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WO2025045657A1 - Compositions comprenant des oligosaccharides de lait humain destinées à être utilisées chez un sujet pour prendre en charge le développement cérébral et/ou le développement émotionnel social - Google Patents

Compositions comprenant des oligosaccharides de lait humain destinées à être utilisées chez un sujet pour prendre en charge le développement cérébral et/ou le développement émotionnel social Download PDF

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Publication number
WO2025045657A1
WO2025045657A1 PCT/EP2024/073332 EP2024073332W WO2025045657A1 WO 2025045657 A1 WO2025045657 A1 WO 2025045657A1 EP 2024073332 W EP2024073332 W EP 2024073332W WO 2025045657 A1 WO2025045657 A1 WO 2025045657A1
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Prior art keywords
subject
development
infant
social
emotional
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Inventor
Jonas HAUSER
Tinu Mary SAMUEL
Norbert Sprenger
Seoyoon CHO
Weiyan YIN
Tengfei Li
Ziliang ZHU
Hongtu ZHU
Weili Lin
Diandra BRKIC
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Societe des Produits Nestle SA
Nestle SA
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Societe des Produits Nestle SA
Nestle SA
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Publication of WO2025045657A1 publication Critical patent/WO2025045657A1/fr
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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/40—Complete food formulations for specific consumer groups or specific purposes, e.g. infant formula
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/20—Reducing nutritive value; Dietetic products with reduced nutritive value
    • A23L33/21—Addition of substantially indigestible substances, e.g. dietary fibres

Definitions

  • compositions comprising human milk oligosaccharides for use in a subject to support brain development and/or social-emotional development
  • This invention relates to nutritional compositions comprising at least one fucosylated human milk oligosaccharide for use in a subject to support brain development and/or social-emotional development.
  • the nutritional composition comprises 3-fucosyllactose (3-FL).
  • the brain development and/or social-emotional development comprises the development of brain network(s) supporting social-emotional functions, such as the default mode network (DMN).
  • DNN default mode network
  • HMOs human milk oligosaccharides
  • the present inventors have surprisingly found that the fucosylated HMO 3-fucosyllactose (3- FL) is significantly associated with brain and social-emotional development, and in particular, the development of social-emotional brain networks, such as the default mode network (DMN), in infants and children. Whereas other fucosylated HMOs, such as A-tetrasaccharide, are not.
  • the invention provides a fucosylated human milk oligosaccharide (HMO) for use in improving brain development and/or social-emotional development in a subject, wherein the fucosylated HMO is 3-fucosyllactose (3-FL), and wherein the subject is an infant, a young child or a child.
  • HMO human milk oligosaccharide
  • the invention provides a nutritional composition comprising a fucosylated human milk oligosaccharide (HMO) for use in improving brain development and/or social- emotional development in a subject, wherein the fucosylated HMO is 3-fucosyllactose (3-FL), and wherein the subject is an infant, a young child or a child.
  • HMO fucosylated human milk oligosaccharide
  • the invention provides a method of improving brain development and/or social-emotional development in a subject comprising administering a fucosylated HMO to the subject, wherein the fucosylated HMO is 3-fucosyllactose (3-FL), and wherein the subject is an infant, a young child or a child.
  • a fucosylated HMO is 3-fucosyllactose (3-FL)
  • the subject is an infant, a young child or a child.
  • the invention provides a method of improving brain development and/or social-emotional development in a subject comprising administering a nutritional composition comprising a fucosylated HMO to the subject, wherein the fucosylated HMO is 3- fucosyllactose (3-FL), and wherein the subject is an infant, a young child or a child.
  • the invention provides a fucosylated HMO for improving brain development and/or social-emotional development in a subject, wherein the fucosylated HMO is 3- fucosyllactose (3-FL), and wherein the subject is an infant, a young child or a child.
  • the fucosylated HMO is 3- fucosyllactose (3-FL)
  • the subject is an infant, a young child or a child.
  • the invention provides a nutritional composition comprising a fucosylated HMO for improving brain development and/or social-emotional development in a subject, wherein the fucosylated HMO is 3-fucosyllactose (3-FL), and wherein the subject is an infant, a young child or a child.
  • a fucosylated HMO for improving brain development and/or social-emotional development in a subject, wherein the fucosylated HMO is 3-fucosyllactose (3-FL), and wherein the subject is an infant, a young child or a child.
  • the improvement in brain development and/or social-emotional development in the subject comprises or consists of an improvement in the development of brain network(s) associated with social-emotional functions. In some embodiments, improving brain development and/or social-emotional development in the subject comprises or consists of promoting the default mode network (DMN).
  • DNN default mode network
  • the invention provides the use of a fucosylated HMO for promoting the default mode network (DMN) in a subject, wherein the fucosylated HMO is 3- fucosyllactose (3-FL), and wherein the subject is an infant, a young child or a child.
  • DNN default mode network
  • the invention provides the use of a nutritional composition comprising a fucosylated HMO for promoting the default mode network (DMN) in a subject, wherein the fucosylated HMO is 3-fucosyllactose (3-FL), and wherein the subject is an infant, a young child or a child.
  • a nutritional composition comprising a fucosylated HMO for promoting the default mode network (DMN) in a subject, wherein the fucosylated HMO is 3-fucosyllactose (3-FL), and wherein the subject is an infant, a young child or a child.
  • the invention provides a method of promoting the default mode network (DMN) in a subject comprising administering a fucosylated HMO to the subject, wherein the fucosylated HMO is 3-fucosyllactose (3-FL), and wherein the subject is an infant, a young child or a child.
  • DNN default mode network
  • the invention provides a method of promoting the default mode network (DMN) in a subject comprising administering a nutritional composition comprising a fucosylated HMO to the subject, wherein the fucosylated HMO is 3-fucosyllactose (3-FL), and wherein the subject is an infant, a young child or a child.
  • DNN default mode network
  • the subject is an infant at least 5 months old, a young child or a child.
  • the nutritional composition is an infant formula, a starter infant formula, a follow-on or follow-up infant formula, a baby food (such as yogurt, pureed or mashed baby food), an infant cereal composition, a growing-up milk, a fortifier or a supplement.
  • 3-FL is present in a total amount of from 50 mg/L to 2000 mg/L of the nutritional composition or of from 38 mg/100g to 1540 mg/100g of the nutritional composition.
  • Figure 1 Scatter plot of the default mode functional network strength and age-regressed-out 3-FL concentration in breastmilk. The line represents the linear regression for the population highlighting the positive association of 3-FL in breastmilk with default mode network strength p ⁇ 0.05). To ensure age did not confound the association analyses between HMOs and brain functional networks, age was regressed out from both the HMOs and the brain functional networks using smooth spline.
  • Figure 2 Scatter plot of the default mode functional network strength and age regressed-out 3-FL concentration in breastmilk levels in subjects aged over 5 months.
  • the line represents the linear regression for the population highlighting the positive association of 3-FL in breastmilk levels with default mode network strength p ⁇ 0.05).
  • age was regressed out from both the HMOs and the brain functional networks using smooth spline.
  • Figure 3 Scatter plot of the default mode functional network strength and age-regressed-out A-tetrasaccharide concentration in breastmilk, where no significant association was observed between the two.
  • subject refers to an infant, a young child, or a child.
  • infant means a child under the age of 12 months.
  • young child means a child aged between one and three years, also called toddler.
  • child means a child aged between three and twelve years. Preferably, the term “child” means a child aged between three and six years.
  • the expression "nutritional composition” means a composition which nourishes a subject. This nutritional composition is usually to be taken orally or intravenously. It may include a lipid or fat source, a carbohydrate source and/or a protein source. In a particular embodiment the nutritional composition is a ready-to-drink composition such as a ready-to-drink formula. In a particular embodiment, the nutritional composition of the present invention is a "synthetic nutritional composition".
  • the expression “synthetic nutritional composition” means a mixture obtained by chemical and/or biological means, which can be chemically identical to the mixture naturally occurring in mammalian milks (i.e. the synthetic nutritional composition is not breast milk).
  • infant formula refers to a foodstuff intended for particular nutritional use by infants during the first months of life and satisfying by itself the nutritional requirements of this category of person (Article 2(c) of the European Commission Directive 91/321/EEC 2006/141/EC of 22 December 2006 on infant formulae and follow-on formulae). It also refers to a nutritional composition intended for infants and as defined in Codex Alimentarius (Codex STAN 72-1981) and Infant Specialities (incl. Food for Special Medical Purpose).
  • infant formula encompasses both "starter infant formula” and “follow-up formula” or “follow-on formula”.
  • follow-up formula or “follow-on formula” is given from the 6th month onwards and includes “growing-up milk”. It constitutes the principal liquid element in the progressively diversified diet of this category of person.
  • growing-up milk refers to a milk-based drink generally with added vitamins and minerals, that is intended for young children or children.
  • baby food means a foodstuff intended for particular nutritional use by infants or young children during the first years of life.
  • infant cereal composition means a foodstuff intended for particular nutritional use by infants or young children during the first years of life.
  • fortifier refers to liquid or solid nutritional compositions suitable for mixing with breast milk or infant formula.
  • the expression “weaning period” means the period during which the mother's milk is substituted by other food in the diet of an infant or young child.
  • the "mother's milk” should be understood as the breast milk including colostrum (first milk), transitional or mature milk of the mother.
  • oligosaccharide is a saccharide polymer containing a small number (typically three to ten) of simple sugars (monosaccharides).
  • HMO human milk oligosaccharide(s). These carbohydrates are resistant to enzymatic hydrolysis by digestive enzymes (e.g. pancreatic and/or brush border), indicating that they may display functions not directly related to their caloric value. It has especially been illustrated that they play a vital role in the early development of infants and young children, such as the maturation of the immune system. Many different kinds of HMOs are found in the human milk.
  • Each individual oligosaccharide is based on a combination of glucose, galactose, sialic acid (N- acetyl neuraminic acid), fucose and/or N- acetylglucosamine with many and varied linkages between them, thus accounting for the enormous number of different oligosaccharides in human milk - over 130 such structures have been identified so far. Almost all of them have a lactose moiety at their reducing end while sialic acid and/or fucose (when present) occupy terminal positions at the non-reducing ends.
  • the HMOs can be acidic (e.g. charged sialic acid containing oligosaccharide) or neutral (e.g.
  • HMOs fucosylated oligosaccharides
  • N-acetylated oligosaccharides the fucosylated oligosaccharides
  • sialylated oligosaccharides Some examples of HMOs are the fucosylated oligosaccharides, the N-acetylated oligosaccharides and/or the sialylated oligosaccharides.
  • a "fucosylated oligosaccharide” is an oligosaccharide having a fucose residue. It has a neutral nature. Some examples are LNFP-I (lacto-N-fucopentaose I), A-tetrasaccharide, 2’-FL (2' fucosyllactose), 3-FL (3’ fucosyllactose).
  • a “sialylated oligosaccharide” is a charged sialic acid containing oligosaccharide, i.e. an oligosaccharide having a sialic acid residue. It has an acidic nature. Some examples are 3-SL (3’-sialyllactose) and 6-SL (6’-sialyllactose). The expressions “sialylated oligosaccharide” and “sialyllactose (SL)” can be used interchangeably.
  • the trisaccharide sialyllactose consists of lactose at the reducing terminus and one sialic acid residue at the non-reducing end via an alpha-2,3 binding or alpha-2,6 binding, resulting in 3'-SL and 6'-SL, respectively.
  • the nutritional composition of the present invention can be in solid form (e.g. powder) or in liquid form.
  • the amount of the various ingredients e.g. the oligosaccharides
  • prebiotic means non-digestible carbohydrates that beneficially affect the host by selectively stimulating the growth and/or the activity of healthy bacteria such as bifidobacteria in the colon of humans (Gibson GR, Roberfroid MB. Dietary modulation of the human colonic microbiota: introducing the concept of prebiotics. J Nutr. 1995;125:1401 -12).
  • A-tetrasaccharide is a-D-GalNAc-(l - 3)-[alpha-L-Fuc-(l- 2)]- -D-Gal-(1 A 4)-D- Glc
  • brain development refers to the hierarchical process of brain growth, including wiring the brain, such that later development depends on early development, that begins around 2 weeks after conception and continues into young adulthood 20 years later. Brain development builds on itself, as initially brain cells grow in number and then start connecting eventually linking with each other in more complex ways, enabling the child to move and speak and think in ever more complex ways.
  • An example of the hierarchical process of brain development is that language development depends critically on sensory and perceptual development (e.g., discrimination of speech sounds).
  • the term “brain development” comprises the development of default mode brain network. Any suitable assessment method for social- emotional development known in the art, including brain magnetic resonance imaging (MRI) to determine default mode network strength, may be employed in the practice of the present invention.
  • MRI brain magnetic resonance imaging
  • compositions of the present invention can comprise, consist of, or consist essentially of the essential elements and limitations of the invention described herein, as well as any additional or optional ingredients, components, or limitations described herein or otherwise depending on the needs.
  • HMOs could yield associations with cognitive development in infants.
  • the present inventors have surprisingly found that the fucosylated HMO 3-FL is significantly associated with brain and social-emotional development, and in particular with the development of the default mode network (DMN).
  • the DMN has been found to be involved in various domains of cognitive and social processing, as reviewed by Li et al. (Li et al., Frontiers in Human Neuroscience, 2014, 8: Article 74; see also Schilbach et al., Conscious.
  • the invention provides a fucosylated human milk oligosaccharide (HMO) for use in improving brain development and/or social-emotional development in a subject, wherein the fucosylated HMO is 3-fucosyllactose (3-FL), and wherein the subject is an infant, a young child or a child.
  • HMO human milk oligosaccharide
  • the invention provides a nutritional composition comprising a fucosylated human milk oligosaccharide (HMO) for use in improving brain development and/or social- emotional development in a subject, wherein the fucosylated HMO is 3-fucosyllactose (3-FL), and wherein the subject is an infant, a young child or a child.
  • the invention provides the use of a fucosylated human milk oligosaccharide (HMO) in the manufacture of a medicament for improving brain development and/or social- emotional development in a subject, wherein the fucosylated HMO is 3-fucosyllactose (3-FL), and wherein the subject is an infant, a young child or a child.
  • the medicament is a nutritional composition as described herein.
  • the invention provides a method of improving brain development and/or social-emotional development in a subject comprising administering a fucosylated HMO to the subject, wherein the fucosylated HMO is 3-fucosyllactose (3-FL), and wherein the subject is an infant, a young child or a child.
  • a fucosylated HMO is 3-fucosyllactose (3-FL)
  • the subject is an infant, a young child or a child.
  • the invention provides a method of improving brain development and/or social-emotional development in a subject comprising administering a nutritional composition comprising a fucosylated HMO to the subject, wherein the fucosylated HMO is 3- fucosyllactose (3-FL), and wherein the subject is an infant, a young child or a child.
  • the invention provides a fucosylated HMO for improving brain development and/or social-emotional development in a subject, wherein the fucosylated HMO is 3- fucosyllactose (3-FL), and wherein the subject is an infant, a young child or a child.
  • the fucosylated HMO is 3- fucosyllactose (3-FL)
  • the subject is an infant, a young child or a child.
  • the invention provides a nutritional composition comprising a fucosylated HMO for improving brain development and/or social-emotional development in a subject, wherein the fucosylated HMO is 3-fucosyllactose (3-FL), and wherein the subject is an infant, a young child or a child.
  • a fucosylated HMO for improving brain development and/or social-emotional development in a subject, wherein the fucosylated HMO is 3-fucosyllactose (3-FL), and wherein the subject is an infant, a young child or a child.
  • brain development and social-emotional development are improved. In some embodiments, brain development is improved. In some embodiments, social- emotional development is improved.
  • the improvement in brain development and/or social-emotional development in the subject comprises or consists of an improvement in the development of brain network(s) associated with social-emotional functions.
  • brain network(s) associated with social-emotional functions e.g. brain network(s) activated during social- emotional functions and tasks
  • MRI brain magnetic resonance imaging
  • candidate network strength coupled with assessment of social-emotional skills may be used.
  • the methods employed herein may be used (see Materials & Methods, Example 1 ).
  • Brain networks associated with social-emotional functions may be referred to herein as “social- emotional brain networks”.
  • the improvement in brain development and/or social-emotional development in the subject comprises or consists of an improvement in the development of social-emotional brain networks.
  • improving brain development and/or social-emotional development in the subject comprises or consists of promoting the default mode network (DMN).
  • DNN default mode network
  • the improvement in brain development in the subject comprises or consists of an improvement in the development of social-emotional brain networks.
  • improving brain development in the subject comprises or consists of promoting the default mode network (DMN).
  • DNN default mode network
  • the improvement in social-emotional development in the subject comprises or consists of an improvement in the development of social-emotional brain networks.
  • improving social-emotional development in the subject comprises or consists of promoting the default mode network (DMN).
  • DNN default mode network
  • the invention provides the use of a fucosylated HMO for promoting the default mode network (DMN) in a subject, wherein the fucosylated HMO is 3- fucosyllactose (3-FL), and wherein the subject is an infant, a young child or a child.
  • DNN default mode network
  • the invention provides the use of a nutritional composition comprising a fucosylated HMO for promoting the default mode network (DMN) in a subject, wherein the fucosylated HMO is 3-fucosyllactose (3-FL), and wherein the subject is an infant, a young child or a child.
  • a nutritional composition comprising a fucosylated HMO for promoting the default mode network (DMN) in a subject, wherein the fucosylated HMO is 3-fucosyllactose (3-FL), and wherein the subject is an infant, a young child or a child.
  • the invention provides the use of a fucosylated HMO in the manufacture of a medicament for promoting the default mode network (DMN) in a subject, wherein the fucosylated HMO is 3-fucosyllactose (3-FL), and wherein the subject is an infant, a young child or a child.
  • the medicament is a nutritional composition as described herein.
  • the invention provides a method of promoting the default mode network (DMN) in a subject comprising administering a fucosylated HMO to the subject, wherein the fucosylated HMO is 3-fucosyllactose (3-FL), and wherein the subject is an infant, a young child or a child.
  • DNN default mode network
  • the invention provides a method of promoting the default mode network (DMN) in a subject comprising administering a nutritional composition comprising a fucosylated HMO to the subject, wherein the fucosylated HMO is 3-fucosyllactose (3-FL) and/or A-tetrasaccharide, and wherein the subject is an infant, a young child or a child.
  • DNN default mode network
  • Bayley Scale of Infant and Toddler Development 3 rd edition or 4 th edition (BSID; Bayley N. Third Edition: Technical Manual. San Antonio, TX: Harcourt Assessment 2006 or Bayley N. Fourth Edition: Technical Manual. Bloomington, MN: NCS Pearson 2019), which provides a standardized assessment of adaptive behaviour, cognition, language, motor and social-emotional abilities for children of all ability levels up to 3.5 years of age, may be used.
  • the Ages and Stages Questionnaire Social-Emotional questionnaires (Squires, J. , Bricker, D. D. , & Twombly, E. (2002). ASQ:SE-2 user’s guide. Paul H. Brookes Publishing Co., Inc.), which provides a standardized assessment of adaptive behaviour, cognition, language, motor and social-emotional abilities for children of all ability levels up to 3.5 years of age, may be used.
  • the Ages and Stages Questionnaire provides a standardized assessment of social and emotional development in children between 0 and 6 years of age in seven key social-emotional areas: self-regulation, compliance, social-communication, adaptive functioning, autonomy, affect, interaction with people.
  • the improvement in brain development and/or social- emotional development comprises or consists of an improvement in social-emotional behaviour based on a score of the Bayley Scale of Infant and Toddler Development or on a score of the Ages and Stages Questionnaire.
  • the improvement in brain development and/or social-emotional development comprises or consists of an improvement in social-emotional behaviour based on a score of the Bayley Scale of Infant and Toddler Development.
  • the improvement in brain development and/or social-emotional development comprises or consists of an improvement in social-emotional behaviour based on a score of the Ages and Stages Questionnaire.
  • the improvement in social-emotional development consists of an improvement in social-emotional behaviour based on a score of the Bayley Scale of Infant and Toddler Development or on a score of the Ages and Stages Questionnaire.
  • the improvement in social-emotional development consists of an improvement in social-emotional behaviour based on a score of the Bayley Scale of Infant and Toddler Development.
  • the improvement in social-emotional development consists of an improvement in social-emotional behaviour based on a score of the Ages and Stages Questionnaire.
  • the determination of an improvement in brain development and/or social-emotional development may be carried out using any method known in the art, including brain magnetic resonance imaging (MRI) to determine default mode network strength.
  • MRI brain magnetic resonance imaging
  • the methods employed herein may be used (see Materials & Methods, Example 1 ).
  • brain development and/or social-emotional development are improved in a subject using 3-FL or a nutritional composition according to the invention, when compared to a corresponding composition which does not comprise 3-FL in accordance with the invention.
  • 3-FL is present in a total amount of from 50 mg/L to 2000 mg/L of the composition or nutritional composition according to the invention or of from 38 mg/100g to 1540 mg/100g of the composition or nutritional composition according to the invention.
  • 3-FL is present in a total amount of from 60 mg/L to 1500 mg/L, for example from 70 mg/L to 1000 mg/L, for example from 80 mg/L to 500 mg/L of the composition or nutritional composition according to the invention.
  • 3-FL is present in a total amount of from 45 mg/100g to 1160 mg/100g, for example from 53 g/100g to 770 mg/100g, for example from 61 mg/100g to 385 mg/ 100g of the composition or nutritional composition (dry weight).
  • the subject is an infant, a young child or a child.
  • the subject is an infant. In one embodiment, the subject is a young child. In one embodiment, the subject is a child.
  • the subject is an infant over 5 months old, a young child or a child.
  • the nutritional composition or 3-FL for use according to the invention may also be used in subject that was born by C-section or that was vaginally delivered.
  • the nutritional composition or 3-FL for use according to the invention can be for use before and/or during the weaning period.
  • the nutritional composition or 3-FL for use according to the invention is for use in a subject at risk and/or in need.
  • the subject at risk and/or in need may be bottle-fed and/or formula-fed.
  • the subject at risk and/or in need may be a subject who has difficulties in social-emotional development.
  • a subject who has difficulties in social-emotional function may be identified using the methods described herein for the assessment of social-emotional development (e.g. the Bayley Scale of Infant and Toddler Development or the Ages and Stages questionnaire).
  • the composition or 3-FL for use according to the invention is given to the subject as a supplementary composition to the mother's milk.
  • the subject receives the mother's milk during at least the first 2 weeks, first 1 , 2, 4, 6 or 12months.
  • the nutritional composition or 3-FL for use according to the invention is given to the subject after such period of mother's nutrition or is given together with such period of mother's milk nutrition.
  • the nutritional composition or 3-FL for use according to the invention is given to the subject as the sole or primary nutritional composition during at least one period of time, e.g. after the 1 st , 2 nd or 4 th month of life, during at least 1 , 2, 4, 6 or 12 months.
  • the nutritional composition of the invention is a complete nutritional composition (fulfilling all or most of the nutritional needs of the subject).
  • the nutritional composition or 3-FL for use according to the invention is a supplement or a fortifier intended for example to supplement human milk or to supplement an infant formula or a follow-on formula.
  • the nutritional composition according to the present invention may also comprise other types of oligosaccharide(s), polysaccharides and/or a fiber(s) and/or a precursor(s) thereof.
  • the other oligosaccharide and/or fiber and/or precursor thereof may be selected from the list comprising human milk oligosaccharides (HMOs), galacto-oligosaccharides (GOS), fructooligosaccharides (FOS), xylooligosaccharides (XOS), cello-oligosaccharides (COS), arabinoxylans, arabinans, xylans, inulin, polydextrose, beta-glucans, pectins and any combination thereof and any derived products, like partial hydrolysis products, thereof. They may be in an amount between 0 and 10% by weight of composition.
  • the nutritional composition or the combination can also contain at least one BMO (bovine milk oligosaccharide).
  • HMOs which may be included in the nutritional composition or combination according to the present invention may be selected from the group consisting of 2’-FL (2’- fucosyllactose), Lacto-difucotetraose (LDFT)), lacto-N-fucopentaose I, lacto-N-fucopentaose II, lacto-N- fucopentaose III, lacto-N-fucopentaose V, lacto-N-fucohexaose, lacto-N-difucohexaose I (LNDFH I), fucosyllacto-N-hexaose, fucosyllacto-N-neohexaose, difucosyllacto-N-hexaose I, difucosyllacto-N-hexaose II, para-lacto-N-neohexaose (para-LNnH), L
  • the nutritional composition according to the invention comprises at least one additional HMO. In other embodiments, the nutritional composition according to the present invention is devoid of any further HMOs. Thus, 3-FL may be the sole HMO in the nutritional composition of the invention.
  • the nutritional composition according to the invention generally contains a protein source.
  • the protein can be in an amount of from 1 .6 to 3 g per 100 kcal. In some embodiments, the protein amount can be between 2.4 and 4 g/100kcal or more than 3.6 g/100kcal. In some other embodiments the protein amount can be below 2.0 g per 100 kcal, e.g. between 1 .8 to 2 g/100 kcal, or in an amount below 1.8 g per 100 kcal.
  • Protein sources based on whey, casein and mixtures thereof may be used as well as protein sources based on soy. As far as whey proteins are concerned, the protein source may be based on acid whey or sweet whey or mixtures thereof and may include alpha-lactalbumin and beta-lactoglobulin in any desired proportions.
  • the protein source is whey predominant (i.e. more than 50% of proteins are coming from whey proteins, such as 60% or 70%).
  • the proteins may be intact or hydrolysed or a mixture of intact and hydrolysed proteins.
  • intact is meant that the main part of the proteins are intact, i.e. the molecular structure is not altered, for example at least 80% of the proteins are not altered, such as at least 85% of the proteins are not altered, preferably at least 90% of the proteins are not altered, even more preferably at least 95% of the proteins are not altered, such as at least 98% of the proteins are not altered. In a particular embodiment, 100% of the proteins are not altered.
  • hydrolysed means in the context of the present invention a protein which has been hydrolysed or broken down into its component amino acids.
  • the proteins may be either fully or partially hydrolysed. It may be desirable to supply partially hydrolysed proteins (degree of hydrolysis between 2 and 20%), for example for infants or young children believed to be at risk of developing cow’s milk allergy.
  • the hydrolysis process may be carried out as desired and as is known in the art.
  • whey protein hydrolysates may be prepared by enzymatically hydrolysing the whey fraction in one or more steps. If the whey fraction used as the starting material is substantially lactose free, it is found that the protein suffers much less lysine blockage during the hydrolysis process. This enables the extent of lysine blockage to be reduced from about 15% by weight of total lysine to less than about 10% by weight of lysine; for example about 7% by weight of lysine which greatly improves the nutritional quality of the protein source.
  • At least 70% of the proteins are hydrolysed, preferably at least 80% of the proteins are hydrolysed, such as at least 85% of the proteins are hydrolysed, even more preferably at least 90% of the proteins are hydrolysed, such as at least 95% of the proteins are hydrolysed, particularly at least 98% of the proteins are hydrolysed. In a particular embodiment, 100% of the proteins are hydrolysed.
  • the proteins of the nutritional composition are hydrolysed, fully hydrolysed or partially hydrolysed.
  • the degree of hydrolysis (DH) of the protein can be between 8 and 40, or between 20 and 60 or between 20 and 80 or more than 10, 20, 40, 60, 80 or 90.
  • the protein component can alternatively be replaced by a mixture or synthetic amino acid.
  • the nutritional composition according to the present invention generally contains a carbohydrate source. This is particularly preferable in the case where the nutritional composition of the invention is an infant formula.
  • any carbohydrate source conventionally found in infant formulae such as lactose, sucrose, saccharose, maltodextrin, starch and mixtures thereof may be used although one of the preferred sources of carbohydrates is lactose.
  • the nutritional composition according to the present invention generally contains a source of lipids. This is particularly relevant if the nutritional composition of the invention is an infant formula.
  • the lipid source may be any lipid or fat which is suitable for use in infant formulae.
  • Some suitable fat sources include palm oil, structured triglyceride oil, high oleic sunflower oil and high oleic safflower oil, medium-chain-triglyceride oil.
  • the essential fatty acids linoleic and a-linolenic acid may also be added, as well small amounts of oils containing high quantities of preformed arachidonic acid and docosahexaenoic acid such as fish oils or microbial oils.
  • the fat source may have a ratio of n-6 to n-3 fatty acids of about 5:1 to about 15:1 ; for example about 8:1 to about 10:1.
  • the nutritional composition of the invention may contain emulsifiers and stabilisers such as soy, lecithin, citric acid esters of mono- and di-glycerides, and the like.
  • the nutritional composition of the invention may also contain other substances which may have a beneficial effect such as lactoferrin, nucleotides, nucleosides, and the like.
  • the nutritional composition of the invention may also contain carotenoid(s). In some particular embodiments of the invention, the nutritional composition of the invention does not comprise any carotenoid.
  • the nutritional composition according to the invention can be for example an infant formula, a starter infant formula, a follow-on or follow-up formula, a growing-up milk, a baby food (such as yogurt, pureed or mashed baby food), an infant cereal composition, a fortifier such as a human milk fortifier or a supplement.
  • the composition of the invention is an infant formula, a fortifier or a supplement that may be intended for the first 4 or 6 months of age.
  • the nutritional composition of the invention is an infant formula.
  • the nutritional composition or 3-FL for use according to the present invention is a fortifier.
  • the fortifier can be a breast milk fortifier (e.g. a human milk fortifier) or a formula fortifier such as an infant formula fortifier or a follow-on/follow-up formula fortifier.
  • the nutritional composition or 3-FL for use according to the invention when the nutritional composition or 3-FL for use according to the invention is a supplement, it can be provided in the form of unit doses. In such cases it is particularly useful to define the amount of oligosaccharides in terms of daily dose to be administered to the infant, young child or child.
  • the nutritional composition or 3-FL for use according to the invention when the nutritional composition or 3-FL for use according to the invention is a supplement, it may comprise 3-FL and no other additional nutrient on top of the excipients necessary to obtain a stable composition.
  • the nutritional composition or 3-FL for use according to the invention when the nutritional composition or 3-FL for use according to the invention is a supplement, it may comprise 3-FL in combination with one or more further HMOs (e.g. one or more further HMOs as described herein) and no other additional nutrient on top of the excipients necessary to obtain a stable composition.
  • the nutritional composition or 3-FL for use according to the invention can be in solid (e.g. powder), liquid or gelatinous form.
  • the nutritional composition or 3- FL for use according to the invention is a supplement, wherein the supplement is in powder form and provided in a sachet, preferably a sachet with 0.1 to 20 g per sachet, for example 1 to 10 g per sachet, or in the form of a syrup, preferably a syrup with a total solid concentration of 5 to 75 g/100 mL (5 to 75% (w/v)).
  • the supplement may comprise a carrier. It is however preferred that the supplement is devoid of a carrier.
  • the components are preferably dissolved or suspended in water acidified with citrate.
  • the nutritional composition or 3-FL for use according to the invention according to the invention is a hypoallergenic composition.
  • the composition or 3-FL for use according to the invention according to the invention is a hypoallergenic nutritional composition.
  • the nutritional composition or 3-FL for use according to the invention according to the invention may be prepared in any suitable manner.
  • a composition will now be described by way of example.
  • a formula such as an infant formula may be prepared by blending together the protein source, the carbohydrate source and the fat source in appropriate proportions. If used, the emulsifiers may be included at this point. The vitamins and minerals may be added at this point but they are usually added later to avoid thermal degradation. Any lipophilic vitamins, emulsifiers and the like may be dissolved into the fat source prior to blending. Water, preferably water which has been subjected to reverse osmosis, may then be mixed in to form a liquid mixture. The temperature of the water is conveniently in the range between about 50°C and about 80°C to aid dispersal of the ingredients. Commercially available liquefiers may be used to form the liquid mixture.
  • the oligosaccharide(s) may be added at this stage, especially if the final product is to have a liquid form. If the final product is to be a powder, they may likewise be added at this stage if desired.
  • the liquid mixture is then homogenised, for example in two stages.
  • the liquid mixture may then be thermally treated to reduce bacterial loads, by rapidly heating the liquid mixture to a temperature in the range between about 80°C and about 150°C for a duration between about 5 seconds and about 5 minutes, for example. This may be carried out by means of steam injection, an autoclave or a heat exchanger, for example a plate heat exchanger.
  • the liquid mixture may be cooled to between about 60°C and about 85°C for example by flash cooling.
  • the liquid mixture may then be again homogenised, for example in two stages between about 10 MPa and about 30 MPa in the first stage and between about 2 MPa and about 10 MPa in the second stage.
  • the homogenised mixture may then be further cooled to add any heat sensitive components, such as vitamins and minerals.
  • the pH and solids content of the homogenised mixture are conveniently adjusted at this point.
  • the homogenised mixture is transferred to a suitable drying apparatus such as a spray dryer or freeze dryer and converted to powder.
  • the powder should have a moisture content of less than about 5% by weight.
  • the oligosaccharide(s) may also or alternatively be added at this stage by dry-mixing or by blending them in a syrup form of crystals, alone or along with one or more other ingredients, and the mixture is spray-dried or freeze-dried.
  • the homogenised mixture may be sterilised then aseptically filled into suitable containers or may be first filled into the containers and then retorted.
  • the composition or combination of the invention may be a supplement.
  • the supplement may be in the form of tablets, capsules, pastilles or a liquid for example.
  • the supplement when it is in the form of a liquid, it can be an aqueous solution containing 1 -50 wt% HMO, preferably 5-35 wt% HMO, more preferably 5-15 wt%, such as 10 wt% HMO.
  • the supplement in the form of a liquid can be a tea or a juice.
  • the supplement may further contain protective hydrocolloids (such as gums, proteins, modified starches), binders, film forming agents, encapsulating agents/materials, wall/shell materials, matrix compounds, coatings, emulsifiers, surface active agents, solubilizing agents (oils, fats, waxes, lecithins etc.), adsorbents, carriers, fillers, co-compounds, dispersing agents, wetting agents, processing aids (solvents), flowing agents, taste masking agents, weighting agents, jellifying agents and gel forming agents.
  • protective hydrocolloids such as gums, proteins, modified starches
  • binders film forming agents, encapsulating agents/materials, wall/shell materials, matrix compounds, coatings, emulsifiers, surface active agents, solubilizing agents (oils, fats, waxes, lecithins etc.), adsorbents, carriers, fillers, co-compounds, dispersing agents, wetting agents, processing aid
  • the supplement may also contain conventional pharmaceutical additives and adjuvants, excipients and diluents, including, but not limited to, water, gelatine of any origin, vegetable gums, lignin-sulfonate, talc, sugars, starch, gum arabic, vegetable oils, polyalkylene glycols, flavouring agents, preservatives, stabilizers, emulsifying agents, buffers, lubricants, colorants, wetting agents, fillers, and the like.
  • conventional pharmaceutical additives and adjuvants, excipients and diluents including, but not limited to, water, gelatine of any origin, vegetable gums, lignin-sulfonate, talc, sugars, starch, gum arabic, vegetable oils, polyalkylene glycols, flavouring agents, preservatives, stabilizers, emulsifying agents, buffers, lubricants, colorants, wetting agents, fillers, and the like.
  • the supplement may contain an organic or inorganic carrier material suitable for oral or parenteral administration as well as vitamins, minerals trace elements and other micronutrients in accordance with the recommendations of Government bodies such as the USRDA.
  • HM samples were extracted until no more HM was expressed. Whenever possible, to minimize the HM compositions diurnal variation, HM samples were standardized to the second feed of the day. An aliquot of at least 30 mL of volume was transferred from the collection bottle to a 50 mL polypropylene Falcon tube, mixed well by vortexing and dispatched in 1 and 2 mL aliquots for storage at -80°C until further use.
  • HMOs 2’-FL, 3-FL, 3’-SL, 6’-SL, Lacto-N-tetraose (LNT), Lacto-N-neotetraose (LNnT), Lacto-N- fucopentaose-l (LNFP-I), and A-tetra, were quantified using standard curves with authentic HMO standards.
  • LNT Lacto-N-tetraose
  • LNnT Lacto-N-neotetraose
  • LNFP-I Lacto-N- fucopentaose-l
  • A-tetra were quantified using standard curves with authentic HMO standards.
  • 3’-SL and 6’-SL were log-transformed to ensure normality in their distribution.
  • rs-fMRI images were preprocessed using FMRIB Software Library (FSL) ((Smith et al., Neuroimage, 2004, 23 Suppl 1 : S208-19), including typical preprocessing steps.
  • FSL FMRIB Software Library
  • Anatomical images were segmented using iBEAT V2.0 (http://www.ibeat.doud) to generate brain tissue segmentation images (Dai et al., Neuroinformatics, 2013, 11 : 211 -225). Each voxel was labeled as gray matter, white matter, or cerebrospinal fluid.
  • tissue segmentation images were then used to register to the MNI template using the advanced normalization tools (ANTS) (Avants et al., NeuroImage, 2011 , 54: 2033-2044; Li et al., NeuroImage, 2014, 90: 266-279; Li et al., Medical Image Analysis, 2015. 25: 22-36; Li et al., NeuroImage, 2019, 185: 906-925; and Wang etal., Volume-Based Analysis of 6-Month-Old Infant Brain MRI for Autism Biomarker Identification and Early Diagnosis, in Medical Image Computing and Computer Assisted Intervention - MICCAI 2018. 2018. Cham: Springer International Publishing) .
  • ALS advanced normalization tools
  • the AAL atlas with 90 regions-of-interest (ROIs) Tzourio-Mazoyer et al., NeuroImage, 2002, 15: 273-289) was deformed back to the subject space to extract the preprocessed time-series BOLD signals of each ROI from rs-fMRI images.
  • a 90x90 functional connectivity (FC) matrix was derived by calculating the Pearson's correlation between each pair of ROIs, reflecting the connection between pairs of brain regions, for each subject.
  • the network construction was adopted by matching the AAL atlas to the functional networks detected by the independent component analysis (Beckmann et al., Philos Trans R Soc Lond B Biol Sci, 2005, 360: 1001 -13; and Tagliazucchi etal., Neuron, 2014, 82: 695-708), including medial visual network (MVN), lateral visual network (LVN), default mode network (DMN), sensorimotor network (SMN), auditory/language processing network (AUD/LANG), and the executive control network (ECN).
  • a network connection strength an average of correlation coefficients of all connections within a given network, was obtained for each network. In the context of early brain development, the network connection strengths have been implicated to be a surrogate marker of brain functional maturation. Thus, the network connection strengths were used as the outcomes in our study.
  • the starting model included all eight HMOs.
  • An age cutoff between 3 and 15 months with an increment of one month was applied for each of the eight HMOs.
  • AIC Akaike information criterion
  • the functional network strength can be evaluated as how strongly are the parts of the functional network interrelated.
  • the default mode network (DMN) strength was derived by calculating the Pearson’s correlation between each pair of the following regions of interest: Cuneus, superior frontal gyrus (both medial and dorsal component), posterior cingulate gyrus, rectus gyrus, angular gyrus, precuneus, thalamus and superior temporal gyrus.
  • These regions of the default mode network largely activate in tasks requiring participants to understand and interact with others, such as perceiving and interpreting other's emotion status, showing empathy to other people, inferring other's belief and intention, and performing moral judgments on other's behaviour (Schilbach et al., Conscious. Cogn., 2008, 17: 457-467; and Laird et al., J. Cogn. Neurosci., 2011 , 23: 4022-4037).
  • benefits associated with this domain are social-emotional skills.

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Abstract

L'invention concerne un oligosaccharide de lait humain (HMO) fucosylé destiné à être utilisé pour améliorer le développement cérébral et/ou le développement émotionnel social chez un sujet, le HMO fucosylé étant le 3-fucosyllactose (3-FL), et le sujet étant un nourrisson, un jeune enfant ou un enfant.
PCT/EP2024/073332 2023-08-29 2024-08-20 Compositions comprenant des oligosaccharides de lait humain destinées à être utilisées chez un sujet pour prendre en charge le développement cérébral et/ou le développement émotionnel social Pending WO2025045657A1 (fr)

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