Polyamines for use in promoting neurodevelopment

Abstract

The present invention relates to compositions comprising at least one source of polyamines or their metabolites for use in promoting neurodevelopment in a young individual.

Description

[0001] POLYAMINES FOR USE IN PROMOTING NEURODEVELOPMENT

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to compositions comprising at least one source of polyamines or their metabolites for use in promoting neurodevelopment in a young individual.

[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 IF 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 neurodevelopment in infants, toddlers and / or young children remains unclear, and there is no report in the prior art on the impact of a blend of nutrients comprising polyamines on the neurodevelopment.

[0009] The human brain undergoes rapid development during the first few years of life, with the majority of brain growth occurring during the first year. This period is critical for the establishment of neural connections and the development of cognitive, motor, language and social-emotional skills. However, many factors can negatively impact neurodevelopment in infants, including malnutrition, environmental toxins, and genetic disorders.

[0010] Impaired neurodevelopment in infants can lead to a range of diseases and conditions, including: Autism Spectrum Disorder (ASD) that is a developmental disorder that affects communication, social interaction, and behavior; Attention Deficit Hyperactivity Disorder (ADHD) that is a neurodevelopmental disorder that affects attention, hyperactivity, and impulsivity; Intellectual Disability that is a condition characterized by significant limitations in intellectual functioning and adaptive behavior; Epilepsy that is a neurological disorder characterized by recurrent seizures; Schizophrenia that is a severe mental disorder that affects thinking, emotions, and behavior; Depression and Anxiety; Language delay that is a condition in which a child's language development is slower than expected for their age; Specific Language Impairment (SLI) that is a language disorder that affects the development of language skills, including grammar, vocabulary, and sentence structure; Dyslexia that is a learning disorder that affects reading skills; Speech Sound Disorder that is a condition in which a child has difficulty producing speech sounds correctly; Stuttering that is a speech disorder characterized by interruptions in the flow of speech; Cerebral Palsy that is a group of disorders that affect movement and posture; Hypotonia that is a condition in which a child has low muscle tone, which can affect their ability to move and control their body; Developmental Coordination Disorder (DCD) that is a condition in which a child has difficulty with motor coordination and movement; Ataxia that is a condition in which a child has difficulty with balance and coordination.

[0011] Overall, impaired neurodevelopment during early childhood can have significant and long-lasting effects on a child's health and well-being. Early intervention and support can help mitigate the effects of impaired neurodevelopment and improve its outcomes.

[0012] It is therefore important to identify nutrients and compositions that can promote healthy neurodevelopment, that includes cognitive, social-emotional, language and motor development in infants, toddlers and children.

[0013] By supporting healthy brain growth and function, these nutrients or compositions could help prevent neurodevelopmental disorders or diseases, improve performance, and enhance overall quality of life. As such, there is a growing need for innovative solutions that can identify such nutrients and compositions and optimize the use of them in young individual’s nutrition.

[0014] SUMMARY OF THE INVENTION

[0015] The inventors have surprisingly found that specific polyamines and metabolites thereof are associated with promoting neurodevelopment, in particular development of cognitive, social- emotional, language and motor skills in infants, toddlers and children. The polyamines and metabolites thereof identified by the inventors have not previously been reported to be associated with neurodevelopmental outcomes in young individuals.

[0016] The present invention provides a composition comprising at least one source of polyamines and / or metabolites thereof in an effective amount for use in promoting neurodevelopment in a young individual. In an embodiment, neurodevelopment comprises social-emotional, motor, language and / or cognitive development.

[0017] In an embodiment, the at least one source of polyamines comprises agmatine, putrescine, spermidine, spermine, and / or cadaverine.

[0018] In an embodiment, the at least one source of metabolites comprises acetylagmatine, acetylputrescine, N1 -acetylspermidine, N1 ,N8-diacetylspermidine, N1 -acetylspermine, N1 ,N12- diacetylspermine, N-Acetylcadaverine, N6-Acetyl-L-lysine, N2-Acetylornithine, and / or N-acetyl agmatine.

[0019] In an embodiment, the composition is for use in promoting social-emotional development in a young individual and the at least one source of metabolites is N1 ,N8-diacetylspermidine.

[0020] In an embodiment, N1 ,N8-diacetylspermidine is administered to the young individual in an amount of from at least about 0.83 nmol / L to at least about 6.99 nmol / L.

[0021] In an embodiment, the composition is for use in promoting motor development in a young individual and the at least one source of polyamines is putrescine.

[0022] In an embodiment, putrescine is administered to the young individual in an amount of from at least about 0.31 nmol / L to at least about 2121 .33 nmol / L.

[0023] In an embodiment, the composition is for use in promoting cognitive development in a young individual and the at least one source of polyamines is selected from putrescine, spermidine.

[0024] In an embodiment, putrescine is administered to the young individual in an amount of from at least about 0.31 nmol / L to at least about 2121.33 nmol / L and / or spermidine is administered to the young individual in an amount of from at least 2539.68 nmol / L to at least about 19972.57 nmol / L.

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

[0026] In an embodiment, the composition is administered to the young individual from birth to about 5 years of age, preferably from about 4 to about 12 weeks of age.

[0027] In an embodiment, neurodevelopment is promoted in the young individual from birth to about 5 years of age, preferably from birth to about 24 months of age, more preferably between the age of about 6 to about 12 months of age. In an embodiment, the composition is for use in preventing and / or treating neurodevelopmental disorders and / or diseases.

[0028] In an embodiment, neurodevelopment disorder and / or disease is at least one selected from: autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), intellectual disability, epilepsy, depression, anxiety, language delay, specific language impairment (SLI), dyslexia, speech sound disorder, stuttering, cerebral palsy, hypotonia, developmental coordination disorder (DCD), ataxia.

[0029] 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.

[0030] Benefits from this improvement are in preventing impaired neurodevelopment and, thus, preventing and / or treating neurodevelopment conditions, disorders and / or diseases as mentioned above.

[0031] Additional features and advantages are described herein and will be apparent from the following Figures and Detailed Description.

[0032] BRIEF DESCRIPTION OF FIGURES

[0033] Figure 1 is a graph showing a positive correlation between the concentration of N1 ,N8- diacetylspermidine at 4 weeks and the degree of social-emotional outcomes on ASQ-SE when at 24 months of the young individual as described in the Example.

[0034] Figure 2 is a graph showing a positive correlation between the concentration of putrescine at 6 weeks and the degree of motor development at 6 months of the young individual as described in the Example.

[0035] Figure 3 is a graph showing a positive correlation between the concentration of putrescine at 6 weeks and spermidine at 4 weeks and the degree of cognitive development at 24 months of the young individual as described in the Example.

[0036] DETAILED DESCRIPTION OF THE INVENTION

[0037] 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.

[0038] Definitions

[0039] 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.

[0040] 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.

[0041] 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.

[0042] 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.

[0043] 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.

[0044] 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.

[0045] “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.

[0046] 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.

[0047] 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.

[0048] 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. 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.

[0049] 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.)

[0050] 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.The term "young individual" as used herein refers to an infant, a toddler, a young child or a child.

[0051] 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.

[0052] The terms “toddler” or “young child” mean a child aged between one and three years.

[0053] The term “child” means a child aged between one and 6 years, including toddlers and pre-school children.

[0054] 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.

[0055] The expression "baby food" means a foodstuff intended for particular nutritional use by infants or young children during the first years of life.

[0056] The expression "infant cereal composition" means a foodstuff intended for particular nutritional use by infants or young children during the first years of life.

[0057] The term "fortifier" refers to liquid or solid nutritional compositions suitable for mixing with breast milk or infant formula.

[0058] The expression “mother’s milk” should be understood as the breast milk or the colostrum of the mother.

[0059] 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 USRDA.

[0060] 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). 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.

[0061] The term "cfu" should be understood as colony-forming unit. All percentages are by weight unless otherwise stated.

[0062] The further probiotic microorganisms most commonly used are principally bacteria and yeasts of the following genera: Lactobacillus spp., Lacticaseibacillus spp, Umosilactobacillus spp, Streptococcus spp., Enterococcus spp., Bifidobacterium spp. and Saccharomyces spp.

[0063] In some particular embodiments, the probiotic is a probiotic bacterial strain. In some specific embodiments, it is particularly Bifidobacteria and / or Lactobacilli.

[0064] 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 1-3446 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).

[0065] 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.

[0066] 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. 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).

[0067] 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.

[0068] As used herein the term “Average nucleotide identity (ANI)” 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).

[0069] 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). 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.

[0070] 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.

[0071] 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.

[0072] 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.

[0073] Galactooligosaccharides (GOS) are a prebiotic, and optionally the infant formula further comprises an additional prebiotic.

[0074] Galactooligosaccharides (GOS) as used herein typically consist of [3-linked galactose moieties with galactose or glucose at the reducing end. Such GOS contains (3-(1 — >2), (3-(1 — >3), (3-(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.

[0075] Galactooligosaccharides (GOS) are defined as polymers of galactose (minimum 2 galactose monomers) with a terminal [3-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).

[0076] In some embodiments, the galactose source is selected from galactooligosaccharides (GOS), Bovine Milk-derived Oligosaccharides (BMOS) and combinations thereof.

[0077] 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 [3- galactosidase (Duncan et al., Nutrients, 2020, 12: 2007).

[0078] 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).

[0079] 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), Fucosy l-lactose (FL), Lacto-N-Neotetraose (LNNT), lactulose (LA), palatinose-oligosaccharides (PAO), malto-oligosaccharides, gums and / or hydrolysates thereof, pectins, starches, and / or hydrolysates thereof.

[0080] 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.

[0081] 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).

[0082] 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.

[0083] 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.

[0084] 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.

[0085] A "precursor of HMO" is a key compound that intervenes in the manufacture of HMO, such as sialic acid and / or fucose. 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.

[0086] 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.

[0087] 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.

[0088] We analyzed the three Bayley subscales for cognition, language and motor development. We applied a functional analysis of variance (R package fdANOVA) to test whether the Bayley scales are associated longitudinally with delivery method, child’s gender, income and mother’s education. For gestational age (a continuous variable) we fitted linear mixed models with random intercepts, with each of the Bayley scales as response variable and gestational age as predictor. P-values were estimated using a Kenward-Roger approximation. Since the ASQ score is age-standardized, we analyzed it cross-sectionally.

[0089] Within the context of the present invention, the term “neurodevelopment” relates to the process by which the nervous system develops and matures, from the formation of neural cells to the establishment of neural networks and the development of cognitive, motor, language and social- emotional skills.

[0090] Within the context of the present invention, the expressions “social-emotional development” or social-emotional skills” 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). Within the context of the present invention, the expression “cognitive development” refers to the process by which a child's thinking, problem-solving, and reasoning abilities develop and mature over time. This process begins in infancy and continues throughout childhood and adolescence, with significant changes occurring during each stage of development.

[0091] Within the context of the preset invention, the expression “motor development” refers to the process by which a child's ability to move and control their body develops and matures over time. During early childhood, motor development is characterized by the development of gross motor skills, such as crawling, walking, and running, as well as fine motor skills, such as grasping and manipulating objects. As children grow older, they begin to develop more complex motor skills, such as throwing, catching, and riding a bike.

[0092] Within the context of the present invention, the expression “language development” refers to the process by which a child's ability to communicate through language develops and matures over time. During early childhood, language development is characterized by the development of receptive language skills, such as understanding words and sentences, and expressive language skills, such as using words and sentences to communicate. As children grow older, they begin to develop more complex language skills, such as grammar, vocabulary, and narrative skills.

[0093] The terms “promote”, “promoting” and “promotion” can be used interchangeably. They should be understood as comprising support or help to the health of an individual, for example to support or help the development or growth of an individual. The individual may not suffer from a disease but may be susceptible to the development of unhealthy conditions, for example later in life.

[0094] 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 questionnairy. 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.

[0095] 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. 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 promoting neurodevelopment in a young individual.

[0096] 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.

[0097] Polyamines

[0098] Polyamines are small polycationic molecules with a wide array of biological functions including gene regulation, stress resistance, cell proliferation and differentiation, and are associated to both eukaryotic and prokaryotic cells.

[0099] Spermidine, putrescine and spermine are the dominate polyamines in eukaryotes. These polyamines regulate important cellular functions, including growth and proliferation, RNA and DNA stability, RNA-to-protein translation, autophagy and immune responses.

[0100] The inventors have surprisingly found that specific polyamines and / or metabolites thereof are associated with promoting neurodevelopment, in particular development of cognitive, social- emotional, language and motor skills in infants, toddlers and children. The polyamines and metabolites thereof identified by the inventors have not previously been reported to be associated with neurodevelopmental outcomes in young individuals.

[0101] Embodiments of the invention

[0102] The invention will be now described in further details.

[0103] The present invention provides a composition comprising at least one source of polyamines and / or metabolites thereof in an effective amount for use in promoting neurodevelopment in a young individual.

[0104] In an embodiment, neurodevelopment comprises social-emotional, motor, language and / or cognitive development.

[0105] In an embodiment, the at least one source of polyamines comprises agmatine, putrescine, spermidine, spermine, and / or cadaverine. The sources of the polyamines are from their precursors such as ornithine, arginine and citrulline and these are present in human milk or dietary intake of the infants from formula. These polyamines are also synthesized by gut microbiota.

[0106] In an embodiment, the at least one source of metabolites comprises acetylagmatine, acetylputrescine, N1 -acetylspermidine, N1 ,N8-diacetylspermidine, N1 -acetylspermine, N1 ,N12- diacetylspermine, N-Acetylcadaverine, N6-Acetyl-L-lysine, N2-Acetylornithine, and / or N-acetyl agmatine.

[0107] In an embodiment, the composition is for use in promoting social-emotional development in a young individual and the at least one source of metabolites is N1 ,N8-diacetylspermidine.

[0108] In an embodiment, N1 ,N8-diacetylspermidine is administered to the young individual in an amount of from at least about 0.83 nmol / L to at least about 6.99 nmol / L.

[0109] In an embodiment, the composition is for use in promoting motor development in a young individual and the at least one source of polyamines is putrescine.

[0110] In an embodiment, putrescine is administered to the young individual in an amount of from at least about 0.31 nmol / L to at least about 2121 .33 nmol / L.

[0111] In an embodiment, the composition is for use in promoting cognitive development in a young individual and the at least one source of polyamines is selected from putrescine, spermidine.

[0112] In an embodiment, putrescine is administered to the young individual in an amount of from at least about 0.31 nmol / L to at least about 2121.33 nmol / L and / or spermidine is administered to the young individual in an amount of from at least 2539.68 nmol / L to at least about 19972.57 nmol / L.

[0113] In an embodiment, the young individual is an infant, a young child or a child.

[0114] In an embodiment, the composition is administered to the young individual from birth to about 5 years of age, preferably from about 4 to about 12 weeks of age.

[0115] In an embodiment, neurodevelopment is promoted in the young individual from birth to about 5 years of age, preferably from birth to about 24 months of age, more preferably between the age of about 6 to about 12 months of age.

[0116] In an embodiment, the composition is for use in preventing and / or treating neurodevelopmental disorders and / or diseases. In an embodiment, neurodevelopment disorder and / or disease is at least one selected from: autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), intellectual disability, epilepsy, depression, anxiety, language delay, specific language impairment (SLI), dyslexia, speech sound disorder, stuttering, cerebral palsy, hypotonia, developmental coordination disorder (DCD), ataxia.

[0117] 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.

[0118] Benefits from this improvement are in preventing impaired neurodevelopment and, thus, preventing and / or treating neurodevelopment conditions, disorders and / or diseases.

[0119] The nutritional composition of the present invention can be in solid (e.g. powder), liquid or gelatinous form.

[0120] The combination or the nutritional composition according to the present invention advantageously promotes neurodevelopment, including social-emotional, motor, language and / or cognitive development.

[0121] It supports or promotes healthy neurodevelopment in infants and prevents or addresses developmental problems, disorders or diseases that may arise if infants have difficulties with social-emotional, motor, language and / or cognitive development.

[0122] The conditions, disorders or diseases related to impaired neurodevelopment include: autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), intellectual disability, epilepsy, depression, anxiety, language delay, specific language impairment (SLI), dyslexia, speech sound disorder, stuttering, cerebral palsy, hypotonia, developmental coordination disorder (DCD), ataxia.

[0123] 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.

[0124] The nutritional composition can be administered (or given or fed) at an age and for a period that depends on the possibilities and needs.

[0125] 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.

[0126] 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. 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.

[0127] 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.

[0128] 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.

[0129] 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.

[0130] 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.

[0131] 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 contribute 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.

[0132] 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.

[0133] 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.

[0134] 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.

[0135] 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.

[0136] 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. 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 drymixing. 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.

[0137] 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.

[0138] Suitably, the nutritional composition may be intended for administration twice daily. Thus, the nutritional composition may be formulated to provide two servings per day.

[0139] Suitably, the nutritional composition may be provided in a serving size of 31 g or 36 g total dry weight.

[0140] 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.

[0141] Further advantages and features of the present invention are apparent from the figure and nonlimiting examples.

[0142] EXAMPLES

[0143] The inventors analyzed the composition of breast milk at 3 time points in the first 3 months postpartum and investigated the associations with developmental outcomes, such as social and / or emotional development, across the first 2 years of life. 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.

[0144] 60 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.

[0145] Breast milk samples were taken at 2-5 weeks (V0), 6 weeks (V1), 3 months (V2).

[0146] We tested the effect of the following covariates on each cognitive scale: maternal education, sex, mode of delivery, gestational age, income. We analyzed the three Bayley subscales for cognition, language and motor development. We applied a functional analysis of variance (R package fdANOVA) to test whether the Bayley scales are associated longitudinally with delivery method, child’s gender, income and mother’s education. For gestational age (a continuous variable) we fitted linear mixed models with random intercepts, with each of the Bayley scales as response variable and gestational age.

[0147] Results

[0148] The inventors found a positive correlation between the concentration of N1 ,N8-diacetylspermidine at 4 weeks and the degree of social-emotional outcomes on ASQ-SE when at 24 months of the young individual as described in the Example.

[0149] Additionally, a positive correlation between the concentration of putrescine at 6 weeks and the degree of motor development at 6 months of the young individual as described in the Example. Additionally, a positive correlation between the concentration of putrescine at 6 weeks and spermidine at 4 weeks and the degree of cognitive development at 24 months of the young individual as described in the Example.

[0150] Additionally, a positive correlation between concentration of Spermidine at 4 weeks and the degree of cognitive development at 24 months of the young individual as described in the Example

[0151] This finding supports the impact of specific polyamines and metabolites thereof on aspects of neurodevelopment of infants, such as development of social-emotional, motor and / or language skills. This adds important knowledge in a population where nutritional intervention studies are still scarce.

[0152] Embodiments

[0153] Various preferred features and embodiments of the present invention will now be described with reference to the following paragraphs (para).

[0154] 1. A composition comprising at least one source of polyamines and / or metabolites thereof in an effective amount for use in promoting neurodevelopment in a young individual.

[0155] 2. The composition according to para 1 , wherein neurodevelopment comprises social-emotional, motor, language and / or cognitive development.

[0156] 3. The composition according to any one of the preceding paras, wherein the at least one source of polyamines comprises agmatine, putrescine, spermidine, spermine, and / or cadaverine.

[0157] 4. The composition according to any one of the preceding paras, wherein the at least one source of metabolites comprises acetylagmatine, acetylputrescine, N1- acetylspermidine, N1 ,N8-diacetylspermidine, N1 -acetylspermine, N1 ,N12- diacetylspermine, N-Acetylcadaverine, N6-Acetyl-L-lysine, N2-Acetylornithine, and / or N-acetyl agmatine.

[0158] 5. The composition according to any one of the preceding paras, wherein it is for use in promoting social-emotional development in a young individual and the at least one source of metabolites is N1 ,N8-diacetylspermidine.

[0159] 6. The composition according to para 5, wherein N1 ,N8-diacetylspermidine is administered to the young individual in an amount of from at least about 0.83 nmol / L to at least about 6.99 nmol / L. 7. The composition as claimed in any of paras 1 to 4, wherein it is for use in promoting motor development in a young individual and the at least one source of polyamines is putrescine.

[0160] 8. The composition according to para 7, wherein putrescine is administered to the young individual in an amount of from at least about 0.31 nmol / L to at least about 2121.33 nmol / L.

[0161] 9. The composition according to any one of paras 1 to 4, wherein it is for use in promoting cognitive development in a young individual and the at least one source of polyamines is selected from putrescine, spermidine.

[0162] 10. The composition according to para 9, wherein putrescine is administered to the young individual in an amount of from at least about 0.31 nmol / L to at least about 2121.33 nmol / L and / or spermidine is administered to the young individual in an amount of from at least 2539.68 nmol / L to at least about 19972.57 nmol / L.

[0163] 11 . The composition as claimed in any of the preceding paras, wherein the young individual is an infant, a young child or a child.

[0164] 12. 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 about 4 to about 12 weeks of age.

[0165] 13. The composition according to any one of the preceding paras, wherein neurodevelopment is promoted in the young individual from birth to about 5 years of age, preferably from birth to about 24 months of age, more preferably between the age of about 6 to about 12 months of age.

[0166] 14. The composition according to any one of the preceding paras for use in preventing and / or treating neurodevelopmental disorders and / or diseases.

[0167] 15. The composition according to para 14, wherein the neurodevelopment disorder and / or disease is at least one selected from: autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), intellectual disability, epilepsy, depression, anxiety, language delay, specific language impairment (SLI), dyslexia, speech sound disorder, stuttering, cerebral palsy, hypotonia, developmental coordination disorder (DCD), ataxia.

[0168] 16. 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. 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.

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[0173] PCT

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[0176] FOR RECEIVING OFFICE USE ONLY (Original in Electronic Form)

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[0178] FOR INTERNATIONAL BUREAU USE ONLY

Claims

CLAIMS1. A composition comprising at least one source of polyamines and / or metabolites thereof in an effective amount for use in promoting neurodevelopment in a young individual.

2. The composition according to claim 1 , wherein neurodevelopment comprises social-emotional, motor, language and / or cognitive development.

3. The composition according to any one of the preceding claims, wherein the at least one source of polyamines comprises agmatine, putrescine, spermidine, spermine, and / or cadaverine.

4. The composition according to any one of the preceding claims, wherein the at least one source of metabolites comprises acetylagmatine, acetylputrescine, N1 -acetylspermidine, N1 ,N8-diacetylspermidine, N1 -acetylspermine, N1 ,N12-diacetylspermine, N-Acetylcadaverine, N6-Acetyl-L-lysine, N2-Acetylornithine, and / or N-acetyl agmatine.

5. The composition according to any one of the preceding claims, wherein it is for use in promoting social-emotional development in a young individual and the at least one source of metabolites is N1 ,N8-diacetylspermidine.

6. The composition according to claim 5, wherein N1 ,N8-diacetylspermidine is administered to the young individual in an amount of from at least about 0.83 nmol / L to at least about 6.99 nmol / L.

7. The composition as claimed in any of claims 1 to 4, wherein it is for use in promoting motor development in a young individual and the at least one source of polyamines is putrescine.

8. The composition according to claim 7, wherein putrescine is administered to the young individual in an amount of from at least about 0.31 nmol / L to at least about 2121 .33 nm / l.

9. The composition according to any one of claims 1 to 4, wherein it is for use in promoting cognitive development in a young individual and the at least one source of polyamines is selected from putrescine, spermidine.

10. The composition according to claim 9, wherein putrescine is administered to the young individual in an amount of from at least about 0.31 nmol / L to at least about 2121.33 nmol / L and / or spermidine is administered to the young individual in an amount of from at least 2539.68 nmol / L to at least about 19972.57 nmol / L.11 . The composition as claimed in any of the preceding claims, wherein the young individual is an infant, a young child or a child.2712. The composition according to any one of the preceding claims, wherein it is administered to the young individual from birth to about 5 years of age, preferably from about 4 to about 12 weeks of age.

13. The composition according to any one of the preceding claims, wherein neurodevelopment is promoted in the young individual from birth to about 5 years of age, preferably from birth to about 24 months of age, more preferably between the age of about 6 to about 12 months of age.

14. The composition according to any one of the preceding claims for use in preventing and / or treating neurodevelopmental disorders and / or diseases.

15. The composition according to claim 14, wherein the neurodevelopment disorder and / or disease is at least one selected from: autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), intellectual disability, epilepsy, depression, anxiety, language delay, specific language impairment (SLI), dyslexia, speech sound disorder, stuttering, cerebral palsy, hypotonia, developmental coordination disorder (DCD), ataxia.

16. The composition according to any one of the preceding claims, 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.

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