WO2011096809A1 - Utilisation de sialyl oligosaccharides pour moduler le système immunitaire - Google Patents

Utilisation de sialyl oligosaccharides pour moduler le système immunitaire Download PDF

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WO2011096809A1
WO2011096809A1 PCT/NL2011/050079 NL2011050079W WO2011096809A1 WO 2011096809 A1 WO2011096809 A1 WO 2011096809A1 NL 2011050079 W NL2011050079 W NL 2011050079W WO 2011096809 A1 WO2011096809 A1 WO 2011096809A1
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immune system
bacteroides
sialyllactose
infant
composition
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PCT/NL2011/050079
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English (en)
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Ruprecht Jules Joost Van Neerven
Hermiena Christina Schoterman
Arjen Nauta
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Friesland Brands B.V.
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • 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
    • 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
    • A23L33/20—Reducing nutritive value; Dietetic products with reduced nutritive value
    • A23L33/21—Addition of substantially indigestible substances, e.g. dietary fibres
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • 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

  • the invention relates to prebiotics and the use thereof for promoting human health.
  • it relates to milk-derived oligosaccharides capable of enhancing the relative abundance of beneficial micro-organisms in the
  • the gastrointestinal tract is one of the largest organs of the body serving as an important barrier between ingested elements from the external environment and the internal milieu of the human body.
  • the GIT is inhabited by the intestinal microflora, composed of a large diversity of bacteria that perform important functions for the host and can be modulated by environmental factors, such as nutrition.
  • This microbiota can be viewed as the first line of defence, which competes with invading pathogens for space, nutrients and receptors on intestinal cells, and has an important function in health and disease.
  • the human gut microbiota plays an important role in maintaining immune homeostasis in the intestine.
  • a normal commensal microflora is required to protect against intestinal damage (Rakoff-Nahoum et al., Cell.
  • mice have fewer and smaller organized lymphoid tissues in their small intestine, as well as fewer T cells in their lamina intestinal and fewer regulatory T cells in their mesenteric lymph nodes, and have much lower levels of slgA in their intestines.
  • germ free mice are more susceptible to infections by Listeria, Shigella and Salmonella (SRoc et al., Am. J. Pathol. 1961;39:681-95, Maier, et al., Infect. Immun. 1972;6:168-173, Zachar and Savage, Infect. Immun. 1979;23, 168- 74).
  • Regulatory T cells are important for the maintenance of immune homeostasis in the intestine. They exert their effect via the production of antiinflammatory cytokines such as IL-10, IL-35 and TGF- ⁇ .
  • Colonization of the gut (both lumen and epithelium) by microorganisms is initiated at birth when newborns become exposed to the vaginal flora.
  • the development of the intestinal microflora is influenced by various factors such as gestational age, mode of delivery, local environment, type of feeding, and antibiotic treatment.
  • the earliest microbial settlers are facultative anaerobes, which render the gut lumen anaerobic by depleting final traces of oxygen.
  • This initial microbial community comprises only a few species and is dominated by members of the genus Bifidobacterium and Lactobacillus. In breast milk fed babies, this community remains rather stable.
  • formula- fed term infants the intestinal microflora is more diverse, with lower numbers of both genera mentioned above. The shift to a more complex diet after weaning strongly increases the complexity of the microbial community in the gut.
  • Bifidobacteria and lactobacilli constitute important components of the beneficial gut microflora.
  • Bifidobacteria and lactobacilli are abundant in the intestines of breast fed but not bottle-fed children, and are well recognized as beneficial commensal bacteria. Their presence correlates with fewer GI tract and airway infections, and many Lactobacilli and Bifidobacteria species have to date been used as probiotic bacteria.
  • the outgrowth of these bacteria is promoted by complex indigestible carbohydrates (prebiotic oligosaccharides) that are present in breast milk.
  • prebiotic oligosaccharides are now well established as an ingredient for infant formulas to promote the outgrowth of bifidobacteria in the intestine of infants.
  • a number of diet-based microflora management tools have been developed and refined over recent decades including probiotic, prebiotic and synbiotic approaches. Each aims to stimulate numbers and/or activities of the bifidobacteria and lactobacilli within the gut microflora. Some commensal bacteria are used as dietary supplement. Micro-organisms which confer a health benefit on the host when administered in adequate amounts are called probiotics. Strains of the genera Bifidobacterium and Lactobacillus are the most widely used probiotic bacteria and are associated with several beneficial effects on human health. Some of the beneficial effects of
  • Bifidobacteria are the production of vitamins, lowering blood cholesterol levels and inhibition of the growth of potential pathogens (Gibson and Robertfroid, J Nutr. 1995; 125:1401-12). Lactobacillus improves microflora balance in the large intestine by inhibiting the growth of harmful bacteria (Cats et al., Aliment Pharmacol Ther. 2003; 17:429-35). Some studies have proposed that this is a result of local pH reduction due to lactic acid production (Aiba et al., Am J Gastroenterol. 1998; 93:2097-101). Others question this and suggest that the secretion of antibacterial substances by
  • Lactobacillus can inhibit the growth of pathogenic bacteria (Coconnier et al. , Appl Environ Microbiol. 1998; 64:4573-80).
  • Prebiotics have a number of advantages over probiotics; principally the fact that they are not alive means that they can be processed into a much wider range of foods than can the fragile probiotics. Furthermore, prebiotics do not share the problem of probiotic survival upon ingestion by the consumer. Since prebiotics stimulate growth of bacteria that are already present in the gut, they can be seen as more "natural" additives or ingredients than probiotics, which necessitate
  • oligofructose can be utilized efficiently by Lactobacilli and Bifidobacteria.
  • WO2007/101675 relates to preparations comprising a probiotic and a prebiotic mixture which is specifically designed to enhance the efficiency and the efficacy of the probiotic and to food products comprising said preparation.
  • Galacto-oligosaccharides are an example of a prebiotic.
  • GOS consist of short chains of galactose molecules which can only be partially digested by humans. They are not hydrolysed in the stomach or small intestine and should therefore reach the colon intact were they can be selectively fermented by Bifidobacteria and other bacteria.
  • GOS increases the number of Bifidobacteria and Lactobacillus as well as the amount of short chain fatty acids (SCFAs) produced in the colon (Rycroft et al., Lett Appl Microbiol. 2001; 32:156-61).
  • SCFAs are fatty acids with short aliphatic tails consisting of 1 to 6 carbon atoms. They are produced when dietary fiber, non-starch polysaccharides, like GOS are fermented in the colon. Various population survey data show that especially acetate, propionate and butyrate are produced as end products (Cummings et al., Gut. 1987;28: 1221-7). SCFAs have been associated with reduced risk of diseases, including cardiovascular disease, cancer and inflammatory bowel disease (Wong et al., J Biol Chem. 2001;276:44641-6). Studies have shown that butyrate has anti-inflammatory properties in several human epithelial cell lines (Yin et al., J Clin Gastroenterol. 2006;40:235-43, Liihrs et al., Dig Dis Sci. 2001;46:1968-73).
  • prebiotics are suitably used to modulate the relative abundance of micro-organisms of interest in the GIT, in particular
  • Lactobacilli and Bifidobacteria have recently been identified as having anti- inflammatory properties and being capable of supporting maturation of the intestinal immune system. These include Bacteroides fragilis, Bacteroides thetaiotamicron and Faecalibacterium prausnitzii.
  • Bacteroides fragilis has a direct interaction with the immune system through an extracellular polysaccharide, polysaccharide A (PSA), expressed by B. fragilis that can directly activate CD4+ T cells.
  • PSA polysaccharide A
  • PSA expressing B. fragilis but also PSA alone, can restore the decreased peripheral CD4+ T cell numbers when given to germ-free mice, and have a promoting effect on lymphoid organogenesis (Mazmanian et al., Cell. 2005; 122: 107- 18).
  • PSA further balances the Th2-biases responses seen in GF mice (IL-4 down, IFNy up), and also restores immune balance and maturation of the immune system (Mazmanian et al., Nature. 2008;453:620-5).
  • Faecalibacterium prausnitzii (previously referred to as Fusobacterium prausnitzii) is an obligate anaerobic bacterium that is present in human faeces. It produces high levels of butyrate, an anti- inflammatory short chain fatty acid (SCFA). Recent evidence indicates that F. prausnitzii is an anti-inflammatory commensal bacterium. F. prausnitzii is decreased in the microbiota of Crohns disease patients (Sokol et al., Inflamm Bowel Dis. 2009; 15:1183-9) and the presence of F. prausnitzii correlates with improved clinical outcome (Sokol et al., Proc Natl Acad Sci U S A.
  • F. prausnitzii reduces the inflammatory activation of intestinal epithelium as evidenced by IL-8 production through excretion of metabolites, inhibits the production of the proinflammatory cytokines IL-12 and IFN- ⁇ , but stimulates the production of anti-inflammatory cytokine IL- 10 in human peripheral blood cells (Sokol et al, Proc Natl Acad Sci U S A. 2008;105:16731-6).
  • F. prausnitzii has an antiinflammatory effect in a murine TNBS-induced colitis model (Sokol et al., Proc Natl Acad Sci U S A. 2008;105: 16731-6).
  • Faecalibacterium prausnitzii reduces the inflammatory activation of intestinal epithelium as evidenced by IL-8 production through the excretion of metabolites.
  • Bacteroides thetaiotaomicron has been shown to exhibit anti-inflammatory activity on epithelial cells (Kelly et al., Nat Immunol. 2004;5:104-12). This commensal has been shown to suppress proinflammatory cytokine production by intestinal epithelial cells.
  • the present inventors set out to identify further prebiotic(s) capable of enriching the gut microbiota for bacteria having anti- inflammatory properties and/or being capable of supporting maturation of the intestinal immune system, in particular enhancing the maturation of the developing the (neonatal) immune system.
  • a dietetic, nutritional, nutraceutical or pharmaceutical composition comprising at least one prebiotic in an amount effective to increase the relative abundance of Bacteroides fragilis, Bacteroides thetaiotamicron and/or Faecalibacterium prausnitzii in the gastrointestinal tract of an animal.
  • a class of milk-derived oligosaccharides is particularly useful to selectively promote the growth of commensal bacteria having anti-inflammatory properties and/or the capacity to support maturation of the intestinal immune system. More specifically, the inventors found that the growth of B. fragilis is strongly enhanced by a sialyl-containing oligosaccharide (and not by GOS). In addition, prebiotic effects were also observed for the selective outgrowth of Faecalibacterium prausnitzii and Bacteroides thetaiotamicron. Furthermore, sialyl- containing oligosaccharide induced the production of the anti-inflammatory SCFAs propionate, butyrate and isobutyrate.
  • the invention provides in one aspect the use of a sialyl- oligosaccharide in the manufacture of a dietetic, nutraceutical, nutritional or pharmaceutical composition for supporting or enhancing the mammalian immune system.
  • the expression "supporting or enhancing the mammalian immune system” is meant to encompass any effect which is desirable or beneficial to maintain or improve the healthy functioning of the innate and/or adaptive immune system.
  • Microorganisms or toxins that successfully enter an organism will encounter the cells and mechanisms of the innate immune system.
  • the innate response is usually triggered when microbes are identified by pattern recognition receptors, which recognize components that are conserved among broad groups of microorganisms, or when damaged, injured or stressed cells send out alarm signals, many of which (but not all) are recognized by the same receptors as those that recognize pathogens.
  • Innate immune defences are non-specific, meaning these systems respond to pathogens in a generic way. This system does not confer long-lasting immunity against a pathogen.
  • the innate immune system is the dominant system of host defense in most organisms.
  • the adaptive immune system evolved in early vertebrates and allows for a stronger immune response as well as immunological memory, where each pathogen is "remembered” by a signature antigen.
  • the adaptive immune response is antigen- specific and requires the recognition of specific "non-self ' antigens during a process called antigen presentation.
  • Antigen specificity allows for the generation of responses that are tailored to specific pathogens or pathogen-infected cells. The ability to mount these tailored responses is maintained in the body by "memory cells".
  • supporting or enhancing the mammalian immune system comprises enhancing the maturation of the developing immune system, in particular maturation of the neonatal immune system.
  • Immune system maturation refers to development of an immune system characterized by a TH1/TH2 balance that is associated with a healthy adult phenotype. A healthy adult phenotype is to be contrasted with a default TH2 phenotype that is characteristic of atopy, allergic asthma, or certain types of autoimmune disease. Immune system maturation can be assessed by measuring, either at a single point in time or serially over a relevant span of time, relative contributions of at least one TH 1 marker and at least one TH2 marker.
  • a T helper 1 marker refers to an objectively measurable manifestation of a TH1 immune phenotype.
  • TH1 markers include, without limitation, certain cytokines including interferon gamma (IFN- ⁇ ) and interleukin 2 (IL-2), : transcription factors specific for Thl cells including T-bet, Statl, and Stat4, as well as certain immunoglobulin isotypes, e.g., IgGl in humans and IgG2a in mice.
  • TH1 cytokines and immunoglobulin isotypes and transcription and/or differentiation factors are well known in the art and can include, without limitation, appropriate cytokine-specific or isotype-specific enzyme-lined immunosorbent assay (ELISA), bioassay, Western blotting, EMSA, quantitative reverse transcriptase-polymerase chain reaction, and the like.
  • ELISA cytokine-specific or isotype-specific enzyme-lined immunosorbent assay
  • bioassay bioassay
  • Western blotting Western blotting
  • EMSA quantitative reverse transcriptase-polymerase chain reaction
  • a T helper 2 marker refers to an objectively measurable manifestation of a TH2 immune phenotype.
  • TH2 markers include, without limitation, certain cytokines including interleukin 4 (IL-4) and interleukin 5 (IL-5), transcription factors specific for Th2 cells including State, GATA-3, c-Maf, NFATs, as well as certain immunoglobulin isotypes, e.g., IgE in humans and in mice.
  • transcription and/or differentiation factors are well known in the art and can include, without limitation, appropriate cytokine-specific or isotype-specific ELISA, bioassay, Western blotting, EMSA, quantitative reverse transcriptase-polymerase chain reaction, and the like.
  • supporting or enhancing the mammalian immune system comprises balancing the immune system to a status associated with the absence of an inflammatory response.
  • Regulatory T cells are another subset of CD4+ T helper lymphocytes. These Tregs can be CD25+, Foxp3+ cells, but also other subtypes of Tregs have been described. Tregs produce anti-inflammatory cytokines like IL-10 and TGF- ⁇ and are instrumental in inhibiting inflammatory responses.
  • TGF- ⁇ can also promote immunoglobulin class-switching to induce the production of IgA by B cells and plasma cells.
  • IgA is a non-complement binding immunoglobulin isotype, and is considered a non-inflammatory immunoglobulin.
  • a regulatory T cell (Treg marker) as used herein refers to an objectively measurable manifestation of a Treg immune phenotype.
  • Treg markers include, without limitation, certain cytokines including interleukin 10 (IL-10) and transforming growth factor- ⁇ (TGF- ⁇ ), transcription or differentiation factors specific for Treg cells including for example Foxp3 and CD25, as well as certain immunoglobulin isotypes, e.g., IgA in humans and in mice.
  • Treg cytokines, transcription and/or differentiation factors, and immunoglobulin isotypes are well known in the art and can include, without limitation, appropriate cytokine-specific or isotype-specific ELISA, bioassay, Western blotting, EMSA, quantitative reverse transcriptase- polymerase chain reaction, and the like
  • sialyl oligosaccharide means an oligosaccharide having at least one sialic acid moiety with associated charge.
  • Sialic acids comprise a family of about 40 derivates of the nine carbon sugar neuramic acid.
  • Sialic acid is the generic term for the N- or O-substituted derivatives of neuraminic acid.
  • Milk contains sialic acid moieties in different forms. It can be present as a constituent of water soluble free oligosaccharides (e.g. sialyllactose), or bound to either glycoproteins such as lactoferrin and ⁇ -casein and/or glycolipids (GD3 and GM3).
  • the present invention is preferably practiced using a sialyl oligosaccharide selected from the group consisting of sialyloligosaccharides derived from milk (e.g. cow, goat, camel, human milk), whey or egg.
  • the sialyloligosaccharides can for instance be directly separated from milk, whey or egg or produced from components derived here from.
  • components belonging to the group of sialyloligosaccharides are disialyllacto-iV- tetraose, 3'-sialyllactose, 6'-sialyllactose, 3'-sialyllactosamine, 6'-sialyllactosamine, 3'- sialyl-3-fucosyllactose, sialyllacto-iV-tetraose a, sialyllacto-iV-tetraose b, sialyllacto-iV- tetraose c, disialyllactose, 3'-sialyl Lewis A, 3'-sialyl Lewis X, disialyllacto-N-hexaose I, disialyllacto-N-hexaose II, sialyl Lea tetra, sialyllacto-N-
  • An exemplary commercial preparation comprising egg yolk sialyl oligosaccharides is Sunsial E from Tayio Kaguku Co, Japan.
  • Another exemplary preparation is Vivinal SL, a product comprising sialyllactose (FrieslandCampina Domo).
  • sialyl oligosaccharides of human milk sialic acid is attached to a penultimate galactose residue or N-acetylglucosamine residue via a2-3 or a2-6 linkage formed by the action of sialyl transferase (Kunz et al., Annu Rev Nutr.
  • Sialyllactose represents the main part of the sialyl-oligosaccharide fraction in human and cow's milk.
  • the invention provides a dietetic, nutritional or pharmaceutical composition comprising sialyllactose in an amount effective to increase the relative abundance of Bacteroides ssp. in the gastrointestinal tract.
  • sialyl oligosaccharide such as sialyllactose, may be enzymatically produced.
  • the product produced by FrieslandCampina Domo The
  • Vivinal SL comprising sialyllactose
  • Vivinal SL comprising sialyllactose
  • the structures of sialic acid, 3'- sialylactose and 6'-sialyllactose are presented in Table 1.
  • sialyl oligosaccharides 3'sialyllactose and /or 6'sialyllactose may be isolated e.g. by chromatographic or filtration technology from a natural source such as animal milks, preferably cow's milk.
  • the concentration of oligosaccharides in cow's milk is between the 30 and 60 mg/litre. In this fraction, sialyllactose is the most abundant oligosaccharide.
  • the sialyl-oligosaccharide is obtained by a method comprising ion exchange technology, as for example in WO
  • whey permeate streams are used as source of sialyllactose, which is captured selectively from these streams via ion exchange technology.
  • Subsequent downstream processing may include removal of remaining minerals and water, and a drying step.
  • the composition comprises the at least one sialyl oligosaccharide in an amount sufficient or effective to increase the relative abundance of at least one of said bacteria in the gastrointestinal tract.
  • the composition comprises at least one sialyl oligosaccharide in an amount of 0.005— 20 grams per dose unit, for example a daily dose unit.
  • a dose unit may consist of 0,2-500 grams, like 0,5, 15, 100, 150, 200 , 250 or 300 grams, depending among others on the type of composition (solid, liquid), intended use (complete food, pharmaceutical composition, food supplement) and/or the intended consumer (adult, infant).
  • sialyl oligosaccharide may be present in an amount of 0.005— 20 gram per 100 gram or 100 ml of composition, preferably 0.1-2 gram per 100 gram or 100 ml composition.
  • the composition may contain one or more further prebiotic ingredients known in the art.
  • suitable prebiotics are fructo and/or galacto-oligosaccharides, with short or long chains, inulin, fucose-containing oligosaccharides, beta glycans, carob flour, gums, pectins, galactans with short or long chains, glucosaminegalactans and other glucaosamine containing oligosaccharides and nucleotides.
  • a composition comprises sialyllactose and GOS.
  • the composition may also contain one or more milk- or whey- derived components.
  • Examples are sialic acid, alpha-Lactalbumin, lactoferrin, glycoproteins, casein macropeptide, gangliosides, phospholipids, colostrum, immunoglobulins, cytokines, milk calcium and nucleotides.
  • compositions according to the invention may also be supplemented with one or more of these species such that their relative abundance in the intestinal tract is even further enhanced. That way, the maturation of the developing immune system is even further enhanced. Therefore, a composition may further comprise living Bacteroides fragilis, Bacteroides thetaiotamicron,
  • WO 01/60346 discloses inhibiting the binding of pathogenic microorganism to human tissue using nutritional compositions comprising oligofructose and sialyllactose.
  • WO 01/60346 discloses that compositions comprising oligofructose and sialyllactose allegedly do not have an effect on the growth of Bacteroides.
  • the present inventors show that sialyllactose induces growth of Bacteroides species, and enhance SCFA and lactate production in both adult and baby faeces.
  • WO 2010/002241 discloses nutritional compositions comprising inactivated Gram-negative bacteria or bacterial cell fragments in an amount of less than 10 exp3 cfu per gram dry weight of formula and its use in providing nutrition to an infant delivered via caesarean section.
  • the non-living, inactivated bacteria are thought to induce tolerance of the intestinal tract against colonisation with Gram-negative bacteria.
  • the combined use of a sialyl oligosaccharide and living Bacteroides ssp. as disclosed in the present invention is not taught or suggested.
  • WO2010/002241 teaches to avoid the inclusion of live bacteria.
  • compositions for inducing gut barrier maturation which could reduce the risk of allergy and infection.
  • Such compositions may contain specific fats and non-digestible oligosaccharides, such as silalyllactose.
  • Dutch patent NL 1 027 263 discloses compositions comprising proline and sialyloligosaccharides, which may be used for preventing or reducing the permeability of the intestinal wall and for preventing or reducing adhesion of bacteria or viruses to the intestinal wall.
  • WO 2010/002241, WO 2004/112509 and NL 1 027 263 describes compositions containing living Bacteroides fragilis, Bacteroides thetaoiotaomicron, or Faecalibaterium prausnitzii.
  • beneficial probiotic strains including specific strains of the genera Lactobacilli and Bifidobacteria that have been found to be able to colonise at least transiently the intestinal mucosa, to reduce the capability of pathogenic bacteria to adhere to the intestinal epithelium, to have
  • the probiotics are added in an amount of at least 10 5 cfu/g dry weight of formula, preferably 10 6 cfu/g, more preferably 10 7 cfu/g, although generally even larger amounts are preferred, for example up to 10 12 cfu/g of formula.
  • the additional or alternative living probiotic bacterial strain is preferably a lactobacillus or a bifidobacterium.
  • strains which produce only L (+) lactic acid are used.
  • Exemplary Lactobacillus (L.) species are L. rhamnosus, L. paracasei, L. amylovorus, L. ultunensis, L. acidophilus, L. kalixensis, L. delbrueckii subsp. Lactis, L. oris, L. fermentum, L. gastricus, L. antri, L. fermentum, L. parabuchneri, L. brevis, L. plantarum, L. curvatus, L. sakei, L. gasseri, L. vaginalis, L. acidophilus, L.
  • strains are Lactobacillus rhamnosus ATCC 53103, Lactobacillus rhamnosus CGMCC 1.3724, Lactobacillus reuteri ATCC 55730, L. amylovorus DSM20552, L. ultunensis DSM16047, L. acidophilus ATCC4356, L. kalixensis DSM16043, L. delbrueckii subsp. lactis DSM20073, L. oris DSM4864, L. reuteri DSM20016, L. reuteri DSM20053, L. fermentum DSM20055, L.
  • gastricus DSM16045 L. antri DSM16041, L. paracasei subsp. paracasei 43362, L. paracasei subsp. paracasei 43332, L. paracasei subsp. paracasei 43338, L. parabuchneri DSM5707, L. brevis DSM20054, L. plantarum NCD0326, L. plantarum NCIMB8826, L. curvatus NCD02739, L. sakei DSM20100, L. ruminis L5, L. gasseri SR21, L. vaginalis SR213, L. fermentum SR22, L. gasseri CR159, L. acidophilus NCFM, L. acidophilus LA5, L. johnsonii Lj l, L. rhamnosus GG, L. casei DN- 144 001, L. paracasei CRL431, L. reuteri ATCC 55730, L. reuteri
  • B. Bifidobacterium
  • B. Bifidobacterium
  • B. preferred Bifidobacterium species are B. lactis, B. breve B. lactis Bb- 1, B. lactis Bbl2, B. animalis, B. digestivus, B. infantis, B. adolescentis and B.
  • strains are the strain of B. lactis sold by the Christian Hansen company of Denmark under the trade mark Bbl2, Bifidobacterium longum ATCC BAA- 999 obtainable from Morinaga Milk Industry Co. Ltd. of Japan under the trade mark BB536, B. Adolescentis CIP 64.61, B. Adolescentis DSM 20083, B.
  • thermophilum JCM 7027 In a specific embodiment, the combination of B. lactis strain deposited under ATCC number 27536 and the L. casei strain deposited under ATCC number 55544 is used (see WO2008/056983 in the name of the applicant). In another specific embodiment, the combination of B. lactis BB12 and L. paracasei CRL431is used.
  • the composition further comprises at least one immunomodulatory substance originating from a beneficial microorganism such as from Bacteroides fragilis, Bacteroides thetaiotamicron and/or Faecalibacterium prausnitzii.
  • the immunomodulatory substance is for instance a zwitterionic polysaccharide (ZPA) capable of activating CD4+ T cells, preferably it is
  • PSA polysaccharide A
  • a dietetic, nutraceutical, nutritional or pharmaceutical composition for treating or preventing a condition associated with a reduced amount of Bacteroides fragilis, Bacteroides thetaiotamicron and/or Faecalibacterium prausnitzii ssp. in the gastrointestinal tract.
  • the sialyloligosaccharide is preferably selected from the group consisting of disialyllacto-N-tetraose, 3'-sialyllactose, 6'-sialyllactose, 3'- sialyllactosamine, 6'-sialyllactosamine, 3'-sialyl-3-fucosyllactose, sialyllacto-N- tetraose a, sialyllacto-N-tetraose b, sialyllacto-N-tetraose c, disialyllactose, 3'-sialyl Lewis A, 3'-sialyl Lewis X, disialyllacto-N-hexaose I, disialyllacto-N-hexaose II, sialyl Lea tetra, sialyllacto-N-ne
  • the invention provides the use of 3'-sialyllactose, 6'-sialyllactose, or a mixture thereof, for the manufacture of a dietetic, nutraceutical, nutritional or pharmaceutical composition for treating or preventing a condition associated with a reduced amount of Bacteroides fragilis, Bacteroides thetaiotamicron and/or Faecalibacterium prausnitzii ssp. in the gastrointestinal tract.
  • the invention provides the use of at least one sialyloligosaccharide and at least one of the probiotics Bacteroides fragilis, Bacteroides thetaiotamicron and Faecalibacterium prausnitzii or a combination thereof for the manufacture of such a dietetic, nutraceutical, nutritional or pharmaceutical composition.
  • the invention further relates to the use of a sialyloligosaccharide to enhance the in vivo or ex vivo growth of a Bacteroides fragilis, Bacteroides thetaiotamicron and/or Faecalibacterium prausnitzii.
  • a composition of the invention may be in any form suitable for human administration, and in particular for administration in any part of the
  • compositions of the invention can be a solid, semi-solid or liquid nutritional formulation, such as a nutraceutical, nutritional or dietary supplement, functional food, beverage product, meal replacement, or food additive.
  • Such nutritional compositions may be nutritionally complete, i.e. may include vitamins, minerals, trace elements as well as nitrogen, carbohydrate and fatty acid sources so that they may be used as the sole source of nutrition supplying essentially all the required daily amounts of vitamins, minerals, carbohydrates, fatty acids, proteins and the like.
  • the compositions of the invention may be provided in the form of a nutritionally balanced composition, e. g.
  • the composition of the invention may be provided as part of a meal, i.e. a nutritional or dietary supplement, e. g. in the form of a health drink. It may be desirable to provide the composition of the invention in the form of a low calorie composition, e. g. meal replacement.
  • the nutritional composition, e.g. meal replacement is preferably low fat, i.e. less than about 10 en%, or substantially fat-free, i.e. less than about 2.5 en% contributed by fat, such as about 2 en% fat, based on the total caloric content of the composition.
  • a single serving of a low calorie nutritional composition e. g. meal replacement, will have a caloric value of less than about 1000 kcal, and preferably between about 200 kcal and about 500 kcal.
  • Suitable low calorie nutritional composition may include soft drink, such as juice, smoothie or soy-based drink, or dispersed in foods of any sort, such as, dairy bars, soups, cereals, e. g. breakfast cereals, muesli, candies, tabs, cookies, biscuits, crackers, such as a rice crackers, and dairy products, such as milk-shake, yoghurt drink, yoghurts and fruit drinks.
  • the composition is a non-fermented composition.
  • compositions of the invention may be provided as high calorie compositions, e. g. high calorie dietary supplement or meal replacement, for instance with a caloric value of more than about 400 kcal, preferably more than about 600 kcal, more preferably more than about 800 kcal.
  • the composition is an infant formula including follow on formula or growing up milk.
  • beneficial (commensal) bacteria by the approach herein disclosed is applicable to any type of liquid, solid or semi- solid composition for oral or enteral administration, be it for babies, infants, teenagers, adolescents, adults, pregnant women, elderly subjects, and the like.
  • compositions include infant formulas.
  • An infant formula provided herein is especially suitable for supporting or enhancing the neonatal immune system.
  • the infant formula is for example formulated to be administered to an infant of between 0 and 3 months of age, between 0 and 6 months of age, between 3 and 6 months of age, between 6 and 9 months of age, between 9 and 12 months of age (infant formula for infants between 6 and 12 months age are often called follow on formula).
  • an infant formula for infants older than 12 months and even older than 24 months, and up to an age of 6 years (often called growing up milk).
  • a preferred infant formula is formulated for infants of between 0 and 6 months of age.
  • compositions also include products for pregnant women, for maturation of the developing immune system of the unborn infant via the umbilical cord.
  • the bacterial composition in the infant digestive tract (also called the intestinal microflora) follows a pattern of change starting in the newborn, and varies depending on the infant diet. Development of the infant's intestinal microflora is initiated at birth. The aseptic, or sterile, digestive tract of the foetus is inoculated with bacteria during birth by the mother's intestinal and vaginal microflora. During the first week of life, enterobacteria and enterococci predominate in the gut of both breastfed and formula-fed infants. After this, the microflora changes rapidly. Some of the changes that occur depend on whether the infant is breastfed or formula-fed.
  • An infant formula according to the present invention comprising a sialyl oligosaccharide, preferably a sialyllactose, can support, enhance, or balance the neonatal immune system. It can promote maturation of the immune system of a neonatal infant in the first weeks of the life of the infant, in particular by promoting in the first weeks of the life of the infant the development of a beneficial intestinal microbiota resembling the microbiota found in breast fed babies. Furthermore, it can balance the (infants') immune system to a status associated with the absence of an inflammatory response.
  • Infant formulas are commonly used today to provide supplemental or sole source nutrition early in life. These formulas contain protein, carbohydrate, fat, vitamins, minerals, and other nutrients. They are commercially available as powders, ready-to-feed liquids, and liquid concentrates. There are currently a variety of commercially available infant formulas, each one designed to meet the specific nutritional needs of a particular infant group. Milk-based infant formulas, for example, represent the majority of commercially available infant formulas. Soy- based formulas also represent a large portion of the infant formula market by offering an alternative to milk-based formulas, especially in milk- intolerant infants. Lactose-free formulas are also available and can be useful in those infants with lactose sensitivity. Infant formulas with amino acids or partially hydrolyzed proteins are also available for certain infants.
  • the base infant formula comprises fat, protein, carbohydrate, vitamins and minerals, all of which are selected in kind and amount to provide a sole source of nutrition for the targeted infant or defined infant population.
  • the infant formula may be formulated for an infant of between 0 and 6 months of age, between 3 and 6 months of age, 6 and 9 months of age or 9 and 12 months of age.
  • Infant formulas for use as base formulas include any known ready-to-feed infant formula, or any nutritional formula suitable for use in infants, provided that such a formula is a sole source nutritional having caloric density and osmolality values within the ranges defined herein. Many different sources and types of carbohydrates, fats, proteins, minerals and vitamins are known and can be used in the base formulas herein, provided that such nutrients are compatible with the added ingredients in the selected formulation and are otherwise suitable for use in an infant formula.
  • Carbohydrates suitable for use in the base formulas herein may be simple or complex, lactose-containing or lactose-free, or combinations thereof, non-limiting examples of which include hydrolyzed, intact, naturally and/or chemically modified cornstarch, maltodextrin, glucose polymers, sucrose, corn syrup, corn syrup solids, rice or potato derived carbohydrate, glucose, fructose, lactose, high fructose corn syrup and indigestible oligosaccharides such as fructooligosaccharides (FOS),
  • FOS fructooligosaccharides
  • GOS galactooligosaccharides
  • an infant formula comprising the combination of sialyllactose and GOS.
  • Proteins suitable for use in the base formulas herein include hydrolyzed, partially hydrolyzed, and non-hydrolyzed or intact proteins or protein sources, and can be derived from any known or otherwise suitable source such as milk (e.g., casein, whey, human milk protein), animal (e.g., meat, fish), cereal (e.g., rice, corn), vegetable (e.g., soy), or combinations thereof.
  • the composition of the invention comprises a whey fraction comprising the whey proteins a-lactalbumin (a- LA) and casein macropeptide (CMP), wherein the weight ratio between a-LA and CMP is ⁇ 2.
  • Proteins for use herein can also include, or be entirely or partially replaced by, free amino acids known for or otherwise suitable for use in infant formulas, non-limiting examples of which include alanine, arginine, asparagine, carnitine, aspartic acid, cystine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, taurine, threonine, tryptophan, taurine, tyrosine, valine, and combinations thereof. These amino acids are most typically used in their L-forms, although the corresponding D- isomers may also be used when nutritionally equivalent. Racemic or isomeric mixtures may also be used.
  • Fats suitable for use in the base formulas herein include coconut oil, soy oil, corn oil, olive oil, safflower oil, high oleic safflower oil, algal oil, MCT oil (medium chain triglycerides), sunflower oil, high oleic sunflower oil, palm and palm kernel oils, palm olein, canola oil, marine oils, cottonseed oils, and combinations thereof.
  • Vitamins and similar other ingredients suitable for use in the base formulas include vitamin A, vitamin D, vitamin E, vitamin K, thiamine, riboflavin, pyridoxine, vitamin B12, niacin, folic acid, pantothenic acid, biotin, vitamin C, choline, inositol, salts and derivatives thereof, and combinations thereof.
  • Minerals suitable for use in the base formulas include calcium, phosphorus, magnesium, iron, zinc, manganese, copper, chromium, iodine, sodium, potassium, chloride, and combinations thereof.
  • Preferred probiotics for use in an infant formula include those capable of promoting the development of an early bifidogenic intestinal microbiota, e.g. the strains disclosed in EP 1974734.
  • a pharmaceutical composition as provided herein, e.g. clinical product, and nutritional compositions of the invention, e. g. dietary supplements, may be provided in the form of soft gel, sachets, powders, syrups, liquid suspensions, emulsions and solutions in convenient dosage forms.
  • Oral pharmaceutical or dietary supplement forms may be made by conventional compounding procedures known in the pharmaceutical art, that is, by mixing the active substances together with edible pharmaceutical acceptable solid or liquid carriers and/or excipients, e. g.
  • fillers such as cellulose, lactose, sucrose, mannitol, sorbitol, and calcium phosphates and binders, such as starch, gelatin, tragacanth, methylcellulose and/or polyvinylpyrrolidone (PVP).
  • Optional additives include lubricants and flow conditioners, e. g. silicic acid, silicon dioxide, talc, stearic acid, magnesium/calcium stearates, polyethylene glycol (PEG) diluents, disintegrating agents, e. g. starch, carboxymethyl starch, cross-linked PVP, agar, alginic acid and alginates, colouring agents, flavouring agents, and melting agents. Dyes or pigments may be added to the tablets or dragee coatings, for example for identification purposes or to indicate different doses of active ingredient.
  • the invention also provides a method for enhancing the maturation of the immune system in a mammalian subject, preferably a human subject, comprising administering to the subject a composition comprising at least one sialyl oligosaccharide.
  • the method preferably comprises enhancing the maturation of the developing immune system, more preferably the human neonatal immune system.
  • Said enhancement for example comprises an increase in level of one or more of Bacteroides fragilis, Bacteroides thetaiotamicron and Faecalibacterium prausnitzii.
  • a composition administered to the subject further comprises at least one of the probiotics Bacteroides fragilis, Bacteroides thetaiotamicron and
  • Faecalibacterium prausnitzii or a combination thereof Faecalibacterium prausnitzii or a combination thereof.
  • thetaiotamicron and/or Faecalibacterium prausnitzii preferably at least Bacteroides fragilis.
  • Growth can be in vitro or in vivo. Suitable growth promoting
  • sialyloligosaccharides include disialyllacto-iV-tetraose, 3'-sialyllactose, 6'-sialyllactose, 3'-sialyllactosamine, 6'-sialyllactosamine, 3'-sialyl-3-fucosyllactose, sialyllacto-iV- tetraose a, sialyllacto-iV-tetraose b, sialyllacto-iV-tetraose c, disialyllactose, 3'-sialyl Lewis A, 3'-sialyl Lewis X, disialyllacto-N-hexaose I, disialyllacto-N-hexaose II, sialyl Lea tetra, sialyllacto-N-neotetrao
  • a preferred sialyl oligosaccharide for use as prebiotic for the above mentioned beneficial bacteria is a (partially) purified sialyllactose, such as 3'-sialyllactose, 6' -sialyllactose or a mixture thereof.
  • a healthy, or balanced, microbiota has been considered to be one that is predominantly carbohydrate- fermenting (saccharolytic) and comprises significant numbers of bifidobacteria and lactobacilli.
  • carbohydrate- fermenting sacharolytic
  • SCFA principally short-chain fatty acids
  • An important metabolic function of the microbiota is the fermentation of non- digestible carbohydrates and endogenous mucus produced by the epithelia.
  • the overall outcomes of this complex metabolic activity are the recovery of metabolic energy and absorbable substrates for the host , and the supply of energy and nutritive products for bacterial growth and proliferation.
  • the metabolic endpoint is the generation of the SCFA's acetate, propionate and butyrate, having important functions in host physiology.
  • intestinal microbiota Another highly important role of the intestinal microbiota in colon physiology is its trophic effect on the intestinal epithelium. Differentiation of the epithelial cell is considerably influenced by the interaction with resident microorganisms and their metabolic products, mainly SCFA; stimulating epithelial cell proliferation and differentiation of the small and large bowel. Intestinal bacteria also form a barrier against non-indigenous microorganisms, including pathogens: a phenomenon called colonization resistance. Lactic acid-producing bacteria, such as bifidobacteria and lactobacilli are believed to play a significant role in the maintenance of colonization resistance.
  • Gastroenterol. 2006;40:235-43 has also been shown to inhibit T-cell activation (Cavaglieri et al., Life Sci. 2003;73:1683-90). Similar findings have also been reported for acetate and propionate (Tedelind et al., World J Gastroenterol. 2007;13:2826-32), suggesting that the production of short chain fatty acids induced by prebiotics may contribute to the maintenance of a non-inflammatory environment in the intestine.
  • GPR40 There are four different receptors that bind, and are activated by fatty acids, GPR40, GPR41, GPR42 and GPR43. They form a cluster of four orphan G-protein coupled receptors, tandemly located on chromosome 19ql3.1. These receptors exhibit 30-40% homology to one another. Agonists of GRP40 are medium to long-chain fatty acids and those for GPR41 and GPR43 are short chain fatty acids. GPR42 is closely related to GPR41, differing in only seven nucleotide positions. Due to lack of detectable expression in tissue and lack of functional ligand responses following recombinant expression, human GPR42 is currently described as an open reading frame pseudo gene. (Brown et al., DNA Cell Biol. 2005; 24:54-61).
  • GPR43 and GPR41 activation by SCFAs can be determined using a cAMP accumulation assay and a fluorescent-based calcium mobilization assay.
  • Agonist activity can be characterized by the amount of potency.
  • the rank order of potency showed notable differences. The order was propionate > isobutyrate > butyrate > valerate > isovalerate > caproate > pivalate > acetate. Formate was totally inactive on this receptor (Le Poul 2003).
  • the activation properties of lactate are unknown.
  • GPR43 is mainly expressed on leukocyte populations, particularly neutrophils, whereas GPR41 expression is more widely distributed in tissues, including in intestinal epithelium (Brown et al, J Biol Chem. 2003; 278:11312-9).
  • Propionate, isobutyrate and butyrate thus have the highest potency for effects mediated through GPR41 of all the short chain fatty acids.
  • the present inventors found a high production of all three of these SCFA induced by sialyllactose.
  • butyrate and propionate have anti-inflammatory effects on intestinal epithelium that expresses GPR4, induction of high propionate, butyrate, and isobutyrate levels by sialyllactose is expected to have a positive, anti-inflammatory effect on intestinal epithelium.
  • FIGURES Figure 1: Effects of sialyllactose and GOS on micoflora composition of batch cultures inoculated with a pool of adult faeces.
  • the panels show the total amount of bacteria per vessel (A), bacteroides (B), and bifidobacteria (C). numbers quantified by QPCR. Values shown are averages of two separate runs, with error bars indicating the deviation of the mean of the two measurements.
  • Figure 2 Effects of sialyllactose and GOS on micoflora composition of batch cultures inoculated with a pool of adult faeces.
  • Figure 3 Effects of sialyllactose and GOS on micoflora composition of batch cultures inoculated with a pool of infant faeces as described in example 2.
  • the panels show the total amount of bacteria per vessel (A), bacteroides (B), and bifidobacteria (C) numbers quantified by QPCR. Values shown are averages of two separate runs, with error bars indicating the deviation of the mean of the two measurements..
  • Figure 4 Effects of sialyllactose and GOS on microflora composition of batch cultures inoculated with a pool of infant faeces as described in example 2.
  • the panels show the amount of bacteroides (A), and bifidobacteria (B) numbers quantified by QPCR.
  • Figure 5 Effects of purified sialyllactose and purified GOS on the cumulative production of SCFA in batch cultures inoculated with a pool of adult faeces as described in example 1.
  • the panels show the production of total SCFA levels (A), acetate (B), butyrate (C), lactate (D), propionate (E), and formiate (F), all expressed as concentration in mM.
  • Figure 6 Effects of sialyllactose and GOS on the cumulative production of SCFA in batch cultures inoculated with two different pools of infant faeces, essentially as described in example 2. The panels show the production of total SCFA levels
  • Example 1 Effect of sialyl oligosaccharide on adult faeces microflora composition.
  • Improvement of the health of human can be accomplished by selective stimulation of the growth and/or activity of groups of bacteria in the colon. This stimulation can be induced by prebiotics like oligo- and polysaccharides. This example describes a comparison of the selective fermentation of GOS and sialyl-containing
  • GOS Vivinal GOS, FrieslandCampma Domo
  • sialyllactose Vivinal SL, FrieslandCampma Domo
  • a pH-controlled batch fermentation model which represents the distal part of the colon, was used to measure the effect of the oligosaccharides on the composition of the microflora, and the production of short chain fatty acids and lactate.
  • GOS Vivinal GOS
  • sialyllactose Vivinal SL
  • Faecal samples were obtained from 16 adult volunteers (average BMI 23,4, range 18,0 - 27,8) free of known gastrointestinal disorders. None of the volunteers had taken prebiotic products within a three-month period prior to sampling. Individual faecal samples were diluted to a 1 in 10 weight/weight mixture using 0.1M, pH7, phosphate buffered saline (PBS) (Sigma laboratories, Gillingham, Dorset, UK) at pH7.4 and pooled. The PBS was reduced overnight in an anaerobic cabinet (10% 3 ⁇ 4, 10% CO2, 80% N2). This mixture was then homogenised for 120 seconds (Seward Stomacher 80 Biomaster), at normal speed, in the stomacher. The faecal slurry was aliquotted and frozen. The faecal slurry was thawed just prior to the start of the experiment and used to inoculate the batch cultures. pH Controlled, Stirred batch cultures
  • Chemostat nutrient medium was prepared containing the following ingredients: Peptone water 2g/l (Oxoid, Basingstoke, UK), yeast extract 2g/l (Oxoid), NaCl O. lg/1 (Fisher, Loughborough, UK), ⁇ 2 ⁇ 0 4 .3 ⁇ 2 0 0.05g/l (BDH, Poole, UK), KH2PO4 0.04g/l (BDH), MgS0 4 .7H 2 0 O.Olg/1 (Sigma), CaCl 2 .2H 2 0 0.005g/l (BDH), NaHCOs 2g/l (Sigma), Tween 80 (BDH) 2ml, Hemin 0.02g/l, Vitamin Ki ⁇ (Sigma), Cysteine HCl 0.5g/l (Oxoid), Bile Salts 0.5g/l (Oxoid), Resazarin 4ml/l (Sigma), pH7.
  • the chemostat nutrient medium autoclaved, then aseptically poured into the sterile batch culture vessels. This was left overnight with nitrogen pumping through the vessel to provide an anaerobic environment.
  • 0.5ml of 10% cysteine-HCl was added to aid reduction of the medium.
  • pH meters Electrode pH controller, Tewksbury, UK
  • the vessels were maintained at 37°C, and were stirred using magnetic stirrers.
  • test material purified GOS or purified SL were added to the vessel to a final concentration of 10 g/1 oligosaccharide just prior to the addition of 15 ml of faecal slurry of a pool of adult faecal samples (10% w/w).
  • the vessels were left for 24h, with samples taken at 0, 3, 6, 9 and 24h.
  • the samples were centrifuged for 5 min at 13 200 rpm and supernatants and pellet fractions were stored at—20 C until SCFA measurement (supernatants) or DNA preparation for QPCR analysis (pellet).
  • the pH-controlled fermentation experiments were conducted in two independent experiments using samples from the same faeces pool as indicated.
  • DNA was isolated from frozen pellets of fermented faecal samples using the QIAamp DNA Stool Mini Kit (Qiagen). The number of total bacteria and bacteria of specific groups were quantified by quantitative PCR essentially as described in EP1997907. The primers and probes for the detection of total bacteria, Bifidobacteria, and Bacteroides were based on 16S rDNA gene sequences, retrieved by
  • Example 2 Effect of sialyl oligosaccharide on baby faeces microflora composition.
  • This example demonstrates the effect of oligo- and polysaccharides on the microbial population of baby faeces by in vitro fermentation.
  • the experiments were essentially carried out as described in Example 1, only now with a batch of in vitro prefermented infant faeces.
  • the test groups included a control vessel, a vessel containing purified GOS (10 g/L oligosaccharide), and a vessel containing purified SL (lOg/L
  • Figure 3B shows the amounts of Bacteroides present during batch
  • FIG. 4A shows that the total growth of bacteria was stimulated by GOS and SL up to a 2-5 fold increase during 24 h. The total bacteria count of control was stable.
  • Figure 3C illustrates that the Bifidobacteria were stimulated by GOS and SL compared to the Bifidobacteria in the control vessel present.
  • Short oligonucleotide sequences (approx 20 nt) were used with a melting temperature of 60°C according to the Wallace rule for which a one nucleotide mismatch already resulted in an absence (or very strong decrease) of signal after hybridization.
  • Figure 5 shows the effect of GOS and Sialyllactose on SCFA and lactate production in batch cultures inoculated with adult faeces.
  • GOS induced the production of high levels of lactate
  • Sialyllactose induced no lactate.
  • Sialyllactose induced the formation of much higher propionate levels than GOS, and comparable but slightly higher levels of formiate, acetate, and butyrate. The maximum production of isobutyrate did not exceed a concentration of 5 mM (not shown).
  • Figure 6B shows similar results in another batch culture experiment performed with a different infant faeces pool and a different batch of Sialyllactose.
  • the production levels of propionate, butyrate, and acetate induced by Sialyllactose were comparable to GOS, but were slightly lower in this experiment than in the experiment shown in Figure 6A.
  • the production of isobutyrate was much higher, and the production of formiate was much lower with Sialyllactose compared to GOS.
  • Table 4 shows the composition of three exemplary nutritional formulas according to the invention, e.g. infant formulas for the age group between 0-6 months, for supporting or enhancing the infant's immune system.

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Abstract

L'invention concerne des prébiotiques et leur utilisation pour stimuler la santé humaine. En particulier, l'invention concerne des oligosaccharides issus du lait, du lactosérum ou de l'œuf qui sont capables de renforcer l'abondance relative de microorganismes bénéfiques. L'invention concerne l'utilisation d'un sialyl oligosaccharide dans la fabrication d'une composition diététique, nutraceutique, nutritionnelle ou pharmaceutique pour soutenir ou renforcer le système immunitaire d'un mammifère, en particulier pour renforcer la maturation du système immunitaire néonatal humain en développement.
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