CN118086152A - Composite probiotics for improving bacterial vaginitis, probiotics preparation and application thereof - Google Patents
Composite probiotics for improving bacterial vaginitis, probiotics preparation and application thereof Download PDFInfo
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- CN118086152A CN118086152A CN202410497649.2A CN202410497649A CN118086152A CN 118086152 A CN118086152 A CN 118086152A CN 202410497649 A CN202410497649 A CN 202410497649A CN 118086152 A CN118086152 A CN 118086152A
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- probiotic
- bacterial
- bacterial vaginitis
- vaginal
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Landscapes
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Abstract
The invention relates to a composite probiotic for improving bacterial vaginitis, a probiotic agent and application thereof, wherein the composite probiotic for improving bacterial vaginitis consists of a lactobacillus paracasei LC86 strain and a lactobacillus rhamnosus LRa66 strain. The compound probiotics can obviously regulate and balance the pH value of the vaginal environment and optimize the health state of the vagina; remarkably improves the level of cytokines in the vagina environment and promotes the balance of inflammatory reaction in the vagina; remarkably regulate the diversity of vaginal flora and restore the healthy microbial community structure. Under the condition of consistent bacterial use, compared with a single LC86 strain or a single LRa66 strain, the compound of the two bacteria is obviously improved in the efficacy, namely, the LC86 strain and the LRa66 strain have potential interaction and can be mutually matched, so that the synergistic effect is achieved in the efficacy of improving bacterial vaginitis.
Description
Technical Field
The invention belongs to the technical field of probiotics, and relates to composite probiotics and probiotics preparation for improving bacterial vaginitis and application thereof.
Background
Bacterial Vaginitis (BV) is characterized by a disruption of the normal flora balance in the vagina, especially by a significant decrease in the number of lactobacilli, leading to an excessive increase in harmful bacteria. Currently, conventional treatments for bacterial vaginitis include antibiotic therapy, however antibiotic therapy has various limitations including high recurrence rate, possibility of disrupting normal flora in vagina and antibiotic resistance. Probiotics have great potential in restoring and maintaining vaginal microecological balance as a natural and safe intervention. Probiotics, particularly lactobacillus, are capable of combating bacterial vaginitis by a variety of mechanisms, including the production of antibacterial substances (such as lactic acid and hydrogen peroxide) to inhibit the growth of harmful bacteria, lowering the vaginal pH to promote the growth of healthy flora, and competing with host cell adhesion to prevent the adhesion and invasion of harmful bacteria. Therefore, it is very interesting to develop more probiotic intervention modes with high activity and specificity, and to provide more effective and safe treatment strategies for bacterial vaginitis.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide composite probiotics and probiotics for improving bacterial vaginitis and application thereof, in particular to composite probiotics and probiotics for improving bacterial vaginitis and application thereof in preparing products for preventing, relieving or treating bacterial vaginitis.
In order to achieve the aim of the invention, the invention adopts the following technical scheme:
In a first aspect, the invention provides a composite probiotic for improving bacterial vaginitis, which consists of a Lactobacillus paracasei strain PARACASEI LC with a preservation number of CGMCC No.1.12731 and a Lactobacillus rhamnosus Lactobacillus rhamnosus LRa strain with a preservation number of CGMCC No. 24282.
The compound probiotics related to the invention can obviously regulate and balance the pH value of the vaginal environment and optimize the health state of the vagina; remarkably improves the level of cytokines in the vagina environment and promotes the balance of inflammatory reaction in the vagina; remarkably regulate the diversity of vaginal flora and restore the healthy microbial community structure. Under the condition of consistent bacterial use, compared with a single LC86 strain or a single LRa66 strain, the compound of the two bacteria is obviously improved in the efficacy, namely, the LC86 strain and the LRa66 strain have potential interaction and can be mutually matched, so that the synergistic effect is achieved in the efficacy of improving bacterial vaginitis.
Preferably, the ratio of the viable count of Lactobacillus paracasei PARACASEI LC strain to Lactobacillus rhamnosus Lactobacillus rhamnosus LRa strain is 1:10-10:1, for example, 1:10, 1:9, 1:8, 1:7, 1:6, 1:5, 1:4, 1:3, 1:2, 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, etc., and other specific values within the above numerical ranges are selectable, and will not be described herein in detail.
In a second aspect, the present invention provides a probiotic for the amelioration of bacterial vaginitis, the strain of which comprises the complex probiotic of the first aspect.
Preferably, in the probiotic agent, the total number of viable bacteria is not lower than 2×10 9 CFU/mL or 2×10 9 CFU/g, such as 5×109 CFU/mL（CFU/g）、1×1010 CFU/mL（CFU/g）、5×1010 CFU/mL（CFU/g）、1×1011 CFU/mL（CFU/g）、1×1012 CFU/mL（CFU/g）、1×1013 CFU/mL（CFU/g）, etc.; other specific point values within the numerical range can be selected, and will not be described in detail herein.
Preferably, the formulation of the probiotic agent comprises freeze-dried powder, capsules, tablets or granules.
Preferably, the probiotic agent is in the form of freeze-dried powder, and is prepared by the following preparation method:
Respectively inoculating an LC86 strain and an LRa66 strain into a culture medium to sequentially perform activation and fermentation culture to obtain a fermentation broth; respectively centrifuging the fermentation liquid, mixing with a freeze-drying protective agent, and freeze-drying to obtain LC86 bacterial powder and LRa66 bacterial powder; mixing LC86 bacterial powder and LRa66 bacterial powder according to the ratio of the viable count to obtain the probiotic agent for improving bacterial vaginitis.
Preferably, the lyoprotectant is selected from any one or a combination of at least two of skim milk, gelatin, dextrin, acacia, dextran, sodium alginate, polyvinylpyrrolidone, sucrose, lactose, trehalose, sorbitol or xylitol.
In a third aspect, the present invention provides the use of a complex probiotic according to the first aspect or a probiotic according to the second aspect in the manufacture of a product for the prevention, alleviation or treatment of bacterial vaginitis.
Preferably, the product also contains auxiliary materials.
Preferably, the auxiliary material is selected from any one or a combination of at least two of fructo-oligosaccharide, galacto-oligosaccharide, xylo-oligosaccharide, isomalto-oligosaccharide, soy oligosaccharide, inulin, spirulina, arthrospira, coriolus versicolor polysaccharide, stachyose or polydextrose.
Compared with the prior art, the invention has the following beneficial effects:
The compound probiotics related to the invention can obviously regulate and balance the pH value of the vaginal environment and optimize the health state of the vagina; remarkably improves the level of cytokines in the vagina environment and promotes the balance of inflammatory reaction in the vagina; remarkably regulate the diversity of vaginal flora and restore the healthy microbial community structure. Under the condition of consistent bacterial use, compared with a single LC86 strain or a single LRa66 strain, the compound of the two bacteria is obviously improved in the efficacy, namely, the LC86 strain and the LRa66 strain have potential interaction and can be mutually matched, so that the synergistic effect is achieved in the efficacy of improving bacterial vaginitis. And as the composite probiotics are probiotics, the composite probiotics have high safety and are not easy to generate resistance when being used for preparing products with related effects.
The LC86 strain related by the invention is classified and named as Lactobacillus paracasei Lactobacillus paracasei, the preservation unit is China general microbiological culture Collection center, the preservation time is 7 months and 20 days in 2020, the preservation number is CGMCC No.1.12731, and the address is: the korean district North Star, beijing city, part No.1, no. 3.
The LRa66 strain related by the invention is classified and named as lactobacillus rhamnosus Lactobacillus rhamnosus, the preservation unit is China general microbiological culture Collection center (China Committee for culture Collection of microorganisms), the preservation time is 2022, 1 month and 10 days, the preservation number is CGMCC No.24282, and the address is: the korean district North Star, beijing city, part No. 1, no. 3.
Drawings
FIG. 1 is a graph of vaginal pH statistics for each group of rats;
FIG. 2 is a graph showing statistics of interleukin-1β (IL-1β) levels in vaginal lavage fluid of each group of rats;
FIG. 3 is a graph showing statistics of interleukin-2 (IL-2) levels in vaginal lavage fluid of each group of rats;
FIG. 4 is a graph showing statistical results of interleukin-13 (IL-13) levels in vaginal lavage fluid of each group of rats;
FIG. 5 is a graph showing statistics of immunoglobulin A (IgA) levels in vaginal lavage fluid of each group of rats;
FIG. 6 is a graph of Chao1 index statistics of microflora in vaginal secretions of rats of each group;
FIG. 7 is a graph showing the statistical results of shannon index of the microbial community in vaginal secretions of rats of each group.
Detailed Description
The technical scheme of the invention is further described by the following specific embodiments. It will be apparent to those skilled in the art that the examples are merely to aid in understanding the invention and are not to be construed as a specific limitation thereof.
The medium formulations referred to in the examples below were as follows:
MRS Medium (g/L): 10g/L of peptone, 10g/L of beef extract, 20g/L of glucose, 2g/L of sodium acetate, 5g/L of yeast powder, 1ml/L of 2g/L、K2PO4·3H2O 2.6g/L、MgSO4·7H2O 0.1g/L、MnSO4 0.05g/L、 Tween 80 and 0.5g/L of cysteine hydrochloride.
The LC86 strain according to the following examples was classified as Lactobacillus paracasei Lactobacillus paracasei, and was deposited for a period of time of 7 months and 20 days in 2020, with a accession number of CGMCC No.1.12731.
The classification of the LRa66 strain related to the following embodiment is named as lactobacillus rhamnosus Lactobacillus rhamnosus, the preservation time is 2022, 1 month and 10 days, and the preservation number is CGMCC No.24282.
The preparation method of the bacterial suspension comprises the following steps: inoculating the required strain into MRS liquid culture medium, culturing at 37deg.C for 24 hr for activation, and continuously activating for 2 times to obtain activating solution; inoculating the activating solution into MRS liquid culture medium according to an inoculum size of 4% (v/v), and culturing at 37 ℃ for 30 h to obtain bacterial solution; centrifuging the bacterial liquid at 5000rpm at 4deg.C for 6 min, filtering to obtain bacterial cells, and re-suspending bacterial cells with PBS solution.
Statistical analysis of experimental results data using ggplot of R language, # represents p <0.001, # represents p <0.01, # represents p <0.05, compared to CTL group; compared to the MC group, p <0.001, p <0.01, p <0.05, ns represents no significant difference.
Examples
This example explores the symptom improvement ability of probiotics on bacterial vaginitis rat models:
(1) Test animals: SPF-class female SD rats (56, 180-200 g, purchased from Shanghai laboratory animal center). The rats were kept under a controlled environment, maintained at room temperature of 22.+ -. 2 ℃ and humidity of 55%.+ -. 5%, following a 12h light/dark cycle. They can eat and drink water at will. All experimental procedures involving rats were in compliance with the ethical guidelines for animal care and use prescribed by the Shanghai laboratory animal Care and animal Experimental center.
(2) Grouping animals: after 1 week of adaptive feeding, 56 mice were randomly divided into 7 groups (8 per group): control group (CTL group), model group (MC group), interference group by LC86 strain (LC 86 group, denoted as S1 group), interference group by LRa66 strain (LRa 66 group, denoted as S2 group), interference group by commercial lactobacillus paracasei strain ATCC11582 (ATCC 11582 group, denoted as S3 group), combined interference group by LC86 strain and LRa66 strain (LC 86+lra66 group, ratio of viable count of two strains 2:1, denoted as S4 group), combined interference group by commercial lactobacillus paracasei strain ATCC11582 and LRa66 strain (ATCC 11582 +lra66 group, ratio of viable count of two strains 2:1, denoted as S5 group).
(3) Animal modeling and intervention method:
The rats of each group except the control group were induced to a state of pseudo-oestrus by subcutaneous injection of 0.2g of estradiol benzoate injection, 1 time per day, for 6 days. Subsequently, a bacterial vaginitis model was constructed by injecting a suspension of Escherichia coli (20. Mu.L each) at a concentration of 2X 10 8 CFU/mL through the vagina for 6 consecutive days. The successful standard for model construction was that the appearance of the vaginal orifice of the rat appeared to be hyperemic and red with a large amount of white viscous secretions, and the examination of the secretions showed vigorous strain growth. Rats in the control group and the model group were fed with normal feed and sterile water from the beginning to the end of the experiment (total 30 days), and rats in each probiotic-intervention group were fed with feed containing probiotics and sterile water from the beginning to the end of the experiment (total 30 days) (total bacterial load of each group was 1X 10 9 CFU/day).
(4) And (3) index analysis:
(4.1) determination of vaginal pH:
After 24 hours of last dose, the rat vaginal orifice was inserted using pH paper to ensure adequate contact with vaginal secretions and then removed quickly and then compared to a standard colorimetric card to record vaginal pH.
As a result, as shown in FIG. 1, the vaginal pH of the rats in the MC group was abnormally elevated, which is a key index for bacterial vaginitis, compared with that in the CTL group, reflecting imbalance between the vaginal microflora imbalance, particularly, the decrease in the number of beneficial lactobacilli and the excessive increase in harmful bacteria. After probiotic intervention, especially after S4 group dry prognosis, the vaginal pH of the bacterial vaginitis rats was significantly reduced. The result shows that the probiotics intervention can effectively restore the microecological balance of the vagina, increase the number of beneficial bacteria such as lactobacillus and the like, thereby reducing the pH value of the vagina, creating an acidic environment which is unfavorable for harmful bacteria and indicating the conversion of the vaginal environment to a healthy state.
(4.2) After completion of the pH assay, all rats were fasted and kept water-out overnight in preparation for cytokine detection. The next day, the vagina of the rat was washed three times with 100. Mu.L of physiological saline, and vaginal lavage fluid was collected, and after the lavage fluid was left at 25℃for 30min, it was centrifuged at 3000 r/min for 10min at 4℃to separate the supernatant. Finally, the level of interleukin-1 beta (IL-1 beta), interleukin-2 (IL-2), interleukin-13 (IL-13) and immunoglobulin A (IgA) cytokines is detected by adopting a double antibody sandwich method and combining an enzyme-labeled instrument according to the strict operation of the instruction of a corresponding kit (Wuhan purity biotechnology Co., ltd.).
As shown in fig. 2 to 5, the results show that the levels of interleukin-1 beta (IL-1 beta) and interleukin-2 (IL-2) in the vaginal lavage fluid of the rats in the MC group were abnormally increased and the levels of interleukin-13 (IL-13) and immunoglobulin a (IgA) were abnormally decreased, compared with the CTL group, and this result indicates that the bacterial vaginitis model was successfully established, and the typical inflammatory reaction of the vaginal environment in the bacterial vaginitis state, namely, the increase of inflammatory factors and the decrease of anti-inflammatory factors, were simulated, reflecting the inflammatory state of the vaginal microenvironment and the disturbance of immune function. But after the intervention of probiotics, the effect of the S4 group is most obvious, the levels of interleukin-1 beta (IL-1 beta) and interleukin-2 (IL-2) in the vaginal lavage fluid of the rat with bacterial vaginitis are obviously reduced, and the levels of interleukin-13 (IL-13) and immunoglobulin A (IgA) are obviously increased. These changes indicate that probiotic intervention can effectively inhibit inflammatory response, reduce production of inflammatory-related cytokines, reflect reduction of local inflammatory response, promote expression of anti-inflammatory cytokines and immunoglobulins, help to enhance immune protection of vaginal mucosa, and improve defensive power against pathogens, thereby restoring the healthy state of vaginal microenvironment.
(4.3) Vaginal appearance score:
The vaginal lipstick and secretion status was observed and scored in detail for each group of rats 24 hours after the last dose. Scoring criteria quantitative scoring was performed based on the specific appearance of the vaginal appearance of the rats, including the extent of redness and the nature and quantity of secretions. The higher the score obtained, the more severe the vaginal inflammation condition of the rats. The method comprises the following steps: the red and swollen condition of the vaginal orifice is divided into 0 to 3 parts according to the fold compactness and the red and swollen eversion degree (0 parts: the vaginal orifice is compact in folds and has no red and swollen eversion; 1 part: the vaginal orifice is slightly enlarged, the red and swollen is not obvious; 2 parts: the vaginal orifice is obviously enlarged, the red and swollen eversion is caused; 3 parts: the vaginal orifice is obviously enlarged, and the red and swollen eversion is serious). The vaginal secretion is divided into 0 to 3 parts according to the dryness degree, secretion outflow and adhesion (0 parts: dry vaginal orifice, no obvious secretion, 1 part: slightly moist vaginal orifice, no obvious secretion outflow, 2 parts: moist vaginal orifice, liquid secretion outflow, 3 parts: moist vaginal orifice, solid secretion adhesion).
As shown in table 1, the MC group rats had higher vaginal lipstick score and vaginal secretion score than the CTL group, and the reversion occurred after the probiotic intervention, and in particular, the S4 group had the most remarkable effect, and the vaginal lipstick score and vaginal secretion score were decreased. The result shows that the probiotic intervention can effectively relieve the vaginal inflammation symptoms caused by bacterial vaginitis and improve the vaginal health state, wherein the reduction of the vaginal lipstick score reflects the inhibition effect of the probiotics on the vaginal inflammation reaction, and the reduction of the vaginal secretion score indicates that the probiotics can effectively regulate the vaginal microenvironment and reduce the generation of abnormal secretion.
TABLE 1
(4.4) Vaginal flora diversity test:
Microbial total DNA was extracted from a vaginal secretion sample of rats, the V3-V4 region of the 16S rRNA gene was amplified by PCR using 341F and 805R primers, followed by double ended sequencing on a sequencing platform. The sequencing data is subjected to quality control and filtering, cluster analysis is carried out, and the phylogenetic relationship is determined. Finally, the diversity of the microbial communities (Chao 1 index and Shannon index) was assessed using software.
As shown in fig. 6 and 7, the diversity of the vaginal flora of rats in the MC group was reduced, and the Chao1 index and shannon index were significantly reduced, compared to the CTL group, indicating that the richness and uniformity of the vaginal microbial flora in the bacterial vaginitis state were significantly affected, reflecting the microbial imbalance caused by the decrease of the beneficial flora and the excessive increase of the harmful flora. After probiotic intervention, the diversity of the vaginal flora of the bacterial vaginitis rats tended to be normal, which is shown by a significant increase in the Chao1 index and the Shannon index. The invention shows that the probiotic intervention can effectively restore the richness and uniformity of the vaginal microbial community, promote the growth of beneficial microbial community, inhibit the excessive growth of harmful microbial community, and thus improve the microbial imbalance state caused by bacterial vaginitis.
The applicant states that the technical solution of the present invention is illustrated by the above embodiments, but the present invention is not limited to the above embodiments, i.e. it does not mean that the present invention must be implemented by the above embodiments. It should be apparent to those skilled in the art that any modification of the present invention, equivalent substitution of raw materials for the product of the present invention, addition of auxiliary components, selection of specific modes, etc., falls within the scope of the present invention and the scope of disclosure.
The preferred embodiments of the present invention have been described in detail above, but the present invention is not limited to the specific details of the above embodiments, and various simple modifications can be made to the technical solution of the present invention within the scope of the technical concept of the present invention, and all the simple modifications belong to the protection scope of the present invention.
In addition, the specific features described in the above embodiments may be combined in any suitable manner, and in order to avoid unnecessary repetition, various possible combinations are not described further.
Claims (10)
1. The composite probiotics for improving the bacterial vaginitis is characterized by comprising a Lactobacillus paracasei strain Lactobacillus PARACASEI LC with a preservation number of CGMCC No.1.12731 and a Lactobacillus rhamnosus Lactobacillus rhamnosus LRa strain with a preservation number of CGMCC No. 24282.
2. The complex probiotics for improving bacterial vaginitis as claimed in claim 1 wherein the ratio of viable count of Lactobacillus paracasei strain PARACASEI LC to Lactobacillus rhamnosus strain Lactobacillus rhamnosus LRa is 1:10-10:1.
3. A probiotic for ameliorating bacterial vaginitis, wherein the strain in said probiotic comprises the complex probiotic of claim 1 or 2.
4. A probiotic agent for the amelioration of bacterial vaginosis according to claim 3, wherein in said probiotic agent, the total number of viable bacteria is not less than 2 x 10 9 CFU/mL or 2 x 10 9 CFU/g.
5. A probiotic agent for the amelioration of bacterial vaginitis as claimed in claim 3 wherein said probiotic agent is in the form of a lyophilized powder, capsule, tablet or granule.
6. The probiotic agent for improving bacterial vaginitis as claimed in claim 5, wherein the probiotic agent is in the form of a freeze-dried powder, prepared by the following preparation method:
Respectively inoculating an LC86 strain and an LRa66 strain into a culture medium to sequentially perform activation and fermentation culture to obtain a fermentation broth; respectively centrifuging the fermentation liquid, mixing with a freeze-drying protective agent, and freeze-drying to obtain LC86 bacterial powder and LRa66 bacterial powder; mixing LC86 bacterial powder and LRa66 bacterial powder according to the ratio of the viable count to obtain the probiotic agent for improving bacterial vaginitis.
7. The probiotic agent for improving bacterial vaginosis according to claim 6, wherein the lyoprotectant is selected from any one or a combination of at least two of skim milk, gelatin, dextrin, acacia, dextran, sodium alginate, polyvinylpyrrolidone, sucrose, lactose, trehalose, sorbitol or xylitol.
8. Use of a complex probiotic according to claim 1 or 2 or a probiotic according to any one of claims 3 to 7 for the preparation of a product for the prevention, alleviation or treatment of bacterial vaginitis.
9. The use according to claim 8, wherein the product further comprises an auxiliary material.
10. The use according to claim 9, wherein the adjuvant is selected from any one or a combination of at least two of fructo-oligosaccharides, galacto-oligosaccharides, xylo-oligosaccharides, isomalto-oligosaccharides, soy-oligosaccharides, inulin, spirulina, arthrospira, coriolus polysaccharide, stachyose or polydextrose.
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| CN110917174A (en) * | 2018-09-20 | 2020-03-27 | 广东怡和科洁科技有限公司 | Oral probiotic capsule for regulating balance of female vaginal flora and preparation method thereof |
| CN112007067A (en) * | 2020-09-22 | 2020-12-01 | 上海泓商生物科技有限公司 | Privacy protecting probiotic compositions |
| CN115252655A (en) * | 2022-07-14 | 2022-11-01 | 金华银河生物科技有限公司 | Probiotic postbiotic product for improving vagina inflammation and preparation method and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105193860A (en) * | 2015-09-25 | 2015-12-30 | 南昌大学 | Method for application of artificially-cultured vaginal flora transplantation in treating gynecological inflammation |
| CN110917174A (en) * | 2018-09-20 | 2020-03-27 | 广东怡和科洁科技有限公司 | Oral probiotic capsule for regulating balance of female vaginal flora and preparation method thereof |
| CN112007067A (en) * | 2020-09-22 | 2020-12-01 | 上海泓商生物科技有限公司 | Privacy protecting probiotic compositions |
| CN115252655A (en) * | 2022-07-14 | 2022-11-01 | 金华银河生物科技有限公司 | Probiotic postbiotic product for improving vagina inflammation and preparation method and application thereof |
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