US20100278795A1 - Lactic acid bacterium-containing preparation - Google Patents

Lactic acid bacterium-containing preparation Download PDF

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US20100278795A1
US20100278795A1 US12/743,485 US74348508A US2010278795A1 US 20100278795 A1 US20100278795 A1 US 20100278795A1 US 74348508 A US74348508 A US 74348508A US 2010278795 A1 US2010278795 A1 US 2010278795A1
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lactic acid
acid bacteria
function
mice
composition according
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Airo Tategaki
Toyoki Watanabe
Kazuya Hamada
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Kaneka Corp
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Kaneka Corp
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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
    • A61K35/741—Probiotics
    • A61K35/744—Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
    • A61K35/747—Lactobacilli, e.g. L. acidophilus or L. brevis
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K10/00—Animal feeding-stuffs
    • A23K10/10—Animal feeding-stuffs obtained by microbiological or biochemical processes
    • A23K10/16—Addition of microorganisms or extracts thereof, e.g. single-cell proteins, to feeding-stuff compositions
    • A23K10/18—Addition of microorganisms or extracts thereof, e.g. single-cell proteins, to feeding-stuff compositions of live microorganisms
    • 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
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • 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
    • 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
    • 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
    • A23V2400/00—Lactic or propionic acid bacteria
    • A23V2400/11—Lactobacillus

Definitions

  • the present invention relates to a preparation that contains a novel lactic acid bacterium or a component derived from this lactic acid bacterium as an active ingredient.
  • the number of patients with allergic diseases and particularly hay fever and atopic dermatitis is increasing annually, and therapeutic and preventive measures are also required from the standpoint of patient quality of life (QOL).
  • the group I allergic diseases such as hay fever and atopic dermatitis, start with the recognition of a substance introduced into the body as an allergen and subsequent induction of the production of IgE antibody.
  • the allergen binds to IgE antibodies that have become bound to receptor molecules on mast cells and granulocytes, which results in excessive release of chemical mediators, such as histamine and leukotriene, from the mast cells and granulocytes and causes allergy symptoms such as asthma, dermatitis, nasal discharge, and so forth.
  • antiallergic agents that relieve allergy symptoms by inhibiting the release of these chemical mediators
  • antihistamine agents that inhibit the transmission of information by the chemical mediators to the peripheral nerves
  • steroidal agents that reduce inflammation
  • lifestyle diseases i.e., diabetes, hyperlipidemia, hypertension, and so forth
  • diseases are believed to be caused by an accumulation of undesirable lifestyles, e.g., unbalanced diet, lack of exercise, alcohol consumption, and smoking, and so forth.
  • dietary therapy and exercise therapy are regarded as effective methods for the treatment and prevention of these diseases, it is difficult to rigorously sustain these therapies, and therapeutic and preventive methods are thus required that are not accompanied by severe mental and physical demands.
  • fermented food products that employ lactic acid bacteria include fermented food products that have health effects, e.g., intestinal regulatory actions, preventive effects with respect to lifestyle diseases, immunostimulatory effects, and so forth, and these products have been receiving attention.
  • health effects e.g., intestinal regulatory actions, preventive effects with respect to lifestyle diseases, immunostimulatory effects, and so forth
  • these products have been receiving attention.
  • the lactic acid bacteria cells used for fermentation and the milk peptides in the fermented milk are reported to exhibit health functions as described above.
  • attention is being paid for example, to the antiallergic functions (for example, Patent References 1 and 2: Japanese Patent Application Laid-open No. H9-2959 and Japanese Patent No. 3585487), the anti-hyperlipidemic functions (Patent Reference 3: Japanese Patent Application Laid-open No.
  • Patent Reference 4 Japanese Patent Application Laid-open No. H10-7577
  • the Lactobacillus paracasei strain KW3110 (FERM BP-08634) described in Patent Reference 2 is reported to have a particularly high antiallergic action, but it still cannot be said that this is satisfactory.
  • lactic acid bacteria individually having multiple functions at a high level are not well known.
  • Patent Reference 1 Japanese Patent Application Laid-open No. H9-2959
  • Patent Reference 2 Japanese Patent No. 3585487
  • Patent Reference 3 Japanese Patent Application Laid-open No. H10-298083
  • Patent Reference 4 Japanese Patent Application Laid-open No. H10-7577
  • An object of the present invention is to provide a useful composition that contains a highly safe lactic acid bacterium or a component derived from this lactic acid bacterium.
  • a further object is to provide a preparation that contains a lactic acid bacterium, or a component derived from this lactic acid bacterium, that has, e.g., an antiallergic function, an anti-autoimmune disease function, a diabetes-improving function, and/or a neutral fat-lowering function.
  • a specific lactic acid bacterium belonging to Lactobacillus delbrueckii subsp. lactis has an excellent antiallergic function and also has at least one other function selected from an anti-autoimmune disease function, a diabetes-improving function, a neutral fat-lowering function, and so forth.
  • the present invention was achieved based on this finding.
  • the present invention relates to a composition
  • a composition comprising at least one lactic acid bacterium selected from the group consisting of Lactobacillus delbrueckii subsp. lactis strain KR-037 (NITE BP-395), Lactobacillus delbrueckii subsp. lactis strain KLAB-4 (NITE BP-394), and variants thereof, or comprising a component derived from the lactic acid bacterium.
  • the present invention can provide a composition that contains a highly safe lactic acid bacterium or a component derived from this lactic acid bacterium.
  • the composition according to the present invention can be used not only as an antiallergic agent effective for preventing or improving allergies which are currently regarded as national diseases, but can also be employed as a preparation such as an anti-autoimmune disease agent, a diabetes-improving agent, and/or a neutral fat-lowering agent.
  • FIG. 1 shows effects of the composition of the present invention on the time course of the dermatitis score for mice with induced atopic dermatitis
  • FIG. 2 shows effects of the composition of the present invention on the time course of the auricular thickness in mice with induced atopic dermatitis
  • FIG. 3 shows effects of the composition of the present invention on the time course of the blood glucose value after the oral administration of an aqueous maltose solution.
  • composition of the present invention comprises at least one lactic acid bacterium selected from the group consisting of Lactobacillus delbrueckii subsp. lactis strain KR-037 (NITE BP-395), Lactobacillus delbrueckii subsp. lactis strain KLAB-4 (NITE BP-394), and variants thereof, or comprises a component derived from the lactic acid bacterium.
  • the Lactobacillus delbrueckii subsp. lactis strain KR-037 (also referred to below as the “KR-037 strain”) in the composition of the present invention is a novel lactic acid bacterium isolated from fermented milk and belongs to Lactobacillus delbrueckii subsp. lactis. It has been deposited under accession number NITE BP-395 with the Patent Microorganisms Depositary, Incorporated Administrative Agency National Institute of Technology and Evaluation (2-5-8 Kazusakamatari, Kisarazu-shi, Chiba Prefecture, Japan) (Thereafter, the national deposit strain originally deposited on Aug. 9, 2007 was transferred to an international deposit based on the Budapest Treaty (Sep. 22, 2008).).
  • the KR-037 strain in the present invention was identified as Lactobacillus delbrueckii subsp. lactis due to the observation of at least 90% homology with a Lactobacillus delbrueckii subsp. lactis reference strain when sequencing was performed up to 544 bases from the base at the 5′ terminal of the 16S rRNA gene of the KR-037 strain.
  • Lactobacillus delbrueckii subsp. lactis strain KLAB-4 (also referred to below as the “KLAB-4 strain”) is also a novel lactic acid bacterium isolated from fermented milk and belongs to Lactobacillus delbrueckii subsp. lactis . It has been deposited under accession number NITE BP-394 with the Patent Microorganisms Depositary, Incorporated Administrative Agency National Institute of Technology and Evaluation (2-5-8 Kazusakamatari, Kisarazu-shi, Chiba Prefecture, Japan) (Thereafter, the national deposit strain originally deposited on Aug. 9, 2007 was transferred to an international deposit based on the Budapest Treaty (Sep. 22, 2008).).
  • the KLAB-4 strain in the present invention was identified as Lactobacillus delbrueckii subsp. lactis due to the observation of at least 90% homology with a Lactobacillus delbrueckii subsp. lactis reference strain when sequencing was performed up to 544 bases from the base at the 5′ terminal of the 16S rRNA gene of the KLAB-4 strain.
  • the antiallergic function in the present invention can be evaluated, for example, as in the examples provided below, by culturing splenocytes from ovalbumin (OVA)-immunized BALB/c mice in a medium supplemented with OVA and the investigational substance and measuring the cytokines (IL-12, IL-4) produced by the splenocytes.
  • OVA ovalbumin
  • the investigational substance is considered as having an antiallergic function if, in comparison to the amount of production of cytokines IL-12 and IL-4 by splenocytes cultured in a medium lacking the investigational substance, the addition of the investigational substance results in the induction of the IL-12 production by the splenocytes and the inhibition of the IL-4 production.
  • the antiallergic function can also be evaluated by administering the investigational substance orally to mice and then immunizing the mice with OVA, and measuring the total IgE level in the blood from these mice.
  • the investigational substance is considered as having an antiallergic function if the total blood IgE level in these mice is reduced in comparison to that of mice not receiving the investigational substance.
  • the anti-autoimmune disease function can be evaluated in accordance with the usual methods, for example, by the following method as shown in the examples provided below.
  • a mouse model of collagen-induced arthritis (DBA/1J mice) is immunized with bovine type II collagen and the investigational substance is administered orally to the arthritis-induced mice.
  • the investigational substance can be considered as having an anti-autoimmune disease function when the mice receiving the investigational substance by oral administration are observed to have a lower incidence of arthritis than mice not receiving the investigational substance.
  • the anti-autoimmune disease efficacy can also be evaluated by observing the changes in the disease state in mice treated as described above.
  • the investigational substance can also be considered as having an anti-autoimmune disease function when, in comparison to a continual increase in the arthritis disease state score for mice not receiving the investigational substance, the disease state score for mice receiving the investigational substance orally is found to be stable so that the disease is prevented from worsening.
  • the diabetes-improving function (anti-diabetic function) can be evaluated, for example, as shown in the examples provided below, by measuring the time course of the blood glucose value in a sugar tolerance test in a mouse model of type 2 diabetes (KK-Ay mice) and observing a rapid decline of the blood glucose level that has been elevated by the sugar load.
  • the neutral fat-lowering function can be evaluated, as shown in the examples provided below, by measuring the neutral fat level in the blood of a mouse model of type 2 diabetes (KK-Ay mice) and noting a significant reduction compared to the blood neutral fat level in mice not receiving the investigational substance.
  • lactic acid bacteria that have an antiallergic function can be exemplified by Lactobacillus delbrueckii subsp. lactis strain KR-188 (accession number: NITE P-396), Enterococcus durans strain KR-211 (accession number: NITE P-397), and Leuconostoc mesenteroides subsp. mesenteroides strain KLAB-2 (accession number: NITE P-393).
  • the technical scope of the present invention encompasses not only the previously described KR-037 strain and KLAB-4 strain, but also their variants insofar as these latter have the same functions, and these variants can be incorporated in the composition of the present invention instead of the previously described KR-037 strain or KLAB-4 strain.
  • These variants are not particularly limited and can be exemplified by variants provided by natural mutation and variants obtained by the artificial induction of mutation by known methods, for example, exposure to radiation or exposure to mutagenic substances.
  • Any culture medium can be used for the cultivation of the previously described KR-037 strain, KLAB-4 strain, or their variants, as long as the particular organism can grow in the culture medium.
  • cultivation can be carried out, for example, by test tube cultivation, flask cultivation, fermentation tank cultivation, and so forth, and there are no particular limitations thereon.
  • the MRS medium generally used for lactic acid bacteria cultivation may be used and ordinary lactic acid bacteria cultivation may be carried out under generally used conditions.
  • the KR-037 strain, KLAB-4 strain, or variant thereof incorporated in the composition of the present invention may be viable or dead (killed).
  • viable refers to the live lactic acid bacteria per se
  • dead (killed) refers to the cells after a microbicidal treatment such as the application of heat, the application of pressure, chemical treatment, and so forth.
  • the technical scope of the present invention also encompasses a lactic acid bacteria-derived component from the previously described KR-037 strain, KLAB-4 strain, or their variants insofar as this component has the same functions, and this component can be incorporated in the composition of the present invention instead of the previously described KR-037 strain, KLAB-4 strain, or variants thereof.
  • this lactic acid bacteria-derived component examples include a processed material (processed cell material) provided by the execution of at least one process selected from grinding or disruption of the previously described lactic acid bacteria; conversion thereof into a liquid material by, for example, extraction; concentration; conversion into a paste; drying (spray drying, freeze drying, vacuum drying, drum drying, and so forth); and dilution, and also include a residue from the extraction of the lactic acid bacteria.
  • a preferred extraction residue is, for example, a hot water extraction residue comprising the sedimented material obtained when the cells are treated with boiling water or hot water and a residue from the extraction of an extract from the cells is then collected by centrifugal separation.
  • composition of the present invention which incorporates the KR-037 strain, KLAB-4 strain, a variant of the preceding, or a lactic acid bacteria-derived component from the preceding (also referred to below simply as the “composition of the present invention”), has an excellent antiallergic effect and can therefore be used as a preparation that has an antiallergic function, i.e., as an antiallergic agent.
  • a characteristic feature of the antiallergic agent of the present invention is that it has a very high antiallergic function.
  • the antiallergic agent of the present invention acts to shift the immune response to antigen stimulation to a Th1-type immune response and can also limit the amount of production (antibody titer) of antigen-specific IgE. Accordingly, it can prevent or improve allergic diseases such as hay fever, atopic dermatitis, bronchial asthma, allergic rhinitis, and allergic conjunctivitis.
  • composition of the present invention also has at least one selection from an anti-autoimmune disease function, an anti-diabetic function, a neutral fat-lowering function, and so forth, and thus can be used not only as an antiallergic agent, but also as an anti-autoimmune disease agent, a diabetes-improving agent, and/or a neutral fat-lowering agent.
  • the anti-autoimmune disease agent of the present invention can prevent the onset of an autoimmune disease, e.g., chronic rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, ulcerative colitis, Crohn's disease, and so forth, or can delay onset; or can inhibit the increase in the disease state score of these diseases to prevent the disease from worsening; or can improve the disease state.
  • the diabetes-improving agent of the present invention can improve diabetes, e.g., can rapidly lower a blood glucose level that has been elevated by sugar loading so that abnormalities in sugar metabolism are improved; or can prevent the onset of diabetes.
  • the neutral fat-lowering agent of the present invention acts to prevent or improve hyperlipidemia and abnormalities in fat metabolism by lowering the neutral fat level in the blood and controlling the neutral fat concentration in the blood.
  • composition of the present invention can be used as feed (including pet food), as an animal drug, or as a drug.
  • composition of the present invention as feed or as an animal drug
  • its dosage form is not particularly limited and may be exemplified by capsules, syrups, tablets, pills, powders, granules, drinks, injectables, transfusion fluids, nose drops, eye drops, suppositories, adhesive skin patches, sprays, and so forth.
  • formulation production may be carried out with the suitable addition of other pharmaceutically acceptable formulating agents, for example, excipients, disintegrants, lubricants, binders, oxidation inhibitors, colorants, aggregation inhibitors, absorption promoters, dissolution auxiliaries, stabilizers, and so forth.
  • the preparation may be mixed into a blended feed or mixed feed and may also be given suspended in drinking water.
  • the composition of the present invention may be mixed as such into a feed.
  • the composition of the present invention is given a single time or divided into a plurality of times so as to enable the intake, regardless of the animal species, of preferably 0.01 to 1000 mg/kg body weight per day and more preferably 0.1 to 30 mg/kg body weight per day as the lactic acid bacteria or lactic acid bacteria-derived component.
  • composition of the present invention as a drug, its dosage form is not particularly limited and may be exemplified by capsules, syrups, tablets, pills, powders, granules, drinks, injectables, transfusion fluids, nose drops, eye drops, suppositories, adhesive skin patches, sprays, and so forth.
  • formulation production may be carried out with the suitable addition of other pharmaceutically acceptable formulating agents, for example, excipients, disintegrants, lubricants, binders, oxidation inhibitors, colorants, aggregation inhibitors, absorption promoters, dissolution auxiliaries, stabilizers, and so forth.
  • the dosage of the composition of the present invention in this case, it is administered a single time or divided into a plurality of times so as to enable the intake of preferably 0.1 to 1000 mg/kg body weight per day per person for adults and more preferably 10 to 300 mg/kg body weight per day per person for adults as the lactic acid bacteria or lactic acid bacteria-derived component.
  • the composition of the present invention can also be consumed on an everyday basis as a food.
  • the form of the food that contains the composition of the present invention is not particularly limited and can be exemplified by ordinary foods, e.g., edible oil and fat compositions, cooking oils, spray oils, butters, margarines, shortenings, whipping creams, condensed milks, whiteners, dressings, pickle liquids, breads, cakes, pies, cookies, Japanese confections, snack confections, fried confections, chocolate and chocolate confections, rice confections, rouxs, sauces, bastes, toppings, iced desserts, noodles, bakery mixes, fried foods, processed meat products, other processed food products such as tofu and konjac food products, fish paste products, frozen foods (e.g., frozen entrees, frozen livestock food products, frozen agricultural foods, and so forth), cooked rice, jams, cheeses, cheese foods, imitation cheese products, gums, candies, fermented milk products, canned goods, beverages, and so forth; and
  • the representation can also be made that the product can be used for the prevention or improvement of allergy symptoms.
  • the content of the lactic acid bacteria or lactic acid bacteria-derived component when the composition of the present invention is made into a food can be incorporated so as to constitute 0.00001 to 100% by weight of the food, preferably 0.001 to 50% by weight, and more preferably 0.1 to 30% by weight.
  • the composition of the present invention inhibits the production of IL-4 and promotes the production of IL-12 and as a consequence can shift a Th2-biased in vivo immunity to a Th1-type immune response; it also restrains the amount of antibody-specific IgE production.
  • the composition of the present invention can control or improve allergy symptoms and can prevent or improve allergic diseases such as atopic dermatitis.
  • another embodiment of the present invention is a method of treating an allergic disease, in which the composition of the present invention is administered to a subject.
  • the subject in this case is not particularly limited, but can be exemplified by allergic disease patients, individuals that exhibit allergy symptoms, and healthy persons or healthy animals that do not currently present allergy symptoms but are recognized as having a potential risk thereof as a result of, for example, antibody testing.
  • the present invention is more specifically described by the examples given below, but the present invention is in no way limited to these examples.
  • the antiallergic function, anti-autoimmune disease function, diabetes-improving function, and neutral fat-lowering function were evaluated in the examples using the following methods.
  • Splenocytes from a mouse model of allergy (BALB/c mice) that had been immunized with OVA antigen were co-cultured with OVA and the investigational substance.
  • the antiallergic function was evaluated based on whether IL-4 production was inhibited and IL-12 production was promoted during this co-culture.
  • mice receiving the investigational substance by oral administration were subjected to serial OVA immunizations and the serum IgE was measured.
  • the antiallergic function was also evaluated based on whether the increase in the serum IgE level in mice receiving the investigational substance by oral administration was inhibited relative to an increase over time in the serum IgE level in mice not receiving the investigational substance.
  • Murine atopic dermatitis was induced by the application of picryl chloride to the right and left auricles (both inside and outside) and the back of a mouse model of atopic dermatitis (SPF male Nc/Nga mice) that received the investigational substance per os, and the dermatitis score and auricular thickness were recorded.
  • the atopic dermatitis-improving function was evaluated based on whether an inhibitory trend was seen in the increase with time in the dermatitis score and auricular thickness in mice receiving the investigational substance per os in comparison to an increase over time in the dermatitis score and auricular thickness in mice not receiving the investigational substance.
  • a mouse model of collagen-induced arthritis (DBA/1J mice) was immunized with bovine type II collagen; the investigational substance was administered orally to the arthritis-induced mice; and the arthritis incidence was recorded after 40 to 45 days. The evaluation was based on whether the incidence of arthritis was lowered by the oral administration of the investigational substance in comparison to the 100% incidence of arthritis generally seen in the collagen-induced arthritis mouse model after 40 to 45 days. The anti-autoimmune disease function was also evaluated by observation of the changes with time in the disease state score in these mice.
  • the diabetes-improving function was evaluated by measuring the time course of the blood glucose value in a sugar tolerance test in a mouse model of type 2 diabetes (KK-Ay mice). More specifically, the diabetes-improving function was evaluated based on whether the blood glucose level elevated by the sugar tolerance test was thereafter rapidly lowered in mice that had received the investigational substance per os in comparison to a slow decline over time of the blood glucose level elevated by the sugar tolerance test in mice that had received water per os instead of the investigational substance.
  • the neutral fat-lowering function was evaluated by measuring the neutral fat level in the blood of a mouse model of type 2 diabetes (KK-Ay mice). More specifically, the neutral fat-lowering function was evaluated based on whether the neutral fat level in the blood of mice receiving the investigational substance per os was significantly reduced in comparison to the neutral fat level in the blood of mice receiving water per os instead of the investigational substance.
  • Lactic acid bacteria suspensions 1 to 5 were prepared by suspending the freeze-dried cells at 1 mg/mL in PBS( ⁇ ) (trade name: Phosphate Buffer Saline, from Sigma); sterilizing the suspension for 10 minutes on a boiling water bath; thereafter obtaining a residue by centrifugal separation; and resuspending the residue in PBS( ⁇ ).
  • PBS( ⁇ ) trade name: Phosphate Buffer Saline, from Sigma
  • mice Five-week-old female BALB/c mice were used in this experiment after acclimation onsite for one week.
  • 100 ⁇ g OVA and 2 mg aluminum hydroxide gel were mixed and brought to 200 ⁇ L with physiological saline to provide an antigen solution, and the BALB/c mice were subjected to intraperitoneal immunization with this antigen solution (primary immunization); intraperitoneal immunization was performed again with the same amount of antigen solution after one week (secondary immunization).
  • primary immunization intraperitoneal immunization was performed again with the same amount of antigen solution after one week (secondary immunization).
  • the OVA-specific IgE antibody titer was measured by ELISA in order to check the antibody titer.
  • the splenocytes were prepared from mice that demonstrated a rise in antibody titer (allergy mouse model) and were then suspended in RPMI 1640 medium (trade name: RPMI 1640, from Sigma) containing 10% fetal bovine serum to give 2.0 ⁇ 10 6 cells/mL, and OVA (1 mg/mL) for antigen stimulation and one of lactic acid bacteria suspensions 1 to 5 (1 ⁇ g/mL) as shown in Table 1 were each added.
  • RPMI 1640 medium trade name: RPMI 1640, from Sigma
  • Lactic acid bacteria strain added IL-4 IL-12 Example 1 Lactobacillus delbrueckii subsp. lactis KR 037 198.3 339.1 (Lactic acid bacteria (Accession No.: NITE BP-395) suspension 1) Example 2 Lactobacillus delbrueckii subsp. lactis KI AR-4 274.4 78.8 (Lactic acid bacteria (Accession No.: NITE BP-394) suspension 2) Reference Example 1 Lactobacillus delbrueckii subsp.
  • a lactic acid bacteria suspension as a positive control using lactic acid bacteria was prepared in the same manner as in Production Examples 1 to 5 using Lactobacillus casei strain L14 (Japan Dairy Technical Association, identical to Lactobacillus paracasei KW3110, FERM BP-08634), a lactic acid bacterium regarded as having an antiallergic activity, in place of the lactic acid bacteria used in Production Examples 1 to 5.
  • the antiallergic function was then measured using the same conditions as in Examples 1 and 2. The results are shown in Table 1.
  • Table 1 shows the amount of IL-4 production and the amount of IL-12 production for the co-culture of the lactic acid bacteria and OVA with splenocytes from an allergy mouse model.
  • Comparative Example 1 which lacked the addition of lactic acid bacteria, IL-4 production was induced in the OVA-stimulated splenocytes of allergy mouse model, while IL-12 production was below the detection limit, and a strong Th2-type immune response was thus shown.
  • Reference Example 4 which used Picibanil, IL-4 production was inhibited and IL-12 production was induced in the OVA-stimulated splenocytes of allergy mouse model, and a Th1-type immune response was thus shown.
  • Example 5 which used Lactobacillus casei strain L14
  • a Th1-type immune response was seen as in Reference Example 4.
  • the inhibition of IL-4 production and the induction of IL-12 production were also seen in Examples 1 and 2 and Reference Examples 1 to 3.
  • the results in Example 1 demonstrated that a strong antiallergic activity with induction of a Th1-type immune response was seen for the KR-037 strain; moreover, a high level of antiallergic activity was demonstrated from the fact that the IL-12 production was activated by about twofold and the IL-4 production was inhibited to about two-thirds relative to the lactic acid bacterium of Reference Example 5.
  • the KLAB-4 strain as shown by the results of Example 2, while weakly inducing IL-12 production activity, provided a stronger inhibitory activity on IL-4 production than the lactic acid bacterium of Reference Example 5, which suggested the possibility of a strong antiallergic function.
  • a lactic acid bacteria preparation was first produced by thoroughly mixing in advance 0.05 parts by weight of the freeze-dried KR-037 strain cells that had been produced in Production Example 1 with 0.45 parts by weight of an excipient (trade name: Pinedex #2, from Matsutani Chemical Industry Co., Ltd.). 0.5 Parts by weight of the produced lactic acid bacteria preparation was mixed with 99.5 parts by weight of a powdered mouse feed (product name: CE-2, from Oriental Yeast Co., Ltd.) to provide a lactic acid bacteria preparation-supplemented feed that contained 0.5% by weight of the lactic acid bacteria preparation.
  • mice Five-week-old female BALB/c mice (from Charles River Japan) were acclimated onsite for one week, after which administration of the lactic acid bacteria preparation-supplemented feed was started (ad libitum ingestion of an average of approximately 15 mg/day as the lactic acid bacteria preparation).
  • Intraperitoneal immunization was performed with an antigen solution—prepared by mixing 100 ⁇ g OVA with 2 mg aluminum hydroxide gel and bringing the mixture to 200 pd, with physiological saline—one week (Day 7) after the start day. Immunization with the OVA antigen solution was similarly performed after 2 weeks (Day 14), after 4 weeks (Day 28), after 6 weeks (Day 42), and after 8 weeks (Day 56).
  • Lactic acid bacteria added to feed Day 0 Day 21 Day 35 Day 49 Day 63
  • Lactobacillus delbrueckii subsp. lactis KR-037 0 147 450 510 547 * (Accession No.: NITE BP-395)
  • Lactobacillus delbrueckii subsp. lactis KLAB-4 0 207 732 890 994 (Accession No.: NITE BP-394) Reference Lactobacillus delbrueckii subsp.
  • the total IgE level in the collected serum was measured as in Example 3, but in this case using the freeze-dried KLAB-4 strain cells produced in Production Example 2 in place of the freeze-dried KR-037 strain cells. The individual measured values are shown in Table 2.
  • the total IgE level in the collected serum was measured as in Example 3, but in this case using, respectively, the freeze-dried lactic acid bacteria cells produced in Production Examples 3 to 5 in place of the freeze-dried KR-037 strain cells.
  • the individual measured values are shown in Table 2.
  • the total IgE level in the collected serum was measured as in Example 3, but in this case using a powdered mouse feed (product name: CE-2, from Oriental Yeast Co., Ltd.) that had not been supplemented with the lactic acid bacteria preparation in place of the lactic acid bacteria preparation-supplemented feed.
  • the individual measured values are shown in Table 2.
  • the total IgE level in the collected serum was measured as in Example 3, but in this case using, as the lactic acid bacteria preparation-supplemented feed, a lactic acid bacteria-supplemented feed provided by mixing 99.925 parts by weight of the powdered mouse feed with 0.075 parts by weight of a health supplement comprising Lactobacillus paracasei KW3110 (product name: Noale Capsule, from Kirin Yakult Nextstage Co., Ltd.). The individual measured values are shown in Table 2.
  • the results in Table 2 demonstrate the following.
  • the total blood IgE level in the mice that received the feed according to Reference Example 9 was reduced at Day 63 in comparison to that in the control group (Comparative Example 2), in which a lactic acid bacteria preparation was not incorporated in the feed.
  • the total blood IgE level in the mice receiving the lactic acid bacteria preparation-supplemented feed in Examples 3 and 4 and Reference Examples 6 to 8 was similarly reduced at Day 63 in comparison to that in the Comparative Example 2 control.
  • the results in Table 2 showed that the preparation that contained the freeze-dried KR-037 strain cells of Production Example 1 was, like the preparation of Reference Example 9, a preparation that had a high antiallergic activity.
  • the change in the total IgE level in this experiment since it is considered to be equivalent to the change in the OVA-specific IgE level, shows that an antiallergic effect was seen for the composition of the present invention.
  • mice Seven-week-old SPF male Nc/Nga mice (from Charles River Japan) were acclimated onsite for one week, after which administration of the previously described lactic acid bacteria-supplemented feed was started (ad libitum ingestion of an average of approximately 10 mg/day as the preparation).
  • the induction of atopic dermatitis was performed 4 days (Day 5) after the sensitization by applying 150 ⁇ L of a PiC1 induction solution (0.8% (w/v) PiC1 solution (solvent: olive oil)) to the back and the right and left auricles (both inside and outside) of the mice.
  • This atopic dermatitis induction step was performed every week, totally 7 times.
  • the condition of the skin was observed twice a week from the day on which sensitization was started (Day 1).
  • auricular thickness was also measured once a week using a micrometer from the test start day (Day 0). The results of measurement of the total dermatitis score are shown in FIG. 1 and the results of measurement of the auricular thickness are shown in FIG. 2 .
  • the total score and auricular thickness were measured as in Example 5, but in this case using a powdered mouse feed (product name: CE-2, from CLEA Japan, Inc.) that had not been supplemented with freeze-dried lactic acid bacteria cells. The results are shown in FIGS. 1 and 2 .
  • FIGS. 1 and 2 demonstrate the following.
  • the control group Comparative Example 3
  • the total score and auricular thickness increased from the 4th atopic dermatitis induction.
  • the increase in the total score and the increase in the auricular thickness were both inhibited in the mice in the group (Example 5) that received feed supplemented with the freeze-dried KR-037 strain cells, and the increase was significantly inhibited from Day 34 in the case of the total score and from Day 35 in the case of the auricular thickness.
  • DBA/1J mice (eight week old, male, from Japan SLC, Inc.), a mouse model of collagen-induced arthritis, were used in this experiment.
  • an arthritis induction collagen solution was prepared by dissolving bovine type II collagen (COSMO BIO Co., Ltd.) in 0.05 M acetic acid to provide 2.7 mg/mL and mixing with an equal amount, on a volumetric basis, of Freund's complete adjuvant (Wako Pure Chemical Industries, Ltd.), and arthritis onset was induced by the dorsal intradermal injection of 150 ⁇ L of this arthritis induction collagen solution (Day 0) followed, after 14 days (Day 14), by the intradermal immunization at the base of the tail with 150 ⁇ L of the same arthritis induction collagen solution as on Day 0.
  • a lactic acid bacteria preparation was produced by mixing 40 parts by weight of the freeze-dried lactic acid bacteria (strain KLAB-4) cells produced in Production Example 2 and 60 parts by weight of an excipient (trade name: Pinedex #2, from Matsutani Chemical Industry Co., Ltd.) and was suspended in PBS( ⁇ ) so as to provide 1 mg/mouse/day of the lactic acid bacteria preparation and this was forcibly administered from after 7 days (Day 7) using a plastic mouse feeding needle and a 1 mL tuberculin syringe.
  • strain KLAB-4 freeze-dried lactic acid bacteria
  • an excipient trade name: Pinedex #2, from Matsutani Chemical Industry Co., Ltd.
  • the arthritis disease state of the afflicted mice in each of the groups in Example 6, Reference Example 10, and Comparative Example 4 was evaluated based on the arthritis disease state score.
  • the arthritis disease state score was evaluated based on grading the disease states in all the limbs (both front and rear and on both sides) on a four point scale (0: no change, 1: swelling of the toes, 2: swelling of the toes and footpads, 3: swelling of the entire limb, 4: severe swelling) and adding the scores; 1 additional point was added in the case of bone degeneration.
  • the results are given in Table 4.
  • the average score for the mice in Comparative Example 4 was 1.3 after 44 days (Day 44), but 4 days later, i.e., after 48 days (Day 48), had risen to 2.5.
  • the disease state score was 0.2 after 46 days (Day 46), but even after 48 days (Day 48) an increase in the disease state score from this 0.2 was not seen.
  • the preparation that used the KLAB-4 strain of Production Example 2 in particular exhibited an excellent function in that it inhibited arthritis onset and also slowed the disease progression.
  • a lactic acid bacteria preparation was first produced by mixing 0.1 parts by weight of the freeze-dried KLAB-4 strain cells that had been produced in Production Example 2 with 4.9 parts by weight of skim milk powder and 5 parts by weight of an excipient (trade name: Pinedex #2, from Matsutani Chemical Industry Co., Ltd.). 10 Parts by weight of this preparation was mixed with 90 parts by weight of a powdered mouse feed (product name: MF, from Oriental Yeast Co., Ltd.) to provide a lactic acid bacteria preparation-supplemented feed that contained 10% by weight of the lactic acid bacteria preparation with reference to the supplemented feed as a whole.
  • a powdered mouse feed product name: MF, from Oriental Yeast Co., Ltd.
  • mice Six-week-old male KK-Ay mice (from CLEA Japan, Inc.) were acclimated onsite for one week, after which administration of the aforementioned lactic acid bacteria preparation-supplemented feed was started (ad libitum ingestion of an average of approximately 150 mg/day as the preparation). At four weeks after this start day, the diabetes-improving function was evaluated on the mice using a sugar tolerance test. This evaluation was performed as follows.
  • a fermented milk preparation was produced by mixing 5 parts by weight of this KLAB-4 strain fermented milk powder and 5 parts by weight of an excipient (trade name: Pinedex #2, from Matsutani Chemical Industry Co., Ltd.). It is noted that the lactic acid bacteria concentration in this fermented milk preparation was about the same as the lactic acid bacteria concentration in the lactic acid bacteria preparation produced in Example 7. 90 Parts by weight of a powdered mouse feed (product name: MF, from Oriental Yeast Co., Ltd.) was mixed with this fermented milk preparation to provide a fermented milk preparation-supplemented feed. An evaluation was performed as in Example 7, but in this case using this fermented milk preparation-supplemented feed.
  • Example 7 An evaluation was performed as in Example 7, but in this case using a powdered mouse feed (product name: MF, from Oriental Yeast Co., Ltd.) that had not been supplemented with the lactic acid bacteria preparation.
  • a powdered mouse feed product name: MF, from Oriental Yeast Co., Ltd.
  • Example 8 An evaluation was performed as in Example 8, but in this case using 5 parts by weight of skim milk powder and 5 parts by weight of an excipient (trade name: Pinedex #2, from Matsutani Chemical Industry Co., Ltd.) in place of the fermented milk preparation and mixing them with 90 parts by weight of a powdered mouse feed (product name: MF, from Oriental Yeast Co., Ltd.).
  • an excipient trade name: Pinedex #2, from Matsutani Chemical Industry Co., Ltd.
  • the results of the sugar tolerance test in the diabetes mouse model are shown in FIG. 3 .
  • the blood glucose levels in the mice in Examples 7 and 8 underwent a decline with time and, while presenting the maximum blood glucose levels at 20 to 40 minutes after sugar loading, had declined at 120 minutes to the levels of the blood glucose values at minute 0 (fasting blood glucose).
  • a lactic acid bacteria preparation-admixed liquid was first prepared by suspending in distilled water, so as to provide a concentration of 10% by weight, a lactic acid bacteria preparation itself prepared by mixing 33 parts of an excipient (trade name: Pinedex #2, from Matsutani Chemical Industry Co., Ltd.) with 67 parts of the freeze-dried KR-037 strain cells produced in Production Example 1.
  • an excipient trade name: Pinedex #2, from Matsutani Chemical Industry Co., Ltd.
  • mice Eight-week-old male KK-Ay mice (from CLEA Japan, Inc.) were acclimated onsite for two weeks with ad libitum intake of a mouse feed (product name: CE-2, from Oriental Yeast Co., Ltd.) and sterilized water, after which the aforementioned lactic acid bacteria preparation-admixed liquid was forcibly administered using a plastic mouse feeding needle and a 1 mL tuberculin syringe so as to provide 7.5 mL per 1 kg mouse body weight per day (forcible administration of an average of approximately 30 mg/day of the preparation per mouse).
  • mice feed product name: CE-2, from Oriental Yeast Co., Ltd.
  • sterilized water were freely available to the mice.
  • blood collection was performed and the neutral fat in the serum was measured using a measurement kit (Triglyceride E-Test Wako, from Wako Pure Chemical Industries, Ltd.). The measured values are shown in Table 5.
  • Example 9 360.1 Reference 387.1
  • Example II Reference 477.2
  • Example 12 Reference 359.8
  • Example 13 Reference 463.3
  • Example 14 Comparative 596.6
  • Example 7 Comparative 596.6
  • the neutral fat level in the collected serum was measured as in Example 9, but in this case using the freeze-dried lactic acid bacteria cells produced in Production Example 3 in place of the freeze-dried KR-037 strain cells.
  • the measured values are given in Table 5.
  • the neutral fat level in the collected serum was measured as in Example 9, but in this case using the freeze-dried lactic acid bacteria cells produced in Production Example 4 in place of the freeze-dried KR-037 strain cells.
  • the measured values are given in Table 5.
  • the neutral fat level in the collected serum was measured as in Example 9, but in this case using distilled water free of a lactic acid bacteria preparation in place of the lactic acid bacteria preparation-admixed liquid.
  • the measured values are given in Table 5.
  • the neutral fat level in the collected serum was measured as in Example 9, but in this case the lactic acid bacteria preparation-admixed liquid was replaced with a distilled water dilution of Pioglitazone (from Takeda Pharmaceutical Co., Ltd.), which is a drug that improves insulin resistance and acts to lower the blood level of neutral fats, that had been diluted to have a concentration of 0.4% by weight.
  • Pioglitazone from Takeda Pharmaceutical Co., Ltd.
  • the neutral fat level in the collected serum was measured as in Example 9, but in this case replacing the lactic acid bacteria preparation-admixed liquid with a lactic acid bacteria suspension obtained by suspending a health supplement comprising Lactobacillus paracasei KW3110 (product name: Noale Capsule, from Kirin Yakult Nextstage Co., Ltd.) in distilled water to provide a concentration of 10% by weight.
  • a health supplement comprising Lactobacillus paracasei KW3110 (product name: Noale Capsule, from Kirin Yakult Nextstage Co., Ltd.) in distilled water to provide a concentration of 10% by weight.
  • the measured values are given in Table 5.

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JP6747724B2 (ja) * 2018-05-28 2020-08-26 株式会社ライフ・クオリティ研究所 低血糖改善剤及び低血糖改善用組成物
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WO2021111983A1 (ja) * 2019-12-02 2021-06-10 株式会社ライフ・クオリティ研究所 機能性身体症候群の予防又は改善用剤及びそれを含む組成物
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JP7057039B2 (ja) * 2019-12-02 2022-04-19 株式会社ライフ・クオリティ研究所 認知症の予防又は改善用剤及びそれを含む組成物
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