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WO2020017390A1 - Bactérie lactique, agent d'activation immunitaire naturel issu de bactérie lactique, et médicament préventif/thérapeutique pour une infection et aliment ou boisson - Google Patents

Bactérie lactique, agent d'activation immunitaire naturel issu de bactérie lactique, et médicament préventif/thérapeutique pour une infection et aliment ou boisson Download PDF

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Publication number
WO2020017390A1
WO2020017390A1 PCT/JP2019/027090 JP2019027090W WO2020017390A1 WO 2020017390 A1 WO2020017390 A1 WO 2020017390A1 JP 2019027090 W JP2019027090 W JP 2019027090W WO 2020017390 A1 WO2020017390 A1 WO 2020017390A1
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Prior art keywords
lactic acid
acid bacterium
bacterium
weissella
food
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PCT/JP2019/027090
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English (en)
Japanese (ja)
Inventor
関水　和久
洋 浜本
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Teikyo University
Genome Pharmaceuticals Institute Co Ltd
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Teikyo University
Genome Pharmaceuticals Institute Co Ltd
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Priority to CN201980004577.0A priority Critical patent/CN111328285B/zh
Priority to JP2019555711A priority patent/JP6675703B1/ja
Publication of WO2020017390A1 publication Critical patent/WO2020017390A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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 OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L11/00—Pulses, i.e. fruits of leguminous plants, for production of food; Products from legumes; Preparation or treatment thereof
    • A23L11/60—Drinks from legumes, e.g. lupine drinks
    • A23L11/65—Soy drinks
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • 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
    • C12N1/20—Bacteria; Culture media therefor

Definitions

  • the present invention relates to a lactic acid bacterium, a natural immunity activator derived from the lactic acid bacterium, a preventive / therapeutic agent for infectious disease derived from the lactic acid bacterium, and a food or drink. More specifically, the present invention relates to "a lactic acid bacterium belonging to Weissella Helenica, A natural immunity activator comprising, as an active ingredient, a killed bacterium, a product of the lactic acid bacterium, or a processed product of the lactic acid bacterium; a food or drink derived from the lactic acid bacterium; a novel lactic acid bacterium;
  • Lactic acid bacteria are a general term for bacteria that produce lactic acid by metabolism. They have been used in fermented foods for a long time, and have been used in the production of foods and beverages, pharmaceuticals, probiotics, and others. Weissella Helenica (Weissella Helenica) The belonging lactic acid bacteria are also used for various uses.
  • Patent Literature 1 describes a livestock antibacterial agent containing a protease-resistant bacteriocin derived from a lactic acid bacterium.
  • a lactic acid bacterium belonging to Weissella helenica is mentioned.
  • Patent Document 2 describes a food containing a specific antimicrobial peptide, and mentions a specific strain belonging to Weissella helenica as a bacterium that produces the antimicrobial peptide.
  • Patent Literature 3 discloses that a culture of a specific lactic acid bacterium belonging to Weissella helenica isolated from squid black skull is capable of inhibiting angiotensin converting enzyme activity, scavenging DPPH radicals, or converting L-glutamic acid to ⁇ -aminobutyric acid.
  • Patent Document 4 discloses that a crushed anti-inflammatory lactic acid bacterium belonging to the genus Weissella has an effect of preventing and ameliorating arthritis, which is a type of autoimmune disease, and also lists Weissella herrenica species. It is described that the crushed lactic acid bacteria belonging to the genus Weissera suppressed the activation of innate immunity.
  • lactic acid bacteria belonging to Weissella Herenica generally contribute to the activation of innate immunity, and products of lactic acid bacteria of a specific subspecies (specific strain) belonging to Weissera Herenica, It has not been known that the culture supernatant or the like gives an agent particularly excellent in innate immunity activation.
  • innate immune response for example, it is known that immune cells such as dendritic cells and macrophages produce cytokines in response to an innate immune activator derived from bacteria or viruses, and a subsequent immune response occurs.
  • the innate immunity mechanism is an infection defense mechanism commonly possessed by organisms, and is generally characterized by non-specificity, so that it responds quickly and functions effectively against many infection sources.
  • lactic acid bacteria are considered to be good for health, in most cases no scientific evidence has been provided. In order to show scientific evidence, it is necessary to establish a system with a clear therapeutic effect and analyze the mechanism at the molecular level. However, there have been few examples of lactic acid bacteria that have achieved this.
  • Patent Document 5 Non-Patent Document 1
  • the method can evaluate (screen for) a natural immunity activator having a natural immunity activating effect on vertebrates such as humans (Patent Document 5, etc.). That is, this “silkworm infection model” has been established. It has been confirmed by the present inventors that silkworms are useful as model animals for evaluating resistance to infectious diseases (Patent Documents 6, 7 and the like).
  • Activation of innate immunity is effective in preventing or treating infectious diseases against pathogenic bacteria or viruses, and is also extremely effective against (multidrug) resistant bacteria, and against opportunistic infections in which many types exist. It is extremely effective for prevention and treatment.
  • lactic acid bacteria have demonstrated the above effects with scientific evidence, and the development of excellent innate immunity activators and infectious disease preventive and therapeutic agents by activating innate immunity has been desired.
  • development of foods and drinks containing lactic acid bacteria-derived products or natural immunity activators, and foods and drinks using lactic acid bacteria having the above-mentioned excellent performance has been desired.
  • An object of the present invention is to provide a natural immunity activator comprising a lactic acid bacterium having a high ability to activate innate immunity, a killed lactic acid bacterium, a product of the lactic acid bacterium, a processed product of the lactic acid bacterium, and the like as an active ingredient.
  • Another object of the present invention is to provide a prophylactic / therapeutic agent for infectious diseases and a food or beverage containing the lactic acid bacterium or a natural immunity activator derived from the lactic acid bacterium.
  • the present invention provides a food or beverage that has been fermented (fermentation for innate immunity activation).
  • the present inventors have conducted intensive studies to solve the above-described problems, and as a result, lactic acid bacteria belonging to Weissella hellenica, and killed, produced, and processed products of the lactic acid bacteria are compared with lactic acid bacteria of other genera. In addition, they have found that the ability to activate innate immunity is higher than that of other species of lactic acid bacteria of the same genus (Weissella genus). That is, the present inventor is able to prevent or treat infectious diseases against a plurality of pathogenic bacteria using an infection model using silkworms as experimental animals, and to use “lactic acid bacteria (derived material)” and “effectively using the lactic acid bacteria (derived material)”.
  • the present invention has been achieved by finding "natural immunity activator contained as a component", "food and drink having natural immunity fermented with the lactic acid bacteria” and the like.
  • the present invention is a natural immunity activator comprising a lactic acid bacterium belonging to Weissella hellenica, a killed lactic acid bacterium, a product of the lactic acid bacterium, or a processed product of the lactic acid bacterium as an active ingredient
  • the processed product of the lactic acid bacterium is a group consisting of culture, culture supernatant, concentrate, paste, dried, liquefied, diluted, crushed, sterilized, and extract of the lactic acid bacterium.
  • the present invention also provides an infectious disease preventive / therapeutic agent containing the above-described innate immunity activator and for preventing or treating infectious diseases against pathogenic bacteria or viruses.
  • the present invention also provides a food or drink characterized by containing the above-described innate immunity activator.
  • the present invention also provides a fermented food or drink for activating innate immunity, which is obtained by fermentation using a lactic acid bacterium belonging to Weissella hellenica.
  • the present invention provides the above-mentioned innate immunity activator, wherein the lactic acid bacterium belonging to Weissella hellenica is a lactic acid bacterium having an accession number of NITE BP-02710 or a lactic acid bacterium naturally or artificially mutated. To provide.
  • the present invention provides a lactic acid bacterium belonging to the genus Weissella having an accession number of NITE BP-02710 or a lactic acid bacterium naturally or artificially mutated.
  • the present invention also provides an isolated or purified lactic acid bacterium of the lactic acid bacterium.
  • the present invention also provides the above-mentioned lactic acid bacterium having a base sequence of the 16S rDNA region represented by SEQ ID NO: 1 in the sequence listing.
  • the present invention also provides a food or drink containing the lactic acid bacterium, and provides a fermented food or drink obtained by fermentation using the lactic acid bacterium.
  • the innate immunity activator which has innate immunity activation ability with respect to a human etc. can be provided.
  • the innate immunity activator is useful as an infectious disease preventive / therapeutic agent for preventing or treating infectious diseases against pathogenic bacteria or viruses.
  • infectious disease preventive / therapeutic agent for preventing or treating infectious diseases against pathogenic bacteria or viruses.
  • innate immunity since innate immunity is activated, it is particularly useful when the pathogenic bacterium is a (multi-drug) drug-resistant bacterium, and when the innate immunity is reduced (or a person who has decreased). Are especially useful for the prevention or treatment of opportunistic infections of many types (many bacteria are the causative bacteria).
  • the innate immunity activity of lactic acid bacteria belonging to Weissella hellenica (Weissella hellenica), and that the lactic acid bacteria subspecies belonging to a specific Weissella helenica species have particularly high innate immunity activity, are based on the present inventors. Since it was found and examined in a silkworm infection model (which confirms the life and death of an individual), it also takes into account the superiority of the therapeutic effect (which also depends on the pharmacokinetics of the agent in the individual). Therefore, the innate immunity activator of the present invention has an excellent therapeutic effect on infectious diseases against bacteria or viruses.
  • a lactic acid bacterium belonging to Weissella hellenica (live bacterium), a dead bacterium of the lactic acid bacterium, a product of the lactic acid bacterium, or a processed product of the lactic acid bacterium
  • live bacterium live bacterium
  • dead bacterium of the lactic acid bacterium a product of the lactic acid bacterium
  • a processed product of the lactic acid bacterium hereinafter simply referred to as ""
  • the silkworm to which the lactic acid bacterium (derived substance) was previously administered is compared with the silkworm to which the lactic acid bacterium (derived substance) was not administered beforehand. Therefore, the survival rate of the individual was significantly higher (see Examples).
  • lactic acid bacteria derived from Weissella helenica did not inhibit the growth of pathogenic bacteria (Example 6). That is, it was found that the lactic acid bacterium derived from Weissella Herenica had no antibacterial activity. Moreover, when a lactic acid bacterium derived from Weissella Herenica was administered to the silkworm simultaneously with the pathogenic bacterium, no significant difference was observed in the survival rate of the silkworm (no increase in the survival rate was observed). That is, pre-administration was necessary for imparting resistance to pathogenic bacterial infections derived from lactic acid bacteria derived from Weissa helenica (Examples, particularly Example 6).
  • the silkworm infection model is also applied (useful) to infectious diseases of mammals such as humans.
  • the immune system of silkworms does not have an acquired immune system but only an innate immune system.
  • the lactic acid bacterium derived from Weissella helenica lactic acid bacterium has no antibacterial activity, and pre-administration is necessary to increase the survival rate of the individual.
  • the resistance to pathogenic bacteria derived from lactic acid bacteria derived from Weissella helenica was confirmed for a plurality of pathogenic bacteria such as Pseudomonas aeruginosa and Klebsiella pneumoniae (see Example 7 and Table 8). From this, it can be said that a product derived from lactic acid bacteria of Weissella Herenica is not only effective against specific pathogens but also has a property of activating the innate immunity mechanism itself.
  • the ability to activate innate immunity is a property unique to lactic acid bacteria belonging to Weissella helenica and all its derivatives. Therefore, the extension of the lactic acid bacteria (derived material) that is the source of the innate immunity activator of the present invention is extremely clear, and any lactic acid bacteria (derived material) belonging to Weissella helenica are included in the present invention, and are included in the present invention. -A lactic acid bacterium (origin) not belonging to Helenica is excluded from the present invention.
  • the innate immunity activator of the present invention can be ingested by humans and the like in various ways, and can be used in pharmacies such as pharmaceuticals and pharmaceuticals manufactured and sold by pharmacies. It can be applied to drugs such as prescription drugs; In addition, since it is effective even orally, it can be applied to foods such as general foods such as clear foods and health foods; health functional foods; etc., and also to probiotics, fermented foods and drinks, drugs and feeds for animals, etc. Can also be applied.
  • the method of ingesting the innate immunity activator of the present invention with "human mammals” is not particularly limited, but it is particularly preferable because oral ingestion shows an effect and oral ingestion is simple and easy.
  • Examples of the (fermented) food or beverage containing the innate immunity activator of the present invention include fermented (bean) milk, lactic acid bacteria beverages, yogurt, pickles, and the like. In addition to its ability, it also has the effect of being excellent in flavor. That is, the lactic acid bacterium of the present invention is useful for use as a lactic acid bacterium starter or the like for producing the above product.
  • a lactic acid bacterium belonging to Weissella helenica by taking advantage of the property of lactic acid bacterium, can ferment the food to obtain a fermented food or drink for innate immunity activation, and can be commonly used in daily life as a food or drink. However, it is also possible to always raise innate immunity.
  • foods and beverages fermented with lactic acid bacteria Wh0916-4-2 are delicious and can provide a group of foods and beverages with new tastes.
  • FIG. 2 is a graph showing the transition of the survival rate of silkworms over time, particularly showing an increase in resistance to Pseudomonas aeruginosa by oral administration of the lactic acid bacterium (derived product) of the present invention (Example 1). It is a photograph which shows the state of the silkworm by administration of Pseudomonas aeruginosa.
  • A Silkworm that has survived due to prior administration of the lactic acid bacterium (origin) of the present invention.
  • (B) Silkworm that died due to no prior administration of lactic acid bacterium (origin) of the present invention.
  • the innate immunity activator of the present invention contains a lactic acid bacterium belonging to Weissella hellenica, a killed lactic acid bacterium, a product of the lactic acid bacterium, or a processed product of the lactic acid bacterium as an active ingredient.
  • lactic acid bacteria belonging to the genus Weissella and hellenica have high ability to activate natural immunity in all of the evaluated lactic acid bacteria, and lactic acid bacteria not belonging to the genus Weissella and Weicella.
  • all of the lactic acid bacteria evaluated had low innate immunity activating ability.
  • the active ingredient of the innate immunity activator of the present invention exerts a preventive / therapeutic effect by a host-mediated mechanism.
  • Invertebrates such as silkworms, lack antibodies and therefore have no adaptive immune system. It is a mechanism called innate immunity that works to prevent infection.
  • innate immunity that works to prevent infection.
  • Recent studies have revealed that mammals also have an innate immune system, and that the molecular mechanism is common to invertebrates.
  • the present invention activates innate immunity in mammals such as humans.
  • the evaluation of innate immunity activation was performed using the silkworm infection model that the present inventors have already established.
  • the evaluation method in the present invention is, specifically, the evaluation sample is administered to the silkworm, diet, intestinal injection, blood injection and the like, and then the survival rate when the pathogenic bacteria and the like are administered to the silkworm, This was performed by comparing the survival rate when the sample was not administered.
  • the survival rate when the evaluation sample and the pathogen were simultaneously administered was also measured, and it was confirmed that the survival rate was significantly increased only when the administration of the pathogen was performed after the administration of the evaluation sample. It was confirmed that it was caused by activation of innate immunity.
  • the innate immunity activator of the present invention includes lactic acid bacteria themselves (live lactic acid bacteria), killed lactic acid bacteria, products of lactic acid bacteria, or processed lactic acid bacteria belonging to Weissella helenica. May be included. Further, they can be contained in various states, such as a state containing a suspension, a lactic acid bacterium, a culture supernatant, and a medium component.
  • the above-mentioned "processed product of lactic acid bacteria” is a culture of lactic acid bacteria, a culture supernatant, a concentrate, a paste, a dried product, a liquefied product, a diluted product, a crushed product, a sterilized product, and an extract from the culture product. At least one processed product selected from the group consisting of:
  • a part is duplicated as a “thing”.
  • examples of the live or dead bacteria of the lactic acid bacteria include live cells, wet bacteria, dried bacteria, and the like, and those that have been subjected to heat sterilization, radiation sterilization, crushing, and the like.
  • the product may be contained in live or dead bacteria of lactic acid bacteria, or may be isolated.
  • examples of the dried product include a spray-dried product, a freeze-dried product, a vacuum-dried product, a drum-dried product, and the like.
  • the active ingredient in the innate immunity activator of the present invention a lactic acid bacterium, a killed lactic acid bacterium, a product of the lactic acid bacterium, or a processed product of the lactic acid bacterium
  • the content of the entire innate immunity activator is particularly There is no limitation, and it can be appropriately selected according to the purpose.
  • the entire innate immunity activator is 100 parts by mass, "lactic acid bacteria, killed bacteria of the lactic acid bacteria, products of the lactic acid bacteria, or the lactic acid bacteria
  • the total amount of the treated product is preferably 0.001 to 100 parts by mass, more preferably 0.01 to 99 parts by mass, particularly preferably 0.1 to 95 parts by mass, and further preferably 1 to 95 parts by mass. It is contained in up to 90 parts by mass.
  • the active ingredient may be used alone or in combination of two or more.
  • the content ratio of each active ingredient in the innate immunity activator is not particularly limited and can be appropriately selected depending on the purpose.
  • the innate immunity activator of the present invention contains the above-mentioned components as active ingredients, and may contain "other components” in addition to the active ingredients.
  • the “other components” in the innate immunity activator are not particularly limited and may be appropriately selected depending on the intended purpose within a range that does not impair the effects of the present invention, and are pharmaceutically acceptable. And the like.
  • Such carriers are not particularly limited, and include, for example, the same carriers as those described below, which are used by being compounded according to the dosage form and the like.
  • the types of antibacterial drugs against the causative bacteria of opportunistic infections, especially Pseudomonas aeruginosa, are limited. In particular, it is extremely difficult to find an orally effective antibacterial drug.
  • One of the reasons is that methods for evaluating the therapeutic effect are limited.
  • the silkworm infection model has the advantage that it is not only inexpensive but also avoids the ethical problems from the viewpoint of animal welfare, which are problems with the mouse system conventionally used.
  • the present invention is to screen as many lactic acid bacteria as are problematic from the viewpoint of animal welfare in a mouse system, and to evaluate including the therapeutic effect irrespective of the antibacterial effect (specifically, measuring the survival rate) Made by
  • the innate immunity activator of the present invention is effective in preventing or treating infectious diseases of various pathogenic bacteria and viruses. It is also a prophylactic and therapeutic agent for infectious diseases characterized by the following:
  • the present invention is also the above-mentioned prophylactic / therapeutic agent for infectious diseases, wherein the pathogenic bacterium is a drug-resistant bacterium.
  • the present invention is effective against all kinds of bacteria and viruses by activating innate immunity, and is particularly effective against various opportunistic infections that become serious when innate immune function is reduced. Therefore, the present invention is also the above-mentioned prophylactic / therapeutic agent for infectious diseases, wherein the infectious disease is an opportunistic infection.
  • the present invention is also a food or drink characterized by containing a natural immunity activator, and is also obtained by fermentation using lactic acid bacteria belonging to Weissella hellenica. It is also a fermented food and drink for activating natural immunity.
  • No. 1 which is a lactic acid bacterium belonging to the species Weissella Herenica.
  • No. 18 strain name (subspecies name) 0916-4-2
  • No. 27 strain name (subspecies name) 0928-7-2
  • No. 48 strain name (subspecies name) 1026-04-2
  • All 75 strain name (subspecies name) 1109-7-1) exhibited resistance to Pseudomonas aeruginosa and had high ability to activate innate immunity.
  • Example 5 among the above four kinds of lactic acid bacteria, no. 18 (strain name (subspecies name) 0916-4-2) exhibited the highest resistance to Pseudomonas aeruginosa, and specifically had a high ability to activate innate immunity (see Table 7).
  • the lactic acid bacterium Wh0916-4-2 which is a sub-species of the lactic acid bacterium belonging to Weissella hellenica, will be described in detail.
  • Morphology The lactic acid bacterium Wh0916-4-2 of the present invention was isolated for the first time.
  • Physiological properties Physiological and chemical taxonomic properties of the lactic acid bacterium Wh0916-4-2 of the present invention are as follows.
  • the physiological and chemical taxonomic properties of the lactic acid bacterium Wh0916-4-2 are described in the classification by Bergey's Manual of Systematic Bacteriology (Bergey's Manual of Systematic Bacteriology, vol. 3 1989) and the contents of other documents.
  • the lactic acid bacterium Wh0916-4-2 of the present invention is a microorganism belonging to the genus Weissella, and is a microorganism belonging to the species Weissella hellenica.
  • the base sequence corresponding to almost the entire length of 16S rDNA used as an index for the molecular biological phylogenetic classification of lactic acid bacteria Wh0916-4-2 is as described in SEQ ID NO: 1 in the sequence listing.
  • the homology was found to be 99%. Therefore, the lactic acid bacterium Wh0916-4-2 is a microorganism belonging to the species Weissella hellenica.
  • the lactic acid bacterium Wh0916-4-2 was a species of Weissella Helenica. This was not inconsistent with the above judgment that the microorganism belongs to.
  • lactic acid bacteria Wh0916-4-2 were examined as a result of comprehensive examination including the highest ability to activate innate immunity as compared with known strains (subspecies) belonging to the species Weissella hellenica and the like. Was determined to be a new (isolated) microorganism strain (a subspecies of lactic acid bacteria).
  • “Lactic acid bacterium Wh0916-4-2” is available from National Institute of Technology and Evaluation; hereinafter referred to as "NITE", Room 2-5-8 Kazusa-Kamashita, Kisarazu-shi, Chiba. And deposited in Japan under the Patent Microorganism Depositary Center (NPMD) of Japan, and deposited (deposited) under the accession number: NITE P-02710 (receipt date (deposit date): May 14, 2018).
  • “Lactic acid bacterium Wh0916-4-2” was originally deposited at the Patent Microorganisms Depositary Center (NPMD) of the National Institute of Technology and Evaluation (NITE), Room No. 2-5-8 Kazusa Kamatari, Kisarazu-shi, Chiba Prefecture.
  • the lactic acid bacterium Wh0916-4-2 has a possibility that it does not remain within the range of the physiological properties described above because the nature of the strain is easily mutated. Needless to say, such “mutations” include both natural mutations and artificial mutations.
  • the lactic acid bacterium Wh0916-4-2 may be cultured according to a general culture method performed on a microorganism of the genus Weissera. 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, and D-cellobiose.
  • D-maltose sucrose, D-trehalose, gentiobiose, molasses, starch syrup, oils and the like
  • nitrogen sources include meat extract, casein, peptone, yeast extract, dried yeast, germ, soybean Organic and inorganic nitrogen compounds such as powder, urea, amino acids, and ammonium salts can be used.
  • inorganic salts such as sodium salts, potassium salts, calcium salts, magnesium salts, phosphates, iron salts, copper salts, zinc salts, and cobalt salts are appropriately added as needed.
  • a growth promoting substance such as biotin, vitamin B1, cystine, methyl oleate, and lard oil
  • an antifoaming agent such as silicone oil and a surfactant may be added.
  • the prepared medium for example, an MRS medium, a GAM medium, or the like is preferably used.
  • the cultivation conditions may be in accordance with the general cultivation conditions for microorganisms of the genus Weissera as described above.
  • the liquid culture method static culture is desirable. If the scale is small, a stationary culture method using a glass bottle with a lid may be used.
  • the culture temperature is preferably maintained between 25 ° C. and 37 ° C., and more preferably between 28 ° C. and 32 ° C.
  • the culture is preferably performed at around pH 7.
  • the cultivation period is a factor that varies depending on the medium composition, the cultivation temperature, etc. used.
  • a sufficient amount of the desired product is preferably 12 to 72 hours, more preferably 24 to 48 hours. Can be secured. It is also preferable to pick up a colony obtained by culturing and form a single colony again on the medium.
  • the present invention also relates to the natural immunity activator, wherein the lactic acid bacterium belonging to the aforementioned Weissella hellenica is a lactic acid bacterium having an accession number of NITE BP-02710 or a naturally or artificially mutated lactic acid bacterium. is there. Further, the present invention is also a lactic acid bacterium belonging to the genus Weissella having an accession number of NITE BP-02710 or a naturally or artificially mutated lactic acid bacterium. The present invention also relates to the lactic acid bacterium described above, which has the base sequence of the 16S rDNA region represented by SEQ ID NO: 1 in the sequence listing. The lactic acid bacterium having the accession number of NITE BP-02710 is the aforementioned "lactic acid bacterium Wh0916-4-2".
  • the present invention is also a food or drink containing the lactic acid bacterium Wh0916-4-2 (accession number: NITE @ BP-02710), which is fermented using the lactic acid bacterium (strain) (subspecies). It is also a fermented food or drink.
  • the innate immunity activator containing the lactic acid bacterium of the present invention a killed bacterium of the lactic acid bacterium, a product of the lactic acid bacterium, or a processed product of the lactic acid bacterium as an active ingredient can be added to a pharmaceutical product; a general food and drink; a health food and the like. It is possible and can be applied to various medicines, foods and drinks, etc., regardless of their form.
  • the dosage form of the innate immunity activator or infectious disease preventive / therapeutic agent of the present invention and forms such as lactic acid bacteria, killed lactic acid bacteria, products of lactic acid bacteria, and processed products of various lactic acid bacteria described above ( It can be appropriately selected according to the embodiment. In addition, for example, it can be appropriately selected according to a desired administration method as described later. Specifically, for example, oral solid preparations (tablets, coated tablets, granules, powders, hard capsules, soft capsules, etc.), oral liquid preparations (oral liquids, syrups, elixirs, etc.), injections (solvents, suspensions) Preparations), gels, creams, powders for external use, sprays, inhalants and the like.
  • oral solid preparation examples include, for example, excipients and, if necessary, additives such as a binder, a disintegrant, a lubricant, a coloring agent, and a flavoring / odoring agent, and the like. 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, hydroxypropylstarch, methylcellulose, ethylcellulose, shellac, calcium phosphate, polyvinylpyrrolidone and the like.
  • disintegrant examples include dry starch, sodium alginate, powdered agar, sodium bicarbonate, calcium carbonate, sodium lauryl sulfate, monoglyceride stearate, lactose and the like.
  • Examples of the lubricant include purified talc, stearate, borax, polyethylene glycol and the like.
  • Examples of the coloring agent include titanium oxide and iron oxide.
  • Examples of the flavor / odorant include sucrose, orange peel, citric acid, tartaric acid and the like.
  • the oral liquid preparation can be produced, for example, by adding additives such as a flavoring / flavoring agent, a buffering agent, a stabilizer and the like to the above-mentioned active ingredient by a conventional method.
  • Examples of the flavoring / flavoring agent include sucrose, orange peel, citric acid, tartaric acid and the like.
  • Examples of the buffer include sodium citrate and the like.
  • Examples of the stabilizer include tragacanth, gum arabic, gelatin and the like.
  • a pH adjuster, a buffer, a stabilizer, an isotonic agent, a local anesthetic, etc. are added to the active ingredient, and the mixture is subcutaneously, intramuscularly, or intravenously according to a conventional method.
  • 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 tonicity agent include sodium chloride, glucose and the like.
  • the local anesthetic include procaine hydrochloride, lidocaine hydrochloride and the like.
  • the innate immunity activator and the infectious disease preventive / therapeutic agent of the present invention are suitably used, for example, in individuals requiring activation of the innate immunity mechanism, individuals seeking to obtain acquired immunity against bacteria and the like. it can. 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 who is infected with bacteria, fungi, viruses, and the like; Can be used.
  • the animal to which the innate immunity activator or infectious disease preventive / therapeutic agent of the present invention is administered is not particularly limited.
  • humans experimental animals such as mice and rats; monkeys; horses; cows, pigs, goats, Domestic animals such as chickens; pets such as cats and dogs; and the like.
  • the method of administering the innate immunity activator is not particularly limited, and is appropriately selected according to, for example, the form of the lactic acid (killed) bacterium or the processed product thereof, or the dosage form described above.
  • oral administration intraperitoneal administration, injection into the blood, infusion into the intestine and the like. Among them, oral administration is preferred because it is simple and exhibits the above effects.
  • the dose of the innate immunity activator of the present invention or the infectious disease preventive / therapeutic agent of the present invention is not particularly limited, and is appropriately selected depending on the age, body weight, desired effect level, and the like 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.
  • the timing of administration there is no particular limitation on the timing of administration, and it can be appropriately selected according to the purpose. For example, it may be administered prophylactically or therapeutically.
  • Natural immunity in foods and drinks, fermented foods and drinks, fermented foods and drinks for activating natural immunity (hereinafter sometimes abbreviated as “foods and drinks of the present invention”) containing the natural immunity activator of the present invention.
  • the content of the activator is not particularly limited and can be appropriately selected depending on the purpose and the mode (kind) of the food or drink.
  • the content is preferably 100 parts by mass, more preferably 0.01 to 95 parts by mass, and particularly preferably 0.1 to 90 parts by mass.
  • the food or drink of the present invention has an ability to activate innate immunity and prevent and treat infectious diseases.
  • the food or drink of the present invention can further contain “other components” in addition to the innate immunity activator of the present invention described above.
  • the “other components” are not particularly limited and may be appropriately selected depending on the intended purpose without impairing the effects of the present invention. Examples thereof include various food materials.
  • the content of “other components” is not particularly limited, and can be appropriately selected depending on the purpose. In the case of fermented foods and beverages for innate immunity activation obtained by fermentation using lactic acid bacteria belonging to Weissella hellenica, various substances produced during the fermentation can be included.
  • the lactic acid bacteria of the present invention can be applied to foods such as general foods such as obvious foods and health foods; health functional foods; etc., and can also be applied to probiotics, fermented foods and drinks, veterinary drugs and feeds, and the like.
  • the fermented foods and drinks are particularly suitable for use as fermented milk, fermented soy milk, lactic acid bacteria drinks, yogurt, pickles, lactic acid bacteria starters for pickle production, and the like.
  • the type of the food is not particularly limited and can be appropriately selected depending on the purpose.
  • examples thereof include confectionery such as jelly, candy, chocolate, biscuit, and gummy; preference for green tea, black tea, coffee, and soft drinks.
  • (soy) milk products such as yogurt, fermented milk, and fermented soy milk are preferable.
  • the food may be a health food or a health functional food, in addition to the above-mentioned apparent food, for example, tablets, granules, oral solids such as capsules, oral liquids, oral liquids such as syrups and the like. Is also preferable.
  • the food or drink of the present invention is particularly useful as a health food such as a functionally labeled food for the purpose of activating the innate immune system or giving resistance to infectious diseases.
  • a health food such as a functionally labeled food for the purpose of activating the innate immune system or giving resistance to infectious diseases.
  • the production method can be performed by a method well known to those skilled in the art.
  • a person skilled in the art is a process of mixing the (dead) cells or processed product of the lactic acid bacterium of the present invention with other components, a molding process, a sterilization process, a fermentation process, a baking process, a drying process, a cooling process, a granulation process, It is possible to produce a desired food or drink by appropriately combining the packaging steps and the like.
  • the lactic acid bacterium of the present invention When used for the production of various fermented milks, it can be produced using a method well known to those skilled in the art. For example, foods and drinks manufactured using a process of adding a required amount of the lactic acid bacteria of the present invention to fermented milk as dead bacteria, and foods and drinks manufactured using a process of fermenting with the lactic acid bacteria of the present invention as a lactic acid bacteria starter are used. No. When fermentation is performed using the lactic acid bacterium of the present invention as a lactic acid bacterium starter, the fermentation can be performed under the same conditions as the culture conditions of the lactic acid bacterium of the present invention.
  • Example 1 As shown in Tables 1 to 3 below, 124 strains of lactic acid bacteria were isolated, lactic acid-producing ability was confirmed, and a library was prepared. From this library (Tables 1-3), lactic acid bacteria that confer resistance to infection of silkworm PAO1 strain PAO1 were searched.
  • FIG. 1 shows the results of the change in the survival rate of the silkworm.
  • Example 2 Bacteria were collected by centrifuging 20 mL of full growth of lactic acid bacteria cultured to full growth, mixed with 1 g of artificial silkworm-free diet containing no antibiotics, and fed to the silkworm for one day. Thereafter, the overnight culture of the Pseudomonas aeruginosa PAO1 strain was diluted 10-5 times with physiological saline, and 50 ⁇ L of the diluted solution was injected into the blood of the silkworm, and a decrease in the number of living silkworms over time was observed. . Experiment 1 and Experiment 2 were performed in such a manner.
  • Example 3 Among the 124 lactic acid bacteria listed in Tables 1 to 3, four kinds of lactic acid bacteria belonging to the genus Helenica of the genus Weissera (Nos. 18, 27, 48, and 75 in Tables 1 to 3) were used as test samples in Example 1 for lactic acid bacteria. Instead of using a 67% ethyl alcohol-soluble fraction of the culture supernatant of lactic acid bacteria, and diluting the overnight culture of the P. aeruginosa PAO1 strain 10 -6 times with physiological saline. A decrease in the number of surviving silkworms was observed, and survival after 1 to 3 days was confirmed.
  • the silkworms survived for 34 hours in all cases given four lactic acid bacteria belonging to the genus Welena spp. (Nos. 18, 27, 48, and 75 in Tables 1 to 3).
  • the lactic acid bacteria which do not belong to the genus Welena spp. Did not have the ability to activate innate immunity or were extremely low.
  • Lactic acid bacteria belonging to the species Weissella helenica have a specific activity of conferring Pseudomonas aeruginosa resistance compared to lactic acid bacteria belonging to other genera or lactic acid bacteria belonging to the genus Weissella but not belonging to the species Helenica. Noh was high.
  • Example 4 Lactic acid bacteria were cultured in the MRS liquid medium for 2 days, mixed with 6 g of artificial silkworm bait, and fed to 6 fifth-instar silkworms. After 21 hours, a bacterial solution of Pseudomonas aeruginosa diluted 10-5 times with physiological saline was injected into the blood of the silkworm, and the number of the silkworms after 51 hours was examined. Table 6 shows the results.
  • the therapeutic effect of the lactic acid bacterium Wh0916-4-2 was specific, and no activity was observed in other bacterium of the genus Weissera.
  • the lactic acid bacterium Wh0916-4-2 which does not belong to the lactic acid bacterium Wh0916-4-2 (No. 27 "W. @hellnica $ 0928-7-2"), belongs to the species Weissera Herenica. It was suggested that it was inferior to 2.
  • Example 5 Five days old silkworms were fed 1 g of artificial diet, and one day later, the culture supernatant of lactic acid bacteria (Nos. 18, 27, 48, and 75) belonging to four kinds of Weissella hellenica in Tables 1 to 4 was removed. , And diluted with physiological saline to 10 -4 times and 10 -3 times, respectively, and 50 ⁇ L thereof was injected into the blood of a fifth-instar silkworm. Six hours later, 50 ⁇ L of Pseudomonas aeruginosa PAO1 strain diluted 1000-fold with physiological saline was injected into the silkworm blood. 34 hours after that, the number of surviving silkworms (3 animals per group) was counted. Table 7 shows the results.
  • Example 6 Even when the culture supernatant of the lactic acid bacterium Wh0916-4-2 was mixed with an artificial silkworm bait and ingested orally for 1 day, the silkworm was given resistance to Pseudomonas aeruginosa infection in the same manner as live bacteria. In addition, the activity of inhibiting the growth of Pseudomonas aeruginosa was not observed in the culture supernatant of the lactic acid bacterium Wh0916-4-2. That is, it was found that this was not an antibacterial substance.
  • Example 7 Five-year-old silkworms were fed with 1 g of artificial feed impregnated with the ethanol fraction of the culture supernatant of the lactic acid bacterium Wh0916-4-2. Seventeen hours later, 50 ⁇ L of the bacterial solution shown in Table 8 was injected into the silkworm blood. For Pseudomonas aeruginosa, the overnight culture was used after diluting it 10-6 times, and for Klebsiella pneumoniae, 5 mL of the overnight culture was centrifuged (8000 rpm, 5 minutes). Then, the bacteria were collected and suspended in 5 mL of physiological saline for use. Thereafter, the number of surviving silkworms was observed over time. Table 8 shows the results.
  • the agent according to the present invention can be said to be an innate immunity activator.
  • Example 8 In Example 6, the bacteria were similarly evaluated in place of the multidrug-resistant Pseudomonas aeruginosa (MDRP).
  • MDRP multidrug-resistant Pseudomonas aeruginosa
  • Wh0916-4-2 the active ingredient contained therein
  • MDRP multidrug-resistant Pseudomonas aeruginosa
  • MDRP multidrug-resistant Pseudomonas aeruginosa
  • MDRP multidrug-resistant Pseudomonas aeruginosa
  • MDRP multidrug-resistant Pseudomonas aeruginosa
  • Example 9 Soy milk yogurt was prepared using lactic acid bacteria Wh0916-4-2.
  • lactic acid bacteria belonging to Weissella Herenica are known as vegetable lactic acid bacteria.
  • the lactic acid bacterium Wh0916-4-2 hardly proliferated in milk due to lack of amino acids, but proliferated in soy milk to form an acidic state. That is, yogurt was produced by culturing the lactic acid bacteria Wh0916-4-2 in soy milk. This yogurt tasted similar to tofu and was delicious.
  • Lactic acid bacteria belonging to Weissella Helenica are plant lactic acid bacteria and are known to grow in various plants. Therefore, vegetables fermented using lactic acid bacteria Wh0916-4-2 can be widely expected to be used as general foods and health foods.
  • the innate immunity activator of the present invention has a high innate immunity activating ability and also has an effect of preventing and treating infectious diseases containing it. Therefore, the use of the specific lactic acid bacterium of the present invention can provide a natural immunity activator, a preventive / therapeutic agent for infectious diseases, food and drink containing them, and the like, and can provide the pharmaceutical industry, health food industry, and general food industry. It can be widely used.
  • SEQ ID NO: 1 is the base sequence of almost unknown 16S rDNA of an unknown strain belonging to the genus Weissella.

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Abstract

La présente invention vise à proposer une bactérie lactique ayant une excellente capacité d'activation immunitaire naturelle, un agent d'activation immunitaire naturel comprenant un produit, un produit de traitement, etc. de la bactérie lactique en tant que principe actif, et un médicament préventif/thérapeutique pour une infection et un aliment ou une boisson comprenant celui-ci, et vise également à proposer un médicament préventif/thérapeutique pour une infection comprenant un principe actif issu de la bactérie lactique et un aliment ou une boisson fermenté(e) à l'aide de la bactérie lactique. À cet effet, la présente invention concerne une bactérie lactique appartenant à Weissella hellenica ; un agent d'activation immunitaire naturel comprenant des cellules mortes de la bactérie lactique, un produit de la bactérie lactique ou un produit de traitement de la bactérie lactique en tant que principe actif, le produit de traitement de la bactérie lactique étant une culture, un surnageant de culture, un concentré, un produit collé, un produit séché, un produit liquéfié, une dilution, un produit broyé, un produit traité pasteurisé ou un extrait de culture de la bactérie lactique ; et un médicament préventif/thérapeutique pour une infection caractérisé en ce qu'il comprend l'agent d'activation immunitaire naturel et est destiné à être utilisé pour prévenir ou traiter une infection par une bactérie ou un virus pathogène.
PCT/JP2019/027090 2018-07-19 2019-07-09 Bactérie lactique, agent d'activation immunitaire naturel issu de bactérie lactique, et médicament préventif/thérapeutique pour une infection et aliment ou boisson Ceased WO2020017390A1 (fr)

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CN115053955A (zh) * 2022-06-07 2022-09-16 聚慧食品科技(重庆)有限公司 一种基于复合菌分段发酵的玉米发酵酱及其制备方法

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JP7475586B2 (ja) 2020-05-01 2024-04-30 株式会社ゲノム創薬研究所 免疫抑制剤のスクリーニング方法
CN115053955A (zh) * 2022-06-07 2022-09-16 聚慧食品科技(重庆)有限公司 一种基于复合菌分段发酵的玉米发酵酱及其制备方法

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