CN119662439A - Lactobacillus gasseri VB247 and application thereof - Google Patents
Lactobacillus gasseri VB247 and application thereof Download PDFInfo
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- CN119662439A CN119662439A CN202410065320.9A CN202410065320A CN119662439A CN 119662439 A CN119662439 A CN 119662439A CN 202410065320 A CN202410065320 A CN 202410065320A CN 119662439 A CN119662439 A CN 119662439A
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- lactobacillus gasseri
- vaginal
- fermentation
- microbial agent
- lactobacillus
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Classifications
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N1/00—Microorganisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
- C12N1/20—Bacteria; Culture media therefor
- C12N1/205—Bacterial isolates
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/135—Bacteria or derivatives thereof, e.g. probiotics
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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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Abstract
本发明公开了一种格氏乳杆菌(Lactobacillus gasseri)VB247，于2023年02月20日保藏于中国微生物菌种保藏管理委员会普通微生物中心，保藏编号为CGMCC No.26575。本发明的格氏乳杆菌VB247能够显著提高女性宫颈阴道上皮细胞中的AQP2mRNA表达水平，其可用于预防和/或缓解和/或治疗由于围绝经期、卵巢早衰等原因导致的阴道润滑障碍；并且，本发明的格氏乳杆菌VB247在制备如食品、保健食品、药品、卫生用品等产品中具有巨大的应用前景。The present invention discloses a Lactobacillus gasseri VB247, which was deposited in the General Microbiological Center of China National Committee for the Preservation of Microorganisms on February 20, 2023, with a deposit number of CGMCC No. 26575. The Lactobacillus gasseri VB247 of the present invention can significantly increase the expression level of AQP2mRNA in female cervical vaginal epithelial cells, and can be used to prevent and/or alleviate and/or treat vaginal lubrication disorders caused by perimenopause, premature ovarian failure, etc.; and the Lactobacillus gasseri VB247 of the present invention has great application prospects in the preparation of products such as food, health food, medicine, and sanitary products.
Description
Case division information
The application relates to a kind of Lactobacillus gasseri VB247 and the application of the same, which is filed by 20 days of 2023 and 09 to China national intellectual property agency, the patent application number is 202311216998.4, and the patent name is a divisional application of the patent application.
Technical Field
The invention belongs to the technical field of microorganisms, and particularly relates to lactobacillus gasseri VB247 capable of remarkably improving the expression level of AQP2 mRNA in female cervical and vaginal epithelial cells and application thereof, and more particularly relates to lactobacillus gasseri VB247, fermentation supernatant, fermentation liquor, microbial inoculum, food, health-care food, medicine or sanitary products and application thereof.
Background
At present, for the treatment of vaginal lubrication disorder, an oral or vaginal topical estrogen application method is mostly adopted, and the method can effectively relieve vaginal lubrication disorder caused by estrogen deficiency in perimenopause, premature ovarian failure and the like. However, intake of excessive estrogen causes side effects to the body, such as nausea, vomiting, headache, and menstrual flow changes, and there is a risk of breast cancer.
It has been found that aquaporins (aquaporin, AQP) are important substances regulating the water balance in cells, cells and whole organisms, in the aquaporin family, aquaporin2 (aquaporin, AQP 2) is mainly expressed in vaginal epithelial cells, healthy females are in a state of open channel during sexual excitation, and the expression level of AQP2 mRNA in vaginal epithelial cells of females suffering from vaginal lubrication disorder is low.
Therefore, there is a need to develop a bacterial strain that can effectively increase the expression level of AQP2 mRNA without affecting the environment of vaginal colonies.
Disclosure of Invention
The present invention aims to solve at least one of the technical problems existing in the prior art to at least some extent. Therefore, the invention provides the lactobacillus gasseri VB247 for the first time, and the lactobacillus gasseri VB247 is derived from the vagina of healthy women of childbearing age in China, has the advantages of low pH resistance, high lactic acid yield, resistance to 5 common vaginal pathogenic bacteria, strong vaginal cell adhesion capacity and the like, can obviously improve the AQP2 mRNA expression level in the epithelial cells of the cervical vagina of women, and can be used for preventing and/or relieving and/or treating the vaginal lubrication disorder caused by perimenopause, premature ovarian failure and other reasons.
Based on this, a first object of the present invention is to provide a lactobacillus gasseri (Lactobacillus gasseri) VB247. According to the embodiment of the invention, the lactobacillus gasseri VB247 is preserved in China general microbiological culture Collection center with the preservation number of CGMCC No.26575, the preservation date of 2023 and 02 month of 20 days, and the preservation address of North Star Xiya No. 1 and 3 of the Chaiyang district of Beijing city. The lactobacillus gasseri VB247 has the advantages of low pH resistance, vagina pH environment regulation, high lactic acid yield, resistance to 5 common vagina pathogenic bacteria, strong vagina cell adhesion capacity and the like, and can obviously improve the expression level of AQP2mRNA in female cervical and vaginal epithelial cells.
A second object of the present invention is to provide a fermentation supernatant comprising the aforementioned Lactobacillus gasseri VB247 and/or the metabolite of the aforementioned Lactobacillus gasseri VB 247.
It is a third object of the present invention to provide a fermentation broth comprising the aforementioned Lactobacillus gasseri VB247.
The fourth object of the present invention is to provide a microbial agent comprising the aforementioned Lactobacillus gasseri VB247, and/or the aforementioned fermentation supernatant, and/or the aforementioned fermentation broth. As described above, the Lactobacillus gasseri VB247 has the advantages of low pH resistance, adjusting the pH environment of vagina, high lactic acid yield, resistance to 5 common vaginal pathogenic bacteria, strong adhesion capacity of vaginal cells and the like, and the microbial agent of the invention has the same advantages and can be used for preventing and/or relieving and/or treating vaginal lubrication disorder caused by perimenopause, premature ovarian failure and the like.
As a specific embodiment, the lactobacillus gasseri VB247 is in the form of living and/or non-living cells.
As a specific embodiment, the microbial agent may further comprise at least one strain acceptable in foods, medicines, health foods and feeds.
As a specific embodiment, the microbial agent further comprises a pharmaceutically acceptable auxiliary material or carrier, or a food or health food acceptable auxiliary material or carrier.
A fifth object of the present invention is to provide a food, health food or sanitary product comprising at least one of the above lactobacillus gasseri VB247, the above fermentation supernatant, the above fermentation broth and the above microbial agent.
The sixth object of the invention is to provide the application of the lactobacillus gasseri VB247, the fermentation supernatant, the fermentation broth or the microbial agent in preparing medicines, wherein the medicines have at least one of the following application in preventing and/or relieving and/or treating vaginal lubrication disorder caused by perimenopause, premature ovarian failure and other reasons, in preventing and/or relieving and/or treating vaginal pathogenic bacteria infection or related diseases caused by vaginal pathogenic bacteria infection, in increasing the expression level of AQP2 mRNA of vaginal epithelial cells, and in regulating the vaginal pH environment.
As a specific embodiment, the pathogenic bacteria is selected from at least one of staphylococcus aureus, escherichia coli, candida albicans, gardnerella vaginalis, and clostridium perfringens.
A seventh object of the present invention is to provide a medicament comprising at least one of the aforementioned lactobacillus gasseri VB247, the aforementioned fermentation supernatant, the aforementioned fermentation broth and the aforementioned microbial agent.
As a specific embodiment, the medicament further comprises an excipient and/or carrier.
As a specific embodiment, the excipient includes at least one selected from the group consisting of a binder, a disintegrant, a lubricant, a glidant, a stabilizer, a filler, a diluent, and a slow-release agent.
As a specific embodiment, the carrier includes at least one selected from the group consisting of saccharides, cellulose and derivatives thereof, calcium phosphates, alkaline earth metal stearates, vegetable oils, nonionic surfactants, cationic surfactants, anionic surfactants, fatty alcohols, and cereal hydrolytic solids.
In a specific embodiment, the dosage form of the drug comprises at least one selected from oral liquid, powder, granules, capsules, tablets and dripping pills.
The beneficial effects are that:
(1) Compared with other Lactobacillus gasseri isolates, the Lactobacillus gasseri VB247 obtained by screening of the invention has the advantages of faster growth start, higher slope in the logarithmic phase of growth, higher OD 600 in the stationary phase of growth, higher activation rate and stronger growth activity, and shows that the Lactobacillus gasseri VB247 has faster growth start under a low pH environment (pH=4.0).
(2) Compared with other Lactobacillus gasseri isolates, the Lactobacillus gasseri VB247 obtained by screening of the invention has higher content of lactic acid (L-lactic acid and D-lactic acid) in fermentation supernatant, which indicates that the strain can produce lactic acid with high yield.
(3) Compared with other Lactobacillus gasseri isolates, the Lactobacillus gasseri VB247 can lower the pH faster, which shows that the strain has stronger pH adjusting capability and can create and maintain a healthy vaginal pH environment.
(4) The Lactobacillus gasseri VB247 has the inhibitory activity of various pathogenic bacteria, can inhibit the growth of the vaginal pathogenic bacteria such as escherichia coli, staphylococcus aureus, candida albicans, gardnerella vaginalis, clostridium perfringens and the like, and can be used for the auxiliary treatment of various gynecological diseases such as colpitis, vaginal lubrication disorder and the like, alone or in combination with other probiotics.
(5) The lactobacillus gasseri VB247 has stronger vaginal cell adhesion capability, and is easier to colonize in the vagina.
(6) The lactobacillus gasseri VB247 can obviously improve the expression level of the AQP2mRNA in female cervical and vaginal epithelial cells, so that the vaginal dryness is improved, and the lactobacillus gasseri VB247 can be used for preventing and/or relieving and/or treating vaginal lubrication disorder caused by perimenopause, premature ovarian failure and other reasons.
Additional aspects and advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention.
Drawings
The foregoing and/or additional aspects and advantages of the invention will become apparent and may be better understood from the following description of embodiments taken in conjunction with the accompanying drawings in which:
FIG. 1 is a scanning electron micrograph of Lactobacillus gasseri VB247 in example 1 of the present invention;
FIG. 2 is a graph showing the change in OD 600 over time at pH=4.0 of Lactobacillus gasseri VB247 and Lactobacillus gasseri isolate #86 according to example 2 of the present invention;
FIG. 3 is a graph showing the pH of fermentation broths of Lactobacillus gasseri VB247 and Lactobacillus gasseri isolate #86 according to the embodiment 4 of the present invention;
FIG. 4 shows the adhesion of Lactobacillus gasseri VB247 to Lactobacillus gasseri isolate #86 to HeLa cells in example 6 of the present invention;
FIG. 5 is a graph showing the effect of Lactobacillus gasseri VB247 and Lactobacillus gasseri isolate #86 on the expression of AQP2 mRNA in VK2/E6E7 human vaginal epithelial cells in example 7 of the present invention.
Detailed Description
Embodiments of the present invention are described in detail below. The following examples are illustrative only and are not to be construed as limiting the invention.
It should be noted that the terms "first," "second," and "second" are used for descriptive purposes only and are not to be construed as indicating or implying a relative importance or implying a number of technical features being indicated. Thus, a feature defining "a first" or "a second" may explicitly or implicitly include one or more such feature. Further, in the description of the present invention, unless otherwise indicated, the meaning of "a plurality" is two or more.
The terms "comprising," "including," or "comprising" are used herein in an open-ended fashion, i.e., to include what is indicated by the present invention, and not to exclude other aspects.
In this document, the terms "optionally," "optional," or "optionally" generally refer to the subsequently described event or condition may, but need not, occur, and the description includes instances in which the event or condition occurs, as well as instances in which the event or condition does not.
"Prevent" and "prevent" are used interchangeably herein. These terms refer to methods of achieving a beneficial or desired result, including but not limited to prophylactic benefit. To obtain a "prophylactic benefit," lactobacillus fermentum or a product containing the same may be administered to a subject at risk of suffering from a particular disease, or to a subject reporting one or more physiological symptoms of the disease, even though a diagnosis of the disease may not have been made.
In this context, the terms "treatment" and "alleviation" both refer to the use of the terms "treatment" and "alleviation" in order to obtain a desired pharmacological and/or physiological effect. The effect may be prophylactic in terms of completely or partially preventing the disease or symptoms thereof, and/or may be therapeutic in terms of partially or completely curing the disease and/or adverse effects caused by the disease. "treating" as used herein encompasses diseases in mammals, particularly humans, including (a) preventing the occurrence of a disease or disorder in an individual susceptible to the disease but not yet diagnosed with the disease, (b) inhibiting the disease, e.g., arresting the development of the disease, or (c) alleviating the disease, e.g., alleviating symptoms associated with the disease. As used herein, "treating" or "treatment" encompasses any administration of a drug or compound to an individual to treat, cure, alleviate, ameliorate, reduce or inhibit a disease in the individual, including, but not limited to, administration of a drug comprising a compound described herein to an individual in need thereof.
The invention provides lactobacillus gasseri VB247, fermentation supernatant, fermentation liquor, microbial agent, food, health food, medicine or sanitary product and application thereof, and the detailed description will be given below.
Bacterial strain
In one aspect of the invention, the invention provides a lactobacillus gasseri (Lactobacillus gasseri) VB247. According to the embodiment of the invention, the preservation number of the lactobacillus gasseri VB247 is CGMCC No.26575. The lactobacillus gasseri VB247 has the advantages of low pH resistance, vagina pH environment regulation, high lactic acid yield, resistance to 5 common vagina pathogenic bacteria, strong vagina cell adhesion capacity and the like, and can obviously improve the expression level of AQP2mRNA in female cervical and vaginal epithelial cells.
Herein, "lactobacillus gasseri (Lactobacillus gasseri) VB247" is synonymous with "lactobacillus gasseri VB 247".
Fermentation supernatant
In another aspect of the invention, the invention provides a fermentation supernatant. According to an embodiment of the invention, the fermentation supernatant comprises the aforementioned Lactobacillus gasseri VB247 and/or the metabolite of the aforementioned Lactobacillus gasseri VB 247.
The term "fermentation supernatant" means a supernatant of a fermentation broth after centrifugation and filtration, and mainly contains metabolites of lactobacillus gasseri VB247.
Fermentation liquor
In yet another aspect of the invention, the invention provides a fermentation broth. According to an embodiment of the invention, the fermentation broth comprises the aforementioned lactobacillus gasseri VB247.
The term "fermentation liquid" as used herein refers to a solution obtained by culturing lactobacillus gasseri VB247 for a period of time.
Microbial agent
In yet another aspect of the invention, the invention provides a microbial agent. According to an embodiment of the invention, the microbial agent comprises the lactobacillus gasseri VB247 and/or the fermentation supernatant and/or the fermentation broth. The microbial agent of the invention is used for preventing and/or treating related diseases caused by vaginal flora disorder.
The microbial agent of the invention can be a microbial liquid agent, including but not limited to fermentation broth, and the like, or a microbial solid agent, including but not limited to freeze-dried powder, and the like.
According to an embodiment of the invention, the lactobacillus gasseri VB247 is present in the form of living and/or non-living cells.
As used herein, "viable cells" means that Lactobacillus gasseri VB247 has the ability to metabolize, reproduce or replicate.
Illustratively, the living cells may be immobilized cells. As used herein, "immobilized cells" refer to Lactobacillus gasseri VB247 immobilized on a carrier and capable of performing vital activities such as growth, development, reproduction, inheritance, and metabolism in a certain spatial range.
As used herein, "non-living cells" refers to cells that do not have the ability to metabolize, reproduce, and replicate, including but not limited to stem cells. Illustratively, the microbial agent is a lyophilized powder.
As a specific embodiment, the lactobacillus gasseri VB247 is present as living cells, as dry cells, as immobilized cells or in any other form.
As a specific embodiment, the dry cell is obtained by freeze-drying the lactobacillus gasseri VB 247.
As a specific embodiment, the microbial agent may further comprise at least one strain acceptable in foods, medicines, health foods and feeds.
As a specific embodiment, the microbial agent further comprises a pharmaceutically acceptable auxiliary material or carrier, or a food or health food acceptable auxiliary material or carrier.
Herein, "food acceptable" refers to a substance or composition that is edible to humans, which can be tailored to the food requirements of different countries.
As used herein, "acceptable in a health food" refers to a substance or composition that is edible to humans and that can be tailored to the health food requirements of different countries.
As used herein, "pharmaceutically acceptable" means that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients comprising the formulation and/or the mammal being treated therewith. Preferably, the term "pharmaceutically acceptable" as used herein refers to use in animals, particularly humans, approved by the federal regulatory agency or a state government or listed in the U.S. pharmacopeia or other generally recognized pharmacopeia.
Herein, the term "pharmaceutically acceptable carrier" includes any solvent, pharmaceutical stabilizer, or combination thereof, which are known to those of skill in the art. Except insofar as any conventional carrier is incompatible with the active ingredient, its use in therapeutic or pharmaceutical compositions is contemplated.
As used herein, the term "pharmaceutically acceptable excipients" may include any solvent suitable for the particular target dosage form. In addition to the extent to which any conventional adjuvant is incompatible with lactobacillus gasseri VB247 of the present disclosure, such as any adverse biological effects produced or interactions with any other component of the pharmaceutically acceptable composition in a deleterious manner, their use is also contemplated by the present disclosure.
Use of the same
In a further aspect of the invention, the invention provides the use of the lactobacillus gasseri VB247, the fermentation supernatant, the fermentation broth or the microbial agent in the preparation of medicaments, wherein the medicaments have at least one of the following uses for preventing and/or relieving and/or treating vaginal lubrication disorder, preventing and/or relieving and/or treating vaginal pathogenic bacteria infection or related diseases caused by vaginal pathogenic bacteria infection, improving the expression level of AQP2 mRNA of vaginal epithelial cells and regulating the vaginal pH environment.
As a specific embodiment, the vaginal lubrication disorder includes, but is not limited to, perimenopausal and premature ovarian failure and the like, vaginal lubrication disorder caused by estrogen deficiency.
As a specific embodiment, the pathogenic bacteria is selected from at least one of staphylococcus aureus, escherichia coli, candida albicans, gardnerella vaginalis, and clostridium perfringens.
Food, health food or sanitary article
In a further aspect of the invention, the invention provides a food, a health food or a sanitary product comprising at least one of the aforementioned lactobacillus gasseri VB247, the aforementioned fermentation supernatant, the aforementioned fermentation broth and the aforementioned microbial agent.
Medicament
In a further aspect of the invention, the invention provides a medicament comprising at least one of the aforementioned lactobacillus gasseri VB247, the aforementioned fermentation supernatant, the aforementioned fermentation broth and the aforementioned microbial agent.
As a specific embodiment, the medicament further comprises an excipient and/or carrier.
As a specific embodiment, the excipient includes at least one selected from the group consisting of a binder, a disintegrant, a lubricant, a glidant, a stabilizer, a filler, a diluent, and a slow-release agent.
As a specific embodiment, the carrier includes at least one selected from the group consisting of saccharides, cellulose and derivatives thereof, calcium phosphates, alkaline earth metal stearates, vegetable oils, nonionic surfactants, cationic surfactants, anionic surfactants, fatty alcohols, and cereal hydrolytic solids.
In a specific embodiment, the dosage form of the drug comprises at least one selected from oral liquid, powder, granules, capsules, tablets and dripping pills.
The scheme of the present invention will be explained below with reference to examples. It will be appreciated by those skilled in the art that the following examples are illustrative of the present invention and should not be construed as limiting the scope of the invention. The examples are not to be construed as limiting the specific techniques or conditions described in the literature in this field or as per the specifications of the product. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
Example 1 Strain harvesting and identification
68 Vaginal fluid samples of women (Hangzhou, china) passing through the healthy physical examination are collected by using a disposable sterile cotton swab, the vaginal fluid samples are coated on an MRS solid culture medium, after anaerobic culture is carried out for 48 hours at 37 ℃, single bacterial colonies of suspected lactobacillus are selected, the bacterial 16S rDNA is amplified and sequenced, sequencing results are BLAST compared, strains are analyzed according to the comparison results and are respectively stored by glycerol tubes, and a total 157 strains of lactobacillus griseus with the numbers of #1- #157 are obtained. After the 157 strains of lactobacillus gasseri are subjected to low-pH environment growth activity, lactic acid production capability, pH regulation capability, antagonism capability to five vaginal pathogenic bacteria, heLa cell adhesion capability and antibiotic sensitivity test, a strain of lactobacillus gasseri #18 with the best performance is obtained by screening, which is named as lactobacillus gasseri VB247 and is preserved in China general microbiological culture Collection center (China general microbiological culture Collection center) for 20 months in 2023, with a preservation address of North Star West line No. 1, a region of Korea of Beijing, and a preservation number of CGMCC No.26575. The scanning electron microscope image of the Lactobacillus gasseri VB247 is shown in figure 1, and the bacterium has a better appearance form and is cylindrical.
The sequencing result of 16S rDNA of the Lactobacillus gasseri VB247 is shown in SEQ ID NO. 1.
CTGCTATCACTCTTGGATGGACCTGCGGTGCATTAGCTAGTTGGTAAGGTAACGGCTTACCAAGGCAATGATGCATAGCCGAGTTGAGAGACTGATCGGCCACATTGGGACTGAGACACGGCCCAAACTCCTACGGGAGGCAGCAGTAGGGAATCTTCCACAATGGACGCAAGTCTGATGGAGCAACGCCGCGTGAGTGAAGAAGGGTTTCGGCTCGTAAAGCTCTGTTGGTAGTGAAGAAAGATAGAGGTAGTAACTGGCCTTTATTTGACGGTAATTACTTAGAAAGTCACGGCTAACTACGTGCCAGCAGCCGCGGTAATACGTAGGTGGCAAGCGTTGTCCGGATTTATTGGGCGTAAAGCGAGTGCAGGCGGTTCAATAAGTCTGATGTGAAAGCCTTCGGCTCAACCGGAGAATTGCATCAGAAACTGTTGAACTTGAGTGCAGAAGAGGAGAGTGGAACTCCATGTGTAGCGGTGGAATGCGTAGATATATGGAAGAACACCAGTGGCGAAGGCGGCTCTCTGGTCTGCAACTGACGCTGAGGCTCGAAAGCATGGGTAGCGAACAGGATTAGATACCCTGGTAGTCCATGCCGTAAACGATGAGTGCTAAGTGTTGGGAGGTTTCCGCCTCTCAGTGCTGCAGCTAACGCATTAAGCACTCCGCCTGGGGAGTACGACCGCAAGGTTGAAACTCAAAGGAATTGACGGGGGCCCGCACAAGCGGTGGAGCATGTGGTTTAATTCGAAGCAACGCGAAGAACCTTACCAGGTCTTGACATCCAGTGCAAACCTAAGAGATTAGGTGTTCCCTTCGGGGACGCTGAGACAGGTGGTGCATGGCTGTCGTCAGCTCGTGTCGTGAGATGTTGGGTTAAGTCCCGCAACGAGCGCAACCCTTGTCATTAGTTGCCATCATTAAGTTGGGCACTCTAATGAGACTGCCGGTGACAAACCGGAGGAAGGTGGGGATGACGTCAAGTCATCATGCCCCTTATGACCTGGGCTACACACGTGCTACAATGGACGGTACAACGAGAAGCGAACCTGCGAAGGCAAGCGGATCTCTGAAAGCCGTTCTCA GTTCGGACTGTAGGCTGCAACTCGCCTACACGAAGCTGGAATCGCTAGTAATCGCGGATCAGCACGCCGCGGTGAATACGTTCCCGGGCCTTGTACACACCGCCCGTCACACCATGAGAGTCTGTAACACCCAAAGCCGGTGGGATAACCTTTATAGGAGTCAGCCGTCTAAGCTGTCTCG(SEQ ID NO:1).
The 16S rDNA sequencing result of Lactobacillus gasseri isolate #86 is shown in SEQ ID NO. 2.
ATTAGCTAGTTGGTAAGGTAACGGCTTACCGAGGCAATGATGCATAGCCGAGTTGAGAGACTGATCGGCCACATTGGGACTGAGACACGGCCCAAACTCCTACGGGAGGCAGCAGTAGGGAATCTTCCACAATGGACGCAAGTCTGATGGAGCAACGCCGCGTGAGTGAAGAAGGGTTTCGGCTCGTAAAGCTCTGTTGGTAGTGAAGAAAGATAGAGGTAGTAACTGGCCTTTATTTGACGGTAATTACTTAGAAAGTCACGGCTAACTACGTGCCAGCAGCCGCGGTAATACGTAGGTGGCAAGCGTTGTCCGGATTTATTGGGCGTAAAGCGAGTGCAGGCGGTTCAATAAGTCTGATGTGAAAGCCTTTGGCTCAACCGGAGAATTGCATCAGAAACTGTTGAACTTGAGTGCAGAAGAGGAGAGTGGAACTCCATGTGTAGCGGTGGAATGCGTAGATATATGGAAGAACACCAGTGGCGAAGGCGGCTCTCTGGTCTGCAACTGACGCTGAGGCTCGAAAGCATGGGTAGCGAACAGGATTAGATACCCTGGTAGTCCATGCCGTAAACGATGAGTGCTAAGTGTTGGGAGGTTTCCGCCTCTCAGTGCTGCAGCTAACGCATTAAGCACTCCGCCTGGGGAGTACGACCGCAAGGTTGAAACTCAAAGGAATTGACGGGGGCCCGCACAAGCGGTGGAGCATGTGGTTTAATTCGAAGCAACGCGAAGAACCTTACCAGGTCTTGACATCCAGTGCAAACCTAAGAGATTAGGTGTTCCCTTCGGGGACGCTGAGACAGGTGGTGCATGGCTGTCGTCAGCTCGTGTCGTGAGATGTTGGGTTAAGTCCCGCAACGAGCGCAACCCTTGTCATTAGTTGCCATCATTAAGTTGGGCACTCTAATGAGACTGCCGGTGACAAACCGGAGGAAGGTGGGGATGACGTCAAGTCATCATGCCCCTTATGACCTGGGCTACACACGTGCTACAATGGACGGTACAACGAGAAGCGAACCTGCGAAGGCAAGCGGATCTCTGAAAGCCGTTCTCAGTTCGGACTGTAGGCTGCAACTCGCCTACACGAAGCTGGAATCGCTAGTAATCGCGGATCAGCACGCCGCGGTGAATACGTTCCCGGGCCTTGTACACACCGCCCGTCACACCATGAGAGTCTGTAACACCCAAAGCCGGTGGGATAACCTTTATAGGAGTCAGCCGTCTATGTGATAG(SEQ ID NO:2).
Physiological and biochemical characteristics analysis was performed on lactobacillus gasseri VB247 and lactobacillus gasseri isolate #86, specific experiments were performed with reference to the berkovich bacteria identification manual, the detection results are shown in table 1, and the strain VB247 obtained by screening in this example can utilize milk, and various carbohydrates such as L-rhamnose, mannitol and sorbitol, compared with lactobacillus gasseri isolate # 86.
TABLE 1 physiological and biochemical characteristics of different Lactobacillus gasseri
| Authentication item | VB247 | #86 |
| Inulin | + | + |
| Lactose and lactose | + | + |
| Glucose | + | + |
| D-ribose | - | - |
| Melezitose | - | - |
| Galactose | + | + |
| Gluconate salt | - | - |
| Mannose | + | + |
| Fructose | + | + |
| Trehalose | + | + |
| Xylose | + | + |
| Melibiose | + | + |
| Melezitose | + | + |
| Methyl red (M.R) | - | + |
| V-P assay | - | + |
| Gelatin liquefaction | - | - |
| Starch hydrolysis | - | - |
Note that +is positive and-negative.
Example 2 growth Activity experiments in Low pH Environment
After the activation of different lactobacillus gasseri (lactobacillus gasseri VB247 and lactobacillus gasseri isolate #86 obtained in example 1 of the present invention), the respective inoculated amounts were 1% and anaerobic cultured in MRS broth medium at 37 ℃ for 48 hours at ph=4.0, and OD 600 of the fermentation broth was measured every 4 hours. Fig. 2 shows the change curve of OD 600 with time of lactobacillus gasseri VB247 and lactobacillus gasseri isolate #86 at ph=4.0, and it can be seen from fig. 2 that when cultured for 4 hours, the OD 600 of lactobacillus gasseri VB247 is increased by 20.9% compared with the initial value, while lactobacillus gasseri isolate #86 is increased by only 1.2%, when cultured for 8 hours, the OD 600 of lactobacillus gasseri VB247 is increased by 101.2% compared with the initial value, while lactobacillus gasseri isolate #86 is increased by only 18.5%, and the slope of lactobacillus gasseri VB247 in the logarithmic phase of growth is higher, the OD 600 value of the stationary phase of growth is higher, which indicates that the growth of lactobacillus gasseri VB247 in the low pH environment is started faster, the activation rate is higher, and the growth activity is stronger.
EXAMPLE 3 lactic acid producing Capacity
The fermentation broths of the different Lactobacillus gasseri (Lactobacillus gasseri VB247 and Lactobacillus gasseri isolate #86 obtained in example 1 of the present invention) after 48 hours of cultivation in example 2 were centrifugally filtered to obtain fermentation supernatants, and the L-lactic acid content in the fermentation supernatants was measured by a biological process analyzer, and the D-lactic acid content was measured by a D-lactic acid detection kit, and the results are shown in Table 2.
The study shows that lactic acid produced by metabolism of lactobacillus in vagina can inhibit growth of pathogenic bacteria in vagina and maintain vaginal health, and from table 2, lactobacillus gasseri VB247 obtained by the invention can produce more L-lactic acid and D-lactic acid compared with lactobacillus gasseri isolate #86, the amount of L-lactic acid and D-lactic acid is nearly twice that of isolate #86, and lactobacillus gasseri VB247 can produce more L-lactic acid and D-lactic acid, so that the lactobacillus gasseri VB247 of the invention is more beneficial to maintaining vaginal health of human body.
TABLE 2 lactic acid content in 48h fermentation broths of different Lactobacillus gasseri
| Lactobacillus gasseri | VB247 | #86 |
| L-lactic acid content (g/L) | 6.35 | 3.74 |
| D-lactic acid content (g/L) | 12.60 | 6.51 |
Example 4 pH ability to adjust
It has been found that in normal female vaginal environments, pH values between 3.8 and 4.4 are usually accompanied by elevated vaginal pH when the vaginal flora is disturbed, due to excessive proliferation of other pathogenic bacteria, mainly aerobic bacteria.
After the activation of different lactobacillus gasseri (lactobacillus gasseri VB247 and lactobacillus gasseri isolate #86 obtained in example 1 of the present invention), the respective inoculated amounts were inoculated in an MRS broth medium having a ph=6.5 at 37 ℃ for anaerobic culture for 48 hours, and the pH of the fermentation broth was measured every 4 hours, and the detection results are shown in fig. 3.
As can be seen from fig. 3, the lactobacillus gasseri VB247 obtained by the present invention can lower pH faster than lactobacillus gasseri isolate #86 and reach an acid-base balance at pH 4, which indicates that the strain can create and maintain a healthy vaginal pH environment.
Example 5 antagonism against five common vaginal pathogens
The bacteriostatic activity of different Lactobacillus gasseri (Lactobacillus gasseri VB247 and Lactobacillus gasseri isolate #86 obtained in example 1 of the invention) on five common vaginal pathogenic bacteria was measured by a double plate method, and the specific method is as follows:
After different Lactobacillus gasseri (Lactobacillus gasseri VB247 and Lactobacillus gasseri isolate #86 obtained in example 1 of the present invention) were activated, 2. Mu.L of each of the strain was inoculated on MRS solid plates and cultured anaerobically at 37℃for 48 hours.
The activated indicator bacteria (staphylococcus aureus ATCC 6538, escherichia coli ATCC 8099, candida albicans ATCC 10231, gardnerella vaginalis ATCC 14018 and clostridium perfringens ATCC 13124) bacterial liquid and a melted agar medium cooled to 40-45 ℃ after sterilization are mixed according to a certain proportion, the indicator bacteria concentration is 10 6 CFU/mL, the mixture is poured into a plate of the lactobacillus griseus after 48h culture, the plate is placed in an environment suitable for the indicator bacteria for 16-18h, the size of a bacteriostasis circle is observed and recorded to compare the bacteriostasis activities of different lactobacillus griseus, and the detection results are shown in table 3.
As shown in Table 3, the Lactobacillus gasseri VB247 has antibacterial effect on Escherichia coli, staphylococcus aureus, candida albicans, gardnerella vaginalis and Clostridium perfringens with the antibacterial ring diameter larger than 7mm, and has stronger antibacterial effect on five bacteria than Lactobacillus gasseri isolate # 86.
TABLE 3 results of inhibition zone tests of different Lactobacillus gasseri against 5 pathogenic bacteria
EXAMPLE 6 adhesion HeLa cell assay
After different Lactobacillus gasseri (Lactobacillus gasseri VB247 and Lactobacillus gasseri isolate #86 obtained in example 1 of the present invention) were activated, inoculated into MRS broth medium having a pH of 6.5, cultured overnight at 37℃and centrifuged to wash the cells 2 times, the PBS was resuspended to 10 8 CFU/mL to obtain a bacterial suspension containing different Lactobacillus gasseri, 100. Mu.L of the bacterial suspension containing different Lactobacillus gasseri was aspirated into HeLa cell-containing six-well cell culture plates (3X 10 5/well), allowed to stand at 37℃for incubation for 2 hours, washed 2 times with sterile PBS to wash free Lactobacillus, and after HeLa cells were digested to spherical in a 37℃incubator, 75. Mu.L of DMEM medium (containing 10% fetal bovine serum) was added to each well, and after repeated pipetting was homogenized, 20. Mu.L of the bacterial suspension was aspirated, diluted with sterile PBS, and a proper gradient was selected for plating, and the results were shown in FIG. 4.
As shown in FIG. 4, the Lactobacillus gasseri VB247 obtained by the screening according to the present invention has a higher number of bacteria adhered per HeLa cell than Lactobacillus gasseri isolate #86, which indicates that the strain is easier to colonize in the vagina.
Example 7 Effect on AQP2 mRNA expression in vaginal epithelial cells
VK2/E6E7 human vaginal epithelial cells were purchased from Shanghai Gejia biotechnology Co., ltd, resuscitated and passaged according to the product instructions and seeded in 36 well plates. Then, three groups of 3 were divided into each of 6-well plates, wherein 100. Mu.L of the fermentation supernatant of Lactobacillus gasseri VB247 cultured for 48 hours in example 2 was added to two wells, and the cells were collected by culturing for 24 hours and 48 hours, 100. Mu.L of the fermentation supernatant of Lactobacillus gasseri isolate #86 cultured for 48 hours in example 2 was added to two wells, and the cells were collected by culturing for 24 hours and 48 hours, and 100. Mu.L of progesterone was added to two wells at a final concentration of 10nmol/L, and the cells were collected as positive controls. Among them, progesterone is an estrogen which can relieve vaginal lubrication disorder during menopause, and there are reports that progesterone can promote the expression of AQP 2mRNA (tensor, etc. the influence of factors related to vaginal microenvironment on the expression of aquaporin 2mRNA in vaginal epithelial cells [ J ]. Chinese science 2021,30 (4): 4.). AQP 2mRNA expression in vaginal epithelial cells was observed using REAL TIME PCR technique and the results are shown in FIG. 5.
As shown in FIG. 5, the Lactobacillus gasseri VB247 obtained by screening according to the invention can significantly increase the expression level of AQP2 mRNA in female cervical/vaginal epithelial cells compared with Lactobacillus gasseri isolate # 86.
In the description of the present specification, a description referring to terms "one embodiment," "some embodiments," "examples," "specific examples," or "some examples," etc., means that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the present invention. In this specification, schematic representations of the above terms are not necessarily directed to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, the different embodiments or examples described in this specification and the features of the different embodiments or examples may be combined and combined by those skilled in the art without contradiction.
While embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are illustrative and not to be construed as limiting the invention, and that variations, modifications, alternatives and variations may be made to the above embodiments by one of ordinary skill in the art within the scope of the invention.
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| KR101860552B1 (en) * | 2015-04-16 | 2018-07-02 | 주식회사 고바이오랩 | Lactobacilli having inhibitory effect against pathogenic microorganisms in vagina |
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| KR101953072B1 (en) * | 2018-11-09 | 2019-02-27 | 에스케이바이오랜드 주식회사 | Novel lactic acid bacteria Lactobacillus gasseri SKB1102, or Cosmetic composition comprising the same for anti-pollution |
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