WO2023232882A1 - Formule pour nourrisson permettant d'améliorer le développement cognitif - Google Patents

Formule pour nourrisson permettant d'améliorer le développement cognitif Download PDF

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Publication number
WO2023232882A1
WO2023232882A1 PCT/EP2023/064569 EP2023064569W WO2023232882A1 WO 2023232882 A1 WO2023232882 A1 WO 2023232882A1 EP 2023064569 W EP2023064569 W EP 2023064569W WO 2023232882 A1 WO2023232882 A1 WO 2023232882A1
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lipid
nutritional composition
infant
mother
formula
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PCT/EP2023/064569
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English (en)
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Anniek Lidewij SCHIPPER
Harvey LOUISE
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N.V. Nutricia
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Publication of WO2023232882A1 publication Critical patent/WO2023232882A1/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 COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/115—Fatty acids or derivatives thereof; Fats or oils
    • A23L33/12—Fatty acids or derivatives thereof
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • 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
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system

Definitions

  • the present invention relates to a nutritional composition for infants at risk for cognitive impairment due to being born to a mother with hyperglycemia during pregnancy.
  • Human milk is the uncontested gold standard concerning infant nutrition. However, in some cases breastfeeding is inadequate or unsuccessful for medical reasons or because of a choice not to breastfeed. For such situations infant or follow-on formulas have been developed.
  • Commercial infant formulas are commonly used today to provide supplemental or sole source of nutrition early in life. These formulas comprise a range of nutrients to meet the nutritional needs of the growing infant, and typically include fat, carbohydrate, protein, vitamins, minerals, and other nutrients helpful for optimal infant growth and development.
  • Commercial infant formulas are designed to mimic, as closely as possible, the composition and function of human milk.
  • Human milk lipids are known to have a distinct physical structure composed of large lipid globules with a mode diameter, based on volume, of about 4 pm existing of a triglyceride core coated by a tri-layer of membranes, the milk fat globule membrane (MFGM).
  • the mode diameter, based on volume, of lipid droplets in standard infant formula is typically about 0.3-0.5 pm due to the industrial processing procedures applied to achieve stable and reproducible products, and the lipid droplets are not surrounded by MFGM but mostly by milk proteins.
  • Infant formula with lipid globules with an architecture more similar to the lipid globules in human milk have been described.
  • Hyperglycemia is a condition in which a high amount of glucose circulates in the blood plasma. Hyperglycemia is typically caused by diabetes type 1 , diabetes type 2, gestational diabetes mellites (GDM) or other endocrine disorders. In 2021 , about 21 million live births were affected by hyperglycemia during pregnancy (https://diabetesatlas.org/data/en/indicators/13/). GDM is characterized by spontaneous hyperglycemia and alterations in lipid metabolism during pregnancy. Worldwide, 7-10% pregnancies are affected by GDM.
  • Ornoy et al. doi: 10.1515/jpem.2001 ,14.s1 .681 , describes a study wherein the neurobehavioral function at school age is measured of 57 children born to 48, well controlled, diabetic mothers and of 32 children born to 32 women with gestational diabetes. Their development was compared with 57 control children matched by age, birth order and parental socio-economic status, using a number of cognitive, behavioral, sensory and motor neurological tests. Pregestational or gestational diabetes was found to adversely affect attention span and motor functions of offspring at school age, but not their cognitive ability.
  • WO2011/115490 describes a nutritional composition comprising phospholipids for use in altering the brain membrane fatty acid composition and for the amelioration of cognitive performance and behavioral performance in a human subject.
  • WO2011/115491 describes a nutritional composition comprising lipid globules with a defined particle size distribution for use in altering the brain membrane fatty acid composition and for the amelioration of cognitive performance and behavioral performance in a human subject.
  • WO2016/024864 describes a nutritional composition with lipid globules with a defined particle size distribution for improving behavior selected from increasing novel object recognition, increasing the preference for novelty, increasing the attention for surroundings and increasing exploratory behavior/activity.
  • W02018/104512 describes a nutritional composition with lipid globules with a defined particle size distribution and further comprising an increased level of sn-2 palmitate for altering the cell membrane fatty acid composition, in particular in brain and red blood cell membranes, and for improving cognitive development and behavioral performance in a human subject.
  • WO2019/244137 describes methods of treating or preventing gestational diabetes mellitus (GDM) and/or treating or preventing one or more GDM associated risks or one or more sequelae of GDM by administering one or more polar lipids to a subject in need thereof, which includes both the mother and the child.
  • GDM gestational diabetes mellitus
  • a clinical trial is described in this document, wherein a maternal milk product with enhanced levels of polar lipids was assessed for its effect on reducing the risk of developing GDM during pregnancy.
  • W02006/050975 describes the use of long chain polyunsaturated fatty acid compositions for feeding an infant of a mother who suffered from a metabolic disorder during pregnancy and a nutritional composition with polyunsaturated fatty acids suitable for such use.
  • the present inventors have surprisingly found that the consumption of a nutritional composition comprising phospholipids beneficially affects the cognitive development of infants born to a mother with hyperglycemia during pregnancy.
  • a mouse model was used, wherein a GDM-like phenotype was induced in dams by feeding them a short-term high-fat diet and exposing them to three mild streptozotocin triggers (to reduce beta cell capacity).
  • the offspring of these GDM dams were exposed to hyperglycemia in utero.
  • dams were fed the high-fat diet, but not exposed to the streptozotocin triggers.
  • These dams did not develop a GDM-like phenotype and their offspring was exposed to normal levels of glucose during pregnancy.
  • the maternal blood glucose was determined at gestational day 16.
  • the maternal blood glucose levels positively correlated to offspring brain omega-6/omega-3 ratio at postnatal day 2 and 21 .
  • higher ARA/DHA ratio, higher LA/ALA ratio, lower EPA content and increased content of omega-6 docosapentaenoic acid (n6 DPA) correlated with higher maternal blood glucose levels.
  • stearic acid was negatively correlated with higher maternal blood glucose levels.
  • maternal blood glucose was negatively correlated to offspring brain weight at postnatal day 21 .
  • a suboptimal balance of omega-6 and omega-3 fatty acids (/.e.
  • omega-6 to omega-3 ratio in brain cell membranes is associated with suboptimal brain development and neurocognitive impairments.
  • the ratio of omega-6 to omega-3 poly-unsaturated fatty acids in the membrane influences neurotransmission and prostaglandin formation, processes that are vital for normal brain development, maintenance and function [Haag, doi: 10.1177/070674370304800308],
  • EPA which is known to be a critical omega-3 fatty acid during brain development. Higher EPA levels in the brain are considered advantageous.
  • EPA in brain cell membranes serves as precursor for DHA, which is essential to pre- and postnatal brain development and cognition. Moreover, EPA beneficially effects neuronal differentiation , a process important during brain development.
  • EPA in the membrane is also a precursor to anti-inflammatory and pro-resolutive metabolites, and therefore plays an essential role in neuroprotection, which is associated with mood and behavior [Martinat et al., doi: 10.3390/nu13041185], n6 DPA is an omega-6 LCPUFA that typically accumulates in the brain when the supply or synthesis of DHA is not sufficient to meet the high needs of the developing brain.
  • n6 DPA is a structural homologue of DHA, is does not fulfil the same beneficial effects as DHA for brain development such as neurite outgrowth [Novak et al., doi: 10.1016/j.brainres.2008.07.107; Calderon et al., doi: 10.11 11/j.1471-4159.2004.02520.x], High brain n6 DPA during development is considered disadvantageous and is typically associated with neurocognitive dysfunction.
  • Stearic acid (C18:0) is one of the most abundant saturated fatty acids (SFA) in the brain and is important during development in early life for e.g. myelin formation and protection of neurons against oxidative stress and other environmental challenges [Wang et al., doi: 10.1 111/j.1745-7254.2007.00512.x; Wang et al., doi: 10.111 1/j.1745-7254.2006.00259.x], C18:0 is also used as a precursor for oleic acid (C18:1 n-9), these fatty acids accumulate in the brain during early life and a reduced content may be indicative of delayed brain development.
  • SFA saturated fatty acids
  • C18:0 and C18:1 n-9 are important for neuronal differentiation and myelinization [Martinez, doi: 10.1016/s0022-3476(05)81247-8], Infants born to mothers with gestational diabetes were shown to have abnormal brain white matter (myelin) structure development [Xuan et al., doi: 10.1097/RCT.0000000000001 110]
  • Lower brain volume is indicative of brain growth impairments during fetal and/or early postnatal life.
  • Low brain volume is typically associated with neurocognitive dysfunction and/or intellectual disability [Bach et al., doi: 10.1038/S41390-019-0683-2]
  • the offspring when the offspring was fed the (i) or (ii) nutritional composition according to the invention, the correlation between the maternal blood glucose levels and the aforementioned fatty acid levels in the brain fatty acid composition was not present anymore. This was unexpected, since the overall fatty acid composition in all the nutritional compositions (i)-(iii) was similar. Since the consumption of the nutritional composition (i) or (ii) corrects the impaired brain fatty acid profile in the GDM offspring, the cognitive development of the GDM offspring is improved by the consumption of these nutritional compositions according to the invention.
  • the offspring was fed the (ii) nutritional composition according to the invention, besides the beneficial effect on the brain fatty acid composition, the negative correlation between the maternal blood glucose levels and the brain weight was also not present anymore.
  • the present invention hence relates to nutritional compositions, in particular infant formula, follow-on formula and young child formula, comprising higher levels of phospholipids that can be used to improve the cognitive development in infants at risk of developing impaired neurodevelopmental outcomes due to being born to a mother with hyperglycemia during pregnancy.
  • a first aspect of the invention relates to a nutritional composition, selected from infant formula, follow- on formula and young child formula, comprising digestible carbohydrates, protein and lipid, wherein the lipid comprises 0.5 to 20 wt.% phospholipids based on total lipid, for use in improving the cognitive development in a human subject, wherein the human subject is an infant born to a mother with hyperglycemia during pregnancy.
  • the invention may also be worded as a method for improving the cognitive development in a human subject, wherein the human subject is an infant born to a mother with hyperglycemia during pregnancy, said method comprising feeding said human subject a nutritional composition, selected from infant formula, follow-on formula and young child formula, comprising digestible carbohydrates, protein and lipid, wherein the lipid comprises 0.5 to 20 wt.% phospholipids based on total lipid.
  • the invention may also be worded as the use of phospholipids in the manufacture of a nutritional composition for improving the cognitive development in a human subject, wherein the human subject is an infant born to a mother with hyperglycemia during pregnancy, wherein the nutritional composition is selected from infant formula, follow-on formula and young child formula and wherein the nutritional composition comprises digestible carbohydrates, protein and lipid, wherein the lipid comprises 0.5 to 20 wt.% phospholipids based on total lipid.
  • administering a nutritional composition to an infant is considered non-therapeutic.
  • the invention may be worded as defined above by way of a method comprising administering a nutritional composition.
  • the method can also be defined as a non-therapeutic method.
  • the words “non-therapeutic” exclude any therapeutic effect.
  • a ‘mother with hyperglycemia during pregnancy’ is a mother who has been diagnosed by a health care professional to have hyperglycemia for prolonged periods of time during pregnancy.
  • Hyperglycemia is a high blood sugar level of at least 10 mM.
  • a prolonged period of time could be for example at least 2 weeks, preferably at least 1 month, more preferably at least 2 months.
  • a ‘mother with diabetes at the time of conception’ is a mother who has been diagnosed by a health care professional with diabetes mellitus type 1 or diabetes mellitus type 2.
  • this diagnosis of diabetes mellitus type 1 or 2 was made by a health care professional at the latest at the end of the 1 st trimester during the pregnancy of the infant.
  • the mother with diabetes at the time of conception is a mother with diabetes mellitus type 2.
  • a ‘mother with gestational diabetes’ is a mother who has been diagnosed by a health care professional to suffer from gestational diabetes mellitus (GDM) during pregnancy.
  • GDM gestational diabetes mellitus
  • the GDM diagnosis is preferably based on IADPSG criteria (IADPSG: International Association of Diabetes and Pregnancy Study Group).
  • IADPSG International Association of Diabetes and Pregnancy Study Group.
  • a GDM diagnosis is made at the earliest in the second trimester during pregnancy. GDM occurs in pregnant women without a previous history of diabetes and is transient, i.e. the pathology disappears when the woman is not pregnant anymore.
  • the infant born to a mother with hyperglycemia during pregnancy is preferably selected from the group consisting of:
  • GDM gestational diabetes
  • the infant born to a mother with hyperglycemia during pregnancy is an infant born to a mother with gestational diabetes (GDM).
  • GDM gestational diabetes
  • the cognitive development is neurocognitive development.
  • the improvement in cognitive development in the human subject is compared to similar human subjects who did not consume the nutritional composition according to the invention, but a standard or control nutritional composition.
  • the standard or control nutritional composition is fed to a human subject from the same group, of the same age and for the same period of time.
  • the improvement of cognitive development in the human subject is compared to an infant born to a mother with hyperglycemia during pregnancy, which consumed a nutritional composition, selected from infant formula, follow-on formula and young child formula, comprising digestible carbohydrates, protein and lipid, wherein the lipid comprises less than 0.5 wt.% phospholipids based on total lipids.
  • the improvement of cognitive development in the human subject is compared to an infant born to a mother with hyperglycemia during pregnancy, which consumed a nutritional composition, selected from infant formula, follow-on formula and young child formula, comprising digestible carbohydrates, protein and lipid, wherein the lipid comprises less than 0.5 wt.% phospholipids based on total lipids; and wherein the lipid is in the form of lipid globules and wherein the lipid globules have a mode diameter, based on volume, of around 0.5 pm and/or less than 45 volume %, based on total lipid volume, of the lipid globules have a diameter above 2 pm.
  • the cognitive function in the human subject is improved by normalizing the fatty acid levels in the brain cell membranes of said human subject to the fatty acid levels in the brain cell membranes of infants who were born to mothers with normal glucose blood levels during pregnancy.
  • ‘normalizing the fatty acid levels in the brain cell membranes’ preferably means that the nutritional composition removes or largely reduces the medical pathologies that are associated with sub-optimal fatty acid levels due to exposure to hyperglycemia in utero, such as cognitive dysfunction.
  • the normalizing of the fatty acids in the brain cell membranes is by normalizing one or more fatty acids selected from: a. stearic acid (C18:0); b. eicosapentaenoic acid (EPA; 20:5 n-3); c. omega-6 docosapentaenoic acid (n6 DPA; n-6 C22:5); d. omega-6 to omega-3 PUFA ratio; and e. omega-6 to omega-3 LCPUFA ratio.
  • the normalizing of the fatty acids in the brain cell membranes is by normalizing stearic acid and/or omega-6 docosapentaenoic acid. Most preferably, the normalizing of the fatty acids in the brain cell membranes is by normalizing stearic acid.
  • the lipid in the nutritional composition is in the form of lipid globules and wherein: a) the lipid globules have a mode diameter, based on volume, of at least 1 .0 pm; and/or b) at least 45 volume %, based on total lipid volume, of the lipid globules have a diameter of 2 to 12 pm; wherein the lipid globules are at least partly coated on the surface with phospholipids and wherein the lipid comprises 0.5 to 20 wt.% phospholipids based on total lipid, wherein the cognitive function is improved by normalizing the brain weight of said human subject to the brain weight of infants who were born to mothers with normal glucose blood levels during pregnancy.
  • ‘normalizing the brain weight’ preferably means that the nutritional composition removes or largely reduces the medical pathologies that are associated with impaired brain growth due to exposure to hyperglycemia in utero, such as cognitive dysfunction.
  • the nutritional composition for use according to the present invention comprises lipid.
  • Lipid in the present invention comprises one or more selected from the group consisting of triglycerides, polar lipids (such as phospholipids, cholesterol, glycolipids, sphingomyelin), free fatty acids, monoglycerides and diglycerides.
  • the composition comprises at least 70 wt.%, more preferably at least 80 wt.%, even more preferably at least 85 wt.% triglycerides, most preferably at least 90 wt.% triglycerides based on total lipid.
  • the lipid provides preferably 30 to 60% of the total calories of the nutritional composition. More preferably the nutritional composition comprises lipid providing 35 to 55% of the total calories, even more preferably the nutritional composition comprises lipid providing 40 to 50% of the total calories.
  • the lipid is preferably present in an amount of 3 to 7g per 100 kcal, more preferably in an amount of 4 to 6g lipid per 100 kcal and most preferably in an amount of 4.5 to 5.5g lipid per 100 kcal.
  • the nutritional composition preferably comprises 2.1 to 6.5g lipid per 100 ml, more preferably 3.0 to 4.0g per 100 ml. Based on dry weight the nutritional composition preferably comprises 10 to 50 wt.%, more preferably 12.5 to 40 wt.% lipid, even more preferably 19 to 30 wt.% lipid.
  • the lipid preferably comprises vegetable lipid.
  • the presence of vegetable lipid advantageously enables an optimal fatty acid profile high in polyunsaturated fatty acids and/or more reminiscent to human milk fat.
  • Lipid from non-human mammalian milk alone, e.g. cow milk, does not provide an optimal fatty acid profile.
  • the amount of essential fatty acids is too low in non-human mammalian milk.
  • the nutritional composition comprises at least one, preferably at least two vegetable lipid sources selected from the group consisting of linseed oil (flaxseed oil), rape seed oil (such as colza oil, low erucic acid rape seed oil and canola oil), sunflower oil, high oleic sunflower oil, safflower oil, high oleic safflower oil, olive oil, coconut oil, palm oil and palm kernel oil.
  • linseed oil flaxseed oil
  • rape seed oil such as colza oil, low erucic acid rape seed oil and canola oil
  • sunflower oil high oleic sunflower oil
  • safflower oil high oleic safflower oil
  • olive oil coconut oil, palm oil and palm kernel oil.
  • the nutritional composition comprises 30 to 90 wt.% vegetable lipid based on total lipid, more preferably 35 to 80 wt.%, more preferably 40 to 70 wt.%, more preferably 40 to 60 wt.% vegetable lipid based on total lipid.
  • the lipid in the nutritional composition preferably further comprises mammalian milk fat, preferably ruminants milk fat, more preferably the mammalian milk fat is derived from cow milk, goat milk, sheep milk, buffalo milk, yak milk, reindeer milk, and/or camel milk, most preferably the mammalian milk fat is cow milk fat.
  • the mammalian milk fat is not human milk fat.
  • the mammalian milk fat comprises at least 70 wt.% triglycerides, more preferably at least 90 wt.%, more preferably at least
  • the mammalian milk fat is derived from butter, butter fat, butter oil, and/or anhydrous milk fat, more preferably the mammalian milk fat is derived from anhydrous milk fat and/or butter oil.
  • Such mammalian milk fat sources are high in triglyceride levels.
  • These mammalian milk fat sources may be in the form of a continuous lipid phase or a water-in-oil emulsion. The use of these mammalian milk fat sources during the manufacture of the nutritional composition of the present invention enables the formation of lipid globules, wherein each globule comprises a mixture of vegetable fat and mammalian milk fat.
  • Mammalian milk fat in the present invention refers to all lipid components of milk, as produced by the mammalians, such as the cow, and is found in commercial milk and milk-derived products.
  • Butter in the present invention is a water-in-oil emulsion comprised of over 80 wt.% milk fat.
  • Butterfat in the present invention relates to all of the fat components in milk that are separable by churning, in other words, present in butter.
  • Anhydrous milk fat (AMF) is a term known in the art and relates to extracted milk fat. Typically AMF comprises more than 99 wt.% lipid based on total weight. It can be prepared from extracting milk fat from cream or butter.
  • Anhydrous butter oil in the present invention is synonymous with AMF.
  • Butteroil also is a term known in the art. It typically relates to a milk fat extract with more than
  • lipid typically is a precursor in the process of preparing anhydrous milk fat or anhydrous butter oil.
  • the composition comprises 10 to 70 wt.% mammalian milk fat based on total lipid, more preferably 20 to 65 wt.%, more preferably 30 to 60 wt.%, more preferably 40 to 60 wt.% based on total lipid.
  • the ratio of vegetable fat to mammalian milk fat ranges from 3/7 to 9/1.
  • the lipid in the nutritional composition comprises: a) 35 to 80 wt.% vegetable lipid based on total lipid, and b) 20 to 65 wt.% mammalian milk fat based on total lipid, wherein the mammalian milk fat is selected from butter, butter fat, butter oil or anhydrous milk fat.
  • the lipid in the nutritional composition comprises: a) 40 to 70 wt.% vegetable lipid based on total lipid, and b) 30 to 60 wt.% mammalian milk fat based on total lipid, wherein the mammalian milk fat is selected from butter, butter fat, butter oil or anhydrous milk fat.
  • the lipid in the nutritional composition comprises: a) 40 to 60 wt.% vegetable lipid based on total lipid, and b) 40 to 60 wt.% mammalian milk fat based on total lipid, wherein the mammalian milk fat is selected from butter, butter fat, butter oil or anhydrous milk fat.
  • the nutritional composition preferably also comprises one or more of fish oil, egg lipid, and microbial, algal, fungal or single cell oils.
  • the lipid in the nutritional composition comprises at least 10 wt.% PA based on total fatty acids and at least 15 wt.% of PA, based on total palmitic acid, is located at the sn-2 position of a triglyceride.
  • the amount of PA is below 30 wt.% based on total fatty acids. More preferably, the amount of PA is from 12 to 26 wt.% based on total fatty acids, even more preferably from 14 to 24 wt.%.
  • At least 15 wt.% PA, more preferably at least 20 wt.% PA, even more preferably at least 25 wt.% PA, most preferably at least 30 wt.% PA, based on total PA is in the sn-2 or beta position in a triglyceride.
  • the amount of PA in the sn-2 position in a triglyceride is not more than 45 wt.%, preferably not more than 40 wt.% based on total PA present in the lipid.
  • the amount of PA in the sn-2 position in a triglyceride is from 25 to 40 wt.% based on total PA.
  • the lipid in the nutritional composition comprises 0.6 to 5 wt.% SCFA being the sum of BA and CA based on total fatty acids.
  • the nutritional composition comprises less than 5 wt.% BA based on total fatty acids, preferably less than 4 wt.%.
  • the nutritional composition comprises at least 0.5 wt.% butyric acid based on total fatty acids, preferably at least 0.6 wt.%, preferably at least 0.9 wt.%, more preferably at least 1 .2 wt.% BA based on total fatty acids.
  • the lipid in the nutritional composition comprises:
  • SCFA • 0.6 to 5 wt.% SCFA being the sum of BA and CA based on total fatty acids.
  • SFA relates to saturated fatty acids and/or acyl chains
  • MUFA relates to mono-unsaturated fatty acid and/or acyl chains
  • PUFA refers to polyunsaturated fatty acids and/or acyl chains with 2 or more unsaturated bonds
  • LC-PUFA refers to long chain polyunsaturated fatty acids and/or acyl chains comprising at least 20 carbon atoms in the fatty acyl chain and with 2 or more unsaturated bonds
  • Medium chain fatty acids (MCFA) refer to fatty acids and/or acyl chains with a chain length of 6, 8 or 10 carbon atoms.
  • n3 or omega-3 PUFA refers to polyunsaturated fatty acids and/or acyl chains with 2 or more unsaturated bonds with an unsaturated bond at the third carbon atom from the methyl end of the fatty acyl chain
  • n6 or omega-6 PUFA refers to polyunsaturated fatty acids and/or acyl chains with 2 or more unsaturated bonds with an unsaturated bond at the sixth carbon atom from the methyl end of the fatty acyl chain.
  • a weight percentage of fatty acids based on total fatty acids is calculated as if all fatty acids are free fatty acids, hence it is not taken into account whether a fatty acid is attached to a glycerol backbone or not.
  • EPA refers to eicosapentaenoic acid and/or acyl chain (20:5 n3); ARA refers to arachidonic acid and/or acyl chain (20:4 n6).
  • LA refers to linoleic acid and/or acyl chain (18:2 n6); ALA refers to alphalinolenic acid and/or acyl chain (18:3 n3).
  • PA relates to palmitic acid and/or acyl chains (C16:0).
  • BA refers to butyric acid (C4:0).
  • CA refers to caproic acid (C6:0).
  • LA refers to linoleic acid and/or acyl chain and is an n6 PUFA (18:2 n6) and the precursor of n6 LC- PUFA and is an essential fatty acid as it cannot be synthesized by the human body.
  • the nutritional composition preferably comprises LA.
  • LA preferably is present in a sufficient amount to promote a healthy growth and development, yet in an amount as low as possible to prevent negative, competitive, effects on the formation of n3 PUFA and a too high n6/n3 ratio.
  • the nutritional composition therefore preferably comprises less than 20 wt.% LA based on total fatty acids, preferably 5 to 16 wt.%, more preferably 10 to 14.5 wt.%.
  • the nutritional composition comprises at least 5 wt.% LA based on total fatty acids, preferably at least 6 wt.% LA, more preferably at least 7 wt.% LA based on total fatty acids.
  • the nutritional composition preferably comprises 350 - 1400 mg LA.
  • ALA refers to alpha-linolenic acid and/or acyl chain and is an n3 PUFA (18:3 n3) and the precursor of n3 LC-PUFA and is an essential fatty acid as it cannot be synthesized by the human body.
  • the nutritional composition preferably comprises ALA.
  • ALA is present in a sufficient amount to promote a healthy growth and development of the infant.
  • the nutritional composition preferably comprises at least 1 .0 wt.%, more preferably the nutritional composition comprises at least 1 .5 wt.%, even more preferably at least 2.0 wt.% ALA based on total fatty acids.
  • the nutritional composition comprises less than 10 wt.% ALA, more preferably less than 5.0 wt.%, based on total fatty acids.
  • the nutritional composition comprises a weight ratio of LA/ALA from 2 to 20, more preferably from 3 to 16, even more preferably from 4 to 14, most preferably from 5 to 12.
  • the lipid in the nutritional composition preferably comprises 5 to 35 wt.% PUFA, based on total fatty acids, comprising LA and ALA in a weight ratio LA/ALA of 2 to 20.
  • the nutritional composition comprises n3 LC-PUFA, such as EPA, DPA and/or DHA, more preferably DHA.
  • EPA EPA
  • DPA DPA
  • DHA DHA
  • both ALA and DHA are present in the nutritional composition.
  • the nutritional composition comprises at least 0.05 wt.%, preferably at least 0.1 wt.%, more preferably at least 0.2 wt.%, of DHA based on total fatty acids.
  • the nutritional composition comprises not more than 2.0 wt.%, preferably not more than 1 .0 wt.% of DHA based on total fatty acids.
  • the nutritional composition preferably comprises ARA.
  • the nutritional composition comprises at least 0.05 wt.%, preferably at least 0.1 wt.%, more preferably at least 0.2 wt.% of ARA based on total fatty acids.
  • the nutritional composition preferably comprises relatively low amounts of ARA.
  • the nutritional composition comprises not more than 2.0 wt.%, preferably not more than 1 .0 wt.% of ARA based on total fatty acids.
  • the weight ratio between DHA and ARA is between 1 :4 to 4:1 , more preferably between 1 :2 to 2:1 , more preferably between 0.6 and 1 .5.
  • the lipid in the nutritional composition is in the form of lipid globules and wherein: a. the lipid globules have a mode diameter, based on volume, of at least 1 .0 pm; and/or b. at least 45 volume %, based on total lipid volume, of the lipid globules have a diameter of 2 to 12 pm.
  • Lipid is typically present in the nutritional composition in the form of lipid globules. When the nutritional composition is in liquid form, these lipid globules are emulsified in the aqueous phase. Alternatively, when the nutritional composition is in powder form, the lipid globules are present in the powder and the powder is suitable for reconstitution with water or another food grade aqueous phase.
  • the lipid globules comprise a core and a surface.
  • the lipid globules in the nutritional composition preferably have mode diameter, based on volume, of at least 1 .0 pm, more preferably at least 2.0 pm, and most preferably at least 3.0 pm.
  • the lipid globules have a mode diameter, based on volume, between 1.0 and 10 pm, more preferably between 2.0 and 8.0 pm, even more preferably between 3.0 and 7.0 pm, and most preferably between 4.0 pm and 6.0 pm.
  • the size distribution of the lipid globules is preferably in such a way that at least 45 volume % (vol.%), preferably at least 55 vol.%, even more preferably at least 65 vol.%, and most preferably at least 75 vol.% of the lipid globules have a diameter between 2 and 12 pm.
  • at least 45 vol.%, preferably at least 55 vol.%, more preferably at least 65 vol.%, and most preferably at least 75 vol.% of the lipid globules have a diameter between 2 and 10 pm.
  • At least 45 vol.%, more preferably at least 55 vol.%, yet even more preferably at least 65 vol.%, and most preferably at least 75 vol.% of the lipid globules have a diameter between 4 and 10 pm. Preferably less than 5 vol.% of the lipid globules have a diameter above 12 pm.
  • Standard infant formulas, follow-on formulas or young child formulas typically have lipid globules with a mode diameter, based on volume, of about 0.3-0.5 pm and/or less than 45 vol.% of the lipid globules have a diameter above 2 pm.
  • the volume percentage of lipid globules is based on volume of total lipid.
  • the mode diameter relates to the diameter which is the most present based on volume % of total lipid, or the peak value in a graphic representation, having on the X-as the diameter and on the Y-as the volume %.
  • the volume of the lipid globule and its size distribution can suitably be determined using a particle size analyzer such as a Mastersizer 2000 (Malvern Instruments, Malvern, UK), for example by the method described in Michalski et al, 2001 , Lait 81 : 787-796.
  • a particle size analyzer such as a Mastersizer 2000 (Malvern Instruments, Malvern, UK), for example by the method described in Michalski et al, 2001 , Lait 81 : 787-796.
  • the nutritional composition comprises 0.5 to 20 wt.% phospholipid based on total lipid, preferably 0.5 to 10 wt.%, even more preferably 0.75 to 8 wt.%, even more preferably 1 .2 to 8 wt.%, and most preferably 1 .5 to 5 wt.% phospholipid based on total lipid.
  • the lipid in the nutritional composition is in the form of lipid globules and wherein: a. the lipid globules have a mode diameter, based on volume, of at least 1 .0 pm; and/or b. at least 45 volume %, based on total lipid volume, of the lipid globules have a diameter of 2 to 12 pm. wherein the lipid globules are at least partly coated on the surface with phospholipids.
  • coating is meant that the outer surface layer of the lipid globules comprises phospholipid, whereas phospholipid is virtually absent in the core of the lipid globule.
  • a suitable way to determine whether phospholipid is located on the surface of lipid globules is confocal laser scanning microscopy or transmission electron microscopy; see for instance Gallier et al. (A novel infant milk formula concept: Mimicking the human milk fat globule structure, Colloids and Surfaces B: Biointerfaces 136 (2015) 329- 339).
  • the nutritional composition preferably comprises glycerophospholipids.
  • glycerophospholipids are phosphatidylcholine (PC), phosphatidylserine (PS), phosphatidylethanolamine (PE), phosphatidylinositol (PI) and phosphatidylglycerol (PG).
  • PC phosphatidylcholine
  • PS phosphatidylserine
  • PE phosphatidylethanolamine
  • PI phosphatidylinositol
  • PG phosphatidylglycerol
  • the nutritional composition comprises one or more of PC, PS, PI and PE, more preferably the nutritional composition comprises at least PC.
  • the nutritional composition preferably comprises sphingomyelin. Sphingomyelins have a phosphorylcholine or phosphorylethanolamine molecule esterified to the 1 -hydroxy group of a ceramide.
  • the nutritional composition comprises 0.05 to 10 wt.% sphingomyelin based on total lipid, more preferably 0.1 to 5 wt.%, even more preferably 0.2 to 2 wt.% based on total lipid.
  • the nutritional composition comprises at least 5 wt.%, more preferably 5 to 40 wt.% sphingomyelin based on total phospholipid, more preferably 10 to 35 wt.%, even more preferably 15 to 35 wt.%, based on total phospholipid.
  • the nutritional composition preferably comprises glycosphingolipids.
  • the nutritional composition comprises 0.1 to 10 wt.% glycosphingolipids based on total lipid, more preferably 0.5 to 5 wt.%, even more preferably 2 to 4 wt.%, based on total lipid.
  • glycosphingolipids in the present context particularly refers to glycolipids with an amino alcohol sphingosine.
  • the sphingosine backbone is O-linked to a charged head-group such as ethanolamine, serine or choline backbone.
  • the backbone is also amide linked to a fatty acyl group.
  • Glycosphingolipids are ceramides with one or more sugar residues joined in a beta-glycosidic linkage at the 1 -hydroxyl position, and include gangliosides.
  • the nutritional composition contains gangliosides, more preferably at least one ganglioside selected from the group consisting of GM3 and GD3.
  • the nutritional composition preferably comprises phospholipid derived from mammalian milk.
  • the nutritional composition comprises phospholipid and glycosphingolipid derived from mammalian milk.
  • the nutritional composition preferably comprises phospholipid and optionally glycosphingolipid from mammalian milk from cows, mares, sheep, goats, buffalos, horses and/or camels. More preferably the nutritional composition comprises phospholipid and optionally glycosphingolipid from cow’s milk.
  • Phospholipid derived from milk includes preferably phospholipid that is isolated from milk fat, cream lipid, cream serum lipid, butter serum lipid (beta serum lipid), whey lipid, cheese lipid and/or buttermilk lipid.
  • Buttermilk lipid is typically obtained during the manufacture of buttermilk.
  • Butter serum lipid or beta serum lipid is typically obtained during the manufacture of anhydrous milk fat from butter.
  • the phospholipid and optionally glycosphingolipid is obtained from milk cream.
  • suitable commercially available sources for phospholipid from milk are BAEF, SM2, SM3 and SM4 powder of Corman, Salibra of Glanbia, Lipamin M20 of Lecico and LacProdan MFGM-10 or PL20 of Aria.
  • the use of phospholipid from milk fat advantageously comprises the use of milk fat globule membranes, which are more pronounced to the situation in human milk.
  • the concomitant use of phospholipid derived from milk and triglycerides derived from a mix of vegetable lipid and mammalian milk fat therefore enables the manufacture of coated lipid globules with a coating more similar to human milk, while at the same time providing an optimal fatty acid profile.
  • the phospholipid is derived from mammalian milk fat, more preferably from cow’s mammalian milk fat.
  • the phospholipid is derived from or forms part of the milk fat globule membrane (MFGM), more preferably is derived from or forms part of cow’s MFGM.
  • the nutritional composition comprises phospholipid and glycosphingolipid.
  • the weight ratio of phospholipid : glycosphingolipid is from 2:1 to 12:1 , more preferably from 2:1 to 10:1 and even more preferably 2:1 to 5:1 .
  • Methods for obtaining lipid globules with an increased size and coating with phospholipid are for example disclosed in WO 2010/027258 and WO 2010/027259.
  • the nutritional composition comprises digestible carbohydrates.
  • the digestible carbohydrates preferably provide 25 to 75% of the total calories of the nutritional composition.
  • Preferably the digestible carbohydrates provide 40 to 60% of the total calories.
  • the nutritional composition preferably comprises of 5 to 20g of digestible carbohydrates per 100 kcal, more preferably 6 to 16g per 100 kcal.
  • the nutritional composition preferably comprises 3 to 30g digestible carbohydrate per 100 ml, more preferably 6 to 20g, even more preferably 7 to 10g per 100 ml.
  • Based on dry weight the nutritional composition preferably comprises 20 to 80 wt.%, more preferably 40 to 65 wt.% of digestible carbohydrates.
  • Preferred digestible carbohydrate sources are one or more of lactose, glucose, sucrose, fructose, galactose, maltose, starch and maltodextrin.
  • Lactose is the main digestible carbohydrate present in human milk. Lactose has a low glycemic index.
  • the nutritional composition preferably comprises lactose.
  • the nutritional composition preferably comprises digestible carbohydrate, wherein at least 35 wt.%, more preferably at least 50 wt.%, more preferably at least 75 wt.%, even more preferably at least 90 wt.%, most preferably at least 95 wt.% of the digestible carbohydrate is lactose. Based on dry weight the nutritional composition preferably comprises at least 25 wt.% lactose, preferably at least 40 wt.% lactose.
  • the nutritional composition comprises protein.
  • the protein preferably provides 5 to 20% of the total calories.
  • the nutritional composition comprises protein that provides 6 to 12% of the total calories.
  • the nutritional composition comprises less than 3.5g protein per 100 kcal, more preferably the nutritional composition comprises between 1 .5 and 2.1g protein per 100 kcal, even more preferably between 1.6 and 2.0g protein per 100 kcal.
  • a low protein concentration advantageously is closer to human milk as human milk comprises a lower amount of protein based on total calories compared to cow’s milk.
  • the protein concentration in a nutritional composition is determined by the sum of protein, peptides and free amino acids.
  • the nutritional composition preferably comprises less than 12 wt.% protein, more preferably between 9.6 and 12 wt.%, even more preferably between 10 and 11 wt.%.
  • the nutritional composition preferably comprises less than 1.5g protein per 100ml, more preferably between 1.2 and 1.5g per 100ml, even more preferably between 1 .25 and 1 ,35g per 100ml.
  • the source of the protein is preferably selected in such a way that the minimum requirements for essential amino acid content are met and satisfactory growth is ensured.
  • protein sources based on cows' milk proteins such as whey, casein and mixtures thereof and proteins based on soy, potato or pea are preferred.
  • the protein source is preferably based on acid whey or sweet whey, whey protein isolate or mixtures thereof.
  • the nutritional composition comprises at least 3 wt.% casein based on dry weight.
  • the casein is intact and/or non-hydrolyzed.
  • the nutritional composition preferably comprises non-digestible oligosaccharides.
  • the nutritional composition comprises non-digestible oligosaccharides with a degree of polymerization (DP) between 2 and 250, more preferably between 3 and 60.
  • DP degree of polymerization
  • the nutritional composition comprises fructo-oligosaccharides, galacto-oligosaccharides and/or galacturonic acid oligosaccharides, more preferably fructo-oligosaccharides and/or galactooligosaccharides, even more preferably galacto-oligosaccharides, most preferably transgalactooligosaccharides.
  • the nutritional composition comprises a mixture of galactooligosaccharides and fructo-oligosaccharides, more preferably transgalacto-oligosaccharides and fructo-oligosaccharides.
  • Suitable non-digestible oligosaccharides are for example VivinalOGOS (FrieslandCampina DOMO), RaftilinOHP or Raftilose® (Orafti).
  • the nutritional composition comprises 80 mg to 2g non-digestible oligosaccharides per 100 ml, more preferably 150 mg to 1.5g per 100 ml, even more preferably 300 mg to 1g per 100 ml.
  • the nutritional composition preferably comprises 0.25 wt.% to 20 wt.%, more preferably 0.5 wt.% to 10 wt.%, even more preferably 1 .5 wt.% to 7.5 wt.% of non-digestible oligosaccharides.
  • the use according to the present invention requires the administration of an infant formula, a follow-on formula or a young child formula.
  • the composition that is administered is not human milk. It also means that the composition that is administered is not native cow’s milk or native milk from another mammal.
  • young child formula can also be named growing-up milk.
  • infant formula or “follow-on formula” or “young child formula” means that it concerns a composition that is artificially made or in other words that it is synthetic.
  • the nutritional composition that is administered is an artificial infant formula or an artificial follow-on formula or an artificial young child formula or a synthetic infant formula or a synthetic follow-on formula or a synthetic young child formula.
  • infant formula refers to nutritional compositions, artificially made, intended for infants of 0 to about 4 to 6 months of age and are intended as a substitute for human milk.
  • infant formulae are suitable to be used as sole source of nutrition.
  • Such infant formulae are also known as starter formula.
  • follow-on formula for infants starting with at 4 to 6 months of life to 12 months of life are intended to be supplementary feedings for infants that start weaning on other foods.
  • Infant formulae and follow-on formulae are subject to strict regulations, for example for the EU regulations no. 609/2013 and no. 2016/127.
  • young child formula refers to nutritional compositions, artificially made, intended for infants of 12 months to 36 months, which are intended to be supplementary feedings for infants.
  • the nutritional composition is preferably an infant formula or a follow-on formula. More preferably the nutritional composition is an infant formula.
  • the nutritional composition comprises digestible carbohydrates, protein and lipid, wherein the lipid preferably provides 30 to 60% of the total calories, the protein provides 5 to 20% of the total calories and the digestible carbohydrates provide 25 to 75% of the total calories.
  • the nutritional composition is preferably an infant formula or follow-on formula and preferably comprises 3 to 7g lipid/100 kcal, preferably 4 to 6g lipid/100 kcal, more preferably 4.5 to 5.5g lipid/100 kcal, preferably comprises 1.7 to 3.5g protein/100 kcal, more preferably 1.8 to 2.1g protein/100 kcal, more preferably 1.8 to 2.0g protein/100 kcal and preferably comprises 5 to 20g digestible carbohydrate/100 kcal, preferably 6 to 16g digestible carbohydrate/100 kcal, more preferably 10 to 15g digestible carbohydrate/100 kcal.
  • the nutritional composition is an infant formula or follow-on formula, and preferably has an energy density of 60 to 75 kcal/100 ml, more preferably 60 to 70 kcal/100 ml, when in a ready-to-drink form. This density ensures an optimal balance between hydration and caloric intake.
  • the nutritional composition is a powder.
  • the nutritional composition is in a powdered form, which can be reconstituted with water or other food grade aqueous liquid, to form a ready-to drink liquid, or is in a liquid concentrate form that should be diluted with water to a ready-to- drink liquid. It was found that lipid globules maintained their size and coating when reconstituted.
  • a second aspect of the invention relates to a nutritional composition, selected from infant formula, follow- on formula and young child formula, comprising digestible carbohydrates, protein and lipid, wherein the lipid comprises 0.5 to 20 wt.% phospholipids based on total lipid, for use in normalizing the fatty acid levels in the brain cell membranes of a human subject, wherein the human subject is an infant born to a mother with hyperglycemia during pregnancy, wherein the fatty acid levels in the brain cell membranes of said human subject are normalized to the fatty acid levels in the brain cell membranes of infants who were born to mothers with normal glucose blood levels during pregnancy.
  • a third aspect of the invention relates to a nutritional composition, selected from infant formula, follow- on formula and young child formula, comprising digestible carbohydrates, protein and lipid, wherein the lipid is in the form of lipid globules and wherein: a) the lipid globules have a mode diameter, based on volume, of at least 1 .0 pm; and/or b) at least 45 volume %, based on total lipid volume, of the lipid globules have a diameter of 2 to 12 pm; wherein the lipid globules are at least partly coated on the surface with phospholipids and wherein the lipid comprises 0.5 to 20 wt.% phospholipids based on total lipid, for use in normalizing the brain weight of a human subject, wherein the human subject is an infant born to a mother with hyperglycemia during pregnancy, wherein the brain weight of said human subject is normalized to the brain weight of infants who were born to mothers with normal glucose blood levels during pregnancy.
  • Figure 1 Three graphs showing the data points for offspring brain weight (g) at PN21 on the y-axis vs. the maternal glucose (mM) at gestational day 16 (E16) on the x-axis for the Test 1 , Test 2 and Control groups.
  • the offspring diets comprised a macronutrient and micronutrient composition following AIN93G.
  • the offspring diets consisted of 28.3% (w/w) IMF.
  • the fat components were derived entirely from the IMF. Protein, carbohydrates, and micronutrients were added to match AIN93G.
  • the fat content and fatty acid profile of the different diets comprising Test 1 , Test 2 and Control were similar (Table 1).
  • Test 1 IMF was prepared in a similar way as described in example 1 B of WO 2010/0027259.
  • the lipid globules of Test 1 IMF were large and coated with phospholipids.
  • Test 1 IMF comprised butter serum powder as a source of milk derived phospholipids including parts of milk fat globule membrane (MFGM). The butter serum powder was added before homogenization, which resulted in phospholipids being present in the coating of the lipid globules.
  • Control and Test 2 IMFs were prepared in the conventional way with a high pressure homogenization, resulting in small lipid globules.
  • Test 2 also comprised butter serum powder, which was added after homogenization.
  • a GDM mouse model was used to generate offspring which was exposed to GDM conditions during gestation.
  • the dams received 2 triggers before pregnancy in order to induce a transient GDM condition.
  • C57BL/6N dams were fed with a high fat diet (HFD) for 4 weeks to reduce insulin sensitivity.
  • HFD high fat diet
  • the HFD was based on the AIN93G diet with an adjusted lipid fraction containing 60 energy % lipid.
  • a low dose of streptozotocin 60 mg STZ/kg was administered on three consecutive days prior to mating (at 16 weeks of age).
  • STZ is an alkylating agent that selectively kills pancreatic beta-cells via cell necrosis and/or apoptosis.
  • GDM dams and sham treated dams were allowed to mate at 16 weeks.
  • the blood glucose level of all dams was determined during pregnancy at gestational day 16 (E16). After birth the offspring was breastfed/lactated with breast milk till post-natal day 16 (PN16). At PN2 litters were culled to 6 pups per dam.
  • the GDM and sham treated dams and offspring were split into 3 sub-groups, wherein each sub-group received a different diet (Test 1 , Test 2, or Control). The different diets were fed from PN16 till PN21.
  • mice At PN21 mice offspring were sacrificed and the brains were weighed. Of each brain, 1 hemisphere was homogenized (Utra-Turrax T25 basic, IKA, VWR international) in 50 volumes of ice cold deionized water (MiliQ). Subsequently, brain fatty acid (FA) profile was quantified by means of gas chromatographic analysis. 1 ml brain homogenate was extracted according to the procedure of Bligh & Dyer (dichloromethane / methanol extraction). The lipids were converted into methyl esters with concentrated sulfuric acid in methanol. The fatty acid methyl esters (FAME) were extracted from the methanol solution with hexane and analyzed on a gas chromatograph (GC) equipped with a flame ionization detector (FID).
  • GC gas chromatograph
  • FID flame ionization detector
  • Correlation analyses were performed for each diet group including all offspring from both GDM and sham-treated dams to explore the relation between maternal blood glucose at E16 and offspring brain weight and brain cell membrane fatty acid content at PN21 .
  • the consumption of the diets Test 1 orTest 2 normalized the fatty acid levels in the brain cell membranes of the offspring exposed to hyperglycemia in utero to the fatty acid levels in the brain cell membranes of offspring exposed to normal glucose levels in utero.
  • Infant formula intended for infants of 0 to 6 months of age, comprising per 100 ml, after reconstituting 13.7 g powder to an end volume of 100 ml:
  • non-digestible oligosaccharides of which 0.08 g long chain fructo-oligosaccharides (source RaftilineHP) and 0.72 g trans-galacto-oligosaccharides (source Vivinal GOS) minerals, vitamins, trace elements and other micronutrients as according to directives for infant formula.
  • the formula comprises lipid globules with a volume mode diameter of about 5.6 pm and the volume % of lipid globules with a mode diameter between 2 and 12 pm is above 45.
  • mice offspring born to dams that were kept on an omega 3 deficient diet throughout gestation and lactation The omega 3 deficient diet of the dams will result in an impaired brain fatty acid profile in the offspring and this may be mitigated by adding specific phospholipids to the diet of the offspring.
  • the offspring experimental diets comprised a macronutrient and micronutrient composition following AIN93G.
  • the offspring diets consisted of 28.3% (w/w) of infant milk formula (IMF).
  • the fat components were derived entirely from the IMF. Protein, carbohydrates, and micronutrients were added to match AIN93G.
  • the diets differed in the source of phospholipids (PL), the MILK-PL diets comprised milk- derived PL and the SOY-PL comprised soy-derived PL.
  • the fat content and fatty acid profile of the different diets were similar (Table 4).
  • the omega 3-deficient diet was continued throughout pregnancy and lactation. The day that the litter was born was considered postnatal day (PN) 0. At PN2, litters were culled to 6 pups per dam. From PN16 onwards litters (with dam) were randomly assigned to receive either of the two experimental diets.
  • Tissue fatty acid fatty acid species were expressed as a percentage of total fatty acids (% FA) in Table 5. The values between brackets are the standard deviation.
  • Table 5 Brain cell membrane fatty acid composition
  • the type of phospholipid in the diet did not differ in the effect on the fatty acid composition of brain cell membranes.

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Abstract

L'invention concerne une composition nutritionnelle comprenant des glucides digestibles, des protéines et des lipides, les lipides comprenant des phospholipides, destinée à être utilisée dans l'amélioration du développement cognitif chez un nourrisson né d'une mère atteinte d'hyperglycémie pendant la grossesse.
PCT/EP2023/064569 2022-05-31 2023-05-31 Formule pour nourrisson permettant d'améliorer le développement cognitif WO2023232882A1 (fr)

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