WO2011069987A1 - Lait maternisé comprenant des probiotiques et des composants de membrane de globule gras du lait - Google Patents

Lait maternisé comprenant des probiotiques et des composants de membrane de globule gras du lait Download PDF

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Publication number
WO2011069987A1
WO2011069987A1 PCT/EP2010/069016 EP2010069016W WO2011069987A1 WO 2011069987 A1 WO2011069987 A1 WO 2011069987A1 EP 2010069016 W EP2010069016 W EP 2010069016W WO 2011069987 A1 WO2011069987 A1 WO 2011069987A1
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Prior art keywords
mfgm
composition
probiotics
peptide
nutritional composition
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PCT/EP2010/069016
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English (en)
Inventor
Jalil Benyacoub
Stéphanie Blum-Sperisen
Mohamed Nabil Bosco
Lionel Jean René BOVETTO
Isabelle Bureau-Franz
Anne Donnet-Hughes
Eduardo Schiffrin
Laurent Favre
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Nestec S.A.
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Application filed by Nestec S.A. filed Critical Nestec S.A.
Priority to BR112012013766A priority Critical patent/BR112012013766A2/pt
Priority to US13/514,513 priority patent/US9226521B2/en
Priority to MX2012006640A priority patent/MX2012006640A/es
Priority to RU2012128546/10A priority patent/RU2563355C2/ru
Priority to EP10800906A priority patent/EP2509429A1/fr
Priority to CA2783768A priority patent/CA2783768A1/fr
Priority to AU2010329990A priority patent/AU2010329990B2/en
Priority to CN2010800555185A priority patent/CN102665428A/zh
Publication of WO2011069987A1 publication Critical patent/WO2011069987A1/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
    • A23L33/40—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 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
    • 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
    • A23L33/135—Bacteria or derivatives thereof, e.g. probiotics
    • 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
    • A23L33/17—Amino acids, peptides or proteins
    • A23L33/19—Dairy proteins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/20—Milk; Whey; Colostrum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/02—Nutrients, e.g. vitamins, minerals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23C—DAIRY PRODUCTS, e.g. MILK, BUTTER OR CHEESE; MILK OR CHEESE SUBSTITUTES; MAKING THEREOF
    • A23C2240/00—Use or particular additives or ingredients
    • A23C2240/05—Milk products enriched with milk fat globule membrane
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs

Definitions

  • This invention relates to an infant formula with probiotics and Milk Fat Globule Membranes components (MFGM) and /or bioactive proteins.
  • MFGM Milk Fat Globule Membranes components
  • E P 0 1 99 535, E P 0 768 375, WO 97/00078 , EP 0 577 903 and WO 00/53200 disclose specific strains of Lactobacilli and Bifidobacteria and their beneficial effects.
  • GALT gut associated lymphoid tissue
  • This process is in large part responsible for the sentinel capacity of gut immune cells to distinguish harmless and danger signals and as a consequence establish tolerance or immunity.
  • Large differences exist with respect to the composition of the gut microbiota in response to the infant's feeding .
  • the fecal flora of breast-fed infants includes appreciable populations of Bifidobacteria with some Lactobacillus species, whereas formula-fed infants have more complex microbiota, with Bifidobacteria, Bacteroides, Clostridia and Streptococci all usually present.
  • probiotics have been shown to stimulate immune defense mechanisms, antagonize pathogenic bacteria, promote a healthy microbiota, and down-regulate immune-related disorders such as allergies or inflammation in animals and humans.
  • the abil ity of specific probiotic bacterial strains to modulate the components of the intestinal microbiota of the host is one mechanism by which they affect the immune system.
  • a direct interaction with the mucosal immune system to stimulate the generation of immune-regulating cytokines has also been postulated and is further supported by recent findings of possible direct sampling of luminal bacteria by dendritic cells that extend dendrites across the intestinal epithelium. More recently, Benyacoub et al.
  • WO 2007/009187 A1 discloses the use of sour cream or buttermilk with probiotics.
  • Burn et al P. Burns, G Vinderola, F Molinari, J . Reinhemer. (2008) Suitability of whey and butterm il k for the growth and frozen storage of probiotic lactobacill i, International Journal of Dairy Technology 61 , Issue 2, 1 56-1 64 discloses in the abstract the use of whey or buttermilk as culture media for the growth and storage of probiotic lactobacilli.
  • Rodas et al (B.A. Rodas, J .O. Angulo, J . Cruz, H .S. Garcia (2002). Preparation of probiotic butterm il k with Lactobacill us reuteri . M ilchwissenschaft, 57(1 ), 26-28) discloses the use of Lactobacillus reuteri to prepare a probiotic buttermilk.
  • UA 30 063 discloses a drink comprising buttermilk, or a mix of buttermilk with cheese whey, or a mix of buttermilk with nonfat mil k and cheese whey as the milk vehicle together with a symbiotic probiotic starter culture of specific bifidobacteria and lactobacilli.
  • WO 2004/1 12509 provides an infant formula preparation containing MFGM and at least one microorganism for inducing a maturation of the physical barrier provided by the intestine in manner that is similar to that obtained with breast-feeding.
  • US 2008/0003330 A1 describes the use of an enriched whey protein concentrate containing MFGM, to provide bioactive lipids for brain and cognitive development and function in the infant.
  • FR 2908605 A1 discloses a nutritional product containing MFGM as a source of lipids for application in the gastrointestinal tract. It also discloses the use of specific strains of lactic acid bacteria. However, these bacteria are considered for their technological properties and not as probiotics. The present invention extends the use of MFGM to its use with probiotics with specific health benefits.
  • the invention relates to a composition, preferably an infant formula, comprising probiotics and MFGM.
  • the invention also relates to a composition for educating the immune system, promoting immune maturation, promoting immune maturation, and for treating or preventing a range of physio-pathological conditions such as treating or preventing inflammation, treating or preventing infections, treating or preventing dysregulated gut barrier function, improving gut comfort or combination thereof.
  • the invention is more particularly suitable for use in infants, pre-term infants, babies or individuals in needs.
  • Figure 1 Human Milk from 1 mother, 7 days postpartum. Bacterial DNA (Bands 1 and 2) appearing in particular in samples 5 and 6, i .e. in the cream fractions containing MFGM).
  • Figure 2 Human Milk from 2 mothers, Bacterial DNA (Bands indicated by the middle 2 arrows) appearing in particular in samples 2 and 3, i.e in the cream fractions containing MFGM).
  • FIG. 3 Electron micrographs of MFGM (N RC, F. Morgan) showing bacterial structures alone or in chains (marked with arrows), associated with the MFGM.
  • FIG. 5 Epithelial cell response to LPS. Probiotics and MFGM lower epithelial cells responsiveness to endotoxin challenge (LPS) and related inflammatory reaction. A cumulative effect could be observed with the combination of probiotics and MFGM, suggesting a synergy between the two ingredients.
  • LPS endotoxin challenge
  • FIG. 6 T cell activation. MFGM and probiotics promote T lymphocyte activation. A synergy could be observed between MFGM and B. lactis.
  • Figure 7 B cell activation. MFGM promotes B lymphocyte activation. Probiotics alone are less effective. A synergy could be observed between MFGM and probiotics.
  • FIG. 8 Non-specific intestinal IgA production. IgA-secreting cells levels isolated from Peyer's patches of mice fed MFGM for 1 week (A) and 4 weeks (B). Detailed Description of the Invention
  • infant means a child under the age of 36 months
  • infant formula means a foodstuff intended for the complete nutrition of infants during the first 12 months of life; In the context of the invention this applies more particularly to infants up to the age of 6 months.
  • “individual in need” means any infant, baby, child , adolescent or adult having particu lar physiolog ical needs in regard to the physio-pathological conditions considered and for which the proposed invention offers an improved or alternative solution. This includes patients of all ages suffering from such physio-pathological conditions.
  • prebiotic means a non-digestible food ingredient that beneficially affects the host by selectively stimulating the growth and/or activity of one or a limited number of bacteria in the colon and thus improves host health (Gibson and Roberfroid "Dietary Modulation of the Human Colonic Microbiota: Introducing the Concept of Prebiotics" J. Nutr 125:1401 - 1412).
  • probiotic means, in the context of bacterial strains, microbial cell preparations or components of microbial cells with a beneficial effect on the health or well-being of the host.
  • the first few weeks of the life of an infant means the period up to the end of the second month of life of the infant.
  • MFGM Milk Fat Globule Membrane
  • the present inventors recently observed that bacteria in human milk are associated inter alia with the cream fraction of the mil k. Th is d iscovery prompted further investigations into the association of bacteria and lipid as well as protein components in human milk and the effects of this association leading to the present invention.
  • the present invention provides a nutritional composition
  • a nutritional composition comprising a probiotic bacterial strain in an amount equivalent to from 10 3 to 10 12 cfu/g of dry formula and milk fat globule membrane (MFGM) in an amount of from 0.01 g to 0.1 g for 100g of liquid composition or formula, preferably from 0.03 to 0.1 g for 100g of liquid composition or formula, and/or from 0.01 g to 0.8 g for 1 00g of dry composition or formula, preferably from 0.1 to 0.5g for 1 00g of dry composition or formula.
  • the composition comprises M FGM in an amount of between 0.1 % and 1 0% w/w of total proteins, preferably between 0.5% and 5%.
  • the nutritional composition comprises MFGM in an amount between 0.01 g and 7g of MFGM per 100g of composition (w/w).
  • the invention MFGM originates from bovine, buffalo, horse, goat and/or human milk.
  • the Human milk fat globule membrane protein composition is still largely unknown, although it counts for 2-4% of the total milk protein content (Stephania Quaranta et al . Human proteome en hancement: H igh-recovery method and improved two dimensional map of colostral fat globule membrane proteins. Electrophoresis 2001 , 22, 1 81 0-1818).
  • the invention encompasses an amount of Human milk fat globule membrane ranging from 0.1 % to 1 0% of the total protein of the com position or formula, preferably from 0.5% to 2% of the total protein of the composition or formula
  • the invention also extends to the use of a probiotic bacterial strain and m il k fat globule membrane in the manufacture of a nutritional composition for promoting the maturation of the immune system of a neonatal infant in the first few weeks of life.
  • the invention further extends to the use of a probiotic bacterial strain and milk fat globule membrane in the manufacture of a nutritional composition for the prevention or treatment of pathogenic infections in a neonatal infant in the first few weeks of life.
  • the invention extends to a method for promoting the maturation of the immune system of a neonatal infant in need thereof in the first few weeks of life.
  • the method comprises administering to the infant a therapeutic a mou nt of a nutritional composition comprising a probiotic bacteria and milk fat globule membrane.
  • the invention extends to a method for the prevention or treatment of pathogenic infections in a neonatal infant in need thereof in the first few weeks of life. It comprises administering to the infant a therapeutic amount of a nutritional composition com prising a probiotic bacteria and m il k fat globu le membrane.
  • the fat phase In mammalian milk, the fat phase generally accounts for around 40g/L and is mainly composed of triglycerides (96% of total fat), diglycerides (2% of total fat), and complex lipids (1 % of total fat).
  • Triglycerides synthesized in the smooth endoplasmic reticulum of the mammary alveolar cell coalesce into large droplets which migrate to the apical plasma membrane of the cell. The lipid droplets then push against and progressively become enveloped in the membrane of the mammary gland epithelial cells.
  • These membranes, budded off around the m il k l ipids as they are being secreted by the cells, are named the milk fat globule membranes.
  • the Milk fat globule membrane contains specific glycoproteins such as lactoferrin, mucins, lactadherin and xanth ine oxidase as wel l as com plex polar l i pids such as glycerophospholipids and sphingolipids. Many of these components are present in human milk in much higher concentrations than in bovine milk.
  • probiotics have been widely demonstrated to protect the host against infections and potentially improve specific disease outcomes.
  • probiotics Among the key criteria often used for probiotic strain selection is their capacity to adhere to the intestinal mucosa. This appears to be important for blocking pathogen adherence in vitro and for modulating protective immune functions.
  • bacteria binding to, or encapsulation of bacteria and/or their components within, the milk fat globule membrane may facil itate transport of the m icrobial components through the gastrointestinal system, ensure their del ivery to appropriate sites in the mucosal tissues of the suckling neonate and, together with other factors in the milk fat globule membrane, modulate immunological processes. It is hypothesized that the association of MFGM and probiotics leads to potentiation (synergy) of the beneficial effects seen using probiotics or milk fat globule membrane alone.
  • the present invention reveals immune modulating properties of MFGM in association with probiotics that are beyond what cou ld be ach ieved us ing the ind ivid ual ingredients alone.
  • probiotics and prebiotics are both recogn ised to have beneficial effects on health , their protective effects aga inst d iarrhoea in infants are lost when the two ing red ients are com bi ned (Chouraqui et al. 2007).
  • the cooperation and/or synergy between the probiotic and MFGM observed in the present invention could not have been predicted.
  • the present invention reports that the combination of probiotics with MFGM on the one hand may l im it some pro-inflammatory signals and as such, may l imit tissue da mage but on th e other h and en han ces m ucosa l protection by i ncreasi ng prod uction of secretory IgA by intestinal cel ls .
  • Th is suggests that combining probiotics with MFGM leads to a physiolog ical synergy by promoting distinct but complementary mechanisms which together provide an improved protection of the host.
  • co-administration of probiotics and MFGM may impact biological responses in different tissue sites or in different cell types from those targeted by the individual components. For example, through their co-administration, the survival of live probiotics during intestinal transit as well as the homing of probiotics and/or their attachment to specific intestinal sites may be improved.
  • the present invention extends the use of MFGM and probiotics to further aspects of gut barrier maturation such as immune maturation . Furthermore, since the coadministration of probiotics and MFGM may also influence anti-inflammatory processes, the present invention extends to their combined use not only in infants but in at-risk populations irrespective of age. As such, it may not be necessary that a product containing such ingredients be the sole source of nutrition during the period of administration
  • MFGM is a significant source of lipids to the infant and that certain bacteria may increase the expression of molecules involved in lipid absorption. It follows that it should be possible to produce similar beneficial effects in formula-fed infants by supplementing the formula with probiotics and milk fat globule membrane.
  • the probiotics can be pre-blended with MFGM before addition to the composition or the two preparations (probiotics, MFGM) can be added separately to the composition of the invention.
  • the nutritional composition of the invention is an infant formula.
  • the composition can be a children's food, liquid, semi-liquid or solid, especially for children between 0 and 7 years, or between 0 and 3 years.
  • the composition can be a baby cereal.
  • the composition of the invention can also be targeted to adolescent and adults suffering from particular physio-pathological conditions, especially those in need and/or having compromised gastro-intestinal systems and/or compromised immune / defense systems.
  • the probiotic is present in the formula in an amount equivalent to between 10 3 and 10 12 cfu/g of dry composition.
  • the bacteria may be used live, inactivated or dead or even be present as fragments such as DNA or cell wall materials.
  • the quantity of bacteria wh ich the formula contains is expressed in terms of the equivalent colony forming units of bacteria irrespective of whether they are, all or partly, live, inactivated, dead or fragmented
  • the probiotic is present in an amount equivalent to between 10 7 to 10 12 cfu/ g of dry composition.
  • the probiotic bacterial strain may be any lactic acid bacteria or Bifidobacteria with established probiotic characteristics.
  • the probiotic of the invention may be any probiotic bacterium or probiotic microorganism ("probiotics"), especially of human origin, in particular probiotics that have been or can be originated from, found in, extracted or isolated from milk upon excretion, preferably in human breast milk.
  • Suitable probiotic lactic acid bacteria include Lactobacillus rhamnosus ATCC 53103 obtainable inter alia from Va l io Oy of F i n l a nd u nd er th e trad e m a rk LG G , Lactobacillus rhamnosus CGMCC 1 .3724, Lactobacillus reuteri ATCC 55730 and Lactobacillus reuteri DSM 17938 obtainable from Biogaia, Lactobacillus fermentum VRI 003 and Lactobacillus paracasei CNCM 1-21 16, Lactobacillus johnsonii CNCM I- 1225, Lactobacillus helveticus CNCM I-4095, Bifidobacterium breve CNCM I-3865, Bifidobacterium longum CNCM 1-2618
  • Suitable probiotic Bifidobacteria strains include Bifidobacterium longum ATCC BAA- 999 sold by Morinaga Milk Industry Co. Ltd . of Japan under the trade mark BB536, the strain of Bifidobacterium breve sold by Danisco under the trade mark Bb-03, the strain of Bifidobacterium breve sold by Morinaga under the trade mark M-16V and the strain of Bifidobacterium breve sold by Institut Rosell (Lallemand) under the trade mark R0070.
  • a particularly preferred Bifidobacterium strain is Bifidobacterium lactis CNCM I-3446 which may be obtained from the Christian Hansen Company of Denmark under the trade mark Bb1 2.
  • a m ixture of su itable probiotic lactic acid bacteria and Bifidobacteria may be used.
  • MFGM can be present in cream, buttermilk and whole milk.
  • buttermilk fractions are the source most often used due to their relatively high concentration of MFGM components.
  • Examples of commercially available buttermilk products include butterm il k (product code 26048) from Land O'Lakes, Inc. M N, buttermilk protein concentrate fractions from Fonterra Cooperative Group (Auckland, New Zealand); a phospholipid-rich fraction derived from MFGM from the Fonterra Cooperative Group Ltd. (Auckland, New Zealand); buttermilk from Bullinger Butterei (Bullingen, Belgium), Foster Farms Dairy (Modesto, California), Dairy America Inc.
  • material may include Promilk 602 E from Ingredia Lacto familia AG (Ingredia SA , Arras France), and from any suppl iers containing MFGM (at least 1 .5% of M FGM components; in order to be able to adjust the amount of MFGM to total protein).
  • MFGM casein based or milk based
  • the MFGM can comprise proteins, gangliosides and/or phospholipids or combination thereof.
  • the MFGM may originate from butter milk , butter milk fractions, defatted butter milk, delactosylated butterm il k, butterm il k fraction obtained by m icrofiltration , or ultrafiltration, fractions recovered from whey protein concentrate, sweet whey, acid whey, whey cream or fat associated fraction from whey containing phospholipids; and/or wherein said MFGM comprises sphingomyelin, phosphatidyl ethanolamine, phosphatidylchol ine, phosphatidyl inositol , phosphatidyl serine, Cholesterol , gangliosides, Mucinl (MUC 1 ), Xantine-oxidase/dehydrogenase, Periodicacid Schiff (PAS III), CD36, Butyrophilin(BTN), ,Adipophilin(ADPH), PAS 6/7, Fatty-acid binding protein (FABP), lactoferrin , lactal
  • composition of the invention comprises proteins able to bind to the probiotic.
  • the MFGM and the probiotic of the invention can interact together at the biological level.
  • the MFGM can enhance or promote the biological effect of the probiotic.
  • the MFGM enables the probiotic to have a biological effect that it would otherwise not have in the absence of MFGM.
  • the MFGM and probiotics could have a synergistic effect in that the beneficial biological effect of the probiotic will be increased.
  • Such a biological effect can comprise the effect on the maturation of the immune system and/or of the gut, the promotion of the anti-infection effect and/or the reduction of inflammation.
  • the probiotic can enhance or promote the biological effect of the MFGM.
  • the probiotic enables the MFGM to have a biological effect that it would otherwise not have in the absence of the probiotic.
  • the probiotic and the MFGM could have a synergistic effect in that the beneficial biological effect of the MFGM will be increased.
  • Such a biological effect can comprise the effect on the maturation of the immune system and/or of the gut, the promotion of the anti-infection effect and/or the reduction of inflammation.
  • An infant formula according to the present invention may contain a protein source in an amount of not more than 3.7 or 2.0 g/1 OOkcal, preferably 1 .8 to 2.0 g/1 OOkcal.
  • the source and type of protein (for example from whey or from casein or mixture thereof) in the composition of the invention i.e. the protein content not originating from MFGM) is not believed to be critical to the present invention provided that the minimum requirements for essential amino acid content are met and provided that satisfactory growth is ensured.
  • more than 50% or more than 60% by weight of the protein source is whey (hence insuring a best balanced amino-acid profile).
  • protein sources based on whey, casein and mixtures thereof may be used as well as protein sources based on soy.
  • the protein source may be based on acid whey or sweet whey or m ixtures thereof and may include alpha-lactalbumin and beta- lactoglobulin in whatever proportions are desired.
  • the major protein source is based on modified sweet whey.
  • Sweet whey is a readily available by-product of cheese making and is frequently used in the manufacture of infant formulas based on cows' milk.
  • sweet whey includes a component wh ich is undesirably rich in threonine and poor in tryptophan called caseino-glyco-macropeptide (CGMP). Removal of the CGMP from sweet whey results in a protein with a threonine content closer to that of human milk.
  • This modified sweet whey can then be supplemented with those amino acids in respect of which it has a low content (principally histidine and tryptophan).
  • modified sweet whey as the principal protein in the protein source enables all essential am ino acids to be provided at a protein content between 1 .8 and 2.0g/100kcal .
  • Such protein sources have been shown in animal and human studies to have a protein efficiency ratio, n itrogen d igestibil ity, biolog ical value and net protein utilization comparable to standard whey-adapted protein sources with a much higher protein content per 100 kcal and to result in satisfactory growth despite their reduced protein content.
  • modified sweet whey is used as the protein source, it is preferably supplemented by free histidine in an amount of from 0.1 to 1 .5% by weight of the protein source.
  • the proteins may be intact or hydrolyzed or a mixture of intact and hydrolyzed proteins. It may be desirable to supply partially hydrolyzed proteins (degree of hydrolysis between 2 and 20%), for example for infants bel ieved to be at risk of developing cows' milk allergy. If hydrolyzed proteins are required, the hydrolysis process may be carried out as desired and as is known in the art. For example, a whey protein hydrolysate may be prepared by enzymatically hydrolyzing the whey fraction in one or more steps.
  • the whey proteins may be subjected to triple hydrolysis using Alcalase 2.4L (EC 940459), then Neutrase 0.5L (obtainable from Novo Nordisk Ferment AG) and then pancreatin at 55°C.
  • the whey may be subjected to a two-stage hydrolysis using trypsin, chymotrypsin or pancreatin or mixtures thereof as described in EP 322589. If the whey fraction used as the starting material is substantially lactose free, it is fou nd that the protein suffers much less lysine blockage during the hydrolysis process.
  • the MFGM preparation is subjected to the same proteolytic treatment.
  • An infant formula according to the present invention may contain a carbohydrate source. Any carbohydrate source conventionally found in infant formulas such as lactose, saccharose, maltodextrin, starch and mixtures thereof may be used although the preferred source of carbohydrates is lactose. Preferably the carbohydrate sources contribute between 35 and 65% of the total energy of the formula.
  • An infant formula according to the present invention may contain a source of lipids, beside the lipids from the MFGM components.
  • the lipid source may be any lipid or fat which is suitable for use in infant formulas. Preferred fat sources include high oleic sunflower oil and high oleic safflower oil.
  • the essential fatty acids linoleic and a- linolenic acid may also be added as may small amounts of oils containing high quantities of preformed arachidonic acid and docosahexaenoic acid such as fish oils or microbial oils.
  • the fat content is preferably such as to contribute between 30 to 55% of the total energy of the formula.
  • the fat source preferably has a ratio of n-6 to n-3 fatty acids of about 5:1 to about 15:1 ; for example about 8:1 to about 10:1.
  • the infant formula may also contain all vitamins and minerals understood to be essential in the daily diet and in nutritionally significant amounts. Minimum requirements have been established for certain vitamins and minerals. Examples of minerals, vitamins and other nutrients optionally present in the infant formula include vitamin A, vitamin Bi, vitamin B 2 , vitamin B 6 , vitamin Bi 2 , vitamin E, vitamin K, vitamin C, vitamin D, folic acid, inositol, niacin, biotin, pantothenic acid, choline, calcium, phosphorous, iodine, iron, magnesium, copper, zinc, manganese, chloride, potassium, sodium, selenium, chromium, molybdenum, taurine, and L-carnitine. Minerals are usually added in salt form. The presence and amounts of specific minerals and other vitamins will vary depending on the intended infant population.
  • the infant formula may contain emulsifiers and stabilizers such as soy lecithin, citric acid esters of mono- and di-glycerides, and the like. This is especially the case if the formula is provided in liquid form.
  • the infant formula may optionally contain other substances which may have a beneficial effect such as lactoferrin, nucleotides, nucleosides, and the like.
  • the infant formula also comprises a prebiotic.
  • Suitable prebiotics include certain oligosaccharides, such as fructooligosaccharides (FOS) and galactooligosaccharides (GOS).
  • a combination of prebiotics may be used such as 90% GOS with 10% short chain fructo-oligosaccharides such as the product sold under the trade mark Beneo® P95 or 10% inulin such as the product sold under the trade mark Beneo® HP, ST or HSI.
  • a particularly preferred prebiotic is a mixture of galacto-oligosaccharide(s), N- acetylated oligosaccharide(s) and sialylated oligosaccharide(s) in which the N- acetylated oligosaccharide(s) comprise 0.5 to 4.0% of the oligosaccharide mixture, the galacto-oligosaccharide(s) comprise 92.0 to 98.5% of the oligosaccharide mixture and the sialylated oligosaccharide(s) comprise 1.0 to 4.0% of the oligosaccharide mixture.
  • This mixture is hereinafter referred to as "the preferred prebiotic mixture”.
  • a composition for use according to the invention contains from 2.5 to 15.0 wt% of the preferred prebiotic mixture on a dry matter basis with the proviso that the composition comprises at least 0.02 wt% of an N-acetylated oligosaccharide, at least 2.0 wt% of a galacto-oligosaccharide and at least 0.04 wt% of a sialylated oligosaccharide.
  • Suitable N-acetylated oligosaccharides include GalNAccd ,3Gai i ,4Glc and Gai i,6GalNAca1,3Gai i,4Glc.
  • the N-acetylated oligosaccharides may be prepared by the action of glucosaminidase and/or galactosaminidase on N-acetyl- glucose and/or N-acetyl galactose. Equally, N-acetyl-galactosyl transferases and/or N-acetyl-glycosyl transferases may be used for this purpose.
  • keto-hexoses e.g. fructose
  • Suitable galacto-oligosaccharides include Gal 1,6Gal, Gal l ,6Gal 1 ,4Glc Gal 1,6Gal 1,6Glc, Gal l ,3Gal 1 ,3Glc, Gal l ,3Gal 1 ,4Glc,
  • Ga ⁇ 1,6Ga ⁇ 1,3Ga ⁇ 1,4Glc and Ga ⁇ 1 ,3Ga ⁇ 1 ,6Ga ⁇ 1 ,4Glc, Ga ⁇ 1 ,4Ga ⁇ 1 ,4Glc and Ga ⁇ 1 ,4Ga ⁇ 1 ,4Glc and mixtures thereof are commercially available under the trade marks Vivinal ® and Elix'or ®.
  • Other suppliers of oligosaccharides are Dextra Laboratories, Sigma-Aldrich Chemie GmbH and Kyowa Hakko Kogyo Co., Ltd.
  • specific glycoslytransferases, such as galactosyltransferases may be used to produce neutral oligosaccharides.
  • Suitable sialyl ated oligosaccharides include NeuAca2,3Ga ⁇ 1 ,4Glc and NeuAca2,6Ga ⁇ 1,4Glc. These sialylated oligosaccharides may be isolated by chromatographic or filtration technology from a natural source such as animal milks. Alternatively, they may also be produced by biotechnology using specific sialyltransferases either by enzyme based fermentation technology (recombinant or natural enzymes) or by microbial fermentation technology. In the latter case microbes may either express their natural enzymes and substrates or may be engineered to produce respective substrates and enzymes. Single microbial cultures or mixed cultures may be used.
  • the infant formula may be prepared in any suitable manner. For example, 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 in the blend. The vitamins and minerals may be added at this point but are usually added later to avoid thermal degradation. Any lipophilic vitamins, emulsifiers and the like may be dissolved into the fat source prior to blending. Water, preferably water which has been subjected to reverse osmosis, may then be mixed in to form a liquid mixture.
  • the liquid mixture may then be thermally treated to reduce undesired viable bacterial loads.
  • the liquid mixture may be rapidly heated to a temperature in the range of about 80°C to about 110°C for about 5 seconds to about 5 minutes. This may be carried out by steam injection or by heat exchanger; for example a plate heat exchanger.
  • the liquid mixture may then be cooled to about 60°C to about 85°C; for example by flash cooling.
  • the liquid mixture may then be homogenized; for example in two stages at about 7 MPa to about 40 MPa in the first stage and about 2 MPa to about 14 MPa in the second stage.
  • the homogenized mixture may then be further cooled to add any heat sensitive components; such as vitamins and minerals.
  • the pH and solids content of the homogenized mixture is conveniently standardized at this point.
  • the homogenized mixture is transferred to a suitable drying apparatus such as a spray drier or freeze drier and converted to powder.
  • a suitable drying apparatus such as a spray drier or freeze drier and converted to powder.
  • the powder should have a moisture content of less than about 5% by weight.
  • the selected probiotic(s) may be cultured according to any suitable method and prepared for addition to the infant formula by freeze-drying or spray-drying for example.
  • bacterial preparations can be bought from specialist suppliers such as Christian Hansen and Morinaga already prepared in a suitable form for addition to food products such as infant formula.
  • the selected probiotic may be blended to any MFGM preparation before drying.
  • This blend could be homogenized to favor association between MFGM, probiotics and probiotic (s). After drying the blend can be used as a module (added to liquid formula) or MFGM can be mixed to formula powder.
  • Probiotic powder and MFGM powders could be mixed by dry mixing, forming a specific blend. This blend could be added together in the final infant formula powder. Alternately the blend can be added extemporary to the liquid formula.
  • MFGM preparation could also be considered as a good natural emulsifier to reduce the emulsifiers conventionally used in Infant Formula or nutritional compositions.
  • the probiotic and/or the MFGM preparations care added separately or together to a ready-to-drink or ready-to-dilute nutritional composition such as a powder infant formula.
  • Such addition(s) can occur during one of the last process steps of the manufacturing/packaging of the composition or can occur just before the use of the composition by the intended user.
  • the MFGM preparation and/or the probiotic preparation can be provided separately from the powder or liquid nutritional composition.
  • MFGM Lacprodan MFGM 10 from Aria Food 4% (w/w)
  • the MFGM ingredient can be used in such amount to achieve a ratio MFGM/ total protein of 0.5%.
  • compositions comprising both MFGM and probiotics present an advantageous effect.
  • Figure 3 shows microbial components co-located with MFGM.
  • the inventors hypothesize that bacterial binding to or encapsulation of bacteria and/or their components within the M F GM , m ay faci l itate tran sport of the m icrobial components through the gastrointestinal system The inventors believe that this may enhance their delivery to appropriate sites in the mucosal tissues of the suckling neonate. Together with other factors in the MFGM it may further modulate immunological processes.
  • TLRs Toll-l ike receptors
  • the M FGM comprises molecules wh ich are co-receptors/molecules of TLR signall ing complexes as well as potential ligands for these complexes.
  • Combinations of M FGM and/or MFGM fractions with probiotic organ isms and/or microbial components could be used to educate the immune system and provide protection against early life infections.
  • M FGM and/or M FGM fractions when associated with probiotics and/or probiotic components, could promote the interaction of probiotics with the host and modulate downstream processes involved in defense mechanisms.
  • the inventors believe that MFGM and/or MFGM fractions, in combination with probiotics and/or probiotic components, may help modulate the neonatal microbiota composition, support immune development and trigger efficient protective host defense reactions. Th is can i ncl ude im m u ne responses, aga inst various pathogens or other environmental danger. This can be linked to capacity of the probiotics to confer optimal delivery to the host and/or promote host responsiveness to exogenous and endogenous signals.
  • the HT-29 (human colonic epithelial cells) cell line expresses endogenous TLRs. TLR signalling activates the NF-kB transcription factor either through MyD88 or TRIF adaptator proteins and leads to expression of inflammatory genes.
  • HT-29 cell lines were also transfected with a reporter construct, such that the secreted alkaline posphatase (SeAP) is expressed under the control of a NF-kB inducible promoter.
  • This transfected cell line, HT-29CI34 has been developed at the Nestle Research Center.
  • the HT-29CI34 reporter gene system was used to measure levels of NF-kB activation after a pre-treatment with Bifidobacterium lactis NCC2818 (B. lactis) at 10e 6 or 10e 7 CFU/mL and / or MFGM preparation at 50 ug/mL or 100 ug/mL final, followed by incubation with or without LPS (100ng/mL). SeAP activity was assessed by a fluorometric assay and expressed in relative fluorescent units.
  • B. lactis Bifidobacterium lactis NCC2818
  • Bifidobacterium lactis NCC2818 (B. lactis) was selected as a representative of the bifidobacteria! species that are important early colonizers of the infant gut.
  • Figure 5 shows the cumulative, synergistic effect obtained by combining MFGM and probiotics in this modelMFGM alone decreases the responsiveness of epithelial cells to an endotoxin challenge.
  • MFGM + probiotics (B. lactis) exhibits a stronger effect than MFGM alone or probiotics alone (Figure 5 upper and lower panels).
  • Lymphocyte suspensions were prepared from pooled mesenteric and inguinal lymph nodes isolated from 6-8 week old C57BL/6 mice. Cells were suspended in IMDM culture medium supplemented with 5x1 0 "5 M P-mercaptoethanol, 1 mM glutamine, 100 U/mL penicillin, 100 ⁇ -g/mL streptomycin and 1 0% FCS.
  • 96-well flat-bottom plates were coated with 50 ⁇ -L PBS containing 2.5 ug/mL anti-CD3 (clone: 2C1 1 ) or 5 ug/mL anti- CD40 (clone: FGK-45) 1 -3h at 37°C. After extensive washing, serial 3-fold dilutions of lymph node cell suspensions were added per well. After 3 days, 1 ⁇ -Ci/well 3 H- thymidine was added for the last 18 h prior to harvesting. When said NCC2818 (B.
  • lactis obtained from standard cultures were added to the well together with the MFGM preparation at MOI 100 and/or 100 ug/mL final concentration .
  • mice 28 day old were fed for 1 week (A) and 4 weeks (B) as below:
  • Group 2 Bifidobacterium lactis BL818 (108 CFU/day)
  • MFGM was administered daily at a dose of 0.6 mg/g of body weight.
  • the ingredients, B. lactis and/or MFGM were administrated orally.
  • Recently weaned animals were used to avoid an effect of the MFGM naturally present in mouse breastmilk.
  • IgA-secreting cell numbers in Peyer's patches cell suspensions were evaluated in 10 animals per group using a standard ELISPOT protocol.
  • Our data show that MFGM can have strong effects on adaptive immune B cells. Indeed, we observed a significant increase in the number of intestinal IgA-secreting cells isolated from the Peyer's patches of mice fed with MFGM and/or probiotics. Interestingly, we observed that the combination of MFGM and B.
  • lactis significantly increases the IgA-secreting mucosal B cells numbers after 28 days of feeding and the numbers are greater than those observed after feeding of the individual ingredients. Even more interestingly, we observed a long-lasting immune boost effect of MFGM and B. lactis feeding. More specifically, the increase in IgA-secreting mucosal B cell numbers persists and indeed, is further increased 84 days after feeding of the ingredients was stopped (day 1 1 2). Importantly, the effect of the combination of probiotics and MFGM was sign ificantly h igher than that obtained with the ind ividual ingred ients, wh ich demonstrates a synergistic effect when feeding the combination of probiotics and MFGM.

Abstract

La présente invention concerne une composition nutritionnelle comprenant des probiotiques et une membrane de globule gras du lait (MFGM). La MFGM et les probiotiques potentialisent mutuellement leurs effets respectifs et favorisent les mécanismes protecteurs bénéfiques complémentaires qui reflètent une synergie physiologique. La composition nutritionnelle peut avoir la forme d'un lait maternisé, de céréales pour bébé, d'aliments pour nourrissons ou d'un produit nutritionnel diététique. L'effet de synergie peut consister à favoriser la maturation immunitaire et/ou l'éducation immunitaire et/ou à réduire l'inflammation et/ou à traiter ou à prévenir une maladie ou des infections.
PCT/EP2010/069016 2009-12-08 2010-12-07 Lait maternisé comprenant des probiotiques et des composants de membrane de globule gras du lait WO2011069987A1 (fr)

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BR112012013766A BR112012013766A2 (pt) 2009-12-08 2010-12-07 "fórmula infantil com probióticos e componentes de membrana do glóbulo de gordura do leite"
US13/514,513 US9226521B2 (en) 2009-12-08 2010-12-07 Infant formula with probiotics and milk fat globule membrane components
MX2012006640A MX2012006640A (es) 2009-12-08 2010-12-07 Formula infantil con probioticos y componentes de la membrana del globulo graso de la leche.
RU2012128546/10A RU2563355C2 (ru) 2009-12-08 2010-12-07 Смесь для грудных детей с пробиотиками и компонентами оболочек жировых шариков молока
EP10800906A EP2509429A1 (fr) 2009-12-08 2010-12-07 Lait maternisé comprenant des probiotiques et des composants de membrane de globule gras du lait
CA2783768A CA2783768A1 (fr) 2009-12-08 2010-12-07 Lait maternise comprenant des probiotiques et des composants de membrane de globule gras du lait
AU2010329990A AU2010329990B2 (en) 2009-12-08 2010-12-07 Infant formula with probiotics and milk fat globule membrane components
CN2010800555185A CN102665428A (zh) 2009-12-08 2010-12-07 含有益生菌和乳脂肪球膜组分的婴儿配方

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RU2563355C2 (ru) 2015-09-20
AU2010329990B2 (en) 2015-07-16
AU2010329990A1 (en) 2012-06-21
CA2783768A1 (fr) 2011-06-16
CN102665428A (zh) 2012-09-12
US9226521B2 (en) 2016-01-05
BR112012013766A2 (pt) 2015-09-15
RU2012128546A (ru) 2014-01-20
TW201143633A (en) 2011-12-16
EP2509429A1 (fr) 2012-10-17
US20120321600A1 (en) 2012-12-20
MX2012006640A (es) 2012-06-25

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