Compositions comprising human milk oligosaccharides for use in a subject to support brain development and / or social-emotional development

Abstract

The invention provides a fucosylated human milk oligosaccharide (HMO) for use in improving brain development and / or social-emotional development in a subject, wherein the fucosylated HMO is 3-fucosyllactose (3-FL), and wherein the subject is an infant, a young child or a child.

Description

[0001] Compositions comprising human milk oligosaccharides for use in a subject to support brain development and / or social-emotional development

[0002] Field of the invention

[0003] This invention relates to nutritional compositions comprising at least one fucosylated human milk oligosaccharide for use in a subject to support brain development and / or social-emotional development. In particular, the nutritional composition comprises 3-fucosyllactose (3-FL). The brain development and / or social-emotional development comprises the development of brain network(s) supporting social-emotional functions, such as the default mode network (DMN).

[0004] Background of the invention

[0005] Identifying the potential relationship between human milk oligosaccharides (HMOs) and early brain development has gained substantial interest in recent years. Preliminary evidence based on animal studies have indicated that HMOs could play a significant role in the central nervous system development. For example, using chronic oral administration of 2’-FL to rodents, Vazquez et al. demonstrated that the treated animals exhibit significantly better learning and working memory function (Vazquez et al., 2015, Journal of nutritional biochemistry, 26(5):455- 465).

[0006] However, there is a paucity of data on the potential effects of other HMOs on brain functional development in infancy and early childhood. To the best of our knowledge, the present study is the first study to determine the association of any HMOs, let alone the fucosylated HMO 3- fucosyllactose (3-FL) specifically, on social-emotional development.

[0007] There is a need for nutritional compositions which can deliver such health benefits. There is a need to deliver such health benefits in the subject in a manner that does not induce side effects and / or in a manner that is easy to deliver (e.g. as a nutritional composition or during a meal), and well accepted by the parents or health care practitioners. There is also a need to deliver such benefits in a manner that keeps the cost of such delivery reasonable and affordable by most.

[0008] Summary of the invention

[0009] The present inventors have surprisingly found that the fucosylated HMO 3-fucosyllactose (3- FL) is significantly associated with brain and social-emotional development, and in particular, the development of social-emotional brain networks, such as the default mode network (DMN), in infants and children. Whereas other fucosylated HMOs, such as A-tetrasaccharide, are not.

[0010] Accordingly, in a first aspect, the invention provides a fucosylated human milk oligosaccharide (HMO) for use in improving brain development and / or social-emotional development in a subject, wherein the fucosylated HMO is 3-fucosyllactose (3-FL), and wherein the subject is an infant, a young child or a child.

[0011] In a further aspect, the invention provides a nutritional composition comprising a fucosylated human milk oligosaccharide (HMO) for use in improving brain development and / or social- emotional development in a subject, wherein the fucosylated HMO is 3-fucosyllactose (3-FL), and wherein the subject is an infant, a young child or a child.

[0012] In a further aspect, the invention provides a method of improving brain development and / or social-emotional development in a subject comprising administering a fucosylated HMO to the subject, wherein the fucosylated HMO is 3-fucosyllactose (3-FL), and wherein the subject is an infant, a young child or a child.

[0013] In a further aspect, the invention provides a method of improving brain development and / or social-emotional development in a subject comprising administering a nutritional composition comprising a fucosylated HMO to the subject, wherein the fucosylated HMO is 3- fucosyllactose (3-FL), and wherein the subject is an infant, a young child or a child.

[0014] In a further aspect, the invention provides a fucosylated HMO for improving brain development and / or social-emotional development in a subject, wherein the fucosylated HMO is 3- fucosyllactose (3-FL), and wherein the subject is an infant, a young child or a child.

[0015] In a further aspect, the invention provides a nutritional composition comprising a fucosylated HMO for improving brain development and / or social-emotional development in a subject, wherein the fucosylated HMO is 3-fucosyllactose (3-FL), and wherein the subject is an infant, a young child or a child.

[0016] In some embodiments, the improvement in brain development and / or social-emotional development in the subject comprises or consists of an improvement in the development of brain network(s) associated with social-emotional functions. In some embodiments, improving brain development and / or social-emotional development in the subject comprises or consists of promoting the default mode network (DMN).

[0017] Accordingly, in a further aspect the invention provides the use of a fucosylated HMO for promoting the default mode network (DMN) in a subject, wherein the fucosylated HMO is 3- fucosyllactose (3-FL), and wherein the subject is an infant, a young child or a child.

[0018] In a further aspect, the invention provides the use of a nutritional composition comprising a fucosylated HMO for promoting the default mode network (DMN) in a subject, wherein the fucosylated HMO is 3-fucosyllactose (3-FL), and wherein the subject is an infant, a young child or a child.

[0019] In a further aspect, the invention provides a method of promoting the default mode network (DMN) in a subject comprising administering a fucosylated HMO to the subject, wherein the fucosylated HMO is 3-fucosyllactose (3-FL), and wherein the subject is an infant, a young child or a child.

[0020] In a further aspect, the invention provides a method of promoting the default mode network (DMN) in a subject comprising administering a nutritional composition comprising a fucosylated HMO to the subject, wherein the fucosylated HMO is 3-fucosyllactose (3-FL), and wherein the subject is an infant, a young child or a child.

[0021] In some embodiments, the subject is an infant at least 5 months old, a young child or a child.

[0022] In some embodiments, the nutritional composition is an infant formula, a starter infant formula, a follow-on or follow-up infant formula, a baby food (such as yogurt, pureed or mashed baby food), an infant cereal composition, a growing-up milk, a fortifier or a supplement.

[0023] In some embodiments, wherein 3-FL is present in a total amount of from 50 mg / L to 2000 mg / L of the nutritional composition or of from 38 mg / 100g to 1540 mg / 100g of the nutritional composition.

[0024] Brief description of the Figures

[0025] Figure 1 : Scatter plot of the default mode functional network strength and age-regressed-out 3-FL concentration in breastmilk. The line represents the linear regression for the population highlighting the positive association of 3-FL in breastmilk with default mode network strength p<0.05). To ensure age did not confound the association analyses between HMOs and brain functional networks, age was regressed out from both the HMOs and the brain functional networks using smooth spline.

[0026] Figure 2: Scatter plot of the default mode functional network strength and age regressed-out 3-FL concentration in breastmilk levels in subjects aged over 5 months. The line represents the linear regression for the population highlighting the positive association of 3-FL in breastmilk levels with default mode network strength p<0.05). To ensure age did not confound the association analyses between HMOs and brain functional networks, age was regressed out from both the HMOs and the brain functional networks using smooth spline.

[0027] Figure 3: Scatter plot of the default mode functional network strength and age-regressed-out A-tetrasaccharide concentration in breastmilk, where no significant association was observed between the two.

[0028] Detailed description of the invention

[0029] Definitions

[0030] As used herein, the following terms have the following meanings.

[0031] The term "subject" refers to an infant, a young child, or a child.

[0032] The term "infant" means a child under the age of 12 months.

[0033] The expression "young child" means a child aged between one and three years, also called toddler.

[0034] The term “child” means a child aged between three and twelve years. Preferably, the term “child” means a child aged between three and six years.

[0035] The expression "nutritional composition" means a composition which nourishes a subject. This nutritional composition is usually to be taken orally or intravenously. It may include a lipid or fat source, a carbohydrate source and / or a protein source. In a particular embodiment the nutritional composition is a ready-to-drink composition such as a ready-to-drink formula. In a particular embodiment, the nutritional composition of the present invention is a "synthetic nutritional composition". The expression "synthetic nutritional composition" means a mixture obtained by chemical and / or biological means, which can be chemically identical to the mixture naturally occurring in mammalian milks (i.e. the synthetic nutritional composition is not breast milk).

[0036] 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).

[0037] The expression "infant formula" encompasses both "starter infant formula" and "follow-up formula" or "follow-on formula".

[0038] A "follow-up formula" or "follow-on formula" is given from the 6th month onwards and includes “growing-up milk”. It constitutes the principal liquid element in the progressively diversified diet of this category of person.

[0039] The expression “growing-up milk” (or “GUM”) refers to a milk-based drink generally with added vitamins and minerals, that is intended for young children or children.

[0040] The expression "baby food" means a foodstuff intended for particular nutritional use by infants or young children during the first years of life.

[0041] The expression "infant cereal composition" means a foodstuff intended for particular nutritional use by infants or young children during the first years of life.

[0042] The term "fortifier" refers to liquid or solid nutritional compositions suitable for mixing with breast milk or infant formula.

[0043] The expression “weaning period” means the period during which the mother's milk is substituted by other food in the diet of an infant or young child. The "mother's milk" should be understood as the breast milk including colostrum (first milk), transitional or mature milk of the mother.

[0044] An “oligosaccharide” is a saccharide polymer containing a small number (typically three to ten) of simple sugars (monosaccharides).

[0045] The term "HMO" or "HMOs" refers to human milk oligosaccharide(s). These carbohydrates are 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- acetyl neuraminic 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.

[0046] A "fucosylated oligosaccharide" is an oligosaccharide having a fucose residue. It has a neutral nature. Some examples are LNFP-I (lacto-N-fucopentaose I), A-tetrasaccharide, 2’-FL (2' fucosyllactose), 3-FL (3’ fucosyllactose).

[0047] 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.

[0048] A "precursor of HMO" is a key compound that intervenes in the manufacture of HMO, such as sialic acid and / or fucose.

[0049] The nutritional composition of the present invention can be in solid form (e.g. powder) or in liquid form. The amount of the various ingredients (e.g. the oligosaccharides) can be expressed in g / 100g of composition on a dry weight basis when it is in a solid form, e.g. a powder, or as a concentration in g / L 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 milk, water..., e.g. a reconstituted infant formula or a follow- on / follow-up formula or a growing-up milk or an infant cereal product or any other formulation designed for infant nutrition).

[0050] The term “prebiotic” means 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).

[0051] The structure of "A-tetrasaccharide" is a-D-GalNAc-(l - 3)-[alpha-L-Fuc-(l- 2)]- -D-Gal-(1A4)-D- Glc

[0052] Wherein

[0053] GalNAc = N-acetylgalactosamine

[0054] Fuc = Fucose

[0055] Gal = Galactose

[0056] Glc = Glucose

[0057] The term “brain development” refers to the hierarchical process of brain growth, including wiring the brain, such that later development depends on early development, that begins around 2 weeks after conception and continues into young adulthood 20 years later. Brain development builds on itself, as initially brain cells grow in number and then start connecting eventually linking with each other in more complex ways, enabling the child to move and speak and think in ever more complex ways. An example of the hierarchical process of brain development is that language development depends critically on sensory and perceptual development (e.g., discrimination of speech sounds). The term “brain development” comprises the development of default mode brain network. Any suitable assessment method for social- emotional development known in the art, including brain magnetic resonance imaging (MRI) to determine default mode network strength, may be employed in the practice of the present invention.

[0058] All percentages are by weight unless otherwise stated.

[0059] All weights expressed in g per 100g of composition are dry weight unless otherwise stated. In addition, in the context of the invention, the terms "comprising" or "comprises" do not exclude other possible elements. The composition of the present invention, including the many embodiments described herein, can comprise, consist of, or consist essentially of the essential elements and limitations of the invention described herein, as well as any additional or optional ingredients, components, or limitations described herein or otherwise depending on the needs.

[0060] 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.

[0061] The invention will now be described in further details. It is noted that the various aspects, features, examples and embodiments described in the present application may be compatible and / or combined together any combination thereof.

[0062] Improving brain development and / or social-emotional development

[0063] Over the past few decades, numerous animal and clinical studies have supported the potential relationships between HMOs and the host’s cognition and health (such as obesity and cardiovascular disease). Collectively, it is highly plausible that HMOs could yield associations with cognitive development in infants. The present inventors have surprisingly found that the fucosylated HMO 3-FL is significantly associated with brain and social-emotional development, and in particular with the development of the default mode network (DMN). The DMN has been found to be involved in various domains of cognitive and social processing, as reviewed by Li et al. (Li et al., Frontiers in Human Neuroscience, 2014, 8: Article 74; see also Schilbach et al., Conscious. Cogn., 2008, 17: 457-467; Eickhoff et al., Hum. Brain Mapp., 2009, 30: 2907-2926; and Laird et al., J. Cogn. Neurosci., 2011 , 23: 4022-4037).

[0064] Accordingly, in a first aspect, the invention provides a fucosylated human milk oligosaccharide (HMO) for use in improving brain development and / or social-emotional development in a subject, wherein the fucosylated HMO is 3-fucosyllactose (3-FL), and wherein the subject is an infant, a young child or a child.

[0065] In a further aspect, the invention provides a nutritional composition comprising a fucosylated human milk oligosaccharide (HMO) for use in improving brain development and / or social- emotional development in a subject, wherein the fucosylated HMO is 3-fucosyllactose (3-FL), and wherein the subject is an infant, a young child or a child. In a further aspect, the invention provides the use of a fucosylated human milk oligosaccharide (HMO) in the manufacture of a medicament for improving brain development and / or social- emotional development in a subject, wherein the fucosylated HMO is 3-fucosyllactose (3-FL), and wherein the subject is an infant, a young child or a child.

[0066] Suitably, the medicament is a nutritional composition as described herein.

[0067] In a further aspect, the invention provides a method of improving brain development and / or social-emotional development in a subject comprising administering a fucosylated HMO to the subject, wherein the fucosylated HMO is 3-fucosyllactose (3-FL), and wherein the subject is an infant, a young child or a child.

[0068] In a further aspect, the invention provides a method of improving brain development and / or social-emotional development in a subject comprising administering a nutritional composition comprising a fucosylated HMO to the subject, wherein the fucosylated HMO is 3- fucosyllactose (3-FL), and wherein the subject is an infant, a young child or a child.

[0069] In a further aspect, the invention provides a fucosylated HMO for improving brain development and / or social-emotional development in a subject, wherein the fucosylated HMO is 3- fucosyllactose (3-FL), and wherein the subject is an infant, a young child or a child.

[0070] In a further aspect, the invention provides a nutritional composition comprising a fucosylated HMO for improving brain development and / or social-emotional development in a subject, wherein the fucosylated HMO is 3-fucosyllactose (3-FL), and wherein the subject is an infant, a young child or a child.

[0071] In some embodiments, brain development and social-emotional development are improved. In some embodiments, brain development is improved. In some embodiments, social- emotional development is improved.

[0072] In some embodiments, the improvement in brain development and / or social-emotional development in the subject comprises or consists of an improvement in the development of brain network(s) associated with social-emotional functions. Suitably, brain network(s) associated with social-emotional functions (e.g. brain network(s) activated during social- emotional functions and tasks) may be identified using any suitable method known in the art. Suitably, brain magnetic resonance imaging (MRI) to determine candidate network strength coupled with assessment of social-emotional skills may be used. By way of further example, the methods employed herein may be used (see Materials & Methods, Example 1 ). Brain networks associated with social-emotional functions may be referred to herein as “social- emotional brain networks”.

[0073] In some embodiments, the improvement in brain development and / or social-emotional development in the subject comprises or consists of an improvement in the development of social-emotional brain networks.

[0074] In some embodiments, improving brain development and / or social-emotional development in the subject comprises or consists of promoting the default mode network (DMN).

[0075] In some embodiments, the improvement in brain development in the subject comprises or consists of an improvement in the development of social-emotional brain networks.

[0076] In some embodiments, improving brain development in the subject comprises or consists of promoting the default mode network (DMN).

[0077] In some embodiments, the improvement in social-emotional development in the subject comprises or consists of an improvement in the development of social-emotional brain networks.

[0078] In some embodiments, improving social-emotional development in the subject comprises or consists of promoting the default mode network (DMN).

[0079] Accordingly, in a further aspect the invention provides the use of a fucosylated HMO for promoting the default mode network (DMN) in a subject, wherein the fucosylated HMO is 3- fucosyllactose (3-FL), and wherein the subject is an infant, a young child or a child.

[0080] In a further aspect, the invention provides the use of a nutritional composition comprising a fucosylated HMO for promoting the default mode network (DMN) in a subject, wherein the fucosylated HMO is 3-fucosyllactose (3-FL), and wherein the subject is an infant, a young child or a child.

[0081] In a further aspect the invention provides the use of a fucosylated HMO in the manufacture of a medicament for promoting the default mode network (DMN) in a subject, wherein the fucosylated HMO is 3-fucosyllactose (3-FL), and wherein the subject is an infant, a young child or a child. Suitably, the medicament is a nutritional composition as described herein.

[0082] In a further aspect, the invention provides a method of promoting the default mode network (DMN) in a subject comprising administering a fucosylated HMO to the subject, wherein the fucosylated HMO is 3-fucosyllactose (3-FL), and wherein the subject is an infant, a young child or a child.

[0083] In a further aspect, the invention provides a method of promoting the default mode network (DMN) in a subject comprising administering a nutritional composition comprising a fucosylated HMO to the subject, wherein the fucosylated HMO is 3-fucosyllactose (3-FL) and / or A-tetrasaccharide, and wherein the subject is an infant, a young child or a child.

[0084] Any suitable assessment method for social-emotional development known in the art may be employed in the practice of the present invention.

[0085] Suitably, the Bayley Scale of Infant and Toddler Development 3rdedition or 4thedition (BSID; Bayley N. Third Edition: Technical Manual. San Antonio, TX: Harcourt Assessment 2006 or Bayley N. Fourth Edition: Technical Manual. Bloomington, MN: NCS Pearson 2019), which provides a standardized assessment of adaptive behaviour, cognition, language, motor and social-emotional abilities for children of all ability levels up to 3.5 years of age, may be used.

[0086] Suitably, the Ages and Stages Questionnaire: Social-Emotional questionnaires (Squires, J. , Bricker, D. D. , & Twombly, E. (2002). ASQ:SE-2 user’s guide. Paul H. Brookes Publishing Co., Inc.), which provides a standardized assessment of adaptive behaviour, cognition, language, motor and social-emotional abilities for children of all ability levels up to 3.5 years of age, may be used. The Ages and Stages Questionnaire provides a standardized assessment of social and emotional development in children between 0 and 6 years of age in seven key social-emotional areas: self-regulation, compliance, social-communication, adaptive functioning, autonomy, affect, interaction with people.

[0087] Accordingly, in some embodiments, the improvement in brain development and / or social- emotional development comprises or consists of an improvement in social-emotional behaviour based on a score of the Bayley Scale of Infant and Toddler Development or on a score of the Ages and Stages Questionnaire. In some embodiments, the improvement in brain development and / or social-emotional development comprises or consists of an improvement in social-emotional behaviour based on a score of the Bayley Scale of Infant and Toddler Development.

[0088] In some embodiments, the improvement in brain development and / or social-emotional development comprises or consists of an improvement in social-emotional behaviour based on a score of the Ages and Stages Questionnaire.

[0089] In some embodiments, the improvement in social-emotional development consists of an improvement in social-emotional behaviour based on a score of the Bayley Scale of Infant and Toddler Development or on a score of the Ages and Stages Questionnaire.

[0090] In some embodiments, the improvement in social-emotional development consists of an improvement in social-emotional behaviour based on a score of the Bayley Scale of Infant and Toddler Development.

[0091] In some embodiments, the improvement in social-emotional development consists of an improvement in social-emotional behaviour based on a score of the Ages and Stages Questionnaire.

[0092] The determination of an improvement in brain development and / or social-emotional development may be carried out using any method known in the art, including brain magnetic resonance imaging (MRI) to determine default mode network strength. By way of further example, the methods employed herein may be used (see Materials & Methods, Example 1 ).

[0093] Suitably, brain development and / or social-emotional development are improved in a subject using 3-FL or a nutritional composition according to the invention, when compared to a corresponding composition which does not comprise 3-FL in accordance with the invention.

[0094] In some embodiments, 3-FL is present in a total amount of from 50 mg / L to 2000 mg / L of the composition or nutritional composition according to the invention or of from 38 mg / 100g to 1540 mg / 100g of the composition or nutritional composition according to the invention. Suitably, 3-FL is present in a total amount of from 60 mg / L to 1500 mg / L, for example from 70 mg / L to 1000 mg / L, for example from 80 mg / L to 500 mg / L of the composition or nutritional composition according to the invention. Suitably, 3-FL is present in a total amount of from 45 mg / 100g to 1160 mg / 100g, for example from 53 g / 100g to 770 mg / 100g, for example from 61 mg / 100g to 385 mg / 100g of the composition or nutritional composition (dry weight). Subject

[0095] The subject is an infant, a young child or a child.

[0096] In one embodiment, the subject is an infant. In one embodiment, the subject is a young child. In one embodiment, the subject is a child.

[0097] In a preferred embodiment, the subject is an infant over 5 months old, a young child or a child.

[0098] The nutritional composition or 3-FL for use according to the invention may also be used in subject that was born by C-section or that was vaginally delivered.

[0099] In some embodiments the nutritional composition or 3-FL for use according to the invention can be for use before and / or during the weaning period.

[0100] In some embodiments the nutritional composition or 3-FL for use according to the invention is for use in a subject at risk and / or in need.

[0101] The subject at risk and / or in need may be bottle-fed and / or formula-fed. The subject at risk and / or in need may be a subject who has difficulties in social-emotional development. Suitably, a subject who has difficulties in social-emotional function may be identified using the methods described herein for the assessment of social-emotional development (e.g. the Bayley Scale of Infant and Toddler Development or the Ages and Stages questionnaire).

[0102] In one embodiment the composition or 3-FL for use according to the invention is given to the subject as a supplementary composition to the mother's milk. In some embodiments the subject receives the mother's milk during at least the first 2 weeks, first 1 , 2, 4, 6 or 12months. In one embodiment the nutritional composition or 3-FL for use according to the invention is given to the subject after such period of mother's nutrition or is given together with such period of mother's milk nutrition. In another embodiment the nutritional composition or 3-FL for use according to the invention is given to the subject as the sole or primary nutritional composition during at least one period of time, e.g. after the 1st, 2ndor 4thmonth of life, during at least 1 , 2, 4, 6 or 12 months. In one embodiment the nutritional composition of the invention is a complete nutritional composition (fulfilling all or most of the nutritional needs of the subject). In another embodiment the nutritional composition or 3-FL for use according to the invention is a supplement or a fortifier intended for example to supplement human milk or to supplement an infant formula or a follow-on formula.

[0103] Other ingredients

[0104] The nutritional composition according to the present invention may also comprise other types of oligosaccharide(s), polysaccharides and / or a fiber(s) and / or a precursor(s) thereof. The other oligosaccharide and / or fiber and / or precursor thereof may be selected from the list comprising human milk oligosaccharides (HMOs), galacto-oligosaccharides (GOS), fructooligosaccharides (FOS), xylooligosaccharides (XOS), cello-oligosaccharides (COS), arabinoxylans, arabinans, xylans, inulin, polydextrose, beta-glucans, pectins and any combination thereof and any derived products, like partial hydrolysis products, thereof. They may be in an amount between 0 and 10% by weight of composition. In a particular embodiment, the nutritional composition or the combination can also contain at least one BMO (bovine milk oligosaccharide).

[0105] HMOs which may be included in the nutritional composition or combination according to the present invention may be selected from the group consisting of 2’-FL (2’- fucosyllactose), Lacto-difucotetraose (LDFT)), lacto-N-fucopentaose I, lacto-N-fucopentaose II, lacto-N- fucopentaose III, lacto-N-fucopentaose V, lacto-N-fucohexaose, lacto-N-difucohexaose I (LNDFH I), fucosyllacto-N-hexaose, fucosyllacto-N-neohexaose, difucosyllacto-N-hexaose I, difucosyllacto-N-neohexaose II, para-lacto-N-neohexaose (para-LNnH), LNT (lacto-N- tetraose), LNnT (lacto-N-neotetraose), 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, lacto-N-decaose, 3’-SL (3' sialyllactose), 6’-SL (6’ sialyllactose), A-tetrasaccharide and any combination thereof.

[0106] In some embodiments, the nutritional composition according to the invention comprises at least one additional HMO. In other embodiments, the nutritional composition according to the present invention is devoid of any further HMOs. Thus, 3-FL may be the sole HMO in the nutritional composition of the invention.

[0107] The nutritional composition according to the invention generally contains a protein source. The protein can be in an amount of from 1 .6 to 3 g per 100 kcal. In some embodiments, the protein amount can be between 2.4 and 4 g / 100kcal or more than 3.6 g / 100kcal. In some other embodiments the protein amount can be below 2.0 g per 100 kcal, e.g. between 1 .8 to 2 g / 100 kcal, or in an amount below 1.8 g per 100 kcal. Protein sources based on whey, casein and mixtures thereof may be used as well as protein sources based on soy. As far as whey proteins are concerned, the protein source may be based on acid whey or sweet whey or mixtures thereof and may include alpha-lactalbumin and beta-lactoglobulin in any desired proportions.

[0108] In some advantageous embodiments, the protein source is whey predominant (i.e. more than 50% of proteins are coming from whey proteins, such as 60% or 70%).

[0109] The proteins may be intact or hydrolysed or a mixture of intact and hydrolysed proteins. By the term “intact” is meant that the main part of the proteins are intact, i.e. the molecular structure is not altered, for example at least 80% of the proteins are not altered, such as at least 85% of the proteins are not altered, preferably at least 90% of the proteins are not altered, even more preferably at least 95% of the proteins are not altered, such as at least 98% of the proteins are not altered. In a particular embodiment, 100% of the proteins are not altered.

[0110] The term “hydrolysed” means in the context of the present invention a protein which has been hydrolysed or broken down into its component amino acids. The proteins may be either fully or partially hydrolysed. It may be desirable to supply partially hydrolysed proteins (degree of hydrolysis between 2 and 20%), for example for infants or young children believed to be at risk of developing cow’s 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, whey protein hydrolysates 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, it is found that the protein suffers much less lysine blockage during the hydrolysis process. This 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.

[0111] In an embodiment of the invention, at least 70% of the proteins are hydrolysed, preferably at least 80% of the proteins are hydrolysed, such as at least 85% of the proteins are hydrolysed, even more preferably at least 90% of the proteins are hydrolysed, such as at least 95% of the proteins are hydrolysed, particularly at least 98% of the proteins are hydrolysed. In a particular embodiment, 100% of the proteins are hydrolysed.

[0112] In one particular embodiment, the proteins of the nutritional composition are hydrolysed, fully hydrolysed or partially hydrolysed. The degree of hydrolysis (DH) of the protein can be between 8 and 40, or between 20 and 60 or between 20 and 80 or more than 10, 20, 40, 60, 80 or 90.

[0113] The protein component can alternatively be replaced by a mixture or synthetic amino acid.

[0114] The nutritional composition according to the present invention generally contains a carbohydrate source. This is particularly preferable in the case where the nutritional composition of the invention is an infant formula. In this case, any carbohydrate source conventionally found in infant formulae such as lactose, sucrose, saccharose, maltodextrin, starch and mixtures thereof may be used although one of the preferred sources of carbohydrates is lactose.

[0115] The nutritional composition according to the present invention generally contains a source of lipids. This is particularly relevant if the nutritional composition of the invention is an infant formula. In this case, the lipid source may be any lipid or fat which is suitable for use in infant formulae. Some suitable fat sources include palm oil, structured triglyceride oil, high oleic sunflower oil and high oleic safflower oil, medium-chain-triglyceride oil. The essential fatty acids linoleic and a-linolenic acid may also be added, as well small amounts of oils containing high quantities of preformed arachidonic acid and docosahexaenoic acid such as fish oils or microbial oils. The fat source may have 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.

[0116] The nutritional composition of the invention may also 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 minerals, vitamins and other nutrients optionally present in the composition of the invention include vitamin A, vitamin B1 , vitamin B2, vitamin B6, vitamin B12, vitamin E, vitamin K, vitamin C, vitamin D, folic acid, inositol, niacin, biotin, pantothenic acid, choline, calcium, phosphorous, iodine, iron, magnesium, copper, zinc, manganese, chlorine, potassium, sodium, selenium, chromium, molybdenum, taurine, and L-carnitine. Minerals are usually added in salt form. The presence and amounts of specific minerals and other vitamins will vary depending on the intended population.

[0117] If necessary, the nutritional composition of the invention may contain emulsifiers and stabilisers such as soy, lecithin, citric acid esters of mono- and di-glycerides, and the like. The nutritional composition of the invention may also contain other substances which may have a beneficial effect such as lactoferrin, nucleotides, nucleosides, and the like.

[0118] The nutritional composition of the invention may also contain carotenoid(s). In some particular embodiments of the invention, the nutritional composition of the invention does not comprise any carotenoid.

[0119] Nutritional composition

[0120] The nutritional composition according to the invention can be for example an infant formula, a starter infant formula, a follow-on or follow-up formula, a growing-up milk, a baby food (such as yogurt, pureed or mashed baby food), an infant cereal composition, a fortifier such as a human milk fortifier or a supplement. In some particular embodiments, the composition of the invention is an infant formula, a fortifier or a supplement that may be intended for the first 4 or 6 months of age. In a preferred embodiment the nutritional composition of the invention is an infant formula.

[0121] The 3-FL for use according to the invention can be for example formulated as an infant formula, a starter infant formula, a follow-on or follow-up formula, a growing-up milk, a baby food (such as yogurt, pureed or mashed baby food), an infant cereal composition, a fortifier such as a human milk fortifier or a supplement.

[0122] In some other embodiments the nutritional composition or 3-FL for use according to 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.

[0123] When the nutritional composition or 3-FL for use according to the invention is a supplement, it can be provided in the form of unit doses. In such cases it is particularly useful to define the amount of oligosaccharides in terms of daily dose to be administered to the infant, young child or child.

[0124] Suitably, when the nutritional composition or 3-FL for use according to the invention is a supplement, it may comprise 3-FL and no other additional nutrient on top of the excipients necessary to obtain a stable composition. Suitably, when the nutritional composition or 3-FL for use according to the invention is a supplement, it may comprise 3-FL in combination with one or more further HMOs (e.g. one or more further HMOs as described herein) and no other additional nutrient on top of the excipients necessary to obtain a stable composition.

[0125] The nutritional composition or 3-FL for use according to the invention can be in solid (e.g. powder), liquid or gelatinous form. In a specific embodiment the nutritional composition or 3- FL for use according to the invention is a supplement, wherein the supplement is in powder form and provided in a sachet, preferably a sachet with 0.1 to 20 g per sachet, for example 1 to 10 g per sachet, or in the form of a syrup, preferably a syrup with a total solid concentration of 5 to 75 g / 100 mL (5 to 75% (w / v)). When the supplement is in powder form, it may comprise a carrier. It is however preferred that the supplement is devoid of a carrier. When the supplement is in the form of a syrup, the components are preferably dissolved or suspended in water acidified with citrate.

[0126] In a particular embodiment the nutritional composition or 3-FL for use according to the invention according to the invention is a hypoallergenic composition. In another particular embodiment the composition or 3-FL for use according to the invention according to the invention is a hypoallergenic nutritional composition.

[0127] The nutritional composition or 3-FL for use according to the invention according to the invention may be prepared in any suitable manner. A composition will now be described by way of example.

[0128] For example, a formula such as an infant formula may be prepared by blending together the protein source, 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 they 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 in the range between about 50°C and about 80°C to aid dispersal of the ingredients. Commercially available liquefiers may be used to form the liquid mixture.

[0129] The oligosaccharide(s) may be added at this stage, especially if the final product is to have a liquid form. If the final product is to be a powder, they may likewise be added at this stage if desired.

[0130] The liquid mixture is then homogenised, for example in two stages. The liquid mixture may then be thermally treated to reduce bacterial loads, by rapidly heating the liquid mixture to a temperature in the range between about 80°C and about 150°C for a duration between about 5 seconds and about 5 minutes, for example. This may be carried out by means of steam injection, an autoclave or a heat exchanger, for example a plate heat exchanger.

[0131] Then, the liquid mixture may be cooled to between about 60°C and about 85°C for example by flash cooling. The liquid mixture may then be again homogenised, for example in two stages between about 10 MPa and about 30 MPa in the first stage and between about 2 MPa and 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.

[0132] If the final product is to be a powder, the homogenised mixture is transferred to a suitable drying apparatus such as a spray dryer or freeze dryer and converted to powder. The powder should have a moisture content of less than about 5% by weight. The oligosaccharide(s) may also or alternatively be added at this stage by dry-mixing or by blending them in a syrup form of crystals, alone or along with one or more other ingredients, and the mixture is spray-dried or freeze-dried.

[0133] If a liquid composition is preferred, the homogenised mixture may be sterilised then aseptically filled into suitable containers or may be first filled into the containers and then retorted.

[0134] In another embodiment, the composition or combination of the invention may be a supplement. The supplement may be in the form of tablets, capsules, pastilles or a liquid for example. When the supplement is in the form of a liquid, it can be an aqueous solution containing 1 -50 wt% HMO, preferably 5-35 wt% HMO, more preferably 5-15 wt%, such as 10 wt% HMO. The supplement in the form of a liquid can be a tea or a juice.

[0135] 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.

[0136] 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.

[0137] The different embodiments, details and examples previously described in the specification (e.g. related to the types and amounts of oligosaccharide, the nutritional composition, the administration, the targeted population...) also apply to all these other objects.

[0138] Examples

[0139] The following examples illustrate some specific embodiments of the composition for use according to the present invention. The examples are given solely for the purpose of illustration and are not to be construed as limitations of the present invention, as many variations thereof are possible without departing from the spirit of the invention.

[0140] Materials & Methods

[0141] Study Subjects

[0142] Parents enrolled in this study provided written informed consent for the participation of both themselves and their infants. The University of North Carolina at Chapel Hill and University of Minnesota Institutional Review Boards approved all study activities. Using site-based research registries, subjects were enrolled from both universities. Local newborn nurseries, institutional centers with research interest on early brain development, local flyers, and university listservs were additionally used for recruitment. The inclusion criteria were: 1 ) birth at gestational age of 37-42 weeks; 2) birth weight appropriate at gestational age; and 3) no major complications related to pregnancy and delivery. The exclusion criteria included: 1 ) adoption; 2) detection of autism, schizophrenia, intellectual disability, or bipolar disorder related first degree; 3) birth weight less than 2 kilograms; 4) neonatal hypoxia (10 minute APGAR < 5); 5) having illness necessitating more than two days of newborn intensive care unit (NICU) stay; 6) chromosomal or major congenital abnormality; 7) previous MRI showing abnormal magnetic resonance; 8) significant medical illness or developmental delay, or significant genetic or medical conditions impacting development, growth, or cognition (includes visual / hearing impairment); 9) contraindication in MRI; and 10) maternal HIV status, pre-eclampsia, placental abruption, and alcohol or illicit drug use during pregnancy.

[0143] Finally, additional inclusion criteria for subjects included in this study were infants younger than 12 months old and exclusively / predominantly breastfed during the first four months of life, defined as the infants who were fed less than 20g or 4 teaspoons per day of complementary foods / liquids (water, apple juice, etc.) and non-formula.

[0144] An accelerated longitudinal design was employed where the first and follow-up visits vary among subjects. At each visit, infants underwent non-sedated MR imaging sessions during natural sleep while human milk (HM) samples were collected from the mothers.

[0145] Human Milk Collections and Analyses

[0146] At each visit, we obtained HM samples from the right breast using a hospital-grade, electric Medela Symphony breast pump. To assure the HM composition at each feeding, the HM samples were extracted until no more HM was expressed. Whenever possible, to minimize the HM compositions diurnal variation, HM samples were standardized to the second feed of the day. An aliquot of at least 30 mL of volume was transferred from the collection bottle to a 50 mL polypropylene Falcon tube, mixed well by vortexing and dispatched in 1 and 2 mL aliquots for storage at -80°C until further use.

[0147] A representative 1 mL aliquot of HM was shipped to Neotron Spa (Italy) on dry ice for HMO quantifications. After labelling with 2-aminobenzamide, HMO analyses were done using liquid chromatography with fluorescence detection (Austin et al., Anal Chim Acta. 2018 Jun 20;1010:86-96; Zhang et al., NeuroImage, 2019, 185: 664-684). The following eight HMOs: 2’-FL, 3-FL, 3’-SL, 6’-SL, Lacto-N-tetraose (LNT), Lacto-N-neotetraose (LNnT), Lacto-N- fucopentaose-l (LNFP-I), and A-tetra, were quantified using standard curves with authentic HMO standards. Among the eight HMO quantifications, 3’-SL and 6’-SL were log-transformed to ensure normality in their distribution.

[0148] Image acquisition, preprocessing, and network construction

[0149] A detailed description on subject preparation and the imaging protocol can be found in Howell et al. (2019) (Howell et al., NeuroImage, 2019, 185: 891 -905). In short, prior to the imaging session, infants were swaddled with an MRI safe blanket, caregivers followed typical bedtime routines for their infants, and earplugs were carefully placed into the ear canals for the infants. The light was dimmed both inside and on the way to the scanner room. Once the infant fell asleep, the study coordinator or technologist guided the caregiver to place the infant on the scanner table. During the scan, the caregivers could either stay or leave the room, but a well- trained staff member remained in the room. All images were acquired using 3 Tesla (3T) Siemens MR scanners. All subjects were imaged without sedation and during natural sleep. Both anatomical and rs-fMRI images were acquired and the imaging parameters are provided in the Supporting Materials.

[0150] For each subject, rs-fMRI images were preprocessed using FMRIB Software Library (FSL) ((Smith et al., Neuroimage, 2004, 23 Suppl 1 : S208-19), including typical preprocessing steps. Anatomical images were segmented using iBEAT V2.0 (http: / / www.ibeat.doud) to generate brain tissue segmentation images (Dai et al., Neuroinformatics, 2013, 11 : 211 -225). Each voxel was labeled as gray matter, white matter, or cerebrospinal fluid. The tissue segmentation images were then used to register to the MNI template using the advanced normalization tools (ANTS) (Avants et al., NeuroImage, 2011 , 54: 2033-2044; Li et al., NeuroImage, 2014, 90: 266-279; Li et al., Medical Image Analysis, 2015. 25: 22-36; Li et al., NeuroImage, 2019, 185: 906-925; and Wang etal., Volume-Based Analysis of 6-Month-Old Infant Brain MRI for Autism Biomarker Identification and Early Diagnosis, in Medical Image Computing and Computer Assisted Intervention - MICCAI 2018. 2018. Cham: Springer International Publishing) . Using the deformation field, the AAL atlas with 90 regions-of-interest (ROIs) Tzourio-Mazoyer et al., NeuroImage, 2002, 15: 273-289) was deformed back to the subject space to extract the preprocessed time-series BOLD signals of each ROI from rs-fMRI images. Subsequently, a 90x90 functional connectivity (FC) matrix was derived by calculating the Pearson's correlation between each pair of ROIs, reflecting the connection between pairs of brain regions, for each subject. The network construction was adopted by matching the AAL atlas to the functional networks detected by the independent component analysis (Beckmann et al., Philos Trans R Soc Lond B Biol Sci, 2005, 360: 1001 -13; and Tagliazucchi etal., Neuron, 2014, 82: 695-708), including medial visual network (MVN), lateral visual network (LVN), default mode network (DMN), sensorimotor network (SMN), auditory / language processing network (AUD / LANG), and the executive control network (ECN). A network connection strength, an average of correlation coefficients of all connections within a given network, was obtained for each network. In the context of early brain development, the network connection strengths have been implicated to be a surrogate marker of brain functional maturation. Thus, the network connection strengths were used as the outcomes in our study. Statistical Analyses

[0151] The RStudio with R version 4.0.3 (The R Foundation for Statistical Computing, Vienna, Austria) was used for all statistical analyses. Linear mixed effects models with a random intercept for subjects were fitted for the statistical analyses to capture the dependency within the same subject across visits. To ensure age did not confound the association analyses between HMOs and brain functional networks (mean FCs), age was regressed out from both the HMOs and the brain functional networks using smooth spline (Hastie et al., Statistical Science, 1986, 1 : 297-310, 14). Standardization was applied on both the age-regressed-out brain network strengths and HMO concentrations so that the two measures are within the same range. Specifically, three statistical models were employed for the subsequent association analyses, enabling a comprehensive understanding of the potential relations between HMOs and brain functional networks. All models controlled for site and frame-wide displacement (FD), which quantitatively estimated the extent of subject motion during imaging, as adjusting covariates.

[0152] First, linear mixed effects models spanning over the entire age range of our cohort were employed with the eight HMOs for each brain functional network strength. This model captured mean associations and provided the overall association trend between the HMOs and each network strength. Corrections of multiple comparisons over the six networks using false discovery rate were applied.

[0153] Second, one of the main assumptions of the above approach was that the associations between HMOs and brain functional networks are consistent throughout the entire evaluated age range in our study. As outlined above, both the developmental paces and HMO concentrations vary among different cognitive abilities (Prevention, Prevention, Centers for Disease Control and Prevention, C.f.D.C.a. Developmental Milestones. 2013; Available from: https: / / www.cdc.gov / ncbddd / actearly / milestones / ) and with postnatal ages (Austin et al., Nutrients, 2016, 8: 346), respectively. Consequently, it is plausible that associations between brain functional networks and HMOs vary within different age ranges. We employed age-cutoff regression approaches, which allowed different associations between a given functional network strength and an HMO before and after a specific age to uncover these potential association behaviors. Specifically, the starting model included all eight HMOs. An age cutoff between 3 and 15 months with an increment of one month was applied for each of the eight HMOs. When an HMO was identified to have a better fit with an age-cutoff when compared to that without any age-cutoff using Akaike information criterion (AIC) (Akaike et al., IEEE Transactions on Automatic Control, 1974, 19: 716-723), the specific HMO was then fitted with an age-cutoff, i.e., allowing to have different slopes before and after the age-cutoff month. Conversely, the HMO that did not have an identified age-cutoff was fitted for the entire age range. The final model with the smallest AIC using the backward elimination variable selection was chosen. Here, since the final models had different covariates (due to different age-cutoff months and selected HMOs) for each brain functional network, multiple comparison correction was not applied.

[0154] For the association analyses between HMOs and DMN, age is regressed out and the values represent the distance from the fitted line by age with each points. The original unit is mg / L for the HMOs breastmilk levels.

[0155] Example 1

[0156] In this study, a total of 91 subjects with 156 longitudinal scans were included in the analysis, age ranging between 0.3 and 20 months.

[0157] The functional network strength can be evaluated as how strongly are the parts of the functional network interrelated.

[0158] Based on these seeds used in the study, we can hypothesize the following functions.

[0159] The default mode network (DMN) strength was derived by calculating the Pearson’s correlation between each pair of the following regions of interest: Cuneus, superior frontal gyrus (both medial and dorsal component), posterior cingulate gyrus, rectus gyrus, angular gyrus, precuneus, thalamus and superior temporal gyrus. These regions of the default mode network largely activate in tasks requiring participants to understand and interact with others, such as perceiving and interpreting other's emotion status, showing empathy to other people, inferring other's belief and intention, and performing moral judgments on other's behaviour (Schilbach et al., Conscious. Cogn., 2008, 17: 457-467; and Laird et al., J. Cogn. Neurosci., 2011 , 23: 4022-4037). Thus, benefits associated with this domain are social-emotional skills.

[0160] The results show a significant positive association between 3-FL and default mode network (Figure 1 ), which can be linked to benefits in social-emotional skills. Although these effects were observed across all ages (Figure 1 ), the positive association between 3-FL and the DMN is more prominent in infants at least 5 months old (Figure 2; effect size <0.0001 , p-value = 0.009 following age cut-off regression) compared to infants under 5 months old.

[0161] Surprisingly, the results show no association between A-tetrasaccharide and the DMN (Figure 3). Therefore, these findings indicate that the effect of fucosylation of the oligosaccharides could not have been predicted. For example, the fucosylated HMO A-tetrasaccharide exhibited no significant positive association or negative association with the DMN, indicating that the effects of 3-FL cannot be attributed to the fucosylation alone, rather the interactions between the HMO and brain networks is more complex.

[0162] Social-emotional skills require adequate maturation of the relevant brain architecture to properly develop, as such, providing a nutritional solution supporting such maturation in infants, young children and children is important. This study is the first to evidence an association between breast milk nutrient, specifically 3-FL, and maturation of the DMN, which is known to be activated during social-emotional behaviour. Hence, this study provides new nutritional interventions to promote the maturation of the DMN underlying the development of social-emotional skills.

Claims

Claims1 . A fucosylated human milk oligosaccharide (HMO) for use in improving brain development and / or social-emotional development in a subject, wherein the fucosylated HMO is 3- fucosyllactose (3-FL), and wherein the subject is an infant, a young child or a child.

2. A nutritional composition comprising a fucosylated HMO for use in improving brain development and / or social-emotional development in a subject, wherein the fucosylated HMO is 3-fucosyllactose (3-FL), and wherein the subject is an infant, a young child or a child.

3. The fucosylated HMO for use according to claim 1 or the nutritional composition for use according to claim 2, wherein the infant is at least 5 months old.

4. The fucosylated HMO for use according to claim 1 or claim 3, or the nutritional composition for use according to claim 2 or claim 3, wherein the improvement in brain development and / or social-emotional development in the subject comprises or consists of an improvement in the development of brain network(s) associated with social-emotional functions.

5. The fucosylated HMO for use according to any one of claims 1 , 3, or 4, or the nutritional composition for use according to any one of claims 2 to 4, wherein improving brain development and / or social-emotional development in the subject comprises or consists of promoting the default mode network (DMN).

6. The nutritional composition for use according to any one of claims 2 to 5, wherein the nutritional composition is an infant formula, a starter infant formula, a follow-on or follow-up infant formula, a baby food, an infant cereal composition, a growing-up milk, a fortifier or a supplement.

7. The nutritional composition for use according to any one of claims 2 to 6, wherein 3-FL is present in a total amount of from 50 mg / L to 2000 mg / L of the nutritional composition or of from 38 mg / 100g to 1540 mg / 100g of the nutritional composition.

8. Use of a fucosylated HMO for improving brain development and / or social-emotional development in a subject, wherein the fucosylated HMO is 3-fucosyllactose (3-FL), and wherein the subject is an infant, a young child or a child, preferably wherein the infant is at least 5 months old.

9. Use of a nutritional composition comprising a fucosylated HMO for improving brain development and / or social-emotional development in a subject, wherein the fucosylated HMO is 3-fucosyllactose (3-FL), and wherein the subject is an infant, a young child or a child, preferably wherein the infant is at least 5 months old.

10. The use according to claim 8 or claim 9, wherein the improvement in brain development and / or social-emotional development in the subject comprises or consists of an improvement in the development of brain network(s) associated with social-emotional functions, preferably wherein improving brain development and / or social-emotional development in the subject comprises or consists of promoting the default mode network (DMN).1 1. Use of a fucosylated HMO for promoting the default mode network (DMN) in a subject, wherein the fucosylated HMO is 3-fucosyllactose (3-FL), and wherein the subject is an infant, a young child or a child, preferably wherein the infant is at least 5 months old.

12. Use of a nutritional composition comprising a fucosylated HMO for promoting the default mode network (DMN) in a subject, wherein the fucosylated HMO is 3-fucosyllactose (3-FL), and wherein the subject is an infant, a young child or a child, preferably wherein the infant is at least 5 months old.

13. The use according to any one of claims 9, 10 or 12, wherein the nutritional composition is an infant formula, a starter infant formula, a follow-on or follow-up infant formula, a baby food, an infant cereal composition, a growing-up milk, a fortifier or a supplement.

14. A method of improving brain development and / or social-emotional development in a subject, the method comprising administering a fucosylated HMO to the subject, wherein the fucosylated HMO is 3-fucosyllactose (3-FL), and wherein the subject is an infant, a young child or a child, preferably wherein the infant is at least 5 months old.

15. A method of improving brain development and / or social-emotional development in a subject, the method comprising administering a nutritional composition comprising a fucosylated HMO to the subject, wherein the fucosylated HMO is 3-fucosyllactose (3-FL), and wherein the subject is an infant, a young child or a child, preferably wherein the infant is at least 5 months old.

16. A method of promoting the default mode network (DMN) in a subject, the method comprising administering a fucosylated HMO to the subject, wherein the fucosylated HMO is3-fucosyllactose (3-FL), and wherein the subject is an infant, a young child or a child, preferably wherein the infant is at least 5 months old.

17. A method of promoting the default mode network (DMN) in a subject, the method comprising administering a nutritional composition comprising a fucosylated HMO to the subject, wherein the fucosylated HMO is 3-fucosyllactose (3-FL), and wherein the subject is an infant, a young child or a child, preferably wherein the infant is at least 5 months old.

18. The method according to claim 14 or claim 15, wherein the improvement in brain development and / or social-emotional development in the subject comprises or consists of an improvement in the development of brain network(s) associated with social-emotional functions, preferably wherein improving brain development and / or social-emotional development in the subject comprises or consists of promoting the default mode network (DMN).

19. The method according to any one of claims 15, 17 or 18, wherein the nutritional composition is an infant formula, a starter infant formula, a follow-on or follow-up infant formula, a baby food, an infant cereal composition, a growing-up milk, a fortifier or a supplement.

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