introduction of solid food;

[0256] (c) orally administering one or more food allergens to the subject at an exposure dose for one or more days, wherein the administration of the one or more food allergens begins within about 1-8 months after birth of the subject, more specifically, within about 2-6 months after birth of the subject; and

[0257] (d) after step (c), orally administering the one or more food allergens to the subject at a maintenance dose for one or more days.

[0258] Embodiment 2 is a method according to any one of embodiments 1-1b, 1d-1e and 1g-1h, wherein the first composition is administered at least once a day.

[0259] Embodiment 2a is a method according to any one of embodiments 1-1b, 1d-1e and 1g-2, wherein the first composition is administered at least twice a day.

[0260] Embodiment 2b is a method according to any one of embodiments 1-1b, 1d-1e and 1g-2a, wherein the first composition is initiated within about two days after birth of the subject.

[0261] Embodiment 3 is a method according to any one of embodiments 1-1b, 1d-1e and 1g-2b, wherein the first composition is applied to the skin of the subject all over the body.

[0262] Embodiment 3a is a method according to any one of embodiments 1-1b, 1b-1e and 1g-3, wherein the first composition is formulated into a dosage form selected from the group consisting of a balm, a cream, a lotion, an emulsion, a serum, an ointment and a paste.

[0263] Embodiment 4 is a method according to any one of embodiments 1-1b, 1d-1e and 1g-3a, wherein the first composition comprises one or more ingredients selected from the group consisting of: glycerin, water, cetearyl alcohol, isocetyl alcohol, polydimethylsiloxane, cetyl alcohol, oat kernel flour, oat kernel extract, oat kernel oil, caprylic / capric triglyceride, ceramide 3, ethylhexylglycerin, p-methoxybenzoic acid, sodium cetearyl sulfate, palmitic acid, stearic acid, sodium sulfate, sodium chloride, citric acid, dipotassium hydrogen phosphate, potassium phosphate, sodium hydroxide, tocopherol, benzyl alcohol, benzoic acid and potassium sorbate, and a carrier.

[0264] Embodiment 4a is a method according to any one of embodiments 1-1b, 1d-1e and 1d-3a, wherein the first composition comprises two or more ingredients selected from the group consisting of: glycerin, water, cetearyl alcohol, isocetyl alcohol, polydimethylsiloxane, cetyl alcohol, oat kernel flour, oat kernel extract, oat kernel oil, caprylic / capric triglyceride, ceramide 3, ethylhexylglycerin, p-methoxybenzoic acid, sodium cetearyl sulfate, palmitic acid, stearic acid, sodium sulfate, sodium chloride, citric acid, dipotassium hydrogen phosphate, potassium phosphate, sodium hydroxide, tocopherol, benzyl alcohol, benzoic acid and potassium sorbate, and a carrier.

[0265] Embodiment 4b is a method according to any one of embodiments 1-1b, 1d-1e and 1d-3a, wherein the first composition comprises three or more ingredients selected from the group consisting of: glycerin, water, cetearyl alcohol, isocetyl alcohol, polydimethylsiloxane, cetyl alcohol, oat kernel flour, oat kernel extract, oat kernel oil, caprylic / capric triglyceride, ceramide 3, ethylhexylglycerin, p-methoxybenzoic 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.

[0266] Embodiment 4c is a method according to any one of embodiments 1-1b, 1d-1e and 1d-3a, wherein the first composition comprises an emollient, more specifically, the first composition further comprises colloidal oatmeal, ceramide and distearyldimonium chloride.

[0267] Embodiment 4d is a method according to any one of embodiments 1-1b, 1d-1e and 1d-3a, wherein the first composition comprises one or more of the following ingredients in the amounts shown below:

[0268] a. caprylic / capric triglyceride, preferably from about 0.0% to about 1.0%, more preferably from about 0.005% to about 1.0%;

[0269] b. citric acid, preferably from about 0.0% to about 0.1%, more preferably from about 0.005% to about 0.1%;

[0270] c. benzoic acid, preferably from about 0.0% to about 2.0%, more preferably from about 0.1% to about 2.0%;

[0271] d. potassium phosphate, preferably from about 0.0% to about 2.0%, more preferably from about 0.05% to about 2.0%;

[0272] e. polydimethylsiloxane, preferably from about 0.0% to about 10.0%, more preferably from about 1.0% to about 10.0%;

[0273] f. stearic acid; palmitic acid, preferably from about 0.0% to about 2.0%, more preferably from about 0.1% to about 2.0%;

[0274] g. isocetyl alcohol, preferably from about 0.0% to about 10.0%, more preferably from about 1.0% to about 10.0%;

[0275] h. oat kernel flour, preferably from about 0.0% to about 2.0%, more preferably from about 0.1% to about 2.0%;

[0276] i. Ceramide 3, preferably from about 0.0% to about 0.1%, more preferably from about 0.005% to about 0.1%;

[0277] j. ethylhexylglycerin, preferably from about 0.0% to about 2.0%, more preferably from about 0.1% to about 2.0%;

[0278] k. oat kernel oil, preferably from about 0.0% to about 1.0%, more preferably from about 0.005% to about 1.0%;

[0279] l. an oat kernel extract comprising glycerin, potassium sorbate and water, preferably from about 0.0% to about 1.0%, more preferably from about 0.005% to about 1.0%;

[0280] m. water, preferably from about 15.0% to about 40.0%, more preferably from about 20.0% to about 40.0%;

[0281] n. glycerol, preferably from about 20.0% to about 50.0%, more preferably from about 30.0% to about 50.0%;

[0282] o. Sodium cetearyl sulfate, preferably from about 0.0% to about 2.0%, more preferably from about 0.1% to about 2.0%;

[0283] p. dipotassium hydrogen phosphate, preferably from about 0.0% to about 2.0%, more preferably from about 0.1% to about 2.0%;

[0284] q. sodium hydroxide, preferably from about 0.0% to about 1.0%, more preferably from about 0.005% to about 1.0%;

[0285] r. cetyl alcohol, preferably from about 0.0% to about 10.0%, more preferably from about 1.0% to about 10.0%;

[0286] s. Cetearyl alcohol, preferably from about 0.0% to about 10.0%, more preferably from about 1.0% to about 10.0%;

[0287] t. benzyl alcohol, preferably from about 0.0% to about 2.0%, more preferably from about 0.1% to about 2.0%; and / or

[0288] u. p-Anisic acid, preferably from about 0.0% to about 2.0%, more preferably from about 0.1% to about 2.0%.

[0289] Embodiment 5 is a method according to any one of embodiments 1-1a, 1c-1d and 1f-4d, wherein the probiotics include but are not limited to bacterial strains selected from the genera Lactobacillus, Lactobacillus and Bifidobacterium.

[0290] Embodiment 5-1 is a method according to embodiment 5, wherein the bifidobacterium in the second composition is selected from the group consisting of: Bifidobacterium longum, Bifidobacterium breve, Bifidobacterium bifidum, Bifidobacterium pseudochain, Bifidobacterium globulum, Bifidobacterium adolescentis, Bifidobacterium mukalababa, Bifidobacterium reuteri, Bifidobacterium pseudolongum, Bifidobacterium dentate, Bifidobacterium chain, B.sp002742445, Bifidobacterium pilosula, Bifidobacterium skaduwei, Bifidobacterium tsii, Bifidobacterium elongatum, Bifidobacterium gallinarum, Bifidobacterium suis, Bifidobacterium angularis, Bifidobacterium primary, Bifidobacterium creatinine, Bifidobacterium mongoliaensis, Bifidobacterium ruminantum, Bifidobacterium lemurensis, and Bifidobacterium stellenbosch. Bifidobacterium sphaeroides, Bifidobacterium squamosum, Bifidobacterium cactus, Bifidobacterium chickii, Bifidobacterium ferdiei, Bifidobacterium authentic, Bifidobacterium rabbit, Bifidobacterium fine hair A, Bifidobacterium bilactifolium, Bifidobacterium anserinum, Bifidobacterium van eigen, B.sp900551485, B.sp003952945, B.sp003952025, B.sp003952005, Bifidobacterium simian, Bifidobacterium pseudolongum _C, Bifidobacterium parma, Bifidobacterium martensii, Bifidobacterium krusei _A, Bifidobacterium italicum, Bifidobacterium imperial tamarin, Bifidobacterium circulum, Bifidobacterium feline, Bifidobacterium soft hair, Bifidobacterium animalis, Bifidobacterium chicken and combinations thereof.

[0291] 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 krusei, and combinations thereof.

[0292] Embodiment 5b is a method according to any one of embodiments 5-5a, wherein the Bifidobacterium is Bifidobacterium longum, preferably a subspecies of Bifidobacterium longum selected from the group consisting of Bifidobacterium longum, porcine and infantis.

[0293] Embodiment 5c is a method according to any one of embodiments 5-5b, wherein the Bifidobacterium cell is a Bifidobacterium infantis cell.

[0294] Embodiment 5d is a method according to embodiment 5c, wherein the Bifidobacterium infantis comprises strain EVC001.

[0295] Embodiment 6 is a method according to any one of embodiments 1-1a, 1c-1d and 1f-5d, wherein the second composition comprises about 100 million to about 100 billion, more specifically about 5 billion to about 15 billion colony forming units (CFU) of Bifidobacterium infantis.

[0296] Embodiment 6a is a 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.

[0297] Embodiment 7 is a method according to any one of embodiments 1-1a and 1c-6a, wherein the second composition is administered at least once a day.

[0298] Embodiment 7a is a 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.

[0299] Embodiment 7b is a method according to any one of embodiments 1-1a, 1c-1d and 1f-7a, wherein the administration of the second composition continues for at least 12 weeks.

[0300] Embodiment 7c is a method according to any one of embodiments 1-1a, 1c-1d and 1f-7b, wherein administration of the second composition continues until the desired intestinal microbiota is established.

[0301] Embodiment 7d is a method according to any one of embodiments 1-1a, 1c-1d and 1f-7c, wherein the subject receives one, two, three, four, five or more administrations of the second composition.

[0302] Embodiment 8 is a method according to any one of embodiments 1-7d, wherein the subject is breastfed or fed with a supplement comprising one or more human human milk oligosaccharides or prebiotics.

[0303] Embodiment 8a is a method according to any one of embodiments 1-8, wherein the subject is exclusively breastfed.

[0304] Embodiment 8b is a method according to any one of embodiments 1-8a, wherein the supplement comprises infant formula.

[0305] Embodiment 8c is a method according to embodiment 8, wherein the prebiotic is other oligosaccharides, polysaccharides or fibers.

[0306] Embodiment 8d is a method according to embodiment 8, wherein the supplement is infant formula.

[0307] Embodiment 9 is the method according to any one of embodiments 1-1a, 1c-1d and 1f-8d, wherein the bifidobacterium is mixed into breast milk before administering the second composition to the subject.

[0308] Embodiment 9a is a method according to any one of embodiments 1-1a, 1c-1d and 1f-8d, wherein the bifidobacterium is mixed into the supplement, such as infant formula, prior to administering the second composition to the subject.

[0309] Embodiment 9b is a method according to any one of embodiments 1-1a, 1c-1d and 1f-8d, wherein the Bifidobacterium is mixed with about 3 mL to about 5 mL of breast milk, infant formula or water prior to administering the second composition to the subject.

[0310] Embodiment 10 is a method according to any one of embodiments 1-1a, 1c-1d and 1f-9b, wherein the Bifidobacterium is in powder form.

[0311] Embodiment 10a is a method according to embodiment 10, wherein the bifidobacterium is in the form of a powder mixed with lactose.

[0312] Embodiment 10b is a method according to any one of embodiments 1-1a, 1c-1d, and 1f-10a, wherein the second composition is not naturally occurring human milk.

[0313] Embodiment 11 is a method according to any one of embodiments 1, 1b-1f, and 1h-10a, wherein the administration of the one or more food allergens comprises:

[0314] i. administering the first food allergen to the subject at an exposure dose of the first food allergen for one or more days;

[0315] ii. subsequently administering the first food allergen to the subject at a maintenance dose of the first food allergen for a plurality of days;

[0316] iii. subsequently administering the first food allergen to the subject at the maintenance dose and administering the second food allergen to the subject at an exposure dose of a second food allergen for one or more days; and

[0317] iv. subsequently administering both the first food allergen and the second food allergen at a maintenance dose of each food allergen for a number of days.

[0318] Embodiment 11a is a method according to embodiment 11, wherein the exposure dose is optionally gradually increased.

[0319] Embodiment 11b is a 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 lower than the maintenance dose of the first food allergen and the maintenance dose of the second food allergen, respectively.

[0320] Embodiment 11c is a method according to any one of embodiments 11-11b, wherein the method further comprises continuing the maintenance dose of the first food allergen and the second food allergen until the pre-measured dose of each of the food allergens is completely consumed.

[0321] Embodiment 11d is a method according to any one of embodiments 11-11c, wherein the maintenance dose is continued for several months until the subject regularly consumes food containing the first food allergen and the second food allergen as part of the subject's diet.

[0322] Embodiment 12 is a method according to any one of embodiments 11-11d, wherein the method further comprises:

[0323] v. administering to the subject a third food allergen at an exposure dose of the third food allergen for one or more days, and

[0324] vi. subsequently administering to said subject said first food allergen, said second food allergen, and said third food allergen at a maintenance dose of each of said food allergens for a plurality of days.

[0325] Embodiment 12a is a method according to embodiment 12, wherein the method further comprises continuing the maintenance dose of the first food allergen, the second food allergen, and the third food allergen until the pre-measured dose of each of the food allergens is consumed.

[0326] Embodiment 12b is a method according to embodiment 12 or 12a, wherein the pre-measured doses of each of the first food allergen, the second food allergen, and the third food allergen are consumed over 12 days.

[0327] Embodiment 13 is a method according to any one of embodiments 1, 1b-1f, and 1h-12b, wherein administration of the one or more food allergens begins within about 2-6 months of birth of the subject.

[0328] Embodiment 14 is a method according to any one of embodiments 1, 1b-1f and 1h-12b, wherein the first food allergen and the second food allergen are each independently selected from the group consisting of: milk, eggs, peanuts, wheat, soy, sesame, fish, shellfish and tree nuts.

[0329] Embodiment 14a is a method according to embodiment 14, wherein the first food allergen is milk.

[0330] Embodiment 14b is a method according to embodiment 14 or 14a, wherein the second food allergen is egg.

[0331] Embodiment 15 is a method according to any one of embodiments 1, 1b-1f and 1h-14b, wherein the third food allergen is selected from the group consisting of milk, eggs, peanuts, wheat, soy, sesame, fish, shellfish and tree nuts.

[0332] Embodiment 15a is a method according to embodiment 15, wherein the third food allergen is peanut.

[0333] Embodiment 16 is a method according to any one of embodiments 1, 1b-1f and 1h-15a, wherein the pre-measured dose of the food allergen is mixed into breast milk, a supplement or a food prior to administering the allergen to the subject.

[0334] Embodiment 17 is a method according to any one of embodiments 1, 1b-1f, and 1h-16, wherein the pre-measured dose of the food allergen is in powder form.

[0335] Embodiment 17a is a method according to embodiment 17, wherein the allergen consists of particles having a particle size of less than about 200 microns.

[0336] Embodiment 18 is a method according to any one of embodiments 1, 1b-1f and 1h-17a, wherein the exposure dose of each allergen is between about 0.01 grams and 0.3 grams, and the maintenance dose of each food allergen is between about 0.05 grams and 1 gram.

[0337] Embodiment 18a is a method according to any one of embodiments 1, 1b-1f and 1h-18, wherein the first food allergen comprises milk and the exposure dose of the first food allergen is about 0.2 grams of milk protein, wherein the maintenance dose of the first food allergen is about 0.4 grams of milk protein.

[0338] Embodiment 18b is a method according to any one of embodiments 1, 1b-1f, and 1h-18a, wherein the second food allergen comprises egg and the exposure dose of the second food allergen is about 0.03 grams of egg protein, wherein the maintenance dose of the second food allergen is about 0.1 grams of egg protein.

[0339] Embodiment 18c is a method according to any one of embodiments 1, 1b-1f, and 1h-18b, wherein the third food allergen comprises peanut and the exposure dose of the third food allergen is about 0.1 grams of peanut protein, and wherein the maintenance dose of the third food allergen is about 0.4 grams of peanut protein.

[0340] Embodiment 19 is a first composition for use in a method of treating a pediatric atopic disease such as atopic dermatitis in a subject in need thereof or reducing the onset or occurrence thereof, the method comprising performing at least two of the following:

[0341] (a) topically applying the first composition to the skin area of ​​the subject, wherein the first composition comprises a skin barrier function composition, and the application of the first composition starts within about seven days after the birth of the subject, more specifically, starts within about six days, five days, four days, three days, two days or one day after the birth of the subject, and continues until at least about two months after the birth of the subject;

[0342] (b) orally administering to the subject a second composition comprising an effective amount of probiotics such as Bifidobacterium cells, wherein 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 at least until the introduction of solid food; and

[0343] (c) orally administering a pre-measured dose of one or more food allergens to the subject, wherein administration of the one or more food allergens begins within about 1-8 months after birth of the subject, more specifically, within about 2-6 months after birth of the subject.

[0344] Embodiment 19a is the first composition for use according to embodiment 19, wherein the first composition is administered at least once a day.

[0345] 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.

[0346] Embodiment 19c is the first composition for use according to any one of embodiments 19-19b, wherein said first composition is initiated within about two days after birth of said subject.

[0347] Embodiment 19d is the first composition for use according to any one of embodiments 19-19c, wherein the first composition is applied to the skin of the subject all over the body.

[0348] Embodiment 19e is the first composition for use according to any one of embodiments 19-19d, wherein the first composition is formulated into a dosage form selected from the group consisting of a balm, a cream, a lotion, an emulsion, a serum, an ointment and a paste.

[0349] Embodiment 19f is the first composition for use according to any one of embodiments 19-19e, wherein the first composition comprises one or more ingredients selected from the group consisting of 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-methoxybenzoic acid, sodium cetearyl sulfate, palmitic acid, stearic acid, sodium sulfate, sodium chloride, citric acid, dipotassium hydrogen phosphate, potassium phosphate, sodium hydroxide, tocopherol, benzyl alcohol, benzoic acid and potassium sorbate and a carrier.

[0350] Embodiment 19g is a first composition for use according to any one of embodiments 19-19f, wherein the first composition comprises two or more ingredients selected from the group consisting of 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-methoxybenzoic 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.

[0351] Embodiment 19h is a first composition for use according to any one of embodiments 19-19b, wherein the first composition comprises three or more ingredients selected from the group consisting of: 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-methoxybenzoic acid, sodium cetearyl sulfate, palmitic acid, stearic acid, sodium sulfate, sodium chloride, citric acid, dipotassium hydrogen phosphate, potassium phosphate, sodium hydroxide, tocopherol, benzyl alcohol, benzoic acid and potassium sorbate, and a carrier.

[0352] Embodiment 19i is the first composition for use according to any one of embodiments 19-19b, wherein the first composition comprises an emollient, more specifically, the second composition further comprises colloidal oatmeal, ceramide and distearyldimonium chloride.

[0353] Embodiment 19j is the first composition for use according to any one of embodiments 19-19b, wherein the first composition comprises one or more of the following ingredients in the amounts shown below:

[0354] a. caprylic / capric triglyceride, preferably from about 0.0% to about 1.0%, more preferably from about 0.005% to about 1.0%;

[0355] b. citric acid, preferably from about 0.0% to about 0.1%, more preferably from about 0.005% to about 0.1%;

[0356] c. benzoic acid, preferably from about 0.0% to about 2.0%, more preferably from about 0.1% to about 2.0%;

[0357] d. potassium phosphate, preferably from about 0.0% to about 2.0%, more preferably from about 0.05% to about 2.0%;

[0358] e. polydimethylsiloxane, preferably from about 0.0% to about 10.0%, more preferably from about 1.0% to about 10.0%;

[0359] f. stearic acid; palmitic acid, preferably from about 0.0% to about 2.0%, more preferably from about 0.1% to about 2.0%;

[0360] g. isocetyl alcohol, preferably from about 0.0% to about 10.0%, more preferably from about 1.0% to about 10.0%;

[0361] h. oat kernel flour, preferably from about 0.0% to about 2.0%, more preferably from about 0.1% to about 2.0%;

[0362] i. Ceramide 3, preferably from about 0.0% to about 0.1%, more preferably from about 0.005% to about 0.1%;

[0363] j. ethylhexylglycerin, preferably from about 0.0% to about 2.0%, more preferably from about 0.1% to about 2.0%;

[0364] k. oat kernel oil, preferably from about 0.0% to about 1.0%, more preferably from about 0.005% to about 1.0%;

[0365] l. an oat kernel extract comprising glycerin, potassium sorbate and water, preferably from about 0.0% to about 1.0%, more preferably from about 0.005% to about 1.0%;

[0366] m. water, preferably from about 15.0% to about 40.0%, more preferably from about 20.0% to about 40.0%;

[0367] n. glycerol, preferably from about 20.0% to about 50.0%, more preferably from about 30.0% to about 50.0%;

[0368] o. Sodium cetearyl sulfate, preferably from about 0.0% to about 2.0%, more preferably from about 0.1% to about 2.0%;

[0369] p. dipotassium hydrogen phosphate, preferably from about 0.0% to about 2.0%, more preferably from about 0.1% to about 2.0%;

[0370] q. sodium hydroxide, preferably from about 0.0% to about 1.0%, more preferably from about 0.005% to about 1.0%;

[0371] r. cetyl alcohol, preferably from about 0.0% to about 10.0%, more preferably from about 1.0% to about 10.0%;

[0372] s. Cetearyl alcohol, preferably from about 0.0% to about 10.0%, more preferably from about 1.0% to about 10.0%;

[0373] t. benzyl alcohol, preferably from about 0.0% to about 2.0%, more preferably from about 0.1% to about 2.0%; and / or

[0374] u. p-Anisic acid, preferably from about 0.0% to about 2.0%, more preferably from about 0.1% to about 2.0%.

[0375] Embodiment 20 is a second composition for use in a method of treating a pediatric atopic disease such as atopic dermatitis in a subject in need thereof or reducing the onset or occurrence thereof, the second composition comprising an effective amount of probiotics, such as bifidobacterium cells, the method comprising performing at least two of the following:

[0376] (a) topically applying a first composition to the skin area of ​​the subject, wherein the first composition comprises a skin barrier function composition, and the application of the first composition starts within about seven days after the birth of the subject, more specifically, starts within about six days, five days, four days, three days, two days or one day after the birth of the subject, and continues until at least about two months after the birth of the subject;

[0377] (b) orally administering the second composition to the subject, wherein 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 at least until the introduction of solid food; and

[0378] (c) orally administering a pre-measured dose of one or more food allergens to the subject, wherein administration of the one or more food allergens begins within about 1-8 months after birth of the subject, more specifically, within about 2-6 months after birth of the subject.

[0379] Embodiment 20a is the second composition for use according to embodiment 20, wherein the probiotics include but are not limited to bacterial strains selected from the genera Lactobacillus, Lactobacillus and Bifidobacterium.

[0380] Embodiment 20a-1 is a method according to embodiment 20 or 20a, wherein the bifidobacterium in the second composition is selected from the group consisting of: Bifidobacterium longum, Bifidobacterium breve, Bifidobacterium bifidum, Bifidobacterium pseudochain, Bifidobacterium globulus, Bifidobacterium adolescentis, Bifidobacterium mukalababa, Bifidobacterium reuteri, Bifidobacterium pseudolongum, Bifidobacterium dentate, Bifidobacterium chain, B.sp002742445, Bifidobacterium pilosula, Bifidobacterium skaduwei, Bifidobacterium tsii, Bifidobacterium elongatum, Bifidobacterium gallinarum, Bifidobacterium suis, Bifidobacterium angularis, Bifidobacterium primary, Bifidobacterium creatinine, Bifidobacterium mongoliaensis, Bifidobacterium ruminantum, Bifidobacterium lemurensis, Bifidobacterium scyphoensis, Bifidobacterium terenbosch, Bifidobacterium squamosum, Bifidobacterium cactus, Bifidobacterium chickii, Bifidobacterium ferdie, Bifidobacterium eu, Bifidobacterium rabbit, Bifidobacterium fine hair _A, Bifidobacterium bilactifolium, Bifidobacterium anserinum, Bifidobacterium van eigen, B.sp900551485, B.sp003952945, B.sp003952025, B.sp003952005, Bifidobacterium simian, Bifidobacterium pseudolongum _C, Bifidobacterium parma, Bifidobacterium martensii, Bifidobacterium krusei _A, Bifidobacterium italicum, Bifidobacterium imperial tamarin, Bifidobacterium circulum, Bifidobacterium feline, Bifidobacterium soft hair, Bifidobacterium animalis, Bifidobacterium chicken and combinations thereof.

[0381] Embodiment 20b is the second composition for use according to any one of embodiments 20-20a-1, wherein the bifidobacterium is selected from the group consisting of Bifidobacterium longum, Bifidobacterium breve, Bifidobacterium krusei and combinations thereof.

[0382] Embodiment 20c is the second composition for use according to any one of embodiments 20-20b, wherein the Bifidobacterium is Bifidobacterium longum, preferably a subspecies of Bifidobacterium longum selected from the group consisting of Bifidobacterium longum, Porcine and Infantile.

[0383] Embodiment 20d is the second composition for use according to any one of embodiments 20-20c, wherein the Bifidobacterium cells are Bifidobacterium infantis cells.

[0384] Embodiment 20e is the second composition for use according to any one of embodiments 20-20d, wherein the Bifidobacterium infantis comprises strain EVC001.

[0385] Embodiment 20f is the second composition for use according to any one of embodiments 20-20e, wherein the second composition comprises about 100 million to about 100 billion, more specifically about 5 billion to about 15 billion colony forming units (CFU) of Bifidobacterium infantis.

[0386] Embodiment 20g is the second composition for use according to any one of embodiments 20-20f, wherein the second composition comprises about 8 billion colony forming units (CFU) of Bifidobacterium infantis.

[0387] Embodiment 20h is the second composition for use according to any one of embodiments 20-20g, wherein the second composition is administered at least once a day.

[0388] Embodiment 20i is the second composition for use according to any one of embodiments 20-20h, wherein administration of the second composition begins within 14 days after birth of the subject.

[0389] Embodiment 20j is the second composition for use according to any one of embodiments 20-20i, wherein the administration of the second composition continues for at least 12 weeks.

[0390] Embodiment 20k is a second composition for use according to any one of embodiments 20-20j, wherein the subject is breastfed or fed with a supplement comprising one or more human human milk oligosaccharides or prebiotics.

[0391] Embodiment 20k(1) is the second composition for use according to embodiment 20k, wherein the prebiotic is other oligosaccharides, polysaccharides or fibers.

[0392] Embodiment 201 is the second composition for use according to any one of embodiments 20-20k, wherein the subject is exclusively breastfed.

[0393] Embodiment 20m is a second composition for use according to any one of embodiments 20-201, wherein the supplement comprises an infant formula.

[0394] Embodiment 20n is the second composition for use according to any one of embodiments 20-20m, wherein the bifidobacterium is mixed into breast milk before administering the second composition to the subject.

[0395] Embodiment 20o is the second composition for use according to any one of embodiments 20-20n, wherein said bifidobacterium is mixed into said supplement, such as infant formula, prior to administering said second composition to said subject.

[0396] Embodiment 20p is a second composition for use according to any one of embodiments 20-20o, wherein the Bifidobacterium is mixed with about 3 mL to about 5 mL of breast milk, infant formula or water prior to administering the second composition to the subject.

[0397] Embodiment 20q is the second composition for use according to any one of embodiments 20-20p, wherein the Bifidobacterium is in powder form.

[0398] Embodiment 20r is the second composition for use according to any one of embodiments 20-20q, wherein the bifidobacterium is in the form of a powder mixed with lactose.

[0399] Embodiment 20s is a second composition for use according to any one of embodiments 20-20r, wherein the second composition is not naturally occurring human milk.

[0400] Embodiment 21 is a pre-measured dose of one or more food allergens for use in a method of treating or reducing the onset or occurrence of a pediatric atopic disease such as atopic dermatitis in a subject in need thereof, the method comprising performing at least two of the following:

[0401] (a) topically applying the first composition to the skin area of ​​the subject, wherein the first composition comprises a skin barrier function composition, and the application of the first composition starts within about seven days after the birth of the subject, more specifically, starts within about six days, five days, four days, three days, two days or one day after the birth of the subject, and continues until at least about two months after the birth of the subject;

[0402] (b) orally administering to the subject a second composition comprising an effective amount of probiotics such as Bifidobacterium cells, wherein 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 at least until the introduction of solid food; and

[0403] (c) orally administering the pre-measured dose of one or more food allergens to the subject, wherein the administration of the one or more food allergens begins within about 1-8 months after birth of the subject, more specifically, within about 2-6 months after birth of the subject.

[0404] Embodiment 21a is a pre-measured dose of one or more food allergens for use according to embodiment 21, wherein administration of the one or more food allergens comprises:

[0405] i. administering the first food allergen to the subject at an exposure dose of the first food allergen for one or more days;

[0406] ii. subsequently administering the first food allergen to the subject at a maintenance dose of the first food allergen for a plurality of days;

[0407] iii. subsequently administering the first food allergen to the subject at the maintenance dose and administering the second food allergen to the subject at an exposure dose of a second food allergen for one or more days; and

[0408] iv. subsequently administering both the first food allergen and the second food allergen at a maintenance dose of each food allergen for a number of days.

[0409] Embodiment 21b is the use of a pre-measured dose of one or more food allergens as described in embodiment 21a, wherein the exposure dose is optionally gradually increased.

[0410] Embodiment 21c is a pre-measured dose of one or more food allergens 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 lower than the maintenance dose of the first food allergen and the maintenance dose of the second food allergen, respectively.

[0411] Embodiment 21d is a pre-measured dose of one or more food allergens for use according to any one of embodiments 21-21c, wherein the method further comprises continuing the maintenance dose of the first food allergen and the second food allergen until the pre-measured dose of each of the food allergens is completely consumed.

[0412] Embodiment 21e is a pre-measured dose of one or more food allergens for use according to any one of embodiments 21-21d, wherein the maintenance dose continues for several months until the subject regularly consumes food containing the first food allergen and the second food allergen as part of the subject's diet.

[0413] Embodiment 21f is a pre-measured dose of one or more food allergens for use according to any one of embodiments 21-21e, wherein the method further comprises:

[0414] v. administering to the subject a third food allergen at an exposure dose of the third food allergen for one or more days, and

[0415] vi. subsequently administering to said subject said first food allergen, said second food allergen, and said third food allergen at a maintenance dose of each of said food allergens for a plurality of days.

[0416] Embodiment 21g is a pre-measured dose of one or more food allergens for use according to any one of embodiments 21-21f, wherein the method further comprises continuing the maintenance dose of the first food allergen, the second food allergen, and the third food allergen until the pre-measured dose of each of the food allergens is consumed.

[0417] Embodiment 21h is a pre-measured dose of one or more food allergens for use according to any one of embodiments 21-21g, wherein the pre-measured dose of each of the first food allergen, the second food allergen and the third food allergen is consumed over 12 days.

[0418] Embodiment 21i is a pre-measured dose of one or more food allergens for use according to any one of embodiments 21-21h, wherein administration of said one or more food allergens begins within about 2-6 months after birth of said subject.

[0419] Embodiment 21j is a pre-measured dose of one or more food allergens for use according to any one of embodiments 21-21i, wherein the first food allergen and the second food allergen are each independently selected from the group consisting of: milk, eggs, peanuts, wheat, soy, sesame, fish, shellfish and tree nuts.

[0420] Embodiment 21k is a pre-measured dose of one or more food allergens for use according to any one of embodiments 21-21j, wherein the first food allergen is milk.

[0421] Embodiment 211 is a pre-measured dose of one or more food allergens for use according to any one of embodiments 21-21k, wherein the second food allergen is egg.

[0422] Embodiment 21m is a pre-measured dose of one or more food allergens for use according to any one of embodiments 21-211, wherein the third food allergen is selected from the group consisting of: milk, eggs, peanuts, wheat, soy, sesame, fish, shellfish and tree nuts.

[0423] Embodiment 21n is a pre-measured dose of one or more food allergens for use according to any one of embodiments 21-21m, wherein the third food allergen is peanut.

[0424] Embodiment 21o is a pre-measured dose of one or more food allergens for use according to any one of embodiments 21-21n, wherein the pre-measured dose of the food allergens is mixed into breast milk, a supplement or a food before administering the allergens to the subject.

[0425] Embodiment 21p is a pre-measured dose of one or more food allergens for use according to any one of embodiments 21-21o, wherein said pre-measured dose of said food allergens is in powder form.

[0426] Embodiment 21q is a pre-measured dose of one or more food allergens for use according to any one of embodiments 21-21p, wherein the food allergens consist of particles having a particle size of less than about 200 microns.

[0427] Embodiment 21r is a pre-measured dose of one or more food allergens for use as described in any of embodiments 21-21c, wherein the exposure dose of each food allergen is between about 0.01 grams and 0.3 grams, and the maintenance dose of each food allergen is between about 0.05 grams and 1 gram.

[0428] Embodiment 21s is a pre-measured dose of one or more food allergens for use according to any one of embodiments 21-21r, wherein the first food allergen comprises milk and the exposure dose of the first food allergen is about 0.2 grams of milk protein, wherein the maintenance dose of the first food allergen is about 0.4 grams of milk protein.

[0429] Embodiment 21t is a pre-measured dose of one or more food allergens for use according to any one of embodiments 21-21s, wherein the second food allergen comprises egg and the exposure dose of the second food allergen is about 0.03 grams of egg protein, wherein the maintenance dose of the second food allergen is about 0.1 grams of egg protein.

[0430] Embodiment 21o is a pre-measured dose of one or more food allergens for use according to any one of embodiments 21-21t, wherein the third food allergen comprises peanut and the exposure dose of the third food allergen is about 0.1 grams of peanut protein, and wherein the maintenance dose of the third food allergen is about 0.4 grams of peanut protein.

[0431] Embodiment 22 is a kit or combination, the kit or combination containing at least two of the following:

[0432] (a) a first composition, which comprises a skin barrier function composition;

[0433] (b) a second composition comprising an effective amount of probiotics, such as Bifidobacterium cells; and

[0434] (c) a pre-measured dose of one or more food allergens.

[0435] Embodiment 22a is a kit or combination according to embodiment 22, wherein the kit or combination is used to treat a pediatric atopic disease or reduce the onset or occurrence thereof in a subject in need thereof.

[0436] Embodiment 22b is a kit or combination according to embodiment 22 or 22a, wherein the first combination is the first combination of any one of embodiments 2-4d.

[0437] Embodiment 22c is a kit or combination according to any one of embodiments 22-22b, wherein the second combination is the second combination of any one of embodiments 5-10b.

[0438] Embodiment 22d is a kit or combination according to any one of embodiments 22-22c, wherein the food allergen is the food allergen of any one of embodiments 11-18c.

[0439] Embodiment 23 is any one of the preceding embodiments, wherein the probiotics include but are not limited to bacterial strains selected from the genera Lactobacillus, Lactobacillus, and Bifidobacterium.

[0440] Embodiment 23 is any one of the preceding embodiments, wherein the probiotics include but are not limited to bacterial strains of Bifidobacterium infantis, Bifidobacterium longum (subspecies other than Bifidobacterium infantis), Bifidobacterium breve, Bifidobacterium chain, Bifidobacterium adolescentis, Bifidobacterium animalis, Bifidobacterium gallicus, Bifidobacterium lactis, Bifidobacterium pseudochain, Bifidobacterium bifidum, Lactobacillus paracasei, Lactobacillus acidophilus, Lactobacillus johnsonii, Lactobacillus delbrueckii, Lactobacillus crispatus, Lactobacillus gasseri, Lactobacillus zeae, Lactobacillus casei, Lactobacillus rhamnosus, Lactobacillus plantarum, Lactobacillus fermentum, Lactobacillus salivarius, or a combination thereof.

[0441] Example

[0442] Example 1: STOP AD (Short-Term Topical Application for Prevention of Atopic Dermatitis), a Randomized, Open-Label Controlled clinical trials

[0443] This clinical trial study was designed to investigate the efficacy of short-term neonatal skin barrier protection using the following skin treatment regimen and composition in preventing 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 morebe 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).

[0444] High-risk infants were identified using parental history of atopic disease and recruited from shortly postpartum (approximately 4 days) up to eight weeks of age in the postpartum ward and randomized to skin treatment regimens and compositions or standard routine care, each as described below. For the first 2 months, the intervention and standard care groups were advised to use standardized routine bathing.

[0445] Skin treatment regimen and composition: Twice daily whole body application Dermexa Fast & Long-Lasting Balm, on its packaging, contains 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-methoxybenzoic 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.

[0446] Control: Standard routine care without moisturizer in the first two months.

[0447] Both groups received: Baby Daily Care Gentle Wash, which contains the following ingredients on the package: water, glycerin, cocamidopropyl betaine, sodium laurylamphoacetate, coco-glucoside, sodium chloride, hydroxypropyl starch phosphate, oat kernel powder, aloe barbadensis leaf juice, olea europaea leaf extract, chamomile extract, helianthus annuus seed oil, sarcosine, magnesium aspartate, potassium aspartate, polyquaternium-7, polysorbate 20, sodium cocoyl amino acids, acrylates / C10-30 alkyl acrylate crosspolymer, propylene glycol, citric acid, sodium hydroxide, tocopherol, tocopheryl acetate, sodium benzoate, potassium sorbate, sodium sulfite, fragrance.

[0448] Infants with a positive history of at least one parent with an atopic disease (AD, allergic rhinitis, or asthma) were eligible for enrollment. Other inclusion or exclusion criteria were described below.

[0449] Inclusion criteria:

[0450] ○ Healthy full-term infants, gestational age > 36+6 weeks.

[0451] ○ At least one parent has self-reported atopic dermatitis, food allergy, allergic rhinitis, or asthma.

[0452] ○ No need to enter the neonatal ward.

[0453] Exclusion criteria:

[0454] ○ No parental history of atopic disease.

[0455] ○ Admission to the neonatal unit is required due to problems other than establishing normal feeding.

[0456] ○Antibiotics have been administered orally or parenterally.

[0457] ○Receive phototherapy for hyperbilirubinemia.

[0458] ○ Siblings that have been recruited, including twins.

[0459] ○ Other serious health problems (e.g., abdominal wall defects, congenital heart disease, etc.) or severe large-area skin disorders (e.g., collodion dermatosis).

[0460] o Any condition that makes the use of skin barrier protectants undesirable or impossible (e.g., developmental dysplasia of the ankle lip or hip requiring a Pavlik sling or plaster cast).

[0461] ○ Participation in any other clinical trial of an investigational medicinal product.

[0462] Within approximately 4 days of birth, infants were randomized to receive either treatment with the skin treatment regimen and composition or standard routine skin care without moisturizer until 2 months of age. 260 infants participated in the study, including 120 in the intervention group and 140 in the control group.

[0463] The study involved repeated measurements of body weight, transepidermal water loss (TEWL), and Raman-derived natural moisturizing factor (NMF) to assess skin barrier function and structure, in addition to monitoring skin health and feeding, during the first year of life, within four days of birth, and at six visits at two, four, and eight weeks, and at six and 12 months. Questionnaires were completed regarding infant health, bathing, feeding, and skin care, and skin swabs were taken for microbiome and immune biomarker analysis.

[0464] The primary outcome of the study was the effect of the intervention on the incidence of atopic dermatitis at 12 months. Secondary outcomes included the effect of the intervention on the incidence of atopic dermatitis at 6 months and the evolution of TEWL and NMF values ​​from 0 to 12 months.

[0465] Skin swabs were collected at baseline and again at 8 weeks and 12 months. Health care workers blinded to treatment assignment assessed the presence (yes / no), extent, and severity of atopic dermatitis at 6 and 12 months. DNA samples were collected to test for filaggrin loss-of-function mutations associated with risk of atopic dermatitis.

[0466] I-SEAL (Insights towards understanding Skin Function in Early Life) involves collecting skin microbiome and immune biomarkers within the larger intervention trial STOP AD in order to:

[0467] To examine temporal shifts in the skin microbiome between birth and 12 months of age and its impact on the development of atopic dermatitis.

[0468] To investigate the effects of skin regimens and compositions used during the first two months of life on infant skin microbiota.

[0469] To study the dynamics of immune biomarkers collected from infant skin surfaces during the first 12 months of life and examine associations with atopic dermatitis.

[0470] result

[0471] Recruitment / Retention

[0472] Between April 2019 and November 2020, a total of 3059 infants were screened for eligibility, of whom 321 were randomized (161 to intervention and 160 to control). Baseline characteristics of the groups were balanced (Table 1). There were 61 withdrawals (41 intervention and 20 control, 19% attrition), most of which (80%) occurred before the 2-week visit. The mean (SD) age at randomization was 1.9 (0.9) days.

[0473] Table 1: Baseline characteristics

[0474]

[0475]

[0476]

[0477] Data are n (%) unless otherwise indicated.

[0478] Abbreviations: TEWL = transepidermal water loss, NMF = natural moisturizing factor, FLG = gene encoding filaggrin

[0479] Regimen compliance

[0480] In the questionnaire, most parents in the IG reported applying emollients at least once a day in the first 8 weeks; 2 weeks: 89%, 4 weeks: 91.7%, 8 weeks: 86.6% (Table 2). 63.3% at 2 weeks, 69.2% at 4 weeks and 73.1% at 8 weeks reported twice daily application. Among the IG participants who took questionnaires at all three time points (n=114), 89 (78.1%) reported daily use of emollients at all three time points. At any of these time points, less than 20% of the CG reported using emollients ≥4 days per week; 19% at 2 weeks, 17.5% at 4 weeks and 13.5% at 8 weeks. Among the CG participants who took questionnaires at all time points (n=132), 90 (68.2%) reported using emollients <4 days per week at all three time points. There was no significant difference in bathing frequency between the groups during the intervention period.

[0481] Table 2: Parent-reported frequency of emollient application at 2, 4, and 8 weeks (questionnaire data)

[0482]

[0483]

[0484] The data are n(%).

[0485] 95% (114 / 120) of the IG and 82.1% (115 / 140) of the CG returned diaries measuring adherence. The mean (SD) age of initiation of emollient use in the IG was 3.5 (1.5) days, and 41.2% (47 / 114) reported that they applied emollients at least once on ≥90% of the recorded days (>6 days / week). An additional 41.2% (47 / 114) reported emollient use on ≥75% of the recorded days (>5 days / week). Eighty percent (92 / 115) of the CG applied emollients on ≤43% of the recorded days (≤3 days a week).

[0486] There were no significant differences in the prevalence of regular emollient use (≥4 days per week) between groups at 6 and 12 months (intervention vs. control: 29.6% vs. 29.7% at 6 months, p=1.000, and 28.4% vs. 25.8% at 12 months, p=0.868).

[0487] Security

[0488] No families sought urgent medical evaluation related to the study intervention. During the 8-week intervention period, parent-reported skin infections occurred in 5% (6 / 120) of IG and 5.7% (8 / 140) of CG. One IG infant was advised to stop using emollients and was withdrawn from the study after developing a rash with a potential temporal relationship to the emollient. Two suspected reactions to the study emollients were investigated and confirmed to be unrelated.

[0489] Key results

[0490] 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 (where children met the UKWPDC at the time of assessment) was 20.5% in the IG vs. 38.2% in the IG, p = 0.003 [RR (95% CI): 0.536 (0.354, 0.813)].

[0491] Secondary AD Outcomes

[0492] 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 vs. 35.0% in the CG, p = 0.004 [RR (95% CI): 0.524 (0.337, 0813)], Table 3.

[0493] Table 3: Atopic dermatitis outcomes at 6 and 12 months

[0494]

[0495] Point prevalence.

[0496] Abbreviation: AD = atopic dermatitis

[0497] Time-to-event survival analysis using the Kaplan-Meier method showed that the IG maintained AD-free skin for a longer period of time within the first 12 months compared with the CG (p=0.016, log-rank test, Figure 3). Among those with AD outcome data at 6 and 12 months (n=117 intervention, n=137 control), 7.7% of IG infants and 8.0% of CG infants were diagnosed at ≤6 months but no longer met the criteria at 12 months (p=1.0). The prevalence of AD onset between 6 and 12 months was 13.7% and 9.5% in the IG and CG, respectively (p=0.397), and 10.3% versus 29.2% met the criteria at both 6 and 12 months (p<0.001) (see Supplementary Figure 1). Those diagnosed ≥6 months completed SCORAD (n=55). There was no significant difference in the SCORAD total score at diagnosis between the groups [median (IQR) SCORAD: IG 11.3 (8.0, 18.4) vs. CG 12.3 (7.4, 16.0), p = 0.888].

[0498] In the per-protocol analysis, similar but non-significant relative risks were observed for the primary outcome [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].

[0499] Food allergen sensitization

[0500] By 12 months, all infants had been introduced to dairy products, and nearly all had been introduced to eggs (99.6%) and peanuts (98.0%). Nine infants had a positive SPT to at least one food [Intervention; 3.3% (4 / 120), Control; 3.6% (5 / 120), p=1.0].

[0501] TEWL and NMF evolution

[0502] There were no significant differences in TEWL or thenar NMF between the intervention and control groups at birth, 2 weeks, 4 weeks, 8 weeks, or 6 and 12 months.

[0503] discuss

[0504] In this RCT of high-risk infants, daily use of emollients starting within the first week of life until 2 months was found to be associated with a significant reduction in the cumulative incidence of AD at 12 months. Daily use of emollients was associated with a 50% and 29% lower risk of the cumulative incidence of AD at 6 and 12 months, respectively. Similar risk reductions were observed in the per-protocol analysis, which included only those in the intervention and control groups if they used emollients at least once daily and <4 days per week, respectively. However, these were nonsignificant for the primary outcome, which may be due to the application of conservative adherence criteria, resulting in a lower number included in the analysis and, therefore, lower power to detect differences between the groups.

[0505] Although some cases of AD diagnosed before 6 months had resolved by 12 months, there was no difference in the transient cases between the groups. As we did not collect longer-term data, we cannot exclude the possibility that the intervention simply delayed the onset of AD by more than 12 months. A recent meta-analysis reported a protective effect of emollients, but only if there was no interval between emollient treatment and AD assessment. 14 However, there was significant heterogeneity between the four studies included in this analysis. In our study, the 29% reduction in the cumulative risk of AD at 12 months was maintained until 10 months after the intervention.

[0506] This finding is inconsistent with recent findings from two large RCTs, which found no evidence that the use of emollients within the first year had a protective effect against AD (Chalmers JR, Haines RH, Bradshaw LE, et al., "Dailyemollient 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): afactorial, multicentre, cluster-randomised trial," Lancet Lond. Engl., 2020, 395(10228): 951-961). The most significant difference between these RCTs and ours is the timing of the intervention. Treatment in STOP AD begins within a few days of birth during a dynamic period of skin maturation and adaptation to the dramatic environmental changes of life outside the womb. In STOP AD, infants were randomized within 4 days of birth and the IG was advised to start emollient treatment immediately. In BEEP, the median (IQR) age of initiation of emollient use was 11 days (7, 17) days, with only 89% initiating emollient use before 3 weeks of age. In PreventADALL, intervention was initiated from 2 weeks of age.

[0507] The emollients used in BEEP and PreventADALL are basic petroleum-based and paraffin-based formulations, respectively. The emollient used in this study consisted of a formulation with added ceramides developed specifically for very dry, itchy skin. Two other small studies using more complex ceramide-rich emollients reported non-significant trends for protection against 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 studies, a larger RCT (PEBBLES study) is ongoing involving twice-daily application of the same ceramide-based emollient from 0 to 6 months. 25 Here, we show that a reduction in AD risk at 12 months with an intervention period as short as 2 months may represent a more feasible and family-friendly strategy for AD prevention.

[0508] Our high adherence rate demonstrates the feasibility of implementing a regimen of daily emollient use during the first 2 months of life. Adherence rates using diaries were lower than those reported on questionnaires, but 82.4% still reported using emollients on ≥75% of days (equal to more than 5 days per week). Although infants in this study were closely followed during the intervention, similar adherence rates were observed in the BEEP, which involved limited contact but used a less stringent definition of adherence (emollient use ≥3 days / week). 10 Only 27% of the IGs fully adhered to the regimen in PreventADALL, which may have influenced the lack of protective effect.

[0509] Although we did assess food allergy outcomes, this study was not powered to detect a reduction in the risk of food allergy. Unlike the BEEP, which has prominently reported a nonsignificant increase in food allergy in the IG, we found no difference in the prevalence of food allergy between the groups. Although we did not use the SPT to screen for food allergy, almost all infants had tried the most common food allergens—milk, egg, and peanut—by 12 months of age, so the reported rates of food sensitization and allergy may reflect the true rates in our group. The BEEP reported a higher rate of skin infections in the IG, suggesting that the use of emollients may result in greater pathogen exposure. We found no evidence of an increased risk of skin infections with short-term use of emollients.

[0510] Despite the reduced risk of AD in the IG, TEWL did not differ between the groups during the first year. Other studies on the use of emollients during infancy have similarly reported no effect of intervention on TEWL. TEWL measurement is influenced by environmental factors and, more critically for infants, subject-specific parameters, including stress and crying. 26 This may have affected our ability to detect differences between groups.

[0511] The main strength of this study is that the use of emollients was started within a few days of birth in the IG. Other strengths include the close follow-up of infants, the high compliance rate in the IG, and the low contamination rate in the CG.

[0512] A limitation of the study was that many AD diagnoses were made remotely due to the COVID-19 pandemic. To mitigate this, detailed information and photographs were collected when the diagnosis was made. The SCORAD assessment was also completed remotely, which may have affected the assessment of AD severity. When early-onset AD (<6 months) is diagnosed, validated diagnostic criteria cannot be applied as cases are diagnosed based on the presence of AD lesions. However, of the 73 infants diagnosed with AD ≤6 months, 71 (97.3%) met the UKWPDC at 6 months. The cumulative AD prevalence in this group was higher than expected based on the rate in infants with a parental history of atopy in the Irish birth cohort 23. A possible explanation for this is the pre-recruitment of high-risk infants in this study and close monitoring of skin health. Only one-third (32.1%) of the participants who were eligible for this study were recruited. One of the main reasons for refusal to participate was the demanding follow-up schedule involved, especially during the intervention period that started before going home with the newborn, suggesting that more motivated individuals were recruited. We also had higher dropout rates in the first two weeks of life, particularly in the intervention group, which was mainly due to withdrawal of consent rather than to the early onset of AD at this time, which is a factor to consider when assessing the feasibility of recommending daily emollient use in the general population in the early postnatal period.

[0513] We have demonstrated that early initiation of daily use of specialized emollients until 2 months of age in high-risk infants during the first year of life reduces the incidence of AD. The underlying mechanisms are unclear, but analyses of microbiome diversity and inflammatory biomarkers in a subgroup of this study are ongoing and may provide more information. Although several recent studies do not support a protective role for emollient use during infancy, future studies should examine the use of more complex emollients to enhance the skin barrier while identifying a therapeutic window that is both effective and acceptable to parents.

[0514] Example 2: BACH clinical trial, a study targeting Bifidobacterium infantis (strain EVC001; Evolve BioSystems, Inc., Davis, CA) supplements for clinical and immunological effects

[0515] The clinical trial study was a randomized, placebo-controlled experimental study designed to reduce or eliminate known confounding effects caused by factors other than the study intervention (Clinical Trials.gov Identifier: NCT04662619). This type of study design is therefore considered rigorous because it is able to test a causal relationship between the study intervention (in this case, the study supplement) and the study endpoint.

[0516] Target:

[0517] The primary objective of this study was to evaluate the effect of Bifidobacterium infantis (EVC001) supplementation relative to placebo on the cumulative incidence of physician-diagnosed AD during the first year of life in healthy breastfed infants at risk of developing AD. The secondary objectives of this study were to evaluate the effect of Bifidobacterium infantis (EVC001) supplementation relative to placebo on the following in healthy breastfed infants at risk of developing AD:

[0518] The proportion of infants with adverse events (AEs) to assess safety and tolerability

[0519] Cumulative incidence of AD at other time points

[0520] ·Onset of AD

[0521] Intestinal colonization of infants with Bifidobacterium infantis

[0522] AD severity in subjects with AD

[0523] Other objectives of this study are to:

[0524] 1) To evaluate the effects of Bifidobacterium infantis (EVC001) supplementation relative to placebo in healthy breastfed infants at risk of developing AD on:

[0525] The incidence of atopic diseases other than AD (food allergy, allergic rhinitis, asthma)

[0526] Allergic sensitization

[0527] Gut and skin microbiome

[0528] Overview of skin immunology biomarkers

[0529] The incidence of infantile colic

[0530] Baby sleep

[0531] Infant anthropometry

[0532] Relationship between baseline maternal gut microbiome and infant gut microbiome development

[0533] 2) Characterize and compare the microbiome and immunological profiles of infants who did not develop AD and those who developed AD within 1 year in the B. infantis (EVC001) supplemented and placebo supplemented groups.

[0534] 3) To determine the immune response phenotype in the Bifidobacterium infantis (EVC001) supplemented group and the placebo supplemented group.

[0535] 4) Identify genetic profiles of subjects associated with benefit from supplementation intervention.

[0536] Overview

[0537] This study is a randomized, double-blind, placebo-controlled, 2-arm, parallel-group (Group 1 and Group 2) study. The study will enroll approximately 286 infants who have at least one first-degree relative with a history of atopic disease (i.e., biological parent or sibling with maternally reported, physician-diagnosed AD, allergic rhinitis, or asthma) who are currently breastfeeding 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 ("caregiver").

[0538] Infant eligibility assessments will be performed within the first 14 days of life. Eligible infants will be enrolled and randomized evenly (1:1) to one of two groups: placebo (Group 1) or Bifidobacterium infantis (EVC001) (Group 2). Randomization will be stratified according to the number (one vs. more than one) of the infant's first-degree relatives with a relevant history of atopic disease (as defined above). All baseline assessments will be performed prior to the first administration of the designated study supplement.

[0539] Administration of the designated study supplement will begin on Day 0 and continue for 12 weeks. Caregivers will be instructed to make their best efforts to maintain exclusive breastfeeding for at least this 12-week period and will be encouraged to continue breastfeeding as long as possible during the first year of life. Following the 12-week supplementation period, infants will be followed through scheduled and unscheduled visits until Week 104 (approximately 2 years).

[0540] A sub-study is planned in a subgroup of the main study cohort (approximately 80-100 subjects) to evaluate possible relationships between the gut microbiome, the frequency and function of specific immune cells in peripheral circulation, circulating cytokine profiles, and the development of AD.

[0541] Subject selection and enrollment

[0542] Eligibility criteria are designed to select subjects deemed appropriate for protocol procedures. Infants are assessed for eligibility within the first 14 days of life. Initial verification of eligibility may be performed by individuals who are not medically qualified.

[0543] Inclusion criteria for infants included the following:

[0544] 1) Male or female newborns aged ≤14 days at study entry (Day 0).

[0545] 2) Healthy full-term infants.

[0546] 3) At least one first-degree relative (i.e., biological parent or sibling) had a history of atopic disease (i.e., maternal-reported, physician-diagnosed AD, allergic rhinitis, or asthma).

[0547] 4) Breastfeeding was established at study entry (Day 0) and the mother intended to maintain exclusive breastfeeding for ≥12 weeks.

[0548] Exclusion criteria for infants included the following:

[0549] 1) Premature birth (gestational age < 36 weeks [252 days]).

[0550] 2) Admission to the neonatal unit due to problems other than establishing normal feeding.

[0551] 3) Evidence of a baseline disease / condition (e.g., abnormal birth weight) or a significant risk of developing a disease / condition that, in the opinion of the PI or designee, would pose a significant safety concern or otherwise preclude study participation if the infant were to participate in the study (based on review of maternal / pregnancy information).

[0552] 4) Major birth defects / complications (e.g., abdominal wall defects, congenital heart disease) that the PI or designee believes will pose a safety concern or otherwise interfere with the study.

[0553] 5) Severe, widespread skin disease (e.g., collodion).

[0554] 6) Medical conditions (infants) or maternal medication / supplement use (e.g., daily or routine antibiotics or systemic antifungals) that the PI or designee believes could significantly alter the gut or skin microbiome.

[0555] 7) Consumed prebiotics or (a) probiotic supplements / milk / formulated food containing Bifidobacterium longum before enrollment (Day 0).

[0556] 8) Consume >100 mL of formula food per day within 48 hours before enrollment (Day 0).

[0557] 9) Medical condition (infant) or maternal surgery / injury / condition that would interfere with breastfeeding.

[0558] 10) Infants are known to be sensitive or intolerant to soy or dairy protein.

[0559] 11) The mother is infected with human immunodeficiency virus, tuberculosis, hepatitis C or hepatitis B.

[0560] 12) Caregiver condition that, in the opinion of the PI or designee, will not allow the caregiver and / or infant to comply with the requirements of the study protocol.

[0561] 13) Twins or multiple births.

[0562] During the study, the infants' caregivers will be instructed to make their best efforts to ensure that the infants are exclusively breastfed until at least week 12, and they will be encouraged to continue breastfeeding as long as possible during the first year of life. Caregivers will also administer the designated study supplements to the infants once daily for 12 weeks according to the instructions and training provided. Caregivers will be instructed to avoid routine infant intake of probiotics during the first 12 weeks of the study (or during breastfeeding, if longer), unless specifically prescribed by the HCP, such as to prevent or treat antibiotic-associated diarrhea or treat gastroenteritis. Caregivers will also be instructed to ensure that the infants do not ingest any prebiotics or any probiotic supplements / milk / formula containing bifidobacteria during the first 24 weeks of the study.

[0563] Sample size, randomization / study supplement allocation, and blinding

[0564] Approximately 200-400 subjects will be randomly assigned in a 1:1 ratio to receive Bifidobacterium infantis (EVC001) or placebo. Enrolled infants will be randomized uniformly (1:1) to the active supplement group or the placebo supplement group according to the randomization schedule. Infants will be stratified according to the number of first-degree relatives with a history of atopy (one vs. more than one). The study will be double-blind, so caregivers and PI / designees will not know the assignment of study supplements.

[0565] Researching the identification and use of supplements

[0566] The following study supplements will be provided as shown in Table 4 below:

[0567] Table 4: Supplements studied

[0568]

[0569] The active ingredient supplement is Bifidobacterium infantis supplement Probiotic powder, available in sachets from Evolve BioSystems, Inc., and has the following ingredients: Purified lactose per dose, Bifidobacterium longum infantis subsp. EVC001. Each sachet contains 625 mg of probiotic powder and contains 8 billion CFU of Bifidobacterium infantis (EVC001). The placebo sachet contains 625 mg of lactose.

[0570] Infants will take the contents of a single-serving sachet of Bifidobacterium infantis (EVC001) or a matching placebo study supplement once daily for 12 weeks. At supplementation, mix the contents of a single-serving sachet with approximately 3 mL to 5 mL of expressed or pumped breast milk (or infant formula, if desired) in the provided reservoir. Using the provided syringe, dispense the mixture into the infant's mouth to ensure that the infant takes the entire dose.

[0571] Study duration, procedures and evaluation schedule

[0572] Infant eligibility assessments will be performed within the first 14 days of the infant's life. After enrollment and randomization (Day 0), study supplements will be administered daily from Day 0 until Week 12. Caregivers will be instructed to do their best to maintain exclusive breastfeeding for ≥ 12 weeks. After the 12-week supplementation period, study subjects will be followed for an additional 92 weeks to complete the 104-week (2-year) study.

[0573] Assessment tools and additional study procedure details

[0574] Medical, Family, Medication, and Supplement History Questionnaire:

[0575] At screening, the investigators will interview each infant's caregiver to complete a Medical, Family, Medication, and Supplement History Questionnaire to record the infant's medical and medication / supplement history, including exposures during / since pregnancy, delivery, and breastfeeding. The questionnaire will also obtain information reported by the mother about the infant's first-degree relatives with a history of atopic disease, such as AD (including age of onset and details of diagnostic testing), 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 testing), other skin conditions, or current or past history of immune-mediated diseases.

[0576] Diagnosis of AD:

[0577] Infants identified by the investigator as possible cases of AD will be evaluated by trained physicians 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 (face and extensor involvement), 3) chronic or chronic relapsing dermatitis, 4) personal or family history of atopic disease (Rajka G, Langeland T. Grading of the severity of atopic dermatitis. Acta DermVenereol Suppl (Stockh) 1989; 144: 13-4.; A, Svedman C, BM, Johansson AC, Wahlgren CF. Usefulness of Rajka & Langeland EczemaSeverity Score in clinical practice. Acta Derm Venereol 2016;96:521-4.).

[0578] If an infant is diagnosed with AD, its severity will be assessed at diagnosis and at weeks 12, 52, and 104 using the EASI and POEM as described below.

[0579] Eczema Area and Severity Index (EASI) < 8 years:

[0580] EASI is a tool for measuring 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.). The instrument assesses four body regions: head and neck (including face, neck and scalp), trunk (including genital area), upper extremities (including hands) and lower extremities (including buttocks and feet), which are assigned 20%, 30%, 20% and 30% of proportional body surface area, respectively. An area score was determined for each of the four body regions based on the percentage of skin affected by AD (defined by the four key signs listed below) in that body region (0 = none, 1 = 1-9%, 2 = 10-29%, 3 = 30-49%, 4 = 50-69%, 5 = 70-89%, 6 = 90-100%).

[0581] The severity of the four key signs of AD - erythema, induration / papules / edema, excoriations, and lichen sclerosis - for each of these four body regions uses a 0 to 3 scale: 0 = none; 1 = mild; 2 = moderate; and 3 = severe (note: half a point is allowed). The total score for each body region is determined by multiplying the sum of the severity scores for 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 to 72. Designated trained physicians will assess AD severity using the EASI at the time of AD diagnosis and (for subjects with AD only) at Weeks 12, 52, and 104.

[0582] Patient-Oriented Eczema Measurement (POEM):

[0583] 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.). Caregivers will be interviewed at AD diagnosis and (for subjects with AD only) at Weeks 12, 52, and 104 to rate seven symptoms (itching, sleep disturbance, bleeding from the skin, weeping / oozing from the skin, flaking of the skin, cracked skin, dry / rough skin) using a 5-point scale (none, 1-2 days, 3-4 days, 5-6 days, every day) for frequency of occurrence during the previous week. The maximum total POEM score is 28.

[0584] Infant colic

[0585] Researchers will interview caregivers to record signs and symptoms of infantile colic based on the Rome IV criteria at baseline (day 0) and at weeks 6, 12, and 24 (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). The occurrence of infantile colic as defined by the Rome IV criteria will be determined using these caregiver interviews combined with daily caregiver records in a diary. Caregivers will use diaries to record the occurrence and duration of crying, fussiness, and other related symptoms (such as defecation) at baseline and during weeks 5-7, 11-13, and 23-24. "Fussiness" will refer to intermittent distress vocalizations and has been defined as "no intense crying but no awake and contented [behavior]" (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). The occurrence of infantile colic as defined by the Rome IV criteria will be determined using caregiver diary records combined with caregiver interviews conducted at the visit.

[0586] Infant Anthropometry

[0587] The infant's length / height (using an infant length board), weight, and head circumference will be measured during all study visits. Body mass index (BMI) will be calculated based on weight and body length / height measurements according to the following equation: BMI (kg / m 2 ) = weight (kg) / ([length or height (cm) / 100] 2 ).

[0588] Brief Infant Sleep Questionnaire-Revised (BISQ-R)

[0589] At weeks 12, 24, 52, and 76, caregivers will record their infants' sleep routines and patterns over the previous 2 weeks using the BISQ-R. The BISQ-R is an age-based, norm-referenced scoring system that provides a comprehensive assessment of infant sleep patterns (5 items related to sleep latency, number and duration of nighttime awakenings, longest sleep period, and total nighttime sleep) that may affect sleep outcomes, as well as parental perceptions (3 items related to bedtime difficulties, nighttime sleep, and overall child sleep problems) and parental behavior (11 items related to consistency of bedtime routines, bedtime, parental behavior at bedtime and after nighttime awakenings, and sleeping position at bedtime and after nighttime 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.). For each subscale, a score ranging from 0 to 100 was derived, with higher scores indicating better sleep quality, more positive perceptions of sleep quality, and parental practices that promote healthy sleep behaviors and independent infant sleep, respectively. The total score was calculated as the average of the infant sleep, parental perceptions, and parental behaviors subscale scores.

[0590] Solid Food Introduction Checklist

[0591] Caregivers will record when the infant first consumes a new solid food to include the type and amount of solid food used.

[0592] Infant feeding and study supplement use log

[0593] Caregivers will record details of maternal breastfeeding, infant formula use (if applicable), and study supplement administration in a diary daily until Week 12 and optionally thereafter. Caregivers will also record any missed, incomplete, or extra administration of study supplements in the diary; missed supplements will not be made up on subsequent days.

[0594] Blood samples

[0595] 2.0 mL venous whole blood samples will be collected from infants at weeks 24, 52, and 104. The blood will be processed and archived for future analysis according to the instructions provided in the Laboratory Reference Manual. Allergen-specific serum IgE testing will be performed using venous whole blood samples to evaluate the development of allergic sensitization. In addition, blood samples can also be used to study the infant immune response phenotype by comparing the serial RNA expression profiles of subjects in the Bifidobacterium infantis (EVC001) supplement group and the placebo supplement group. Blood samples can also be used for exome sequencing to determine whether there are variations in different genes (including the FLG gene) that may be associated with atopic diseases (such as AD, asthma, and allergic sensitization) and ichthyosis vulgaris.

[0596] Stool samples

[0597] Maternal stool samples will be collected for future microbiome analysis 2-6 weeks postpartum if the mother consents to collection (optional). Caregivers will collect stool from infants within 5 days (preferably within 3 days) prior to baseline (day 0) and the 6-, 12-, 24-, 52-, and 104-week visits. The baseline sample should be a non-meconium sample; if this is not possible before starting supplementation, a deviation should be documented, and a non-meconium sample should be collected as soon as possible (preferably within 24 hours) after starting supplementation.

[0598] All stool samples will be collected using the supplies provided and stored frozen in the provided collection tubes and biohazard bags until collected by the study staff during an in-person visit. Frozen stool samples will be transported to the study center using a soft-sided cooler equipped with ice packs where they will be stored at -80°C for future analysis.

[0599] Stool collected at baseline (day 0) and at weeks 6, 12, 24, 52, and 104 will be analyzed for the overall bacterial profile of the intestine, including the presence of B. infantis, to determine the extent of colonization (percentage of each infant colonized with B. infantis) and prevalence (percentage of infants with intestinal B. infantis colonization). Infants will be considered to have a colonized intestine if the stool concentration of B. infantis as determined by shotgun sequencing is ≥ 50% of the total bacteria.

[0600] Skin swab sample

[0601] Caregivers will be instructed to avoid applying any topical treatments within 3 hours prior to the study visit so as not to interfere with the collection of skin samples. All skin samples collected as detailed below will be stored frozen at -80°C at the study center for future analysis as detailed in the laboratory reference manual.

[0602] Skin Biomarkers: To evaluate the effects of B. infantis (EVC001) supplementation on immune regulation in the skin and understand biomarkers associated with AD flare, researchers will collect two skin samples at baseline (Day 0), Week 12, and Week 52 using the FibroTX Skin Sample Collection Swab, a highly sensitive multi-analyte research tool for non-invasive biomarker measurements directly from the skin; if AD is diagnosed, two additional samples will be collected at these time points from the lesion site and an adjacent clear non-lesion site.

[0603] Skin Microbiome: To assess the systemic effects of study supplements on the skin microbiome, investigators will collect two skin samples using pre-moistened swabs, one from the antecubital fossa (elbow crease) and one at a location determined by the investigator or sponsor, at baseline (Day 0), Week 6, Week 12, and Week 52. If AD is confirmed, two additional samples will be obtained from lesional skin and adjacent clear non-lesional skin at these time points.

[0604] Study Visits and Assessments:

[0605] A summary of the study procedures and evaluation schedule is shown in Table 5 below.

[0606] Table 5: Timeline of events.

[0607]

[0608]

[0609] Study Endpoints and Data Analysis

[0610] Primary endpoint: Cumulative incidence of AD up to Week 52. The cumulative incidence of AD up to Week 52 will be compared between supplement groups.

[0611] Secondary endpoints:

[0612] The distribution of time to AD onset up to week 104 will be compared between supplement groups

[0613] Cumulative incidence of AD up to week 24 and week 104

[0614] Proportion of infants with intestinal colonization with B. infantis at week 12: Stool samples from week 12 will be analyzed for B. infantis colonization and total bacterial load to determine the proportion of infants with intestinal colonization with B. infantis. Infants will be considered to have their intestine colonized, as defined above.

[0615] AD severity based on EASI scores at AD onset and at weeks 12, 52, and 104

[0616] AD severity based on POEM scores at AD onset and at weeks 12, 52, and 104

[0617] Other endpoints:

[0618] Cumulative incidence of atopic diseases other than AD through Week 24, Week 52, and Week 104: Investigators will record the development of allergic rhinitis, asthma, and food allergies (confirmed by specialist / pediatric allergist) throughout the study, and the cumulative incidence of these conditions will be determined at Week 24, Week 52, and Week 104.

[0619] Cumulative incidence of allergic sensitization through Weeks 24, 52, and 104: Investigators will record the development of allergic sensitization, such as to dietary or inhaled allergens (confirmed by specific serum IgE testing), and the cumulative incidence will be determined at Weeks 24, 52, and 104.

[0620] Changes from baseline in the gut and skin microbiome through Week 104: Changes from baseline in the fecal (Weeks 6, 12, 24, 52, and 104) and skin (Weeks 6, 12, and 52) microbiome will be determined.

[0621] • Proportion of infants with B. infantis intestinal colonization at week 24: Stool samples collected in connection with the Week 24 visit will be analyzed for B. infantis intestinal colonization as detailed above.

[0622] Change from baseline in skin immunological biomarker profiles at Week 12 and Week 52: Changes from baseline in skin biomarkers at Week 12 and Week 52 will be determined.

[0623] Cumulative incidence of infantile colic through weeks 6, 12, and 24: The diagnosis of infantile colic will be based on the Rome IV criteria, which includes data generated through visit interviews and caregiver diaries.

[0624] BISQ-R Scores at Weeks 12, 24, 52, and 76: The BISQ-R Infant Sleep, Parent Perceptions, and Parent Behavior subscale scores and the total BISQ-R score will be determined at weeks 12, 24, 52, and 76.

[0625] Changes from baseline in infant anthropometrics at weeks 6, 12, 24, 52, 76, and 104: Changes from baseline in infant length / height, weight, head circumference, and BMI at weeks 6, 12, 24, 52, 76, and 104 will be determined.

[0626] Impact of the maternal gut microbiome on infant gut microbiome development from baseline to two years of age: The microbiome of maternal stool samples collected 2-6 weeks postpartum will be assessed for association with infant gut microbiome development (including B. infantis gut colonization) at baseline (day 0) and at weeks 6, 12, 24, 52, and 104.

[0627] • Microbiome and immunological profiles in infants with and without AD: Outcome measures related to the microbiome and immunological profile will be characterized and compared in infants who do not develop AD by 1 year versus infants who develop AD in the B. infantis (EVC001)-supplemented and placebo-supplemented groups.

[0628] Serial RNA expression analysis at weeks 24, 52, and 104: Characterization and comparison of outcome measures associated with serial RNA expression profiles will be performed in subjects in the B. infantis (EVC001) supplemented and placebo supplemented groups at weeks 24, 52, and 104 to investigate infant immune response phenotypes.

[0629] • Subject genetic analysis: Outcome measures related to subject genetic profiles will be characterized and compared in infants who do not develop AD and infants who develop AD up to 1 year of age in the B. infantis (EVC001) supplementation group to identify subjects who may benefit from the intervention.

[0630] Success Criteria

[0631] The success of the study will be determined primarily by a statistically significant effect of supplementation versus placebo on the cumulative incidence of AD through Week 52.

[0632] Summarize

[0633] The above examples constitute a method comprising administering a composition comprising bifidobacterium (B. infantis) to a breastfed infant at increased risk of developing atopic disease. The breastfed infant will be monitored and evaluated for signs of prevention, delay and / or improvement of atopic dermatitis, food allergies, allergic rhinitis and asthma. Infant colic, infant sleep and infant anthropometry will also be monitored and evaluated.

[0634] Example 3: LEAP (Early Understanding Peanut) and LEAP-On (Follow-up Study) trials: studying how best to prevent Clinical trials for peanut allergy

[0635] These clinical trials have investigated how early introduction and regular consumption of peanuts in infants at high risk for food allergy may prevent peanut allergy and potentially induce durable, long-term tolerance (see, e.g., www.1eapstudy.co.uk; Elissa M. Abrams et al., “International Peanut Allergy prevention, 6 Years After the Learning Early About Peanut Smdy,” J. Allergy Clin. Immunol Pract., January 2022, Vol. 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, Vol. 372(9):803-813).

[0636] Denier mark:

[0637] How long-lasting the effects of early childhood exposure to peanuts are.

[0638] Whether the treatment affects the risk of siblings developing peanut allergy.

[0639] Whether parental characteristics influence the development of peanut allergy.

[0640] result:

[0641] Among the 530 infants in the intention-to-treat population with an initial negative skin-prick test result, 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 the 98 participants in the intention-to-treat population with an initial positive test result, the prevalence of peanut allergy was 35.3% in the avoidance group and 10.6% in the consumption group (P=0.004). There were no significant between-group differences in the incidence of serious adverse events. Increases in peanut-specific IgG4 antibody levels occurred primarily in the consumption group; a greater percentage of participants in the avoidance group had elevated peanut-specific IgE antibody titers. Larger wheals on skin-prick testing and lower peanut-specific IgG4:IgE ratios were associated with peanut allergy.

[0642] Example 4: EAT (Earning Tolerance) trial: Feasibility of early allergenic food introduction program

[0643] The Asking Tolerance (EAT) study was designed to test the hypothesis that early introduction of multiple allergenic foods starting at 3 months of age in an unselected population of exclusively breastfed infants would reduce the prevalence of food allergies as a primary outcome and affect the prevalence of asthma, eczema, allergic rhinitis, and comorbid allergic diseases at 3 years of age as a secondary outcome. (See, e.g., 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).

[0644] Target:

[0645] To determine the feasibility of early introduction of multiple allergenic foods to exclusively breastfed infants, starting at three months of age, and the effects on breastfeeding performance.

[0646] result:

[0647] One thousand three hundred and three infants were enrolled. By 5 months of age, the median frequency of consumption of all 6 foods was 2 to 3 times per week for each food in the EIG, and none of the foods were consumed in the standard introduction group (P < .001 for each comparison). By 6 months of age, the nonintroduction of allergenic foods in the EIG was less than 5% for each of the 6 foods. Achieving the strict protocol consumption goals of the EIG proved more difficult (42% of the evaluable EIG participants). Breastfeeding rates in both groups significantly exceeded UK government data for equivalent mothers (P < .001 at 6 and 9 months of age).

[0648] It should be understood that the examples and embodiments described herein are for illustrative purposes only and that modifications may be made to the above embodiments without departing from the broad inventive concept of the present invention. Therefore, it should be understood that the present invention is not limited to the specific embodiments disclosed, but the present invention is intended to cover modifications consistent with the spirit and scope of the present invention, as defined in the appended claims.

Claims

1. A method for treating a pediatric atopic disease in a subject in need thereof or reducing the onset or occurrence thereof, the method comprising: (1) Perform at least one of the following: (a) topically applying a first composition to the skin area of ​​the subject, wherein the first composition comprises a skin barrier function composition, and the application of the first composition starts within about seven days after the birth of the subject, more specifically, starts within about six days, five days, four days, three days, two days or one day after the birth of the subject, and continues until at least about two months after the 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 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 at least until the introduction of solid food; and (2) orally administering a pre-measured dose of one or more food allergens to the subject, wherein the administration of the one or more food allergens begins within about 1-8 months after birth of the subject, more specifically, within about 2-6 months after birth of the subject.

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

3. The method of claim 1, comprising performing (1)(b) and (2).

4. The method of claim 1, comprising performing (1)(a), (1)(b) and (2).

5. The method according to any one of claims 1, 2 and 4, wherein the first composition is administered at least once a day.

6. The method of any one of claims 1, 2, 4 and 5, wherein the first composition is administered at least twice a day.

7. The method of any one of claims 1, 2, and 4-6, wherein the administration of the first composition begins within about two days after birth of the subject.

8. The method of any one of claims 1, 2, and 4-7, wherein the first composition is applied to the skin of the subject all over the body.

9. The method of any one of claims 1, 2, and 4-8, wherein the first composition further comprises colloidal oatmeal, ceramides, and distearyldimonium chloride.

10. The method according to any one of claims 1, 2 and 4-9, wherein the first composition comprises one or more of the following ingredients in the amounts shown 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. polydimethylsiloxane, 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. oat kernel flour, 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. oat kernel oil, preferably from about 0.0% to about 1.0%, more preferably from about 0.005% to about 1.0%; l. an oat kernel extract comprising 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. glycerol, preferably from about 20.0% to about 50.0%, more preferably from about 30.0% to about 50.0%; o. Sodium cetearyl sulfate, preferably from about 0.0% to about 2.0%, more preferably from about 0.1% to about 2.0%; p. dipotassium hydrogen 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. Cetearyl 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 u. p-Anisic acid, preferably from about 0.0% to about 2.0%, more preferably from about 0.1% to about 2.0%.

11. The method according to any one of claims 1, 3-10, wherein the second composition is administered at least once a day.

12. The method according to any one of claims 1 and 3-11, wherein the administration of the second composition continues for at least 12 weeks, or the administration of the second composition continues until a desired intestinal microbiota is established in the subject.

13. The method according to any one of claims 1 and 3-12, wherein the Bifidobacterium cell is a Bifidobacterium infantis cell.

14. The method of any one of claims 1 and 3-13, wherein the second composition comprises about 100 million to about 100 billion, more specifically about 5 billion to about 15 billion colony forming units (CFU) of Bifidobacterium infantis.

15. The method of any one of claims 1 and 3-14, wherein the second composition comprises about 8 billion colony forming units (CFU) of Bifidobacterium infantis.

16. The method according to any one of claims 1-15, wherein the subject is breastfed or fed by a supplement such as infant formula comprising one or more human human milk oligosaccharides.

17. The method of any one of claims 1-16, wherein the subject is exclusively breastfed.

18. The method of any one of claims 1-17, wherein the supplement comprises infant formula.

19. The method according to any one of claims 16-18, wherein the Bifidobacterium is mixed into the breast milk or the supplement before administering the second composition to the subject.

20. The method according to any one of claims 1 and 3-19, wherein the Bifidobacterium is in powder form.

21. The method of any one of claims 1-20, wherein said administering of said one or more food allergens comprises: i. administering the first food allergen to the subject at an exposure dose of the first food allergen for one or more days; ii. subsequently administering the first food allergen to the subject at a maintenance dose of the first food allergen for a plurality of days; iii. subsequently administering the first food allergen to the subject at the maintenance dose and administering the second food allergen to the subject at an exposure dose of a second food allergen for one or more days; as well as iv. subsequently administering both the first food allergen and the second food allergen at a maintenance dose of each food allergen for a number of days.

22. The method of claim 21, further comprising continuing the maintenance dose of the first food allergen and the second food allergen until the pre-measured dose of each of the food allergens is completely consumed.

23. The method of claim 21 or 22, wherein the maintenance dose is continued for several months until the subject regularly consumes food containing the first food allergen and the second food allergen as part of the subject's diet.

24. The method according to any one of claims 21 to 23, further comprising: v. administering to the subject a third food allergen at an exposure dose of the third food allergen for one or more days, and vi. subsequently administering to said subject said first food allergen, said second food allergen, and said third food allergen at a maintenance dose of each of said food allergens for a plurality of days.

25. The method of claim 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 of each of the food allergens is consumed.

26. The method of claim 25, wherein the pre-measured doses of each of the first food allergen, the second food allergen, and the third food allergen are consumed over 12 days.

27. The method according to any one of claims 1-26, wherein the first food allergen and the second food allergen are each independently selected from the group consisting of: milk, eggs, peanuts, wheat, soy, sesame, fish, shellfish and tree nuts, preferably milk and eggs, respectively.

28. The method according to any one of claims 24-27, wherein the third food allergen is selected from the group consisting of milk, eggs, peanuts, wheat, soy, sesame, fish, shellfish and tree nuts, preferably peanuts.

29. The method of any one of claims 1-28, wherein the pre-measured dose of the food allergen is mixed into breast milk, a supplement, or food prior to administering the food allergen to the subject.

30. The method of any one of claims 1-29, wherein the pre-measured dose of the food allergen is in powder form.

31. The method of any one of claims 1-30, wherein the exposure dose of each allergen is between about 0.01 grams and 0.3 grams, and the maintenance dose of each food allergen is between about 0.05 grams and 1 gram.

32. The method of any one of claims 1-31, wherein the first food allergen comprises milk and the exposure dose of the first food allergen is about 0.2 grams of milk protein, wherein the maintenance dose of the first food allergen is about 0.4 grams of milk protein.

33. The method of any one of claims 1-32, wherein the second food allergen comprises egg and the exposure dose of the second food allergen is about 0.03 grams of egg protein, wherein the maintenance dose of the second food allergen is about 0.1 grams of egg protein.

34. The method of any one of claims 1-33, wherein the third food allergen comprises peanut and the exposure dose of the third food allergen is about 0.1 grams of peanut protein, and wherein the maintenance dose of a third food allergen is about 0.4 grams of peanut protein.

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

36. The kit of claim 35, wherein the kit is for treating or reducing the onset or occurrence of a pediatric atopic disease in a subject in need thereof.

37. A method or kit according to any preceding claim, wherein the probiotic comprises a bacterial strain selected from the genera Lactobacillus, Lactobacillus and Bifidobacterium.

38. The method or kit of claim 37, wherein the probiotic comprises a bacterial strain of Bifidobacterium infantis, Bifidobacterium longum (subspecies other than Bifidobacterium infantis), Bifidobacterium breve, Bifidobacterium chain, Bifidobacterium adolescentis, Bifidobacterium animalis, Bifidobacterium gallicus, Bifidobacterium lactis, Bifidobacterium pseudochain, Bifidobacterium bifidum, Lactobacillus paracasei, Lactobacillus acidophilus, Lactobacillus johnsonii, Lactobacillus delbrueckii, Lactobacillus crispatus, Lactobacillus gasseri, Lactobacillus zeae, Lactobacillus casei, Lactobacillus rhamnosus, Lactobacillus plantarum, Lactobacillus mucofermentans, Lactobacillus salivarius, or a combination thereof.

39. A method of treating a pediatric atopic disease or reducing the onset or occurrence of a pediatric atopic disease in a subject in need thereof, the method comprising: (1) (a) topically applying a first composition to the skin area of ​​the subject, wherein the first composition comprises a skin barrier function composition, and the application of the first composition starts within about seven days after the birth of the subject, more specifically, starts within about six days, five days, four days, three days, two days or one day after the birth of the subject, and continues until at least about two months after the 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 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 at least until the introduction of solid food; and (2) optionally orally administering a pre-measured dose of one or more food allergens to the subject, wherein the administration of the one or more food allergens begins within about 1-8 months after birth of the subject, more specifically, within about 2-6 months after birth of the subject.

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

41. The method of any one of claims 39-40, wherein the first composition is administered at least once a day.

42. The method of any one of claims 39-41, wherein the first composition is administered at least twice a day.

43. The method of any one of claims 39-42, wherein the administration of the first composition begins within about two days after birth of the subject.

44. The method of any one of claims 39-43, wherein the first composition is applied to the skin of the subject all over the body.

45. The method of any one of claims 39-44, wherein the first composition further comprises colloidal oatmeal, ceramides, and distearyldimonium chloride.

46. ​​The method of any one of claims 39-45, wherein the first composition comprises one or more of the following ingredients in the amounts indicated 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. polydimethylsiloxane, 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. oat kernel flour, 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. oat kernel oil, preferably from about 0.0% to about 1.0%, more preferably from about 0.005% to about 1.0%; 1. An oat kernel extract comprising 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. glycerol, preferably from about 20.0% to about 50.0%, more preferably from about 30.0% to about 50.0%; o. Sodium cetearyl sulfate, preferably from about 0.0% to about 2.0%, more preferably from about 0.1% to about 2.0%; p. dipotassium hydrogen 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. Cetearyl 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 u. p-Anisic acid, preferably from about 0.0% to about 2.0%, more preferably from about 0.1% to about 2.0%.

47. The method of any one of claims 39-46, wherein the second composition is administered at least once a day.

48. The method of any one of claims 39-47, wherein the administration of the second composition continues for at least 12 weeks, or the administration of the second composition continues until after a desired intestinal microbiota is established in the subject.

49. The method of any one of claims 39-48, wherein the Bifidobacterium cell is a Bifidobacterium infantis cell.

50. The method of any one of claims 39-49, wherein the second composition comprises about 100 million to about 100 billion, more specifically about 5 billion to about 15 billion colony forming units (CFU) of Bifidobacterium infantis.

51. The method of any one of claims 39-50, wherein the second composition comprises about 8 billion colony forming units (CFU) of Bifidobacterium infantis.

52. The method of any one of claims 39-51, wherein the subject is breastfed or fed with a supplement such as an infant formula comprising one or more human breast milk oligosaccharides.

53. The method of any one of claims 39-52, wherein the subject is exclusively breastfed.

54. The method of any one of claims 39-53, wherein the supplement comprises infant formula.

55. The method of any one of claims 39-54, wherein the Bifidobacterium is mixed into the breast milk or the supplement prior to administering the second composition to the subject.

56. The method according to any one of claims 39-55, wherein the Bifidobacterium is in powder form.

57. The method of any one of claims 39-56, wherein said administering of said one or more food allergens comprises: i. administering the first food allergen to the subject at an exposure dose of the first food allergen for one or more days; ii. subsequently administering the first food allergen to the subject at a maintenance dose of the first food allergen for a plurality of days; iii. subsequently administering the first food allergen to the subject at the maintenance dose and administering the second food allergen to the subject at an exposure dose of a second food allergen for one or more days; as well as iv. subsequently administering both the first food allergen and the second food allergen at a maintenance dose of each food allergen for a number of days.

58. The method of any one of claims 39-57, further comprising continuing the maintenance dose of the first food allergen and the second food allergen until the pre-measured dose of each of the food allergens is completely consumed.

59. The method of any one of claims 39-58, wherein the maintenance dose is continued for several months until the subject regularly consumes food containing the first food allergen and the second food allergen as part of the subject's diet.

60. The method according to any one of claims 39-59, further comprising: vii. administering to the subject a third food allergen at an exposure dose of the third food allergen for one or more days, and viii. subsequently administering to said subject, for a plurality of days, a maintenance dose of each of said food allergens, said first food allergen, said second food allergen, and said third food allergen.

61. The method of any one of claims 39-60, 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 of each of the food allergens is consumed.

62. The method of any one of claims 39-61, wherein the pre-measured doses of each of the first food allergen, the second food allergen, and the third food allergen are consumed over 12 days.

63. The method of any one of claims 39-62, wherein the first food allergen and the second food allergen are each independently selected from the group consisting of milk, eggs, peanuts, wheat, soy, sesame, fish, shellfish and tree nuts, preferably milk and eggs, respectively.

64. The method according to any one of claims 39-63, wherein the third food allergen is selected from the group consisting of: milk, eggs, peanuts, wheat, soy, sesame, fish, shellfish and tree nuts, preferably peanuts.

65. The method of any one of claims 39-64, wherein the pre-measured dose of the food allergen is mixed into breast milk, a supplement, or food prior to administering the food allergen to the subject.

66. The method of any one of claims 39-65, wherein the pre-measured dose of the food allergen is in powder form.

67. The method of any one of claims 39-66, wherein the exposure dose of each allergen is between about 0.01 grams and 0.3 grams, and the maintenance dose of each food allergen is between about 0.05 grams and 1 gram.

68. The method of any one of claims 39-67, wherein the first food allergen comprises milk and the exposure dose of the first food allergen is about 0.2 grams of milk protein, wherein the maintenance dose of the first food allergen is about 0.4 grams of milk protein.

69. The method of any one of claims 39-68, wherein the second food allergen comprises egg and the exposure dose of the second food allergen is about 0.03 grams of egg protein, wherein the maintenance dose of the second food allergen is about 0.1 grams of egg protein.

70. The method of any one of claims 39-69, wherein the third food allergen comprises peanut and the exposure dose of the third food allergen is about 0.1 grams of peanut protein, and wherein the maintenance dose of a third food allergen is about 0.4 grams of peanut protein.

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