NUTRITIONAL COMPOSITION TO STIMULATE EMOTIONAL DEVELOPMENT

Abstract

The present invention relates to a nutritional composition comprising osteopontin as an active ingredient for use in promoting emotional development in a young individual, preferably in an infant. The present invention further relates to uses and methods for promoting emotional development in a young individual, preferably in an infant.

Description

[0001] NUTRITIONAL COMPOSITION FOR PROMOTING EMOTIONAL DEVELOPMENT

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to a nutritional composition comprising osteopontin as an active ingredient for use in promoting emotional development in a young individual, preferably in an infant. The present invention further relates to uses and methods for promoting emotional development in a young individual, preferably in an infant.

[0004] BACKGROUND OF THE INVENTION

[0005] Breast feeding is considered as the ideal source of nutrition and is the preferred choice for feeding infants up to at least 6 months of age. Consequently, human milk (HM) has long been considered as the model for the design of infant formulas (IF). Even if many improvements in the nutrient composition of I F have been made during the last decades, there are still important differences in composition as well as in functional benefits conveyed by HM.

[0006] Identifying the potential relationship between human breast milk components and early brain development and associated functions has gained substantial interests in recent years.

[0007] Nutritional deficiencies have been associated with hypomyelination, altered myelin composition, or decreased myelin synthesis.

[0008] The relationship between human breast milk composition and its impact on the socio- emotional development in infants, toddlers and / or young children remains unclear.

[0009] Social-emotional skills develop together from birth and during childhood and include behaviors that represent children’s emotional growth and their ability to successfully interact with adults and peers. Socio-emotional milestones focus on children’s developing abilities to understand, experience, express and manage emotions, regulate their emotions, actions and behavior in different social environment, and to develop meaningful relationships with others. As such, socio-emotional development encompasses a large range of skills and constructs, including but not limited to self-awareness, knowledge of others, autonomy, compliance, affect, sociability, play and interaction, empathy, self-esteem, self-regulation, friendship and relationship development.

[0010] An important aspect of social-emotional development is development of emotional skills and competencies. Emotional development refers to the ability to effectively regulate emotions to accomplish one’s goal. Healthy emotional development therefore entails experiencing, managing, and expressing a full range of positive and negative emotions. It included behaviors such as the willingness to demonstrate own feelings as well as empathy for other, selfregulation or the ability to calm down or to adjust to the environment or stimulation.

[0011] Both social and emotional skills and behaviors mature alongside brain development, in particular brain regions and their connections to link to social and / or emotional information processing.

[0012] It is believed that lack of emotional skills can lead in poor outcomes in child development such as hindering child’s ability to create relationship, affecting child’s adjustment at school, influencing mood difficulties, leading to aggressive or disruptive behaviors, leading to loneliness and cause behavioral problems later in life. If preschoolers do not learn to identify and label their emotions for example, tantrums and inappropriate regulations of emotions may escalate later in life. In some instances, shy, inhibited children are at risk for later anxiety and depression, or behavior or conduct problems. Anxiety disorders are a cluster if mental disorders characterized by significant and uncontrollable feelings of anxiety and fear such that person’s social, occupational, and personal function are significantly impaired. Many anxiety disorders have their onset 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. 2012 Jan; 26(1): 102-110; doi:10.1016 / j.janxdis.2011.09.006.Epub 2011 Oct7). 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 thought to be among the most common, earliest-onset childhood psychiatric disorders and depression in adulthood and for continuing comorbidity and impaired quality of life throughout the lifespan (Copeland WE, Shanahan L, Costello EJ, Angold A. Childhood and adolescent psychiatric disorders as predictors of young adult disorders. Arch Gen Psychatry. 2009 Jul; 66(7): 764-772; doi:10.1001 / archgenpsychiatry.2009.85).

[0013] Conduct problems or disorders are diagnosed when children show an ongoing pattern of aggression toward others, and serious violation of rules and social norms at home, in school and with peers. Children with conduct problems are more likely to get injured and may have difficulties getting along with peers.

[0014] Current approach to avoid anxiety disorders and to promote development of social behavioral skills and social skills rely mainly on education of parents and caregivers, usually through early 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. 2017 Oct; 51 : 32-38; doi: 10.1016 / j.janxdis.2017.08.007.Epub 2017 Sep 1) to promote communication, promoting play, helping the child to understand emotions and develop empathy, telling stories and promoting group activities.

[0015] Temperament broadly refers to consistent individual differences in behavior that are biologically based and are relatively independent of learning, system of values and attitudes. Some searchers point to association of temperament with formal dynamical features of behavior, such as energetic aspects, plasticity, sensitivity to specific reinforcers and emotionality. Temperament traits (such as Neuroticism, Sociability, impulsivity, etc) are distinct patterns in behavior throughout lifetime, but they are more noticeable and most studied in children. Temperament is defined through specific behavioral profiles, usually focusing on those that are both easily measurable and testable early in childhood. Commonly tested factors include traits related to energetic capacities (named as “Activity”, “Endurance”, “Extraversion”), traits related to emotionality (such as irritability, frequency of smiling), and approach or avoidance of unfamiliar events. Manifestation of temperament change over time as a child develops, with rapid development during infancy.

[0016] The present study reports human results and investes impact of certain myelinating nutrients, in particular osteopontin, present in human breast milk on emotional development.

[0017] There is a need to deliver such benefit on emotional development in the young individual in a manner that does not induce side effects and / or in a manner that is easy to deliver, and well accepted by the parents or health care practitioners. There is also a need to deliver such benefits in a manner that does keep the cost of such delivery reasonable and affordable by most.

[0018] Any reference to prior art documents in this specification is not to be considered an admission that such prior art is widely known or forms part of the common general knowledge in the field.

[0019] SUMMARY OF THE INVENTION

[0020] The object of the present invention is achieved by the subject matter of the independent claims. The dependent claims further develop the idea of the present invention.

[0021] The inventors have surprisingly found that osteopontin or a nutritional composition comprising osteopontin as an active ingredient administered to an infant, a toddler or a young child, preferably to an infant, promotes emotional development in the young individuals. This could be in a healthy subject (non-therapeutic), such as in a healthy infant, a young child or a child or in a fragile subject, such as an infant, a young child or a child born by C- section and / or preterm, and / or small for gestational age (SGA) and / or with a low, very low, or extremely low weight at birth (LWB, VLBW, or ELBW) and / or experienced intra-uterine growth retardation (IUGR) and / or with impaired or immature tissue development.

[0022] The present invention relates to composition comprising osteopontin as an active ingredient in an effective amount for use in promoting emotional development in a young individual.

[0023] In an embodiment, osteopontin is comprised at amount ranging from at least about 50 ng / pL to at least about 900 ng / pL.

[0024] In an embodiment, the composition is for use in promoting regulation of emotions and / or behavior or regulation domain on Infant Behavior Questionnaire-Revised (IBQ-R) scale in a young individual.

[0025] In an embodiment, the young individual is an infant, a toddler or a young child, preferably an infant.

[0026] In an embodiment, the composition is administered to the young individual from birth to about 5 years of age, preferably from birth to 18 weeks of age, more preferably during first 6 weeks of life of the young individual.

[0027] In an embodiment, emotional development is promoted in a young individual from birth to about 5 years of age, preferably from birth to 18 months of age, more preferably from about 2 to about 6 months of age, more preferably in about 3 months of age.

[0028] In an embodiment, regulation of emotions and / or behavior is promoted in a young individual from birth to about 5 years of age, preferably from birth to 18 months of age, more preferably from about 2 to about 6 months of age, more preferably in about 3 months of age.

[0029] In an embodiment, the composition is for use in preventing social-emotional disorders or diseases induced by impaired emotional development from birth to about 5 years of age, preferably from birth to 18 months of age of life of the young individual.

[0030] In an embodiment, the social-emotional disorder and / or disease includes: autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), intellectual disability, anxiety, depression, and / or conduct disorder.

[0031] In an embodiment, the composition is a synthetic nutritional composition. In an embodiment, the composition is an infant formula, a starter infant formula, a follow-on or follow-up infant formula, a baby food, a growing-up milk, an infant cereal composition, a fortifier or a supplement.

[0032] In an embodiment, the composition is to be administered to mothers of the young individuals during pregnancy or lactation.

[0033] The present invention relates to non-therapeutical use of the composition according to any one of the preceding claims for promoting emotional development in the young individual.

[0034] The present invention relates to a method for promoting emotional development in a young individual, the method comprising administering to said young individual an effective amount of osteopontin.

[0035] The present invention relates to a method for promoting emotional development in a young individual, the method comprising administering to said young individual the composition as disclosed above.

[0036] BRIEF DESCRIPTION OF THE DRAWINGS

[0037] Figure 1 is a heatmap (using gray gradient to quantify the strength of the association, with negative numbers for negative association and positive number for positive association) showing three factors FA1 , FA2, FA3, interpretable respectively as “Surgency / Extraversion”, “Negative Affectivity”, “Orienting / Regulation” for Infant Behavior Questionnaire-Revised (IBQ- R) at 6 months of an infant.

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

[0039] DETAILED DESCRIPTION OF THE INVENTION

[0040] Various preferred features and embodiments of the present invention will now be described by way of non-limiting examples. The skilled person will understand that they can combine all features of the invention disclosed herein without departing from the scope of the invention as disclosed.

[0041] Definitions Some definitions are provided hereafter. Nevertheless, definitions may be located in the “Embodiments” section below, and the above header “Definitions” does not mean that such disclosures in the “Embodiments” section are not definitions.

[0042] All percentages expressed herein are by weight of the total weight of the composition unless expressed otherwise. As used herein, “about,” “approximately” and “substantially” are understood to refer to numbers in a range of numerals, for example the range of -10% to +10% of the referenced number, preferably -5% to +5% of the referenced number, more preferably -1 % to +1 % of the referenced number, most preferably -0.1 % to +0.1% of the referenced number. All numerical ranges herein should be understood to include all integers, whole or fractions, within the range. Moreover, these numerical ranges should be construed as providing support for a claim directed to any number or subset of numbers in that range. For example, a disclosure of from 1 to 10 should be construed as supporting a range of from 1 to 8, from 3 to 7, from 1 to 9, from 3.6 to 4.6, from 3.5 to 9.9, and so forth.

[0043] As used in this disclosure and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “an amino acid” or “the amino acid” includes two or more amino acids.

[0044] The words “comprise,” “comprises” and “comprising” are to be interpreted inclusively rather than exclusively. Likewise, the terms “include,” “including” and “or” should all be construed to be inclusive, unless such a construction is clearly prohibited from the context. Nevertheless, the compositions and methods disclosed herein may lack any element that is not specifically disclosed herein. Thus, a disclosure of an embodiment using the term “comprising” includes a disclosure of embodiments “consisting essentially of’ and “consisting of” the components or steps identified.

[0045] The terms “at least one of” and “and / or” used respectively in the context of “at least one of X and Y” and “X and / or Y” should be interpreted as “X without Y,” or “Y without X,” or “both X and Y.” Where used herein, the terms “example” and “such as,” particularly when followed by a listing of terms, are merely exemplary and illustrative and should not be deemed to be exclusive or comprehensive.

[0046] As used herein, “related to,” “associated with” and “linked with” mean occurring concurrently, preferably mean caused by the same underlying condition, more preferably mean that one of the identified conditions is at least indirectly caused by the other identified condition, and most preferably mean that one of the identified conditions is directly caused by the other identified condition. “Prevention” includes reduction of risk, incidence and / or severity of a condition or disorder. The terms “treatment” and “treat” include both prophylactic or preventive treatment (that prevent and / or slow the development of a targeted pathologic condition or disorder) and curative, therapeutic or disease-modifying treatment, including therapeutic measures that cure, slow down, lessen symptoms of, and / or halt progression of a diagnosed pathologic condition or disorder; and treatment of patients at risk of contracting a disease or suspected to have contracted a disease, as well as patients who are ill or have been diagnosed as suffering from a disease or medical condition.

[0047] The terms “treatment” and “treat” do not necessarily imply that a subject is treated until total recovery. The terms “treatment” and “treat” also refer to the maintenance and / or promotion of health in an individual not suffering from a disease but who may be susceptible to the development of an unhealthy condition. The terms “treatment” and “treat” are also intended to include the potentiation or otherwise enhancement of one or more primary prophylactic or therapeutic measures. As non-limiting examples, a treatment can be performed by a patient, a caregiver, a doctor, a nurse, or another healthcare professional.

[0048] The expression "later in life" and "in later life" can be used interchangeably. They refer to effects measured in the individual (infant or young child) after the age of some weeks, some months or some years after birth, such as after the age of 6 months after birth, such as after the age of 8 months after birth, such as after the age of 10 months after birth, such as after the age of 1 year after birth, such as after the age of 2 years, preferably after the age of 4 years, more preferably after the age of 5 years, even more preferably after the age of 7 years after birth, or even more, and as a comparison to average observations for subjects of the same age. Preferably it refers to an effect observed after at least 1 year of life, or after at least 2, 5, 7, 10 or 15 years of life. So the expression "later in life" might refer to an observation during infancy, during childhood, during the adolescent period, or during adulthood. Preferably it refers to an observation during childhood, during the adolescent period, or during adulthood. The term "later in life" encompasses the effect after the termination of the intervention.

[0049] As used herein, a prophylactically or therapeutically “effective amount” is an amount that prevents a deficiency, treats a disease or medical condition in an individual, or, more generally, reduces symptoms, manages progression of the disease, or provides a nutritional, physiological, or medical benefit to the individual.

[0050] The term “composition” may mean a food, beverage, dietary supplement, complete nutrition, or oral nutritional supplement (ONS) or medical food composition, or mixture thereof. The terms “food,” “food supplement,” “food product” and “food composition” mean a product or composition that is intended for ingestion by an individual such as a human and provides at least one nutrient to the individual. The compositions of the present disclosure, including the many embodiments described herein, can comprise, consist of, or consist essentially of the elements disclosed herein, as well as any additional or optional ingredients, components, or elements described herein or otherwise useful in a diet supplement.

[0051] The composition can be in solid form (e.g., powder) or in liquid form. The amount of the various ingredients can be expressed in g / 100 g of the composition on a dry weight basis when it is in a solid form, e.g. a powder, or as a concentration in g / 100 mL of the composition when it refers to a liquid form (this latter also encompasses liquid composition that may be obtained from a powder after reconstitution in a liquid such as water.)

[0052] The term “unit dosage form,” as used herein, refers to physically discrete units suitable as unitary dosages for human and animal subjects, each unit containing a predetermined quantity of the composition disclosed herein in an amount sufficient to produce the desired effect, in association with an acceptable diluent, carrier or vehicle. The specifications for the unit dosage form depend on the particular compounds employed, the effect to be achieved, and the pharmacodynamics associated with each compound in the host.

[0053] The term "young individual" as used herein refers to an infant, a toddler, a young child or a child.

[0054] The term “infant” means a child under the age of 12 months. The term infant includes both infants born at term or infant born preterm.

[0055] The terms “toddler” or “young child” mean a child aged between one and three years.

[0056] The term “child” means a child aged between one and 6 years, including toddlers and preschool children.

[0057] The expression "infant formula" as used herein refers to a foodstuff intended for particular nutritional use by infants during the first months of life and satisfying by itself the nutritional requirements of this category of person (Article 2(c) of the European Commission Directive 91 / 321 / EEC 2006 / 141 / EC of 22 December 2006 on infant formulae and follow-on formulae). It also refers to a nutritional composition intended for infants and as defined in Codex Alimentarius (Codex STAN 72-1981) and Infant Specialities (incl. Food for Special Medical Purpose). The expression "infant formula" encompasses both "starter infant formula" and "follow-up formula" or "follow-on formula". A "follow-up formula" or "follow-on formula" is given from the sixth month onwards and includes growing-up milk. It constitutes the principal liquid element in the progressively diversified diet of this category of person.

[0058] The expression "baby food" means a foodstuff intended for particular nutritional use by infants or young children during the first years of life.

[0059] The expression "infant cereal composition" means a foodstuff intended for particular nutritional use by infants or young children during the first years of life.

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

[0061] A "preterm" or "premature" subject means an infant or young child who was not born at term. Generally it refers to an infant or young child born prior 36 weeks of gestation.

[0062] By the expression "small for gestational age" or "SGA" it is referred to an infant or young child who is smaller in size than normal for their gestational age at birth, most commonly defined as a weight below the 10th percentile for the gestational age. In some embodiments, SGA may be associated with intrauterine growth restriction (IUGR), which refers to a condition in which a foetus is unable to achieve its potential size.

[0063] A "preterm" or "premature" means an infant or young child who was not born at term. Generally, it refers to an infant or young child born prior 37 weeks of gestation.

[0064] An "infant having a low birth weight" or “low weight at birth” means a preterm having a body weight below 2500g (5.5 pounds) either because of preterm birth or restricted fetal growth. It therefore encompasses:

[0065] - infant or young child who has / had a body weight from 1500 to 2500 g at birth (usually called "low birth weight" or LBW)

[0066] - infant or young child who has / had a body weight from 1000 to 1500 g at birth (called "very low birth weight" or VLBW)

[0067] - infant or young child who has / had a body weight under 1000 g at birth (called "extremely low birth weight" or ELBW). The expression “mother’s milk” should be understood as the breast milk or the colostrum of the mother.

[0068] The supplement may be in the form of tablets, capsules, pastilles or a liquid for example. The supplement may further contain protective hydrocolloids (such as gums, proteins, modified starches), binders, film forming agents, encapsulating agents / materials, wall / shell materials, matrix compounds, coatings, emulsifiers, surface active agents, solubilizing agents (oils, fats, waxes, lecithins etc.), adsorbents, carriers, fillers, co compounds, dispersing agents, wetting agents, processing aids (solvents), flowing agents, taste masking agents, weighting agents, jellifying agents and gel forming agents. The supplement may also contain conventional pharmaceutical additives and adjuvants, excipients and diluents, including, but not limited to, water, gelatine of any origin, vegetable gums, lignin-sulfonate, talc, sugars, starch, gum arabic, vegetable oils, polyalkylene glycols, flavouring agents, preservatives, stabilizers, emulsifying agents, buffers, lubricants, colorants, wetting agents, fillers, and the like. Further, the supplement may contain an organic or inorganic carrier material suitable for oral or parenteral administration as well as vitamins, minerals trace elements and other micronutrients in accordance with the recommendations of Government bodies such as the LISRDA.

[0069] The terms "prebiotic", "fibre(s)" and "fiber(s)" can be used interchangeably. They refer to non- digestible carbohydrates that beneficially affect the host by selectively stimulating the growth and / or the activity of healthy bacteria such as bifidobacteria in the colon of humans (Gibson GR, Roberfroid MB. Dietary modulation of the human colonic microbiota: introducing the concept of prebiotics. J Nutr. 1995;125:1401-12).

[0070] The term "probiotic" means microbial cell preparations or components of microbial cells with a beneficial effect 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 yeasts.

[0071] The term "cfu" should be understood as colony-forming unit. All percentages are by weight unless otherwise stated.

[0072] The further probiotic microorganisms most commonly used are principally bacteria and yeasts of the following genera: Lactobacillus spp., Lacticaseibacillus spp, Limosilactobacillus spp, Streptococcus spp., Enterococcus spp., Bifidobacterium spp. and Saccharomyces spp.

[0073] In some particular embodiments, the probiotic is a probiotic bacterial strain. In some specific embodiments, it is particularly Bifidobacteria and / or Lactobacilli. Suitable probiotic bacterial strains include Lactobacillus rhamnosus ATCC 53103 available from Valio Oy of Finland under the trademark LGG, Lactobacillus rhamnosus CGMCC 1 .3724, Lactobacillus paracasei CNCM 1-2116, Lactobacillus johnsonii CNCM 1-1225, Streptococcus salivarius DSM 13084 sold by BLIS Technologies Limited of New Zealand under the designation KI2, Bifidobacterium lactis CNCM I-3446 sold inter alia by the Christian Hansen company of Denmark under the trademark Bb 12, B. longum CNCM 1-2618 (B. longum NCC2705), Bifidobacterium breve sold by Danisco under the trademark Bb-03, Bifidobacterium breve sold by Morinaga under the trade mark M-16V, Bifidobacterium infantis sold for example by Procter & Gamble 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), B. kashiwanohense (JCM 15439) and / or B. kashiwanohense (DSM 21854).

[0074] The nutritional composition or combination according to the invention may contain from 10e3 to 10e12 cfu of the at least one (further) probiotic strain, more preferably between 10e7 and 10e12 cfu such as between 10e8 and 10e10 cfu of probiotic strain per g of composition on a dry weight basis.

[0075] In one embodiment, the probiotics are viable. In another embodiment, the probiotics are nonreplicating or inactivated. There may be both viable probiotics and inactivated probiotics in some other embodiments. Probiotic components and metabolites can also be added.

[0076] B. kashiwanohense was isolated from healthy infant faeces. For example, this bacterium has previously been characterized by determining its phenotypic and biochemical features and phylogenetic positions based on partial 16S rRNA gene 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 B. kashiwanohense are (i) AB491757 and AB578933 and (ii) are AB425276.2 and AB491759.2, respectively. One strain of B. kashiwanohense is publicly available from two collections with the accession numbers JCM 15439 and DSM 21854 (Morita et al., International Journal of Systematic and Evolutionary Microbiology, 2011 , 61 : 2610- 2615).

[0077] The B. kashiwanohense may be a B. kashiwanohense having at least 99% (suitably, at least 99.9%) Average Nucleotide Identity (ANI) to any B. kashiwanohense known to the skilled person. As used herein the term “Average nucleotide identity (AN I)” refers to a distance-based approach to delineate species based on pair-wise comparisons of their genome sequences. ANI is an in silico approach for phylogenetic definition of a species and has become the gold standard for species delineation (Goris et al., 2007, Int. J. Syst. Evol. Microbiol. 57: 81-91 ; Kim et al., 2014, Int. J. Syst. Evol. Mier. 64: 346-351 ; Richter et al., 2009, P Natl Acad Sci USA 106: 19126-19131 ; and Chan et al., 2012, Bmc. Microbiol. 12).

[0078] The ANI of the shared genes between two strains is known to be a robust means to compare genetic relatedness among strains. Strains with ANI values of at least about 96% can be considered to belong to the same species (Konstantinidis and Tiedje, 2005, Proc Natl Acad Sci USA, 102(7):2567-72; and Goris et al., 2007, Int Syst Evol Microbiol. 57(Pt 1 ):81 -91), while ANI values of at least about 99% indicate that the bacterial genomes belong to the same strain. The ANI between two bacterial genomes is calculated from pair-wise comparisons of all sequences shared between 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); ANI Calculator, JSpecies (Richter and Rossello-Mora, 2009, Proc Natl Acad Sci USA 106:19126-19131); 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, K. T. and Tiedje, 2005, J. M., Proc. Natl. Acad. Sci. U.S.A., 102: 2567-2572; and Varghese et al., 2015, Nucleic Acids Research, 43(14):6761-6771).

[0079] Suitably, the B. kashiwanohense has 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%) ANI to B. kashiwanohense JCM 15439 and / or B. kashiwanohense DSM 21854. Preferably, the B. kashiwanohense has at least 99.9% ANI to B. kashiwanohense JCM 15439 and / or B. kashiwanohense DSM 21854.

[0080] The term "oligosaccharide" is a saccharide polymer containing a small number (typically three to ten) of simple sugars (monosaccharides). Oligosaccharide as used herein refers to a carbohydrate having a degree of polymerisation (DP) ranging from 2 to 20 inclusive. "Degree of polymerisation" or "DP" refers to the total number of saccharide units in an oligosaccharide chain or polysaccharide chain.

[0081] The term "galactooligosaccharide" as used herein refers to a non-digestible oligosaccharide comprising two or more galactose molecules. The galactooligosaccharides (GOS) used in embodiments disclosed herein have a DP of 2 to 20, preferably a DP of 2 to 10. Preferably at least 30% of the saccharide units are galactose units, preferably at least 50%, more preferably at least 60%, based on monomeric subunits.

[0082] Suitable galactooligosaccharides are commercially available and include for example Purimune GOS (from ComProducts International), King GOS (from King Prebiotics), 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.

[0083] Galactooligosaccharides (GOS) are a prebiotic, and optionally the infant formula further comprises an additional prebiotic.

[0084] Galactooligosaccharides (GOS) as used herein typically consist of p-linked galactose moieties with galactose or glucose at the reducing end. Such GOS contains p-(1 — >2), p-(1 — >3), p- (1^4), or p-(1 — >6) linked galactose moieties and may have a degree of polymerization (DP) of 3-8 galactose units. The term GOS is therefore preferably referred to as oligosaccharide(s) comprising at least three galactose units, more preferably as oligosaccharide(s) comprising at least four galactose units, preferably having a degree of polymerization (DP) of 3-8 galactose units.

[0085] Galactooligosaccharides (GOS) are defined as polymers of galactose (minimum 2 galactose monomers) with a terminal p-linked galactose or glucose monomer. GOS is a commonly- added prebiotic substrate in infant formula compositions, for example as commercially available in the form of Vivinal-GOS (sold by Friesland Campina of the Netherlands), or in the form of Bovine Milk-derived Oligosaccharides (BMOS) (Estorninos et al., Am J Clin Nutr., 2022,115: 142-153). BMOS in particular promote the selective growth Bifidobacterium species such as Bifidobacterium longum subsp. infantis (Roberfroid et al., 2010, British Journal of Nutrition, 104(S2): S1-S63).

[0086] In some embodiments, the galactose source is selected from galactooligosaccharides (GOS), Bovine Milk-derived Oligosaccharides (BMOS) and combinations thereof.

[0087] In a particular embodiment, the nutritional composition according to the invention can comprise BMOS. BMOS may be oligosaccharide preparations derived from bovine milk and / or whey fractions. One route to increasing oligosaccharides in bovine milk derived fractions is to transform part of the lactose in such fractions to GOS. BMOS can typically be obtained from concentrating whey permeate to obtain a concentrated bovine milk oligosaccharide composition and either adding GOS or generating the GOS in situ from hydrolysis of lactose by the action of a p-galactosidase (Duncan et al., Nutrients, 2020, 12: 2007). In a particular embodiment, the nutritional composition comprises an oligosaccharide mixture (“BMOS”) that comprises from 0.1 to 4.0 wt% of N-acetylated oligosaccharide(s), from 92.0 to 98.5 wt% of the galacto-oligosaccharide(s) and from 0.1 to 4.0 wt% of the sialylated oligosaccharide(s).

[0088] A combination of prebiotics may be used such as 90% GOS with 10% short chain fructooligosaccharides such as the product sold under the trade mark Raftilose® or 10% inulin such as the product sold under the trade mark Raftiline®. Other examples of optional additional prebiotics that can be used in the infant formula include sialo-oligosaccharides (SOS), fructooligosaccharides (FOS), human milk oligosaccharides (HMO), isomalto-oligosaccharides (IMO), xylo-oligosaccharides (XOS), arabino-xylo oligosaccharides (AXOS), mannan oligosaccharides (MOS), oligosaccharides of soy, glycosylsucrose (GS), lactosucrose (LS), sialyl-lactose (SL), Fucosyl-lactose (FL), Lacto-N-Neotetraose (LNNT), lactulose (LA), palatinose-oligosaccharides (PAO), malto-oligosaccharides, gums and / or hydrolysates thereof, pectins, starches, and / or hydrolysates thereof.

[0089] Human milk oligosaccharides are carbohydrates resistant to enzymatic hydrolysis by digestive enzymes (e.g. pancreatic and / or brush border), indicating that they may display functions not directly related to their caloric value. It has especially been illustrated that they play a vital role in the early development of infants and young children, such as the maturation of the immune system. Many different kinds of HMOs are found in the human milk. Each individual oligosaccharide is based on a combination of glucose, galactose, sialic acid (N- acetylneuraminic acid), fucose and / or N-acetylglucosamine with many and varied linkages between them, thus accounting for the enormous number of different oligosaccharides in human milk - over 130 such structures have been identified so far. Almost all of them have a lactose moiety at their reducing end while sialic acid and / or fucose (when present) occupy terminal positions at the non-reducing ends. The HMOs can be acidic (e.g. charged sialic acid containing oligosaccharide) or neutral (e.g. fucosylated oligosaccharide). Some examples of HMOs are the fucosylated oligosaccharides, the N-acetylated oligosaccharides and / or the sialylated oligosaccharides.

[0090] A "fucosylated oligosaccharide" is an oligosaccharide having a fucose residue. It has a neutral nature. Some examples are LNFP-I (lacto-N-fucopentaose I), 2’-FL (2' fucosyllactose), 3-FL (3-fucosyllactose).

[0091] The expressions “fucosylated oligosaccharides comprising an alpha-1 , 2-fucosyl-epitope” and “2-fucosylated oligosaccharides” encompass fucosylated oligosaccharides with a certain homology of form since they contain an alpha-1 , 2-fucosyl-epitope, therefore a certain homology of function can be expected.

[0092] The expression “N-acetylated oligosaccharide(s)” encompasses both “N-acetyl-lactosamine” and “oligosaccharide(s) containing N-acetyl-lactosamine”. They are neutral oligosaccharides having an N-acetyl-lactosamine residue. Suitable examples are LNT (lacto-N-tetraose), para- lacto-N-neohexaose (para-LNnH), LNnT (lacto-N-neotetraose) and any combinations thereof. Other examples are lacto-N-hexaose, lacto-N-neohexaose, para- lacto-N-hexaose, para- lacto-N-neohexaose, lacto-N-octaose, lacto-N- neooctaose, iso- lacto-N-octaose, para- lacto- N-octaose and lacto-N-decaose.

[0093] A "sialylated oligosaccharide" is a charged sialic acid containing oligosaccharide, i.e. an oligosaccharide having a sialic acid residue. It has an acidic nature. Some examples are 3’- SL (3’-sialyllactose) and 6’-SL (6’-sialyllactose). The expressions "sialylated oligosaccharide" and "sialyllactose (SL)" can be used interchangeably. The trisaccharide sialyllactose consists of lactose at the reducing terminus and one sialic acid residue at the non-reducing end via an alpha-2,3 binding or alpha-2,6 binding, resulting in 3'-SL and 6'-SL, respectively.

[0094] A "precursor of HMO" is a key compound that intervenes in the manufacture of HMO, such as sialic acid and / or fucose.

[0095] Because of the configuration of their glycosidic bonds, galactooligosaccharides (GOS) largely resist hydrolysis by salivary and intestinal digestive enzymes. GOS are classified as prebiotics, non-digestible carbohydrates that beneficially affect the host by stimulating the growth and / or activity of beneficial bacteria in the colon.

[0096] As used herein, “added fiber” or “added dietary fiber” indicates an ingredient mainly or totally constituted by fiber which is added to the complementary nutritional composition and whose content in fiber contributes to the total fiber content of the composition. The total fiber content of the complementary nutritional composition is provided by the sum of amount of fiber naturally present in ingredients used in the recipe (for example from whole grain cereal flour) plus amount of added fiber. Suitably, the present composition may be a probiotic composition.

[0097] Any reference to prior art documents in this specification is not to be considered an admission that such prior art is widely known or forms part of the common general knowledge in the field. All publications mentioned in the specification are herein incorporated by reference.

[0098] The “IBQ-R (revised Infant Behavior Questionnaire) questionnaire” is a widely used parentreport measure for assessing dimensions of temperament along 14 scales, as reported in Table 1 below, in infants between 3 and 12 months of age (Garstein MA ; Rothbart AK.

[0099] Studying infant temperament via Revised Infant Behavior Questionnaire. Infant Behavior & Development 2003: 26: 64-86).

[0100] Table 1 Scale definitions: Infant Behavior Questionnaire -Revised

[0101] Within the context of the present invention, the terms “anxiety” and “fear” are used interchangeably. “Social fearfulness” refers to the developmental context of an inhibited approach and / or distress in social situations that involve novelty and / or uncertainty.

[0102] Within the context of the present invention, the expressions “social skill” or “social skills” encompass any competence or behavior observed in a social situation or environment and / or facilitating interaction and communication with others, both verbally and non-verbally, and development of social skills starts in the first few months of life. For example, infants begin to show signs of emotions, such as joy, anger, sadness, interest, fear, disgust and surprise as distinct facial expression. Infants begin also to laugh out and begin to socialize with people through babbling. Social skills continue developing in toddlers and children, including for example to begin imitating the environments around 15 months, clinging to caretakers in new situation (social fearfulness) at 18 months, parallel playing with other children at around 24 months, etc.

[0103] Within the context of the present invention, the expressions “social-emotional” or “social- emotional development” relates to social-emotional skills that develop from birth onwards allowing for increasing autonomy, self-regulation, and relationships. Social-emotional development can be assessed and monitored behaviorally using clinical interviews, direct behavior observations, and rating systems as well as parent-and teacher-report questionnaires (Schneider N et al. Child Development 2022:93:359-371. Doi:10.1111 / cdev.13649).

[0104] Within the context of the present invention, the expressions “emotional skill” or “emotional skills” relate to the capacity to experience and express personal feelings, as well as recognize and interpret those of others. Emotional skills are linked for example to mood, pleasure, sadness. The development of emotional skills occurs in conjunction with neural, cognitive and behavioral development from birth throughout childhood, adolescence and adulthood.

[0105] Within the context of the present invention, the expression “emotional development” refers to the growth and changes in an individual's emotional abilities and experiences over time. It involves the development of a wide range of emotions, including basic emotions like joy, sadness, anger, and fear, as well as more complex emotions such as empathy, guilt, and pride. Emotional development also includes the ability to recognize and label emotions in oneself and others, regulate emotional responses, and express emotions in socially appropriate ways. It is a complex process that is influenced by both biological and environmental factors, such as genetics, temperament, attachment experiences, and cultural norms. Emotional development is a critical aspect of human development, as it plays an important role in shaping an individual's personality, social relationships, and overall wellbeing.

[0106] Within the context of the present invention, the term “emotional regulation” refers to the process by which an individual recognizes and manages their emotions in order to respond to situations in a more adaptive and appropriate way. Emotional regulation involves the ability to recognize and label one's emotions, understand the triggers for those emotions, and then use strategies to manage or modify them in order to achieve a desired outcome. Effective emotional regulation can help individuals cope with stress, build positive relationships, and make better decisions. Some common strategies for emotional regulation include mindfulness practices, relaxation techniques, cognitive restructuring, and problem-solving skills.).

[0107] Within the context of the present invention, the term “regulation domain” on the Infant Behavior Questionnaire-Revised (IBQ-R) scale is a set of items that assesses an infant's ability to selfregulate their emotional and behavioral responses to various situations. The IBQ-R is a widely used measure of infant temperament that assesses three main domains: Surgency / Extraversion, Negative Affectivity, and Regulation. The Regulation domain includes items that assess the infant's ability to regulate their behavior and emotional responses, such as the frequency and intensity of crying, fussiness, and soothability. Items on the Regulation domain include, for example, "Duration of orienting" and "Cuddliness / behaviors elicited by physical contact". The IBQ-R is used by researchers and clinicians to assess temperament in infants, which can be useful for understanding individual differences in emotional and behavioral regulation early in life and for identifying infants who may be at risk for later developmental problems.

[0108] Within the context of the present invention, the expression “reducing the risk of experiencing” or “reduce the risk of experiencing” should be understood as reducing the frequency or intensity of certain behavioral traits that are involved in temperament or sociability according to the IBQ-R questionnaire. In one embodiment, the expression “reducing the risk of experiencing” comprises a decreased frequency and / or intensity of certain behavioral traits that are involved in temperament or sociability in the presence of a nutrient or number of nutrients.

[0109] Within the context of the present invention, the expressions “improve social-emotional skills” indicate an amelioration in social-emotional competences or behaviors in an infant, a toddler or a young child.

[0110] The objective of the present invention is hence to enrich or improve the state of the art and in particular to provide a nutrient or a nutritional composition for use in improving emotional development in a young individual, preferably in infants.

[0111] The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that such publications constitute prior art to the claims appended hereto. Embodiments of the invention

[0112] The invention will be now described in further details.

[0113] The present invention relates to composition comprising osteopontin as an active ingredient in an effective amount for use in promoting emotional development in a young individual.

[0114] Osteopontin (OPN) is a minor, acidic, highly phosphorylated glycoprotein, also present at higher concentrations in human milk compared with bovine milk. It has been reported that average OPN concentrations in human milk, bovine milk and infant formula to be 138, 18, and 9 mg / L, respectively.

[0115] In an embodiment, osteopontin is comprised at amount ranging from at least about 50 ng / pL to at least about 900 ng / pL.

[0116] In an embodiment, the composition is for use in promoting regulation of emotions and / or behavior or regulation domain on Infant Behavior Questionnaire-Revised (IBQ-R) scale in a young individual.

[0117] In an embodiment, the young individual is an infant, a toddler or a young child, preferably an infant.

[0118] In an embodiment, the composition is administered to the young individual from birth to about 5 years of age, preferably from birth to 18 weeks of age, more preferably during first 6 weeks of life of the young individual.

[0119] In an embodiment, emotional development is promoted in a young individual from birth to about 5 years of age, preferably from birth to 18 months of age, more preferably from about 2 to about 6 months of age, more preferably in about 3 months of age.

[0120] In an embodiment, regulation of emotions and / or behavior is promoted in a young individual from birth to about 5 years of age, preferably from birth to 18 months of age, more preferably from about 2 to about 6 months of age, more preferably in about 3 months of age.

[0121] In an embodiment, the composition is for use in preventing social-emotional disorders or diseases induced by impaired emotional development from birth to about 5 years of age, preferably from birth to 18 months of age of life of the young individual.

[0122] In an embodiment, the social-emotional disorder and / or disease includes: autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), intellectual disability, anxiety, depression, and / or conduct disorder. 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 contribute to social and behavioral challenges.

[0123] Attention-Deficit / Hyperactivity Disorder (ADHD) is a neurodevelopmental disorder characterized by inattention, hyperactivity, and impulsivity. Individuals with ADHD may struggle with emotional regulation and may have difficulty controlling their emotions and behavior in certain situations.

[0124] Intellectual Disability is a condition characterized by significant limitations in intellectual functioning and adaptive behavior.

[0125] - Anxiety disorders: 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.

[0126] 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 in the development or maintenance of depression.

[0127] Conduct Disorder is a behavioral disorder characterized by a persistent pattern of violating the rights of others and social norms. Impaired emotional development may contribute to difficulties with impulse control, anger management, and behavioral regulation, which can be features of Conduct Disorder.

[0128] In an embodiment, the composition is a synthetic nutritional composition.

[0129] In an embodiment, the composition is an infant formula, a starter infant formula, a follow-on or follow-up infant formula, a baby food, a growing-up milk, an infant cereal composition, a fortifier or a supplement.

[0130] Suitably, the synthetic nutritional composition may be for example an infant formula, a starter infant formula, a follow-on or follow-up infant formula, a baby food, a growing-up milk, an infant cereal composition, a fortifier or a supplement.

[0131] In an embodiment, the composition of the invention is an infant formula, a fortifier or a supplement that may be intended for the first 3 or 6 months of age. In a preferred embodiment the nutritional composition of the invention is an infant formula. In some other embodiments the nutritional composition of the present invention is a fortifier. The fortifier can be a breast milk fortifier (e.g. a human milk fortifier) or a formula fortifier such as an infant formula fortifier or a follow-on / follow-up formula fortifier.

[0132] When the nutritional composition is a supplement, it can be provided in the form of unit doses. The nutritional composition of the present invention can be in solid (e.g. powder), liquid or gelatinous form.

[0133] In an embodiment, the composition is to be administered to mothers of the young individuals during pregnancy or lactation.

[0134] The present invention relates to non-therapeutical use of the composition according to any one of the preceding claims for promoting emotional development in the young individual.

[0135] The present invention relates to a method for promoting emotional development in a young individual, the method comprising administering to said young individual an effective amount of osteopontin.

[0136] The present invention relates to a method for promoting emotional development in a young individual, the method comprising administering to said young individual the composition as disclosed above.

[0137] Suitably, osteopontin and / or the nutritional composition according to the present invention promotes emotional development of a young individual at about from birth to 5 about years of age, or to about 18 months of age. In one embodiment osteopontin and / or the nutritional composition according to the present invention promotes emotional development of a young individual aged between about 2 to about 6 months. In another embodiment, osteopontin and / or the nutritional composition according to the present invention promotes emotional development of a young individual of at least about 2 months of age, of at least about 3 months of age, or of at least about 6 months of age. In some embodiments, osteopontin and / or the nutritional composition promotes emotional development of a young individual when administered to a young individual during the first 1 , 3, 6, 9, 12 or 18 weeks of life.

[0138] The inventors have surprisingly found that osteopontin and / or the nutritional composition according to the present invention improves regulation of emotions and / or behavior or improving regulation domain on Infant Behavior Questionnaire-Revised (IBQ-R) scale (Figure 1 , 2 and Example) in an infant in 3 months. In one embodiment, the osteopontin and / or nutritional composition comprising osteopontin as an active ingredient, according to the present invention promotes regulation of emotions and / or behavior or regulation domain on Infant Behavior Questionnaire-Revised (IBQ-R) scale when administered to a young individual during the first 1 , 3, 6, 9, 12 or 18 weeks of life.

[0139] If a metabolic precursor and / or metabolite of osteopontin is used in a composition in place of or in combination with a osteopontin, said compounds may be used in amounts such that the level of them physiologically delivered by said composition is in line with those set out hereinabove. It is well within the purview of the skilled person to determine appropriate amounts.

[0140] Osteopontin and / or the nutritional composition according to the present invention advantageously improves emotional development.

[0141] Particularly, osteopontin and / or the nutritional composition of the present invention supports or / and enhances an infant's ability to self-regulate their emotional and behavioral responses to various situations. This can involve various strategies, such as providing a calm and consistent environment, promoting responsive and sensitive caregiving, or using positive reinforcement techniques to encourage self-soothing behaviors. It supports or promotes healthy emotional and behavioral development in infants and prevents or addresses developmental problems, disorders or diseases that may arise if infants have difficulties with emotional and behavioral regulation.

[0142] Those skilled in the art will understand that they can freely combine all features of the present invention disclosed herein. In particular, features described for the product of the present invention may be combined with the method of the present invention and vice versa. Further, features described for different embodiments of the present invention may be combined. Where known equivalents exist to specific features, such equivalents are incorporated as if specifically referred to in this specification.

[0143] The nutritional composition can be administered (or given or fed) at an age and for a period that depends on the possibilities and needs.

[0144] Since the nutritional composition is also used for prevention purposes (prevention of a later in life health disorder), it can be for example given immediately after birth of the infants. The composition of the invention can also be given during the first week of life of the infant, or during the first 2 weeks of life, or during the first 3 weeks of life, or during the first month of life, or during the first 2 months of life, or during the first 3 months of life, or during the first 4 months of life, or during the first 6 months of life, or during the first 8 months of life, or during the first 10 months of life, or during the first year of life, or during the first two years of life or even more. In some particularly advantageous embodiments of the invention, the nutritional composition is given (or administered) to an infant within the first 4 or 6 months of birth of said infant.

[0145] In one embodiment, the use according to the present invention is non-therapeutic when the nutritional composition is for use in a healthy infant, toddler and / or young child.

[0146] In another embodiment, the use according to the present invention is therapeutic when the nutritional composition is for use in a fragile subject, such as an infant, a young child or a child born by C- section and / or preterm, and / or small for gestational age (SGA) and / or with a low, very low, or extremely low weight at birth (LWB, VLBW, or ELBW) and / or experienced intrauterine growth retardation (IIIGR) and / or with impaired or immature tissue development.

[0147] In another embodiment, the use according to the present invention is therapeutic when the nutritional composition is for use in an infant, toddler and / or young child who is at risk of developing behavioural problems later in life.

[0148] In another embodiment, the use according to the present invention is therapeutic when the nutritional composition is for use in an infant, toddler and / or young child who is at risk of developing social-emotional disorders and / or diseases induced by impaired social development.

[0149] In some other embodiments, the nutritional composition of the invention is given few days (e.g. 1 , 2, 3, 5, 10, 15, 20...), or few weeks (e.g. 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10...), or few months (e.g.

[0150] 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10... ) after birth. This may be especially the case when the infant is premature, but not necessarily.

[0151] In one embodiment the composition of the invention is given to the infant or young child as a supplementary composition to the mother’s milk. In some embodiments the infant or young child receives the mother’s milk during at least the first 2 weeks, first 1 , 2, 4, or 6 months. In one embodiment the nutritional composition of the invention is given to the infant or young child after such period of mother’s nutrition, or is given together with such period of mother’s milk nutrition. In another embodiment the composition is given to the infant or young child as the sole or primary nutritional composition during at least one period of time, e.g. after the 1st, 2nd or 4th month of life, during at least 1 , 2, 4 or 6 months. In a preferred embodiment, the composition is orally administered to the infant or toddler in an infant formula. The infant formula may contain a protein source in an amount up to 4.0 g / 100kcal, preferably up to 3.0 g / 100kcal, more preferably up to 2.0 g / 100kcal, most preferably 1.8 to 2.0 g / 100kcal. In some embodiments, over 50% by weight of the protein source is whey. In one embodiment, the protein content is between 30% and 80% whey proteins. Protein sources based on whey, casein and mixtures thereof may be used, as well as protein sources based on soy. For whey proteins, the protein source may be based on acid whey or sweet whey or mixtures thereof and may include alpha-lactalbumin and beta-lactoglobulin in desired proportions.

[0152] The proteins may be intact or hydrolysed or a mixture of intact and hydrolysed proteins. Partially hydrolysed proteins (degree of hydrolysis between 2 and 20%) may be particularly beneficial for infants believed to be at risk of developing cows' milk allergy. If hydrolysed proteins are required, the hydrolysis process may be carried out as desired and as is known in the art. For example, a whey protein hydrolysate may be prepared by enzymatically hydrolysing the whey fraction in one or more steps. If the whey fraction used as the starting material is substantially lactose free, the protein suffers much less lysine blockage during the hydrolysis process, which enables the extent of lysine blockage 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.

[0153] The infant formula may contain a carbohydrate source. Any carbohydrate source conventionally found in infant formulae, such as lactose, saccharose, maltodextrin, starch and mixtures thereof, may be used; although the preferred source of carbohydrates is lactose. Preferably the carbohydrate sources contribute between 35% and 65% of the total energy of the formula. In a preferred embodiment, the carbohydrates comprise rice carbohydrates, for example rice carbohydrates in an amount of at least 5% at least 10%, at least 25% or at least 50%, at least 70%, at least 90%, or about 100% of the carbohydrates (w / w), which can bring a substantial benefit in the sleep pattern. The higher the content in rice carbohydrates, the higher the possible sleep improvement.

[0154] The infant formula may contain a source of lipids. The lipid source may be any lipid or fat which is suitable for use in infant formulas. Preferred fat sources include palm olein, high oleic sunflower oil and high oleic safflower oil. The essential fatty acids linoleic and a-linolenic acid may also be added as may small amounts of oils containing high quantities of preformed arachidonic acid and docosahexaenoic acid such as fish oils or microbial oils. In total, the fat content preferably contributew between 30 to 55% of the total energy of the formula. The fat source preferably has a ratio of n-6 to n-3 fatty acids of about 5:1 to about 15:1 ; for example about 8:1 to about 10:1.

[0155] The infant formula may optionally contain one or more vitamins. For example, the infant formula may contain all vitamins and minerals understood to be essential in the daily diet and in nutritionally significant amounts. Minimum requirements have been established for certain vitamins and minerals. Examples of additional minerals and vitamins optionally present in the infant formula include vitamin A, vitamin B12, vitamin E, vitamin K, vitamin C, vitamin D, folic acid, inositol, niacin, biotin, pantothenic acid, choline, calcium, phosphorous, iodine, magnesium, manganese, chloride, potassium, sodium, selenium, chromium, molybdenum, taurine, and L-carnitine. Minerals are usually added in salt form. The presence and amounts of specific additional minerals and vitamins will vary depending on the intended infant population.

[0156] If necessary, the infant formula may contain emulsifiers and stabilizers such as soy lecithin, citric acid esters of mono- and di-glycerides, and the like. The infant formula may optionally contain other substances which may have a beneficial effect such as fibres, lactoferrin, nucleotides, nucleosides, and the like. For example, the infant formula may contain a probiotic bacterial strain in an amount of 103 to 1012 cfu / g infant formula, more preferably 106 to 109 cfu / g formula.

[0157] The infant formula described above may be prepared in any suitable manner. For example, they may be prepared by blending together the protein, the carbohydrate source, and the fat source in appropriate proportions. If used, the emulsifiers may be included at this point. The vitamins and minerals may be added at this point but are usually added later to avoid thermal degradation. Any lipophilic vitamins, emulsifiers and the like may be dissolved into the fat source prior to blending. Water, preferably water which has been subjected to reverse osmosis, may then be mixed in to form a liquid mixture. The temperature of the water is conveniently about 50°C to about 80°C to aid dispersal of the ingredients. Commercially available liquefiers may be used to form the liquid mixture. The liquid mixture is then homogenised; for example in two stages.

[0158] The liquid mixture may then be thermally treated to reduce bacterial loads, by rapidly heating the liquid mixture to a temperature in the range of about 80°C to about 150°C for about 5 seconds to about 5 minutes, for example. This may be carried out by steam injection, autoclave or by heat exchanger; for example a plate heat exchanger. Then, the liquid mixture may be cooled to about 60°C to about 85°C; for example by flash cooling. The liquid mixture may then be again homogenised; for example in two stages at about 10 MPa to about 30 MPa in the first stage and about 2 MPa to about 10 MPa in the second stage. The homogenised mixture may then be further cooled to add any heat sensitive components; such as vitamins and minerals. The pH and solids content of the homogenised mixture are conveniently adjusted at this point.

[0159] The homogenised mixture may be transferred to a suitable drying apparatus such as a spray drier or freeze drier and converted to powder. The powder should have a moisture content of less than about 5% by weight. A probiotic bacterial strain may optionally be added at this stage by dry-mixing. The powder may then be packaged in unit dosage form. The powder may be reconstituted in a diluent, such as water or milk, prior to the administration to the infant or toddler.

[0160] The combination may be administered to the infant or toddler in a unit dosage form, wherein the unit dosage form comprises an amount of the combination effective for increasing levels of propionate in the infant or toddler. The unit dosage form may be a predetermined amount of a powder comprising the combination, and the method comprises reconstituting the powder in a diluent to form a nutritional composition in which the combination is orally administered to the infant or toddler.

[0161] Suitably, the nutritional composition may be intended for administration twice daily. Thus, the nutritional composition may be formulated to provide two servings per day.

[0162] Suitably, the nutritional composition may be provided in a serving size of 31 g or 36 g total dry weight.

[0163] In some embodiments, the composition of the invention may be administered once daily. In other embodiments, the composition of the invention is administered in multiple servings, for example in two servings (unit doses) per day. When the nutritional composition is provided in the form of unit doses (or “servings”) it is particularly useful to define the amount of oligosaccharides and probiotics in terms of the daily dose to be administered to the infant, or young child or child.

[0164] Further advantages and features of the present invention are apparent from the figure and non-limiting examples.

[0165] EXAMPLES The inventors analyzed the composition of breast milk at 3 time points in the first 3 months post-partum and investigated the associations with developmental outcomes, such as emotional development, across the first 2 years of life. Factor analysis was applied to the behavioral scales composing the infant behavior questionnaire (IBQR).

[0166] The data for these analyses come from the observational arm of a prospective, longitudinal, two-center (Memorial Hospital of Rhode Island and Pennington Biomedical Research Center, USA), study with a 12-month intervention period and follow-up assessments up to 2 years of life. Seven visits occurred: V1 (6 ± 1 week of life), V2 (3 months ± 2 weeks), V3 (6 months ± 2 weeks), V4 (9 months ± 2 weeks), and V5 (12 months ± 2 weeks), V6 (18 months ± 3 weeks), V7 (24 months ± 4 weeks). Exclusion criteria included: a) delayed birth (> 41 weeks + 6 days gestation) as reported in medical record when available, b) Birth Weight < 2000 g or small for gestation age birth weight less than the 10th percentile for the gestational age) or large for gestational age (weight, length, or head circumference that lies above the 90th percentile) as reported in medical record medical record when available, c) any unsafe psychopharmacological treatment of mother using prohibited medications during pregnancy or lactation as assessed by medical interview.

[0167] 107 breastfeeding mothers with their child were followed from 0 to 24 months. Breast milk was sampled from mothers longitudinally at defined study visits, each time between 10 AM-12PM from the right breast using a hospital grade electric breast pump. Additionally, mothers were asked to empty the right breast approximately 2h prior to milk sampling and the time of milk sampling complete breast was emptied using a pump (single full breast milk sampling methodology). Only a fraction of the collected milk will be aliquoted for research and the rest was be returned to mother for feeding the baby at a later time.

[0168] Breast milk samples were taken at 2-5 weeks (V0), 6 weeks (V1), 3 months (V2).

[0169] Factor analysis for IBQR and correlations with breast milk nutrients

[0170] Factor analysis postulates a model of the form -scale n Fscale ^scale,lfl,n^~- ■ ■ ~^^scale,kfk,n T ^scale,n or simply:

[0171] X — M = LF + e

[0172] Its aim is to identify latent factors, that can be interpreted as broad categories of behavior and temperament. The main benefit is to reduce the number of variables, and therefore reduce the number of statistical comparisons. The inventors correlated the scores F with the concentrations of breast milk nutrients, to measure the association of nutrients with each given behavioral dimension.

[0173] The Infant Behavior Questionnaire-Revised (IBQ-R) is a widely-used parent-report measure developed to assess dimensions of temperament along 14 scales. The use of factor analysis applied to the IBQ-R scales has been published in several papers (see, for example Factor Structure and Measurement Invariance of the Very Short Form of Infant Behavior Questionnaire-Revised (IBQR-VSF): A Study among Vietnamese Children, 10.3390 / healthcarel 0040689, 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).

[0174] Factor loadings defined three factors FA1 , FA2, FA3, interpretable respectively as “Surgency / Extraversion”, “Negative Affectivity”, “Orienting / Regulation”, as shown in the Figure 1. This naming replicates the one proposed in the reference above (10.1016 / j.infbeh.2016.04.001)

[0175] Correlations with osteopontin:

[0176] The correlations of osteopontin concentrations with factor scores are reported below in Table 1 . The correlations were calculated for all the combinations of timepoints for breastmilk and IBQ-R. Below, the reported are only the significant ones (after adjustment for multiple comparisons).

[0177] Table 1

[0178] Table 2 shows an association between ostepontin from breastmilk at 6 weeks with emotion reulation at 3 months.

[0179] Table 2 corr nut outcome time.point.nut time.point.outcome p N p.adj

[0180] 0.40 OSTEOPONTIN FA3 6 wk 3 mo 0.00 68 0.00

[0181] (OPN)

[0182] Results

[0183] The total protein in breast milk of mothers at 6 weeks positively correlated with 2 factors surgency on the IBQR-R scale. More specifically, osteopontin levels in the breast milk at 6 weeks postpartum positively correlated with regulation factor on the IBQ-R when the infants were 3 months of age, please see figure 2.

[0184] This finding supports the impact of osteopontin on aspects of emotional development of infants, such regulation of emotions and / or behavior. This adds important knowledge in a population where nutritional intervention studies are still scarce.

[0185] Embodiments

[0186] Various preferred features and embodiments of the present invention will now be described with reference to the following paragraphs (para).

[0187] 1 . A composition comprising osteopontin as an active ingredient in an effective amount for use in promoting emotional development in a young individual.

[0188] 2. The composition according to para 1 , wherein osteopontin is comprised at amount ranging from at least about 50 ng / pL to at least about 900 ng / pL.

[0189] 3. The composition as claimed in anyone of the preceding paras, for use in promoting regulation of emotions and / or behavior or regulation domain on Infant Behavior Questionnaire-Revised (IBQ-R) scale in a young individual.

[0190] 4. The composition according to any one of the preceding paras, wherein the young individual is an infant, a toddler or a young child, preferably an infant.

[0191] 5. The composition according to any one of the preceding paras, wherein it is administered to the young individual from birth to about 5 years of age, preferably from birth to 18 weeks of age, more preferably during first 6 weeks of life of the young individual.

[0192] 6. The composition according to anyone of the preceding paras, wherein emotional development is promoted in a young individual from birth to about 5 years of age, preferably from birth to 18 months of age, more preferably from about 2 to about 6 months of age, more preferably in about 3 months of age. 7. The composition according to any one of the preceding paras, wherein regulation of emotions and / or behavior is promoted in a young individual from birth to about 5 years of age, preferably from birth to 18 months of age, more preferably from about 2 to about 6 months of age, more preferably in about 3 months of age.

[0193] 8. The composition according to any one of the preceding claims, wherein it is for use in preventing social-emotional disorders or diseases induced by impaired emotional development from birth to about 5 years of age, preferably from birth to 18 months of age of life of the young individual.

[0194] 9. The composition according to para 8, wherein the social-emotional disorder and / or disease includes: autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), intellectual disability, anxiety, depression, and / or conduct disorder.

[0195] 10. The composition according to any one of the preceding paras which is a synthetic nutritional composition.

[0196] 11. The composition according to any one of the preceding paras, wherein it is an infant formula, a starter infant formula, a follow-on or follow-up infant formula, a baby food, a growing-up milk, an infant cereal composition, a fortifier or a supplement.

[0197] 12. The composition according to any one of the preceding paras, wherein the composition is to be administered to mothers of the young individuals during pregnancy or lactation.

[0198] 13. Non-therapeutical use of the composition according to any one of the preceding paras for promoting emotional development in the young individual.

[0199] 14. A method for promoting emotional development in a young individual, the method comprising administering to said young individual an effective amount of osteopontin.

[0200] 15. A method for promoting emotional development in a young individual, the method comprising administering to said young individual the composition according to any one of paras 1 to 12.

[0201] It should be understood that various changes and modifications to the presently preferred embodiments described herein will be apparent to those skilled in the art. Such changes and modifications can be made without departing from the spirit and scope of the present subject matter and without diminishing its intended advantages. It is therefore intended that such changes and modifications be covered by the appended claims. (Original in Electronic Form)

[0202] (This sheet is not part of and does not count as a sheet of the international application)

[0203] (Original in Electronic Form)

[0204] (This sheet is not part of and does not count as a sheet of the international application) (Original in Electronic Form)

[0205] (This sheet is not part of and does not count as a sheet of the international application) (Original in Electronic Form)

[0206] (This sheet is not part of and does not count as a sheet of the international application)

[0207] FOR RECEIVING OFFICE USE ONLY

[0208] FOR INTERNATIONAL BUREAU USE ONLY -5 This form was rec international Bure -5-1 Authorized officer

Claims

1. A composition comprising osteopontin as an active ingredient in an effective amount for use in stimulating emotional development in a young individual.

2. The composition of claim 1, wherein osteopontin is contained in an amount of at least about 50 ng / μL to at least about 900 ng / μL.

3. A composition according to any of the preceding claims for use in stimulating emotion and / or behavior regulation or a domain of regulation as measured by the Infant Behavior Questionnaire-Revised (IBQ-R) in a young individual.

4. A composition according to any one of the preceding claims, wherein the young individual is an infant, toddler, or young child, preferably an infant.

5. A composition according to any one of the preceding claims, which is administered to a young individual between the age of birth and about 5 years, preferably between the age of birth and 18 weeks, more preferably within the first 6 weeks of the young individual's life.

6. A composition according to any one of the preceding claims, wherein emotional development is stimulated in a young individual between the ages of birth and about 5 years, preferably between the ages of birth and 18 months, more preferably between the ages of about 2 months and about 6 months, more preferably between the ages of about 3 months.

7. A composition according to any one of the preceding claims, wherein the regulation of emotions and / or behavior is promoted in a young individual between the ages of birth and about 5 years, preferably between the ages of birth and 18 months, more preferably between the ages of about 2 months and about 6 months, more preferably between the ages of about 3 months.

8. A composition according to any one of the preceding claims, which is intended for use in the prevention of social-emotional disorders or diseases caused by impaired emotional development, in an individual from birth to about 5 years of age, preferably from birth to 18 months of age.

9. The composition of claim 8, wherein the social-emotional disorder and / or disease comprises: autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), mental retardation, anxiety, depression and / or conduct disorder.

10. A composition according to any of the preceding claims, which is an artificial nutritional composition.

11. A composition according to any of the preceding claims which is an infant formula, a starter infant formula, a follow-on infant formula or a follow-on formula, baby food, a milk formula for children aged 1 to 3 years, a cereal-based infant composition, a fortifier or a supplement.

12. A composition according to any of the preceding claims, which is to be administered to mothers of young individuals during pregnancy or lactation.

13. The non-therapeutic use of a composition according to any of the preceding claims to stimulate emotional development in a young individual.

14. A method for stimulating emotional development in a young individual, comprising administering to said young individual an effective amount of osteopontin.

15. A method for stimulating emotional development in a young individual, comprising administering to said young individual a composition according to any one of paragraphs 1-12.