EP2696880A1 - Lactobacillus paracasei ncc2461 (st11) zur verwendung mittels perinataler maternaler verabreichung zur verringerung und vorbeugung von allergien bei nachkommen - Google Patents

Lactobacillus paracasei ncc2461 (st11) zur verwendung mittels perinataler maternaler verabreichung zur verringerung und vorbeugung von allergien bei nachkommen

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Publication number
EP2696880A1
EP2696880A1 EP12713982.2A EP12713982A EP2696880A1 EP 2696880 A1 EP2696880 A1 EP 2696880A1 EP 12713982 A EP12713982 A EP 12713982A EP 2696880 A1 EP2696880 A1 EP 2696880A1
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EP
European Patent Office
Prior art keywords
progeny
lactobacillus paracasei
paracasei ncc
cfu
mothers
Prior art date
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Application number
EP12713982.2A
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English (en)
French (fr)
Inventor
Annick Mercenier
Adrian Zuercher
Sophie Nutten
Ursula Wiedermann
Irma Schabussova
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Nestec SA
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Nestec SA
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Priority to EP12713982.2A priority Critical patent/EP2696880A1/de
Publication of EP2696880A1 publication Critical patent/EP2696880A1/de
Withdrawn legal-status Critical Current

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    • 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
    • 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
    • A23L33/40—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
    • A61P37/08—Antiallergic agents
    • 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

  • Lactobacillus paracasei NCC2461 ST11 for use by perinatal maternal administration in the reduction and prevention of allergies in progeny
  • This invention relates to perinatal administration of probiotic bacteria capable of modulating the infant immune response to allergens.
  • Primary prevention is the effect of preventing or reducing the risk of sensitization of patients to allergens, characterized by absence or reduced levels of allergen-specific IgE antibodies. Preventing or reducing sensitization will result in absence or reduction of allergic symptoms upon re-exposure to the same allergen.
  • the current invention is concerned with primary prevention of allergies.
  • “Secondary prevention” is the effect of modulating the symptoms of allergies, i.e. the occurrence or intensity of the allergic reaction in patient already sensitized to one or several allergens when the patient is re-exposed to said allergen(s).
  • Secondary prevention the negative impact on the quality of life of the allergy sufferer, that is associated with allergies, is minimized.
  • the faecal microbiota of breast-fed infants includes appreciable populations of bifidobacteria with some Lactobacillus species, whereas formula-fed i nfants have m ore com plex m i crobiota , with Bifidobacterium species and Bacteroides species, Clostridia and streptococci being usually present.
  • a pattern of gut microbiota resembling that of an adult pattern becomes established over time [Penders, J., et al. (2006); Gut microbiota composition and development of atopic manifestations in infancy: the KOALA birth cohort study. Gut 56: 661-667].
  • the immunological status of the newborn is important. This status includes the protection present at the birth of the infant and the acquisition of such immunological protection during the first hours, days or weeks of the infant life. The ability to acquire and maintain such protection is a crucial factor in the health of the infant faced with his new environment.
  • pre-, peri-, and/or postnatal interventions correspond to a promising approach to modulate immune responses promoting and/or sustaining a non-atopic status.
  • interventions during pregnancy/lactation may have considerable advantages in terms of convenience and compliance compared to child- directed interventions.
  • Lactobacillus rhamnosus GG administration to mothers 4 to 6 weeks before expected delivery and then to the offspring during a period of 6 months neither reduced the incidence of atopic dermatitis nor altered the severity of atopic dermatitis in affected children.
  • the paper concluded that Lactobacillus rhamnosus GG cannot be generally recommended for primary prevention.
  • the present invention provides a probiotic, Lactobacillus paracasei NCC 2461 , i.e. ST1 1 , for use by administration to expectant females and/or lactating mothers, and to their progeny for the reduction or prevention of the development of allergic immune responses in progeny.
  • the reduction in allergic immune response is with respect to progeny of mothers not treated with ST1 1.
  • the progeny may be those at risk of atopic diseases.
  • the allergic immune responses concerned by the invention are to food or airborne allergens, especially birch pollen allergens Bet v 1 and Bet v 2.
  • the allergic immune responses may be allergen- specific recall responses or non allergen -specific (mitogen)-induced responses.
  • the reduction in the allergy immune response may be manifested as a reduction in I L-4 and I L-5 production, in the case of al lergen specific recall responses, and/or a reduction in IL-5 production by committed lymphocytes in the case of mitogen- induced responses.
  • the infant immune responses to allergens are thus reduced, resulting in a "dampened" allergic response in the progeny.
  • allergy, including atopy may be prevented in the progeny.
  • the ST1 1 is administered to expectant mothers for at least two weeks before delivery and, after delivery, to the progeny either directly or via mothers milk, for at least 2 months, preferably up to six months or even up to one year after delivery.
  • the mother receives the ST1 1 as a daily dose during at least part or all of her pregnancy and, after delivery, during at least part or all of the lactation period if she is lactating.
  • the ST1 1 may be administered orally to the expectant or lactating mothers, preferably in foods, drinks, dietary supplements or pharmaceutical compositions.
  • a daily dose of ST11 is administered to the newborn infant for at least two months, preferably up to six months, after delivery either directly or via the mother's milk. It may be administered in its pure form or diluted in water, breast milk or in an infant formula.
  • the invention also concerns a method for primary prevention or reduction of the development of allergic immune responses in infants, comprising
  • Panels A and D correspond to non sensitized/non challenged and non probiotic-treated mice; panels B and E correspond to mice sensitized with Bet v 1 and challenged with birch pollen; panels C and E correspond to mice sensitized with Bet v 1 and challenged with birch pollen and having received a treatment with L paracasei ST1 1 perinatally.
  • Panel A shows cellular infiltration (macrophages, lymphocytes, neutrophils and eosinophils counts) in bronchoalveolar lavage (BAL) fluid of progeny.
  • Panels B, C and D show levels of interleukin 5 (I L-5) in BAL fluid, lung and lung draining mediastinal lymph nodes, respectively.
  • White bars correspond to progeny (sensitized and challenged to birch pollen) of mothers which were not treated with L paracasei ST1 1 .
  • Black bars correspond to progeny (sensitized and challenged to birch pollen) of mothers which were treated with ST1 1.
  • paracasei ST11 was assessed using spleen cells of offspring of sham (control)-treated mothers: splenocytes were incubated with L. paracasei ST1 1 (10 cfu/ml) admixed to rBet v 1 (10 g/ml) for 48 h.
  • Weight period' is the period during which infants are adapting from pure liquid nutrition to solid or semi-solid foods, and adapting from quasi unique food type (generally mother milk or infant formula) to a variety of foods.
  • Sensitization means induction/development of allergen-specific IgE antibodies.
  • Non allergen-specific immune responses means cytoki ne prod uction upon stimulation of immune cells by Concanavalin A (Con A), which is a mitogen stimulating lymphocytes i.e. committed T cells, in a non specific manner.
  • Con A Concanavalin A
  • non allergen-specific immune response is synonymous with “mitogen induced immune response”.
  • Probiotic means microbial cell preparations or components of microbial cells with a beneficial effect on the health or well-being of the host. (Salminen S, Ouwehand A. Benno Y. et al "Probiotics: how should they be defined” Trends Food Sci. Technol. (1999): 10 107-10). The definition of probiotic is generally admitted and in line with the WHO definition.
  • the probiotic can comprise a unique strain of micro-organism, a mix of various strains and/or a mix of various bacterial species and genera. In case of mixtures, the singular term “probiotic” can still be used to designate the probiotic mixture or preparation.
  • probiotic can still be used to designate the probiotic mixture or preparation.
  • micro-organisms of the genus Lactobacillus are considered as probiotics.
  • Prebiotic generally means a non digestible food ingredient that beneficially affects the host by selectively stimulating the growth and/or activity of micro-organisms present in the gut of the host, and thus attempt to improve host health.
  • Lactobacillus paracasei (L. paracasei) strain NCC 2461 (Nestle Culture collection) is the L. paracasei with the alternative name of ST1 1 , used throughout the text and the international identification reference CNCM 1-2116 (Collection Nationale de Cultures de Microorganismes at Institute Pasteur, Paris, France). The CNCM identification refers to the Collection Nationale de Cultures de Microorganismes at Institut Pasteur, 22 rue du dondel Roux, 75724 Paris, France.
  • At risk of allergy and/or atopic disease means a subject either (a) having a positive family history of allergies, with at least 1 first degree relative parent or sibling having a declared allergic disease such as atopic eczema, asthma, hay fever, or food allergy, or (b) having exhibited at least one episode of allergy such as atopic eczema, asthma, hay fever, or food allergy.
  • This definition is in-line with the general definition of infants at risk of allergy used for example in scientific publications such as J . Allergy Clin. Immunol, Vol 121 , #6, p1443-1447, Berg et al., page 1443 paragraph "Subjects”.
  • the present invention provides a probiotic, ST1 1 , for use by administration to expectant mothers, and to their progeny for the reduction or prevention of the development of allergic immune responses in progeny.
  • the invention provides a method for primary prevention or reduction of development of allergies in infants. All infants may benefit from the present invention, including those at risk of developing atopic diseases because of their family history.
  • a daily dose of ST11 is administered to a pregnant woman for at least two weeks before delivery and, after delivery, the daily dose of ST11 is administered to the newborn infant for at least two months, either directly or via the mother's milk.
  • the invention also relates to a composition comprising ST1 1 , for use by administration to expectant mothers, and to their progeny, according to the regimen as indicated above, for the reduction or prevention of the development of allergic immune responses in progeny.
  • the intestinal microbiota of the infant is affected propitiously.
  • the immune responses to allergens are reduced, thus the allergic response is "dampened” and allergy, including atopy, may be prevented. This effect is elaborated upon in the paragraphs below.
  • the daily dose suitable for newborn babies ranges from 1x10 2 to 1x10 10 , preferably, 1x10 2 to 1x10 4 cfu.
  • ST11 may be present in the composition in a wide range of percentages provided that it delivers the immunity protective effect described.
  • the ST1 1 is present in the composition in an amount equivalent to between 1 x10 2 and 1x10 11 cfu/g of dry composition.
  • the quantity of bacteria which the formula contains is expressed in terms of the colony forming ability of that quantity of bacteria as if all the bacteria were live irrespective of whether they are, in fact, live, inactivated or dead, fragmented or a mixture of any or all of these states.
  • the probiotic is present in an amount equivalent to between 1x10 4 to 1x10 9 cfu/g of dry composition, even more preferably in an amount equivalent to between 1x10 6 to 1x10 8 cfu/ g of d ry composition.
  • the amount of probiotic present per gram of dry composition for administration to the progeny may be lower and the daily doses described above should be respected.
  • the composition can be administered to the expectant mothers by various ways as long as it induces a contact between the composition and the gastro-intestinal tract of the females.
  • the composition is orally administered as part of the food, drinks or dietary supplements of the expectant mothers.
  • the composition can also be administered in a pharmaceutical composition.
  • the administration is oral.
  • the administration of the composition can be added to the enteral feeding.
  • the ST11 can also be administered orally directly to the progeny alone (pure or diluted in water or mother's milk for example) as a food supplement or as an ingredient in an infant milk formula.
  • a formula may be an infant "preterm formula” if the progeny is born before term or has a low birth weight, a "starter formula” or a “follow-on formula”.
  • the formula may also be an hypoallergenic (HA) formulas in which the cow milk proteins are hydrolysed.
  • HA hypoallergenic
  • the ST1 1 or the composition comprising ST11 or part of the composition comprising ST1 1 is administered to the infants via the lactating mother.
  • the lactati ng mother receive the ST1 1 or the compostion comprising ST1 1 as described above.
  • ST1 1 can in certain instances deliver a benefit to the infant via the human breast milk. Without being bound by the theory, it is believed that such benefit can be delivered to the infant either directly by passage of ST1 1 to the milk or indirectly by passage of ST1 1 - induced compounds or metabolites to the human breast milk, or by modulating the breast milk content in immunomodulatory compounds (such as immonoglobulins, soluble CD14, TGF-beta, or cytokines, etc... .).
  • the ST11 is administered to the infants via the human breast milk of the lactating mother being administered the ST1 1.
  • the ST1 1 is administered to the lactating mother and the beneficial effect of the ST11 is transmitted to the infants by the human breast milk (for example by ST1 1 -induced compounds in the mother's body).
  • the ST11 can be administered alone (pure or diluted in water or milk, including breast milk for example) or in a mixture with other compounds (such as dietary supplements, nutritional supplements, medicines, carriers, flavours, digestible or non- digestible ingredients). Vitamins and minerals are examples of typical dietary supplements.
  • the composition is administered together with other compounds that enhance the described effect on the immunity of the progeny.
  • Such synergistic compounds may be carriers or a matrix that facilitates the ST11 delivery to the intestinal tract of the expectant mother or they may otherwise enhance the effect of the composition on the immune system of the progeny.
  • Such compounds can be other active compounds that synergistically or separately influence the immune response of the infant and/or potentiates the effect of the probiotic.
  • An example of such synergistic compounds is maltodextrin.
  • One of the effect of maltodextrin is to provide a carrier for the probiotic, enhancing its effect, and to prevent aggregation.
  • ⁇ токтивное ples include known prebiotic compounds such as carbohydrate compounds selected from the group consisting of inulin, fructooligosaccharide (FOS), short-chain fructooligosaccharide (short chain FOS), galacto-oligosaccharide (GOS), xylooligosaccharide (XOS), glangliosides, partially hydrolysed guar gum (PHGG) acacia gum, soybean-gum, apple extract, lactowolfberry, wolfberry extracts or mixture thereof.
  • FOS fructooligosaccharide
  • short chain FOS short-chain fructooligosaccharide
  • GOS galacto-oligosaccharide
  • XOS xylooligosaccharide
  • PHGG partially hydrolysed guar gum
  • soybean-gum soybean extract
  • lactowolfberry lactowolfberry extracts or mixture thereof.
  • Other carbohydrates may be present such as a second carbohydrate acting in synergy with the first carbohydrate and that is selected from the group consisting of xylooligosaccharide (XOS), gum, acacia gum, starch, partially hydrolysed guar gum or mixture thereof.
  • XOS xylooligosaccharide
  • the carbohydrate or carbohydrates may be present at about 1 g to 20g or 1 % to 80% or 20% to 60% in the daily doses of the composition. Alternatively, the carbohydrates are present at 10% to 80% of the dry composition.
  • the daily doses of carbohydrates, and all other compounds administered with the ST1 1 should always comply with the published safety guidelines and regulatory requirements. This is particularly important with respect to the administration to newborn babies.
  • a nutritional composition preferably comprises a source of protein.
  • Dietary protein is preferred as a source of protein.
  • the dietary protein may be any suitable dietary protein, for example animal proteins (such as milk proteins, or meat proteins), vegetable proteins (such as soy proteins, wheat proteins, rice proteins or pea proteins), a mixture of free amino acids, or a combination thereof. Milk proteins such as casein and whey proteins are particularly preferred.
  • the composition may also comprise a source of carbohydrates and/or a source of fat. If the composition of the invention is a nutritional composition and includes a fat source, the fat source preferably provides about 5% to about 55% of the energy of the nutritional composition; for example about 20% to about 50% of the energy.
  • Lipid making up the fat source may be any suitable fat or fat mixture.
  • Vegetable fat is particularly suitable, for example soy oil, palm oil, coconut oil, safflower oil, sunflower oil, corn oil, canola oil, lecithin and the like.
  • Animal fat such as milk fat may also be added if desired.
  • An additional source of carbohydrate may be added to the nutritional composition. It preferably provides about 40% to about 80% of the energy of the nutritional composition. Any suitable carbohydrate may be used, for example sucrose, lactose, glucose, fructose , corn syru p sol ids , m altodextri n , or a m ixtu re thereof. Additional dietary fibre may also be added if desired. If added, it preferably comprises up to about 5% of the energy of the nutritional composition. The dietary fibre may be from any suitable origin, including for example soy, pea, oat, pectin, guar gum, acacia gum, fructooligosaccharide or a mixture thereof. Suitable vitamins and minerals may be included in the nutritional composition in an amount to meet the appropriate guidelines.
  • LC-PU FAs One or more essential long chain fatty acids
  • DHA docosahexaenoic acid
  • AA arachidonic acid
  • the LC-PUFAs may be added at concentrations so that they constitute greater than 0.01 % of the fatty acids present in the composition.
  • One or more food grade emulsifiers may be included in the nutritional composition if desired; for example diacetyl tartaric acid esters of mono- and di- glycerides, lecithin and mono- or d i-glycerides or a mixture thereof. Similarly suitable salts and/or stabilisers may be included. Flavours can be added to the composition.
  • the expectant mother may start to take the ST11 as soon as she is aware of her pregnancy.
  • the administration period may also start before pregnancy starts, for example if the female is trying to become pregnant.
  • Administration may start at any time after the pregnancy starts. It may start relatively late in the pregnancy, preferably at month 3, 4, 5, 6, 7 or 8 of the pregnancy, in the case of human pregnancy, or in corresponding periods for other mammals, or up to two weeks before the expected delivery date.
  • the period of administration can be continuous (for example, up to and including lactation up to weaning), or discontinuous. Continuous administration is preferred for a more sustained effect. However, it is speculated that a discontinuous pattern (for example, daily administration during one week per month, or during alternate weeks) can induce positive effects on the progeny.
  • the duration of the administration may vary. While positive effects are expected with relatively short duration of administration (for example, daily administration during one week for newborns and one or two months for adults), longer durations are believed to provide enhanced effect (for example, a duration of three, five or eight months in humans, and corresponding periods in other mammals).
  • the administration should cover at least part of the gestation period and at least part of the lactation period, or the equivalent period should the newborn not be breastfed.
  • the administration period to the expectant mother covers substantially the full length of the gestation period, although this may be less.
  • the administration period for the lactating mother preferably covers substantially the full length of the lactation period, although, again, this period may be less.
  • the administration to the mother is by daily intake (to be taken once or twice a day), or weekly intake (to be taken one or twice a week).
  • the ST11 may be administered to the infant directly. This is the case particularly if the mother does not breastfeed or after she discontinues breastfeeding. However, an infant who is being breastfed may also receive the ST1 1 by direct administration.
  • the administration to the infant, either via breastfeeding, or by direct administration, or both methods, may be continued up until the age of six months or even one year.
  • the ST11 may be administered during lactation if lactation takes place, or after partial or full weaning.
  • the administration to the infant is by daily intake (to be taken once or twice a day), or weekly intake (to be taken one or twice a week).
  • Effect of the probiotic administration is by daily intake (to be taken once or twice a day), or weekly intake (to be taken one or twice a week).
  • ST11 administered to expectant mothers protects the progeny from the development of allergy.
  • ST1 1 has been found in at least one other study to exhibit no effect or very low effect in the prevention of allergies : For example in Vaccine 29(201 1)1981-1990 (available on-line 7/1 /201 1 ), I . Schabussova et a l showed that, i n a mouse m odel of polysensitization to grass and birch pollen allergens, intranasal administration of ST1 1 , in a prevention mode (prior to sensitization) did not protect the mice, when NCC3011 (B. longum) did. I n the same paper, ST1 1 given for management of symptoms (at the time of sensitization and challenge) protected the mice as well as NCC3001. The conclusion of the paper was that the choice of probiotic strain and the timing of the application are crucial for immune tolerance induction.
  • the administration of ST1 1 to pregnant mothers and its effect on the progeny can be explained by the passage of ST1 1 and/or ST1 1- induced compounds and/or metabolites to the infant.
  • This passage can arise in-utero and can further synergize (e.g. potentialization) with the administration of ST1 1 after birth.
  • the exact mechanisms of this passage however remain subject of on-going scientific studies.
  • the positive effect of ST1 1 can start in the very early life of the infant (in-utero) during crucial phases of immune or gut developments and extend to the maturation phases after birth.
  • ST1 1 administered to expectant mothers protects the progeny from the development of allergy.
  • the progeny of ST1 Itreated mothers that were sensitized with a specific allergen and then challenged with the same allergen had a reduction in allergic response (in this case, an allergen specific recall response) compared to progeny of non-treated mothers.
  • a reduced level of immune response i.e. a non-specific response
  • maternal ST1 1 administration reduces the development of airway inflammation in progeny which have been sensitised to air borne allergens, for example birch pollen (see Example 1 , Figure 1 for study outline) and then challenged to the same allergen. This may be demonstrated by lower eosinophilic infiltration into the airway lumen in comparison to sensitized and challenged progeny from mothers who have not been treated with ST1 1 (see Fig. 3A).
  • the inventors have also demonstrated that maternal ST11 -supplementation does not have an adverse effect on the progeny's ability to fight infection. While the number of eosinophils- these are cells directly implicated in mounting an allergic response- are reduced, the number of macrophages and lymphocytes in bronchoalveolar lavage (BAL) fluid of progeny of Example 1 are not affected (see Fig. 3A) compared to progeny of ST1 1 non treated mothers. Histological analysis of lung sections revealed that airway inflammation, goblet cell metaplasia and mucus production were reduced in lungs of the progeny of ST11 - treated mothers in contrast to progeny of control mothers (See Figure 2).
  • Progeny of control mice showed massive cellular infiltration around bronchi and blood vessels (Fig. 2B, E) .
  • Considerably reduced peribronchial inflammation with only rare mononuclear cell infiltrates were detected in progeny derived from ST11-exposed mothers (Fig. 2C , F) .
  • No infiltrates were found in the lungs of naive animals (Fig. 2A, D).
  • periodic acid-Schiff (PAS) staining of lung sections revealed that the development of goblet cell hyperplasia and mucus hypersecretion was strongly reduced in progeny of ST1 1-treated mothers (Fig. 2F) as compared to the control group, whose mothers received water instead of ST1 1 , (Fig. 2E).
  • maternal ST1 1 administration reduces the levels of interleukin 5 (IL-5) in BAL fluid (Fig. 3B), lung (Fig. 3C) and lung associated lymph nodes (Fig. 3D) in mice which have been sensitised to an air borne allergen, for example Bet v 1 (Example 1) and then aerosol challenged with birch pollen.
  • IL-5 interleukin 5
  • Fig. 3B BAL fluid
  • Fig. 3C lung
  • Fig. 3D lung associated lymph nodes
  • the levels of IL-5 were found to be significantly higher in the progeny of mothers which were not treated with ST1 1 .
  • maternal ST11 administration reduces allergen specific recall response in progeny.
  • splenocytes of sensitized and challenged progeny were stimulated with Bet v 1.
  • Bet v 1 levels of Th2 cytokines (IL-4 and I L-5) secretion were observed in splenocytes from the progeny of ST11-supplemented mothers compared with progeny derived from control mothers (Fig. 4A, B).
  • the suppressive effect of ST1 1 on I L-5 production which is key for the recruitment and survival of eosinophils, provides a mechanistic explanation for the reduced airway eosinophilia in progeny of ST11 -treated mothers.
  • maternal ST11 administration reduces allergen specific recall response.
  • maternal ST11 administration reduces the levels of interleukin 5 (I L-5) secretion in splenocytes of progeny sensitised to birch pollen and stimulateded with the mitogen Concanavalin A (Con A)(Example 1 ).
  • Con A is a lectin known for its ability to stimulate T cell subsets giving rise to functionally distinct T cells populations (Dwyer et al. (1981), Clin Exp Immunol 46(2): 237-249). IL -4 levels remained unchanged (see Figure 5A, B).
  • the reduction or prevention of the development of allergic immune responses in the progeny of ST11-treated mothers may be the reduction or prevention of allergic immune responses to air borne allergens, food allergens or contact allergens such as nickel.
  • the air borne allergens may be house dust mites, animal danders, and tree and grass pollen, especially birch pollen.
  • Bet v 1 , Bet v 2 profilins and cross reactive carbohydrate determinants (CDD) are some of the known allergens of birch pollen.
  • the reduction or prevention of the development of allergic immune responses in progeny of ST11-treated mothers may be the reduction or prevention of allergic immune responses to allergens that are cross reactive with birch pollen.
  • These may be food allergens such as apples, stone fruits, celery, carrot, nuts, and soybeans that may contain allergens that are cross-reactive to Bet v 1. These also may be peach, orange, lychee fruit, strawberry, persimmon, zucchini, and carrot as these are known to be reactive to the Bet v 2 allergen.
  • the reduction or prevention of the development of allergic immune responses in progeny of ST11-treated mothers may be a reduction of at least 5 %, more preferably 10%, more preferably at least 30% and most preferably at least 50% compared to the progeny of non treated mothers.
  • the ST1 1 strain is a probiotic isolated from the fecal microbiota of a breastfed child.
  • the administration of ST1 1 may provide an advantage over other strains that are not found in breastfed children.
  • a mouse model of birch pollen allergy was used to demonstrate that maternal supplementation with ST11 protects progeny from the development of an allergic phenotype.
  • BALB/c mice received ST11 daily in drinking water during the last week of gestation and for the period of lactation.
  • the pregnant and lactating female mice mothers were fed daily with the live probiotic bacterial strain ST11 in drinking water.
  • Progeny of ST11 - or sham-treated mothers was sensitized with the recombinant major birch pollen allergen Bet v 1 and challenged with birch pollen extract (Fig. 1 Experimental design).
  • Pregnant BALB/c mice (day 14 of pregnancy) were purchased from Charles River (Sulzfeld, Germany) and maintained under conventional housing conditions.
  • Female TLR2- and TLR4-deficient and wild type mice with C57BL/6 genetic background were obtained from the University of Veterinary Medicine of Vienna (Austria).AII experiments were approved by the Animal Experimentation Committee of the University of Vienna and by the Federal ministry of Science and Research.
  • Probiotic strain ST1 1 is L. paracasei NCC 2461 CNCM 1-21 16 (L. paracasei) and belongs to Nestle Research Center bacterial collection (Lausanne, Switzerland). For perinatal oral application, spray-dried bacterial preparation diluted in drinking water was used. For in vitro experiments, L. paracasei preparation was inactivated with 1 % formaldehyde-PBS for 3 h at room temperature, washed twice with sterile PBS, and stored at -20°C. Perinatal ST11 exposure:
  • Pregnant BALB/c mice received 5x10 8 cfu/ml of ST11 in drinking water every day (reaching average daily dose of 2x10 9 cfu/mouse) for a total of 4 weeks, starting from the third trimester of gestation (day -7) and continuing throughout the lactation period until the day of the weaning (day 21) (Experimental design; Fig. 1).
  • Age-matched control animals received only water.
  • mice Progeny from perinatally ST11-exposed or control-treated mother mice were sensitized three times subcutaneously (s.c.) with ⁇ g of recombinant major birch pollen allergen Bet v 1 (rBet v 1 ; Biomay, Vienna, Austria) emulsified in aluminium hydroxide (alum, Serva, Heidelberg, Germany) in a total volume of 150 ⁇ on days 21 , 35 and 49 (Experimental design; Fig. 1). To induce airway inflammation, mice were challenged 1 week after the last sensitization by exposure to aerosolized 1 % birch pollen extract (BP; Allergon, Valinge, Sweden) on two consecutive days (days 56-57). Mice were terminally anesthetized with Sevofluran (Abbott, Vienna, Austria) 72 h after final airway challenge (day 60).
  • Progeny from ST11- or control-treated mother mice were terminally anesthetized and BAL was collected two times using 2 ml PBS containing protease inhibitor cocktail (Roche, Mannheim , Germany) .
  • Total leukocytes were counted and cytospins (Shadon Cytospin , Shadon Southern I nstruments , U SA) were stai ned with haematoxylin and eosin (H&E; Hemacolor ® , Merck, Darmstadt, Germany). Standard morphological criteria were used to identify cell types and 200 cells were counted per cytospin via light microscopy. Cell-free supernatants were stored at -20°C for further analysis.
  • Proliferative responses of spleen and MLN cell cultures were determined by scintillation counting after addition of 3 [H]- thymidine (0.5 ⁇ / ⁇ , Amersham, Buchter, Braunschweig, Germany) for the last 18 h.
  • spleen cells of progeny sham-treated mothers were incubated with ST11 (10 7 cfu/ml) admixed to rBet v 1 (10 ⁇ g/ml) for 48 h.
  • composition of an infant formula for use according to the present invention is given below. This composition is given by way of illustration only.
  • the protein source is a conventional mix of whey protein and casein.
  • Vitamin E (mg TE) 0.8 5.4
  • Vitamin B1 (mg) 0.07 0.47
  • Vitamin B2 (mg) 0.15 1.0
  • Vitamin B6 (mg) 0.075 0.50
  • Pantothenic acid (mg) 0.45 3 Vitamin B12 g) 0.3 2

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EP12713982.2A 2011-04-15 2012-04-11 Lactobacillus paracasei ncc2461 (st11) zur verwendung mittels perinataler maternaler verabreichung zur verringerung und vorbeugung von allergien bei nachkommen Withdrawn EP2696880A1 (de)

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EP11162632A EP2510932A1 (de) 2011-04-15 2011-04-15 Lactobacillus paracasei NCC2461 (ST11) zur Verwendung mittels perinataler maternaler Verabreichung zur Verringerung und Vorbeugung von Allergien bei den Nachkommen
EP12713982.2A EP2696880A1 (de) 2011-04-15 2012-04-11 Lactobacillus paracasei ncc2461 (st11) zur verwendung mittels perinataler maternaler verabreichung zur verringerung und vorbeugung von allergien bei nachkommen
PCT/EP2012/056503 WO2012140031A1 (en) 2011-04-15 2012-04-11 Lactobacillus paracasei ncc2461 (st11) for use by perinatal maternal administration in the reduction and prevention of allergies in progeny

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TR201809987T4 (tr) 2011-06-20 2018-08-27 Heinz Co Brands H J Llc Probiyotik bileşimler ve yöntemler.
AU2013277316B2 (en) 2012-06-18 2018-03-01 H.J. Heinz Company Brands Llc Gluten-related disorders
BR112015028164B1 (pt) 2013-05-10 2022-02-08 H.J. Heinz Company Brands Llc Usos da bactéria probiótica, lactobacillus paracasei, para tratar uma infecção microbiana e para prevenir ou reduzir a gravidade de uma infecção microbiana
WO2015090349A1 (en) * 2013-12-16 2015-06-25 Nestec S.A. Probiotic nutritional intervention during pregnancy and optionally lactation to reduce risk of allergy in infants
WO2016013928A1 (en) 2014-07-24 2016-01-28 N.V. Nutricia Prevention or treatment of food allergy in infants and toddlers
IT201800004072A1 (it) * 2018-03-29 2019-09-29 Smart Farma S R L Composizione alimentare come coadiuvante nello sviluppo della microflora intestinale e del sistema immunitario dei neonati
CN110892990B (zh) * 2019-10-11 2023-03-31 内蒙古伊利实业集团股份有限公司 益生菌益生元食用组合物及其应用

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EP1034787A1 (de) * 1999-03-11 2000-09-13 Société des Produits Nestlé S.A. Lactobacillus Stämme die gegen pathogenische Bacteria veranlassende Diarrhöe schutzen
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EP1364586A1 (de) * 2002-05-24 2003-11-26 Nestec S.A. Probiotika und Oraltoleranz
FR2876029B1 (fr) * 2004-10-04 2008-11-14 Oreal Composition cosmetique et/ou dermatologique pour peaux sensibles.
ES2399993T3 (es) * 2007-03-02 2013-04-04 Protectimmun Gmbh Composición farmacéutica para la protección frente a alergias y enfermedades inflamatorias
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ES2390620T3 (es) * 2008-03-10 2012-11-14 Nestec S.A. Ácidos dicarboxílicos de cadena mediana y sus derivados y trastornos metabólicos
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