CN106102755B - Agent for producing retinoic acid - Google Patents
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- CN106102755B CN106102755B CN201580013813.7A CN201580013813A CN106102755B CN 106102755 B CN106102755 B CN 106102755B CN 201580013813 A CN201580013813 A CN 201580013813A CN 106102755 B CN106102755 B CN 106102755B
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Abstract
The present invention provides an agent capable of inducing a biodefense function by a novel mechanism, in particular, a retinoic acid-producing agent comprising lactobacillus as an active ingredient and an immunopotentiator comprising the retinoic acid-producing agent.
Description
Technical Field
The present invention relates to an agent for producing retinoic acid and an agent for enhancing immune function, which are based on the effect of the agent in promoting the production of retinoic acid.
Background
When pathogenic bacteria, fungi, viruses or the like invade and grow in the mammal body including human, symptoms such as diarrhea, gastrointestinal diseases or fever develop. Severe symptoms can sometimes lead to death. Despite the advanced medicine possessed by modern society, such infectious mammalian diseases have not been completely cleared. The defense against infectious diseases is a major concern for humans who have pursued a healthy life.
People of an age that are less resistant (including with respect to the ability to defend against infection) than healthy adults, such as the elderly, infants and children, are more likely to be affected by such infectious diseases. Since a decrease in the self-defense function against infection is associated with aging, for example, the elderly are often infected with indigenous bacteria (i.e., Staphylococcus aureus (Staphylococcus aureus) present in the nasal mucosa) while healthy adults are not infected therewith. If the development of an infectious disease is observed in the elderly, the patient with the infectious disease is physically isolated and the facility where the patient with the developing infectious disease has stayed or visited is closed to prevent the spread of the infectious disease. Furthermore, infants and/or children have immature immune systems and, therefore, are more susceptible to infectious diseases than healthy adults due to their low ability to defend themselves against infection.
Generally, in order to cope with infectious diseases, the cause of such infectious diseases is first identified, and then a drug having antimicrobial activity is administered for treatment. However, when a drug having an antimicrobial activity is administered to a patient, the drug having an antimicrobial activity attacks intestinal bacteria, such as so-called nonpathogenic bifidobacteria, which do not cause an infectious disease and which naturally colonize the body, in addition to specific bacteria or viruses causing the infectious disease. Thus, side effects such as diarrhea may develop as a result of infection with other pathogens. In addition, due to repeated administration or long-term administration of the same drug having antimicrobial activity, pathogenic bacteria, fungi and viruses causing infectious diseases can gradually acquire tolerance to the drug, and the antimicrobial effect may occasionally decline. Treatment of infectious diseases becomes difficult if the pathogen gains drug resistance. Therefore, development of a substance capable of preventing or treating infectious diseases based on a new mechanism is expected.
It has long been the basic knowledge that organisms exert immune functions to prevent the invasion and colonization by pathogenic bacteria, fungi and viruses that cause infectious diseases. For example, retinoic acid, which is known to be an indicator of immune function, is involved in the differentiation of regulatory T cells, cell migration, and induction of IgA production. In addition, retinoic acid has been used to treat various skin conditions such as acne, wrinkles, psoriasis, age spots and darkness (statins) (patent document 1).
Reference list
Patent document
Patent document 1: JP patent publication No. 10-036249A (1998)
Summary of The Invention
Problems to be solved by the invention
The object of the present invention is to provide an agent capable of inducing the body's own biodefense function in vivo based on a novel mechanism.
Means for solving the problems
In view of the above object, the inventors of the present invention have conducted intensive studies. As a result, they have obtained the following findings. Specifically, the inventors of the present invention have found that the intake and/or action of a certain type of lactic acid bacteria enhances the gene expression of retinal dehydrogenase, which is an indicator of immune function, and thereby promotes the production of retinoic acid, which is also an indicator of immune function, which can solve the above-mentioned problems. The lactic acid bacteria used as an active ingredient in the present invention have been consumed for a long period of time in the form of, for example, fermented foods. Therefore, agents for producing retinoic acid and agents for enhancing immune function are highly safe and have low risk of side effects.
The agent for producing retinoic acid or the agent for enhancing immune function of the present invention is ingested by a subject and/or acts on the subject, thereby more strongly inducing the production of retinoic acid from retinol using retinol dehydrogenase in vivo and thus enhancing immune function. According to the present invention, for example, a preventive and/or therapeutic effect on an infectious disease caused by opportunistic pathogens, an infectious disease caused by pathogenic bacteria or fungi, a Helicobacter pylori (Helicobacter pylori) infection, an infectious disease caused by viruses, bacterial translocation, chronic intestinal mucositis, a change in the intestinal flora balance (for example, disruption of the intestinal flora balance), a disease caused by the above-mentioned inflammation, an inflammatory bowel disease such as crohn's disease and ulcerative colitis, severe inflammation, and allergic symptoms can be expected. Furthermore, the promotion of retinoic acid production by lactic acid bacteria according to the present invention can be expected to result in reduction of infection risk, inhibition of inflammation and antiallergic effect in infants and children with immature immune function, elderly people with reduced immune function and patients with various diseases. Such effects can be expected according to the present invention, in particular for elderly humans or elderly mammals.
Specifically, the present invention includes the following aspects:
[1] an agent for producing retinoic acid, comprising lactic acid bacteria as an active ingredient.
[2] The agent for producing retinoic acid according to [1], wherein the lactic acid bacterium is a bacterium of the genus Lactobacillus.
[3] The agent for producing retinoic acid according to [1] or [2], wherein the lactic acid bacterium is Lactobacillus delbrueckii subsp.
[4] The agent for producing retinoic acid according to any one of [1] to [3], wherein the lactic acid bacterium is Lactobacillus delbrueckii subsp bulgaricus strain OLL1073R-1 (accession number FERM BP-10741).
[5] The agent for producing retinoic acid according to any one of [1] to [4], wherein the lactic acid bacterium is present in 100,000,000 or more cells per unit package.
[6] An agent for enhancing immune function, which comprises the agent for producing retinoic acid according to any one of [1] to [5 ].
[7] An agent for enhancing immune function, which comprises a lactic acid bacterium as an active ingredient.
[8] The agent for enhancing immune function according to [7], wherein the lactic acid bacterium belongs to the genus Lactobacillus.
[9] The agent for enhancing immune function according to [7] or [8], wherein the lactic acid bacterium is present in 100,000,000 or more cells per unit package.
[10] The agent for enhancing immune function according to any one of [7] to [9], wherein the lactic acid bacterium is Lactobacillus delbrueckii subspecies bulgaricus OLL1073R-1(FERM BP-10741).
This specification includes the disclosure in japanese patent application No. 2014-.
Effects of the invention
The present invention can provide an agent capable of strongly inducing the body's own biological defense function by promoting the production of retinoic acid.
Embodiments for carrying out the invention
The present invention will be described in more detail below, but the present invention is not limited to the embodiments described below.
In the present invention, the term "lactic acid bacteria" refers collectively to taxonomically recognized lactic acid bacteria or also to all bacteria closely related thereto, such as bifidobacteria, without being limited to any species or strain. In the present invention, any lactic acid bacterium having an activity of enhancing retinoic acid production, such as an activity of enhancing expression of a retinal dehydrogenase gene, may be used. Although lactic acid bacteria can be classified as either plant-derived or animal-derived lactic acid bacteria, either plant-derived or animal-derived lactic acid bacteria can be used in the present invention. In particular, the lactic acid bacteria used in the present invention are preferably lactic acid bacteria of the genus lactobacillus (lactobacillus bacteria), and, for example, one or more strains selected from lactic acid bacteria of the genus lactobacillus are preferable because they have a history of being ingested in the form of fermented milk such as yogurt. Also, the lactic acid bacterium of the genus Lactobacillus used in the present invention is more preferably Lactobacillus delbrueckii ssp (bulgaricus), which is called Lactobacillus bulgaricus (Lactobacillus bulgaricus), more preferably and further preferably Lactobacillus bulgaricus strain OLL1073R-1 (accession number FERM BP-10741). Lactobacillus delbrueckii subspecies bulgaricus strain OLL1073R-1 was deposited internationally under the terms of the Budapest treaty at 22.2.1999 (date of original deposit) under accession number FERM BP-10741 at the International patent organism depositary, the national institute of evaluation and technology, International depository for the patent organism (NITE-IPOD) (2-5-8,120 th house, Gentianjin, Japan, Qianye county). This strain was transferred from domestic collection to international collection at 29.11.2006.
The lactic acid bacteria used in the present invention may be viable or dead cells. Also, the lactic acid bacteria used in the present invention may be frozen or lyophilized cells. Further, the lactic acid bacteria used in the present invention may be lactic acid bacteria cells alone, or they may be in the form of containing other components (e.g., cryoprotectant, lyoprotectant, or the like) in addition to the lactic acid bacteria cells, or they may be dispersed in different media such as water or starch that have been used as a medicine or food material.
The lactic acid bacteria used in the present invention may include any substance derived from bacterial cells or metabolites thereof, such as disrupted cells or cell metabolites produced by culture or fermentation, as well as bacterial cells themselves (viable or dead cells), which can be obtained by conventional techniques. For example, lactic acid bacteria such as lactobacillus delbrueckii subsp bulgaricus strain OLL1073R-1 (accession number FERM BP-10741) produce Exopolysaccharides (EPS) during culture. The use of lactic acid bacteria or a culture of lactic acid bacteria comprising exopolysaccharides produced is within the scope of the use of lactic acid bacteria according to the invention.
The present invention provides an agent for producing retinoic acid (or an agent for promoting the production of retinoic acid), which comprises the lactic acid bacterium as described above as an active ingredient. In a preferred embodiment, the lactic acid bacterium (lactic acid bacterium having activity of enhancing retinoic acid production) and the agent for producing retinoic acid comprising the lactic acid bacterium as an active ingredient used in the present invention can enhance expression of a retinal dehydrogenase gene in an animal cell, thereby promoting conversion of retinal to retinoic acid (production of retinoic acid) catalyzed by the retinal dehydrogenase in the animal cell. Whether or not the lactic acid bacterium used in the present invention has an activity of enhancing the expression of a retinal dehydrogenase gene can be determined as described in the following examples. That is, animal cells (preferably mesenteric lymph node cells or dendritic cells derived from mesenteric lymph node cells) are cultured in the presence of a lactic acid bacterium for a given period of time (e.g., 24 hours at 37 ℃), then mRNA is extracted from the cells, mRNA of the retinal dehydrogenase (e.g., RALDH2) gene in the animal cells is quantified using real-time RT-PCR, and it is determined whether the mRNA level is significantly increased relative to the mRNA level of a control (a sample obtained by culturing the animal cells in the absence of the lactic acid bacterium). The mRNA level of the retinal dehydrogenase gene can be increased by generally 20% or more, preferably 40% or more, using the agent for producing retinoic acid according to the present invention, as compared to a control.
The agent for producing retinoic acid according to the present invention can impart various physiological activities to an animal (preferably a mammal) or a cell thereof by promoting retinoic acid production. For example, it is known that retinoic acid confers homing specificity to small intestine tissue to T cells or B cells in intestine-associated lymphoid organs, thereby inducing distribution of cells (lymphocytes) in the small intestine tissue, and that retinoic acid induces production of IgA, which is important for defense against infectious diseases in intestine-associated lymphoid organs. Thus, retinoic acid is considered an indicator of the immune function of the intestinal immune system. Retinoic acid is also known to inhibit the induction of pro-inflammatory T cell differentiation and promote the induction of anti-inflammatory regulatory T cell differentiation, thereby inhibiting inflammatory responses such as autoimmune responses. Therefore, the agent for producing retinoic acid according to the present invention strengthens defense against infectious diseases to exert a preventive effect against infectious diseases, and it can exert a preventive, therapeutic, or ameliorating effect against inflammatory diseases such as autoimmune diseases by suppressing inflammatory responses. Examples of infectious diseases include those caused by opportunistic or pathogenic bacteria, fungi or viruses. Examples of inflammatory diseases, such as autoimmune diseases, include, but are not limited to, inflammatory bowel diseases, such as crohn's disease and ulcerative colitis, and allergic symptoms. The agent for producing retinoic acid according to the present invention can be used to improve various skin conditions such as acne, wrinkles, psoriasis, age spots and darkness by promoting retinoic acid production in the skin. A variety of other physiological activities of retinoic acid are also known. The subject to be administered with the agent for producing retinoic acid according to the present invention may be an animal, preferably a mammal, and particularly preferably an elderly human or an elderly mammal. The agent for producing retinoic acid according to the present invention can be used for treating cells or tissues (e.g., intestine-associated lymphoid organs or dendritic cells thereof, or skin cells such as epidermal cells or dermal cells) of animals such as mammals for the purpose of promoting retinoic acid production in the cells.
The lactic acid bacteria used in the present invention are capable of enhancing immune function based on increased amounts of retinoic acid produced in gut-associated lymphoid organs and particularly dendritic cells thereof. The present invention also provides an agent for enhancing immune function, which comprises an agent for producing retinoic acid according to the present invention. Further, the present invention provides an agent for enhancing immune function, which comprises the lactic acid bacterium as described above.
The agent for enhancing immune function according to the present invention refers to an agent capable of inducing a gene or the like in vivo by the intake of the agent by an organism such as a mammal including a human and/or the action of the agent on the organism, thereby producing an immune indicator derived from the gene. In particular, the agent for enhancing immune function according to the present invention can enhance the expression of retinol dehydrogenase gene, thereby improving immune function of organisms such as mammals. In the present invention, the term "ingestion" refers to the introduction of an active ingredient into the gastrointestinal tract within an organism, including a human. In the present invention, "administration" includes ingestion and parenteral application (e.g., topical application to the skin and the like). The mode of administration is not particularly limited, and includes any known mode of administration, such as oral, tube, enteral, transdermal (e.g., wipe, patch, or spray), and subcutaneous administration.
Examples of the improvement of immune function according to the present invention include prevention and/or treatment of infectious diseases caused by opportunistic pathogens, infectious diseases caused by pathogenic bacteria or fungi, infection with helicobacter pylori, infectious diseases caused by viruses, bacterial translocation, chronic intestinal mucositis, alteration of intestinal flora balance (e.g., disruption of intestinal flora balance), diseases caused by these inflammations, and inflammatory bowel diseases such as crohn's disease and ulcerative colitis. Examples also include the prevention and/or treatment of severe inflammation and allergic symptoms by inducing regulatory T cell differentiation. In addition, examples of the improvement of immune function also include reduction of infection risk, inhibition of inflammation and anti-allergic effect in infants and children having immature immune function, elderly persons having reduced immune function and patients suffering from various diseases. In particular, the subject to be administered with the agent for enhancing immune function according to the present invention is preferably an elderly human or an elderly mammal.
The effect of enhancing immune function according to the present invention can be evaluated by using, as an indicator, an increase in the production amount of any substance that serves as an indicator of immune function in vivo (i.e., an immunological indicator). For example, retinoic acid is involved in the differentiation of regulatory T cells, cell migration, and induction of IgA production, and whether or not immune function is enhanced can be evaluated by using the reactivity causing retinoic acid production in vivo as an indicator. The immunological indicator may be retinoic acid, or it may be a so-called retinoic acid precursor, such as retinal, which is activated at its specific site by hydrolysis. The immune indicator can be a different substance that induces the production of an immune indicator such as retinoic acid, for example, a protein that catalyzes the synthesis of an immune indicator such as retinoic acid or mRNA of a gene encoding the protein. That is, the induction of the production of the immune indicator of the present invention may be the increased expression of a gene encoding a protein that is an immune indicator in vivo, thereby expressing the immune indicator, or the production of another immune indicator by the activity of the immune indicator. Although there is no particular limitation on the gene encoding the immune indicator, an example of a preferred gene is a retinal dehydrogenase (e.g., RALDH2) gene.
The present invention also provides an agent for preventing and/or treating various diseases associated with a decrease or deficiency of retinoic acid. In addition, the present invention provides a method for preventing and/or treating various diseases associated with a reduction or absence of retinoic acid using an agent for producing retinoic acid. Examples of such various diseases include any disease, symptom and syndrome associated with a reduction or absence of retinoic acid, including infectious diseases caused by opportunistic pathogens, infectious diseases caused by pathogenic bacteria or fungi, helicobacter pylori infection, infectious diseases caused by viruses, bacterial translocation, long-term intestinal mucositis, alterations in the intestinal flora balance (e.g., disruption of the intestinal flora balance), diseases caused by such inflammation, inflammatory bowel diseases such as crohn's disease and ulcerative colitis, severe inflammation and allergic symptoms; and any conditions suspected of being diseases, symptoms and syndromes, whether before or after the date and/or priority date of the present invention. In addition, the present invention provides a method of whitening, which comprises parenterally administering an agent for producing retinoic acid according to the present invention to skin or an analog thereof (a prophylactic, therapeutic or cosmetic method) based on the whitening effect disclosed in, for example, patent document 1. The subject to be administered with the agent for producing retinoic acid according to the present invention may be an animal, such as a mammal, and particularly preferably an elderly human or an elderly mammal.
The agent for producing retinoic acid and the agent for enhancing immune function according to the present invention may comprise a material fermented with the aforementioned lactic acid bacterium (lactic acid bacterium having activity of enhancing retinoic acid production). The material fermented with the aforementioned lactic acid bacteria is not particularly limited, provided that the material is prepared by fermenting a material that has been ingested by mammals including humans with lactic acid bacteria. Examples of the material specifically include materials prepared by fermenting milk, soybean, red bean, grain, vegetable, meat, fish, or any mixture thereof with the aforementioned lactic acid bacteria.
Examples of materials prepared by fermenting milk with lactic acid bacteria are materials obtained as follows: raw milk, dairy product and raw water are combined to obtain milk having a fat content of 3.0% by weight and a non-fat solid content of 9.2% by weight, which is optionally homogenized to adjust milk fat globules as needed, and then the resultant is heat-sterilized under aseptic conditions equivalent to holding at 65 ℃ for 30 minutes, cooled to 40 ℃ to 45 ℃, added as lactobacillus lactic acid bacteria a mixed starter comprising lactobacillus delbrueckii subspecies bulgaricus (e.g., lactobacillus delbrueckii subspecies bulgaricus strain OLL1073R-1) and streptococcus salivarius subspecies thermophilus (Steptococcus salivariaussubsp. thermophiles), fermented at 40 ℃ to 45 ℃ for 2 to 12 hours, and the acidity of the lactic acid is adjusted to 0.6% to 1.2% by weight. In this case, the strains of lactobacillus delbrueckii subsp bulgaricus and streptococcus salivarius subsp thermophilus are not particularly limited, and lactic acid bacteria (e.g., lactobacillus, bifidobacterium, Lactococcus (Lactococcus) or Leuconostoc (Leuconostoc)) and other microorganisms, materials or additives useful for fermentation or health may be optionally added in addition to the two bacterial species. The term "raw milk (milk)" as used herein refers to, but is not limited to, so-called fresh or raw milk from cows, goats, sheep, buffalos, etc., or reconstituted milk having the same composition as fresh or raw milk; and may also be milk prepared by adding (or enriching) milk fat and/or non-fat solids (e.g. milk protein, lactose or ash), low or non-fat milk prepared by removing milk fat, or lactose-removed or lactose-degraded milk for human individuals with low tolerance to lactose. In addition, the raw milk may also be demineralized milk prepared for limiting the intake of minerals such as sodium and/or for regulating the salty taste perceived during intake, or milk enriched with calcium prepared for patients in need of intake of minerals such as calcium. When such materials fermented with lactic acid bacteria are used, the agent for producing retinoic acid and the agent for enhancing immune function according to the present invention may contain other lactic acid bacteria such as streptococcal bacteria in addition to the aforementioned lactic acid bacteria having an activity of enhancing retinoic acid production.
There is no particular limitation on the number of lactic acid bacteria contained in the agent for producing retinoic acid and the agent for enhancing immune function according to the present invention, provided that the agent contains lactic acid bacteria. In the agent, the lactic acid bacterium is preferably present in 100,000,000 or more cells/unit pack, more preferably 500,000,000 or more cells/unit pack, and further preferably 1,000,000,000 or more cells/unit pack. Although it is expected that the effect of the present invention becomes stronger as the number of lactic acid bacteria increases, a typical upper limit of the number of lactic acid bacteria is 10,000,000,000,000 cells from the viewpoint of the growth of general lactic acid bacteria.
There is no particular limitation on the weight per unit package of the agent for producing retinoic acid and the agent for enhancing immune function according to the present invention. When the lactic acid bacterium is present at 100,000,000 or more cells per 1g of the agent for producing retinoic acid and the agent for enhancing immune function, the weight of the agent for producing retinoic acid and the agent for enhancing immune function is preferably 10g to 500g per unit package, more preferably 25g to 250g per unit package, further preferably 50g to 200g per unit package, and still further preferably 75g to 150g per unit package. The term "unit package" as used herein refers not only to the package, box or container itself, but also to a unit dose unit package or a daily dose unit package in such package, box or container.
When the agent for producing retinoic acid or the agent for enhancing immune function according to the present invention is administered orally, for example, lactic acid bacteria or a material fermented with lactic acid bacteria may be administered (or ingested) in an unaltered form. Alternatively, the lactic acid bacteria or material may be administered (or ingested) in the form of, for example, a tablet, granule, powder preparation, capsule or powder. The agent for producing retinoic acid and the agent for enhancing immune function according to the present invention may be parenterally administered to the skin or the like (for example, via transdermal application by rubbing, patch or spray) in the form of a solution, emulsion, gel, powder or cream.
The immune function-enhancing action of the present invention is exerted in the gastrointestinal tract in vivo after intake of the lactic acid bacterium of the present invention. Examples of the gastrointestinal tract include a group of organs including the mouth, pharynx, esophagus, stomach, duodenum, small intestine, large intestine, cecum, and up to the anus. Although representative portions of the gastrointestinal tract are enumerated herein, for example, any portion of the gastrointestinal tract known or within the purview of the ordinary skill in the art, such as the colon (lower portion of the small intestine), ileum, jejunum (upper portion of the small intestine), gastrointestinal tract of the upper abdomen, gastrointestinal tract of the lower abdomen, upper large intestine, and lower large intestine also fall within the scope of the "gastrointestinal tract" according to the present invention.
After the lactobacillus of the present invention is allowed to act (e.g. by brushing, spraying or injection), the immune function-enhancing action according to the present invention may be exerted at different sites in vivo and in vitro. Examples of the sites in and out of the body include the skin, hair, eyeball, nasal mucosa, external ear, middle ear, nail, and the surfaces of various organs.
The agent for enhancing immune function according to the present invention exerts an effect of enhancing immune function on various animals, and preferably mammals, including humans. The present invention therefore provides a method for treating and/or preventing various diseases, which comprises causing an animal to ingest or administering an agent for enhancing immune function to the animal. In the present invention, the mammal may be any known domestic animal, pet animal, ornamental animal, wild animal or the like classified as a mammal. Examples include humans, cows, pigs, sheep, dolphins, whales, tigers, lions, leopards, river horses, giraffes, camels, alpacas, dogs, cats, monkeys, foxes, raccoons, bears, squirrels, white bears, lions, pandas, boars, deer, horses, oranges, and kangaroos. The agent for enhancing immune function of the present invention can also be used to enhance immune function of animals having gastrointestinal tract other than mammals, such as insects, reptiles, birds, fish, amphibians, and mollusks. Various diseases include infectious diseases caused by opportunistic pathogens, infectious diseases caused by pathogenic bacteria or fungi, infection by helicobacter pylori, bacterial translocation, long-term intestinal mucositis, alteration of the intestinal flora balance (e.g., disruption of the intestinal flora balance), diseases caused by these inflammations, inflammatory bowel diseases, such as crohn's disease and ulcerative colitis, severe infections, and allergic symptoms, although they are not particularly limited as long as these diseases can be treated, prevented, or ameliorated by inducing the production of an immunological indicator such as retinoic acid.
Examples
The present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples.
BALB/c mice (aged mice) from 12 months to 13 months of age were used as subjects. Mesenteric lymph node cells and CD11c + dendritic cells derived from mesenteric lymph nodes were removed from the small intestine of mice.
The taken mesenteric lymph node cells and CD11c + dendritic cells derived from the mesenteric lymph node were co-cultured with Lactobacillus delbrueckii subspecies bulgaricus strain OLL1073R-1 (accession number FERM BP-10741), respectively, at 37 ℃ in a 96-well plate on which dead cells of strain OLL1073R-1 had been inoculated at 100. mu.g cell weight/ml. Mesenteric lymph node cells were seeded at 500,000 cells/well and CD11c + dendritic cells derived from mesenteric lymph nodes were seeded at 100,000 cells/well. After 24 hours from the completion of the co-culture, mesenteric lymph node cells or CD11c + dendritic cells were recovered from the resulting culture, mRNA was extracted from the recovered cells according to a conventional technique, and the expression level of mRNA of the retinal dehydrogenase RALDH2(Aldh1a2) gene (GenBank accession No. NM-009022) was measured by a real-time RT-PCR method.
As a control, the culture and the measurement of the gene expression level were carried out in the same manner as described above, except that Lactobacillus delbrueckii subsp. bulgaricus strain OLL1073R-1 (accession number FERM BP-10741) was not inoculated.
The ratio of the gene expression levels of these cells relative to the gene expression level of the control set to 1.0 was determined on the basis of the expression level of the RALDH2 gene obtained by co-culture with lactic acid bacteria.
As a result, the mRNA expression level of RALDH2 gene in mesenteric lymph node cells increased to 3.05. + -. 0.56 when cocultured with Lactobacillus delbrueckii subsp.bulgaricus strain OLL1073R-1 (accession number FERM BP-10741) compared to the control (1.00. + -. 0.52; values after ". + -" in the calculated values represent standard deviations (S.D.)). Also, when co-cultured with Lactobacillus delbrueckii subspecies bulgaricus strain OLL1073R-1 (accession number FERM BP-10741), the mRNA expression level of RALDH2 gene in CD11c + dendritic cells derived from mesenteric lymph nodes increased to 7.91. + -. 1.43 compared to the control (1.00. + -. 0.62). It should be noted that the values after "±" in the calculated values represent the standard deviation (s.d.).
The results demonstrated that Lactobacillus delbrueckii subspecies bulgaricus strain OLL1073R-1 (accession number FERM BP-10741) significantly enhanced the expression level of the retinaldehyde dehydrogenase RALDH2 gene in cells. Retinoic acid is produced by oxidation of retinal, and retinal dehydrogenase RALDH2 catalyzes the retinal oxidation reaction. Thus, enhancement of expression of the retinal dehydrogenase gene can promote the production of retinoic acid in cells.
The results demonstrate that administration of lactobacillus delbrueckii subsp bulgaricus strain OLL1073R-1 can cause an increase in the amount of retinoic acid in vivo which can serve as an indicator of enhanced immune function.
Industrial applicability
The agent for producing retinoic acid according to the present invention may be used to increase the production of retinoic acid in a cell. The present invention can provide a novel agent for enhancing immune function, which induces the human self-defense function with greater safety and fewer side effects. Ingestion and action of the agent for producing retinoic acid and the agent for enhancing immune function according to the present invention can induce retinoic acid as an immunological indicator in vivo. Thus, the agent can be used to enhance defense against various infectious diseases and treatment, prevention or amelioration of inflammatory reactions.
All publications, patents, and patent applications cited herein are incorporated by reference in their entirety.
Claims (2)
1. Use of a lactic acid bacterium in the manufacture of an agent for producing retinoic acid, wherein said lactic acid bacterium is lactobacillus delbrueckii subsp bulgaricus strain OLL1073R-1 (accession number FERM BP-10741), and wherein said agent promotes the production of retinoic acid in gut-associated lymphoid organs, thereby enhancing the immune function of the gut immune system.
2. The use according to claim 1, wherein the lactic acid bacteria are present in a 100,000,000 or more cells per unit package.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2014051065 | 2014-03-14 | ||
| JP2014-051065 | 2014-03-14 | ||
| PCT/JP2015/057560 WO2015137501A1 (en) | 2014-03-14 | 2015-03-13 | Retinoic-acid-producing agent |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN106102755A CN106102755A (en) | 2016-11-09 |
| CN106102755B true CN106102755B (en) | 2020-02-21 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201580013813.7A Active CN106102755B (en) | 2014-03-14 | 2015-03-13 | Agent for producing retinoic acid |
Country Status (5)
| Country | Link |
|---|---|
| JP (1) | JP6543614B2 (en) |
| CN (1) | CN106102755B (en) |
| HK (1) | HK1226296A1 (en) |
| SG (1) | SG11201607674SA (en) |
| WO (1) | WO2015137501A1 (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP6892079B2 (en) * | 2017-06-29 | 2021-06-18 | 京都府公立大学法人 | Regulatory T cell inducers, adjuvants and food compositions |
| CN116096389A (en) * | 2020-10-07 | 2023-05-09 | 株式会社资生堂 | RALDH2 expression enhancer |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102647991A (en) * | 2009-11-25 | 2012-08-22 | 株式会社明治 | Antiviral agent and food/beverage composition |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| JP5571941B2 (en) * | 2009-12-14 | 2014-08-13 | 雪印メグミルク株式会社 | Regulatory T cell increasing agent |
-
2015
- 2015-03-13 CN CN201580013813.7A patent/CN106102755B/en active Active
- 2015-03-13 JP JP2016507856A patent/JP6543614B2/en active Active
- 2015-03-13 WO PCT/JP2015/057560 patent/WO2015137501A1/en active Application Filing
- 2015-03-13 SG SG11201607674SA patent/SG11201607674SA/en unknown
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102647991A (en) * | 2009-11-25 | 2012-08-22 | 株式会社明治 | Antiviral agent and food/beverage composition |
Non-Patent Citations (2)
| Title |
|---|
| Immunomodulatory Effects of Polysaccharides Produced by Lactobacillus delbrueckii ssp. bulgaricus OLL1073R-1;S. Makino等;《Journal of Dairy Science》;20061231;第89卷;第2873-2881页 * |
| Oral supplementation with Lactobacillus delbrueckiisubsp. bulgaricus 8481 enhances systemic immunity in elderly subjects;Marco Antonio Moro-García等;《AGE》;20131231;第35卷;第1311-1326页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2015137501A1 (en) | 2015-09-17 |
| SG11201607674SA (en) | 2016-11-29 |
| JP6543614B2 (en) | 2019-07-10 |
| CN106102755A (en) | 2016-11-09 |
| HK1226296A1 (en) | 2017-09-29 |
| JPWO2015137501A1 (en) | 2017-04-06 |
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