JP2020100660A - Lactic acid bacteria, innate immunity activator derived from lactic acid bacteria, preventive and therapeutic agent for infectious diseases, and foods and drinks - Google Patents

Abstract

To provide lactic acid bacteria having high innate immunity activation ability, to provide innate immunity activators containing the products or processed products of the lactic acid bacteria as active ingredients, and to provide preventive/therapeutic agents for infectious diseases, and foods and drinks, which contain the same, as well as also to provide novel lactic acid bacteria having high innate immunity activation ability, to provide preventive and therapeutic agents for infectious diseases containing active ingredients derived from the same, and to provide foods and drinks fermented with the lactic acid bacteria.SOLUTION: Provided are a lactic acid bacterium belonging to Weissella hellenica; an innate immunity activator containing the killed bacteria of the lactic acid bacterium, the product of the lactic acid bacterium, or the processed product of the lactic acid bacterium as an active ingredient, the processed product of the lactic acid bacterium being a culture, culture supernatant, concentrate, paste, dried product, liquefied product, diluted product, crushed product, sterilized product, or extract from the culture, of the lactic acid bacterium; as well as preventive/therapeutic agent for infectious diseases containing the innate immunity activator and for the prevention or treatment of infectious diseases against pathogenic bacteria or viruses.SELECTED DRAWING: Figure 1

Description

The present invention relates to a lactic acid bacterium, an innate immunity activator derived from the lactic acid bacterium, a prophylactic/therapeutic drug for infectious diseases derived from the lactic acid bacterium, and a food or drink, and more specifically, "lactic acid bacterium belonging to Weissella hellenica, of the lactic acid bacterium. The invention relates to an innate immunity activator containing "killed bacteria, a product of the lactic acid bacterium, or a treated product of the lactic acid bacterium" as an active ingredient; food and drink derived from the lactic acid bacterium;

Lactic acid bacterium is a generic term for bacteria that produce lactic acid by metabolism, and has long been used for fermented foods, food and drink, pharmaceuticals, probiotics, etc., and is used in Weissella hellenica. The lactic acid bacteria to which it belongs are also used for various purposes.

For example, Patent Literature 1 describes an antibacterial agent for livestock, which contains a protease-resistant bacteriocin derived from a lactic acid bacterium, and the lactic acid bacterium includes a lactic acid bacterium belonging to Weissera helena.
Further, Patent Document 2 describes a food containing a specific antibacterial peptide, and a specific strain belonging to Weissera helenica is mentioned as a bacterium producing the antibacterial peptide.

In Patent Document 3, a culture of a specific lactic acid bacterium strain belonging to Weissella helenica isolated from squid black is angiotensin converting enzyme inhibitory activity, DPPH radical scavenging activity, or L-glutamic acid to γ-aminobutyric acid. It is described that it has the conversion ability of.
In Patent Document 4, crushed products of anti-inflammatory lactic acid bacteria belonging to the genus Weissera are said to have a preventive/ameliorating action on arthritis, which is a type of autoimmune disease, and Weissella helenica species are also listed. It is described that the crushed product of the lactic acid bacteria belonging to the genus Weissera suppressed activation of innate immunity.

As described above, lactic acid bacteria belonging to Weissera helenika are hardly known to be ones that generally contribute to innate immunity activation, and the product of lactic acid bacteria of a specific subspecies (specific strain) belonging to the situation or Weissera helena, It has not been known that the culture supernatant or the like gives an agent excellent in activation of innate immunity.

In the innate immune reaction, for example, 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 immune system is a defense mechanism against infections that organisms have in common, and is generally nonspecific, so that it is characterized by a quick reaction and an effective function against many infectious sources.

Lactic acid bacteria are considered to be healthy, but in most cases no scientific evidence is presented. In order to show scientific evidence, it is necessary to prove the system in which the therapeutic effect is clear and to analyze the mechanism at the molecular level. However, in the case of lactic acid bacteria, there are few cases where they were achieved.

So far, the present inventors have developed an evaluation method capable of simply measuring the innate immune activation reaction in silkworms having only an innate immune mechanism (Patent Document 5, Non-Patent Document 1). Furthermore, it has been confirmed that the method can evaluate (screening method) an innate immunity activator having an innate immunity activating effect on vertebrates such as humans (Patent Document 5 etc.). That is, this "silkworm infection model" has been established.
Moreover, 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 and treating infectious diseases against pathogenic bacteria or viruses, and is extremely effective against (multidrug) resistant bacteria, and against many opportunistic infectious diseases that exist. It is extremely effective for prevention and treatment.
However, there are few cases in which lactic acid bacteria have shown the above effects with scientific evidence, and development of excellent innate immunity activators and infectious disease prophylactic/therapeutic agents by activating innate immunity is desired. It was
Further, it has been desired to develop a food or drink containing a lactic acid bacterium-derived product or an innate immunity activator, or a food or drink using lactic acid bacterium excellent in the above performance.

JP 2006-169197 A JP, 2010-22227, A JP, 2013-048586, A JP2012-158568A International Publication No. 2008/126905 JP, 2007-327964, A JP 2012-006917 A

Ishii K, Hamamoto H, Kamimura M, Sekimizu K. Activation of the silkworm cytokine by bacterial and fungal cell wall components via a reactive oxygen species-triggered mechanism. J Biol Chem. 2008 Jan 25;283(4):2185-91.

An object of the present invention is to provide a natural immunity activator having as an active ingredient a lactic acid bacterium having a high ability to activate innate immunity, a killed bacterium of the lactic acid bacterium, a product of the lactic acid bacterium, a treated product of the lactic acid bacterium, and the like. Another object of the present invention is to provide a preventive/therapeutic agent for infectious diseases and food and drink containing the lactic acid bacterium or the innate immunity activator derived from the lactic acid bacterium.
Another object of the present invention is to provide a novel lactic acid bacterium (subspecies/strain) having a high ability to activate innate immunity, which comprises a prophylactic/therapeutic drug for infectious diseases containing an active ingredient derived from the novel lactic acid bacterium, and the lactic acid bacterium. The present invention is to provide food and drink that is fermented by fermentation (fermentation for activation of natural immunity).

The present inventor, as a result of repeated studies to solve the above problems, a lactic acid bacterium belonging to Weissella hellenica, a killed bacterium, a product, and a treated product of the lactic acid bacterium, compared with lactic acid bacteria of other genera. It was also found that the innate immunity activation ability is higher than that of lactic acid bacteria of other species of the same genus (Genus Weissera).
That is, the present inventor can prevent or treat infectious diseases against a plurality of pathogenic bacteria by using an infection model in which silkworm is an experimental animal, "lactic acid bacterium (derived product)", "effective lactic acid bacterium (derived product)" The present invention has been completed by finding "natural immunity activator contained as a component", "a food and drink product having a natural immunity fermented with the lactic acid bacterium" and the like.

That is, the present invention, a lactic acid bacterium belonging to Weissella hellenica, a killed bacterium of the lactic acid bacterium, a product of the lactic acid bacterium, or a natural immunity activator having a treated product of the lactic acid bacterium as an active ingredient,
The processed product of the lactic acid bacterium is a group consisting of a culture, a culture supernatant, a concentrate, a paste, a dried product, a liquefied product, a diluent, a crushed product, a sterilized product, and an extract from the culture of the lactic acid bacterium. The present invention provides an innate immunity activator characterized by being at least one processed product selected from

The present invention also provides an infectious disease preventive/therapeutic agent, which comprises the innate immunity activator described above and is used for preventing or treating infectious diseases against pathogenic bacteria or viruses.

The present invention also provides a food or drink containing the above-mentioned innate immunity activator.

Further, the present invention provides a fermented food or drink for activating natural immunity, which is obtained by fermentation using a lactic acid bacterium belonging to Weissella hellenica.

Further, the present invention provides the above-mentioned innate immunity activator, wherein the lactic acid bacterium belonging to the above Weissella hellenica is a lactic acid bacterium with a deposit number: NITE BP-02710 or a lactic acid bacterium naturally or artificially mutated therein. It is provided.

The present invention also provides a lactic acid bacterium belonging to the genus Weissella whose deposit number is NITE BP-02710, or a lactic acid bacterium that is naturally or artificially mutated. The present invention also provides a lactic acid bacterium in which the lactic acid bacterium is isolated or purified.
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 a fermented food or drink characterized by being obtained by fermentation using the lactic acid bacterium.

According to the present invention, it is possible to provide an innate immunity activator having an ability to activate innate immunity for humans and the like. The innate immunity activator is useful as a prophylactic/therapeutic agent for infectious diseases for preventing or treating infectious diseases against pathogenic bacteria or viruses.
Furthermore, in the present invention, since it activates innate immunity, it is particularly useful when the above-mentioned pathogenic bacterium is a (multidrug) drug-resistant bacterium, and when the innate immunity is reduced (or in a person with reduced innate immunity). It is particularly useful for the prevention or treatment of opportunistic infections of many types (many of which are causative agents).

In addition, in the present invention, the innate immune activity of lactic acid bacteria belonging to Weissella hellenica, and that the lactic acid bacterium subspecies belonging to a specific Weissella helenica species is particularly high in innate immune activity, according to the present inventors. Since it was discovered and examined in a silkworm infection model (which is also confirmed by whether the individual is alive or dead), the superiority or inferiority of the therapeutic effect (which also depends on the pharmacokinetics of the agent in the individual) is taken into consideration. Therefore, the innate immunity activator of the present invention has an excellent therapeutic effect on infectious diseases against fungi or viruses.

That is, in the present invention, "lactic acid bacteria belonging to Weissella hellenica (live bacteria), killed bacteria of the lactic acid bacteria, products of the lactic acid bacteria, or processed products of the lactic acid bacteria" (hereinafter, simply referred to as "" , May be abbreviated as "Weissera helena lactobacillus-derived product") to silkworms, depending on the nature of those derived products, mixed with food, injected into the intestinal tract of silkworms, injected into the blood of silkworms When the silkworms are administered to the silkworms by a method such as, and then the pathogenic bacteria are respectively administered to the silkworms, the silkworms previously administered with the lactic acid bacterium (derived product) are compared to the silkworms not previously administered with the lactic acid bacterium (derived product). The survival rate of the individuals was high with a significant difference (see Examples).

Further, in a separate experiment, the product derived from Weissella helenica lactic acid bacteria did not inhibit the growth of pathogenic bacteria (Example 6). That is, it was found that the product derived from Weissella helenica lactic acid bacteria has no antibacterial activity.
Moreover, when the Weissella helenica lactobacillus-derived product was administered to the silkworm at the same time as the pathogen, 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 required for imparting resistance to the infection of pathogenic bacteria by the Weicella helenica lactic acid bacterium-derived substance (see Examples, especially Example 6).

As described above, it has been confirmed that the silkworm infection model is applicable (useful) to infectious diseases of mammals such as humans. In addition, the immune system of the silkworm does not have an acquired immune system but only an innate immune system. And, as described above, the Weissella helena lactic acid bacterium-derived product does not have antibacterial activity, and since pre-administration is required to increase the individual survival rate, the Weissera helenica lactic acid bacterium-derived product of the present invention contains It has the property of activating innate immunity against mammals such as.
Moreover, the resistance of the Weissella helenica lactic acid bacterium-derived bacterium to pathogens was confirmed in a plurality of pathogens such as Pseudomonas aeruginosa and Klebsiella pneumoniae (see Example 7 and Table 8). From this, it can be said that the product derived from Weissella helenica lactobacillus is not only effective against a specific pathogenic bacterium, but has the property of activating the innate immune mechanism itself.

The above properties were confirmed in all four different subspecies of lactic acid bacteria belonging to the genus Weissella hellenica (Nos. 18, 27, 48, 75 in Tables 1 to 3 of Example 1). ).
On the other hand, in the subspecies of lactic acid bacteria that do not belong to the genus Weissella of Tables 1 to 3 and the subspecies of lactic acid bacteria that belong to the genus Weissella but do not belong to the hellenica species, However, it was confirmed that those lactic acid bacteria (derived products) had extremely low (or no) ability to activate innate immunity (see Examples 1 to 4, Tables 1 to 6 and FIG. 1).

That is, the ability to activate innate immunity is a characteristic peculiar to lactic acid bacteria belonging to Weissera helena and its derivatives in general. Therefore, the extension of the lactic acid bacterium (derived product) that is the source of the innate immunity activator of the present invention is extremely clear, and any lactic acid bacterium (derived product) belonging to Weissella helenica is included in the present invention. -Lactic acid bacteria (derived products) that do not belong to Helenica are excluded from the present invention.

Furthermore, among the lactic acid bacteria belonging to the above-mentioned Weissella helenica species which exerts an effect, the Weissella (Weissella) whose deposit number at the Patent Microorganism Depositary Center (NPMD) of the National Institute for Product Evaluation Technology (NITE) is NITE BP-02710 ) A subspecies of lactic acid bacteria belonging to the genus (hereinafter, this subspecies (strain) of lactic acid bacteria is abbreviated as "lactic acid bacteria Wh0916-4-2") or a derivative thereof, the above-mentioned innate immune activating effect is particularly remarkable. (See Example 5 and Table 7).

The innate immunity activator of the present invention can be taken by humans and the like by various methods according to the form (aspect) of the product derived from the Weissella helenica lactic acid bacterium, and it is a pharmacy such as a medical drug, a pharmacy manufacturing and marketing drug, and the like. Applicable to medicinal products such as medicinal drugs; instructional drugs; non-prescription drugs; In addition, since it is effective even when taken orally, it can also be applied to general foods such as apparent foods and health foods; foods with health claims; etc., and also to probiotics, fermented foods and drinks, drugs and feed for animals, etc. Can also be applied.

The method of ingesting the innate immunity activator of the present invention by "mammals such as humans" is not particularly limited, but it is particularly preferable because oral intake is effective and is easy and convenient.
And, as the food and drink containing the innate immunity activator of the present invention (fermentation), fermented (bean) milk, lactic acid bacteria drink, yogurt, pickles and the like can be mentioned. 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 for producing the above products.

In the present invention, the lactic acid bacterium belonging to Weissera helena can take advantage of the property of being a lactic acid bacterium to ferment a food to obtain a fermented food or drink for innate immune activation, and can also be used as a food or drink in daily life. , It is also possible to always raise the natural immunity.
Further, the food and drink fermented with the lactic acid bacterium Wh0916-4-2 is delicious and can provide a food and drink group with a new taste.

1 is a graph showing changes in the survival rate of silkworms over time, and in particular, showing the 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 survived due to the pre-administration of the lactic acid bacterium (derived product) of the present invention (B) Silkworm that died because there was no pre-administration of the lactic acid bacterium (derived product) of the present invention

Hereinafter, the present invention will be described, but the present invention is not limited to the following specific embodiments and can be arbitrarily modified within the scope of the technical idea.

The innate immunity activator of the present invention contains a lactic acid bacterium belonging to Weissella hellenica, a killed bacterium of the lactic acid bacterium, a product of the lactic acid bacterium, or a treated product of the lactic acid bacterium as an active ingredient.
As shown in Examples 1 to 4, lactic acid bacteria belonging to the genus Weissella and hellenica have high innate immunity activation ability among all the evaluated lactic acid bacteria, and lactic acid bacteria not belonging to the genus Weicella, and Weicella. Among the lactic acid bacteria that belonged to the genus but did not belong to the Helenica species, all of the evaluated lactic acid bacteria had a low ability to activate innate immunity.

It is clear from the above that the innate immunity activator of the present invention exerts a prophylactic/therapeutic effect by the mechanism of the active ingredient via the host.
Invertebrates such as silkworms lack antibodies and therefore have no adaptive immune system. A mechanism called innate immunity works to prevent infection. Recent studies have revealed that mammals also have an innate immune mechanism, and the molecular mechanism is common with invertebrates. The present invention activates innate immunity of mammals such as humans.

The innate immune activation was evaluated using the silkworm infection model already established by the present inventors. The evaluation method in the present invention, specifically, the evaluation sample to silkworm, diet, intestinal tract injection, administered by methods such as blood injection, then, the survival rate when the pathogens etc. are administered to silkworms, It was performed by comparing the survival rate when the sample was not administered.
The survival rate when the evaluation sample and the pathogen, etc. were simultaneously administered was also measured, and it was confirmed that the survival rate significantly increased only when the pathogen, etc. was administered after the administration of the evaluation sample, and the increase in the survival rate was observed. It was confirmed that the cause was activation of innate immunity.

The innate immunity activator of the present invention contains lactic acid bacteria themselves (viable bacteria of lactic acid bacteria), killed bacteria of lactic acid bacteria, products of lactic acid bacteria, or processed products of lactic acid bacteria, which belong to Weissera helenica, and their mixture is used. May be included. Further, they can be contained in various states, and examples thereof include a suspension, a lactic acid bacterium, a culture supernatant, and a state containing a medium component.
The above-mentioned "treated product of lactic acid bacterium" is derived from a culture, 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 of the lactic acid bacterium. It is at least one processed product selected from the group consisting of: In the above expression, there is a case where some of them are duplicated as “object”.

Here, examples of the live or dead bacteria of the lactic acid bacteria include live bacteria, wet bacteria, and dry bacteria, and also those subjected to heat sterilization treatment, radiation sterilization treatment, crushing treatment, and the like. The product may be contained in live or dead bacteria of lactic acid bacteria or may be isolated. Further, examples of the dried product include a spray dried product, a freeze dried product, a vacuum dried product, and a drum dried product.

The content of the lactic acid bacterium, the killed bacterium of the lactic acid bacterium, the product of the lactic acid bacterium, or the treated product of the lactic acid bacterium, which is the active ingredient in the innate immunity activator of the present invention, with respect to the whole natural immunity activator is particularly preferably There is no limitation, and it can be appropriately selected according to the purpose, but when the total amount of the innate immunity activator is 100 parts by mass, "lactic acid bacterium, killed bacterium of the lactic acid bacterium, product of the lactic acid bacterium, or the lactic acid bacterium is used. The total amount of treated products" 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 ˜90 parts by mass.

The active ingredients may be used alone or in combination of two or more. When two or more kinds are used in combination, the content ratio of each active ingredient in the innate immunity activator is not particularly limited and can be appropriately selected according to the purpose.

The innate immunity activator of the present invention contains the above-mentioned ingredients as active ingredients, but may contain "other ingredients" in addition to these active ingredients.
The "other component" in the innate immunity activator is not particularly limited and may be appropriately selected depending on the purpose within a range not impairing the effects of the present invention, and is pharmaceutically acceptable. A carrier etc. are mentioned. The carrier is not particularly limited, and examples thereof include those similar to the ones to be “mixed and used according to the dosage form and the like” described later.

The types of antibacterial drugs against opportunistic infections, especially Pseudomonas aeruginosa, are limited. Especially, it is said that it is very difficult to find an antibacterial drug which is effective orally. One of the reasons is that the methods for evaluating the therapeutic effect are limited.
The silkworm infection model not only has a low cost, but also has the advantage of avoiding the ethical problem from the viewpoint of animal welfare, which is a problem in the conventional mouse system. INDUSTRIAL APPLICABILITY The present invention screens as many lactic acid bacteria as are problematic from the viewpoint of animal welfare in a mouse system, and evaluates the therapeutic effect regardless of the antibacterial effect (specifically, measuring the survival rate). Made by

Therefore, the innate immunity activator of the present invention exerts an effect on the prevention and treatment of various pathogens and viruses, and thus the present invention is for the prevention or treatment of pathogens or viruses. It is also a preventive and therapeutic drug for infectious diseases.

Further, the innate immunity activator of the present invention does not depend on acquired immunity nor on antibacterial effect, and therefore is effective even when the pathogen of the infectious disease is a drug-resistant bacterium. Therefore, the present invention is also the above-mentioned preventive/therapeutic drug for infectious diseases, wherein the pathogenic bacterium is a drug-resistant bacterium.

In addition, the present invention is effective against all kinds of bacteria and viruses by activating innate immunity, and thus is particularly effective against various opportunistic infectious diseases that become serious when innate immunity function is lowered. Therefore, the present invention is also the above-mentioned infectious disease preventive/therapeutic drug, wherein the infectious disease is an opportunistic infectious disease.

As described above, the lactic acid bacteria belonging to the Weissera helenica species had higher innate immunity activation than the lactic acid bacteria belonging to the other species in all the evaluated lactic acid bacteria. Therefore, it is considered that foods and drinks containing the above-mentioned "product derived from Weicella helenica lactic acid bacterium" relating to all lactic acid bacteria belonging to Weicella helena are active ingredients as a whole.
Therefore, the present invention is also a food or drink characterized by containing an innate immunity activator, and is obtained by fermentation using a lactic acid bacterium belonging to Weissella hellenica. It is also a fermented food and drink for innate immune activation.

As shown in Examples 1 to 5 and Tables 1 to 7, of 124 subtypes of lactic acid bacteria, No. 1 which is a lactic acid bacterium belonging to Weissella helenica spp. 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), and No. All of 75 (strain name (subspecies name) 1109-7-1) showed resistance to Pseudomonas aeruginosa and had a high ability to activate innate immunity.

Among them, as shown in Example 5, among the four subspecies of lactic acid bacteria, No. 18 (strain name (subspecies name) 0916-4-2) showed the highest resistance to Pseudomonas aeruginosa and had a specifically high innate immune activation ability (see Table 7).
In the present invention, the above-mentioned "No. 18 (strain name (subspecies name) 0916-4-2)" strain (lactic acid bacterium subspecies) in Table 1 having the highest effect of the present invention was designated as "lactic acid bacterium Wh0916". -4-2".
The lactic acid bacterium Wh0916-4-2, which is a subspecies of the lactic acid bacterium belonging to Weissella hellenica, will be described in detail below.

Morphology: The lactic acid bacterium Wh0916-4-2 of the present invention was isolated for the first time.

Physiological properties: Physiological and chemotaxonomic properties of the lactic acid bacterium Wh0916-4-2 of the present invention are as follows.
(A) Gram staining result: positive (b) cell shape: globular (c) oxygen property (aerobic/anaerobic): anaerobic (d) lactic acid producing ability: yes

(1) Catalase:-
(2) Alkaline phosphatase:-
(3) Esterase (C4):-
(4) Esterase lipase (C8):-
(5) Lipase (C14):-
(6) Leucine allyl amidase:-
(7) Valine allyl amidase:-
(8) Cystine arylamidase:-
(9) Trypsin:-
(10) α-chymotrypsin:-
(11) Acid phosphatase: +
(12) Naphthol-AS-BI-phosphohydrolase: +
(13) α-galactosidase:-
(14) β-galactosidase:-
(15) β-glucuronidase:-
(16) α-Glucosidase:-
(17) β-glucosidase:-
(18) N-acetyl-β-glucosaminidase:-
(19) α-mannosidase:-
(20) α-fucosidase:-

The physiological and chemical taxonomic properties of the lactic acid bacterium Wh0916-4-2 described above are classified according to Bergey's Manual of Systematic Bacteriology (vol.3 1989) and described in other documents. As a result of comparison and judgment, the lactic acid bacterium of the present invention, Wh0916-4-2, is a microorganism belonging to the genus Weissella, and further a microorganism belonging to the species Weissella hellenica.

In addition, the nucleotide sequence corresponding to almost the entire length of 16S rDNA used as an index for the phylogenetic classification of lactic acid bacteria Wh0916-4-2 is as shown in SEQ ID NO: 1 in the sequence listing. Homology search of this nucleotide sequence by NCBI BLAST analysis showed 99% homology. Therefore, lactic acid bacterium Wh0916-4-2 is a microorganism belonging to Weissella hellenica species.

As a result of the identification based on the result of the sugar metabolism test based on the ability to generate acid and gas (see the section "Carbon Source in Medium" below), the lactic acid bacterium Wh0916-4-2 was a Weissella hellenica species. It was not inconsistent with the above judgment that the microorganism belonged to.

Furthermore, as a result of a comprehensive study, including the fact that it exhibits the highest innate immunity activation ability as compared with known strains (subspecies) belonging to Weissella hellenica species, etc., the lactic acid bacterium Wh0916-4-2 Was determined to be a new (isolated) microbial strain (a subspecies of lactic acid bacteria).

"Lactic acid bacterium Wh0916-4-2" is a 2-5-8122 Kazusa Kamafoot, Kisarazu City, Chiba Prefecture, National Institute of Technology and Evaluation (National Institute of Technology and Evaluation; hereinafter abbreviated as "NITE") The microorganism was deposited domestically at the Patent Microorganism Depositary Center (NPMD) of and is deposited (accepted) as the deposit number: NITE P-02710 (receipt date (deposit date): May 14, 2018).
The "lactic acid bacterium Wh0916-4-2" was subsequently deposited at the Patent Microorganism Depositary Center (NPMD) of the National Institute for Product Evaluation Technology (NITE), 2-5-8122, Kazusa Kamafoot, Kisarazu City, Chiba Prefecture. Submit the application form and apply for transfer from domestic deposit (original deposit date: May 14, 2018) to deposit under the Budapest Treaty (Transfer date (international deposit date): October 1, 2018) As a result of receiving the application for transfer to a deposit under the Budapest Treaty (international deposit), it has received the deposit number "NITE BP-02710".

As a general property of the bacterium, the property as a strain is easily changed, and therefore the lactic acid bacterium Wh0916-4-2 has a possibility that it does not stay within the range of the physiological property shown above. It goes without saying that such “mutation” includes both natural mutation and artificial mutation.

The method for culturing the lactic acid bacterium Wh0916-4-2 will be described below. The method for culturing the lactic acid bacterium Wh0916-4-2 may be carried out according to a general culturing method performed for a microorganism of the genus Weicella.
Cultivation is preferably performed under anaerobic conditions. Examples of carbon sources in the medium include D-ribose, D-galactose, D-glucose, D-fructose, D-mannose, D-mannitol, N-acetylglucosamine, amygdalin, arbutin, esculin, salicin, D-cellobiose. , D-maltose, sucrose, D-trehalose, gentiobiose, molasses, starch syrup, fats and oils, and other organic carbon compounds are used, and as the nitrogen source, 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.
As the salts, 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. Furthermore, it is preferable to add growth promoting substances such as biotin, vitamin B1, cystine, methyl oleate, lard oil and the like from the viewpoint of increasing the production amount of the target product.
Further, a defoaming agent such as silicone oil or a surfactant may be added. As the prepared medium, for example, MRS medium, GAM medium, etc. are preferably used.

The culturing conditions may be according to the general culturing conditions performed for the microorganisms of the genus Weicella as described above. If it is a liquid culture method, stationary culture is desirable. If the scale is small, a static culture method using a glass bottle with a lid may be used.
The culture temperature is preferably maintained between 25°C and 37°C, more preferably 28°C to 32°C. The culture pH is preferably around 7. The culturing period is a factor that varies depending on the medium composition used, the culturing temperature, etc., but in the case of lactic acid bacterium Wh0916-4-2, preferably 12 to 72 hours, more preferably 24 to 48 hours, is a sufficient amount of the target product. Can be secured.
It is also preferable to pick up colonies obtained by culturing and perform single colony formation again on the medium.

The present invention also relates to the above-mentioned innate immunity activator, wherein the lactic acid bacterium belonging to the above-mentioned Weissella hellenica is a lactic acid bacterium which has a deposit number: NITE BP-02710, or a lactic acid bacterium which is naturally or artificially mutated. is there.
The present invention also relates to a lactic acid bacterium belonging to the genus Weissella whose deposit number is NITE BP-02710, or a lactic acid bacterium which is naturally or artificially mutated.
The present invention is also 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 lactic acid bacterium with a deposit number of NITE BP-02710 is the above-mentioned "lactic acid bacterium Wh0916-4-2".

The present invention is also a food or drink containing the above-mentioned lactic acid bacterium Wh0916-4-2 (deposition number: lactic acid bacterium which is NITE BP-02710), which is obtained by fermentation using the lactic acid bacterium (strain thereof) (subspecies). It is also a fermented food and drink characterized by being processed.

The lactic acid bacterium of the present invention, a killed bacterium of the lactic acid bacterium, a product of the lactic acid bacterium, or an innate immunity activator containing the treated product of the lactic acid bacterium as an active ingredient may be blended in pharmaceuticals, general foods and drinks, health foods and the like. It is possible and applicable to various medicines, foods and drinks, etc. regardless of their forms.
In addition, the food and drink produced by using the step of fermenting with lactic acid bacteria belonging to the above-mentioned Weissera helena in the present invention, in addition to the usual effects of lactic acid bacteria, because it is easy to exert the natural immune activation effect peculiar to the present invention. Is preferred.

The dosage form of the innate immunity activator or infectious disease preventive/therapeutic agent of the present invention is not particularly limited, and forms such as lactic acid bacteria, killed bacteria of lactic acid bacteria, products of lactic acid bacteria, and processed products of the various lactic acid bacteria described above ( It can be appropriately selected depending on the aspect). In addition, for example, it can be appropriately selected according to a desired administration method as described below.
Specifically, for example, oral solid preparations (tablets, coated tablets, granules, powders, hard capsules, soft capsules, etc.), oral liquid preparations (internal solution, syrup, elixir, etc.), injections (solvent, suspension) Agents, etc.), gels, creams, external powders, sprays, inhalation sprays and the like.

As the oral solid preparation, for example, an excipient, and if necessary, an additive such as a binder, a disintegrating agent, a lubricant, a coloring agent, and a flavoring/flavoring agent are added to the above-mentioned active ingredient, and a conventional method is used. Can be manufactured by.

Examples of the excipient include lactose, sucrose, sodium chloride, glucose, starch, calcium carbonate, kaolin, microcrystalline cellulose, silicic acid and the like.
Examples of the binder include water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl starch, methyl cellulose, ethyl cellulose, shellac, calcium phosphate, polyvinylpyrrolidone and the like. To be
Examples of the disintegrant include dry starch, sodium alginate, agar powder, sodium hydrogen carbonate, calcium carbonate, sodium lauryl sulfate, stearic acid monoglyceride, lactose and the like.
Examples of the lubricant include refined talc, stearate, borax, polyethylene glycol and the like.
Examples of the colorant include titanium oxide and iron oxide.
Examples of the corrigent/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 flavoring/flavoring agent, a buffering agent and a stabilizer to the active ingredient.

Examples of the corrigent/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.

The injection includes, for example, subcutaneously, intramuscularly, and intravenously by adding a pH adjusting agent, a buffering agent, a stabilizer, an isotonicity agent, a local anesthetic, etc. to the above-mentioned active ingredient. And the like can be produced.
Examples of the pH adjuster and the buffer include sodium citrate, sodium acetate, sodium phosphate and the like.
Examples of the stabilizer include sodium pyrosulfite, EDTA, thioglycolic acid, thiolactic acid and the like.
Examples of the tonicity agent include sodium chloride, glucose and the like. Examples of the local anesthetic include procaine hydrochloride, lidocaine hydrochloride and the like.

The innate immunity activator and infectious disease preventive/therapeutic agent of the present invention are suitably used, for example, for individuals who need activation of the innate immune system, individuals who seek to obtain acquired immunity against bacteria and the like. it can.
Specifically, for example, by administering to an individual in need of health maintenance or recovery from fatigue; an individual in need of prevention or treatment of cancer or lifestyle-related disease; an individual infected with bacteria, fungi, viruses, etc. Can be used.

The animals to which the innate immunity activator or infectious disease preventive/therapeutic agent of the present invention is administered are not particularly limited, and examples thereof include humans; experimental animals such as mice and rats; monkeys; horses; cows, pigs, goats, Domestic animals such as chickens; pets such as cats and dogs;

The administration method of the innate immunity activator is not particularly limited and is appropriately selected depending on, for example, the form of the lactic acid (dead) bacterium or the processed product thereof, or the dosage form described above. Oral administration, intraperitoneal administration, blood injection, intestinal infusion and the like can be mentioned. Among them, oral administration is preferable 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, weight, desired degree of effect, etc. of the individual to be administered. However, for example, the daily dose for 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 is also not particularly limited and may be appropriately selected depending on the intended 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 activation of natural immunity (hereinafter, they may be abbreviated as "the 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 aspect (type) of the food or drink, but when the entire food or drink is 100 parts by mass, 0.001 to 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 and drink of the present invention has the ability to activate innate immunity and the ability to 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 above-mentioned “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, and examples thereof include various food materials. The content of the "other components" is not particularly limited and can be appropriately selected according to the purpose.
Further, in the case of a fermented food or drink for activating natural immunity obtained by fermenting with a lactic acid bacterium belonging to Weissella hellenica, various substances produced by the fermentation can also be included.

The lactic acid bacterium of the present invention can be applied to foods such as general foods such as apparent foods and health foods; foods with health claims; The fermented food and drink is particularly suitable for use as fermented milk, fermented soymilk, lactic acid bacterium beverage, yogurt, pickles, lactic acid starter for producing pickles, and the like.

The type of the food is not particularly limited and can be appropriately selected according to the purpose. For example, confectionery such as jelly, candy, chocolate, biscuits, and gummy; preference for green tea, tea, coffee, soft drinks, etc. Beverages; fermented milk, fermented soymilk, yogurt, ice cream, lactoice and other (bean) dairy products; vegetable drinks, fruit drinks, processed fruits and vegetables such as jams; liquid foods such as soups; breads, noodles, etc. Processed grains; various seasonings; and the like. Of these, (bean) dairy products such as yogurt, fermented milk, and fermented soymilk are preferable.

Further, the food, in addition to the obvious food, may be a health food or health functional food, for example, oral solid preparations such as tablets, granules, capsules, oral liquid preparations, oral liquid preparations such as syrups. Is also preferable.

The food and drink of the present invention are particularly useful as health foods such as foods with functional claims for the purpose of activating the innate immune system and imparting resistance to infectious diseases.
When the lactic acid bacterium of the present invention, the killed bacterium, a treated product or the like is used for producing food or drink, the production method can be performed by a method well known to those skilled in the art. A person skilled in the art, a step of mixing the (dead) microbial cell or treated product of the lactic acid bacterium of the present invention with other components, a molding step, a sterilization step, a fermentation step, a baking step, a drying step, a cooling step, a granulation step, It is possible to make the desired food or drink by appropriately combining packaging steps and the like.

When the lactic acid bacterium of the present invention is used for producing various fermented milk, it can be produced by a method well known to those skilled in the art. For example, food and drink produced using the step of adding the required amount of lactic acid bacteria of the present invention to fermented milk as dead bacteria, food and drink produced using the step of fermenting lactic acid bacteria of the present invention as a lactic acid bacterium starter, Can be mentioned.
When fermentation is carried out using the lactic acid bacterium of the present invention as a lactic acid bacterium starter, it can be carried out under the same conditions as the culturing conditions of the lactic acid bacterium of the present invention.

Hereinafter, the present invention will be described in more detail based on Examples and Examination Examples, but the present invention is not limited to the specific ranges of Examples and the like below.

Example 1
As shown in Tables 1 to 3 below, 124 strains of lactic acid bacteria were isolated, their lactic acid producing ability was confirmed, and a library was prepared. From this library (Tables 1 to 3), lactic acid bacteria conferring resistance to infection with the silkworm Pseudomonas aeruginosa strain PAO1 was searched.

80 μL of full-growth of lactic acid bacteria was mixed with 1 g of artificial silkworm feed and fed to silkworms for 1 day. After that, an overnight culture of Pseudomonas aeruginosa PAO1 strain was diluted 10 ⁻⁶ times with physiological saline, and 50 μL of the diluted solution was injected into the blood, and the decrease in the number of surviving silkworms over time was observed. ..
The surviving silkworms are as shown in FIG. 2(A), and the dead silkworms are as shown in FIG. 2(B). The results of the transition of the silkworm survival rate are shown in FIG.

As shown in FIG. 1, all the tested lactic acid bacteria showed a life-prolonging effect as compared with the control by physiological saline. Among them, in particular, the majority of silkworms that were orally administered with No. 18 “lactic acid bacterium Wh0916-4-2” (accession number: NITE BP-02710) in Table 1 survived even 115 hours after Pseudomonas aeruginosa injection. Was. That is, the activity of lactic acid bacterium Wh0916-4-2 was significantly higher than that of other lactic acid bacteria.

Example 2
20 mL of full-growth lactic acid bacteria that had been cultivated to full-growth was centrifuged to collect the bacteria, which was mixed with 1 g of an artificial silkworm artificial diet containing no antibiotics and fed to silkworms for 1 day. After that, an overnight culture of Pseudomonas aeruginosa PAO1 strain was diluted 10 ⁻⁵ times with physiological saline, and 50 μL of the diluted solution was injected into the silkworm, and a decrease in the number of surviving silkworms was observed over time. .. Experiments 1 and 2 were performed in this manner.

The results of Experiment 1 are shown in Table 4 below, and the results of Experiment 2 are shown in Table 5 below.
The number of silkworms in one group was 6, and the time (hrs) until half (3) died was defined as "LT50". The ratio of the evaluated lactic acid bacteria to the control LT50 without lactic acid bacteria is shown in Tables 4 and 5.

As a result, in Experiment 1 and Experiment 2, the LT50 in the control without lactic acid bacteria was 27 hours and 31 hours, respectively. Addition of most lactic acid bacteria to food showed a life-prolonging effect.
The life-prolonging effect of the Lactococcu lactis 11/19-B1 strain reported by the inventor was 1.1 times in both Experiment 1 and Experiment 2. On the other hand, lactic acid bacterium Wh0916-4-2 belonging to Weissella hellenica showed a life-prolonging effect of 3.6 times or more.

The life-prolonging effect (Nishida, Ono, Sekimizu; Drug Discoveries & Therapeutics. 2016; 10(1):49-56.) of the Lactococcu lactis 11/19-B1 strain reported by the inventor has already been reported in Experiment 1 and Reproducibility was observed, although each of Experiments 2 was small.
On the other hand, lactic acid bacterium Wh0916-4-2 belonging to Weissella hellenica showed a life extension effect of 2.9 times or more. This effect was outstanding among the lactic acid bacteria examined.

Example 3
Of the 124 strains of lactic acid bacteria listed in Tables 1 to 4, 4 types of lactic acid bacteria (Nos. 18, 27, 48 and 75 in Tables 1 to 3) belonging to the genus Weicella genus Helenica were tested as lactic acid bacteria in Example 1. Instead of the lactic acid bacterium culture supernatant, a 67% ethyl alcohol-soluble fraction was prepared, and the overnight culture was repeated in the same manner as in Example 1 except that the overnight culture of Pseudomonas aeruginosa PAO1 strain was diluted 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.

As a result, the silkworms survived for 34 hours when all four lactic acid bacteria belonging to the genus Weicella Helenica (Nos. 18, 27, 48, and 75 in Tables 1 to 3) were given. On the other hand, lactic acid bacteria that do not belong to the Weirella genus Helenica have no or very low ability to activate innate immunity as a whole.
Lactic acid bacteria belonging to the Weissera helenica species have a specific Pseudomonas aeruginosa resistance-conferring activity as compared to lactic acid bacteria belonging to other genera and lactic acid bacteria belonging to the genus Weicella but not in Helenica species, and have natural immunity activity. Noh was high.

Example 4
Lactic acid bacteria were cultivated in MRS liquid medium for 2 days, mixed with 6 g of artificial silkworm feed and fed to 6 5th-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 survival number of the silkworm after 51 hours was examined. The results are shown in Table 6.

As a result, no. Half of the silkworms fed 18 "W. hellnica 0916-4-2", that is, "lactic acid bacterium Wh0916-4-2 (accession number: NITE BP-02710)" survived 51 hours after Pseudomonas aeruginosa injection, No. No. 27, "W. hellnica 0928-7-2" of Weissera helenica spp. No survival was observed in silkworms fed 24, 30, 33, and 35 "bacteria belonging to the genus Weicella but of other species".

The therapeutic effect of lactic acid bacterium Wh0916-4-2 was specific, and the activity was not found in other Weissella bacteria. Moreover, even if it belongs to the species Weicella helena, it is not the lactic acid bacterium Wh0916-4-2 (No. 27 "W. hellnica 0928-7-2"), which has the ability to activate innate immunity and the lactic acid bacterium Wh0916-4-. It was suggested to be inferior to 2.

Example 5
Five days old silkworms were fed with 1 g of artificial diet, and one day later, culture supernatants of lactic acid bacteria (No. 18, 27, 48, 75) belonging to the four species of Weissella hellenica in Tables 1 to 4 were added. , 10 ⁻⁴ times and 10 ⁻³ times respectively with physiological saline, and 50 μL thereof was injected into the blood of 5th instar silkworms.
Six hours later, 50 μL 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. The results are shown in Table 7.

As a result, after 34 hours, the all of the silkworm the lactic acid bacteria Wh0916-4-2 (Weissella hellenica 0916-4-2) were alive, the other three strains (other subspecies), ^10-4 Dead silkworms were found in the silkworms fed with the double dilution.
Although all of the four strains of Weissella helenica showed a therapeutic effect, lactic acid bacterium Wh0916-4-2 showed the most remarkable effect among them.

Example 6
Even when the culture supernatant of the lactic acid bacterium Wh0916-4-2 was mixed with an artificial diet of silkworms and orally ingested for 1 day, the silkworms were imparted with resistance to Pseudomonas aeruginosa infection, like live bacteria.
In addition, the activity of inhibiting the growth of Pseudomonas aeruginosa was not observed in the culture supernatant of lactic acid bacterium Wh0916-4-2. That is, it was found that this was not an antibacterial substance.

Furthermore, when the culture supernatant of the lactic acid bacterium Wh0916-4-2 was administered to the silkworm simultaneously with Pseudomonas aeruginosa, resistance impartation to Pseudomonas aeruginosa infection was not observed. That is, it was found that pre-administration of the culture supernatant (derived product) of lactic acid bacteria is required to impart resistance to Pseudomonas aeruginosa infection.
Moreover, when the time from the pre-administration to the administration of Pseudomonas aeruginosa was set to 2 days or more, the activity of the culture supernatant of the lactic acid bacterium Wh0916-4-2 was lost. Therefore, it is considered that the active ingredient contained in the culture supernatant of lactic acid bacterium Wh0916-4-2 disappeared from the body of the silkworm and its activity was lost.

These results suggest that the action of (the active ingredient contained in) the culture supernatant of lactic acid bacterium Wh0916-4-2 is not a direct effect on Pseudomonas aeruginosa but is mediated by the host immune system. ..

Example 7
1-g artificial feed of 1 g impregnated with the ethanol fraction of the culture supernatant of lactic acid bacterium Wh0916-4-2 was given to 5th-instar silkworms. After 17 hours, 50 μL of the bacterial solution shown in Table 8 was injected into the silkworm blood.
For Pseudomonas aeruginosa, an overnight culture solution was used after diluting ^10-6 times, and for Klebsiella pneumoniae, 5 mL of the overnight culture solution was centrifuged (8000 rpm, 5 minutes). The bacteria were collected and suspended in 5 mL of physiological saline for use.
After that, the number of surviving silkworms was continuously observed. The results are shown in Table 8.

Pseudomonas aeruginosa PAO1 strain and two Klebsiella pneumoniae 8140,8705 strains killed silkworms within 22 hours, but the lactic acid bacterium Wh0916-4-2 culture/culture supernatant ( Extract) showed a therapeutic effect.
Not only the infection with Pseudomonas aeruginosa but also the infection with Klebsiella pneumoniae was shown to be therapeutic. Therefore, it can be said that the agent according to the present invention is an innate immunity activator.

Example 8
In Example 6, the fungus was replaced by multidrug-resistant Pseudomonas aeruginosa (MDRP) and evaluated in the same manner.
The culture supernatant of lactic acid bacterium Wh0916-4-2 (active ingredient contained therein) also showed an effect on clinically isolated MDRP.
In human clinical practice, multidrug-resistant Pseudomonas aeruginosa called MDRP has been a problem, but the innate immunity activator of the present invention is also effective against multidrug-resistant Pseudomonas aeruginosa (MDRP) and nosocomial infection. It was suggested that it is also effective as a countermeasure.

Example 9
Soymilk yogurt was produced using lactic acid bacteria Wh0916-4-2. Generally, lactic acid bacteria belonging to Weissera helenica are known as plant lactic acid bacteria.
The lactic acid bacterium Wh0916-4-2 was difficult to grow in milk because of lack of amino acids, but grew in soy milk to form an acidic state. That is, yogurt could be produced by culturing the lactic acid bacterium Wh0916-4-2 in soymilk. The yogurt tasted similar to tofu and was delicious.

Lactic acid bacteria belonging to Weissella hellenica are plant lactic acid bacteria and are known to grow in various plants. Therefore, the vegetables fermented with the lactic acid bacterium Wh0916-4-2 can be expected to be widely used as general foods and health foods.

The innate immunity activator of the present invention has a high ability to activate innate immunity and also has an infectious disease preventive and therapeutic effect containing it. Therefore, by using the specific lactic acid bacterium in the present invention, it is possible to provide an innate immunity activator, a preventive/therapeutic agent for infectious diseases, foods and drinks containing them, and the like. The pharmaceutical industry, health food industry, general food industry It is widely available.

NITE BP-02710

SEQ ID NO: 1 is a nucleotide sequence of almost unknown 16S rDNA of an unknown strain belonging to the genus Weissella.

Claims (6)

A lactic acid bacterium belonging to Weissella hellenica, a killed bacterium of the lactic acid bacterium, a product of the lactic acid bacterium, or a natural immunity activator having a treated product of the lactic acid bacterium as an active ingredient,
The processed product of the lactic acid bacterium is a group consisting of a culture, a culture supernatant, a concentrate, a paste, a dried product, a liquefied product, a diluent, a crushed product, a sterilized product, and an extract from the culture of the lactic acid bacterium. An innate immunity activator, which is at least one processed product selected from: An infectious disease preventive/therapeutic agent comprising the innate immunity activator according to claim 1 for preventing or treating an infectious disease against a pathogenic bacterium or virus. The infectious disease preventive/therapeutic drug according to claim 2, wherein the pathogenic bacterium is a drug-resistant bacterium. The infectious disease preventive/therapeutic agent according to claim 2 or 3, wherein the infectious disease is an opportunistic infectious disease. A food or drink for activating innate immunity, comprising the innate immunity activator according to claim 1. A fermented food or drink for activating natural immunity, which is obtained by fermenting a lactic acid bacterium belonging to Weissella hellenica.