Nutritional composition for promoting emotional development

Abstract

This invention relates to a combination comprising effective amounts of osteopontin and lactoferrin, for use in promoting the socio-emotional development of young individuals. The invention also relates to compositions and methods for promoting the socio-emotional development of young individuals, preferably infants.

Description

Technical Field

[0001] This invention relates to a combination comprising effective amounts of osteopontin and lactoferrin, for use in promoting the socio-emotional development of young individuals. The invention also relates to compositions and methods for promoting the socio-emotional development of young individuals, preferably infants. Background Technology

[0002] Breastfeeding is considered the ideal source of nutrition and the preferred choice for feeding infants up to 6 months of age. Therefore, human milk (HM) has long been considered the design model for infant formula (IF). Despite numerous improvements in the nutrient composition of IF over the past few decades, significant differences remain regarding its composition and the functional benefits derived from HM.

[0003] In recent years, there has been widespread interest in identifying the potential relationship between human breast milk components and early brain development and associated functions.

[0004] Nutritional deficiencies have been associated with reduced myelin formation, altered myelin composition, or reduced myelin synthesis.

[0005] The relationship between the composition of human breast milk and its effects on the socio-emotional development of infants, toddlers, and / or young children remains unclear, and there are no reports in the art regarding the effects of blends of nutrients containing lactoferrin and osteopontin on socio-emotional development.

[0006] Social-emotional skills develop from birth into childhood and encompass behaviors that represent a child's emotional growth, as well as their ability to interact successfully with adults and peers. Social-emotional milestones focus on the development of children's abilities to understand, experience, express, and manage emotions; to regulate their emotions, actions, and behaviors in different social settings; and to develop meaningful relationships with others. Therefore, social-emotional development covers a wide range of skills and constructs, including but not limited to self-awareness, other-awareness, autonomy, compliance, emotion, sociality, play and interaction, empathy, self-esteem, self-regulation, friendship, and relationship development.

[0007] Social skills encompass verbal and nonverbal communication and are crucial in enabling individuals to engage in and maintain positive interactions with others. Children diagnosed with developmental disorders (such as autism spectrum disorder (ASD), persuasive developmental disorder (unspecified), and Asperger's disease) and those diagnosed with mood disorders or anxiety disorders (such as social anxiety disorder) experience difficulties with social skills or behaviors in social situations.

[0008] Developing social skills is an integral part of child development. Social skills enable children to interact with the world around them by understanding themselves and others, developing relationships, communicating verbally, and using body language. A proper set of social skills will facilitate cooperation in a social environment. Furthermore, well-developed social skills form the foundation for the development of cognitive, linguistic, and adaptive life skills.

[0009] Another aspect of socioemotional development is the development of emotional skills and abilities (including emotions). Emotional development refers to the ability to effectively regulate emotions to achieve one's goals. Therefore, healthy emotional development requires experiencing, managing, and expressing the widest range of positive and negative emotions. It includes behaviors such as the willingness to express one's feelings, empathy for others, self-regulation or the ability to calm down or adapt to the environment or stimuli.

[0010] Social and emotional skills and behaviors both mature as the brain develops, particularly as brain regions and their connections to social and / or emotional information processing mature.

[0011] It is believed that a lack of social and / or emotional skills can lead to adverse developmental outcomes in children, such as hindering their ability to build relationships, affecting their adjustment to school, impacting emotional difficulties, causing aggressive or destructive behavior, leading to loneliness, and causing behavioral problems later in life. For example, if preschool children do not learn to identify and categorize their emotions, temper tantrums and inappropriate emotion regulation may worsen later in life. In some cases, shy, inhibited children are at risk of developing anxiety and depression or behavioral or conduct problems later in life. Anxiety disorders are a group of mental disorders characterized by significant and uncontrollable feelings of anxiety and fear that significantly impair a person's social, occupational, and personal functioning. Many anxiety disorders develop in early childhood (Clark C, Rodgers B, Caldwell T, Stansfeld S. Childhood and adulthood psychological ill health as predictors of affective and anxiety disorders: the 1958 British Cohort. British Birth Cohort. Arch Gen Psychatry. 2007; 64: 668-678; doi:10.1001 / archpsyc.64.6.668; Mian N, Godoy L, Briggs-Gowan MJ, Carter AS. Patterns of anxiety symptoms in toddlers and preschool-age children: evidence of early differentiation. J. Anxiety Disord. Jan 2012; 26(1): 102-110; doi:10.1016 / j.janxdis.2011.09.006. Electronic publication October 7, 2011). Examples of anxiety disorders include generalized anxiety disorder, social anxiety disorder (social phobia), and separation disorder.Generalized anxiety disorder, separation anxiety disorder, and social phobia are considered the most common and earliest-onset childhood mental disorders and adult depression, and they persist throughout life and impair quality of life (Copeland WE, Shanahan L, Costello EJ, Angold A. Childhood and adolescent psychiatric disorders as predictors of young adult disorders. Arch Gen Psychatry. 2009 July; 66(7): 764-772; doi:10.1001 / archgenpsychiatry.2009.85).

[0012] Mood disorders are a group of mental disorders, including, for example, bipolar disorder and depressive disorders. Mood is defined as a generalized and persistent emotional tone that persists internally and influences almost every aspect of a person's behavior in the external world. Mood disorders are described as significant disturbances of mood (severe depressed mood is called depression, or severe elevated mood is called major mania or bipolar disorder). These disorders include bipolar disorder, cyclothymic psychosis, hypomania, major depressive disorder, disruptive mood dysregulation, persistent melancholic disorder, and premenstrual anxiety disorder.

[0013] Children are diagnosed with conduct problems or disorders when they exhibit persistent patterns of aggression towards others, as well as serious violations of family, school, and peer rules and social norms. Children with conduct problems are more likely to be injured and may have difficulty getting along with their peers.

[0014] Currently, methods for preventing anxiety disorders and promoting the development of social behavioral and social skills mainly rely on education by parents and caregivers, often through early intervention programs (Lau E, Rapee R, Coplan R. Combining child social skills training with a parent early intervention program for inhibited preschool children. Journal of Anxiety Disorders. Oct 2017; 51: 32-38; doi:10.1016 / j.janxdis.2017.08.007. e-published September 1, 2017) to promote communication, play, help children understand emotions and develop empathy, storytelling, and group activities.

[0015] The relationship between shy-inhibited behavior in childhood (Prior M, Smart D, Sanson A, Oberklaid F. Does shy-inhibited temperament in childhood lead to anxiety problems inadolescence? J Am Acad Child Adolesc Psychatry. April 2000; 39 (4): 461-8. doi: 10.1097 / 00004583-200004000-00015) or fearful behavior (Liu R, Bell M. Fearfultemperament and the risk for child and adolescent anxiety: the role of attention biases and effortful control. Clin Child Fam Psychol Rev. June 2020; 23(2): 205-228. doi: 10.1007 / s10567-019-00306-z.) and the risk of developmental anxiety problems in early adolescence has been reported.

[0016] Temperament broadly refers to consistent individual differences in behavior that are biologically based and relatively independent of learning, values, and attitudes. Some researchers have pointed to a link between temperament and formalized dynamic characteristics of behavior, such as energy levels, plasticity, sensitivity to specific reinforcing stimuli, and emotionality. Temperament traits (such as neuroticism, sociability, and impulsivity) are unique patterns of behavior throughout life, but they are more pronounced and studied in children. Temperament is defined by specific behavioral characteristics, typically focusing on those that are easily measurable and testable in early childhood. Commonly tested factors include traits related to energy capacity (named "activity," "endurance," and "extraversion"), traits related to emotionality (such as irritability and frequency of smiling), and approach or avoidance behaviors towards unfamiliar events. Temperament changes over time as children develop, with rapid development in infancy.

[0017] This study reports human results and investigates the effects of blends of certain myelin nutrients present in human breast milk on the development of socio-emotional skills.

[0018] The benefits of social and emotional development need to be delivered to young individuals in a way that does not cause side effects and / or is not only easy to deliver but also widely accepted by parents or healthcare professionals. These benefits also need to be delivered in a way that keeps such delivery affordable and accessible to most people. Summary of the Invention

[0019] The objective of this invention is achieved through the subject matter of the independent claims. The dependent claims further expand the conception of this invention.

[0020] This invention relates to a combination comprising effective amounts of osteopontin and lactoferrin for use in promoting the socio-emotional development of young individuals. This can be conducted in healthy subjects (non-therapeutic), such as healthy infants, toddlers, or children, or in vulnerable subjects such as infants, toddlers, or children born by cesarean section and / or preterm, and / or small for gestational age (SGA), and / or low birth weight, very low birth weight, or extremely low birth weight (LWB, VLBW, or ELBW), and / or infants, toddlers, or children experiencing intrauterine growth retardation (IUGR) and / or with impaired or immature tissue development.

[0021] In one implementation, the combination includes:

[0022] Osteopontin, the amount of which ranges from approximately 50 ng / μL to approximately 900 ng / μL, and

[0023] Lactoferrin, with levels ranging from approximately 190 ng / μL to approximately 5050 ng / μL.

[0024] In one implementation, the combination is used in the extraversion and / or extraversion, affective and / or behavioral modulation, and / or modulation domains of the Infant Behavior Questionnaire-Revised (IBQ-R) scale for promoting the development of young individuals.

[0025] In one implementation, the young individual is an infant, a toddler, or a preschooler, preferably an infant.

[0026] In one implementation, the combination is administered to the young individual from birth to about 5 years of age, preferably from birth to 18 weeks of age, and more preferably during the first 12 weeks of the young individual's life.

[0027] In one implementation, socio-emotional development is promoted in young individuals from birth to about 5 years of age, preferably from birth to 18 months of age, more preferably from about 2 months of age to about 6 months of age, and even more preferably from about 3 months of age.

[0028] In one implementation, the regulation of at least one of the following is promoted in young individuals from birth to about 5 years of age, preferably from birth to 18 months of age, more preferably from about 2 months of age to about 6 months of age, and even more preferably about 3 months of age: the regulation of extraversion and / or extraversion, affect and / or behavior, or regulation domains on the Infant Behavior Questionnaire-Revised (IBQ-R) scale.

[0029] In one implementation, the combination is used to prevent psychosocial disorders and / or illnesses caused by impaired social and / or emotional development in young individuals from birth to about 5 years of age, preferably from birth to 18 months of age.

[0030] In one implementation plan, socioemotional disorders and / or illnesses include: autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), intellectual disability, anxiety, depression, and behavioral disorders.

[0031] The present invention also relates to a nutritional composition for use in promoting the socio-emotional development of young individuals, wherein the nutritional composition comprises the combination according to any one of the preceding claims.

[0032] In one embodiment, the nutritional composition is infant formula, stage 1 infant formula, stage 2 or later infant formula, baby food, growing milk, infant cereal composition, fortifier, or supplement.

[0033] In one embodiment, the nutritional composition or combination disclosed above is administered to the mother of a young individual during pregnancy or lactation.

[0034] The present invention also relates to non-therapeutic uses of combinations or compositions as disclosed above for promoting the socio-emotional development of young individuals.

[0035] The present invention also relates to a method for promoting the socio-emotional development of young individuals, the method comprising administering effective amounts of osteopontin and lactoferrin to the young individuals.

[0036] The present invention also relates to a method for promoting the socio-emotional development of young individuals, the method comprising administering to the young individual a combination or nutritional composition as disclosed above. Attached Figure Description

[0037] Figure 1 It is a heatmap showing three factors FA1, FA2, and FA3, which can be interpreted as “extroversion / extraversion,” “negative affect,” and “orientation / regulation” of infants at 6 months of age in the Infant Behavior Questionnaire-Revised (IBQ-R).

[0038] Figure 2This is a graph showing the positive correlation between osteopontin concentration at 6 weeks and the degree of regulation of emotion and / or behavior at 3 months in young individuals as described in the examples.

[0039] Figure 3 This is a graph showing the positive correlation between lactoferrin concentration at 6 weeks and extroversion / extroversion level at 6 months in young individuals as described in the examples. Detailed Implementation

[0040] Some definitions are provided below. However, definitions may be located in the “Implementation Scheme” section below, and the title “Definitions” above does not mean that such disclosures in the “Implementation Scheme” section are not definitions.

[0041] All percentages expressed herein are by weight of the total weight of the composition unless otherwise stated. As used herein, “about,” “approximately,” and “substantially” should be understood to mean a value within a certain numerical range, such as -10% to +10% of the mentioned value, preferably -5% to +5%, more preferably -1% to +1%, and most preferably -0.1% to +0.1%. All numerical ranges herein should be understood to include all integers or fractions within the range. Furthermore, these numerical ranges should be understood to support claims that involve any number or subset of numbers within the range. For example, disclosures of 1 to 10 should be understood to support ranges of 1 to 8, 3 to 7, 1 to 9, 3.6 to 4.6, 3.5 to 9.9, etc.

[0042] As used in this disclosure and the appended claims, the singular forms “a,” “an,” and “the” include plural references unless the context clearly specifies otherwise. Thus, for example, the indexing of “an amino acid” or “the amino acid” includes two or more amino acids.

[0043] The term "comprising / including" will be interpreted as inclusive rather than exclusive. Similarly, the terms "comprising / including" and "or" should be considered inclusive unless the context explicitly prohibits this interpretation. However, the compositions and methods disclosed herein may not contain any elements not explicitly disclosed herein. Therefore, the disclosure of embodiments using the term "comprising / including" includes both embodiments "consisting substantially of the specified components or steps" and embodiments "consisting of the specified components or steps."

[0044] The terms “at least one of X and Y” and “and / or” used in the context of “at least one of X and Y” and “X and / or Y” respectively should be interpreted as “X without Y” or “Y without X” or “both X and Y”. Where used herein, the terms “example” and “such as” (especially when followed by a list of terms) are merely exemplary and illustrative and should not be considered exclusive or comprehensive.

[0045] As used herein, “related to,” “associated with,” and “connected to” mean that they occur simultaneously, preferably that they are caused by the same underlying condition, more preferably that one of the specified conditions is at least indirectly caused by the other specified condition, and most preferably that one of the specified conditions is directly caused by the other specified condition.

[0046] "Prevention" includes reducing the risk, incidence, and / or severity of a condition or disorder. The term "treatment" includes both preventative or averting treatment (preventing and / or delaying the development of a target pathological condition or disorder) and curative, therapeutic, or disease-modifying treatment, including therapeutic measures that cure, delay, alleviate symptoms of a diagnosed pathological condition or disorder, and / or halt its progression; and treatment of patients at risk of or suspected of having the disease, as well as treatment of patients who are ill or have been diagnosed with a disease or medical condition.

[0047] The term "treatment" does not necessarily mean that a subject is treated until fully recovered. The term "treatment" also refers to health maintenance and / or promotion in individuals who do not have a disease but may be susceptible to unhealthy conditions. The term "treatment" is also intended to include intensifying or otherwise enhancing one or more major preventative or therapeutic measures. As a non-limiting example, treatment can be administered by a patient, caregiver, physician, nurse, or other healthcare professional.

[0048] The expressions "later in life" and "in later life" are used interchangeably. They refer to effects measured on an individual (infant or toddler) weeks, months, or years after birth, such as after 6 months of age, 8 months of age, 10 months of age, 1 year of age, 2 years of age, preferably 4 years of age, more preferably 5 years of age, and even more preferably 7 years of age or longer, and the effect is measured by comparison with the average observed results of individuals of the same age. Preferably, it refers to an effect observed at least 1 year after birth, or at least 2, 5, 7, 10, or 15 years after birth. Therefore, the expression "later in life" can refer to observations during infancy, childhood, adolescence, or adulthood. Preferably, it refers to observations during childhood, adolescence, or adulthood. The term "later in life" encompasses the effects after the intervention ends.

[0049] As used in this article, the “effective amount” for prevention or treatment is the amount used to prevent an individual’s defect, treat their disease or medical condition, or more generally, the amount used to alleviate an individual’s symptoms, manage the progression of their disease, or provide them with nutritional, physiological, or medical benefits.

[0050] The term "composition" may mean a food, beverage, dietary supplement, complete nutritional or oral nutritional supplement (ONS) or medical food composition or a mixture thereof. The terms "food," "food supplement," "food product," and "food composition" mean a product or composition intended for ingestion by an individual (such as a human) and intended to provide that individual with at least one nutrient. The compositions of this disclosure (including the various embodiments described herein) may comprise, consist of, or consist substantially of the elements disclosed herein, and any additional or optional ingredients, components, or elements described herein or intended for use in dietary supplements.

[0051] The composition may be in solid form (e.g., powder) or liquid form. The content of each component can be expressed in g / 100g composition on a dry weight basis when the composition is in solid form (e.g., powder); or in concentration in g / 100mL composition when the composition is in liquid form (the latter also covers liquid compositions that may be obtained after the powder is reconstituted in a liquid (such as water).

[0052] As used herein, the term "unit dosage form" refers to a physically discrete unit suitable as a unit dose for human and animal subjects, each unit containing a predetermined amount of the composition disclosed herein, associated with an acceptable diluent, carrier, or mediator, sufficient to produce the desired effect. The specifications of a unit dosage form depend on the specific compound used, the effect to be achieved, and the pharmacodynamics associated with each compound in the host. As used herein, the term "young individual" refers to an infant, toddler, toddler, or child.

[0053] The term "infant" refers to a child under 12 months of age. The term "infant" includes both full-term and premature infants.

[0054] The terms "toddler" or "preschooler" refer to children aged between one and three years old.

[0055] The term "child" refers to a child between the ages of one and six, including toddlers and preschoolers.

[0056] As used herein, the term "infant formula" refers to a food intended for specific nutritional purposes in the first few months after birth and which meets the nutritional needs of such infants (in accordance with Article 2(c) of European Commission Directive 91 / 321 / EEC 2006 / 141 / EC of 22 December 2006 concerning infant formula and follow-up formula). It also refers to nutritional compositions intended for use in infants, as defined in the Codex Alimentarius Commission (STAN 72-1981) and in infant specialties (including foods for specific medical purposes). The term "infant formula" encompasses both "starter infant formula," "follow-up formula," and "follow-on formula."

[0057] Stage 2 infant formula or follow-up formula is given starting from the sixth month and includes growth milk. Infant formula constitutes the main liquid element in the gradually diversifying diet of this group.

[0058] The term "infant food" refers to food designed for specific nutritional purposes for infants or young children during the first few years of their lives.

[0059] The term "infant cereal composition" refers to a food intended for specific nutritional purposes for infants or young children during the first few years of their lives.

[0060] The term "fortifier" refers to a liquid or solid nutritional composition suitable for mixing with breast milk or infant formula.

[0061] "Premature infant" or "premature subject" refers to an infant or toddler born before full term. Generally, it refers to an infant or toddler born before 36 weeks of gestation.

[0062] The term "small for gestational age" or "SGA" refers to an infant or toddler whose size is smaller than the normal standard for birth at gestational age (most commonly defined as a weight below the 10th percentile for gestational age). In some implementations, SGA may be associated with intrauterine growth restriction (IUGR), a condition in which a fetus is unable to reach its potential size.

[0063] "Premature infant" or "premature birth" refers to an infant or toddler born before full term. Generally, it refers to an infant or toddler born before 37 weeks of gestation.

[0064] "Low birth weight infant" or "low birth weight" refers to premature infants who weigh less than 2500g (5.5 lbs) due to prematurity or fetal growth restriction. Therefore, it encompasses:

[0065] - Infants or toddlers who weigh between 1500g and 2500g at birth (often referred to as "low birth weight" or LBW)

[0066] - Infants or toddlers who weigh between 1000g and 1500g at birth (referred to as "very low birth weight" or VLBW)

[0067] - Infants or toddlers who weigh less than 1000g at birth (referred to as "extremely low birth weight" or ELBW).

[0068] The term "breast milk" should be understood as the mother's breast milk or colostrum.

[0069] Supplements may be in the form of tablets, capsules, lozenges, or liquids. Supplements may also contain protective hydrocolloids (such as gums, proteins, modified starches), binders, film-forming agents, encapsulation agents / materials, wall / shell materials, matrix compounds, coatings, emulsifiers, surfactants, solubilizers (oils, fats, waxes, lecithin, etc.), adsorbents, carriers, fillers, co-compounds, dispersants, wetting agents, processing aids (solvents), flow agents, flavor masking agents, weighting agents, gelling agents, and gelling agents. Supplements may also contain conventional pharmaceutical additives and adjuvants, excipients, and diluents, including but not limited to water, gelatin of any origin, plant gums, lignin sulfonates, talc, sugar, starch, gum arabic, vegetable oils, polyalkylene glycols, flavoring agents, preservatives, stabilizers, emulsifiers, buffers, lubricants, colorants, wetting agents, and fillers. In addition, based on recommendations from government agencies such as the USRDA, supplements may contain organic or inorganic carrier materials suitable for oral or parenteral administration, as well as vitamins, minerals, trace elements, and other micronutrients.

[0070] The terms “prebiotic” and “fiber” are used interchangeably. They refer to non-digestible carbohydrates that beneficially affect the host by selectively stimulating the growth and / or activity of healthy bacteria, such as Bifidobacteria in the human colon (Gibson GR, Roberfroid MB. Dietary modulation of the human colonic microbiota: introducing the concept of prebiotics. J Nutr. 1995;125:1401-12).

[0071] The term "probiotics" refers to microbial cell preparations or microbial cell components that have beneficial effects on the health or well-being of the host. (Salminen S, Ouwehand A. Benno Y. et al., "Probiotics: how should they be defined" Trends Food Sci. Technol. 1999: 10 107-10). The microbial cells are generally bacteria or yeast.

[0072] The term "cfu" should be understood as colony-forming unit. Unless otherwise specified, all percentages are by weight.

[0073] The most commonly used probiotics are mainly bacteria and yeasts from the following genera: Lactobacillus spp., Lacticaseibacillus spp., Limosilactobacillus spp., Streptococcus spp., Enterococcus spp., Bifidobacterium spp., and Saccharomyces spp.

[0074] In some specific embodiments, the probiotics are probiotic bacterial strains. In some specific embodiments, they are specifically Bifidobacterium and / or Lactobacillus.

[0075] Suitable probiotic strains include: *Lactobacillus rhamnosus* ATCC 53103, *Lactobacillus rhamnosus* CGMCC 1.3724, *Lactobacillus paracasei* CNCM I-2116, and *Lactobacillus johnsonii* CNCMI-1225, all from Valio Oy, Finland; *Streptococcus salivarius* DSM 13084, sold by BLIS Technologies Limited, New Zealand under the name KI2; and *Bifidobacterium lactis* CNCM I-3446 and *Bifidobacterium longum* CNCM, specially sold by Christian Hansen, Denmark under the trademark Bb 12. I-2618 (Bifidobacterium longum NCC2705), Bifidobacterium breve sold by Danisco under the trademark Bb-03, Bifidobacterium breve sold by Morinaga under the trademark M-16V, Bifidobacterium infantis sold by Procter & GambIe Co. under the trademark Bifantis, and Bifidobacterium breve sold by Institut Rosell (Lallemand) under the trademark R0070, Bifidobacterium longum subsp. Infantis LMG 11588 (also known as ATCC 17930), Bifidobacterium kashiwanohense (JCM 15439) and / or Bifidobacterium kashiwanohense (DSM 21854).

[0076] On a dry weight basis, the nutritional composition or combination according to the invention may contain at least one (additional) probiotic strain at 10e3cfu to 10e12cfu per g of composition, more preferably a probiotic strain between 10e7cfu and 10e12cfu (such as between 10e8cfu and 10e10cfu).

[0077] In one embodiment, the probiotics are live. In another embodiment, the probiotics are non-replicating or inactivated. In some other embodiments, both live and inactivated probiotics may be present simultaneously. Probiotic components and metabolites may also be added.

[0078] Bifidobacterium kashiwanohense was isolated from the feces of healthy infants. For example, this bacterium has previously been characterized by its phenotypic and biochemical features, as well as its phylogenetic position, based on partial 16S rRNA sequence analysis (Morita et al., International Journal of Systematic and Evolutionary Microbiology, 2011, 61: 2610–2615). The GenBank / EMBL / DDBJ accession numbers for the 16S rRNA and partial hsp60 gene sequences of two strains of Bifidobacterium kashiwanohense are (i) AB491757 and AB578933 and (ii) AB425276.2 and AB491759.2, respectively. A strain of Bifidobacterium burgdorferi was obtained from two collections with accession numbers JCM 15439 and DSM 21854 (Morita et al., International Journal of Systematic and Evolutionary Microbiology, 2011, 61: 2610–2615).

[0079] Bifidobacterium burgdorferi can be a Bifidobacterium burgdorferi that has at least 99% (suitably, at least 99.9%) average nucleotide identity (ANI) with any Bifidobacterium burgdorferi known to those skilled in the art.

[0080] As used in this paper, the term “average nucleotide identity (ANI)” refers to a distance-based method for describing species based on pairwise comparisons of genome sequences. ANI is a computational method for the phylogenetic definition of species and has become the gold standard for species description (Goris et al., 2007, Int. J. Syst. Evol. Microbiol. 57: 81-91; Kim et al., 2014, Int. J. Syst. Evol. Micr. 64: 346-351; Richter et al., 2009, P NatlAcad Sci USA 106: 19126-19131; and Chan et al., 2012, Bmc. Microbiol. 12).

[0081] The ANI (Aspect-Number Indication) of shared genes between two strains is a robust means of comparing the genetic affinity between strains. An ANI value of at least approximately 96% indicates that the strains belong to the same species (Konstantinidis and Tiedje, 2005, ProcNatl Acad Sci USA, 102(7):2567-72; and Goris et al., 2007, Int Syst EvolMicrobiol.57(Pt 1):81-91), while an ANI value of at least approximately 99% indicates that the bacterial genome belongs to the same strain. The ANI between two bacterial genomes is calculated by pairwise comparisons of all sequences common to any two strains and can be determined, for example, using any of a number of publicly available ANI tools, including but not limited to OrthoANI with usearch (Yoon et al., 2017, Antonie van Leeuwenhoek 110:1281-1286); ANICalculator, JSpecies (Richter and Rossello-Mora, 2009, Proc Natl Acad Sci USA106:19126-19131); and JSpeciesWS (Richter et al., 2016, Bioinformatics 32:929-931). Other methods for determining the ANI of two genomes are known in the art (Konstantinidis, KT and Tiedje, 2005, JM, Proc. Natl. Acad. Sci. USA, 102: 2567-2572; and Varghese et al., 2015, Nucleic Acids Research, 43(14):6761-6771).

[0082] Suitably, *Bifidobacterium burgdorferi* and *Bifidobacterium burgdorferi* JCM 15439 and / or *Bifidobacterium burgdorferi* DSM 21854 have an ANI of at least 99% (suitably, at least 99.1%, at least 99.2%, at least 99.3%, at least 99.4%, at least 99.5%, at least 99.6%, at least 99.7%, at least 99.8%, at least 99.9%). Preferably, *Bifidobacterium burgdorferi* and *Bifidobacterium burgdorferi* JCM 15439 and / or *Bifidobacterium burgdorferi* DSM 21854 have an ANI of at least 99.9%.

[0083] The term "oligosaccharide" refers to a carbohydrate polymer containing a small amount (typically three to ten parts) of common sugars (monosaccharides). As used herein, oligosaccharides refer to carbohydrates with a degree of polymerization (DP) ranging from 2 to 20 (inclusive). "Degree of polymerization" or "DP" refers to the total number of sugar units in an oligosaccharide or polysaccharide chain.

[0084] As used herein, the term "galacto-oligosaccharide" refers to a non-digestible oligosaccharide containing two or more galactose molecules. The galacto-oligosaccharides (GOS) used in the embodiments disclosed herein have a DP of 2 to 20, preferably 2 to 10. Based on monomer subunits, preferably at least 30%, more preferably at least 50%, and more preferably at least 60% of the sugar units are galactose units.

[0085] Suitable galacto-oligosaccharides are commercially available and include, for example, Purimune GOS (from CornProducts International), King GOS (from King Prebiotics), and Vivinal GOS (from Friesland Campina). Other suppliers of oligosaccharides include Clasado, Ingredion, Leprino, Yakult, Dextra Laboratories, Sigma-Aldrich Chemie GmbH, and Kyowa Hakko Kogyo Co., Ltd.

[0086] Galacto-oligosaccharides (GOS) are prebiotics, and optionally, infant formula also contains other prebiotics.

[0087] As used herein, galactooligosaccharides (GOS) typically consist of a β-linked galactose moiety and a galactose or glucose terminal at the reducing end. Such GOS contain β-(1→2), β-(1→3), β-(1→4), or β-(1→6) linked galactose moieties and can have a degree of polymerization (DP) of 3 to 8 galactose units. Therefore, the term GOS is preferably referred to as an oligosaccharide containing at least three galactose units, more preferably as an oligosaccharide containing at least four galactose units, and most preferably has a degree of polymerization (DP) of 3 to 8 galactose units.

[0088] Galacto-oligosaccharides (GOS) are defined as polymers of galactose (at least two galactose monomers) and terminal β-linked galactose or glucose monomers. GOS are prebiotic substrates commonly added to infant formula compositions, commercially available, for example, in the form of Vivinal-GOS (sold by Friesland Campina in the Netherlands) or in the form of milk-derived oligosaccharides (BMOS) (Estorninos et al., Am J Clin Nutr., 2022, 115: 142-153). BMOS particularly promotes the selective growth of Bifidobacterium species, such as Bifidobacterium longum subsp. infantis (Roberfroid et al., 2010, British Journal of Nutrition, 104(S2): S1-S63).

[0089] In some implementations, the galactose source is selected from galacto-oligosaccharides (GOS), milk-derived oligosaccharides (BMOS), and combinations thereof.

[0090] In one specific embodiment, the nutritional composition according to the invention may comprise BMOS. BMOS may be an oligosaccharide formulation derived from milk and / or whey fractions. One way to increase oligosaccharides in milk-derived fractions is to convert a portion of the lactose in these fractions into GOS. BMOS can typically be obtained from concentrated whey permeate powder to obtain a concentrated milk oligosaccharide composition and by adding GOS from the hydrolysis of lactose or generating GOS in situ through the action of β-galactosidase (Duncan et al., Nutrients, 2020, 12: 2007).

[0091] In one embodiment, the nutritional composition comprises an oligosaccharide mixture (“BMOS”) comprising 0.1% to 4.0% by weight of N-acetylated oligosaccharides, 92.0% to 98.5% by weight of galactooligosaccharides, and 0.1% to 4.0% by weight of sialylated oligosaccharides.

[0092] Combinations of prebiotics can be used, such as a combination of 90% GOS and 10% short-chain fructooligosaccharides (e.g., under the trademark Raftilose). ® The product sold), or a combination of it with 10% inulin (such as under the trademark Raftiline). ®(Products sold). Other examples of optional additional prebiotics that may be used in infant formula include sialylated oligosaccharides (SOS), fructooligosaccharides (FOS), human milk oligosaccharides (HMO), isomaltooligosaccharides (IMO), xylooligosaccharides (XOS), arabinoxylan oligosaccharides (AXOS), mannooligosaccharides (MOS), soybean oligosaccharides, sucrose (GS), lactulose oligosaccharides (LS), sialyl-lactose (SL), fucose-lactose (FL), lactose-N-neotetrasaccharide (LNNT), lactulose (LA), paragine oligosaccharides (PAO), maltodextrin, gums and / or their hydrolysates, pectin, starch and / or their hydrolysates.

[0093] Human milk oligosaccharides (HMOs) are carbohydrates resistant to enzymatic hydrolysis by digestive enzymes (e.g., pancreatic and / or brush border), indicating that their potential functions are not directly related to their calorific value. These carbohydrates have been specifically noted in the art to play a crucial role in early infant and toddler development, such as the maturation of the immune system. Many different types of HMOs have been found in human milk. Each individual oligosaccharide is based on a variety of combinations of glucose, galactose, sialic acid (N-acetylneuraminic acid), fucose, and / or N-acetylglucosamine with these molecules, resulting in a large and diverse array of oligosaccharides in human milk; over 130 such structures have been identified to date. Almost all oligosaccharides have a lactose molecule at the reducing end, and the non-reducing terminal positions are occupied by sialic acid and / or fucose (if present). HMOs can be acidic (e.g., oligosaccharides containing charged sialic acid) or neutral (e.g., fucoidylated oligosaccharides). Some examples of HMOs are fucoidylated oligosaccharides, N-acetylated oligosaccharides, and / or sialylated oligosaccharides.

[0094] "Fucosylated oligosaccharides" are oligosaccharides containing fucose residues. These oligosaccharides are neutral. Some examples are LNFP-I (lactose-N-fucopentose I), 2'-FL (2'-fucosyllactose), and 3-FL (3-fucosyllactose).

[0095] The terms “fucosylated oligosaccharides containing α-1,2-fucosylation epitopes” and “2-fucosylated oligosaccharides” encompass fucosylated oligosaccharides with a certain degree of formal homology, as they contain α-1,2-fucosylation epitopes and therefore a certain degree of functional homology can be expected.

[0096] The term "N-acetylated oligosaccharide" encompasses both "N-acetyl-lactoside" and "oligosaccharides containing N-acetyl-lactoside." Such oligosaccharides are neutral oligosaccharides having N-acetyl-lactoside residues. Suitable examples are LNT (lactose-N-tetrasaccharide), para-lactose-N-neohexose (para-LNnH), LNnT (lactose-N-neohexose), and any combination thereof. Other examples are lactose-N-hexasaccharide, lactose-N-neohexose, para-lactose-N-hexasaccharide, para-lactose-N-neohexose, lactose-N-octasaccharide, lactose-N-neohexose, isol-lactose-N-octasaccharide, para-lactose-N-octasaccharide, and lactose-N-decansaccharide.

[0097] "Sialinated oligosaccharides" are oligosaccharides containing charged sialic acid, that is, oligosaccharides containing sialic acid residues. These oligosaccharides are acidic. Some examples are 3'-SL (3'-sialyl-lactose) and 6'-SL (6'-sialyl-lactose). The terms "sialylated oligosaccharides" and "sialyl-lactose (SL)" are used interchangeably. The trisaccharide sialyl-lactose consists of lactose at the reducing end and one sialic acid residue at the non-reducing end, which, via α-2,3 binding or α-2,6 binding, produce 3'-SL and 6'-SL, respectively.

[0098] "HMO precursors" are key compounds used in the production of HMOs, such as sialic acid and / or fucose.

[0099] Due to their glycosidic bond configuration, galactooligosaccharides (GOS) are largely resistant to hydrolysis by saliva and intestinal digestive enzymes. GOS are classified as prebiotics, non-digestible carbohydrates that beneficially influence the host by stimulating the growth and / or activity of beneficial bacteria in the colon.

[0100] As used herein, "added fiber" or "added dietary fiber" indicates an ingredient that consists primarily or entirely of fiber added to a nutritional supplement composition, and the amount of fiber constitutes the total fiber content of the composition. The total fiber content of a nutritional supplement composition is provided by the sum of the amount of naturally occurring fiber (e.g., from whole grain flour) in the ingredients used in the formulation and the amount of added fiber. Suitably, the compositions of the present invention may be probiotic compositions.

[0101] The IBQ-R (Revised Infant Behavior Questionnaire) is a widely used parent-reported measure of temperament with 14 scales, used to assess infants between 3 and 12 months of age, as reported in Table 1 below (Garstein MA; Rothbart AK. Studying infant temperament via Revised Infant Behavior Questionnaire. Infant Behavior & Development 2003: 26: 64-86).

[0102] Table 1. Scale Definitions: Revised Infant Behavior Questionnaire

[0103]

[0104] In the context of this invention, the terms "anxiety" and "fear" are used interchangeably. "Social phobia" refers to a developmental background of approaching behavioral inhibition and / or distress in social situations involving novelty and / or uncertainty.

[0105] In the context of this invention, the expression "social skills" or "multiple social skills" encompasses any ability or behavior observed in a social situation or environment and / or that facilitates interaction and communication with others (verbally and nonverbally), and the development of social skills begins in the first few months of life. For example, infants begin to express signs of emotion, such as pleasure, anger, sadness, interest, fear, disgust, and surprise, through distinctive facial expressions. Infants also begin to laugh and begin to socialize through babbling. Social skills continue to develop in toddlers and children, including, for example, beginning to imitate the environment around 15 months, attaching to a caregiver in new situations at 18 months (social phobia), and engaging in parallel play with other children around 24 months.

[0106] In the context of this invention, the expression "social-emotional competence" or "social-emotional development" refers to the social-emotional competence that develops from birth, which allows for enhanced autonomy, self-regulation, and relationships. Social-emotional development can be assessed and behaviorally monitored using clinical interviews, direct behavioral observation and rating systems, and parent and teacher report questionnaires (Schneider N et al., Child Development 2022:93:359-371. Doi:10.1111 / cdev.13649).

[0107] In the context of this invention, the term "extroversion" refers to a temperament dimension that reflects an individual's tendency toward positive emotions, approach behaviors, sociability, high-intensity pleasure, reward seeking, and high activity levels (Holmboe, K. (2016). Surgency. In: Zeigler-Hill, V., Shackelford, T. (eds) Encyclopedia of Personality and Individual Differences. Springer, Cham. https: / / doi.org / 10.1007 / 978-3-319-28099-8_2123-1 ).

[0108] In the context of this invention, the term "extroversion" refers to an extroverted attitude. Extroverts find communication and interaction within social groups stimulating. https: / / de.wikipedia.org / wiki / Introversion_und_ Extraversion Typically, extroverted traits include being talkative, decisive, active, energetic, assertive, enthusiastic, and adventurous. (Philipp Yorck Herzberg, Marcus Roth: Personality Psychology. Hrsg.: Springer VS. 1. Auflage. Springer VS, Wiesbaden 2014, ISBN 978-3-531-17897-4, p.41).

[0109] In the context of this invention, the expression "emotional skills" or "multiple emotional skills" refers to the ability to experience and express personal feelings as well as to recognize and interpret the feelings of others. Emotional skills are, for example, related to emotions, pleasure, and sadness. The development of emotional skills occurs alongside neural, cognitive, and behavioral development, from birth through childhood, adolescence, and adulthood.

[0110] In the context of this invention, the term "emotional development" refers to the growth and changes in an individual's emotional capacity and experiences over time. It encompasses a broad range of emotional development, including basic emotions such as joy, sadness, anger, and fear, as well as more complex emotions such as sympathy, guilt, and aversion. Emotional development also includes the ability to recognize and label one's own and others' emotions, regulate emotional responses, and express emotions in a socially appropriate manner. This is a complex process influenced by biological and environmental factors such as genetics, temperament, attachment experiences, and cultural norms. Emotional development is a crucial aspect of human development because it plays a significant role in shaping an individual's personality, social relationships, and overall health.

[0111] In the context of this invention, the term "emotion regulation" refers to the process by which an individual identifies and manages their emotions in order to respond to situations in a more adaptive and appropriate manner. Emotion regulation involves the ability to identify and label a person's emotions, understand the triggers of those emotions, and subsequently use strategies to manage or modify them to achieve desired outcomes. Effective emotion regulation can help individuals cope with stress, build positive relationships, and make better decisions. Some common emotion regulation strategies include mental practices, relaxation techniques, cognitive restructuring, and problem-solving skills.

[0112] In the context of this invention, the term "regulation domain" on the Infant Behavior Questionnaire-Revised (IBQ-R) scale is a set of items that assess an infant's ability to self-regulate their emotional and behavioral responses to a variety of situations. The IBQ-R is a widely used measure of infant temperament that assesses three main domains: extraversion / extroversion, negative affect, and regulation. The regulation domain includes items that assess the frequency and intensity of an infant's ability to regulate their behavioral and emotional responses, such as crying, fussiness, and soothing. Items in the regulation domain include, for example, "orientation duration" and "holding preference / behavior induced by physical contact." Researchers and clinicians use the IBQ-R to assess infant temperament, which can be used to understand individual differences in emotional and behavioral regulation in early life and to identify infants who may be at risk of later developmental problems.

[0113] In the context of this invention, the expression "reducing the risk of experiencing" should be understood as reducing the frequency or intensity of certain behavioral traits related to temperament or sociability as determined by the IBQ-R questionnaire. In one embodiment, the expression "reducing the risk of experiencing" includes reducing the frequency and / or intensity of certain behavioral traits related to temperament or sociability in the presence of one or more nutrients.

[0114] In the context of this invention, the expression "improved social-emotional skills" refers to improvements in the social-emotional abilities or behaviors of infants, toddlers, or young children.

[0115] Therefore, the object of the present invention is to enrich or improve the prior art, and in particular to provide nutrients or nutritional compositions for improving the social skills development of young individuals, preferably infants.

[0116] Any references to prior art literature in this specification should not be construed as an admission that such prior art is well-known or part of general common knowledge in the art. All publications mentioned in this specification are incorporated herein by reference.

[0117] Embodiments of the present invention

[0118] The invention will now be described in more detail.

[0119] This invention relates to a combination comprising effective amounts of osteopontin and lactoferrin, the combination being used to promote the socio-emotional development of young individuals. In one embodiment, the combination comprises:

[0120] Osteopontin, the amount of which ranges from approximately 50 ng / μL to approximately 900 ng / μL, and

[0121] Lactoferrin, with levels ranging from approximately 190 ng / μL to approximately 5050 ng / μL.

[0122] Osteopontoprotein (OPN) is a minor, acidic, highly phosphorylated glycoprotein, and its concentration in human milk is higher than in cow's milk. The average OPN concentrations reported in human milk, cow's milk, and infant formula are 138 mg / L, 18 mg / L, and 9 mg / L, respectively.

[0123] Lactoferrin (LF) (also known as lactoferrin (LTF)) is a globular, multifunctional protein. It is found in the milk of most mammalian species. The concentration of this protein is typically about 4.91 g / L in early and 2.10 g / L in mature human milk, while the concentration in cow's milk is about 1 / 10.

[0124] This invention relates to lactoferrin that can be obtained from any source.

[0125] In a preferred embodiment, lactoferrin is derived from milk, particularly whey. Therefore, lactoferrin can be purified, for example, from milk, or it can be recombinantly produced. Lactoferrin derived from milk or whey has the advantage of being a natural component, mostly obtained from food-grade compositions, and thus can be used as an enrichment fraction of food compositions without further purification.

[0126] The recombinant lactoferrin has the following advantages: it can easily prepare high concentrations of lactoferrin.

[0127] In some embodiments, lactoferrin is bovine lactoferrin or human lactoferrin. Suitably, human lactoferrin is preferred.

[0128] In some implementations, lactoferrin is recombinant human lactoferrin.

[0129] In a preferred embodiment, osteopontin and lactoferrin are used as a combined form of lactoferrin and osteopontin, thereby allowing them to be added together with other ingredients of infant formula to a wet mixture and aseptically processed or spray-dried in the infant formula composition. This process is described in WO2023 / 111302.

[0130] In one implementation, the combination is used in the extraversion and / or extraversion, affective and / or behavioral modulation, and / or modulation domains of the Infant Behavior Questionnaire-Revised (IBQ-R) scale for promoting the development of young individuals.

[0131] In one implementation, the young individual is an infant, a toddler, or a preschooler, preferably an infant.

[0132] In one implementation, the combination is administered to the young individual from birth to about 5 years of age, preferably from birth to 18 weeks of age, and more preferably during the first 12 weeks of the young individual's life.

[0133] In one implementation, socio-emotional development is promoted in young individuals from birth to about 5 years of age, preferably from birth to 18 months of age, more preferably from about 2 months of age to about 6 months of age, and even more preferably from about 3 months of age.

[0134] In one implementation, the regulation of at least one of the following is promoted in young individuals from birth to about 5 years of age, preferably from birth to 18 months of age, more preferably from about 2 months of age to about 6 months of age, and even more preferably about 3 months of age: the regulation of extraversion and / or extraversion, affect and / or behavior, or regulation domains on the Infant Behavior Questionnaire-Revised (IBQ-R) scale.

[0135] In one implementation, the combination is used to prevent psychosocial disorders and / or illnesses caused by impaired social and / or emotional development in young individuals from birth to about 5 years of age, preferably from birth to 18 months of age.

[0136] Suitablely, the combination according to the invention promotes the socio-emotional development of young individuals from birth to about 5 years of age or about 18 months of age. In one embodiment, the combination according to the invention promotes the socio-emotional development of young individuals aged between about 2 months and about 6 months. In another embodiment, the combination according to the invention promotes the socio-emotional development of young individuals at least about 2 months of age, at least about 3 months of age, or at least about 6 months of age. In some embodiments, the combination promotes the socio-emotional development of the young individual when applied to the young individual during the first 1 week, first 3 weeks, first 6 weeks, first 9 weeks, first 12 weeks, or first 18 weeks of life, preferably at 6 weeks of life.

[0137] The inventors have surprisingly discovered that the combination of the present invention promotes the modulation or moderating domain of extraversion and / or extraversion, affect and / or behavior on the Infant Behavior Questionnaire-Revised (IBQ-R) scale for infants under 6 months of age. Figure 2 , Figure 3 (and examples). In one embodiment, in young individuals from birth to about 5 years of age, preferably from birth to 18 months of age, more preferably from about 2 months of age to about 6 months of age, and even more preferably at about 3 months of age, and in one embodiment, when the composition is applied to young individuals from birth to about 5 years of age, preferably from birth to 18 weeks of age, more preferably during the first 12 weeks of the young individual's life, or during the first 1, 3, 6, 9, 12, or 18 weeks of the young individual's life, preferably during the first 6 weeks of the young individual's life, it promotes at least one of the following: modulation or modulation domains of extraversion and / or extraversion, affect and / or behavior on the Infant Behavior Questionnaire-Revised (IBQ-R) scale.

[0138] In one implementation scheme, socioemotional disorders and / or illnesses include: autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), intellectual disability, anxiety, depression, and / or behavioral disorders.

[0139] Autism spectrum disorder (ASD) is a developmental disorder that affects social communication and interaction, as well as behavior and interests. Some individuals with ASD may have difficulties with emotional regulation and expression, which can lead to social and behavioral challenges.

[0140] Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by inattention, hyperactivity, and impulsivity. Individuals with ADHD may face challenges in regulating their emotions and may have difficulty controlling their emotions and behaviors in certain situations.

[0141] Intellectual disability is a condition characterized by significant limitations in intellectual functioning and adaptive behavior.

[0142] Anxiety disorders are a group of mental health conditions characterized by excessive worry or fear. Impaired emotional regulation may contribute to the development or maintenance of anxiety disorders.

[0143] Depression is a mood disorder characterized by persistent feelings of sadness, hopelessness, and loss of interest in activities. Impaired emotional regulation may be a contributing factor to the development or maintenance of depression.

[0144] Behavioral disorders are behavioral disturbances characterized by a persistent pattern of violating the rights of others and social norms. Impaired emotional development may lead to difficulties in impulse control, anger management, and behavioral regulation, which may be characteristic of behavioral disorders.

[0145] The present invention also relates to a nutritional composition for use in promoting the socio-emotional development of young individuals, wherein the nutritional composition comprises the combination according to any one of the preceding claims.

[0146] In one embodiment, the nutritional composition is infant formula, stage 1 infant formula, stage 2 or later infant formula, baby food, growing milk, infant cereal composition, fortifier, or supplement.

[0147] In one embodiment, the composition according to the invention is a synthetic nutritional composition.

[0148] In one embodiment, the composition of the present invention is an infant formula, fortifier, or supplement intended for infants aged 3 months or 6 months. In a preferred embodiment, the nutritional composition of the present invention is an infant formula.

[0149] In some other embodiments, the nutritional composition of the present invention is a fortifier. The fortifier may be a breast milk fortifier (e.g., human milk fortifier) ​​or a formula food fortifier (such as an infant formula fortifier or a follow-up formula / stage 2 infant formula fortifier).

[0150] When a nutritional composition is a supplement, it can be provided in unit dose form.

[0151] The nutritional compositions of the present invention may be in solid (e.g., powder), liquid or gel form.

[0152] In one embodiment, the nutritional composition or combination disclosed above is administered to the mother of a young individual during pregnancy or lactation.

[0153] The present invention also relates to non-therapeutic uses of combinations or compositions as disclosed above for promoting the socio-emotional development of young individuals.

[0154] The present invention also relates to a method for promoting the socio-emotional development of young individuals, the method comprising administering effective amounts of osteopontin and lactoferrin to the young individuals.

[0155] The present invention also relates to a method for promoting the socio-emotional development of young individuals, the method comprising administering to the young individual a combination or nutritional composition as disclosed above.

[0156] If a metabolic precursor and / or metabolite of osteopontin and / or lactoferrin is used in the composition in place of or in combination with osteopontin and / or lactoferrin, the amount of said compound is such that the amount of osteopontin and / or lactoferrin physiologically delivered by said composition conforms to those listed above. Determining the appropriate amount is entirely within the capabilities of those skilled in the art.

[0157] The combination or nutritional composition according to the present invention advantageously improves socio-emotional development.

[0158] It supports or promotes healthy socio-emotional development in infants and prevents or resolves developmental problems, disorders or illnesses that may arise in situations where infants have difficulties in social and / or emotional regulation.

[0159] The age and duration of administration (giving or feeding) of the nutritional composition can be determined based on availability and need.

[0160] Because the nutritional composition is also used for preventative purposes (prevention of health problems later in life), it can be provided, for example, immediately after birth. The composition of the invention can also be administered during the first week of an infant's life, or during the first two weeks of life, or during the first three weeks of life, or during the first month of life, or during the first two months of life, or during the first three months of life, or during the first four months of life, or during the first six months of life, or during the first eight months of life, or during the first ten months of life, or during the first year of life, or during the first two years of life, or even longer. In some particularly advantageous embodiments of the invention, the nutritional composition is given (or applied) to the infant within the first four or six months after birth.

[0161] In one embodiment, when the nutritional composition is used in healthy infants, toddlers, and / or young children, its use according to the invention is non-therapeutic.

[0162] In another embodiment, when the nutritional composition is used in a vulnerable subject, the use according to the invention is therapeutic, such as an infant, toddler or child born by cesarean section and / or preterm, and / or small for gestational age (SGA), and / or low birth weight, very low birth weight or extremely low birth weight (LWB, VLBW or ELBW), and / or experiencing intrauterine growth retardation (IUGR) and / or with tissue damage or immaturity.

[0163] In another embodiment, the use according to the invention is therapeutic when the nutritional composition is used for infants, toddlers, and / or young children at risk of developmental behavioral problems later in life.

[0164] In another embodiment, the use of the nutritional composition according to the invention is therapeutic when used in infants, toddlers, and / or young children at risk of developing socioemotional disorders and / or diseases induced by impaired social development.

[0165] In some other embodiments, the nutritional composition of the present invention is given a few days (e.g., 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 20 days…), or a few weeks (e.g., 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks…) or a few months (e.g., 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months…) after birth. This may specifically refer to cases where the infant is premature, but it is not necessary.

[0166] In one embodiment, the composition of the present invention is given to an infant or young child as a supplemental composition to breast milk. In some embodiments, the infant or young child receives breast milk for at least the first 2 weeks, first 1 month, first 2 months, first 4 months, or first 6 months. In one embodiment, the nutritional composition of the present invention is given to the infant or young child after this period of breastfeeding, or given to the infant or young child together with breast milk during this period of breastfeeding. In another embodiment, the composition is given to the infant or young child as the sole or primary nutritional composition for at least a period of time (e.g., after at least the first, second, or fourth month of life), for at least one, two, four, or six months.

[0167] In a preferred embodiment, the composition is administered orally to an infant or toddler in infant formula. The infant formula may contain a protein source in amounts of up to 4.0 g / 100 kcal, preferably up to 3.0 g / 100 kcal, more preferably up to 2.0 g / 100 kcal, and most preferably from 1.8 g / 100 kcal to 2.0 g / 100 kcal. In some embodiments, more than 50% by weight of the protein source is whey. In one embodiment, the protein content is between 30% and 80% whey protein. Protein sources based on whey, casein, and mixtures thereof may be used, as well as soy-based protein sources. For whey protein, the protein source may be based on acidic whey or sweet whey, or mixtures thereof, and may include α-lactalbumin and β-lactoglobulin mixed in a desired proportion.

[0168] The protein can be whole, hydrolyzed, or a mixture of whole and hydrolyzed proteins. Partially hydrolyzed proteins (with a degree of hydrolysis between 2% and 20%) can be particularly beneficial for infants considered to be at risk of developing cow's milk allergy. If hydrolyzed protein is required, the hydrolysis process can be carried out as needed and as is known in the art. For example, whey protein hydrolysates can be prepared by enzymatic hydrolysis of whey fractions in one or more steps. If the whey fraction used as the starting material is substantially lactose-free, the protein suffers much less lysine blockade during hydrolysis, allowing the degree of lysine blockade to be reduced from about 15% by weight of total lysine to less than about 10% by weight of lysine; for example, about 7% by weight of lysine, which greatly improves the nutritional quality of the protein source.

[0169] Infant formula may contain carbohydrate sources. Any carbohydrate source commonly found in infant formula may be used, such as lactose, sucrose, maltodextrin, starch, and mixtures thereof; although lactose is the preferred carbohydrate source. Preferably, the carbohydrate source constitutes between 35% and 65% of the total energy of the formula. In a preferred embodiment, the carbohydrates comprise rice carbohydrates, for example, at least 5%, at least 10%, at least 25%, or at least 50%, at least 70%, at least 90%, or about 100% of the total carbohydrates (w / w), which can provide substantial benefits in sleep patterns. The higher the rice carbohydrate content, the greater the likelihood of improved sleep.

[0170] This infant formula may contain a lipid source. The lipid source can be any lipid or fat suitable for infant formula. Preferred fat sources include palm oil extract, high-oleic sunflower oil, and high-oleic safflower oil. Essential fatty acids linoleic acid and alpha-linolenic acid may be added, as may small amounts of oils containing high-quality pre-formulated arachidonic acid and docosahexaenoic acid, such as fish oil or microbial oil. Overall, the fat content preferably accounts for between 30% and 55% of the total energy of the formula. In the fat source, the ratio of n-6 fatty acids to n-3 fatty acids is preferably from about 5:1 to about 15:1, for example, from about 8:1 to about 10:1.

[0171] Infant formula may optionally contain one or more vitamins. For example, infant formula may contain all vitamins and minerals that are understood to be essential for a daily diet and are necessary in significant amounts. Minimum requirements for certain vitamins and minerals have been determined. Examples of additional minerals and vitamins optionally present in infant formula include vitamin A, vitamin B12, vitamin E, vitamin K, vitamin C, vitamin D, folic acid, inositol, niacin, biotin, pantothenic acid, choline, calcium, phosphorus, iodine, magnesium, manganese, chloride, potassium, sodium, selenium, chromium, molybdenum, taurine, and L-carnitine. Minerals are usually added in salt form. The presence and amount of specific additional minerals and vitamins will vary depending on the target infant population.

[0172] If necessary, infant formula may contain emulsifiers and stabilizers, such as citrates of soy lecithin, monoglycerides, and diglycerides. Infant formula may optionally contain other substances that may have beneficial effects, such as fiber, lactoferrin, nucleotides, and nucleosides. For example, infant formula may contain probiotic strains in amounts ranging from 10³ cfu / g to 10¹² cfu / g, more preferably from 10⁶ cfu / g to 10⁹ cfu / g.

[0173] The infant formula described herein can be prepared by any suitable method. For example, it can be prepared by blending protein, carbohydrate source, and fat source together in appropriate proportions. If used, an emulsifier may be added at this time. Vitamins and minerals may be added at this time, but to avoid thermal degradation, they are usually added at a slightly later time. Before blending, any lipophilic vitamins and emulsifiers may be dissolved in the fat source. Water (preferably water subjected to reverse osmosis) may then be added to form a liquid mixture. The water temperature is preferably from about 50°C to about 80°C to facilitate dispersion of the ingredients. A commercially available liquefying agent may be used to form the liquid mixture. The liquid mixture is then homogenized; for example, in two stages.

[0174] The liquid mixture can then be heat-treated, for example, by rapidly heating it to a temperature in the range of about 80°C to about 150°C for about 5 seconds to about 5 minutes, to reduce the bacterial load. This can be done by steam injection, autoclave, or through a heat exchanger (e.g., plate heat exchanger).

[0175] The liquid mixture can then be cooled, for example, to about 60°C to about 85°C by rapid cooling. The liquid mixture can then be homogenized again; for example, in two stages: the first stage at about 10 MPa to about 30 MPa, and the second stage at about 2 MPa to about 10 MPa. The homogenized mixture can then be further cooled to add any heat-sensitive components, such as vitamins and minerals. The pH and solids content of the homogenized mixture can then be conveniently adjusted.

[0176] The homogenized mixture can be transferred to a suitable drying device (such as a spray dryer or freeze dryer) and converted into a powder. The moisture content of the powder should be less than about 5% by weight. Probiotic strains may optionally be added at this stage via dry mixing. The powder can then be packaged into unit dosage forms. Before administration to infants or toddlers, the powder can be reconstituted in a diluent (such as water or milk).

[0177] The combination can be administered to infants or toddlers in unit dosage forms, wherein the unit dosage form contains an amount of the combination effective for increasing propionate levels in infants or toddlers. The unit dosage form can be a powder containing a predetermined amount of the combination, and the method includes reconstituted the powder in a diluent to form a nutritional composition, in which the combination is orally administered to the infant or toddler.

[0178] Suitable, the nutritional composition may be intended to be applied twice daily. Therefore, the nutritional composition may be formulated to provide two servings per day.

[0179] Suitable, the nutritional composition can be provided in servings of 31g or 36g of total dry weight.

[0180] In some embodiments, the compositions of the present invention may be administered once daily. In other embodiments, the compositions of the present invention may be administered in multiple doses, such as two doses (unit doses) daily. When the nutritional composition is provided in unit dose (or "serving") form, it is particularly useful to define the amount of oligosaccharides and probiotics according to the daily dose to be administered to an infant or toddler or child.

[0181] Those skilled in the art will understand that they are free to combine all the features of the invention disclosed herein. In particular, features described for the products of the invention can be combined with the methods of the invention, and vice versa. Furthermore, features described for different embodiments of the invention can be combined. Where known equivalents exist for a particular feature, such equivalents are incorporated as expressly mentioned in this specification.

[0182] Other advantages and features of the invention will become apparent from the accompanying drawings and non-limiting embodiments.

[0183] Example

[0184] The inventors analyzed the composition of breast milk at three time points during the first three months postpartum and investigated its association with developmental outcomes (such as social and / or emotional development) in the first two years. Factor analysis was applied to the behavioral scales that constitute the Infant Behavior Questionnaire (IBQR).

[0185] Data used for these analyses came from prospective, longitudinal, dual-center (Memorial Hospital of Rhode Island and Pennington Biomedical Research Center, USA) observational groups, with an intervention period of 12 months and follow-up assessments up to 2 years. Seven visits occurred: V1 (6 ± 1 week of life), V2 (3 months ± 2 weeks), V3 (6 months ± 2 weeks), V4 (9 months ± 2 weeks), V5 (12 months ± 2 weeks), V6 (18 months ± 3 weeks), and V7 (24 months ± 4 weeks). Exclusion criteria included: a) delayed birth (>41 weeks + 6 days of gestation), as reported in the medical record (when available); b) birth weight <2000g or smaller than the 10th percentile for gestational age or larger than the 90th percentile for gestational age (weight, length, or head circumference greater than the 90th percentile), as reported in the medical record (when available); c) use of prohibited medications or any unsafe psychopharmacological treatment of the mother during pregnancy or lactation, as assessed by a medical interview.

[0186] One hundred and seven breastfeeding mothers and their infants were followed up for 0 to 24 months. Breast milk was longitudinally sampled from the mothers during scheduled study visits, each time between 10:00 AM and 12:00 PM using a medical-grade electric breast pump from the right breast. Additionally, mothers were instructed to empty their right breast approximately two hours prior to milk sampling and to use a pump to empty the entire breast during the sampling time (single complete breast milk sampling method). Only a portion of the collected milk was used for the study, while the remainder was returned to the mothers for feeding their infants at a later time.

[0187] Breast milk samples were collected at 2 to 5 weeks (V0), 6 weeks (V1), and 3 months (V2).

[0188] Factor analysis of IBQR and its correlation with breast milk nutrients

[0189] Factor analysis assumes the following model form

[0190]

[0191] Or simply:

[0192]

[0193] The aim is to identify latent factors that can be interpreted as broad categories of behavior and temperament. The main benefit is reducing the number of variables, and therefore the number of statistical comparisons.

[0194] The inventor will use fractions It correlates with breast milk nutrient concentrations to measure the association between nutrients and each given behavioral dimension.

[0195] The Infant Behavior Questionnaire-Revised (IBQR-VSF) is a widely used parent-reported measure with 14 scales developed to assess temperament dimensions. The use of factor analysis applied to the IBQR scales has been published in several papers (see, for example, 1- Factor Structure and Measurement Invariance of the Very Short Form of Infant Behavior Questionnaire-Revised (IBQR-VSF): A Study among Vietnamese Children, 10.3390 / healthcare10040689, 2- The Infant Behavior Questionnaire-Revised: Factor Structure in a Culturally and Sociodemographically Diverse Sample in the United States, 10.1016 / j.infbeh.2016.04.001 ).

[0196] Factor loadings define three factors FA1, FA2, and FA3, which can be interpreted as "extraversion / extravagance," "negative affect," and "orientation / regulation," respectively. Figure 1 As shown. This naming is a copy of the naming proposed in the aforementioned references ( 10.1016 / j.infbeh.2016.04.001 )

[0197] Correlation with individual proteins :

[0198] Table 1 reports the correlations between protein concentration and factor scores. Correlation was calculated for all time point combinations for breast milk and IBQ-R. Below, we report only the significant correlations (after adjusting for multiple comparisons).

[0199] Table 1

[0200]

[0201] The table shows the relationship between lactoferrin and extraversion / extroversion on the IBQR at 3 months, as well as the relationship between osteopontin and emotion regulation on the IBQ-R.

[0202] Table 2

[0203]

[0204] result

[0205] At 6 weeks postpartum, total protein in maternal breast milk was positively correlated with the extraversion of two factors on the IBQR-R scale. More specifically, osteopontin levels in breast milk at 6 weeks postpartum were positively correlated with the IBQ-R regulator at 3 months of age, and lactoferrin levels in breast milk at 6 weeks postpartum were positively correlated with the extraversion / extroversion factor of the IBQ-R at 6 months of age (see [link to relevant documentation]). Figure 2 and Figure 3 This finding supports the effects of osteopontin and lactoferrin on infants' socio-emotional development, such as the regulation of emotions and / or behavior, extraversion and / or deportment. This adds important knowledge to populations where nutritional intervention research remains lacking.

[0206] Implementation Plan

[0207] Various preferred features and embodiments of the invention will now be described with reference to the following paragraphs.

[0208] 1. A combination containing effective amounts of osteopontin and lactoferrin, said combination for use in promoting the socio-emotional development of young individuals.

[0209] 2. The combination according to paragraph 1, wherein the combination comprises: osteopontin, the amount of said osteopontin being in the range of about 50 ng / μL to about 900 ng / μL; and lactoferrin, the amount of said lactoferrin being in the range of about 190 ng / μL to about 5050 ng / μL.

[0210] 3. The combination described in any of the preceding paragraphs is used in the extraversion and / or extraversion, affect and / or behavior modulation, and / or modulation domains of the Infant Behavior Questionnaire-Revised (IBQ-R) scale for promoting the development of young individuals.

[0211] 4. The combination of any of the preceding paragraphs, wherein the young individual is an infant, a toddler, or a preschooler, preferably an infant.

[0212] 5. The combination according to any of the preceding paragraphs, wherein the combination is applied to the young individual from birth to about 5 years of age, preferably from birth to 18 weeks of age, more preferably during the first 12 weeks of the young individual's life.

[0213] 6. The combination described in any of the preceding paragraphs, wherein social-emotional development is promoted in young individuals from birth to about 5 years of age, preferably from birth to 18 months of age, more preferably from about 2 months of age to about 6 months of age, and even more preferably from about 3 months of age.

[0214] 7. According to any of the preceding paragraphs, the combination of promoting at least one of the following in young individuals from birth to about 5 years of age, preferably from birth to 18 months of age, more preferably from about 2 months of age to about 6 months of age, and even more preferably about 3 months of age: regulation of extraversion and / or extraversion, affect and / or behavior, or regulation domains on the Infant Behavior Questionnaire-Revised (IBQ-R) scale.

[0215] 8. The combination according to any of the preceding paragraphs, wherein the combination is used for the prevention of socioemotional disorders and / or diseases caused by impaired social and / or emotional development in the young individual from birth to about 5 years of age, preferably from birth to 18 months of age.

[0216] 9. The combination described in paragraph 8, wherein the socio-emotional disorders and / or illnesses include: autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), intellectual disability, anxiety, depression and / or behavioral disorders.

[0217] 10. A nutritional composition for use in promoting the socio-emotional development of young individuals, wherein the nutritional composition comprises the combination described in any of the preceding paragraphs.

[0218] 11. The nutritional composition according to paragraph 10, wherein the nutritional composition is infant formula, stage 1 infant formula, stage 2 or later infant formula, baby food, growing milk, infant cereal composition, fortifier or supplement.

[0219] 12. The nutritional composition or combination described in any of paragraphs 10 to 11 or any of paragraphs 1 to 9, wherein the nutritional composition or combination is to be administered to the mother of the young individual during pregnancy or lactation.

[0220] 13. For non-therapeutic use of the combination described in any of paragraphs 1 to 9 or the composition described in any of paragraphs 10 to 12 to promote the socio-emotional development of young individuals.

[0221] 14. A method for promoting the socio-emotional development of a young individual, the method comprising administering an effective amount of osteopontin and lactoferrin to the young individual.

[0222] 15. A method for promoting the socio-emotional development of a young individual, the method comprising administering to the young individual a combination of the ingredients described in any one of paragraphs 1 to 9 or a nutritional composition described in any one of paragraphs 10 to 12.

[0223] It should be understood that various changes and modifications to the currently preferred embodiments described herein will be apparent to those skilled in the art. These changes and modifications can be made without departing from the spirit and scope of the subject matter of the invention and without diminishing its intended advantages. Therefore, such changes and modifications are intended to be covered by the appended claims.

[0224]

[0225]

[0226]

[0227]

Claims

1. A combination containing effective amounts of osteopontin and lactoferrin, said combination for use in promoting the socio-emotional development of young individuals.

2. The combination of claim 1, wherein the combination comprises: Osteopontin, wherein the amount of osteopontin is in the range of about 50 ng / μL to about 900 ng / μL, and Lactoferrin, wherein the amount of lactoferrin is in the range of about 190 ng / μL to about 5050 ng / μL.

3. The combination according to any one of the preceding claims, wherein the combination is used in the modulation of extraversion and / or extraversion, affect and / or behavior, and / or modulation domains on the Infant Behavior Questionnaire-Revised (IBQ-R) scale for promoting the development of young individuals.

4. The combination according to any one of the preceding claims, wherein the young individual is an infant, a toddler, or a preschooler, preferably an infant.

5. The combination according to any one of the preceding claims, wherein the combination is applied to the young individual from birth to about 5 years of age, preferably from birth to 18 weeks of age, more preferably during the first 12 weeks of the young individual's life.

6. The combination according to any one of the preceding claims, wherein it promotes social-emotional development in young individuals from birth to about 5 years of age, preferably from birth to 18 months of age, more preferably from about 2 months of age to about 6 months of age, and even more preferably from about 3 months of age.

7. The combination according to any one of the preceding claims, wherein in young individuals from birth to about 5 years of age, preferably from birth to 18 months of age, more preferably from about 2 months of age to about 6 months of age, more preferably about 3 months of age, it promotes at least one of the following: regulation of extraversion and / or extraversion, affect and / or behavior, or regulation domains on the Infant Behavior Questionnaire-Revised (IBQ-R) scale.

8. The combination according to any one of the preceding claims, wherein the combination is used for the prevention of socioemotional disorders and / or diseases caused by impaired social and / or emotional development in the young individual from birth to about 5 years of age, preferably from birth to 18 months of age.

9. The combination of claim 8, wherein the socio-emotional disorder and / or illness comprises: Autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), intellectual disability, anxiety, depression and / or behavioral disorders.

10. A nutritional composition for use in promoting the socio-emotional development of young individuals, wherein the nutritional composition comprises a combination according to any one of the preceding claims.

11. The nutritional composition of claim 10, wherein the nutritional composition is infant formula, stage 1 infant formula, stage 2 or later infant formula, baby food, growing milk, infant cereal composition, fortifier or supplement.

12. The nutritional composition according to any one of claims 10 to 11 or a combination according to any one of claims 1 to 9, wherein the nutritional composition or combination is to be administered to the mother of the young individual during pregnancy or lactation.

13. The combination of any one of claims 1 to 9 or the composition of any one of claims 10 to 12 for non-therapeutic use in promoting the socio-emotional development of the young individual.

14. A method for promoting the socio-emotional development of a young individual, the method comprising administering an effective amount of osteopontin and lactoferrin to the young individual.

15. A method for promoting the socio-emotional development of a young individual, the method comprising administering to the young individual a combination of any one of claims 1 to 9 or a nutritional composition of any one of claims 10 to 12.

Images