WO2016144139A2 - Composition pour prévenir ou traiter des maladies inflammatoires, comprenant des vésicules extracellulaires dérivées de bactéries d'acide lactique comme principes actifs - Google Patents

Composition pour prévenir ou traiter des maladies inflammatoires, comprenant des vésicules extracellulaires dérivées de bactéries d'acide lactique comme principes actifs Download PDF

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WO2016144139A2
WO2016144139A2 PCT/KR2016/002473 KR2016002473W WO2016144139A2 WO 2016144139 A2 WO2016144139 A2 WO 2016144139A2 KR 2016002473 W KR2016002473 W KR 2016002473W WO 2016144139 A2 WO2016144139 A2 WO 2016144139A2
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extracellular vesicles
lactic acid
acid bacteria
bacteria
composition
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PCT/KR2016/002473
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Korean (ko)
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WO2016144139A3 (fr
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김윤근
편복양
김민혜
최준표
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주식회사 엠디헬스케어
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Priority claimed from KR1020160029069A external-priority patent/KR20160110232A/ko
Application filed by 주식회사 엠디헬스케어 filed Critical 주식회사 엠디헬스케어
Priority to CN201680014982.7A priority Critical patent/CN107750161B/zh
Priority to EP16762026.9A priority patent/EP3269378B1/fr
Priority to JP2017547484A priority patent/JP6700297B2/ja
Priority to US15/556,953 priority patent/US10406184B2/en
Publication of WO2016144139A2 publication Critical patent/WO2016144139A2/fr
Publication of WO2016144139A3 publication Critical patent/WO2016144139A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • A61K35/741—Probiotics
    • A61K35/744—Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
    • A61K35/747—Lactobacilli, e.g. L. acidophilus or L. brevis

Definitions

  • the present invention relates to a composition for the prevention, improvement or treatment of inflammatory diseases, including lactic acid bacteria-derived extracellular vesicles as an active ingredient, and a method for diagnosing atopic dermatitis.
  • Inflammation is a defense mechanism that occurs in the body when toxins, etc. enter the body from outside, and acute inflammation occurs due to short-term invasion of bacteria and fungi in the environment, and causes substances such as microorganisms and allergens present in the environment. If this body is continuously absorbed, chronic inflammation will occur.
  • the importance of infectious agents has been highlighted in the development of chronic inflammatory diseases that were recognized as non-infectious agents.
  • the bacterium Helicobacter bacterium which is known to be a symbiotic stomach, is found to be an important causative factor for the development of gastritis and gastric cancer. It has recently been in the spotlight as a causative factor.
  • Atopic dermatitis is a skin disease most commonly seen in infants and young children, and is also the first sign of atopic march that leads to asthma or allergic rhinitis.
  • atopic dermatitis is chronic chronic itch and chronic skin inflammation, which is a chronic inflammatory disease that physically and mentally decreases not only the patient but also the quality of life of the family. It is increasing.
  • ISAAC International Study of Allergy and Asthma in Childhood
  • Allergic diseases such as atopic dermatitis, are caused by a combination of genetic and environmental factors. Recent trends are insufficient to explain genetic factors alone. Although the incidence of allergic diseases varies from country to country, it reflects the differences between ethnic groups, the importance of genetic factors, but the consequences, such as a sudden increase in allergic diseases after unification in former East Germany, are also environmental factors. It is important.
  • Staphylococcus aureus is detected in 90% of patients with atopic dermatitis and also in skin lesions without any obvious signs of infection.Toxins of Staphylococcus aureus act as superantigens, increasing the allergic immune response and itching on the skin. It is known to play a role in worsening and lesions.
  • atopic dermatitis The prognosis of atopic dermatitis varies depending on the patient's skin condition, irritation factors, allergic diseases, and bacterial infections. In general, atopic dermatitis tends to improve at a young age with severe symptoms and chronic lesions that continue to increase with age. However, some reports show that about 40% of patients improve around 5 years of age, and there is controversy about the reasons for the improvement.
  • the most representative methods of treatment of atopic dermatitis include the application of topical and systemic steroids or topical immunosuppressants simultaneously with the elimination of causes when aggravated by various causes with the proper use of moisturizers.
  • recent studies suggest that in addition to these factors, taking lactic acid bacteria or a culture of lactic acid bacteria can reduce the degree of atopic dermatitis.
  • Asthma and chronic obstructive pulmonary disease are characterized by airway obstruction caused by chronic airway inflammation, which is characterized by reversible airway obstruction and COPD irreversible airway obstruction.
  • Hypersensitivity reactions by house dust mite-derived allergens as a causative agent of asthma are known to be important for the pathogenesis of eosinophilic asthma, and recently, studies of the importance of bacterial origin in the development of neutrophil inflammation, a characteristic pathology of severe asthma and COPD The results are in the spotlight. In particular, it has been reported that extracellular vesicles derived from pathogenic bacteria present in indoor dust are important for the development of asthma and COPD.
  • symbiotic bacteria and bacteria-derived substances in the nasal cavity play an important role in the pathogenesis of chronic rhinosinusitis, which is due to the decrease in the diversity of the bacterial flora in the nasal cavity and the increase of certain pathogens, especially staphylococci, in the development of chronic sinusitis. It is reported to be important.
  • Extracellular vesicles or outer membrane vesicles derived from gram-negative bacteria possess not only lipopolysaccharides but also toxic proteins and DNA and RNA of bacteria, and gram-positive bacteria.
  • OMVs outer membrane vesicles
  • extracellular vesicles derived from also contain peptidoglycan and lipoteichoic acid, which are the cell wall components of bacteria.
  • Typical Gram-positive bacteria of extracellular vesicles secreted from Staphylococcus aureus was atopic dermatitis, chronic sinusitis, asthma hojung configuration, the major risk factors for COPD to be a recent report, a Pseudomonas aeruginosa (Pseudomonas pathogenic Gram-negative bacteria It has been reported that a large amount of extracellular vesicles derived from aeruginosa ) and Acinetobacter bacumannii is present in indoor dust, and is an important cause of asthma, COPD, and lung cancer when inhaled.
  • Metagenomics also called environmental genomics, is an analysis of metagenomic data obtained from samples taken from the environment. Recently, a method based on 16S ribosomal RNA (16S rRNA) sequences has been possible to list the bacterial composition of the human microflora, and 16S ribosomal RNA is sequenced using the 454FLX titanium platform. Although studies on metagenomes analyzed in patient samples have been conducted, it is not well known that bacteria-derived extracellular vesicles are present in serum or urine. One metagenome analysis study was not performed.
  • inflammatory diseases such as atopic dermatitis, asthma, COPD, chronic rhinitis, chronic sinusitis, and sepsis based on the results of metagenomic analysis using DNA from extracellular vesicles isolated from the serum or urine of patients. It has not been used for the prevention or treatment of the situation.
  • the present inventors conducted a metagenomic analysis using DNA of extracellular vesicles isolated from urine of atopic dermatitis patients and normal people, and significantly increased lactic acid bacteria-derived extracellular vesicles from urine of normal people compared to atopic dermatitis patients.
  • the present invention is confirmed that the lactic acid bacteria-derived extracellular vesicles effectively inhibit the inflammatory response induced by S. aureus and P. aeruginosa- derived extracellular vesicles, which are the main causes of inflammatory diseases. Completed.
  • an object of the present invention is to provide a composition for the prevention, improvement or treatment of inflammatory diseases, including lactic acid bacteria-derived extracellular vesicles as an active ingredient.
  • Another object of the present invention is to provide a method for diagnosing atopic dermatitis.
  • the present invention provides a pharmaceutical composition for the prevention or treatment of inflammatory diseases, including the lactic acid bacteria-derived extracellular vesicles as an active ingredient.
  • the present invention provides a cosmetic composition for improving inflammatory diseases, including the lactic acid bacteria-derived extracellular vesicles as an active ingredient.
  • the present invention provides a health functional food composition for improving inflammatory diseases, including the lactic acid bacteria-derived extracellular vesicles as an active ingredient.
  • the present invention also provides an inhalant composition for preventing or treating inflammatory diseases, comprising an extracellular vesicle derived from lactic acid bacteria as an active ingredient.
  • the lactic acid bacteria may be Lactobacillales ( Lactobacillales ) neck bacteria.
  • the Lactobacillales neck bacteria may be Lactococcus , Lactobacillus , or Leuconostoc bacteria.
  • the bacteria of the genus Lactobacillus may be Lactobacillus plantarum ( Lactobacillus plantarum ).
  • the extracellular vesicles may have an average diameter of 10 ⁇ 300 nm.
  • the extracellular vesicles are characterized in that separated from the lactic acid bacteria culture.
  • the extracellular vesicles are characterized in that the lactic acid bacteria are secreted naturally or artificially.
  • the inflammatory disease may be a disease selected from the group consisting of atopic dermatitis, chronic rhinitis, chronic sinusitis, asthma, chronic obstructive pulmonary disease (COPD), and sepsis.
  • atopic dermatitis chronic rhinitis, chronic sinusitis, asthma, chronic obstructive pulmonary disease (COPD), and sepsis.
  • COPD chronic obstructive pulmonary disease
  • the present invention also provides a method for diagnosing atopic dermatitis, which comprises the following steps.
  • the gene may be DNA or RNA.
  • the clinical sample may be urine or blood.
  • the sequencing may be performed through polymerase chain reaction (PCR).
  • PCR polymerase chain reaction
  • the present invention also provides a method for preventing or treating inflammatory diseases, comprising administering to a subject a composition comprising a lactic acid bacteria-derived extracellular vesicles as an active ingredient.
  • the present invention also provides a prophylaxis or treatment for inflammatory diseases of lactic acid bacteria-derived extracellular vesicles.
  • the present invention also provides a diagnostic use for atopic dermatitis of lactic acid bacteria-derived extracellular vesicles.
  • the present inventors found that the extracellular vesicles derived from lactic acid bacteria are significantly more distributed in normal subjects than in patients with atopic dermatitis. It was confirmed through in vitro and in vivo experiments that the effective inhibition, the composition comprising the lactic acid bacteria-derived extracellular vesicles as an active ingredient is atopic dermatitis, chronic rhinitis, chronic sinusitis, asthma, chronic obstructive pulmonary disease, sepsis, etc. It is expected to be useful in the development of medicines, cosmetics, or dietary supplements to prevent, improve, or treat inflammatory diseases.
  • Figure 1 shows the culture of intestinal bacteria Pseudomonas Cedrina ( P. cedrina ) and Pseudomonas panacis ( P. panacis ) in vitro and then separate the extracellular vesicles from the culture medium, respectively, and extracellular vesicles derived from P. cedrina and P. panacis, respectively . (EVs) were observed with an electron microscope.
  • Pseudomonas Sedrina P. cedrina
  • Pseudomonas waves System P. panacis
  • Sedrina Pseudomonas P. cedrina
  • Pseudomonas waves System P. panacis
  • FIG. 5 shows that P. panacis bacteria and P. panacis- derived extracellular vesicles (EVs) are orally administered to mice, and blood and heart 12 hours after administration. , Lung, liver, and kidney were extracted to photograph the distribution of the bacteria and extracellular vesicles (EVs).
  • EVs extracellular vesicles
  • Figure 6 shows that the extracellular vesicles in the intestinal capillaries 10 minutes after administration of P. panacis- derived extracellular vesicles (EV) directly in the intestine.
  • EV panacis- derived extracellular vesicles
  • 9 is a result of performing a metagenome analysis at the bacterial order level to compare the distribution of bacterial-derived extracellular vesicles isolated from urine and serum of atopic dermatitis patients.
  • 10 is a result of performing a metagenome analysis at the bacterial family level in order to compare the distribution of bacterial-derived extracellular vesicles isolated from urine and serum of atopic dermatitis patients.
  • 11 is a result of performing a metagenome analysis at the genus level of bacteria to compare the distribution of bacterial-derived extracellular vesicles isolated from urine and serum of atopic dermatitis patients.
  • FIG. 13 shows the results of meta-genomic analysis at the bacterial class level to confirm the distribution of bacterial-derived extracellular vesicles isolated from urine of atopic dermatitis patients and normal people.
  • 15 is a result of performing a metagenome analysis at the bacterial family level to confirm the distribution of bacterial-derived extracellular vesicles isolated from the urine of atopic dermatitis patients and normal people.
  • FIG. 16 shows the results of metagenome analysis at the genus level of bacteria to confirm the distribution of bacterial-derived extracellular vesicles isolated from urine of atopic dermatitis patients and normal people.
  • FIG. 17 shows the results of metagenomic analysis of bacteria-derived extracellular vesicles isolated from urine of atopic dermatitis patients and normal persons by heat map.
  • 18 is an electron microscope photograph of the extracellular vesicles isolated from the Lactobacillus plantarum culture solution.
  • NTA Nanotrafficking assay
  • Fig. 22 shows extracellular vesicles derived from Staphylococcus aureus ( S. aureus EV), or acne bacteria-derived extracellular vesicles ( P. acnes ) on skin epithelial cells. 12 hours prior to the administration of EV), the lactic acid bacteria-derived extracellular vesicles (CJLP133 EV) were administered, and IL-6 secretion was measured by ELISA.
  • S. aureus EV Staphylococcus aureus
  • P. acnes acne bacteria-derived extracellular vesicles
  • Fig. 24 shows the administration of lactic acid bacteria-derived extracellular vesicles (CJLP133 EV) 12 hours before administration of Staphylococcus aureus-derived extracellular vesicles ( S. aureus EV) to peritoneal macrophages, followed by IL-6 and TNF. It is the result of measuring - ⁇ secretion amount.
  • FIG. 25 shows the results of evaluating the degree of cell death through MTT assay after administration of lactic acid bacteria-derived vesicles (CJLP133 EV) 12 hours before administration of Staphylococcus aureus-derived extracellular vesicles ( S. aureus EV) to skin epithelial cells. to be.
  • CJLP133 EV lactic acid bacteria-derived vesicles
  • S. aureus EV Staphylococcus aureus-derived extracellular vesicles
  • Fig. 26 shows the administration of lactic acid bacteria-derived extracellular vesicles (CJLP133 EV) 12 hours before administration of Pseudomonas aeruginosa extracellular vesicles ( P. aeruginosa EV) to peritoneal macrophages, followed by IL-6 and TNF- ⁇ . This is the result of measuring the amount of secretion.
  • CJLP133 EV lactic acid bacteria-derived extracellular vesicles
  • Figure 27 shows the administration of Pseudomonas aeruginosa-derived extracellular vesicles ( P. aeruginosa EV) to peritoneal macrophages, and at the same time to administer lactic acid bacteria-derived extracellular vesicles (CJLP133 EV), and then secrete IL-6 and TNF- ⁇ through ELISA. Is the result of measuring.
  • P. aeruginosa EV Pseudomonas aeruginosa-derived extracellular vesicles
  • CJLP133 EV lactic acid bacteria-derived extracellular vesicles
  • FIG. 28 shows a protocol for evaluating the therapeutic effect of skin administration of lactic acid bacteria-derived extracellular vesicles (CJLP133 EV) in atopic dermatitis mouse model induced by Staphylococcus aureus-derived extracellular vesicles ( S. aureus EV). .
  • FIG. 29 is a skin photograph of the atopic dermatitis mouse model induced by Staphylococcus aureus-derived extracellular vesicles ( S. aureus EV), after administration of the lactic acid bacteria-derived extracellular vesicles (CJLP133 EV) to the skin, to evaluate the therapeutic effect.
  • S. aureus EV Staphylococcus aureus-derived extracellular vesicles
  • CJLP133 EV lactic acid bacteria-derived extracellular vesicles
  • Figure 30 shows the concentration of IL-17 in skin tissue after administration of lactic acid bacteria-derived extracellular vesicles (CJLP133 EV) into the skin in atopic dermatitis mouse model by S. aureus EV extracellular vesicles ( S. aureus EV) One result.
  • CJLP133 EV lactic acid bacteria-derived extracellular vesicles
  • FIG. 31 shows a picocol for evaluating the therapeutic effect of oral administration of lactobacillus-derived extracellular vesicles (CJLP133 EV) in an atopic dermatitis mouse model by S. aureus EV-derived extracellular vesicles ( S. aureus EV).
  • CJLP133 EV lactobacillus-derived extracellular vesicles
  • S. aureus EV-derived extracellular vesicles S. aureus EV
  • FIG. 32 is a skin photograph showing the therapeutic effect after oral administration of lactic acid bacteria-derived extracellular vesicles (CJLP133 EV) in an atopic dermatitis mouse model induced by Staphylococcus aureus-derived extracellular vesicles ( S. aureus EV).
  • CJLP133 EV lactic acid bacteria-derived extracellular vesicles
  • FIG. 33 shows oral administration of lactobacillus-derived extracellular vesicles (CJLP133 EV) in an atopic dermatitis mouse model induced by Staphylococcus aureus-derived extracellular vesicles ( S. aureus EV). It is the result of measuring the density
  • Figure 34 depicts a protocol for evaluating toxicity by high dose oral administration of lactic acid bacteria-derived extracellular vesicles (CJLP133 EV).
  • Fig. 35 shows the results of measuring changes in body weight after oral administration of high doses of lactic acid bacteria-derived extracellular vesicles (CJLP133 EV).
  • Fig. 37 shows the results of measuring body temperature changes after oral administration of high dose of lactic acid bacteria-derived extracellular vesicles (CJLP133 EV).
  • CJLP133 EV lactic acid bacteria-derived extracellular vesicles
  • WBC white blood cell count
  • RBC red blood cell count
  • HGB hemoglobin concentration
  • HCT Heglobin concentration
  • MCV average red blood cell volume
  • MCH average hemoglobin number
  • MCHC average hemoglobin concentration
  • PLT platelet number
  • the extracellular vesicles derived from lactic acid bacteria were significantly increased in urine of normal subjects, and the extracellular lactic acid bacteria-derived extracellular vesicles were significantly increased.
  • the present invention was completed by confirming that the endoplasmic reticulum effectively inhibits the inflammatory response induced by S. aureus and P. aeruginosa- derived extracellular vesicles, which are the main causes of inflammatory diseases.
  • the enteric bacterium Pseudomonas Sedrina (Pseudomonas cedrina) and Pseudomonas waves sheath (Pseudomonas panacis) body by administering the bacteria, these bacteria-derived extracellular vesicles in mice by removing the extracellular vesicles orally in distribution
  • intestinal bacteria are not absorbed systemically, whereas intestinal bacteria-derived extracellular vesicles are systemically absorbed and excreted in urine (see Examples 1 and 2).
  • metagenome analysis was performed using DNA of extracellular vesicles isolated from urine of atopic dermatitis patients and normal people.
  • DNA of extracellular vesicles isolated from urine of atopic dermatitis patients and normal people was analyzed using DNA of extracellular vesicles isolated from urine of atopic dermatitis patients and normal people.
  • tumefaciens Metalobacterium
  • Streptomyces phytase Streptophyta
  • propionyl sludge tumefaciens Propionibacterium
  • Pseudomonas was a significant increase in germ cells derived from the endoplasmic reticulum to the outside of methyl.
  • Lactobacillales Lactobacillales
  • Lactobacillus Lactobacillus
  • Leuconostoc Luconostoc
  • Lactococcus Lactococcus
  • lactobacillus plantarum which is a lactic acid bacterium isolated from fermented foods
  • lactobacillus plantarum which is a lactic acid bacterium isolated from fermented foods
  • the circular endoplasmic reticulum with an average diameter of about 15 nm was able to be isolated (see Example 5), and the endoplasmic reticulum and macrophages were treated with the endoplasmic reticulum, followed by Staphylococcus aureus and Pseudomonas aeruginosa, which are the main causes of inflammatory diseases. It was confirmed that the inflammatory response induced by the treatment of extracellular vesicles secreted in the rat is markedly inhibited (see Examples 6 to 9).
  • the lactic acid bacteria-derived vesicles orally or dermally administered to the atopic dermatitis mouse model by the Staphylococcus aureus-derived extracellular vesicles based on the results of the in vitro experiments It was confirmed that dermatitis was effectively inhibited by the lactic acid bacteria-derived vesicles (see Examples 10 and 11), and the oral administration of high doses of the lactic acid bacteria-derived extracellular vesicles to the mice was confirmed to be no difference from the control group in various biomarkers. The safety of the extracellular vesicles was confirmed (see Example 12).
  • the present invention provides a pharmaceutical composition for the prevention or treatment of inflammatory diseases, including the lactic acid bacteria-derived extracellular vesicles as an active ingredient.
  • inflammatory disease refers to an infectious inflammatory disease induced by an infectious agent such as a bacterial or bacterial endoplasmic reticulum, toxin, virus, or fungus, allergic inflammation induced by allergen exposure.
  • infectious agent such as a bacterial or bacterial endoplasmic reticulum, toxin, virus, or fungus
  • allergen exposure a bacterial or bacterial endoplasmic reticulum, toxin, virus, or fungus
  • inflammatory disease refers to an inflammatory disease caused by an infectious agent, atopic dermatitis, chronic rhinitis, chronic sinusitis, asthma, chronic obstructive pulmonary disease (COPD), Sepsis and the like.
  • allergic inflammatory disease refers to inflammatory diseases caused by allergens, including atopic dermatitis, chronic rhinitis, chronic sinusitis, asthma, chronic obstructive pulmonary disease (COPD), and the like. It includes.
  • atopic dermatitis refers to a skin disease with itching chronically occurring on the skin.
  • prevention means any action that inhibits or delays the development of an inflammatory disease by administration of a pharmaceutical composition according to the present invention.
  • treatment refers to any action that improves or advantageously changes the symptoms caused by an inflammatory disease by administration of a pharmaceutical composition according to the present invention.
  • the lactic acid bacteria of the present invention may be Lactobacillales ( Lactobacillales ), Lactococcus ( Lactococcus ), Lactobacillus ( Lactobacillus ), or Leukonostoc ( Leuconostoc ) bacteria, but is not limited thereto.
  • the bacterium of the genus Lactobacillus may be preferably Lactobacillus plantarum , but is not limited thereto.
  • the extracellular vesicles of the present invention may be isolated from the culture of lactic acid bacteria or food fermented with lactic acid bacteria, may be secreted naturally or artificially from lactic acid bacteria, but is not limited thereto.
  • the method for separating extracellular vesicles from the culture or fermented food of the lactic acid bacteria of the present invention is not particularly limited as long as the extracellular vesicles.
  • Extracellular vesicles can be separated by methods such as centrifugation, ultrafast centrifugation, filtration by filters, gel filtration chromatography, pre-flow electrophoresis, or capillary electrophoresis, and combinations thereof, and also impurities It may further include the process of washing for the removal of, concentration of the obtained extracellular vesicles and the like.
  • the extracellular vesicles separated by the above method may have an average diameter of 10 to 300 nm, preferably 10 to 200 nm, but are not limited thereto.
  • the pharmaceutical composition according to the present invention includes the lactic acid bacteria-derived extracellular vesicles as an active ingredient, and may include a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable carriers are conventionally used in the preparation, and include, but are not limited to, saline solution, sterile water, Ringer's solution, buffered saline, cyclodextrin, dextrose solution, maltodextrin solution, glycerol, ethanol, liposomes, and the like. If necessary, other conventional additives such as antioxidants and buffers may be further included.
  • diluents, dispersants, surfactants, binders, lubricants and the like may be additionally added to formulate injectable formulations, pills, capsules, granules, or tablets such as aqueous solutions, suspensions, emulsions and the like.
  • Suitable pharmaceutically acceptable carriers and formulations can be preferably formulated according to the individual components using methods disclosed in Remington's literature.
  • the pharmaceutical composition of the present invention is not particularly limited in formulation, but may be formulated as an injection, inhalant, external preparation for skin, oral ingestion, and the like.
  • the pharmaceutical composition of the present invention can be administered orally or parenterally (eg, applied intravenously, subcutaneously, skin, nasal, airways) according to the desired method, and the dosage is determined by the condition and weight of the patient, disease Depending on the degree, drug form, route of administration, and time, it may be appropriately selected by those skilled in the art.
  • composition according to the invention is administered in a pharmaceutically effective amount.
  • pharmaceutically effective amount means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment, and an effective dose level refers to the type, severity, and activity of the patient's disease. , Sensitivity to the drug, time of administration, route of administration and rate of release, duration of treatment, factors including concurrent use of the drug, and other factors well known in the medical arts.
  • the composition according to the present invention may be administered as a separate therapeutic agent or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be single or multiple doses. Taking all of the above factors into consideration, it is important to administer an amount that can achieve the maximum effect with a minimum amount without side effects, which can be readily determined by one skilled in the art.
  • the effective amount of the composition according to the present invention may vary depending on the age, sex, and weight of the patient, and generally 0.001 to 150 mg, preferably 0.01 to 100 mg per kg of body weight is administered daily or every other day or 1 It can be administered in 1 to 3 times a day.
  • the dosage may be increased or decreased depending on the route of administration, the severity of obesity, sex, weight, age, etc., and the above dosage does not limit the scope of the present invention in any way.
  • the present invention also provides a cosmetic composition for improving inflammatory disease comprising lactic acid bacteria-derived extracellular vesicles as an active ingredient.
  • the cosmetic composition of the present invention may include lactic acid bacteria-derived extracellular vesicles, as well as components commonly used in cosmetic compositions, such as conventional adjuvants such as antioxidants, stabilizers, solubilizers, vitamins, pigments, and fragrances. And a carrier.
  • composition of the present invention may be used by mixing not only lactic acid bacteria-derived extracellular vesicles, but also organic sunscreens that have been conventionally used as long as they do not impair skin protection effects.
  • organic sunscreen include glyceryl pava, drometrizole trisiloxane, drometrizole, digaloyltrioleate, disodium phenyldibenzimidazole tetrasulfonate, diethylhexyl butamidotriazone, diethylamino Hydroxybenzoylhexylbenzoate, die-methoxycinnamate, a mixture of lowson and dihydroxyacetone, methylenebis-benzotriazolyltetramethylbutylphenol, 4-methylbenzylidene camphor, menthyl anthranilate, benzophenone -3 (oxybenzone), benzophenone-4, benzophenone-8 (dioxyphenbenzone), butylmethoxy
  • Examples of products to which the cosmetic composition of the present invention may be added include, for example, cosmetics such as astringent cosmetics, soft cosmetics, nourishing cosmetics, various creams, essences, packs, foundations, and the like, cleansing agents, soaps, treatments, and essences.
  • Specific formulations of the cosmetic composition of the present invention include skin lotion, skin softener, skin toner, astringent, lotion, milk lotion, moisture lotion, nutrition lotion, massage cream, nutrition cream, moisture cream, hand cream, essence, nutrition essence, pack, Formulations such as soaps, shampoos, cleansing foams, cleansing lotions, cleansing creams, body lotions, body cleansers, emulsions, lipsticks, makeup bases, foundations, press powders, loose powders, eye shadows and the like.
  • the present invention provides a health functional food composition for improving inflammatory diseases comprising lactic acid bacteria-derived extracellular vesicles as an active ingredient.
  • &quot means any action that at least reduces the parameters associated with the condition being treated, such as the extent of symptoms.
  • the active ingredient may be added to the food as it is, or used together with other foods or food ingredients, and may be appropriately used according to a conventional method.
  • the mixing amount of the active ingredient can be suitably determined according to the purpose of use (prevention or improvement).
  • the compositions of the invention are added in an amount of up to 15% by weight, preferably up to 10% by weight relative to the raw materials.
  • the amount may be below the above range.
  • the health functional food composition of the present invention in addition to containing the active ingredient as an essential ingredient in the indicated ratio, is not particularly limited to other ingredients, and may contain various flavors or natural carbohydrates as additional ingredients, such as ordinary drinks.
  • natural carbohydrates include monosaccharides such as glucose, fructose and the like; Disaccharides such as maltose, sucrose and the like; And conventional sugars such as polysaccharides such as dextrin, cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol.
  • natural flavoring agents such as, tauumatin, stevia extract (for example, rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.) can be advantageously used.
  • the proportion of the natural carbohydrate can be appropriately determined by the choice of those skilled in the art.
  • the nutraceutical composition of the present invention includes various nutrients, vitamins, minerals (electrolytes), synthetic flavors such as synthetic and natural flavors, coloring and neutralizing agents (such as cheese, chocolate), pectic acid and salts thereof, Alginic acid and salts thereof, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated drinks and the like.
  • these components can be used independently or in combination.
  • the proportion of such additives may also be appropriately selected by those skilled in the art.
  • the present invention also provides an inhalant composition for the prophylaxis or treatment of inflammatory diseases comprising the lactic acid bacteria-derived extracellular vesicles as an active ingredient.
  • the active ingredient may be added to the inhalant as it is, or may be used together with other ingredients, and may be appropriately used according to conventional methods.
  • the amount of the active ingredient to be mixed may be suitably determined depending on the purpose of use (prophylactic or therapeutic).
  • the present invention comprises the steps of extracting the gene from the extracellular vesicles isolated from the clinical sample; Analyzing a nucleotide sequence for the gene; And it provides a method for diagnosing atopic dermatitis comprising the step of determining that the risk of inducing atopic dermatitis is high when the distribution of lactic acid bacteria-derived extracellular vesicles through the sequencing analysis is low compared to normal.
  • the gene may be DNA or RNA, but is not limited thereto.
  • the clinical sample may be urine or blood, but is not limited thereto.
  • the sequencing may be performed through polymerase chain reaction (PCR), but is not limited thereto.
  • PCR polymerase chain reaction
  • the present invention provides a method for preventing or treating an inflammatory disease comprising administering to a subject a composition comprising a lactic acid bacteria-derived extracellular vesicles as an active ingredient.
  • “individual” means a subject in need of treatment of a disease, and more specifically, a human or non-human primate, mouse, rat, dog, cat, horse, cow, and the like. Means mammals.
  • extracellular vesicles isolated from the bacterial culture medium were placed on 300-mesh copper grids (Electron Microscopy Sciences) After staining with 2% uranyl acetate for 12 hours. Afterwards, an extracellular vesicle was observed using an JEM1011 microscope (JEOL) to obtain an image under an accelerating voltage of 100 kV.
  • PBS physiological saline
  • JEOL JEM1011 microscope
  • Sedrina Pseudomonas (P. cedrina) and Pseudomonas waves System (P. panacis) derived cells outside the ER (EVs) have the shape of a rectangle.
  • Zetasizer Nano S (Malvern Instruments Ltd., 633-nm laser line, scattered intensity 10 x 30 s) to measure the size of the extracellular vesicles isolated from the bacterial culture medium by dynamic light scattering (DLS). The diameter of the extracellular vesicles was measured using.
  • the Pseudomonas Sedrina (P. cedrina) and Pseudomonas waves System (P. panacis) the diameter of the cells derived from outside the vesicles was determined to be 30-40 nm, 20-30 nm, respectively as shown in Fig.
  • SDS-Polyacrylamide Gel Electrophoresis SDS-PAGE was used as a protein sample.
  • WCL whole cell lysate
  • EV extracellular vesicles
  • Pseudomonas waves System (P. panacis) Cy7 the mouse at a dose of 20 ⁇ g / mouse and then labeled (GE Healthcare) was feed over night after which an empty stomach for one hour the bacteria and the bacteria-derived extracellular vesicles at room temperature. After 0 h, 5 min, 3 h, and 12 h, the whole body image of the mouse was taken at 780-800 nm wavelength using IVIS spectrum CT (SelectScience). .
  • Pseudomonas panassis bacteria Bacteria
  • Pseudomonas panassis-derived extracellular vesicles EV
  • the heart, lung, liver, and kidney were extracted at 12 hours after oral administration to evaluate the tissue distribution of the bacteria and the bacterial-derived extracellular vesicles and the blood was removed.
  • the fluorescent material was detected by IVIS spectrum CT.
  • Pseudomonas panassis-derived extracellular vesicles were present in blood, heart, lung, liver and kidney, and Pseudomonas panassis bacteria were confirmed to be absent.
  • the colons were extracted from night-fasting mice to seal both sides of the colon and derived from Pseudomonas panasis labeled with 10 ⁇ g of GFP showing green fluorescence. Extracellular vesicles were injected into the intestine. After that, the blood of the colonic lamina intestinal was imaged using a TCS SP5 microscope (Leica).
  • metagenome analysis was performed using DNA isolated from extracellular vesicles present in urine and serum of atopic dermatitis patients.
  • each clone was subjected to a polymerase chain reaction (PCR) for DNA analysis using a 16s rDNA fusion primer for amplifying the V1-V3 region and a FastStart High Fidelity PCR System (Roche, Basel, Switzerland). It was.
  • the sequence of the 16s rDNA fusion primer is shown in Table 1 below.
  • the amplification reaction by PCR proceeded with a mixture of oil and amplicon in emulsion, and Tissue Lyser II (Qiagen) using GS-FLX plus emPCR Kit (454 Life Sciences). To make “micro-reactors”. The emulsion was divided into 96-well plates and PCR was performed according to the manufacturer's protocol using 20 ng of each DNA sample in a 50 ⁇ l PCR reaction (Step 1: 3 minutes at 94 ° C., Step 2: 15 seconds at 94 ° C.). , 35 cycles for 55 seconds at 55 ° C., 1 minute at 72 ° C., final step: 8 minutes at 72 ° C.).
  • the amplicon was purified using an AMpure Bead kit (Beckman Coulter, Brea, CA, USA) and purified using the Picogreen method (Invitrogen, Carlsbad, CA, USA). Quantification using The amplicon was then diluted and analyzed using GS-FLX Titanium sequencer (Roche, Basel, Switzerland). After PCR amplification, the emulsion was chemically degraded and the pellets with an amplified DNA library were washed by filtration. Positive beads were purified using biotinylated primer A (complementary to adapter A) and attached to streptavidin-coated magnetic beads.
  • the DNA library beads attached to the magnetic beads were then separated from the magnetic beads by melting the double helix structure and single-stranded DNA was allowed to flow.
  • the sequencing primer was made from single stranded DNA amplified again.
  • the particles containing amplified single-stranded DNA were counted using the Particle Counter (Beckman Coulter). Sequencing was performed on Genome Sequencer FLX titanium (454 Life Sciences) and each sample was loaded on each of a 70 mm-75 mm PicoTiter plate (454 Life Sciences).
  • the genus bacterial composition was plotted on a heat map when more than two-fold significant differences were found between atopic dermatitis patients and normal controls. Hierarchical clustering was performed in the genus stage when more than two-fold significant differences were found between the atopic dermatitis patients and the normal control group or when the mean composition was greater than 1%.
  • Example 3-1 After separating DNA from bacteria-derived extracellular vesicles present in urine and serum of atopic dermatitis patients by the method of Example 3-1, the base sequence of 16S rDNA was analyzed by metagenomic analysis using the method of Example 3-2. The distribution of bacterial extracellular vesicles in the urine and serum was compared.
  • tumefaciens Metalobacterium
  • germ cells derived from outside the ER normal vs. atopic dermatitis: 0.22% vs. 2.02%
  • Extracellular vesicles derived from Streptophyta neck bacteria Normal vs. atopic dermatitis patients: 2.87% vs. 7.89%)
  • Bacterial-derived extracellular vesicles of Propionibacterium normal vs. atopic dermatitis patients: 2.78% vs. 7.6%
  • extracellular vesicles derived from Pseudomonas spp. normal vs.
  • atopic dermatitis patients 9.56% vs. 21.91%).
  • the extracellular vesicles of Lactobacillus genus normal vs. atopic dermatitis: 20.92% vs. 4.61%) were found in the urine of atopic dermatitis patients.
  • Extracellular vesicles derived from bacteria in Leuconostoc normal vs. atopic dermatitis: 14.60% vs. 0.12%
  • extracellular vesicles derived from Lactobacillales neck bacteria normal vs. atopic dermatitis: 18.19% vs. 0.05%)
  • extracellular vesicles derived from bacteria of Lactococcus normal vs. atopic dermatitis patients: 11.57% vs. 0.03%
  • Example 4 As a result of Example 4, it was confirmed that Lactobacillus throat bacteria and Lactobacillus bacteria-derived extracellular vesicles were significantly reduced in urine of atopic dermatitis patients compared to normal people, so that Lactobacillus-derived extracellular vesicles were immune and inflammatory. The purpose of this study was to investigate the effect on the human body.
  • Lactobacillus plantarum lactic acid bacteria isolated from kimchi were incubated, the lactic acid bacteria culture was centrifuged at 10,000 xg for 20 minutes, and only the supernatant was collected and filtered through a 0.22 mm filter. The separated filtrate was concentrated to a certain amount only greater than 100 kDa, and then subjected to ultrafast centrifugation at 150,000 xg, 4 ° C. for 3 hours, and the supernatant was discarded and the remaining extracellular vesicles were diluted with filtered saline (PBS). The concentration was then quantified by BCA protein assay (Pierce, USA). Thereafter, dynamic light scattering and electron microscopy were performed to confirm that the physical properties of the extracellular vesicles isolated from the lactic acid bacteria were the same.
  • LM-10HS nanosite tracking analysis
  • Example 6 Dermal epithelial cells Derived from Staphylococcus aureus Extracellular Identification of the immunomodulatory effects of lactic acid bacteria-derived extracellular vesicles in the generation of immune responses
  • S. aureus EV is known as a major causative agent of inflammatory diseases in skin epithelial cell lines (HaCaT) 2 x 10 5 cells.
  • P. acnes EV-derived extracellular vesicles and the lactic acid bacteria-derived extracellular vesicles (CJLP133 EV) isolated by the method of Example 5 were each treated at a concentration of 10 ng to 25 ⁇ g / ml and incubated for 12 hours. Afterwards, the secretion of IL-6, a cytokine that induces a Th17 immune response in the supernatant, was measured by ELISA. As a result, as shown in Figure 21, when treated with the lactic acid bacteria-derived extracellular vesicles compared to Staphylococcus aureus and acne bacteria-derived vesicles, the secretion amount of IL-6 was much lower.
  • the lactic acid bacteria-derived extracellular vesicles were treated to skin epithelial cells at various concentrations (0.1, 1, 10 ⁇ g / ml) 12 hours before, and the 25 ⁇ g / ml concentration of Staphylococcus aureus or acne bacteria-derived endoplasmic reticulum was carried out. After culturing for 12 hours and incubating the cells, the secretion amount of IL-6, an inflammatory cytokine in the supernatant, was confirmed by ELISA. As a result, as shown in FIG. 22, when pre-treatment of the lactic acid bacteria-derived extracellular vesicles ( S.
  • IL-6 secretion by the Staphylococcus aureus-derived vesicles decreased concentration-dependently, whereas IL-6 secretion by P. acnes EV) did not show the effect of lactic acid bacteria-derived extracellular vesicles.
  • Example 7 Origin of Staphylococcus Aureus from Inflammatory Cells Extracellular Identification of anti-inflammatory effects of lactic acid bacteria-derived extracellular vesicles in the development of inflammatory responses by endoplasmic reticulum stimulation
  • the purpose of this study was to investigate the effects of lactic acid bacteria-derived extracellular vesicles on the development of inflammatory reactions by extracellular vesicles derived from Staphylococcus aureus.
  • 1 ⁇ g of Staphylococcus aureus-derived extracellular vesicles ( S. aureus ) or 10 ng, 100 ng, or 1 ⁇ g of lactic acid bacteria-derived extracellular vesicles (CJLP133) were injected into a mouse celiac macrophage line (Raw 264.7). After treatment for a period of time, the amount of inflammatory cytokines IL-6 and TNF- ⁇ secreted from peritoneal macrophages was measured and compared.
  • the secretion of IL-6 and TNF- ⁇ was significantly decreased when the lactic acid bacteria-derived extracellular vesicles were treated, compared with the treatment with the Staphylococcus aureus-derived ER. This means that when the lactic acid bacteria-derived extracellular vesicles are absorbed into the body, they are much safer than the Staphylococcus aureus-derived endoplasmic reticulum.
  • lactic acid bacteria-derived extracellular vesicles were treated in mouse peritoneal macrophages at various concentrations (0.01, 0.1, 1 ⁇ g / ml concentration), and after 12 hours, Staphylococcus aureus-derived extracellular vesicles were treated with 1 ⁇ g / ml. After 12 hours of treatment, the levels of inflammatory cytokines IL-6 and TNF- ⁇ were measured by ELISA. As a result, as shown in FIG. 24, when pre-treatment of the lactic acid bacteria-derived extracellular vesicles, it was confirmed that IL-6 and TNF- ⁇ secretion by the Staphylococcus aureus-derived extracellular vesicles is suppressed. This means that the lactic acid bacteria-derived extracellular vesicles can effectively inhibit the inflammatory response by inflammatory cells induced by Staphylococcus aureus-derived extracellular vesicles.
  • Example 8 Origin of Staphylococcus aureus Extracellular By endoplasmic reticulum stimulation Skin epithelial cells Confirmation of Inhibitory Effects of Lactic Acid Bacteria-Derived Extracellular Vesicles on Death
  • Example 9 Origin of Pseudomonas aeruginosa Extracellular Inflammation caused by the endoplasmic reticulum Lactic acid bacteria Extracellular Confirmation of anti-inflammatory effects of endoplasmic reticulum
  • P. aeruginosa is a major pathogenic bacterium belonging to the genus Pseudomonas , which causes antibiotic resistance and is known as a major cause of sepsis.
  • Pseudomonas aeruginosa-derived extracellular vesicles have been known to be a major causative factor of chronic lung diseases such as asthma, chronic obstructive pulmonary disease (COPD) and lung cancer by repeated exposure through the airways.
  • COPD chronic obstructive pulmonary disease
  • lactic acid-derived extracellular vesicles (CJLP133 EV) were treated with inflammatory cells in celiac macrophage line (Raw 264.7) at various concentrations (0.01, 0.1, 1 ⁇ g / ml) and after 12 hours, P. aeruginosa-derived extracellular vesicles ( P. aeruginosa EV) was treated at a concentration of 1 ⁇ g / ml and the concentrations of inflammatory cytokines IL-6 and TNF- ⁇ were measured by ELISA. As a result, as shown in FIG.
  • Example 10 Lactic acid bacteria Extracellular Confirmation of inhibitory effect of atopic dermatitis caused by Staphylococcus aureus-derived vesicles by endoplasmic reticulum administration
  • Examples 6 to 8 confirmed the effects of lactic acid bacteria-derived extracellular vesicles derived from Staphylococcus aureus-derived extracellular vesicles immunosuppressive, anti-inflammatory, and skin cell death, atopic dermal administration by lactic acid bacteria-derived extracellular vesicles The purpose of this study was to evaluate the therapeutic effect of dermatitis.
  • SKH-1 hairless mice were repeatedly coated with 10 ⁇ g concentration of Staphylococcus aureus-derived extracellular vesicles ( S. aureus EV) three times a week for 4 weeks to prepare an atopic dermatitis model.
  • lactic acid bacteria-derived extracellular vesicles CJLP133 EV
  • the positive control group was ip injection of dexamethasone (dexamethasone), an immunosuppressive agent used as atopic dermatitis, at 300 ⁇ g concentration, and the experiment was conducted under the same conditions.
  • SKH-1 hairless mice had a concentration of 10 ⁇ g of Staphylococcus aureus-derived vesicles ( S. aureus EV).
  • S. aureus EV Staphylococcus aureus-derived vesicles
  • CJLP133 EV extracellular vesicle derived from Lactobacillus
  • the concentrations of IL-4, IL-5, IL-17, and IFN- ⁇ in skin tissues were measured. As shown in FIG. When oral administration of the endoplasmic reticulum was confirmed that the secretion of the cytokines is significantly suppressed. The above results indicate that when orally administered lactic acid bacteria-derived extracellular vesicles can effectively suppress dermatitis diseases such as atopic dermatitis.
  • Example 12 of high capacity Lactic acid bacteria Extracellular Endoplasmic reticulum Multiple times Safety assessment by oral administration
  • lactic acid bacteria-derived extracellular vesicles 500 ⁇ g of lactic acid bacteria-derived extracellular vesicles (CJLP133) was orally administered three times a week for four weeks (total 12 times) by the method shown in FIG. 34. . Then, the body weight, feed intake, and body temperature of the mice were measured in the control group that did not receive the endoplasmic reticulum and the oral administration of the lactic acid bacteria-derived vesicles.

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Abstract

La présente invention concerne : une composition pour prévenir, améliorer ou traiter des maladies inflammatoires, la composition comprenant, comme principes actifs, des vésicules extracellulaires dérivées de bactéries d'acide lactique isolées de fluide de culture de bactéries d'acide lactique; et un procédé pour diagnostiquer une dermatite atopique. Il a été confirmé, par l'intermédiaire d'expériences in vitro et in vivo, que les vésicules extracellulaires dérivées de bactéries d'acide lactique de la présente invention sont considérablement davantage réparties dans l'urine et le sang d'un patient atteint de maladies inflammatoires qu'une personne normale, et une réponse inflammatoire dans des cellules épithéliales et des cellules inflammatoires causée par une exposition à des vésicules extracellulaires dérivées de Staphylococcus ou Pseudomonas est inhibée efficacement par les vésicules extracellulaires dérivées de bactéries d'acide lactique. Ainsi, la composition comprenant les vésicules extracellulaires dérivées de bactéries d'acide lactique comme principes actifs est supposée être utilisée de façon utile dans le développement de médicaments, de produits cosmétiques ou d'aliment fonctionnel de santé pour prévenir, améliorer ou traiter des maladies inflammatoires, telles que la dermatite atopique, la rhinite chronique, la sinusite chronique, l'asthme, une bronchopneumopathie chronique obstructive, la sepsie, etc. La composition sera utilisée de façon utile pour le diagnostic de dermatite atopique par mesure de la distribution de vésicules extracellulaires dérivées de bactéries d'acide lactique dans un échantillon d'urine ou de sang.
PCT/KR2016/002473 2015-03-11 2016-03-11 Composition pour prévenir ou traiter des maladies inflammatoires, comprenant des vésicules extracellulaires dérivées de bactéries d'acide lactique comme principes actifs WO2016144139A2 (fr)

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EP16762026.9A EP3269378B1 (fr) 2015-03-11 2016-03-11 Composition pour prévenir ou traiter des maladies inflammatoires, comprenant des vésicules extracellulaires dérivées de bactéries d'acide lactique comme principes actifs
JP2017547484A JP6700297B2 (ja) 2015-03-11 2016-03-11 乳酸菌由来の細胞外ベシクルを有効成分として含む、炎症疾患の予防または治療用の組成物
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