Medicaments, compositions and methods for supporting behavioral development

Abstract

The present invention relates to one or more human milk oligosaccharides (HMOs) for use in supporting behavioral development in a subject, wherein the one or more HMOs comprise or consist of: (a) lactose-N-difucohexaose I (LNDFHI); and / or (b) 2 '-fucosyllactose (2' FL), 3-fucosyllactose (3FL), lactose difucotetraose (LDFT), lactose-N-fucopentasaccharide II (LNFPII), lactose-N-fucopentasaccharide I (LNFP-I), lactose-N-fucopentasaccharide III (LNFP-III), lactose-N-difucohexaose I (LND-I), monofucosyl-lactose-N-hexaose III (MFLNH-III), lactose-N-fucopentasaccharide V (LNFP-V), lactose-N-neodifucohexaose (LNnDFH) and lactose-N-fucopentasaccharide VI (LNFP-VI), and a method for preparing the same.

Description

Technical Field

[0001] The present invention relates to agents, compositions and methods for supporting behavioral development. The present invention also relates to agents, compositions and methods for improving social-emotional skills, reducing negative emotions and preventing anxiety disorders and / or mood disorders. Background Art

[0002] Social-emotional skills develop during infancy and throughout childhood and include behaviors that represent a child's emotional growth and their ability to successfully interact with others. Social-emotional development encompasses the development of emotional skills and abilities, including emotions. Emotional development can refer to the ability to effectively regulate emotions to achieve one's goals.

[0003] It is believed that lack of social-emotional skills can lead to adverse consequences in children's behavioral development, which can lead to aggressive or destructive behavior, loneliness, anxiety and depression. Many anxiety disorders develop in early childhood (see, for example, Clark C. et al., 2007. Arch Gen Psychatry.) 64 (6), pp. 668-678 and Mian N. et al., 2012. J. Anxiety Disord.) 26 (1), pp. 102-110).

[0004] Although studies have shown associations between single compounds found in human breast milk and behavioral development, the relationship between nutrition during early life and its effects on the behavioral development of infants, toddlers and / or young children remains unclear (see, e.g., Wachs, TD, 2000. International Journal of Behavioral Development, 24(4), pp. 435-441).

[0005] Therefore, there is a need for new nutritional interventions to promote behavioral development and / or improve social-emotional skills, for example, in infants, toddlers, or young children. Such benefits need to be achieved in a manner that does not cause side effects and / or in a manner that is easy to implement and widely accepted by parents or health care providers. There is also a need to deliver such benefits in a manner that keeps such delivery affordable and accessible to most people. Summary of the Invention

[0006] The present inventors have surprisingly found that specific human milk oligosaccharides (HMOs) are associated with reduced negative emotions in infants fed human milk.The HMOs identified by the inventors have not previously been reported to be associated with socio-emotional outcomes.

[0007] Reductions in negative emotions may be beneficial for behavioral development, as infancy is a critical period for socio-emotional milestones such as experiencing fear, developing separation anxiety from primary care providers, visually recognizing familiar people, and letting parents know when they are happy and upset.

[0008] In one aspect, the present invention provides one or more human milk oligosaccharides (HMOs) for use in supporting behavioral development in a subject.

[0009] In one aspect, the present invention provides one or more human milk oligosaccharides (HMOs) for use in supporting behavioral development in a subject, wherein the one or more HMOs comprise or consist of: (a) lactose-N-difucohexaose I (LNDFHI); and / or (b) 2'-fucosyllactose (2'FL), 3-fucosyllactose (3FL), lactose difucotetraose (LDFT) and lactose-N-fucopentaose II (LNFPII), LNFP-I (lactose-N-fucopentaose I (LNFP-I), lactose-N-fucopentaose III (LNFP-III), lactose-N-difucohexaose I (LND-I), monofucosyl-lactose-N-hexaose III (MFLNH-III), lactose-N-fucopentaose V (LNFP-V), lactose-N-neodifucohexaose (LNnDFH) and lactose-N-fucopentaose VI (LNFP-VI).

[0010] In another aspect, the present invention provides the use of one or more human milk oligosaccharides (HMOs) for supporting behavioral development in a subject.

[0011] In another aspect, the present invention provides a method for supporting behavioral development in a subject, the method comprising administering one or more human milk oligosaccharides (HMOs) to the subject.

[0012] In another aspect, the present invention provides the use of one or more HMOs for improving social-emotional skills, wherein the one or more HMOs comprise or consist of: (a) lactose-N-difucohexaose I (LNDFHI); and / or (b) 2'-fucosyllactose (2'FL), 3-fucosyllactose (3FL), lactose difucotetraose (LDFT), lactose-N-fucopentaose II (LNFPII), lactose-N-fucopentaose I (LNFP-I), lactose-N-fucopentaose III (LNFP-III), lactose-N-difucohexaose I (LND-I), monofucosyl-lactose-N-hexaose III (MFLNH-III), lactose-N-fucopentaose V (LNFP-V), lactose-N-neodifucohexaose (LNnDFH) and lactose-N-fucopentaose VI (LNFP-VI).

[0013] In another aspect, the present invention provides the use of one or more HMOs for reducing negative emotions, wherein the one or more HMOs comprise or consist of: (a) lactose-N-difucohexaose I (LNDFHI); and / or (b) 2'-fucosyllactose (2'FL), 3-fucosyllactose (3FL), lactose difucotetraose (LDFT), lactose-N-fucopentaose II (LNFPII), lactose-N-fucopentaose I (LNFP-I), lactose-N-fucopentaose III (LNFP-III), lactose-N-difucohexaose I (LND-I), monofucosyl-lactose-N-hexaose III (MFLNH-III), lactose-N-fucopentaose V (LNFP-V), lactose-N-neodifucohexaose (LNnDFH) and lactose-N-fucopentaose VI (LNFP-VI).

[0014] Any suitable HMO described herein may be used. Suitably, the one or more HMOs comprise or consist of a combination of fucosylated HMOs. Suitably, the one or more HMOs comprise or consist of: (a) lactose-N-difucohexaose I (LNDFHI); and / or (b) 2'-fucosyllactose (2'FL), 3-fucosyllactose (3FL), lactose difucotetraose (LDFT), lactose-N-fucopentaose II (LNFPII), lactose-N-fucopentaose I (LNFP-I), lactose-N-fucopentaose III (LNFP-III), lactose-N-difucohexaose I (LND-I), monofucosyl-lactose-N-hexaose III (MFLNH-III), lactose-N-fucopentaose V (LNFP-V), lactose-N-neodifucohexaose (LNnDFH) and lactose-N-fucopentaose VI (LNFP-VI). In some embodiments, the one or more HMOs comprise or consist of LNDFHI. In some embodiments, the one or more HMOs comprise or consist of 2'FL, 3FL, LDFT, LNFPII, LNFP-I, LNFP-III, LND-I, MFLNH-III, LNFP-V, LNnDFH, and LNFP-VI.

[0015] The one or more HMOs may be administered by any suitable means and in any suitable amount. Suitably, the one or more HMOs are administered orally. Suitably, the one or more HMOs are administered individually, simultaneously, or sequentially. In a preferred embodiment, the one or more HMOs are administered simultaneously. Suitably, the one or more HMOs are administered to the subject in a total amount of about 0.5 g / day to about 10 g / day. Suitably, the combination of fucosylated HMOs is administered to the subject in a total amount of about 0.5 g / day to about 10 g / day. Suitably, LNDFHI is administered to the subject in an amount of about 0.1 g / day to about 5 g / day. Suitably, 2'FL is administered to the subject in an amount of about 0.1 g / day to about 5 g / day; 3FL is administered to the subject in an amount of about 0.1 g / day to about 5 g / day; LDFT is administered to the subject in an amount of about 0.1 g / day to about 5 g / day; and LNFPII is administered to the subject in an amount of about 0.1 g / day to about 5 g / day. LNFP-I is administered to the subject in an amount of about 0.1 g / day to about 5 g / day; LNFP-III is administered to the subject in an amount of about 0.1 g / day to about 5 g / day; LND-I is administered to the subject in an amount of about 0.1 g / day to about 5 g / day; MFLNH-III is administered to the subject in an amount of about 0.1 g / day to about 5 g / day; LNFP-V is administered to the subject in an amount of about 0.1 g / day to about 5 g / day; LNnDFH is administered to the subject in an amount of about 0.1 g / day to about 5 g / day; and / or LNFP-VI is administered to the subject in an amount of about 0.1 g / day to about 5 g / day.

[0016] The one or more HMOs may be provided in any suitable form. Suitably, the one or more HMOs are in the form of a nutritional composition. In some embodiments, the nutritional composition is an infant formula, a follow-on formula, or a growing-up milk. In a preferred embodiment, the nutritional composition is an infant formula. Suitably, the follow-on formula, the growing-up formula, and the growing-up milk each contain protein in an amount of about 60 kcal / 100 mL to about 80 kcal / 100 mL, protein in an amount of about 1.5 g / 100 kcal to about 2.5 g / 100 kcal, carbohydrates in an amount of about 8 g / 100 kcal to about 15 g / 100 kcal, and lipids in an amount of about 3 g / 100 kcal to about 8 g / 100 kcal.

[0017] The nutritional composition may comprise one or more HMOs in any suitable amount. Suitably, the nutritional composition comprises one or more HMOs in a total amount of about 0.5 g / L to about 10 g / L. Suitably, the nutritional composition comprises a combination of fucosylated HMOs in a total amount of about 0.5 g / L to about 10 g / L. Suitably, the nutritional composition comprises LNDFHI in an amount of about 0.2 g / L to about 2.0 g / L. Suitably, the nutritional composition comprises 2'FL in an amount of about 0.5 g / L to about 3.0 g / L; 3FL in an amount of about 0.2 g / L to about 2.0 g / L; LDFT in an amount of about 0.05 g / L to about 0.5 g / L; LNFPII in an amount of about 0.05 g / L to about 0.5 g / L; LNFP-I in an amount of about 0.2 g / L to about 2.0 g / L; LNFP-III in an amount of about 0.2 g / L to about 2.0 g / L; LND-I in an amount of about 0.2 g / L to about 2.0 g / L; MFLNH-III in an amount of about 0.2 g / L to about 2.0 g / L; LNFP-V in an amount of about 0.2 g / L to about 2.0 g / L; LNnDFH in an amount of about 0.2 g / L to about 2.0 g / L; and / or LNFP-VI in an amount of about 0.2 g / L to about 2.0 g / L.

[0018] The subject can be any suitable subject. The subject can be a human subject. In some embodiments, the subject is an infant, a toddler, or a young child. In preferred embodiments, the subject is an infant. In some embodiments, the subject is about 12 months or younger, about 11 months or younger, about 10 months or younger, or about 9 months or younger.

[0019] One or more HMOs can improve the subject's social-emotional skills. One or more HMOs can reduce the subject's negative affect. The subject's negative affect can be determined using the Infant Behavior Questionnaire (IBQ), such as the IBQ-Revised (IBQ-R). BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 – Association between LNDFHI in breast milk at 2 months and reduced negative affectivity in infants at 9 months

[0021] A regression model approach was used to determine the association between LNDFHI in breast milk and negative affectivity constructed from several Infant Behavior Questionnaire-Revised (IBQR) scales, N = 195, p = 0.0079.

[0022] Figure 2 – Association of 2'FL, 3FL, LDFT, and LNFP II in breast milk at 2 months with reduced negative affect at 9 months Alliance

[0023] A regression model approach was used to determine the association between 2'-fucosyllactose (2'FL), 3-fucosyllactose (3FL), lactodifucotetraose (LDFT), and lacto-N-fucopentaose II (LNFP II) in breast milk and negative affectivity constructed from several Infant Behavior Questionnaire-Revised (IBQR) scales, N = 195, p = 0.026.

[0024] Figure 3 – Association of 3FL in breast milk with (A) gross motor skills and (B) visual perception

[0025] Scatter plot of the Mullen Scales of Early Learning (MSEL) subscale scores for gross motor (A) or visual perception (B) and breast milk 3FL levels. A linear mixed model approach was used, and there was a significant association between 3FL in breast milk and infants' gross motor skills and visual perception MSEL subscale scores (N = 170, p = 0.041 and 0.027, respectively). To remove the potential confounding effect of age, the age effect was removed from the HMO using smoothing spline regression before correlation.

[0026] Figure 4A and B – LNDFH-I, 2'FL, 3FL, LDFT, LNFPII, LNFP-I, Associations of LNFP-III, LND-I, MFLNH-III, LNFP-V, LNnDFH, and LNFP-VI with reductions in negative affect at 9 months

[0027] A regression model approach was used to determine the expression of lactose-N-difucohexaose I (LNDFHI), 2'-fucosyllactose (2'FL), 3-fucosyllactose (3FL), lactose-difucotetraose (LDFT), and lactose-N-fucopentaose II (LNFPII), LNFP-I (lactose-N-fucopentaose I (LNFP-I), lactose-N-fucopentaose III (LNFP-III), lactose-N-difucohexaose I (LND-I) in breast milk. , monofucosyl-lactose-N-hexaose III (MFLNH-III), lactose-N-fucopentaose V (LNFP-V), lactose-N-neodifucohexaose (LNnDFH), and lactose-N-fucopentaose VI (LNFP-VI) were associated with negative affect constructed from several Infant Behavior Questionnaire-Revised (IBQR) scales at 2 months (N=195, p=0.0056) and 3 months (N=195, p=0.0037), respectively. DETAILED DESCRIPTION

[0028] The 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 present invention disclosed herein without departing from the scope of the invention disclosed.

[0029] Any reference to prior art documents in this specification cannot be regarded as an admission that such prior art is well-known technology or forms part of the common general knowledge in the field.All publications mentioned in the specification are incorporated herein by reference.

[0030] As used in this specification, the words "include," "comprising," and similar words should not be construed as having an exclusive or exhaustive meaning. In other words, they are intended to mean "including, but not limited to." The term "includes," "comprising," and similar words also encompass the term "consisting of."

[0031] Unless otherwise indicated, the practice of the present invention will employ conventional techniques within the capabilities of those of ordinary skill in the art. Such techniques are described in the literature. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art.

[0032] Numerical ranges are inclusive of the values ​​defining the range, and unless otherwise indicated, all percentages disclosed herein are on a w / w basis. As used herein, the term "about" means approximately, in the vicinity of, roughly, or around. When the term "about" is used in conjunction with a numerical value or range, it modifies that value or range by extending the boundaries above and below the numerical value indicated. Generally speaking, the terms "about" and "approximately" are used herein to modify numerical values ​​above and below the stated value by 10%.

[0033] Human milk oligosaccharides (HMOs)

[0034] The present invention relates to the use of one or more human milk oligosaccharides (HMOs) for promoting behavioral development, improving social-emotional skills, reducing negative affect, and / or preventing anxiety disorders and / or mood disorders. In some embodiments, one or more HMOs are used in a therapeutic method.

[0035] The one or more HMOs may be administered by any suitable route and in any suitable form. Suitably, the one or more HMOs are administered orally and / or enterally. In a preferred embodiment, the one or more HMOs are administered orally. The one or more HMOs may be administered separately, simultaneously, or sequentially. In a preferred embodiment, the one or more HMOs are administered simultaneously.

[0036] Many different types of HMOs are found in human milk and are generally based on combinations of glucose, galactose, sialic acid (N-acetylneuraminic acid), fucose, and / or N-acetylglucosamine with many different linkages between them. Almost all HMOs have a lactose molecule at their reducing end, and the terminal position of the non-reducing end is occupied by sialic acid and / or fucose (if present). HMOs can be acidic (e.g., oligosaccharides containing charged sialic acid) or neutral (e.g., fucosylated oligosaccharides). See, for example, Chen, X., 2015. Advances in carbohydrate chemistry and biochemistry, 72, pp. 113-190.

[0037] HMOs found in human milk include lactose-N-tetraose (LNT), lactose-N-neotetraose (LNnT), 2'-fucosyllactose (2'FL), 3-fucosyllactose (3FL), lactose-difucotetraose (LDFT), lactose-N-difucohexaose I (LNDFHI), lactose-N-fucopentaose I (LNFP-I), lactose-N-fucopentaose II (LNFP-II), lactose-N-fucopentaose III (LNFP-III), trifucosyllactose-N-hexaose (TF-LNH), 3'-sialyllactose (3'SL), 6'-sialyllactose (6'SL), disialylactose-N-tetraose (DSLNT), sialyllactose-N-neotetraose c (LSTc), and fucosyldisialyllactose-N-hexaose I (FDS-LNH-I). See, e.g., B. et al., 2021. Nutrients, 13(8), p. 2737.

[0038] In some embodiments, the one or more HMOs comprise or consist of (a) lactose-N-difucohexaose I (LNDFHI); or (b) 2'-fucosyllactose (2'FL), 3-fucosyllactose (3FL), lactosedifucotetraose (LDFT), lactose-N-fucopentaose II (LNFPII), lactose-N-fucopentaose I (LNFP-I), lactose-N-fucopentaose III (LNFP-III), lactose-N-difucohexaose I (LND-I), monofucosyl-lactose-N-hexaose III (MFLNH-III), lactose-N-fucopentaose V (LNFP-V), lactose-N-neodifucohexaose (LNnDFH), and lactose-N-fucopentaose VI (LNFP-VI).

[0039] One or more HMOs can be administered to a subject in any suitable form and by any suitable route of administration (eg, in any form and by any route described herein) in any suitable amount.

[0040] Suitable doses of HMOs are described, for example, in the following documents: EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA), 2022. EFSA Journal, 20(5), p. e07257; EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA), 2021. EFSA Journal, 19(6), p. e06662; and EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA), 2022. EFSA Journal, 20(3), p. e07140.

[0041] Suitably, the one or more HMOs are administered to the subject in a total amount of at least about 0.5 g / day, at least about 1 g / day, or at least about 2 g / day. Suitably, the one or more HMOs are administered to the subject in an amount of about 10 g / day or less, about 8 g / day or less, or about 5 g / day or less. Suitably, the one or more HMOs are administered to the subject in an amount of about 0.5 g / day to about 10 g / day, about 1 g / day to about 8 g / day, or about 2 g / day to about 5 g / day.

[0042] HMOs can be obtained by any suitable method. Suitable methods for synthesizing HMOs are well known to those skilled in the art. For example, methods have been developed for preparing oligosaccharides by microbial fermentation, enzymatic methods, chemical synthesis, or a combination of these techniques (see, for example, Zeuner et al., 2019. Molecules, 24(11), p. 2033).

[0043] Fucosylated HMO

[0044] In some embodiments, the one or more HMOs comprise or consist of a combination of fucosylated HMOs. In some embodiments, the one or more HMOs consist of fucosylated HMOs. In some embodiments, the one or more HMOs are fucosylated HMOs.

[0045] As used herein, a fucosylated HMO may refer to a neutral HMO containing one or more fucoses. Fucosylated HMOs may be monofucosylated, difucosylated, or trifucosylated, and preferably do not contain sialic acid. Non-limiting examples of fucosylated HMOs include: 2'-fucosyllactose (2'FL); 3-fucosyllactose (3FL); lactose difucotetraose (LDFT); lactose-N-fucopentaose, such as lactose-N-fucopentaose I (LNFP-I), lactose-N-fucopentaose II (LNFP-II), lactose-N-fucopentaose III (LNFP-III), or lactose-N-fucopentaose V (LNFP-V); lactose-N-fucohexaose, such as lactose-N-fucopentaose I (LNFP-I), lactose-N-fucopentaose II (LNFP-II), lactose-N-fucopentaose III (LNFP-III), or lactose-N-fucopentaose V (LNFP-V); lactose-N-fucohexaose, such as lactose-N-fucopentaose I (LNFP-I), lactose-N-fucopentaose II (LNFP-II), lactose-N-fucopentaose III (LNFP-III), or lactose-N-fucopentaose V (LNFP-V). Such as lactose-N-difucohexaose I (LNDFH-I) and lactose-N-difucohexaose II (LNDFH-II); lactose-N-neofucopentaose V (LNnFP-V); lactose-N-neodifucosylhexaose (LNnDFH), such as lactose-N-neodifucosylhexaose II (LNnDFH-II); fucosyllactose-N-hexaose (FLNH), such as fucosyllactose-N-hexaose I (FLNH-I) and fucosyllactose-N-hexaose Saccharide II (FLNH-II); fucosyllactose-N-neohexaose (F-LNnH), such as fucosyllactose-N-neohexaose I (F-LNnH-I) and fucosyllactose-N-neohexaose II (F-LNnH-II); monofucosyllactose-N-hexaose-III (MFNLH-III); difucosyllactose-N-hexaose (DF-LNH); difucosyllactose-N-neohexaose (DF-LNnH), such as difucosyllactose- N-neohexaose I (DF-LNnH-I) and difucosyllactose-N-neohexaose II (DF-LNnH-II); difucosyllactose-N-hexaose-a (DFLNHa); trifucosyllactose-N-hexaose (TF-LNH); fucosyl-p-lactose-N-hexaose (F-pLNH); difucosyl-p-lactose-N-hexaose (DF-pLNH); trifucosyl-p-lactose-N-hexaose (TF-pLNH); and combinations thereof. See, for example, Chen, X., 2015. Advances in carbohydrate chemistry and biochemistry, 72, pp. 113-190.

[0046] In some embodiments, the combination of fucosylated HMOs comprises or consists of lacto-N-difucohexaose I (LNDFHI), 2'-fucosyllactose (2'FL), 3-fucosyllactose (3FL), lactodifucotetraose (LDFT) and / or lacto-N-fucopentaose II (LNFPII). In some embodiments, the combination of fucosylated HMOs comprises or consists of lacto-N-difucohexaose I (LNDFHI), 2'-fucosyllactose (2'FL), 3-fucosyllactose (3FL), lactodifucotetraose (LDFT), lacto-N-fucopentaose II (LNFPII), lacto-N-fucopentaose I (LNFP-I), lacto-N-fucopentaose III (LNFP-III), lacto-N-difucohexaose I (LND-I), monofucosyl-lacto-N-hexaose III (MFLNH-III), lacto-N-fucopentaose V (LNFP-V), lacto-N-neodifucohexaose (LNnDFH), and lacto-N-fucopentaose VI (LNFP-VI).

[0047] In some embodiments, the combination of fucosylated HMOs comprises or consists of 2'-fucosyllactose (2'FL), 3-fucosyllactose (3FL), lactodifucotetraose (LDFT), lacto-N-fucopentaose II (LNFPII), lacto-N-fucopentaose I (LNFP-I), lacto-N-fucopentaose III (LNFP-III), lacto-N-difucohexaose I (LND-I), monofucosyl-lactose-N-hexaose III (MFLNH-III), lacto-N-fucopentaose V (LNFP-V), lacto-N-neodifucohexaose (LNnDFH) and / or lacto-N-fucopentaose VI (LNFP-VI). In some embodiments, the combination of fucosylated HMOs comprises or consists of 2'-fucosyllactose (2'FL), 3-fucosyllactose (3FL), lactodifucotetraose (LDFT), lacto-N-fucopentaose II (LNFPII), lacto-N-fucopentaose I (LNFP-I), lacto-N-fucopentaose III (LNFP-III), lacto-N-difucohexaose I (LND-I), monofucosyl-lactose-N-hexaose III (MFLNH-III), lacto-N-fucopentaose V (LNFP-V), lacto-N-neodifucohexaose (LNnDFH), and lacto-N-fucopentaose VI (LNFP-VI).

[0048] Suitably, the combination of fucosylated HMOs is administered to a subject in a total amount of at least about 0.5 g / day, at least about 1 g / day, or at least about 2 g / day. Suitably, the combination of fucosylated HMOs is administered to a subject in an amount of about 10 g / day or less, about 8 g / day or less, or about 5 g / day or less. Suitably, the combination of fucosylated HMOs is administered to a subject in an amount of about 0.5 g / day to about 10 g / day, about 1 g / day to about 8 g / day, or about 2 g / day to about 5 g / day.

[0049] Lactose-N-difucohexaose I (LNDFHI)

[0050] In some embodiments, the one or more HMOs comprise or consist of lactose-N-difucohexaose 1 (LNDFHI). In some embodiments, the one or more HMOs consist of LNDFHI. In some embodiments, the one or more HMOs are LNDFHI.

[0051] Lactose-N-difucohexaose I (LNDFHI) is also known as LNDFH-I or LNDI and is a difucosylated, non-sialylated Galβ1-3GlcNAc core human milk oligosaccharide that may have the following structure:

[0052]

[0053] in: is fucose (Fuc), ○ is galactose, ● is glucose, and ■ is N-acetylglucosamine (GlcNAc)

[0054] Suitably, LNDFHI is administered to a subject in an amount of at least about 0.1 g / day, at least about 0.15 g / day, at least about 0.2 g / day, or at least about 0.5 g / day. Suitably, LNDFHI is administered to a subject in an amount of about 5 g / day or less, about 4 g / day or less, about 3 g / day or less, about 2 g / day or less, or about 1 g / day or less. Suitably, LNDFHI is administered to a subject in an amount of about 0.1 g / day to about 5 g / day, about 0.15 g / day to about 4 g / day, about 0.2 g / day to about 3 g / day, or about 0.5 g / day to about 2 g / day.

[0055] 2'-fucosyllactose (2'FL), 3-fucosyllactose (3FL), lactose difucotetraose (LDFT), lactose- N-fucopentaose II (LNFPII), lactose-N-fucopentaose I (LNFP-I), lactose-N-fucopentaose III (LNFP-III), lactose LND-I, Lactose-N-difucohexaose III (MFLNH-III), Lactose-N-fucopentaose V (LNFP-V), lactose-N-neodifucohexaose (LNnDFH), and lactose-N-fucopentaose VI (LNFP-VI)

[0056] In some embodiments, the one or more HMOs comprise or consist of 2'-fucosyllactose (2'FL), 3-fucosyllactose (3FL), lactodifucotetraose (LDFT), lacto-N-fucopentaose II (LNFPII), lacto-N-fucopentaose I (LNFP-I), lacto-N-fucopentaose III (LNFP-III), lacto-N-difucohexaose I (LND-I), monofucosyl-lactose-N-hexaose III (MFLNH-III), lacto-N-fucopentaose V (LNFP-V), lacto-N-neodifucohexaose (LNnDFH), and lacto-N-fucopentaose VI (LNFP-VI). In some embodiments, the one or more HMOs consist of 2'FL, 3FL, LDFT, LNFPII, lacto-N-fucopentaose I (LNFP-I), lacto-N-fucopentaose III (LNFP-III), lacto-N-difucohexaose I (LND-I), monofucosyl-lacto-N-hexaose III (MFLNH-III), lacto-N-fucopentaose V (LNFP-V), lacto-N-neodifucohexaose (LNnDFH), and lacto-N-fucopentaose VI (LNFP-VI). In some embodiments, the one or more HMOs are 2'FL, 3FL, LDFT, LNFPII, lacto-N-fucopentaose I (LNFP-I), lacto-N-fucopentaose III (LNFP-III), lacto-N-difucohexaose I (LND-I), monofucosyl-lacto-N-hexaose III (MFLNH-III), lacto-N-fucopentaose V (LNFP-V), lacto-N-neodifucohexaose (LNnDFH), and lacto-N-fucopentaose VI (LNFP-VI).

[0057] 2'-Fucosyllactose (2'-FL) is a fucosylated neutral trisaccharide composed of L-fucose, D-galactose, and D-glucose units. It is the most prevalent HMO naturally present in human breast milk, accounting for approximately 30% of all HMOs, and can have the following structure:

[0058]

[0059] in: is fucose (Fuc), ○ is galactose, and ● is glucose.

[0060] 3-Fucosyllactose (3-FL) is a fucosylated neutral trisaccharide composed of L-fucose, D-galactose, and D-glucose units and can have the following structure:

[0061]

[0062] in: is fucose (Fuc), ○ is galactose, and ● is glucose.

[0063] Lactose difucotetraose (LDFT) is also known as difucosyllactose (diFL or DFL) and can have the following structure:

[0064]

[0065] in: is fucose (Fuc), ○ is galactose, and ● is glucose.

[0066] Lactose-N-fucopentaose II (LNFPII) is a fucosylated, non-sialylated Galβ1-3GlcNAc core (type 1 core) human milk oligosaccharide and may have the following structure:

[0067]

[0068] in: is fucose (Fuc), ○ is galactose, ● is glucose, and ■ is N-acetylglucosamine (GlcNAc)

[0069] The combination of 2'FL, 3FL, LDFT, LNFPII, LNFP-I, LNFP-III, LND-I, MFLNH-III, LNFP-V, LNnDFH and LNFP-VI can be administered separately, simultaneously or sequentially. In a preferred embodiment, the combination of 2'FL, 3FL, LDFT, LNFPII, LNFP-I, LNFP-III, LND-I, MFLNH-III, LNFP-V, LNnDFH and LNFP-VI is administered simultaneously.

[0070] Suitably, 2'FL, 3FL, LDFT, LNFPII, LNFP-I, LNFP-III, LND-I, MFLNH-III, LNFP-V, LNnDFH and LNFP-VI are administered to the subject in a total amount of at least about 0.5 g / day, at least about 1 g / day or at least about 2 g / day. Suitably, 2'FL, 3FL, LDFT, LNFPII, LNFP-I, LNFP-III, LND-I, MFLNH-III, LNFP-V, LNnDFH and LNFP-VI are administered to the subject in a total amount of about 10 g / day or less, about 8 g / day or less or about 5 g / day or less. Suitably, 2'FL, 3FL, LDFT, LNFPII, LNFP-I, LNFP-III, LND-I, MFLNH-III, LNFP-V, LNnDFH and LNFP-VI are administered to the subject in a total amount of about 0.5 g / day to about 10 g / day, about 1 g / day to about 8 g / day, or about 2 g / day to about 5 g / day.

[0071] Suitably, 2'FL is administered to a subject in an amount of at least about 0.1 g / day, at least about 0.2 g / day, at least about 0.3 g / day, at least about 0.4 g / day, at least about 0.5 g / day, at least about 0.8 g / day, or at least about 1 g / day. Suitably, 2'FL is administered to a subject in an amount of about 5 g / day or less, about 4 g / day or less, or about 3 g / day or less. Suitably, 2'FL is administered to a subject in an amount of about 0.1 g / day to about 5 g / day, about 0.5 g / day to about 5 g / day, about 0.8 g / day to about 4 g / day, or about 1 g / day to about 3 g / day.

[0072] Suitably, 3FL is administered to a subject in an amount of at least about 0.1 g / day, at least about 0.15 g / day, at least about 0.2 g / day, or at least about 0.5 g / day. Suitably, 3FL is administered to a subject in an amount of about 5 g / day or less, about 4 g / day or less, about 3 g / day or less, about 2 g / day or less, or about 1 g / day or less. Suitably, 3FL is administered to a subject in an amount of about 0.1 g / day to about 5 g / day, about 0.15 g / day to about 4 g / day, about 0.2 g / day to about 3 g / day, or about 0.5 g / day to about 2 g / day.

[0073] Suitably, LDFT is administered to a subject in an amount of at least about 0.1 g / day, at least about 0.15 g / day, or at least about 0.2 g / day. Suitably, LDFT is administered to a subject in an amount of about 5 g / day or less, about 1 g / day or less, about 0.8 g / day or less, or about 0.6 g / day or less. Suitably, LDFT is administered to a subject in an amount of about 0.1 g / day to about 5 g / day, about 0.1 g / day to about 1 g / day, about 0.15 g / day to about 0.8 g / day, or about 0.2 g / day to about 0.6 g / day.

[0074] Suitably, LNFPII is administered to a subject in an amount of at least about 0.1 g / day, at least about 0.15 g / day, or at least about 0.2 g / day. Suitably, LNFPII is administered to a subject in an amount of about 5 g / day or less, about 1 g / day or less, about 0.8 g / day or less, or about 0.6 g / day or less. Suitably, LNFPII is administered to a subject in an amount of about 0.1 g / day to about 5 g / day, about 0.1 g / day to about 1 g / day, about 0.15 g / day to about 0.8 g / day, or about 0.2 g / day to about 0.6 g / day.

[0075] Suitably, LNFP-I is administered to a subject in an amount of at least about 0.1 g / day, at least about 0.15 g / day, or at least about 0.2 g / day. Suitably, LNFP-I is administered to a subject in an amount of about 5 g / day or less, about 1 g / day or less, about 0.8 g / day or less, or about 0.6 g / day or less. Suitably, LNFP-I is administered to a subject in an amount of about 0.1 g / day to about 5 g / day, about 0.1 g / day to about 1 g / day, about 0.15 g / day to about 0.8 g / day, or about 0.2 g / day to about 0.6 g / day.

[0076] Suitably, LNFP-III is administered to a subject in an amount of at least about 0.1 g / day, at least about 0.15 g / day, or at least about 0.2 g / day. Suitably, LNFP-III is administered to a subject in an amount of about 5 g / day or less, about 1 g / day or less, about 0.8 g / day or less, or about 0.6 g / day or less. Suitably, LNFP-III is administered to a subject in an amount of about 0.1 g / day to about 5 g / day, about 0.1 g / day to about 1 g / day, about 0.15 g / day to about 0.8 g / day, or about 0.2 g / day to about 0.6 g / day.

[0077] Suitably, LND-I is administered to a subject in an amount of at least about 0.1 g / day, at least about 0.15 g / day, or at least about 0.2 g / day. Suitably, LND-I is administered to a subject in an amount of about 5 g / day or less, about 1 g / day or less, about 0.8 g / day or less, or about 0.6 g / day or less. Suitably, LND-I is administered to a subject in an amount of about 0.1 g / day to about 5 g / day, about 0.1 g / day to about 1 g / day, about 0.15 g / day to about 0.8 g / day, or about 0.2 g / day to about 0.6 g / day.

[0078] Suitably, MFLNH-III is administered to a subject in an amount of at least about 0.1 g / day, at least about 0.15 g / day, or at least about 0.2 g / day. Suitably, MFLNH-III is administered to a subject in an amount of about 5 g / day or less, about 1 g / day or less, about 0.8 g / day or less, or about 0.6 g / day or less. Suitably, MFLNH-III is administered to a subject in an amount of about 0.1 g / day to about 5 g / day, about 0.1 g / day to about 1 g / day, about 0.15 g / day to about 0.8 g / day, or about 0.2 g / day to about 0.6 g / day.

[0079] Suitably, LNFP-V is administered to a subject in an amount of at least about 0.1 g / day, at least about 0.15 g / day, or at least about 0.2 g / day. Suitably, LNFP-V is administered to a subject in an amount of about 5 g / day or less, about 1 g / day or less, about 0.8 g / day or less, or about 0.6 g / day or less. Suitably, LNFP-V is administered to a subject in an amount of about 0.1 g / day to about 5 g / day, about 0.1 g / day to about 1 g / day, about 0.15 g / day to about 0.8 g / day, or about 0.2 g / day to about 0.6 g / day.

[0080] Suitably, LNnDFH is administered to a subject in an amount of at least about 0.1 g / day, at least about 0.15 g / day, or at least about 0.2 g / day. Suitably, LNnDFH is administered to a subject in an amount of about 5 g / day or less, about 1 g / day or less, about 0.8 g / day or less, or about 0.6 g / day or less. Suitably, LNnDFH is administered to a subject in an amount of about 0.1 g / day to about 5 g / day, about 0.1 g / day to about 1 g / day, about 0.15 g / day to about 0.8 g / day, or about 0.2 g / day to about 0.6 g / day.

[0081] Suitably, LNFP-VI is administered to a subject in an amount of at least about 0.1 g / day, at least about 0.15 g / day, or at least about 0.2 g / day. Suitably, LNFP-VI is administered to a subject in an amount of about 5 g / day or less, about 1 g / day or less, about 0.8 g / day or less, or about 0.6 g / day or less. Suitably, LNFP-VI is administered to a subject in an amount of about 0.1 g / day to about 5 g / day, about 0.1 g / day to about 1 g / day, about 0.15 g / day to about 0.8 g / day, or about 0.2 g / day to about 0.6 g / day.

[0082] Nutritional composition

[0083] Suitably, the one or more HMOs are in the form of a composition.The composition may comprise any effective amount of the one or more HMOs.

[0084] In one aspect, the present invention provides compositions (e.g., nutritional compositions, such as infant formula, follow-on formula, or growing-up milk) comprising one or more human milk oligosaccharides (HMOs) for supporting behavioral development, improving social-emotional skills, reducing negative affect, and / or preventing anxiety disorders and / or mood disorders.

[0085] In another aspect, the present invention provides the use of one or more human milk oligosaccharides (HMOs) for the manufacture of a composition (e.g., a nutritional composition such as an infant formula, follow-on formula, or a growing-up milk) for supporting behavioral development, improving social-emotional skills, reducing negative affect, and / or preventing anxiety disorders and / or mood disorders.

[0086] In another aspect, the present invention provides methods for supporting behavioral development, improving social-emotional skills, reducing negative affect, and / or preventing anxiety disorders and / or mood disorders, wherein the method comprises administering a composition (e.g., a nutritional composition such as an infant formula, follow-on formula, or growing-up milk) comprising one or more human milk oligosaccharides (HMOs).

[0087] The composition can be any type of composition into which one or more HMOs can be incorporated, such as a composition in the form of a food or beverage product, a nutritional supplement, or a pharmaceutical composition. The composition can be in solid (e.g., powder), liquid, or semi-liquid form. The one or more HMOs can be in the form of a food composition, a beverage, a nutritional formula, a nutritional supplement, a nutraceutical, or a pharmaceutical composition.

[0088] For the purpose of providing nutrition and / or pleasure, food and beverage products include all products that are intended to be consumed orally by humans. For example, a composition can be a food or beverage product, such as a food or beverage product for an infant, toddler, and / or young child. Examples of food and beverage products include dairy products, such as dairy products or yogurt, soups, sauces, sweet and salty snacks, powdered beverages, and cereal products.

[0089] In some embodiments, the one or more HMOs are in the form of a nutritional composition, a medical food product for clinical nutrition, or a supplement.

[0090] In some embodiments, the one or more HMOs are in the form of a nutritional composition. As used herein, "nutritional composition" may refer to a composition that provides nutrients to a subject. Such nutritional compositions are typically administered orally or intravenously and typically include a lipid or fat source and a protein source.

[0091] The nutritional composition may be a synthetic nutritional composition. As used herein, "synthetic nutritional composition" may mean a nutritional composition obtained by chemical and / or biological means, which may be chemically substantially identical to a natural composition.

[0092] In some embodiments, one or more HMOs are in the form of a medical food product for clinical nutrition. As used herein, a "medical food product for clinical nutrition" may also be referred to as a "food for special medical purposes (FSMP)" and refers to a specialized food designed to help meet the nutritional or dietary needs of a subject with a disease, disorder, or medical condition who is temporarily or permanently unable to obtain adequate nutritional intake from normal foods or through modifications to their normal diet.

[0093] In some embodiments, the one or more HMOs are in the form of an infant formula, a follow-on formula, or a growing-up milk.

[0094] In some embodiments, one or more HMOs are in the form of infant formula. As used herein, the term "infant formula" may refer to a food that is intended for specific nutritional use by infants during the first few months of life and that itself meets the nutritional needs of such individuals (e.g., in accordance with Article 2(c) of European Commission Directive 91 / 321 / EEC and 2006 / 141 / EC of 22 December 2006 on infant formula and follow-on formula). It also refers to nutritional compositions intended for infants and as defined in the Codex Alimentarius Commission (Codex STAN 72-1981) and Specialty Infants (including foods for special medical purposes). Infant formula may be a preterm infant formula, a human milk fortifier, a first-stage infant formula, a follow-on formula, a baby food formula, or an infant cereal formula.

[0095] In some embodiments, the one or more HMOs are in the form of a first-stage infant formula.Typically, a "first-stage infant formula" is intended for use as a breast milk substitute for infants from birth.

[0096] In some embodiments, one or more HMOs are in the form of follow-on formula. A "follow-on formula" or "follow-on formula" may be given starting in the sixth month. It may constitute the main liquid element in the gradually diversified diet of such individuals.

[0097] In some embodiments, the one or more HMOs are in the form of a premature infant formula.As used herein, the term "preterm infant formula" refers to an infant formula intended for premature infants.

[0098] In some embodiments, one or more HMOs are in the form of a milk fortifier. As used herein, the term "milk fortifier" refers to a liquid or solid nutritional composition suitable for mixing with breast milk (or, in the case of a human milk fortifier, human milk) or infant formula. It is used to increase the calories, protein, minerals, and vitamins in breast milk fed to premature infants or infants with low birth weight. The term "breast milk" should be understood as a mother's milk or mother's colostrum, or a breastfeeding mother's milk or a breastfeeding mother's colostrum.

[0099] In some embodiments, the one or more HMOs are in the form of an infant food formula.As used herein, the term "infant food formula" refers to a food intended for specific nutritional use by infants or children, such as toddlers, during the first few years of life.

[0100] In some embodiments, one or more HMOs are in the form of a growing-up milk. As used herein, the term "growing-up milk" (or GUM) refers to a dairy formula food product provided after one year of age. It is typically a dairy-based beverage tailored to the specific nutritional needs of young children (e.g., children aged about 1 to about 3 years). Growing-up milks may also be referred to as "toddler formula" or "toddler milk."

[0101] In some embodiments, the one or more HMOs are in the form of an infant cereal composition.As used herein, the term "infant cereal composition" refers to a food that is intended for specific nutritional use by infants or children, such as toddlers, during the first few years of life.

[0102] In some embodiments, the one or more HMOs are in the form of a dairy formula. As used herein, the term "dairy formula" may refer to a food intended for, for example, childhood nutrition, which may provide the sole source or supplemental nutrition for, for example, children aged about 3 years or older. In some embodiments, the dairy formula is a growing-up milk.

[0103] In some embodiments, the composition is in powder form and is reconstituted in an aqueous medium (e.g., water) before administration. In other embodiments, the composition is in liquid form ready for administration (e.g., a ready-to-feed formula).

[0104] In another embodiment, one or more HMOs are in the form of a supplement. As used herein, a "supplement" or "dietary supplement" can be used to supplement a subject's nutrition (it is typically used as such, but it can also be added to any type of composition intended for ingestion by a subject). When the composition is a supplement, it can be provided in unit dosage form. Supplements are typically in the form of liquids, gels, powders, tablets, or capsules. Powder supplements generally encompass supplements to be dissolved in water or milk or sprayed on food or beverages. Such supplements are intended to provide additional nutritional and / or health benefits to the subject consuming them. Supplements can be used to provide nutrients and / or health benefits to humans as well as animals.

[0105] In another embodiment, the one or more HMOs are in the form of a fortifier. The fortifier can be an infant formula fortifier or a growing-up milk fortifier.

[0106] In another embodiment, the one or more HMOs are in the form of a pharmaceutical product. Pharmaceutical products include, for example, drops, syrups, powders, tablets, or capsules intended to treat or prevent an adverse medical condition in a subject in need thereof.

[0107] Human milk oligosaccharides (HMOs)

[0108] One or more HMOs may be present in the composition in any suitable amount.

[0109] For example, in an infant formula, follow-on formula or growing-up milk, one can base the amount of HMOs on the amounts found in human breast milk, particularly produced by a well-nourished mother for an infant or child of the same age (see, e.g. B. et al., 2021. Nutrients, 13(8), p. 2737). In human breast milk, such amounts may fall within the following ranges: LNDFHI: about 0.2 g / L to about 2.0 g / L; 2'FL: about 0.5 g / L to about 3.0 g / L; 3FL: about 0.2 g / L to about 2.0 g / L; LDFT: about 0.1 g / L to about 1.0 g / L; LNFPII: about 0.1 g / L to about 1.0 g / L. However, they may exceed those in human breast milk, depending on, for example, the bioavailability of the HMO from infant formula.

[0110] Suitably, the nutritional composition (e.g., infant formula, follow-on formula, or growing-up milk) comprises one or more HMOs in a total amount of at least about 0.1 g / L, at least about 0.2 g / L, or at least about 0.5 g / L. Suitably, the nutritional composition (e.g., infant formula, follow-on formula, or growing-up milk) comprises one or more HMOs in a total amount of about 10.0 g / L or less, about 8.0 g / L or less, or about 5.0 g / L or less. Suitably, the nutritional composition (e.g., infant formula, follow-on formula, or growing-up milk) comprises one or more HMOs in a total amount of about 0.1 g / L to about 10.0 g / L, about 0.2 g / L to about 8.0 g / L, or about 0.5 g / L to about 5.0 g / L. If the nutritional composition is in powder form, these amounts can be used after reconstitution with a liquid according to the instructions provided.

[0111] Suitably, the nutritional composition (e.g., infant formula, follow-on formula, or growing-up milk) comprises one or more HMOs in a total amount of at least about 0.5 wt %, at least about 1 wt %, or at least about 2 wt % on a dry weight basis. Suitably, the nutritional composition (e.g., infant formula, follow-on formula, or growing-up milk) comprises one or more HMOs in a total amount of about 10 wt % or less, about 8 wt % or less, or about 5 wt % or less on a dry weight basis. Suitably, the nutritional composition (e.g., infant formula, follow-on formula, or growing-up milk) comprises one or more HMOs in a total amount of about 0.5 wt % to about 10 wt %, about 1 wt % to about 8 wt %, or about 2 wt % to about 5 wt % on a dry weight basis.

[0112] Suitably, the nutritional composition (e.g., infant formula, follow-on formula, or growing-up milk) comprises a total amount of at least about 0.1 g / L, at least about 0.2 g / L, or at least about 0.5 g / L of the combination of fucosylated HMOs. Suitably, the nutritional composition (e.g., infant formula, follow-on formula, or growing-up milk) comprises a total amount of about 10.0 g / L or less, about 8.0 g / L or less, or about 5.0 g / L or less of the combination of fucosylated HMOs. Suitably, the nutritional composition (e.g., infant formula, follow-on formula, or growing-up milk) comprises a total amount of about 0.1 g / L to about 10.0 g / L, about 0.2 g / L to about 8.0 g / L, or about 0.5 g / L to about 5.0 g / L of the combination of fucosylated HMOs. If the nutritional composition is in powder form, these amounts can be used after reconstitution with a liquid according to the instructions provided.

[0113] Suitably, the nutritional composition (e.g., infant formula, follow-on formula, or growing-up milk) comprises a total amount of at least about 0.5 wt %, at least about 1 wt %, or at least about 2 wt % of the combination of fucosylated HMOs based on dry weight. Suitably, the nutritional composition (e.g., infant formula, follow-on formula, or growing-up milk) comprises a total amount of about 10 wt % or less, about 8 wt % or less, or about 5 wt % or less of the combination of fucosylated HMOs based on dry weight. Suitably, the nutritional composition (e.g., infant formula, follow-on formula, or growing-up milk) comprises a total amount of about 0.5 wt % to about 10 wt %, about 1 wt % to about 8 wt %, or about 2 wt % to about 5 wt % of the combination of fucosylated HMOs based on dry weight.

[0114] Suitably, the nutritional composition (e.g., infant formula, follow-on formula, or growing-up milk) comprises LNDFHI in an amount of at least about 0.1 g / L, at least about 0.15 g / L, or at least about 0.2 g / L. Suitably, the nutritional composition comprises LNDFHI in an amount of about 3.0 g / L or less, about 2.5 g / L or less, or about 2.0 g / L or less. Suitably, the nutritional composition (e.g., infant formula, follow-on formula, or growing-up milk) comprises LNDFHI in an amount of about 0.1 g / L to about 3.0 g / L, about 0.15 g / L to about 2.5 g / L, or about 0.2 g / L to about 2.0 g / L. If the nutritional composition is in powder form, these amounts can be used after reconstitution with a liquid according to the instructions provided.

[0115] Suitably, the nutritional composition (e.g., infant formula, follow-on formula, or growing-up milk) comprises 2'FL in an amount of at least about 0.1 g / L, at least about 0.2 g / L, or at least about 0.5 g / L. Suitably, the nutritional composition comprises 2'FL in an amount of about 5.0 g / L or less, about 4.0 g / L or less, or about 3.0 g / L or less. Suitably, the nutritional composition (e.g., infant formula, follow-on formula, or growing-up milk) comprises 2'FL in an amount of about 0.1 g / L to about 5.0 g / L, about 0.2 g / L to about 4.0 g / L, or about 0.5 g / L to about 3.0 g / L. If the nutritional composition is in powder form, these amounts can be used after reconstitution with a liquid according to the instructions provided.

[0116] Suitably, the nutritional composition (e.g., infant formula, follow-on formula, or growing-up milk) comprises 3FL in an amount of at least about 0.1 g / L, at least about 0.15 g / L, or at least about 0.2 g / L. Suitably, the nutritional composition comprises 3FL in an amount of about 3.0 g / L or less, about 2.5 g / L or less, or about 2.0 g / L or less. Suitably, the nutritional composition (e.g., infant formula, follow-on formula, or growing-up milk) comprises 3FL in an amount of about 0.1 g / L to about 3.0 g / L, about 0.15 g / L to about 2.5 g / L, or about 0.2 g / L to about 2.0 g / L. If the nutritional composition is in powder form, these amounts can be used after reconstitution with a liquid according to the instructions provided.

[0117] Suitably, the nutritional composition (e.g., infant formula, follow-on formula, or growing-up milk) comprises LDFT in an amount of at least about 0.05 g / L, at least about 0.08 g / L, or at least about 0.1 g / L. Suitably, the nutritional composition comprises LDFT in an amount of about 2.0 g / L or less, about 1.5 g / L or less, or about 1.0 g / L or less. Suitably, the nutritional composition (e.g., infant formula, follow-on formula, or growing-up milk) comprises LDFT in an amount of about 0.05 g / L to about 2.0 g / L, about 0.08 g / L to about 1.5 g / L, or about 0.1 g / L to about 1.0 g / L. If the nutritional composition is in powder form, these amounts can be used after reconstitution with a liquid according to the instructions provided.

[0118] Suitably, the nutritional composition (e.g., infant formula, follow-on formula, or growing-up milk) comprises LNFPII in an amount of at least about 0.05 g / L, at least about 0.08 g / L, or at least about 0.1 g / L. Suitably, the nutritional composition comprises LNFPII in an amount of about 2.0 g / L or less, about 1.5 g / L or less, or about 1.0 g / L or less. Suitably, the nutritional composition (e.g., infant formula, follow-on formula, or growing-up milk) comprises LNFPII in an amount of about 0.05 g / L to about 2.0 g / L, about 0.08 g / L to about 1.5 g / L, or about 0.1 g / L to about 1.0 g / L. If the nutritional composition is in powder form, these amounts can be used after reconstitution with a liquid according to the instructions provided.

[0119] Suitably, the nutritional composition (e.g., infant formula, follow-on formula, or growing-up milk) comprises LNFP-I in an amount of at least about 0.05 g / L, at least about 0.08 g / L, or at least about 0.1 g / L. Suitably, the nutritional composition comprises LNFP-I in an amount of about 2.0 g / L or less, about 1.5 g / L or less, or about 1.0 g / L or less. Suitably, the nutritional composition (e.g., infant formula, follow-on formula, or growing-up milk) comprises LNFP-I in an amount of about 0.05 g / L to about 2.0 g / L, about 0.08 g / L to about 1.5 g / L, or about 0.1 g / L to about 1.0 g / L. If the nutritional composition is in powder form, these amounts can be used after reconstitution with a liquid according to the instructions provided.

[0120] Suitably, nutritional composition (such as infant formula, larger infant formula or growing-up milk) comprises the LNFP-III of the amount of at least about 0.05g / L, at least about 0.08g / L or at least about 0.1g / L. Suitably, nutritional composition comprises the LNFP-III of the amount of about 2.0g / L or less, about 1.5g / L or less or about 1.0g / L or less. Suitably, nutritional composition (such as infant formula, larger infant formula or growing-up milk) comprises the LNFP-III of the amount of about 0.05g / L to about 2.0g / L, about 0.08g / L to about 1.5g / L or about 0.1g / L to about 1.0g / L. If nutritional composition is in powder form, these amounts can be used after reconstitution with liquid according to the instructions provided.

[0121] Suitably, the nutritional composition (e.g., infant formula, follow-on formula, or growing-up milk) comprises LND-I in an amount of at least about 0.05 g / L, at least about 0.08 g / L, or at least about 0.1 g / L. Suitably, the nutritional composition comprises LND-I in an amount of about 2.0 g / L or less, about 1.5 g / L or less, or about 1.0 g / L or less. Suitably, the nutritional composition (e.g., infant formula, follow-on formula, or growing-up milk) comprises LND-I in an amount of about 0.05 g / L to about 2.0 g / L, about 0.08 g / L to about 1.5 g / L, or about 0.1 g / L to about 1.0 g / L. If the nutritional composition is in powder form, these amounts can be used after reconstitution with a liquid according to the instructions provided.

[0122] Suitably, nutritional composition (such as infant formula, larger infant formula or growing-up milk) comprises the MFLNH-III of at least about 0.05g / L, at least about 0.08g / L or at least about 0.1g / L amount. Suitably, nutritional composition comprises the MFLNH-III of about 2.0g / L or still less, about 1.5g / L or still less or about 1.0g / L or still less amount. Suitably, nutritional composition (such as infant formula, larger infant formula or growing-up milk) comprises the MFLNH-III of the amount of about 0.05g / L to about 2.0g / L, about 0.08g / L to about 1.5g / L or about 0.1g / L to about 1.0g / L. If nutritional composition is in powder form, then these amounts can be used after reconstructing with liquid according to provided instructions.

[0123] Suitably, the nutritional composition (e.g., infant formula, follow-on formula, or growing-up milk) comprises LNFP-V in an amount of at least about 0.05 g / L, at least about 0.08 g / L, or at least about 0.1 g / L. Suitably, the nutritional composition comprises LNFP-V in an amount of about 2.0 g / L or less, about 1.5 g / L or less, or about 1.0 g / L or less. Suitably, the nutritional composition (e.g., infant formula, follow-on formula, or growing-up milk) comprises LNFP-V in an amount of about 0.05 g / L to about 2.0 g / L, about 0.08 g / L to about 1.5 g / L, or about 0.1 g / L to about 1.0 g / L. If the nutritional composition is in powder form, these amounts can be used after reconstitution with a liquid according to the instructions provided.

[0124] Suitably, the nutritional composition (e.g., infant formula, larger infant formula, or growing-up milk) comprises at least about 0.05 g / L, at least about 0.08 g / L, or at least about 0.1 g / L of LNnDFH. Suitably, the nutritional composition comprises about 2.0 g / L or less, about 1.5 g / L or less, or about 1.0 g / L or less of LNnDFH. Suitably, the nutritional composition (e.g., infant formula, larger infant formula, or growing-up milk) comprises about 0.05 g / L to about 2.0 g / L, about 0.08 g / L to about 1.5 g / L, or about 0.1 g / L to about 1.0 g / L of LNnDFH. If the nutritional composition is in powder form, these amounts can be used after reconstitution with a liquid according to the instructions provided.

[0125] Suitably, the nutritional composition (e.g., infant formula, larger infant formula, or growing-up milk) comprises LNFP-VI in an amount of at least about 0.05 g / L, at least about 0.08 g / L, or at least about 0.1 g / L. Suitably, the nutritional composition comprises LNFP-VI in an amount of about 2.0 g / L or less, about 1.5 g / L or less, or about 1.0 g / L or less. Suitably, the nutritional composition (e.g., infant formula, larger infant formula, or growing-up milk) comprises LNFP-VI in an amount of about 0.05 g / L to about 2.0 g / L, about 0.08 g / L to about 1.5 g / L, or about 0.1 g / L to about 1.0 g / L. If the nutritional composition is in powder form, these amounts can be used after reconstitution with a liquid according to the instructions provided.

[0126] Other components

[0127] The nutritional composition of the present invention (e.g., infant formula, follow-on formula, or growing-up milk) may contain a protein source, a carbohydrate source, and a lipid source. However, in some embodiments, particularly if the nutritional composition of the present invention is a supplement or fortifier, only lipid (or a lipid source) may be present.

[0128] The nutritional composition of the present invention (e.g., infant formula, follow-on formula, or growing-up milk) may contain from about 50 kcal / 100 mL to about 90 kcal / 100 ml, from about 55 kcal / 100 mL to about 85 kcal / 100 ml, from about 60 kcal / 100 mL to about 80 kcal / 100 ml, from about 65 kcal / 100 mL to about 75 kcal / 100 ml, or from about 65 kcal / 100 mL to about 70 kcal / 100 ml. If the nutritional composition is in powder form, these amounts can be used after reconstitution with a liquid according to the instructions provided.

[0129] The nutritional composition of the present invention (e.g., infant formula, follow-on formula, or growing-up milk) may comprise, on a dry weight basis, from about 100 to about 1000 kcal / 100 g, from about 200 to about 800 kcal / 100 g, or from about 400 to about 600 kcal / 100 g.

[0130] protein

[0131] The nutritional composition according to the present invention (e.g., infant formula, follow-on formula, or growing-up milk) may contain a protein source. The amount of protein may be from about 1 g to about 4 g / 100 kcal, from about 1.5 g to about 3 g / 100 kcal, or from about 1.5 g to about 2.5 g / 100 kcal.

[0132] Protein sources based on, for example, whey, casein, and mixtures thereof can be used, as well as plant-based (e.g., soy-based) protein sources. With respect to the whey protein of interest, the protein source can be based on acid whey or sweet whey, or a mixture thereof, and can contain α-lactalbumin and β-lactoglobulin in any desired proportion. In some embodiments, the protein source is mainly whey (i.e., more than 50% of the protein comes from whey protein, such as more than 60% or more than 70%). The protein can be intact or hydrolyzed, or a mixture of intact and hydrolyzed proteins. The term "intact" means that the main part of the protein is intact, i.e., the molecular structure has not changed, for example, at least 80% of the protein has not changed, such as at least 85% of the protein has not changed, preferably at least 90% of the protein has not changed, even more preferably at least 95% of the protein has not changed, such as at least 98% of the protein has not changed. In a specific embodiment, 100% of the protein has not changed.

[0133] The term "hydrolyzed" means in the context of the present invention that a protein has been hydrolyzed or broken down into its constituent amino acids.

[0134] The protein can be fully hydrolyzed or partially hydrolyzed. If hydrolyzed protein is desired, a hydrolysis process can be performed as needed and as known in the art. For example, a whey protein hydrolyzate can be prepared by enzymatic hydrolysis of the whey fraction in one or more steps. If the whey fraction used as raw material is substantially lactose-free, it is found that the protein undergoes much less lysine blockage during the hydrolysis process. This makes it possible to reduce the degree of lysine blockage 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.

[0135] In a specific embodiment, the protein of the composition is hydrolyzed, fully hydrolyzed or partially hydrolyzed. The degree of hydrolysis (DH) of the protein can be 2 to 20, 8 to 40, or 20 to 60, or 20 to 80, or greater than 10, 20, 40, 60, 80 or 90.

[0136] At least 70%, 80%, 85%, 90%, 95% or 97% of the protein may be hydrolyzed. In a particular embodiment, 100% of the protein is hydrolyzed.

[0137] In a particular embodiment, the protein of the composition is a plant-based protein.

[0138] carbohydrate

[0139] The nutritional composition according to the present invention (e.g., infant formula, follow-on formula, or growing-up milk) may contain a carbohydrate source. The amount of carbohydrate may be from about 5g to about 20g / 100kcal, from about 10g to about 15g / 100kcal, or from about 8g to about 15g / 100kcal.

[0140] Any carbohydrate source conventionally found in nutritional compositions may be used, such as lactose, sucrose (saccharose), maltodextrin, starch and mixtures thereof, but the preferred carbohydrate source is lactose.

[0141] lipids

[0142] The nutritional composition according to the present invention (e.g., infant formula, follow-on formula, or growing-up milk) may contain lipids and essential fatty acids. The amount of lipid may be from about 1 g to about 10 g / 100 kcal, from about 2 g to about 8 g / 100 kcal, or from about 3 g to about 8 g / 100 kcal.

[0143] Non-limiting examples of lipids include palm olein, high oleic sunflower oil, high oleic safflower oil, canola oil, fish oil, coconut oil, milk fat, and combinations thereof. It may be particularly beneficial if the composition includes fat in an amount of about 25 to about 30 g / 100 g of the dry weight of the composition. Non-limiting examples of essential fatty acids include linoleic acid (LA) and α-linolenic acid (ALA). The compositions of the present invention may also contain gangliosides, monosialoganglioside-3 (GM3) and disialoganglioside-3 (GD3), and combinations thereof.

[0144] other

[0145] Nutritional composition of the present invention (such as infant formula, larger infant formula or growing-up milk) can also contain all vitamins and minerals that are considered to be necessary for daily diet and with the necessary amount of nutrition significance.The minimum requirement of some vitamins and minerals has been determined.The example of mineral matter, vitamin and other nutritive substances that are optionally present in the present composition comprises vitamin A, vitamin B1, vitamin B2, vitamin B3, vitamin B6, vitamin B12, vitamin E, vitamin K1, vitamin K2, vitamin C, vitamin D, folic acid, inositol, niacin, biotin, pantothenic acid, choline, calcium, phosphorus, iodine, iron, magnesium, copper, zinc, manganese, chlorine, potassium, sodium, selenium, chromium, molybdenum, taurine and L-carnitine.Mineral matter is usually added in salt form.The existence and amount of specific mineral matter and other vitamins will be different according to target group.

[0146] If necessary, the nutritional composition of the present invention (eg, infant formula, follow-on formula, or growing-up milk) may contain emulsifiers and stabilizers, such as soy, lecithin, citric acid monoglyceride, citric acid diglyceride, and the like.

[0147] Preparation of composition

[0148] The compositions according to the present invention can be prepared by any known or other suitable means. For example, a nutritional composition (e.g., an infant formula, a follow-on formula, or a growing-up milk) can be completed by blending a protein source with a carbohydrate source and a lipid source in appropriate proportions. If an emulsifier is used, it can be included at this stage. Vitamins and minerals can be added at this stage, but can also be added later to avoid thermal degradation. Water (preferably reverse osmosis water or deionized water) can then be added and mixed to form a liquid mixture. The mixing temperature is preferably room temperature, but can be higher. The liquid mixture can then be heat-treated to reduce the bacterial load. The mixture can then be homogenized.

[0149] If it is desired to produce a powdered composition, the homogenized mixture is dried in a suitable drying apparatus, such as a spray dryer or a freeze dryer, and converted into a powder.

[0150] The method for manufacturing formula food is based on the concept that the product must be nutritionally adequate and safe to eat from a microbiological point of view. Therefore, the steps to eliminate or limit microbial growth are crucial for the production method. The processing technology for each specific formula food belongs to the manufacturer, but generally speaking, for powder products, it involves preserving oil-in-water (o / w) emulsions by dehydration, or for ready-to-eat or concentrated liquid products, it involves sterilization. Powdered formula food can be produced by various methods, such as dry mixing of dehydrated ingredients to form a uniform formula food, or hydrating and wet mixing of a mixture of macro-ingredients (such as fat, protein and carbohydrate ingredients), and then evaporating the resulting mixture and spray drying. A combination of the above two methods can be used, wherein a base powder is first prepared by wet mixing and spray drying of all or some macro-ingredients, and then dry mixing of the remaining ingredients (including carbohydrates, minerals and vitamins and other trace nutrients) to obtain the final formula food. Liquid formula food is provided in ready-to-eat form or as a concentrated liquid, the latter of which requires dilution with water, usually 1:1. The manufacturing methods used for these products are similar to those used to make reconstituted milk.

[0151] If it is desired to produce a liquid formula, the homogenised mixture can be filled into suitable containers, preferably under aseptic conditions. However, the liquid composition can also be cooked in the container, and suitable equipment for carrying out such filling and cooking is commercially available.

[0152] Methods used to support behavioral development

[0153] One or more HMOs may be used to promote behavioral development.

[0154] The terms "support," "promote," "enhance," or "improve" are used interchangeably in the context of the present invention. They should be understood to include supporting or assisting an individual's normal development or growth. For example, one or more HMOs can be used to improve behavioral skills.

[0155] As used herein, "behavioral development" may refer to the development of a subject in behavioral skills (including communication, empathy, and conflict resolution). In particular, the term "behavioral development" may refer to the development of social behavior or social cognition, such as empathy and prosocial behavior towards others, becoming able to cooperate with others, and learning from others more effectively (see, for example, Moore, C., Corbit K. 2019. Social cognition in infancy. Encyclopedia on Early Childhood Development). Suitable methods and parameters for determining behavioral development are known to those skilled in the art (see, for example, Johnson, S. and Marlow, N., 2006. Early human development, 82 (3), pp. 173-183).

[0156] As used herein, "supporting behavioral development" can refer to supporting normal behavioral development, for example, during infancy, childhood, and adolescence. Supporting behavioral development can result in normal behavioral skills.

[0157] In one aspect, the present invention provides one or more HMOs for use in supporting behavioral development in a subject. In another aspect, the present invention provides uses of one or more HMOs for supporting behavioral development in a subject. In another aspect, the present invention provides methods for supporting behavioral development in a subject, the method comprising administering to the subject an effective amount of one or more HMOs.

[0158] In one aspect, the present invention provides a combination of fucosylated HMOs for use in supporting behavioral development in a subject. In another aspect, the present invention provides use of a combination of fucosylated HMOs for supporting behavioral development in a subject. In another aspect, the present invention provides a method for supporting behavioral development in a subject, the method comprising administering to the subject an effective amount of a combination of fucosylated HMOs.

[0159] In one aspect, the present invention provides an LNDFHI for use in supporting behavioral development in a subject. In another aspect, the present invention provides a use of an LNDFHI for supporting behavioral development in a subject. In another aspect, the present invention provides a method for supporting behavioral development in a subject, the method comprising administering to the subject an effective amount of an LNDFHI.

[0160] In one aspect, the present invention provides a combination of 2'FL, 3FL, LDFT, LNFPII, LNFP-I, LNFP-III, LND-I, MFLNH-III, LNFP-V, LNnDFH, and LNFP-VI for use in supporting behavioral development in a subject. In another aspect, the present invention provides a combination of 2'FL, 3FL, LDFT, LNFPII, LNFP-I, LNFP-III, LND-I, MFLNH-III, LNFP-V, LNnDFH, and LNFP-VI for use in supporting behavioral development in a subject. In another aspect, the present invention provides a method for supporting behavioral development in a subject, the method comprising administering to the subject an effective amount of a combination of 2'FL, 3FL, LDFT, LNFPII, LNFP-I, LNFP-III, LND-I, MFLNH-III, LNFP-V, LNnDFH, and LNFP-VI.

[0161] Methods for improving social-emotional skills

[0162] One or more HMOs may be used to improve social-emotional skills.

[0163] In one aspect, the present invention provides one or more HMOs for use in improving the social-emotional skills of a subject. In another aspect, the present invention provides the use of one or more HMOs for improving the social-emotional skills of a subject. In another aspect, the present invention provides a method for improving the social-emotional skills of a subject, the method comprising administering to the subject an effective amount of one or more HMOs.

[0164] In one aspect, the present invention provides a combination of fucosylated HMOs for use in improving the social-emotional skills of a subject. In another aspect, the present invention provides the use of a combination of fucosylated HMOs for improving the social-emotional skills of a subject. In another aspect, the present invention provides a method for improving the social-emotional skills of a subject, comprising administering to the subject an effective amount of the combination of fucosylated HMOs.

[0165] In one aspect, the present invention provides LNDFHI for use in improving the social-emotional skills of a subject. In another aspect, the present invention provides uses of LNDFHI for improving the social-emotional skills of a subject. In another aspect, the present invention provides methods for improving the social-emotional skills of a subject, the method comprising administering to the subject an effective amount of LNDFHI.

[0166] In one aspect, the present invention provides a combination of 2'FL, 3FL, LDFT, LNFPII, LNFP-I, LNFP-III, LND-I, MFLNH-III, LNFP-V, LNnDFH, and LNFP-VI for use in improving the social-emotional skills of a subject. In another aspect, the present invention provides a use of a combination of 2'FL, 3FL, LDFT, LNFPII, LNFP-I, LNFP-III, LND-I, MFLNH-III, LNFP-V, LNnDFH, and LNFP-VI for improving the social-emotional skills of a subject. In another aspect, the present invention provides a method for improving the social-emotional skills of a subject, the method comprising administering to the subject an effective amount of a combination of 2'FL, 3FL, LDFT, LNFPII, LNFP-I, LNFP-III, LND-I, MFLNH-III, LNFP-V, LNnDFH, and LNFP-VI.

[0167] As used herein, "improving social-emotional skills" may refer to, for example, supporting normal social-emotional skills during infancy, childhood, and adolescence. Supporting social-emotional skills may result in normal social-emotional skills. In the context of the present invention, the expressions "social-emotional" or "social-emotional development" may refer to social-emotional skills that develop from birth, which allow for enhanced autonomy, self-regulation, and relationships. Social-emotional development can be assessed and behaviorally monitored using clinical interviews, direct behavioral observations and rating systems, and parent- and teacher-report questionnaires.

[0168] In some embodiments, social-emotional skills are determined by the Infant Behavior Questionnaire (IBQ), such as the IBQ-Revised (IBQ-R). The IBQ-R (Infant Behavior Questionnaire-Revised) questionnaire is a widely used parent-report measure for assessing temperament dimensions with 14 scales in infants between 3 and 12 months of age, as reported below (see, e.g., Gartstein, MA and Rothbart, MK, 2003. Infant behavior and development, 26(1), pp. 64-86).

[0169]

[0170] In some embodiments, social-emotional skills are determined by the Toddler Behavior Assessment Questionnaire (TBAQ). The Toddler Behavior Assessment Questionnaire (TBAQ) is used to measure the behavior of young children between 16 and 36 months (Goldsmith, HH, 1996. Child development, 67 (1), pp. 218-235). The TBAQ contains 120 items and 11 scales: activity level, sensory sensitivity, inhibitory control, soothingness, appropriate attention allocation, sadness, object fear, anger, social phobia, pleasure, and interest. During the past month, the items are rated on a 7-point scale, ranging from 1 = never, 4 = about half the time, to 7 = always.

[0171] One or more HMOs can be used to improve social skills. In one aspect, the present invention provides one or more HMOs for use in improving social skills in a subject. In another aspect, the present invention provides the use of one or more HMOs for improving social skills in a subject. In another aspect, the present invention provides a method for improving social skills in a subject, comprising administering to the subject an effective amount of one or more HMOs.

[0172] In the context of the present invention, " social skills " can encompass any ability or behavior observed in social situations or environments and / or promote interaction and communication (with verbal mode and with non-verbal mode) with others, and the development of social skills begins in the first few months of life. For example, babies begin to show signs of emotion with unique facial expressions, such as pleasure, anger, sadness, interest, fear, disgust and surprise. Babies also begin to laugh and begin to socialize with people by babbling. Social skills continue to develop in toddlers and children, including, for example, starting to imitate the environment around 15 months, becoming attached to caregivers (social phobia) in new situations around 18 months, playing parallel games with other children around 24 months, etc.

[0173] One or more HMOs can be used to improve emotional skills. In one aspect, the present invention provides one or more HMOs for use in improving emotional skills in a subject. In another aspect, the present invention provides the use of one or more HMOs for improving emotional skills in a subject. In another aspect, the present invention provides a method for improving emotional skills in a subject, the method comprising administering to the subject an effective amount of one or more HMOs.

[0174] In the context of the present invention, "emotional skills" can refer to the ability to experience and express personal feelings, as well as to recognize and interpret the feelings of others. Emotional skills are associated with, for example, mood, joy, and sadness. From birth throughout childhood, adolescence, and adulthood, the development of emotional skills occurs alongside neurological, cognitive, and behavioral development.

[0175] One or more HMOs according to the present invention may improve the social-emotional skills of a subject at 9 months of age, 12 months of age, 18 months of age, 24 months of age, or 36 months of age. One or more HMOs according to the present invention may improve the social-emotional skills of a subject between the ages of 9 months and 36 months of age. One or more HMOs according to the present invention may improve the social-emotional skills of a subject at 9 months of age.

[0176] Methods for reducing negative emotions

[0177] One or more HMOs may be used to reduce negative affect.

[0178] In one aspect, the present invention provides one or more HMOs for use in reducing negative affect in a subject. In another aspect, the present invention provides uses of one or more HMOs for reducing negative affect in a subject. In another aspect, the present invention provides methods for reducing negative affect in a subject, the method comprising administering to the subject an effective amount of one or more HMOs.

[0179] In one aspect, the present invention provides a combination of fucosylated HMOs for use in reducing negative affect in a subject. In another aspect, the present invention provides use of a combination of fucosylated HMOs for reducing negative affect in a subject. In another aspect, the present invention provides a method for reducing negative affect in a subject, the method comprising administering to the subject an effective amount of a combination of fucosylated HMOs.

[0180] In one aspect, the present invention provides LNDFHI for use in reducing negative affect in a subject. In another aspect, the present invention provides uses of LNDFHI for reducing negative affect in a subject. In another aspect, the present invention provides methods for reducing negative affect in a subject, comprising administering to the subject an effective amount of LNDFHI.

[0181] In one aspect, the present invention provides a combination of 2'FL, 3FL, LDFT, LNFPII, LNFP-I, LNFP-III, LND-I, MFLNH-III, LNFP-V, LNnDFH, and LNFP-VI for use in reducing a subject's negative emotions. In another aspect, the present invention provides a combination of 2'FL, 3FL, LDFT, LNFPII, LNFP-I, LNFP-III, LND-I, MFLNH-III, LNFP-V, LNnDFH, and LNFP-VI for reducing a subject's negative emotions. In another aspect, the present invention provides a method for reducing a subject's negative emotions, the method comprising administering to the subject an effective amount of a combination of 2'FL, 3FL, LDFT, LNFPII, LNFP-I, LNFP-III, LND-I, MFLNH-III, LNFP-V, LNnDFH, and LNFP-VI.

[0182] As used herein, "negative affectivity" may refer to personality variables that involve experiencing negative emotions and a poor self-concept. Negative affectivity encompasses a wide range of negative emotional states, including fear, anxiety, hostility, contempt, and disgust (see, e.g., Watson, D. et al., 1988. Journal of abnormal psychology, 97(3), p. 346). Appropriately, in the context of the present invention, the term "negative affectivity" may be used interchangeably with the term "negative emotion" or "negative emotional state."

[0183] Negative affectivity in a subject can be determined by any suitable method. In some embodiments, negative affectivity in a subject is determined using the Infant Behavior Questionnaire (IBQ), such as the IBQ-Revised (IBQ-R). For example, negative affectivity can be a domain constructed from the following scales on the IBQ-R: sadness, fear, post-restraint distress, activity level, and emotional withdrawal reactivity. One or more HMOs according to the present invention can reduce sadness, fear, and / or post-restraint distress. One or more HMOs according to the present invention can increase activity level and / or the rate of recovery from distress.

[0184] One or more HMOs according to the present invention may reduce negative affect in subjects aged 9 months, 12 months, 18 months, 24 months, or 36 months. One or more HMOs according to the present invention may reduce negative affect in subjects aged between 9 months and 36 months. One or more HMOs according to the present invention may reduce negative affect in subjects aged 9 months.

[0185] One or more HMOs can promote mood and pleasurable behavior. In the context of the present invention, the term "mood" can refer to an individual's emotional state at a specific time. In the context of the present invention, the term "pleasure" can refer to feelings of intense happiness and joy. Pleasure is a powerful antidote to stress, which has negative effects on infant and child development. Sustained stressful events trigger feelings of anxiety. Promoting pleasure can reduce anxiety. Promoting mood and pleasurable behavior in infants can reduce the risk of experiencing emotional difficulties, which can lead to aggressive or destructive behavior, loneliness, and potentially cause behavioral problems later in life. One or more HMOs can promote high-intensity pleasure, particularly pleasure and enjoyment associated with high stimulus intensity, rate, complexity, novelty, and incongruity, and reduce distress in infants, particularly by reducing low mood and activity associated with distressing physical states, object loss, or the inability to perform an action.

[0186] One or more HMOs according to the present invention may promote mood and pleasurable behavior in subjects aged 9 months, 12 months, 18 months, 24 months, or 36 months. One or more HMOs according to the present invention may promote mood and pleasurable behavior in subjects aged between 9 months and 36 months. One or more HMOs according to the present invention may promote mood and pleasurable behavior in subjects aged 9 months.

[0187] Ways to prevent anxiety or mood disorders

[0188] One or more HMOs may be used to prevent anxiety disorders and / or mood disorders.

[0189] In one aspect, the present invention provides one or more HMOs for use in preventing an anxiety disorder and / or a mood disorder in a subject. In another aspect, the present invention provides the use of one or more HMOs for preventing an anxiety disorder and / or a mood disorder in a subject. In another aspect, the present invention provides a method for preventing an anxiety disorder and / or a mood disorder in a subject, the method comprising administering to the subject an effective amount of one or more HMOs.

[0190] In one aspect, the present invention provides a combination of fucosylated HMOs for use in preventing an anxiety disorder and / or a mood disorder in a subject. In another aspect, the present invention provides use of a combination of fucosylated HMOs for preventing an anxiety disorder and / or a mood disorder in a subject. In another aspect, the present invention provides a method for preventing an anxiety disorder and / or a mood disorder in a subject, the method comprising administering to the subject an effective amount of a combination of fucosylated HMOs.

[0191] In one aspect, the present invention provides an LNDFHI for use in preventing an anxiety disorder and / or a mood disorder in a subject. In another aspect, the present invention provides a use of an LNDFHI for preventing an anxiety disorder and / or a mood disorder in a subject. In another aspect, the present invention provides a method for preventing an anxiety disorder and / or a mood disorder in a subject, the method comprising administering to the subject an effective amount of an LNDFHI.

[0192] In one aspect, the present invention provides a combination of 2'FL, 3FL, LDFT, LNFPII, LNFP-I, LNFP-III, LND-I, MFLNH-III, LNFP-V, LNnDFH, and LNFP-VI for use in preventing anxiety disorders and / or mood disorders in a subject. In another aspect, the present invention provides a use of a combination of 2'FL, 3FL, LDFT, LNFPII, LNFP-I, LNFP-III, LND-I, MFLNH-III, LNFP-V, LNnDFH, and LNFP-VI for preventing anxiety disorders and / or mood disorders in a subject. In another aspect, the present invention provides a method for preventing anxiety disorders and / or mood disorders in a subject, the method comprising administering to the subject an effective amount of a combination of 2'FL, 3FL, LDFT, LNFPII, LNFP-I, LNFP-III, LND-I, MFLNH-III, LNFP-V, LNnDFH, and LNFP-VI.

[0193] In the context of the present invention, "preventing" a disorder may refer to reducing the severity of the disorder or alleviating symptoms induced by the disorder, such as stress and / or reducing complications caused by the disorder. In the context of the present invention, "preventing" a disorder may also refer to reducing the risk of the disorder occurring.

[0194] One or more HMOs can improve the behavior of infants, toddlers, or young children older than 12 months in social interactions, such as play, and / or responses to novelty and / or new situations and / or responses with new people and / or strangers. Improving the social-emotional skills of infants, toddlers, or young children can reduce their risk of developing behavioral problems later in life, such as anxiety disorders or depressive disorders (see, e.g., Watson, D. et al., 1988. Journal of abnormal psychology, 97(3), p. 346), as it is believed that lack of social skills can lead to adverse outcomes in child development, such as hindering a child's ability to build relationships, affecting a child's ability to adjust to school, leading to loneliness, and potentially causing behavioral problems later in life.

[0195] Examples of anxiety disorders include generalized anxiety disorder, social anxiety disorder (social phobia), and separation disorders. Generalized anxiety disorder, separation anxiety disorder, and social phobia are considered the most common, earliest-onset childhood psychiatric disorders and adult depression, and are associated with persistent comorbidity and impaired quality of life throughout life (see, e.g., Copeland, WE et al., 2009. Archives of general psychiatry, 66(7), pp. 764-772).

[0196] Mood disorders are a group of mental disorders that include, for example, bipolar disorder and depressive disorders. Mood is defined as a pervasive and persistent emotional tone that persists internally and affects almost all aspects of a person's behavior in the external world. Mood disorders are described as marked disturbances in mood (severe low moods called depression, or severe high moods called hypermania or mania). These disorders include bipolar disorder, cyclothymia, hypomania, major depressive disorder, disruptive mood dysregulation, persistent depressive disorder, and premenstrual dysphoric disorder.

[0197] Methods used to support gross motor skills and visual perception

[0198] One or more HMOs may be used to support gross motor skills and visual perception.

[0199] In some aspects, the present invention provides 3FL for use in supporting gross motor skills and visual perception in a subject. In another aspect, the present invention provides uses of 3FL for supporting gross motor skills and visual perception in a subject. In another aspect, the present invention provides methods for supporting gross motor skills and visual perception in a subject, the method comprising administering to the subject an effective amount of 3FL.

[0200] In some embodiments, gross motor skills and visual perception are determined using the Mullen Scales of Early Learning (MSEL), a validated, widely used infant cognitive development assessment tool that includes five domains: fine motor, gross motor, visual reception, receptive language, and expressive language (Mullen EM. Mullen scales of early learning. AGS Circle Pines, MN; 1995).

[0201] Subjects

[0202] The subject may be any suitable subject. Suitably, the subject may be a human.

[0203] In preferred embodiments, the subject is an infant, a toddler, or a young child. The term "infant" may refer to a subject having an age of about 0 to about 1 year old. The term "toddler" may refer to a subject having an age of about 1 to about 3 years old. The term "young child" may refer to a subject having an age of about 3 to about 10 years old, about 3 to about 9 years old, about 3 to about 8 years old, about 3 to about 7 years old, about 3 to about 6 years old, or about 3 to about 5 years old.

[0204] In preferred embodiments, the subject is an infant. In some embodiments, the subject is a newborn infant. In some embodiments, the subject is a premature infant.

[0205] In some embodiments, the subject is about 5 years of age or younger, about 4 years of age or younger, about 3 years of age or younger, about 2 years of age or younger, or about 1 year of age or younger. In some embodiments, the subject is about 12 months of age or younger, about 11 months of age or younger, about 10 months of age or younger, about 9 months of age or younger, about 8 months of age or younger, about 7 months of age or younger, or about 6 months of age or younger. In some embodiments, the subject is about 9 months of age or younger.

[0206] In some embodiments, the one or more HMOs are administered to the subject during the first 1, 3, 6, 9, 12, 18, 14, or 36 months of life. For example, the one or more HMOs are administered to the subject from birth until 12, 18, 24, or 36 months of age.

[0207] Subjects may be at risk of behavioral developmental deficiencies. The major risks of adverse child development include intrauterine growth restriction, developmental delay, iodine deficiency, iron deficiency anemia, malaria, lead exposure, HIV, maternal depression, and insufficient cognitive stimulation. In addition, maternal education level and breastfeeding have been identified as protective factors (Walker, SP et al., 2011. Thelancet, 378 (9799), pp. 1325-1338). In some embodiments, subjects suffer from and / or have suffered from intrauterine growth restriction, developmental delay, iodine deficiency, iron deficiency anemia, malaria, lead exposure, HIV, maternal depression, and / or insufficient cognitive stimulation. Subjects may be at risk of insufficient social-emotional skills. Subjects may be at risk of negative emotions.

[0208] The subject may have had and / or may be suffering from behavioral developmental deficiencies. Any suitable screening tool can be used (see, for example, Johnson, S. and Marlow, N., 2006. Early human development, 82(3), pp. 173-183). The subject may have had and / or may be suffering from social-emotional skill deficiencies. The subject may have had and / or may be suffering from negative emotions. This can be determined by any method known in the art, for example, using the Infant Behavior Questionnaire (IBQ), such as the IBQ-Revised (IBQ-R), see, for example, Gartstein, MA and Rothbart, MK, 2003. Infant behavior and development, 26(1), pp. 64-86.

[0209] Example

[0210] The present invention is further described with reference to the following examples. It should be understood that the invention as claimed is not intended to be limited in any way by these examples.

[0211] Example 1 - Association of behavioral outcomes with breast milk concentrations of human milk oligosaccharides (HMOs)

[0212] The present inventors investigated the association of behavioral outcomes with breast milk concentrations of specific human milk oligosaccharides (HMOs) or with a composite score representative of specific HMO groups in human breastfed infants.

[0213] A total of 195 infants were tested. Breast milk HMO levels were measured in breast milk collected at two and three months of age. Infant behavior was assessed using the Infant Behavior Questionnaire-Revised (IBQ-R). A regression model approach was used with covariates including: mother's net income, mother's SES / education level, weight, gestational age, and infant's sex (covariates were imputed, with missing values ​​replaced by the overall mean). The negative affectivity domain was constructed from several scales from the IBQR (which measures infant temperament and is self-reported by mothers), including sadness, fear, distress after restriction, activity level, and emotional withdrawal reactivity.

[0214] Specific fucosylated HMOs (LNDFHI and 2'FL, 3FL, LDFT, LNFPII, LNFP-I, LNFP-III, LND-I, MFLNH-III, LNFP-V, LNnDFH, and LNFP-VI) were associated with reduced negative emotionality at 9 months (see Table 1, below). Figure 1 、 Figure 2 、 Figure 4A and B).

[0215] Table 1: Results of the regression model approach to assess the association between behavioral outcomes and HMOs

[0216]

[0217] Example 2 - Association of gross motor skills and visual perception with breast milk concentrations of human milk oligosaccharides (HMOs)

[0218] The present inventors investigated the association of gross motor skills and visual perception with breast milk concentrations of specific human milk oligosaccharides (HMOs).

[0219] A total of 105 infants between 2 weeks and 12 months of age were assessed on the Mullen Scale of Early Learning (MSEL) and their mothers' breast milk was collected for HMO analysis. Of the 105 infants, 60 were visited once, while the remaining subjects were visited up to four times, resulting in a total of 170 MSEL assessments and breast milk samples. Breast milk was collected using standard procedures at each visit. MSEL was assessed between 3 and 24 months of age. The association between BM levels of the 3FL was evaluated using a linear regression model. Due to the cohort design, we had to use smoothing spline regression to remove potential confounding effects from age (Hastie TJ et al. Generalized additive models, Boca Raton, Florida, USA. CRC Press; 1990), and then performed an association analysis with MSEL scores in all 5 subscales, where significant positive correlations were observed between the 3FL for visual reception (p = 0.041, ES = 6.34) and gross motor skills (p = 0.027, ES = 7.67) (see Figure 3 ).

[0220] Implementation Plan

[0221] Various preferred features and embodiments of the present invention will now be described with reference to the following numbered paragraph(s).

[0222] 1. One or more human milk oligosaccharides (HMOs) for use in supporting behavioral development in a subject, wherein the one or more HMOs comprise or consist of: (a) lactose-N-difucohexaose I (LNDFHI); and / or (b) 2'-fucosyllactose (2'FL), 3-fucosyllactose (3FL), lactose difucotetraose (LDFT), and lactose-N-fucopentaose II (LNFPII).

[0223] 2. Use of one or more human milk oligosaccharides (HMOs) for supporting behavioral development in a subject, wherein the one or more HMOs comprise or consist of: (a) lactose-N-difucohexaose I (LNDFHI); and / or (b) 2'-fucosyllactose (2'FL), 3-fucosyllactose (3FL), lactose difucotetraose (LDFT) and lactose-N-fucopentaose II (LNFPII).

[0224] 3. A method for supporting behavioral development in a subject, the method comprising administering to the subject an effective amount of one or more human milk oligosaccharides (HMOs), wherein the one or more HMOs comprise or consist of: (a) lactose-N-difucohexaose I (LNDFHI); and / or (b) 2'-fucosyllactose (2'FL), 3-fucosyllactose (3FL), lactose difucotetraose (LDFT), and lactose-N-fucopentaose II (LNFPII).

[0225] 4. One or more HMOs for use according to paragraph 1, the use according to paragraph 2, or the method according to paragraph 3, wherein the one or more HMOs comprise or consist of LNDFHI.

[0226] 5. One or more HMOs for use according to paragraphs 1 or 4, the use according to paragraphs 2 or 4, or the method according to paragraphs 3 or 4, wherein the one or more HMOs comprise or consist of 2'FL, 3FL, LDFT, and LNFPII.

[0227] 6. One or more HMOs for use according to any of paragraphs 1 or 4-5, the use according to any of paragraphs 2 or 4-5, or the method according to any of paragraphs 3 or 4-5, wherein the one or more HMOs are administered by oral administration.

[0228] 7. One or more HMOs for use according to any of paragraphs 1 or 4-6, the use according to any of paragraphs 2 or 4-6, or the method according to any of paragraphs 3 or 4-6, wherein the one or more HMOs are administered individually, simultaneously or sequentially, preferably wherein the one or more HMOs are administered simultaneously.

[0229] 8. The one or more HMOs for use according to any of paragraphs 1 or 4-7, the use according to any of paragraphs 2 or 4-7, or the method according to any of paragraphs 3 or 4-7, wherein the one or more HMOs are administered to the subject in a total amount of about 0.5 g / day to about 10 g / day.

[0230] 9. The one or more HMOs for use according to any of paragraphs 1 or 4-8, the use according to any of paragraphs 2 or 4-8, or the method according to any of paragraphs 3 or 4-8, wherein LNDFHI is administered to the subject in an amount of about 0.1 g / day to about 5 g / day.

[0231] 10. The one or more HMOs for use according to any of paragraphs 1 or 4-9, the use according to any of paragraphs 2 or 4-9, or the method according to any of paragraphs 3 or 4-9, wherein: (i) 2'FL is administered to the subject in an amount of about 0.1 g / day to about 5 g / day; (ii) 3FL is administered to the subject in an amount of about 0.1 g / day to about 5 g / day; (iii) LDFT is administered to the subject in an amount of about 0.1 g / day to about 5 g / day; and / or (iv) LNFPII is administered to the subject in an amount of about 0.1 g / day to about 5 g / day.

[0232] 11. One or more HMOs for use according to any of paragraphs 1 or 4-10, the use according to any of paragraphs 2 or 4-10, or the method according to any of paragraphs 3 or 4-10, wherein the one or more HMOs are in the form of a nutritional composition.

[0233] 12. One or more HMOs for use according to paragraph 11, the use according to paragraph 11 or the method according to paragraph 11, wherein the nutritional composition is an infant formula, a follow-on formula or a growing-up milk, preferably wherein the nutritional composition is an infant formula.

[0234] 13. The one or more HMOs for use according to paragraph 11 or 12, the use according to paragraph 11 or 12, or the method according to paragraph 11 or 12, wherein the nutritional composition comprises the one or more HMOs in a total amount of about 0.5 g / L to about 10 g / L.

[0235] 14. The one or more HMOs for use according to any of paragraphs 11-13, the use according to any of paragraphs 11-13, or the method according to any of paragraphs 11-13, wherein the nutritional composition comprises LNDFHI in an amount from about 0.2 g / L to about 2.0 g / L.

[0236] 15. The one or more HMOs for use according to any of paragraphs 11-14, the use according to any of paragraphs 11-14, or the method according to any of paragraphs 11-14, wherein the nutritional composition comprises: (i) 2'FL in an amount of about 0.5 g / L to about 3.0 g / L; (ii) 3FL in an amount of about 0.2 g / L to about 2.0 g / L; (iii) LDFT in an amount of about 0.05 g / L to about 0.5 g / L; and / or (iv) LNFPII in an amount of about 0.05 g / L to about 0.5 g / L.

[0237] 16. One or more HMOs for use according to any of paragraphs 1 or 4-15, the use according to any of paragraphs 2 or 4-15, or the method according to any of paragraphs 3 or 4-15, wherein the subject is a human subject.

[0238] 17. One or more HMOs for use according to any of paragraphs 1 or 4-16, the use according to any of paragraphs 2 or 4-16, or the method according to any of paragraphs 3 or 4-16, wherein the subject is an infant, toddler, or young child.

[0239] 18. One or more HMOs for use according to any of paragraphs 1 or 4-17, the use according to any of paragraphs 2 or 4-17, or the method according to any of paragraphs 3 or 4-17, wherein the subject is an infant.

[0240] 19. The one or more HMOs for use according to any of paragraphs 1 or 4-18, the use according to any of paragraphs 2 or 4-18, or the method according to any of paragraphs 3 or 4-18, wherein the subject is about 12 months or younger, about 11 months or younger, about 10 months or younger, or about 9 months or younger.

[0241] 20. The one or more HMOs for use according to any of paragraphs 1 or 4-19, the use according to any of paragraphs 2 or 4-19, or the method according to any of paragraphs 3 or 4-19, wherein the one or more HMOs improve the subject's social-emotional skills.

[0242] 21. The one or more HMOs for use according to any of paragraphs 1 or 4-20, the use according to any of paragraphs 2 or 4-20, or the method according to any of paragraphs 3 or 4-20, wherein the one or more HMOs reduce negative affect in the subject.

[0243] 22. One or more HMOs for use according to paragraph 21, the use according to paragraph 21, or the method according to paragraph 21, wherein the subject's negative affectivity is determined by the Infant Behavior Questionnaire (IBQ), preferably the IBQ-Revised (IBQ-R).

[0244] 23. Use of one or more HMOs for improving social-emotional skills in a subject, wherein the one or more HMOs comprise or consist of: (a) lactose-N-difucohexaose I (LNDFHI); and / or (b) 2'-fucosyllactose (2'FL), 3-fucosyllactose (3FL), lactose difucotetraose (LDFT), and lactose-N-fucopentaose II (LNFPII).

[0245] 24. Use of one or more HMOs for reducing negative affect in a subject, wherein the one or more HMOs comprise or consist of: (a) lactose-N-difucohexaose I (LNDFHI); and / or (b) 2'-fucosyllactose (2'FL), 3-fucosyllactose (3FL), lactose difucotetraose (LDFT), and lactose-N-fucopentaose II (LNFPII).

[0246] 25. The use according to paragraph 23 or 24, wherein the one or more HMOs comprise or consist of LNDFHI.

[0247] 26. The use according to any of paragraphs 23-25, wherein the one or more HMOs comprise or consist of 2'FL, 3FL, LDFT, and LNFPII.

[0248] 27. The use according to any of paragraphs 23-26, wherein the one or more HMOs are administered by oral administration.

[0249] 28. The use according to any of paragraphs 23-27, wherein the one or more HMOs are administered separately, simultaneously or sequentially, preferably wherein the one or more HMOs are administered simultaneously.

[0250] 29. The use according to any of paragraphs 23-28, wherein the one or more HMOs are administered to the subject in a total amount of about 0.5 g / day to about 10 g / day.

[0251] 30. The use of any of paragraphs 23-29, wherein LNDFHI is administered to the subject in an amount of about 0.1 g / day to about 5 g / day.

[0252] 31. The use of any of paragraphs 23-30, wherein: (i) 2'FL is administered to the subject in an amount of about 0.1 g / day to about 5 g / day; (ii) 3FL is administered to the subject in an amount of about 0.1 g / day to about 5 g / day; (iii) LDFT is administered to the subject in an amount of about 0.1 g / day to about 5 g / day; and / or (iv) LNFPII is administered to the subject in an amount of about 0.1 g / day to about 5 g / day.

[0253] 32. The use of any of paragraphs 23-31, wherein the one or more HMOs are in the form of a nutritional composition.

[0254] 33. The use according to paragraph 32, wherein the nutritional composition is an infant formula, a follow-on formula or a growing-up milk, preferably wherein the nutritional composition is an infant formula.

[0255] 34. The use of paragraph 32 or 33, wherein the nutritional composition comprises the one or more HMOs in a total amount of about 0.5 g / L to about 10 g / L.

[0256] 35. The use of any of paragraphs 32-34, wherein the nutritional composition comprises LNDFHI in an amount from about 0.2 g / L to about 2.0 g / L.

[0257] 36. The use of any of paragraphs 32-35, wherein the nutritional composition comprises: (i) 2'FL in an amount of about 0.5 g / L to about 3.0 g / L; (ii) 3FL in an amount of about 0.2 g / L to about 2.0 g / L; (iii) LDFT in an amount of about 0.05 g / L to about 0.5 g / L; and / or (iv) LNFPII in an amount of about 0.05 g / L to about 0.5 g / L.

[0258] 37. The use of any of paragraphs 23-36, wherein the subject is a human subject.

[0259] 38. The use of any of paragraphs 23-37, wherein the subject is an infant, toddler, or young child.

[0260] 39. The use of any of paragraphs 23-38, wherein the subject is an infant.

[0261] 40. The use of any of paragraphs 23-39, wherein the subject is about 12 months or younger, about 11 months or younger, about 10 months or younger, or about 9 months or younger.

[0262] 41. The one or more HMOs for use according to any of paragraphs 1 or 4-19, the use according to any of paragraphs 2 or 4-19, or the method according to any of paragraphs 3 or 4-19, wherein the one or more HMOs improve the subject's gross motor skills and / or visual perception.

[0263] 42. The one or more HMOs for use according to paragraph 41, the use according to 41, or the method according to paragraph 41, wherein the one or more HMOs comprise or consist of 3FL.

[0264] Although the present invention has been described by way of example, it will be appreciated that variations and modifications may be made without departing from the scope of the invention as defined in the claims. In addition, where known equivalents exist for specific features, such equivalents should be incorporated as if explicitly mentioned in this specification.

Claims

1. One or more human milk oligosaccharides (HMOs) for use in supporting behavioral development in a subject, wherein the one or more HMOs comprise or consist of: (a) lactose-N-difucohexaose I (LNDFHI); and / or (b) 2'-fucosyllactose (2'FL), 3-fucosyllactose (3FL), lactose difucotetraose (LDFT), lactose-N-fucopentaose II (LNFPII), lactose-N-fucopentaose I (LNFP-I), lactose-N-fucopentaose III (LNFP-III), lactose-N-difucohexaose I (LND-I), monofucosyl-lactose-N-hexaose III (MFLNH-III), lactose-N-fucopentaose V (LNFP-V), lactose-N-neodifucohexaose (LNnDFH) and lactose-N-fucopentaose VI (LNFP-VI).

2. One or more HMOs for use according to claim 1, wherein the one or more HMOs comprise or consist of LNDFHI.

3. One or more HMOs for use according to claim 1 or 2, wherein the one or more HMOs comprise or consist of: 2'FL, 3FL, LDFT, LNFPII, LNFP-I, LNFP-III, LND-I, MFLNH-III, LNFP-V, LNnDFH and LNFP-VI.

4. One or more HMOs for use according to any preceding claim, wherein the one or more HMOs are administered by oral administration.

5. One or more HMOs for use according to any preceding claim, wherein the one or more HMOs are administered individually, simultaneously or sequentially, preferably wherein the one or more HMOs are administered simultaneously.

6. One or more HMOs for use according to any preceding claim, wherein the one or more HMOs are administered to the subject in a total amount of about 0.5 g / day to about 10 g / day.

7. One or more HMOs for use according to any preceding claim, wherein the one or more HMOs are in the form of a nutritional composition.

8. One or more HMOs for use according to claim 7, wherein the nutritional composition is an infant formula, a follow-on formula or a growing-up milk, preferably wherein the nutritional composition is an infant formula.

9. One or more HMOs for use according to claim 7 or 8, wherein the nutritional composition comprises the one or more HMOs in a total amount of about 0.5 g / L to about 10 g / L.

10. One or more HMOs for use according to any preceding claim, wherein the subject is an infant, toddler or young child, preferably wherein the subject is an infant.

11. One or more HMOs for use according to any preceding claim, wherein the subject is about 12 months or younger, about 11 months or younger, about 10 months or younger, or about 9 months or younger.

12. One or more HMOs for use according to any preceding claim, wherein the one or more HMOs improve the subject's social-emotional skills.

13. One or more HMOs for use according to any preceding claim, wherein said one or more HMOs reduce negative affect in said subject, preferably wherein said subject's negative affect is determined by the Infant Behavior Questionnaire-Revised (IBQ-R).

14. Use of one or more HMOs for improving social-emotional skills, wherein the one or more HMOs comprise or consist of: (a) lactose-N-difucohexaose I (LNDFHI); and / or (b) 2'-fucosyllactose (2'FL), 3-fucosyllactose (3FL), lactose difucotetraose (LDFT), lactose-N-fucopentaose II (LNFPII), lactose-N-fucopentaose I (LNFP-I), lactose-N-fucopentaose III (LNFP-III), lactose-N-difucohexaose I (LND-I), monofucosyl-lactose-N-hexaose III (MFLNH-III), lactose-N-fucopentaose V (LNFP-V), lactose-N-neodifucohexaose (LNnDFH) and lactose-N-fucopentaose VI (LNFP-VI).

15. Use of one or more HMOs for reducing negative affect, wherein the one or more HMOs comprise or consist of: (a) lactose-N-difucohexaose I (LNDFHI); and / or (b) 2'-fucosyllactose (2'FL), 3-fucosyllactose (3FL), lactose difucotetraose (LDFT), lactose-N-fucopentaose II (LNFPII), lactose-N-fucopentaose I (LNFP-I), lactose-N-fucopentaose III (LNFP-III), lactose-N-difucohexaose I (LND-I), monofucosyl-lactose-N-hexaose III (MFLNH-III), lactose-N-fucopentaose V (LNFP-V), lactose-N-neodifucohexaose (LNnDFH) and lactose-N-fucopentaose VI (LNFP-VI).

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