WO2016125861A1 - 乳酸菌、該乳酸菌由来の自然免疫活性化剤、感染症予防治療剤及び飲食品 - Google Patents
乳酸菌、該乳酸菌由来の自然免疫活性化剤、感染症予防治療剤及び飲食品 Download PDFInfo
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- WO2016125861A1 WO2016125861A1 PCT/JP2016/053378 JP2016053378W WO2016125861A1 WO 2016125861 A1 WO2016125861 A1 WO 2016125861A1 JP 2016053378 W JP2016053378 W JP 2016053378W WO 2016125861 A1 WO2016125861 A1 WO 2016125861A1
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- lactic acid
- acid bacteria
- food
- innate immunity
- acid bacterium
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Classifications
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- A61K35/744—Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/135—Bacteria or derivatives thereof, e.g. probiotics
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L5/00—Preparation or treatment of foods or foodstuffs, in general; Food or foodstuffs obtained thereby; Materials therefor
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- C—CHEMISTRY; METALLURGY
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- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N1/00—Microorganisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
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- A—HUMAN NECESSITIES
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- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
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- A—HUMAN NECESSITIES
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- A23V2200/00—Function of food ingredients
- A23V2200/30—Foods, ingredients or supplements having a functional effect on health
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
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- C—CHEMISTRY; METALLURGY
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- C12R—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES C12C - C12Q, RELATING TO MICROORGANISMS
- C12R2001/00—Microorganisms ; Processes using microorganisms
- C12R2001/01—Bacteria or Actinomycetales ; using bacteria or Actinomycetales
- C12R2001/225—Lactobacillus
Definitions
- the present invention relates to a novel lactic acid bacterium, an innate immunity activator comprising a live bacterium, killed bacterium or treated product of the novel lactic acid bacterium as an active ingredient, an infectious disease preventing / treating agent comprising the peptidoglycan of the novel lactic acid bacterium as an active ingredient, and It relates to the food and drink it contains.
- Lactic acid bacteria have been used for fermented foods for a long time, and have been used for the production of food and drinks, pharmaceuticals, probiotics and the like. Lactic acid bacteria are characterized by Gram-positive, catalase-negative, no endospore formation, no motility, etc.
- Lactobacillus paraplantarum is a lactic acid bacterium related to Lactobacillus plantarum (L. plantarum). It is known (Non-Patent Document 6). In addition, the entire genome has been deciphered in some species and subspecies (Non-Patent Documents 1 and 2), and recently, recombinant L. plantarum has been used to present specific antigens through the intestinal epidermis of animals. It is attracting attention as a preventive agent for live infection that can be taken orally (Non-Patent Documents 3 and 4).
- the innate immune reaction it is known that immune cells such as dendritic cells and macrophages produce cytokines in response to innate immune activators derived from bacteria and viruses, and subsequent immune reactions occur.
- the innate immunity mechanism is an infection defense mechanism common to living organisms, and is generally non-specific, and thus is characterized by a quick reaction and effective function against many infection sources.
- the present inventors have developed an evaluation method (screening method) that can easily measure an innate immune activation reaction in silkworms having only an innate immune mechanism (Patent Document 1, Non-Patent Document 5). Further, it has been confirmed that the method can be used to evaluate an innate immune activator (screening method) having an innate immune activation effect on vertebrates such as humans (Patent Document 1, etc.). Further, it has been confirmed by the present inventors that silkworms are useful as model animals for evaluating resistance to microbial infection (Patent Documents 2, 3, etc.).
- An object of the present invention is to provide a novel lactic acid bacterium having high innate immunity activation ability, and further, an innate immunity activator comprising the lactic acid bacterium or killed bacteria or processed product of the lactic acid bacterium as an active ingredient,
- An object of the present invention is to provide a food or drink containing a lactic acid bacterium or an innate immune activator derived from the lactic acid bacterium. It is another object of the present invention to provide an infectious disease preventive / therapeutic agent and a food and drink comprising a novel lactic acid bacterium-derived substance as an active ingredient.
- lactic acid bacteria having the ability to activate innate immunity have been analyzed as a result of analysis of their properties and analysis of the base sequence of 16S rDNA, etc., and a new lactic acid strain belonging to the genus Lactobacillus (hereinafter referred to as “# 11-1”). It may also be abbreviated).
- silkworms that have eaten the peptidoglycan fraction of lactic acid bacteria have an unexpectedly prolonged survival time after infection with Pseudomonas aeruginosa and have resistance to Pseudomonas aeruginosa infection, despite having no acquired immune mechanism.
- the present invention has been completed by finding that it is given.
- the present invention provides a lactic acid bacterium belonging to the genus Lactobacillus having a deposit number of NITE BP-02005 in the Patent Microorganism Deposit Center (NPMD) of the National Institute of Technology and Evaluation (NITE). . Furthermore, the present invention provides an isolated or purified lactic acid bacterium.
- the present invention also provides a lactic acid bacterium as described above or a lactic acid bacterium that has been naturally or artificially mutated and has an ability to activate innate immunity.
- the present invention also provides the above lactic acid bacterium having the base sequence of the 16S rDNA region represented by SEQ ID NO: 1 in the sequence listing.
- the present invention provides an isolated or purified lactic acid bacterium.
- the present invention is an innate immunity activator comprising as an active ingredient the above-mentioned lactic acid bacteria, killed bacteria of the lactic acid bacteria, or processed products of the lactic acid bacteria
- the processed product of lactic acid bacteria is a culture product of lactic acid bacteria; concentrate; paste product; spray-dried product, freeze-dried product, vacuum-dried product, drum-dried product, etc .; liquefied product; dilution product;
- an innate immunity activation agent characterized by being at least one processed product selected from the group consisting of extracts from the culture.
- the present invention also provides an infectious disease preventive and therapeutic agent comprising the above-mentioned peptidoglycan of lactic acid bacteria as an active ingredient.
- the present invention also provides an infectious disease preventive and therapeutic agent comprising the above-mentioned innate immunity activator as an active ingredient.
- the present invention also provides an infectious disease preventive and therapeutic agent comprising the above-mentioned peptidoglycan of lactic acid bacteria as an active ingredient.
- the present invention also provides a food or drink containing the lactic acid bacterium, the innate immunity activator or the infectious disease preventive or therapeutic agent.
- this invention provides the food / beverage products manufactured using the process fermented using said lactic acid bacteria,
- the said food / beverage products provide the food / beverage products which are fermented milk.
- a novel lactic acid bacterium having an extremely high ability to activate innate immunity can be provided. Furthermore, the novel lactic acid bacteria, dead bacteria of the lactic acid bacteria, or a novel innate immunity activator having an extremely high innate immunity activation activity using the processed product of the lactic acid bacteria as an active ingredient are provided. It is possible to provide a food or drink excellent in innate immunity activation ability containing (derived from) an innate immunity activator.
- an infectious disease preventive and therapeutic agent containing the novel peptidoglycan of lactic acid bacteria as an active ingredient, and the infectious disease preventive and therapeutic agent prevents infection due to bacteria or the like by oral administration. can do. Therefore, foods and drinks containing the infectious disease preventive / therapeutic agent are effective for infectious disease prevention.
- the screening method for finding a novel lactic acid bacterium or a novel innate immunity activator of the present invention utilizes the fact that the muscle contraction of a silkworm specimen occurs in response to an innate immunity activator. Detection of activation ability is suppressed, and because measurement is performed using silkworm individuals, measurement results that take into account ADME (absorption, distribution, metabolism, and excretion) and PK (pharmacokinetics) are obtained. Toxic compounds can be excluded. Therefore, the innate immunity activator, the infectious disease preventive / therapeutic agent and the food and drink according to the present invention have an excellent effect of passing the above test.
- ADME absorption, distribution, metabolism, and excretion
- PK pharmacokinetics
- the lactic acid bacteria of the present invention can be used not only for the production of general foods and drinks, health foods, drugs, fermented foods and drinks, probiotics, etc., but also for the prevention and treatment of diseases due to innate immune activation.
- fermented foods and drinks it is particularly suitable for use as fermented milk, lactic acid bacteria beverages, yogurt, pickles, lactic acid bacteria starters for the production of pickles.
- lactic acid bacteria starters for the production of pickles.
- it since it is resistant to acid, it has the feature that it reaches the small intestine without being decomposed in the stomach.
- FIG. 2 is a continuation of FIG. 1. It is a graph which shows the survival time after a Pseudomonas aeruginosa infection of the silkworm which consumed the peptidoglycan fraction of lactic acid bacteria Lactobacillus plantarum PGN, and the silkworm which does not eat.
- the present invention is a lactic acid bacterium belonging to the genus Lactobacillus having a deposit number of NITE BP-02005 at the Patent Microorganism Deposit Center (NPMD) of the National Institute for Product Evaluation and Technology (NITE).
- NPMD Patent Microorganism Deposit Center
- Physiological properties Physiological and chemical taxonomic properties of # 11-1 of the present invention are as follows. (1) Attitude toward oxygen: Anaerobic (2) Catalase:- (3) Alkaline phosphatase:- (4) Esterase:- (5) Esterase lipase:- (6) Lipase:- (7) Leucine allylamidase: + (8) Valine allylamidase: + (9) Cystine allylamidase:- (10) Trypsin:- (11) ⁇ -chymotrypsin:- (12) Acid phosphatase: + (13) Naphthol-AS-BI-phosphohydrolase: + (14) ⁇ -Galactosidase:- (15) ⁇ -galactosidase:- (16) ⁇ -glucuronidase:- (17) ⁇ -Glucosidase:- (18) ⁇ -Glucosidase:- (19) N-acetyl- ⁇ -glucosaminidase:-
- the analysis results of # 11-1 regarding 16S rDNA used as an index for molecular biological phylogeny are as follows. That is, from the genomic DNA of # 11-1, the base sequence of the 16S rDNA region was amplified by PCR and analyzed by a sequencer. As a result, a base sequence corresponding to almost the entire length of 16S rDNA was found. When this base sequence was subjected to homology search by NCBI BLAST analysis, the base sequence of # 11-1 16S rDNA region was found to be the base sequence of Lactobacillus paraplantarum DSM10667 strain (registration number: NR — 025447.1). # 11-1 belongs to the L. plantarum paraplantarum species. However, since they do not completely match, # 11-1 of the present invention is a lactic acid strain (subspecies) different from the above strain.
- # 11-1 of the present invention is a novel microorganism belonging to the genus Lactobacillus.
- # 11-1 was determined to be an isolated novel microbial strain did.
- NITE National Institute of Technology and Evaluation
- # 11-1 may not be within the range of the physiological properties shown above. Needless to say, such “mutation” includes both natural and artificial mutations.
- the culture method of # 11-1 is described below.
- the culture method of # 11-1 may be performed according to a general culture method performed for a microorganism belonging to the genus Lactobacillus.
- the culture is preferably performed under anaerobic conditions.
- the carbon source in the medium include D-ribose, D-galactose, D-glucose, D-fructose, D-mannose, D-mannitol, N-acetylglucosamine, amygdalin, arbutin, esculin, salicin, D-cellobiose
- Organic carbon compounds such as D-maltose, sucrose, D-trehalose, gentiobiose, molasses, starch syrup, and fats and oils are used
- nitrogen sources include meat extract, casein, peptone, yeast extract, dry yeast, germ, soybean Organic / inorganic nitrogen compounds such as powder, urea, amino acids and ammonium salts can be used.
- inorganic salts such as sodium salt, potassium salt, calcium salt, magnesium salt, phosphate, iron salt, copper salt, zinc salt, cobalt salt and the like are appropriately added as necessary.
- a growth promoting substance such as biotin, vitamin B1, cystine, methyl oleate, lard oil or the like in terms of increasing the production amount of the target product.
- antifoamers such as a silicone oil and surfactant.
- the prepared medium for example, an MRS medium, a GAM medium or the like is preferably used.
- the culture conditions may be performed according to the general culture conditions performed for Lactobacillus microorganisms as described above. If it is a liquid culture method, stationary culture is desirable. If it is a small scale, you may use the stationary culture method by the glass bottle with a lid
- the culture temperature is preferably maintained between 25 ° C. and 37 ° C., more preferably 32 ° C. to 37 ° C.
- the culture pH is preferably performed in the vicinity of 7.
- the culture period is a factor that varies depending on the composition of the medium used, the culture temperature, etc. In the case of # 11-1, a sufficient amount of the target product is ensured preferably in 12 to 72 hours, more preferably in 24 to 48 hours. can do. It is also preferable to pick up a colony obtained by culturing and form a single colony on the medium again.
- the novel lactic acid bacterium “# 11-1” of the present invention has the ability to activate innate immunity as the lactic acid bacterium itself or as a lactic acid bacterium naturally or artificially mutated in the lactic acid bacterium. That is, the present invention is a lactic acid bacterium belonging to the genus Lactobacillus whose accession number is NITE BP-02005, or a lactic acid bacterium naturally or artificially mutated thereof, and having a natural immunity activation ability.
- the innate immunity activation ability was measured by the method specifically described in the Examples, that is, Ishii K., Hamamoto H., Kamimura M., Sekimizu K., J. Biol. Chem. Jan. 25; 283 (4 ): 2185-91 (2008), measured in detail by silkworm slow muscle contraction.
- the “processed product of lactic acid bacteria” includes a culture product, a concentrate, a paste product, a dried product, a liquefied product, a diluted product, a crushed product, a sterilized processed product, and an extract from the culture product.
- the at least 1 processed material chosen from a group is mentioned.
- examples of the “dried product” include spray-dried products, freeze-dried products, vacuum-dried products, and drum-dried products.
- the lactic acid bacterium of the present invention (# 11-1 or a lactic acid bacterium naturally or artificially mutated thereof), a dead bacterium of the lactic acid bacterium, or a processed product of the lactic acid bacterium as an active ingredient”
- An immunoactivator wherein the processed product of lactic acid bacteria is extracted from culture, concentrate, pasted product, dried product, liquefied product, diluted product, crushed product, sterilized processed product, and cultured product of lactic acid bacterium.
- An innate immune activator characterized in that it is at least one processed product selected from the group consisting of products.
- the innate immunity activator of the present invention can contain the lactic acid bacterium of the present invention, a dead bacterium of the lactic acid bacterium, or a processed product of the lactic acid bacterium in various states.
- the state containing a suspension, lactic acid bacteria, a culture supernatant, a culture medium component, etc. are mentioned.
- lactic acid bacteria viable cells, wet bacteria, dry bacteria and the like can be used as appropriate.
- the killed bacteria which performed sterilization ie, heat sterilization process, radiation sterilization process, crushing process, etc. may be sufficient.
- the content of the lactic acid bacterium, the killed lactic acid bacterium, and the processed product of the lactic acid bacterium, which is an active ingredient in the innate immunity activator of the present invention, with respect to the entire innate immunity activator is not particularly limited, depending on the purpose.
- the total amount of lactic acid bacteria, dead bacteria of the lactic acid bacteria, and processed product of the lactic acid bacteria can be 0.001 to 100 parts by mass when the innate immunity activator is 100 parts by mass. It is preferably contained in an amount of 0.01 to 99 parts by mass, particularly preferably 0.1 to 95 parts by mass, and still more preferably 1 to 90 parts by mass.
- any one of the active ingredients may be used alone, or two or more of them may be used in combination.
- the innate immunity activator of the present invention contains the lactic acid bacterium, the killed lactic acid bacterium, or the processed product of the lactic acid bacterium as an active ingredient, and can contain “other ingredients” in addition to these active ingredients. .
- the “other components” in the innate immunity activator are not particularly limited and can be appropriately selected according to the purpose within a range not impairing the effects of the present invention.
- pharmaceutically acceptable And a carrier that can be used.
- carrier There is no restriction
- the content of “other components” in the innate immunity activator is not particularly limited and can be appropriately selected depending on the purpose.
- the aforementioned lactic acid bacteria of the present invention, killed bacteria of the lactic acid bacteria, and processed products of the lactic acid bacteria are useful as an infectious disease preventive and therapeutic agent because of having or having innate immunity activation ability, and in particular, infectious diseases for oral administration. It is useful as a preventive and therapeutic agent.
- the present inventor has confirmed that oral administration of the peptidoglycan of lactic acid bacteria of the present invention has a life-prolonging effect on silkworms infected with Pseudomonas aeruginosa. It has already been confirmed that the resistance of silkworms infected with bacteria or the like is correlated with the resistance in mammals such as humans (for example, Patent Documents 2 and 3).
- the peptidoglycan of Lactobacillus plantarum lactic acid confers resistance to infection with Pseudomonas aeruginosa in silkworms.
- Silkworms have no acquired immune mechanism and cannot produce antibodies against antigens. Therefore, it is considered that peptidoglycan of Lactobacillus plantarum administered orally activated the innate immune mechanism of silkworms in the intestine and the like, and as a result, had an effect on infection control.
- peptidoglycan of lactic acid bacteria imparted resistance to Pseudomonas aeruginosa infection in silkworms that have no acquired immune mechanism and only an innate immune mechanism. It is considered that peptidoglycan activated the innate immunity mechanism of silkworms and resisted infection, which is similar to the lactic acid bacterium of the present invention, the killed bacterium of the lactic acid bacterium, or the lactic acid bacterium. It shows that the innate immunity activator containing the processed product has an effect as an infectious disease preventive and therapeutic agent.
- An agent containing, as an active ingredient, a peptidoglycan of a lactic acid bacterium belonging to the genus Lactobacillus such as Lactobacillus plantarum, Lactobacillus paraparatalum is useful as a preventive / therapeutic agent for infectious diseases for mammals such as humans.
- another aspect of the present invention is an infectious disease preventive and therapeutic agent comprising the innate immunity activator as an active ingredient, and further contains the peptidoglycan of the lactic acid bacterium as an active ingredient. It is an infectious disease prevention and treatment agent characterized by the above.
- the lactic acid bacterium of the present invention and the innate immunity activator of the present invention derived from the lactic acid bacterium can be incorporated into foods and drinks having standards such as pharmaceuticals, quasi drugs, general foods and drinks, health foods, and powdered milk Yes, it can be applied to various medicines, foods and drinks, etc. regardless of their form.
- foods and drinks manufactured using the above-described process of fermenting using the lactic acid bacteria of the present invention, and in particular, fermented milk is easy to exhibit the normal effects of lactic acid bacteria and the effects specific to the present invention. preferable.
- a dosage form of the innate immunity activation agent of this invention or an infectious disease prevention treatment agent
- it can select suitably according to the desired administration method which is mentioned later.
- oral solid preparations tablettes, coated tablets, granules, powders, hard capsules, soft capsules, etc.
- oral liquids internal solutions, syrups, elixirs, etc.
- injections solvents, suspensions Agents
- ointments patches, gels, creams, powders for external use, sprays, inhalation sprays and the like.
- oral solid preparation examples include, for example, excipients and further additives such as binders, disintegrants, lubricants, colorants, flavoring and flavoring agents as necessary, in addition to the active ingredients. Can be manufactured.
- excipient examples include lactose, sucrose, sodium chloride, glucose, starch, calcium carbonate, kaolin, microcrystalline cellulose, silicic acid and the like.
- binder examples include water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropyl starch, methylcellulose, ethylcellulose, shellac, calcium phosphate, polyvinylpyrrolidone and the like. It is done.
- disintegrant examples include dry starch, sodium alginate, agar powder, sodium hydrogen carbonate, calcium carbonate, sodium lauryl sulfate, stearic acid monoglyceride, and lactose.
- Examples of the lubricant include purified talc, stearate, borax, polyethylene glycol and the like.
- Examples of the colorant include titanium oxide and iron oxide.
- Examples of the flavoring / flavoring agent include sucrose, orange peel, citric acid, tartaric acid and the like.
- the oral liquid preparation can be produced by a conventional method, for example, by adding additives such as a taste-masking / flavoring agent, a buffering agent and a stabilizer to the active ingredient.
- Examples of the flavoring / flavoring agent include sucrose, orange peel, citric acid, tartaric acid and the like.
- Examples of the buffer include sodium citrate.
- Examples of the stabilizer include tragacanth, gum arabic, and gelatin.
- a pH adjuster, a buffer, a stabilizer, a tonicity agent, a local anesthetic, etc. are added to the active ingredient, and subcutaneous, intramuscular, intravenous use are performed by a conventional method.
- Etc. can be manufactured.
- the pH adjuster and the buffer include sodium citrate, sodium acetate, sodium phosphate and the like.
- the stabilizer include sodium pyrosulfite, EDTA, thioglycolic acid, thiolactic acid, and the like.
- the isotonic agent include sodium chloride and glucose.
- the local anesthetic include procaine hydrochloride and lidocaine hydrochloride.
- a known base, stabilizer, wetting agent, preservative and the like may be blended with the active ingredient and mixed by a conventional method.
- the base include liquid paraffin, white petrolatum, white beeswax, octyldodecyl alcohol, paraffin and the like.
- the preservative include methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, and the like.
- a cream, gel, paste or the like as the ointment can be applied to a known support by a conventional method.
- the support include woven fabric, nonwoven fabric, soft vinyl chloride, polyethylene, polypropylene, polyurethane and other films made of cotton, suf, and chemical fibers, and foam sheets.
- the innate immunity activator and infectious disease preventive / therapeutic agent of the present invention can be suitably used for, for example, an individual who requires activation of the innate immune mechanism, an individual who wants to obtain acquired immunity against bacteria, etc. . Specifically, for example, by administering to an individual who needs to maintain health or recover from fatigue; an individual who needs prevention or treatment of cancer or lifestyle-related diseases; an individual infected with bacteria, fungi, viruses, etc. Can be used.
- mice and rats mice and rats
- horses cows, pigs, goats, chickens
- domestic animals such as cats, pets such as cats and dogs, etc.
- the method for administering the innate immunity activator is not particularly limited, and can be appropriately selected according to, for example, the above-mentioned dosage form.
- the dose of the innate immunity activator or the infectious disease preventive / therapeutic agent is not particularly limited and can be appropriately selected depending on the age, weight, desired degree of effect, etc. of the individual to be administered.
- the daily dose to an adult is preferably 1 mg to 30 g, more preferably 10 mg to 10 g, and particularly preferably 100 mg to 3 g as the amount of the active ingredient.
- Food or drink containing the lactic acid bacteria of the present invention, killed or treated product of the lactic acid bacteria, innate immunity activator, or infectious disease preventive or therapeutic agent (hereinafter sometimes abbreviated as “food or drink of the present invention”)
- the content of the lactic acid bacterium, the innate immunity activator or the infectious disease preventive / therapeutic agent is not particularly limited and can be appropriately selected according to the purpose and the form (type) of the food or drink.
- the total amount is preferably 0.001 to 100 parts by mass, more preferably 0.01 to 100 parts by mass, and particularly preferably 0.1 to 100 parts by mass. Content.
- Any one of the above may be used alone, or two or more may be used in combination.
- the food / beverage products of this invention have innate immunity activation ability and / or infectious disease prevention-treatment ability.
- the food and drink of the present invention can further contain “other components” in addition to the innate immunity activator and the infectious disease preventive and therapeutic agent of the present invention described above.
- the “other components” are not particularly limited and may be appropriately selected depending on the purpose within a range not impairing the effects of the present invention. Examples thereof include various food materials. Further, the content of “other components” is not particularly limited and can be appropriately selected depending on the purpose.
- the lactic acid bacteria of the present invention can be used for production of general foods and drinks, health foods, drugs, fermented foods and drinks, probiotics, and the like.
- fermented foods and drinks it is particularly suitable for use as fermented milk, lactic acid bacteria beverages, yogurt, pickles, lactic acid bacteria starters for the production of pickles.
- the type of the food is not particularly limited and may be appropriately selected depending on the intended purpose.
- examples thereof include sweets such as jelly, candy, chocolate, biscuits and gummi; preferences for green tea, tea, coffee, soft drinks and the like. Beverages; Dairy products such as fermented milk, yogurt, ice cream and lacto ice; Vegetables and fruit processed products such as vegetable drinks, fruit drinks and jams; Liquid foods such as soups; Grain processed products such as breads and noodles; The charge; etc. are mentioned. Of these, dairy products such as yogurt and fermented milk are preferred. There is no restriction
- the food may be produced as oral solid preparations such as tablets, granules and capsules, or oral liquid preparations such as internal use liquid preparations and syrup preparations.
- the method for producing the oral solid preparation and oral liquid preparation is not particularly limited and can be appropriately selected according to the purpose.
- the preparation can be produced in accordance with the method for producing the oral solid preparation or oral liquid preparation described above. it can.
- the food / beverage products of the present invention are particularly useful as functional foods, health foods, and the like for the purpose of activating the innate immune mechanism and imparting resistance to infectious diseases.
- the production method can be carried out by methods well known to those skilled in the art. If it is an expert, the process which mixes the (dead) microbial cell or processed material of this invention with other components, a shaping
- the lactic acid bacteria of this invention when using the lactic acid bacteria of this invention for manufacture of various fermented milk, it can manufacture using a method well-known to those skilled in the art.
- food and drink manufactured using the process of adding the required amount of lactic acid bacteria of the present invention as dead bacteria to fermented milk and food and drink manufactured using the process of fermenting using the lactic acid bacteria of the present invention as a lactic acid bacteria starter Can be mentioned.
- it can carry out on the conditions similar to the culture conditions of the lactic acid bacteria of this invention, etc.
- GAM medium and MRS agar medium were obtained from Nissui and BD (Becton Dickinson), respectively, and calcium carbonate (CaCO 3 ) was added when necessary.
- AnaeroPak registered trademark (manufactured by Mitsubishi gas chemicals) was used for anaerobic culture.
- the innate immunity activation ability was measured by the method described later to obtain a lactic acid strain (# 11-1) having excellent innate immunity activation ability.
- a lactic acid strain (# 11-1) was isolated. Lactic acid fermentation was confirmed by the formation of white colonies on the CaCO 3 -MRS medium and the formation of zona pellucida, confirming that # 11-1 was a lactic acid bacterium. In addition, the colonies were stained with Gram, and # 11-1 Gram positive was confirmed.
- a 16S rDNA fragment was obtained by colony PCR using the PCR enzyme KOD FX Neo (Toyobo), primers 9F, 1541R.
- the sequence was determined by direct sequencing using BigDye (registered trademark) Terminator v3.1 Cycle Sequencing Kit, ABI PRISM (registered trademark) 3100 Genetic Analyzer. Sequence information was analyzed from 16 S ribosomal RNA sequences databese (Bacteria and Archaea, 7,545 sequences) using NCBI BLASTN 2.2.27+ (8).
- the base sequence of the 16S rDNA region of # 11-1 is shown in SEQ ID NO: 1 in the sequence listing.
- Example 1 ⁇ Measurement of innate immunity activation ability> Lactobacillus paraplantarum # 11-1 (L. paraplantarum # 11-1) strain cultured overnight in MRS medium was sterilized at 121 ° C. for 20 minutes, and 50 ⁇ L was injected into a decapitation muscle specimen of a 5-year-old silkworm. The innate immunity activation ability was measured by slow muscle contraction.
- Example 1 Gram-positive bacteria, # 4, # 11-2 and A shown in Table 1 were used in place of Lactobacillus paraplantarum # 11-1 (L. paraplantarum # 11-1) strain Except for the above, the innate immunity activation ability was measured by silkworm muscle contraction in the same manner as in Example 1.
- Example 1 The origin and properties of Example 1 and Comparative Examples 1 to 3 are shown in Table 1 below.
- Table 1 For reference, the names of closely related strains and “measurement strain and homology measurement results of the strain” are also shown in Table 1.
- the measurement results of innate immunity activation ability are shown in Table 2 below.
- L. paraplantarum # 11-1 of Example 1 was 165 U / mg, which has a very high innate immunity activation ability. there were. Further, as can be seen from the comparison of the measurement results of “innate immunity activation ability (U / mg)” of Example 1 and Comparative Examples 1 and 2 in Table 2, as compared with another strain obtained from bran pickles. Furthermore, it was found that L. paraplantarum # 11-1 of the present invention exhibits a very high innate immunity activation ability.
- Leuconostoc citreum KM20 known as so-called “plant lactic acid bacteria” has an innate immune activation ability of 43 U / mg, which is lower than that of L. paraplantarum # 11-1 of the present invention (Comparative Example 3). ).
- Example 4 Comparative Example 4 In Example 1, except that the Lactobacillus bulgaricus OLL1073 strain was used instead of the Lactobacillus paraplantarum # 11-1 (L. paraplantarum # 11-1) strain, The innate immunity activation ability was measured by muscle contraction.
- Example 5 Comparative Example 5 In Example 1, except that the Lactobacillus casei YIT9029 strain was used instead of the Lactobacillus paraplantarum # 11-1 (L. paraplantarum # 11-1) strain, The innate immune activation ability was measured by muscle contraction.
- Example 6 instead of Lactobacillus paraplantarum # 11-1 (L. paraplantarum # 11-1) strain, Lactococcus lactis JCM5805 strain was used. The innate immune activation ability was measured by muscle contraction.
- Table 3 shows the results of Comparative Examples 4 to 6.
- the lactic acid bacteria of Comparative Examples 4 to 6 are actually lactic acid bacteria that are used in the production of commercially available fermented milk. As shown in Table 3, the lactic acid bacteria # 11-1 of the present invention of Example 1 was found to have higher innate immunity activation ability than the lactic acid bacteria of Comparative Examples 4-6.
- the innate immunity activation ability is extremely high, so that the lactic acid bacterium of the present invention, the dead bacterium of the lactic acid bacterium of the present invention, or Processed product of lactic acid bacteria of the present invention (culture; concentrate; pasted product; spray-dried product, freeze-dried product, vacuum-dried product, drum-dried product, etc .; liquefied product; diluted product; crushed product; sterilized product; Extracts from cultures; etc.) are excellent as innate immune activators.
- Lactobacillus paraplantarum has already been confirmed to be safe as a fermented food as a genus and species.
- a food or drink obtained by fermenting milk using Lactobacillus paraplantarum # 11-1 of the present invention has the ability to activate innate immunity.
- Example 2 ⁇ Effect experiment on bacterial infection> From the Lactobacillus plantarum subsp. Plantarum JCM 1057 (hereinafter abbreviated as “L. plantarum PGN” in FIG. 3), which belongs to Lactobacillus plantarum, obtained from RIKEN was mixed with 2.7% by mass of silkworm artificial food and continued to be given for 2 days. This gives 0.041 g in total before injection. Thereafter, the effect of peptidoglycan of Lactobacillus plantarum lactic acid bacteria on Pseudomonas aeruginosa infection was examined as follows.
- Pseudomonas aeruginosa (PAO1) was cultured overnight at 30 ° C.
- the bacterial solution was diluted 1000 times with physiological saline, and 50 ⁇ L of the diluted solution was injected into the body fluid of silkworm. After the injection, the peptidoglycan diet to the silkworm was stopped, reared at 27 ° C., and the number of survivors (survival ratio) was measured over time.
- the silkworm that ate the peptidoglycan fraction of Lactobacillus plantarum prolongs the survival time after infection with Pseudomonas aeruginosa, compared to the silkworm that does not eat. It was found that the peptidoglycan fraction of Lactobacillus plantarum confers resistance to silkworm Pseudomonas aeruginosa infection. This result is thought to be because the peptidoglycan of Lactobacillus plantarum administered orally activated the innate immunity of the silkworm in the intestine, and as a result, showed an effect on infection control.
- an agent containing a peptidoglycan of lactic acid bacteria Lactobacillus plantarum as an active ingredient is useful as a preventive or therapeutic agent for infectious diseases in mammals such as humans.
- Lactobacillus plantarum has already been confirmed to be safe as a fermented food. Therefore, the infectious disease preventive and therapeutic agent containing the peptidoglycan of lactic acid bacteria Lactobacillus plantarum as an active ingredient is useful as a food or drink for mammals such as humans.
- Example 3 Manufacture of innate immunity activators and infectious disease prevention and treatment agents> ⁇ Tablet >> The cultured # 11-1 was sterilized at 121 ° C. for 20 minutes and then concentrated. The concentrated # 11-1 culture solution 20.0 mg, lactose 40 mg, starch 20 mg, and low-substituted hydroxypropylcellulose 5 mg were uniformly mixed, and then wet-processed using 8% by mass hydroxypropylmethylcellulose aqueous solution as a binder. Granules for tableting were produced by the granulation method. To this, 0.5 mg to 1 mg of magnesium stearate necessary for providing lubricity was added, and then tableted using a tableting machine to obtain tablets.
- the novel lactic acid bacteria and the processed product of the present invention have a high innate immunity activation ability, and further have an effect of preventing and treating infectious diseases. Therefore, it is possible to provide a drug or a food or drink containing an innate immunity activator that activates innate immunity or an infectious disease prevention / treatment agent using the lactic acid bacterium of the present invention, and widely used in the pharmaceutical industry, the food industry, etc. Is possible.
- SEQ ID NO: 1 is a base sequence corresponding to almost the entire length of 16S rDNA of an unknown strain belonging to the genus Lactobacillus.
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Abstract
Description
また、一部の種や亜種では全ゲノムが解読されているほか(非特許文献1、2)、最近では組換えL. plantarumが、動物の腸表皮を通じた特異的抗原の提示に利用され、経口摂取できる生きた感染症予防剤として注目されている(非特許文献3、4)。
また、カイコが微生物感染症に対する抵抗性評価のモデル動物として有用であることは、本発明者らにより確かめられている(特許文献2、3等)。
また、新規な乳酸菌に由来する物質を有効成分とする感染症予防治療剤や飲食品を提供することにある。
更に、上記乳酸菌の単離又は精製された乳酸菌を提供するものである。
また、本発明は、配列表の配列番号1で示される16SrDNA領域の塩基配列を有する上記の乳酸菌を提供するものである。
更に、上記乳酸菌の単離又は精製された乳酸菌を提供するものである。
上記乳酸菌の処理物は、乳酸菌の培養物;濃縮物;ペースト化物;噴霧乾燥物、凍結乾燥物、真空乾燥物、ドラム乾燥物等の乾燥物;液状化物;希釈物;破砕物;殺菌加工物;及び;該培養物からの抽出物よりなる群から選ばれる少なくとも1つの処理物であることを特徴とする自然免疫活性化剤を提供するものである。
また、本発明は、上記の自然免疫活性化剤を有効成分として含有することを特徴とする感染症予防治療剤を提供するものである。
また、本発明は、前記の乳酸菌のペプチドグリカンを有効成分として含有することを特徴とする感染症予防治療剤を提供するものである。
更には、該新規な乳酸菌、該乳酸菌の死菌、又は、該乳酸菌の処理物を有効成分とする極めて高い自然免疫活性化能を有する新規の自然免疫活性化剤を提供し、該乳酸菌又は該自然免疫活性化剤を含有する(に由来する)自然免疫活性化能に優れた飲食品を提供することができる。
従って、本発明の自然免疫活性化剤、感染症予防治療剤及び飲食品は、上記テストを通過したものであるという優れた効果がある。
本発明は、独立行政法人製品評価技術基盤機構(NITE)の特許微生物寄託センター(NPMD)における受託番号がNITE BP-02005であるラクトバチルス(Lactobacillus)属に属する乳酸菌である。
形態:本発明の#11-1は、ぬか漬けを分離源として初めて分離された。
(1)GAM及びMRS寒天培地上では白色のコロニーを形成する。拡散性の色素は認められない。
(2)炭酸カルシウム入りMRS寒天培地上では乳酸の生成に伴う透明帯の形成が認められる。
(1)酸素に対する態度:嫌気的
(2)カタラーゼ:-
(3)アルカリフォスファターゼ:-
(4)エステラーゼ:-
(5)エステラーゼリパーゼ:-
(6)リパーゼ:-
(7)ロイシンアリルアミダーゼ:+
(8)バリンアリルアミダーゼ:+
(9)シスチンアリルアミダーゼ:-
(10)トリプシン:-
(11)α-キモトリプシン:-
(12)酸性フォスファターゼ:+
(13)ナフトール-AS-BI-フォスフォヒドロラーゼ:+
(14)α-ガラクトシダーゼ:-
(15)β-ガラクトシダーゼ:-
(16)β-グルクロニダーゼ:-
(17)α-グルコシダーゼ:-
(18)β-グルコシダーゼ:-
(19)N-アセチル-β-グルコサミニダーゼ:-
(20)α-マンノシダーゼ:-
(21)α-フコシダーゼ:-
グリセロール(Glycerol):-
エリトリトール(Erythritol):-
D-アラビノース(D-Arabinose):-
L-アラビノース(D-Arabinose):-
D-リボース(D-Ribose):±
D-キシロース(D-Xylose):-
L-キシロース(L-Xylose):-
D-アドニトール(D-Adonitol):-
メチル-β-D-キシロピラノサイド(methyl-β-D-xylopyranoside):-
D-ガラクトース(D-Galactose):+
D-グルコース(D-Glucose):+
D-フルクトース(D-Fructose):+
D-マンノース(D-Mannose):+
L-ソルボース(D-Sorbose):-
L-ラムノース(L-Rhamnose):-
ズルシトール(Dulcitol):-
イノシトール(Inositol):-
D-マンニトール(D-Mannitol):+
D-ソルビトール(D-Sorbitol):-
メチル-α-D-マンノピラノサイド(methyl-α-D-mannopyranoside):-
メチル-α-D-グルコピラノサイド(methyl-α-D-glucopyranoside):+
N-アセチルグルコサミン(N-Acetyl glucosamine):+
アミグダリン(Amygdalin):±
アルブチン(Arbutin):+
エスクリン(Esculin):+
サリシン(Salicin):+
D-セロビオース(D-Cellobiose):+
D-マルトース(D-Maltose):+
D-ラクトース(D-Lactose):-
D-メリビオース(D-Melibiose):-
D-スクロース(D-Sucrose):+
D-トレハロース(D-Trehalose):+
インスリン(Insulin):-
D-メレジトース(D-Melezitose):-
D-ラフィノース(D-Raffinose):-
スターチ(Starch):-
グリコーゲン(Glycogen):-
キシリトール(Xylitol):-
ゲンチオビオース(Gentiobiose):+
D-ツラノース(D-Turanose):-
D-リキソース(D-Lyxose):-
D-タガトース(D-Tagatose):-
D-フコース(D-Fucose):-
L-フコース(L-Fucose):-
D-アラビトール(D-Arabitol):-
L-アラビトール(L-Arabitol):-
グルコネート(Gluconate):±
2-ケト-グルコネート(2-Keto-gluconate):-
5-ケト-グルコネート(5-Keto-gluconate):-
すなわち、#11-1のゲノムDNAから、PCRにより、16S rDNA領域の塩基配列を増幅し、シーケンサーによる解析を行った結果、16S rDNAのほぼ全長に当たる塩基配列が見出された。
この塩基配列をNCBIのBLAST解析で相同性検索を行ったところ、#11-1の16S rDNA領域の塩基配列は、ラクトバチルス属であるLactobacillus paraplantarum DSM10667株の塩基配列(登録番号:NR_025447.1)と相同率98%を示したので、#11-1は、L. plantarum paraplantarum種に属するものである。
しかしながら、完全には一致していないので、本発明の#11-1は、上記の株とは異なる乳酸菌株(亜種)である。
ラクトバチルス属に属する既知の株等と比べて、最も高い自然免疫活性化能を示すこと等を含め総合的に検討した結果、#11-1は単離された新規な微生物株であると判断した。
#11-1は、千葉県木更津市かずさ鎌足2-5-8 122号室、独立行政法人製品評価技術基盤機構(Natural Institute of Technology and Evaluation;以下、「NITE」と略記する)の特許微生物寄託センター(NPMD)に国内寄託され、受託番号:NITE P-02005(寄託日:2015年2月5日)として受託された微生物である。
♯11-1は、その後、千葉県木更津市かずさ鎌足2-5-8 122号室、独立行政法人製品評価技術基盤機構(NITE)の特許微生物寄託センター(NPMD)に、原寄託申請書を提出して、国内寄託(原寄託日:2015年2月5日)から、ブタペスト条約に基づく寄託への移管申請を行い(移管日(国際寄託日):2016年1月28日)、生存が証明され、ブタペスト条約に基づく寄託(国際寄託)への移管申請が受領された結果、受託番号「NITE BP-02005」を受けているものである。
培養は嫌気条件下で行うことが好ましい。培地中の炭素源としては、例えば、D-リボース、D-ガラクトース、D-グルコース、D-フルクトース、D-マンノース、D-マンニトール、N-アセチルグルコサミン、アミグダリン、アルブチン、エスクリン、サリシン、D-セロビオース、D-マルトース、シュクロース、D-トレハロース、ゲンチオビオース、糖蜜、水飴、油脂類等の有機炭素化合物が用いられ、窒素源としては、肉エキス、カゼイン、ペプトン、酵母エキス、乾燥酵母、胚芽、大豆粉、尿素、アミノ酸、アンモニウム塩等の有機・無機窒素化合物を用いることができる。
また、塩類は、ナトリウム塩、カリウム塩、カルシウム塩、マグネシウム塩、リン酸塩、鉄塩、銅塩、亜鉛塩、コバルト塩等の無機塩類を必要に応じて適宜添加する。更に、ビオチン、ビタミンB1、シスチン、オレイン酸メチル、ラード油等の生育促進物質を添加することが、目的物の産生量を増加させる点で好ましい。
また、シリコン油、界面活性剤等の消泡剤を添加してもよい。調製済みの培地としては、例えば、MRS培地、GAM培地等を用いることが好ましい。
培養温度は、25℃~37℃間に保つことが好ましく、32℃~37℃で行うことがより好ましい。培養pHは7付近で行うことが好ましい。培養期間は、用いた培地組成、培養温度等により変動するファクターであるが、#11-1の場合、好ましくは12~72時間、より好ましくは24~48時間で充分な量の目的物を確保することができる。
培養して得られたコロニーをピックアップし、再度培地上でシングルコロニー形成を行うことも好ましい。
本発明の新規乳酸菌「#11-1」は、該乳酸菌自身として、また、該乳酸菌の自然的若しくは人工的に変異した乳酸菌として、自然免疫活性化能を有する。
すなわち、本発明は、受託番号がNITE BP-02005であるラクトバチルス(Lactobacillus)属に属する乳酸菌又はその自然的若しくは人工的に変異した乳酸菌であって、自然免疫活性化能を有する乳酸菌である。
自然免疫活性化能の測定は、実施例に具体的に記載した方法、すなわち、Ishii K.,Hamamoto H., Kamimura M., Sekimizu K., J.Biol.Chem. Jan.25;283(4):2185-91(2008)にも詳述されている、カイコの緩行性筋収縮により測定された。
ここで、「乳酸菌の処理物」としては、乳酸菌の、培養物、濃縮物、ペースト化物、乾燥物、液状化物、希釈物、破砕物、殺菌加工物、及び、培養物からの抽出物よりなる群から選ばれる少なくとも1つの処理物が挙げられる。ここで、「乾燥物」としては、噴霧乾燥物、凍結乾燥物、真空乾燥物、ドラム乾燥物等が挙げられる。
本発明の別の態様は、「前記した本発明の乳酸菌(#11-1又はその自然的若しくは人工的に変異した乳酸菌)、該乳酸菌の死菌又は該乳酸菌の処理物を有効成分とする自然免疫活性化剤であって、上記乳酸菌の処理物は、乳酸菌の、培養物、濃縮物、ペースト化物、乾燥物、液状化物、希釈物、破砕物、殺菌加工物、及び、培養物からの抽出物よりなる群から選ばれる少なくとも1つの処理物であることを特徴とする自然免疫活性化剤」である。
乳酸菌としては、生菌体、湿潤菌、乾燥菌等が適宜使用可能である。また、殺菌、すなわち、加熱殺菌処理、放射線殺菌処理、破砕処理等を施した死菌であってもよい。
前記自然免疫活性化剤における、上記「その他の成分」としては、特に制限はなく、本発明の効果を損なわない範囲内で、目的に応じて適宜選択することができ、例えば、薬学的に許容され得る担体等が挙げられる。
かかる担体としては、特に制限はなく、例えば、後述する剤型等に応じて適宜選択される。また、自然免疫活性化剤中の「その他の成分」の含有量としても、特に制限はなく、目的に応じて適宜選択することができる。
前記した本発明の乳酸菌、該乳酸菌の死菌、該乳酸菌の処理物は、自然免疫活性化能を有すると共に又は有するが故に感染症予防治療剤として有用であり、特に、経口投与用の感染症予防治療剤として有用である。
本発明者は、本発明の乳酸菌のペプチドグリカンの経口投与が、緑膿菌に感染したカイコに対し延命効果を奏することを確認した。なお、細菌等に感染したカイコの抵抗性が、ヒト等の哺乳類における抵抗性と相関があることは既に確かめられている(例えば、特許文献2、3等)。
カイコには獲得免疫機構がなく抗原に対して抗体を産生し得ない。従って、経口投与されたラクトバチルス・プランタラムのペプチドグリカンが、腸内等でカイコの自然免疫機構を活性化し、その結果、感染制御に対して効果を奏したためと考えられる。
しかし、本発明においては、獲得免疫機構を有さず自然免疫機構しか有さないカイコにおいて、乳酸菌のペプチドグリカンが緑膿菌感染に対して抵抗性を付与した。ペプチドグリカンがカイコの自然免疫機構を活性化し感染に抵抗したと考えられ、このことは、同様に自然免疫機構を有する哺乳類等の動物に対して、本発明の乳酸菌、該乳酸菌の死菌又は該乳酸菌の処理物を含有する自然免疫活性化剤に、感染症予防治療剤としての効果があることを示している。
従って、本発明の他の態様は、前記の自然免疫活性化剤を有効成分として含有することを特徴とする感染症予防治療剤であり、更には、前記の乳酸菌のペプチドグリカンを有効成分として含有することを特徴とする感染症予防治療剤である。
本発明の乳酸菌や該乳酸菌に由来する本発明の自然免疫活性化剤は、医薬品、医薬部外品、一般飲食品、健康食品、粉ミルク等の規格を有する飲食品等に配合することが可能であり、それらの形態によらず様々な医薬品、飲食品等に応用できる。
中でも、前記した本発明の乳酸菌を用いて醗酵する工程を用いて製造された飲食品、更にその中でも醗酵乳は、乳酸菌の通常の効果や、本発明に特有の前記効果を発揮し易いために好ましい。
具体的には、例えば、経口固形剤(錠剤、被覆錠剤、顆粒剤、散剤、ハードカプセル剤、ソフトカプセル剤等)、経口液剤(内服液剤、シロップ剤、エリキシル剤等)、注射剤(溶剤、懸濁剤等)、軟膏剤、貼付剤、ゲル剤、クリーム剤、外用散剤、スプレー剤、吸入散布剤等が挙げられる。
前記結合剤としては、例えば、水、エタノール、プロパノール、単シロップ、ブドウ糖液、デンプン液、ゼラチン液、カルボキシメチルセルロース、ヒドロキシプロピルセルロース、ヒドロキシプロピルスターチ、メチルセルロース、エチルセルロース、シェラック、リン酸カルシウム、ポリビニルピロリドン等が挙げられる。
該崩壊剤としては、例えば、乾燥デンプン、アルギン酸ナトリウム、カンテン末、炭酸水素ナトリウム、炭酸カルシウム、ラウリル硫酸ナトリウム、ステアリン酸モノグリセリド、乳糖等が挙げられる。
該滑沢剤としては、例えば、精製タルク、ステアリン酸塩、ホウ砂、ポリエチレングリコール等が挙げられる。
該着色剤としては、例えば、酸化チタン、酸化鉄等が挙げられる。
前記矯味・矯臭剤としては、例えば、白糖、橙皮、クエン酸、酒石酸等が挙げられる。
該pH調節剤及び該緩衝剤としては、例えば、クエン酸ナトリウム、酢酸ナトリウム、リン酸ナトリウム等が挙げられる。前記安定化剤としては、例えば、ピロ亜硫酸ナトリウム、EDTA、チオグリコール酸、チオ乳酸等が挙げられる。前記等張化剤としては、例えば、塩化ナトリウム、ブドウ糖等が挙げられる。前記局所麻酔剤としては、例えば、塩酸プロカイン、塩酸リドカイン等が挙げられる。
該基剤としては、例えば、流動パラフィン、白色ワセリン、サラシミツロウ、オクチルドデシルアルコール、パラフィン等が挙げられる。前記保存剤としては、例えば、パラオキシ安息香酸メチル、パラオキシ安息香酸エチル、パラオキシ安息香酸プロピル等が挙げられる。
具体的には、例えば、健康維持や疲労回復を必要とする個体;癌や生活習慣病の予防や治療を必要とする個体;細菌、真菌、ウイルス等に感染した個体;等に投与することにより使用することができる。
また、投与時期としても、特に制限はなく、目的に応じて適宜選択することができ、例えば、予防的に投与されてもよいし、治療的に投与されてもよい。
本発明の飲食品は、前記した本発明の自然免疫活性化剤や感染症予防治療剤に加えて、更に、「その他の成分」を含有することができる。
これらの食品の製造方法としては、特に制限はなく、例えば、通常の各種食品の製造方法に応じて、適宜製造することができる。
本発明の乳酸菌、該死菌若しくは処理物等を飲食品の製造に使用する場合、製造方法は当業者に周知の方法によって行うことができる。当業者であれば、本発明の乳酸菌の(死)菌体又は処理物を他の成分と混合する工程、成形工程、殺菌工程、醗酵工程、焼成工程、乾燥工程、冷却工程、造粒工程、包装工程等を適宜組み合わせ、目的の飲食品を作ることが可能である。
乳酸菌スターターとして本発明の乳酸菌を用いて醗酵を行う場合、本発明の乳酸菌の培養条件と同様の条件等で行うことができる。
<<培地及び培養条件>>
GAM培地、MRS寒天培地は、それぞれ、Nissui社、BD(Becton Dickinson)社より入手し、必要な場合には、炭酸カルシウム(CaCO3)を添加した。
嫌気培養には、AnaeroPak(登録商標)(Mitsubishi gas chemicals社製)を用いた。
醗酵食品としてぬか漬けを用いた。生理食塩水(0.9質量%のNaCl)中で懸濁した液をMRS培地に塗り広げ、37℃で2日間嫌気培養した。
コロニーをピックアップし、CaCO3-MRS培地上でのシングルコロニー形成を行った。
CaCO3-MRS培地上での白いコロニー形成と、透明帯の形成とによって乳酸醗酵を確認し、#11-1が乳酸菌であることを確認した。また、コロニーをグラム染色し、#11-1のグラム陽性を確認した。
PCR酵素KOD FX Neo (Toyobo), primers 9F, 1541Rを用いたコロニーPCRによって、16S rDNA断片を得た。
BigDye(登録商標) Terminator v3.1 Cycle Sequencing Kit, ABI PRISM(登録商標) 3100 Genetic Analyzerを利用したDirect sequencingによって配列を決定した。
配列情報は、NCBI BLASTN 2.2.27+ (8) を用いて16 S ribosomal RNA sequences databese (Bacteria and Archaea, 7,545 sequences) から解析した。
この塩基配列は、図1と図2に示したように、L. paraplantarum DSM10667株(塩基配列:NR_025447.1)に近縁ではあるが、完全には一致しないので、新規の「L. paraplantarum」であることが分かった。
<<寄託>>
実施例において使用する本発明の「#11-1」は、上述の如く、ぬか漬けから分離されたものであり、ラクトバチルス(Lactobacillus)属に属する乳酸菌#11-1として、特許法施行規則に基づく寄託機関として、また、特許手続上の微生物の寄託の国際的承認に関するブダペスト条約に基づく国際寄託当局として認められている、独立行政法人製品評価技術基盤機構特許微生物寄託センター(NPMD)(千葉県木更津市かずさ鎌足2-5-8 122号室)に寄託されている(受託番号:NITE P-02005、寄託日2015年2月5日)。
♯11-1は、その後、千葉県木更津市かずさ鎌足2-5-8 122号室、独立行政法人製品評価技術基盤機構(NITE)の特許微生物寄託センター(NPMD)に、原寄託申請書を提出して、国内寄託(原寄託日:2015年2月5日)から、ブタペスト条約に基づく寄託への移管申請を行い(移管日(国際寄託日):2016年1月28日)、生存が証明され、ブタペスト条約に基づく寄託(国際寄託)への移管申請が受領された結果、受託番号「NITE BP-02005」を受けているものである。
<自然免疫活性化能の測定>
MRS培地で一晩培養したラクトバチルス・パラプランタラム#11-1(L. paraplantarum#11-1)株を、121℃、20分で滅菌処理後、50μLを5齢カイコの断頭筋肉標本に注射し、緩行性筋収縮により自然免疫活性化能を測定した。
すなわち、5齢カイコの断頭筋肉標本に、測定物質の濃度を複数段階に振った試料0.05mLをそれぞれ血液内投与し、収縮した長さが最大となったとき(約10分後)に体長をそれぞれ測定した。
注射前の体長から注射後の体長を引き算し、その値を注射前の体長で割り算した値を「C値(Contraction Value)」とし、C値=0.15を1U(unit(ユニット))と定義した。
また、生理食塩液0.05mLをネガティブコントロール(C値0.05以下を許容)、空気0.2mLをポジティブコントロール(C値が0.2~0.4内に収まる場合を許容)として同時に測定した。
実施例1において、ラクトバチルス・パラプランタラム#11-1(L. paraplantarum#11-1)株に代えて、表1に示したグラム陽性細菌、#4、#11-2及びAを用いた以外は、実施例1と同様に、カイコの筋収縮により自然免疫活性化能を測定した。
自然免疫活性化能の測定結果を以下の表2に示す。
また、表2における、実施例1及び比較例1、2の「自然免疫活性化能(U/mg)」の測定結果の比較からも分かる通り、ぬか漬けから得られた別株と比較しても、本発明のL. paraplantarum#11-1が極めて高い自然免疫活性化能を示すことが分かった。
また、所謂「植物性乳酸菌」として知られている Leuconostoc citreum KM20の自然免疫活性化能は43U/mgであり、本発明のL. paraplantarum#11-1よりも低いものであった(比較例3)。
実施例1において、ラクトバチルス・パラプランタラム#11-1(L. paraplantarum#11-1)株に代えて、ラクトバチルス・ブルガリクス OLL1073株を用いた以外は、実施例1と同様に、カイコの筋収縮により自然免疫活性化能を測定した。
実施例1において、ラクトバチルス・パラプランタラム#11-1(L. paraplantarum#11-1)株に代えて、ラクトバチルス・カゼイ YIT9029株を用いた以外は、実施例1と同様に、カイコの筋収縮により自然免疫活性化能を測定した。
実施例1において、ラクトバチルス・パラプランタラム#11-1(L. paraplantarum#11-1)株に代えて、ラクトコッカス・ラクティス JCM5805株を用いた以外は、実施例1と同様に、カイコの筋収縮により自然免疫活性化能を測定した。
表3に示されるように、実施例1の本発明の乳酸菌#11-1は、比較例4~6の乳酸菌に比べても、より高い自然免疫活性化能を有することが分かった。
本発明のラクトバチルス・パラプランタラム#11-1を用いて、乳を醗酵させて得られる飲食品は、自然免疫活性化能を有する。
<細菌感染に対する効果実験>
独立行政法人理化学研究所より入手した、ラクトバチルス・プランタラムに属する「Lactobacillus plantarum subsp. plantarum JCM 1057」(以下、図3でも「L. plantarum PGN」と略記する)から、常法に従いペプチドグリカン画分を調製し、それをカイコの人工餌に、2.7質量%混ぜて、2日間与え続けた。注射前に総量で、0.041g与えたことになる。
その後、以下のように、緑膿菌感染に対するラクトバチルス・プランタラム乳酸菌のペプチドグリカンの効果を調べた。
注射の後は、カイコへのペプチドグリカンの食餌を中止して、27℃で飼育し、経時的に生存数(生存割合)を計測した。
ラクトバチルス・プランタラムのペプチドグリカン画分によって、カイコの緑膿菌感染に対する抵抗性が付与されたことが分かった。
この結果は、経口投与されたラクトバチルス・プランタラムのペプチドグリカンが、腸内でカイコの自然免疫を活性化し、その結果、感染制御に対して効果を示したためと考えられる。
また、ラクトバチルス・プランタラムは、既に醗酵食品としての安全性が確認されている。従って、乳酸菌ラクトバチルス・プランタラムのペプチドグリカンを有効成分として含有する感染症予防治療剤は、ヒト等の哺乳類の飲食品として有用である。
<自然免疫活性化剤及び感染症予防治療剤の製造>
<<錠剤>>
培養した#11-1を、121℃、20分で滅菌処理後、濃縮した。該濃縮させた#11-1の培養液20.0mg、ラクトース40mg、デンプン20mg、及び、低置換度ヒドロキシプロピルセルロース5mgを均一に混合した後、ヒドロキシプロピルメチルセルロース8質量%水溶液を結合剤として湿式造粒法で打錠用顆粒を製造した。これに、滑沢性を与えるのに必要なステアリン酸マグネシウムを0.5mg~1mg加えてから打錠機を用いて打錠し錠剤とした。
上記濃縮させた#11-1の培養液10.0mgを、2質量%の2-ヒドロキシプロピル-β-サイクロデキストリン水溶液10mLに溶解し注射用液剤とした。
Claims (10)
- 独立行政法人製品評価技術基盤機構(NITE)の特許微生物寄託センター(NPMD)における受託番号がNITE BP-02005であるラクトバチルス(Lactobacillus)属に属する乳酸菌。
- 請求項1に記載の乳酸菌又はその自然的若しくは人工的に変異した乳酸菌であって、自然免疫活性化能を有する乳酸菌。
- 配列表の配列番号1で示される16SrDNA領域の塩基配列を有する請求項1又は請求項2に記載の乳酸菌。
- 請求項1ないし請求項3の何れかの請求項に記載の乳酸菌、該乳酸菌の死菌又は該乳酸菌の処理物を有効成分とする自然免疫活性化剤であって、
上記乳酸菌の処理物は、乳酸菌の、培養物、濃縮物、ペースト化物、乾燥物、液状化物、希釈物、破砕物、殺菌加工物、及び、培養物からの抽出物よりなる群から選ばれる少なくとも1つの処理物であることを特徴とする自然免疫活性化剤。 - 請求項1ないし請求項3の何れかの請求項に記載の乳酸菌のペプチドグリカンを有効成分として含有することを特徴とする感染症予防治療剤。
- 請求項4に記載の自然免疫活性化剤を有効成分として含有することを特徴とする感染症予防治療剤。
- 請求項1ないし請求項3の何れかの請求項に記載の乳酸菌を含有する飲食品。
- 請求項4に記載の自然免疫活性化剤を含有する飲食品。
- 請求項5又は請求項6に記載の感染症予防治療剤を含有する飲食品。
- 請求項1ないし請求項3の何れかの乳酸菌を用いて醗酵する工程を用いて製造された飲食品。
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