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CN118048280B - Probiotic agent for improving spermatogenic disorder and application thereof - Google Patents

Probiotic agent for improving spermatogenic disorder and application thereof Download PDF

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CN118048280B
CN118048280B CN202410452391.4A CN202410452391A CN118048280B CN 118048280 B CN118048280 B CN 118048280B CN 202410452391 A CN202410452391 A CN 202410452391A CN 118048280 B CN118048280 B CN 118048280B
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bacillus coagulans
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CN118048280A (en
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方曙光
张启凤
郭曼仪
蒋大成
夏陈涛
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WeCare Probiotics Co Ltd
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Abstract

The invention relates to a probiotic for improving spermatogenesis disorder and application thereof, wherein strains in the probiotic for improving spermatogenesis disorder comprise bifidobacterium adolescentis Bifidobacterium adolescentis BAC strain and bacillus coagulans Bacillus coagulans BC strain. The invention develops a brand new probiotic compound mode, wherein a BAC30 strain and a BC99 strain are compounded, and potential interaction exists between the two strains, so that the two strains can be matched with each other, and the effects of improving dysspermia are synergistically enhanced, and the method is specifically characterized in that: the sperm density is effectively improved, and the deformity rate is reduced; significantly increasing serum testosterone levels; significantly reduces the oxidative stress of the organism, regulates the immune response and improves the endocrine balance.

Description

Probiotic agent for improving spermatogenic disorder and application thereof
Technical Field
The invention belongs to the technical field of probiotics, and relates to a probiotic for improving dysspermia and application thereof.
Background
Seminiferous disorders involve a decrease in the number, quality and motor capacity of spermatogenesis, which is complicated by factors including genetic factors, environmental toxins, lifestyle, and certain diseases.
In recent years, probiotics are used as a biological agent for regulating the microecological balance of human bodies, and can improve intestinal health and enhance immunity. Specific species of probiotics can positively affect the improvement of spermatogenic function by regulating immune response, improving hormone level balance, reducing genital system inflammation and other mechanisms. While probiotics have demonstrated potential in improving dysspermia, there is currently a lack of probiotic formulations on the market specifically designed for dysspermia. Therefore, the novel and highly targeted probiotic agent is developed, so that not only can a novel treatment choice be provided for patients with dysspermia, but also a novel research direction is opened for the application of probiotics in the field of reproductive health.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a probiotic agent for improving spermatogenic disorder and application thereof, in particular to a probiotic agent for improving spermatogenic disorder and application thereof in preparing products for preventing, relieving or treating oligospermia or oligospermia.
In order to achieve the aim of the invention, the invention adopts the following technical scheme:
In a first aspect, the invention provides a probiotic for improving dysspermia, wherein the strains in the probiotic for improving dysspermia comprise bifidobacterium adolescentis Bifidobacterium adolescentis BAC strain with the preservation number of CGMCC No.19884 and bacillus coagulans Bacillus coagulans BC strain with the preservation number of CGMCC No. 21801.
The invention develops a brand new probiotic compounding mode, and combines the bifidobacterium adolescentis Bifidobacterium adolescentis BAC strain and the bacillus coagulans Bacillus coagulans BC strain, and finds that the bifidobacterium adolescentis Bifidobacterium adolescentis BAC strain and the bacillus coagulans Bacillus coagulans BC strain have potential interaction, can be mutually matched, and synergistically improve the effect of improving the dysspermia, and is specifically characterized in that: (1) effectively improving sperm density and reducing deformity rate; (2) significantly increasing serum testosterone levels; (3) Significantly reduces the oxidative stress of the organism, regulates the immune response and improves the endocrine balance. When the amount of the bacteria used is uniform, the combination of the two bacteria significantly improves the efficacy as compared with the single BAC30 strain or the single BC99 strain. Thus, the probiotic provides a new strategy for improving insemination disorders. Since the bifidobacterium adolescentis Bifidobacterium adolescentis BAC strain and the bacillus coagulans Bacillus coagulans BC strain are probiotics, the bifidobacterium adolescentis Bifidobacterium adolescentis BAC strain and the bacillus coagulans Bacillus coagulans BC strain are high in safety and are not easy to generate resistance when being used for preparing products with related effects.
Preferably, the ratio of the viable count of the bifidobacterium adolescentis Bifidobacterium adolescentis BAC strain to that of the bacillus coagulans Bacillus coagulans BC strain is 1:20-20:1, for example 1:20、1:18、1:16、1:15、1:12、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、12:1、15:1、18:1、20:1, and other specific values within the above numerical range can be selected, and will not be described in detail herein.
Based on the potential interaction relationship between the BAC30 strain and the BC99 strain, the invention also discovers that when the two strains are compounded according to the specific viable count ratio, the effects of improving sperm density, reducing deformity rate, improving serum testosterone level, relieving oxidative stress of an organism, regulating immune response and improving endocrine balance are more remarkable.
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 2×109 CFU/mL（CFU/g）、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.
The formulation of the probiotics related to the invention is not limited, and comprises the most commonly used freeze-dried powder, or further prepared capsules, tablets or granules.
Preferably, the probiotic agent further comprises a lyoprotectant and/or a functional adjuvant.
Preferably, the lyoprotectant comprises 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.
The functional auxiliary agent comprises any one or a combination of at least two of fructo-oligosaccharide, galacto-oligosaccharide, xylo-oligosaccharide, isomalto-oligosaccharide, soybean oligosaccharide, inulin, spirulina, arthrospira, coriolus versicolor polysaccharide, stachyose, polydextrose, alpha-lactalbumin or lactoferrin.
Preferably, the probiotic is prepared by a preparation method comprising:
Respectively inoculating BAC30 strain and BC99 strain into a culture medium for activation and fermentation culture to obtain fermentation liquor; respectively centrifuging the fermentation liquid, mixing with a freeze-drying protective agent, and freeze-drying to obtain BAC30 bacterial powder and BC99 bacterial powder; and mixing BAC30 bacterial powder and BC99 bacterial powder according to the ratio of the viable count to obtain the probiotic agent for improving the spermatogenesis disorder.
Preferably, the medium includes an MRS medium.
Preferably, the MRS medium includes, in concentration: 8-12 g/L of peptone, 8-12 g/L of beef extract, 15-25 g/L of glucose, 1-3 g/L of sodium acetate, 3-7 g/L of yeast powder, 1-3 g/L、K2PO4·3H2O 2-3 g/L、MgSO4·7H2O 0.05-0.2 g/L、MnSO4 0.01-0.1 g/L、 Tween 80 0.5-2 mL/L of diammonium hydrogen citrate and 0.1-1 g/L of cysteine hydrochloride.
Preferably, the BAC30 bacterial powder and the BC99 bacterial powder are mixed according to the viable count ratio and then are mixed with the functional auxiliary agent.
In a second aspect, the present invention provides the use of a probiotic according to the first aspect for the preparation of a product for preventing, alleviating or treating oligospermia or oligospermia.
Preferably, the product further comprises auxiliary materials.
The auxiliary materials comprise any one or a combination of at least two of excipient, filler, adhesive, wetting agent, disintegrating agent, emulsifying agent, cosolvent, solubilizer, osmotic pressure regulator, coating material, colorant, pH regulator, antioxidant, bacteriostat or buffer.
Compared with the prior art, the invention has the following beneficial effects:
The invention develops a brand new probiotic compounding mode, and combines the bifidobacterium adolescentis Bifidobacterium adolescentis BAC strain and the bacillus coagulans Bacillus coagulans BC strain, and finds that the bifidobacterium adolescentis Bifidobacterium adolescentis BAC strain and the bacillus coagulans Bacillus coagulans BC strain have potential interaction, can be mutually matched, and synergistically improve the effect of improving the dysspermia, and is specifically characterized in that: (1) effectively improving sperm density and reducing deformity rate; (2) significantly increasing serum testosterone levels; (3) Significantly reduces the oxidative stress of the organism, regulates the immune response and improves the endocrine balance. When the amount of the bacteria used is uniform, the combination of the two bacteria significantly improves the efficacy as compared with the single BAC30 strain or the single BC99 strain. Thus, the probiotic provides a new strategy for improving insemination disorders. Since the bifidobacterium adolescentis Bifidobacterium adolescentis BAC strain and the bacillus coagulans Bacillus coagulans BC strain are probiotics, the bifidobacterium adolescentis Bifidobacterium adolescentis BAC strain and the bacillus coagulans Bacillus coagulans BC strain are high in safety and are not easy to generate resistance when being used for preparing products with related effects.
The BAC30 strain related to the invention is classified and named as bifidobacterium adolescentis Bifidobacterium adolescentis, the preservation unit is China general microbiological culture Collection center, the preservation time is 05 months and 28 days in 2020, the preservation number is CGMCC No.19884, and the address is: the korean district North Star, beijing city, part No.1, no. 3.
The BC99 strain related by the invention is classified and named as bacillus coagulans Bacillus coagulans, the preservation unit is China general microbiological culture Collection center, the preservation time is 2021, 02 and 01, the preservation number is CGMCC No.21801, and the address is: the korean district North Star, beijing city, part No.1, no. 3.
Drawings
FIG. 1 is a graph of the statistics of sperm density for each group of mice;
FIG. 2 is a graph of statistical results of sperm cell abnormal rates for each group of mice;
FIG. 3 is a graph of statistical results of serum testosterone levels for each group of mice;
FIG. 4 is a graph of statistical results of Lactate Dehydrogenase (LDH) levels in testis tissue of each group of mice;
FIG. 5 is a graph of statistical results of Malondialdehyde (MDA) levels in testis tissue of various groups of mice;
FIG. 6 is a graph of statistical results of Nitric Oxide (NO) levels in testis tissue of each group of mice;
FIG. 7 is a graph of statistical results of interleukin-17 (IL-17) levels in testis tissue of each group of mice;
FIG. 8 is a graph of statistical results of tumor necrosis factor-alpha (TNF-alpha) levels in testis tissue of each group of mice.
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 BAC30 strain related to the following examples is classified and named as bifidobacterium adolescentis Bifidobacterium adolescentis, and the preservation number is CGMCC No.19884.
The BC99 strain related to the following embodiment is classified and named as bacillus coagulans Bacillus coagulans, and the preservation number is CGMCC No.21801.
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 18h for activation, and continuously activating for 2 times to obtain activating solution; inoculating the activating solution into MRS liquid culture medium according to the inoculum size of 2% (v/v), and culturing at 37 ℃ for 24h to obtain bacterial solution; centrifuging the bacterial liquid at 5000rpm at 4deg.C for 10 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 ability of probiotics to improve symptoms in dysspermia mice:
(1) Test animals: SPF class C57BL/6 male mice (purchased from Shanghai laboratory animal center) 6 weeks old were kept in cages with clean and quiet environment, 20-24℃and 50-60% humidity, following 12h light/dark cycle. All experimental procedures involving mice 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 in the above mice, 56 mice were randomly divided into 7 groups (8 per group): control group (CTL group), model group (MC group), BAC30 strain-interfered mice group (BAC 30 group, designated as S1 group), BC99 strain-interfered mice group (BC 99 group, designated as S2 group), commercial bifidobacterium adolescentis strain ATCC 15703-interfered mice group (ATCC 15703 group, designated as S3 group), BAC30 strain-BC 99 strain-combined interfered mice group (bac30+bc 99 group, 1:1 ratio of the number of live bacteria of both strains, designated as S4 group), BC99 strain-combined interfered mice group (ATCC 15703+bc 99 group, 1:1 ratio of the number of live bacteria of both strains, designated as S5 group).
(3) Animal modeling and intervention method: except for the control group, all groups of mice received busulfan (35 mg/kg) intraperitoneal injection to establish a azoospermia mouse model. After 30 days, the CTL group and the MC group are infused with normal saline for 1 time a day for 5 weeks; each probiotic group was treated with different bacterial solutions (1 x 10 10 CFU/dose) at a frequency of 1 time per day for 5 consecutive weeks (35 days of mice seminiferous cycle).
(4) And (3) index analysis:
(4.1) mouse sperm quality detection:
Mice were anesthetized by intraperitoneal injection of 0.3% sodium pentobarbital, and immediately after anesthesia, the left epididymal tail was removed, a semen sample was obtained from the epididymal tail of the mice, and transferred to the medium. The samples were then incubated in a 37 ℃ water bath for 15 min to release sperm. The samples were then filtered and diluted with additional 0.5 mL normal saline, 20 μl of the diluted droplets were applied to a slide, and the samples were analyzed using a semen analyzer to evaluate sperm density and morphology. For sperm count (density), 0.5 mL of the filtered and diluted sperm suspension was placed in a 10 mL EP tube, 0.5 mL of 0.5% NaHCO 3 fixative was added, and after blowing evenly, 20 μl of diluted droplets were counted on a blood cell counting plate.
The statistics of sperm density and sperm malformation rate of each group are shown in fig. 1 and 2, respectively. From the figure, the sperm density of mice in the model group is obviously reduced compared with that of mice in the control group, which indicates that the model establishment successfully induces the damage of the spermatogenic function, has negative effect on the growth and division of spermatids in testes, and leads to reduced spermatogenesis; sperm cell deformity increases significantly, which may be associated with oxidative stress, DNA damage, or endocrine disruption during modeling, which can significantly affect sperm motility and fertility. After each group of probiotics intervenes, especially in the S4 group, the situation is obviously reversed, so that the sperm density is obviously increased and the deformity rate is obviously reduced, and the changes are helpful to restore the normal spermatogenic process and sperm development, thereby improving the number and quality of sperms.
(4.2) Serum testosterone (T) level detection: the serum testosterone (T) levels of each group of mice were detected using enzyme-linked immunosorbent assay (ELISA) technology using a scientific kit provided by Wohan purity Biotechnology Co.
The statistical results of serum testosterone (T) levels for each group are shown in figure 3. From the figure, testosterone levels were significantly reduced in mice in the model group compared to the control group, indicating that model establishment successfully mimics the state of reproductive endocrine dysfunction. After each group of probiotics was intervened, especially in S4 group, serum testosterone levels were significantly increased, indicating the potential effect of probiotics on improving testicular function and promoting testosterone synthesis.
(4.3) Biochemical test of testis:
Mouse testis tissue was taken and examined the day after homogenization, avoiding repeated freeze thawing to reduce enzyme activity. Specifically, a proper amount of physiological saline (with the concentration of 0.9% and the temperature of about 4 ℃) is taken, the mixture is put into testis tissue of a mouse, 10% tissue homogenate is prepared under the ice water bath condition, the homogenate is placed into a centrifugal machine, the centrifugal machine is used for centrifugation at the rotating speed of 3000r/min for 10 min, and the supernatant is carefully taken out in a test tube to obtain the tissue homogenate. The level of Lactate Dehydrogenase (LDH), malondialdehyde (MDA), nitric Oxide (NO), interleukin-17 (IL-17), tumor necrosis factor-alpha (TNF-alpha) in testis tissue was detected according to the procedure shown in the specification using a scientific kit provided by Wohan purity Biotechnology Co.
Statistical results of Lactate Dehydrogenase (LDH), malondialdehyde (MDA), nitric Oxide (NO), interleukin-17 (IL-17), tumor necrosis factor-alpha (TNF-alpha) levels in testis tissue of each group of mice are shown in FIGS. 4-8, respectively.
From the figure, the levels of testosterone, nitric oxide, interleukin-17 and tumor necrosis factor-alpha were significantly increased in the mice in the model group and the lactate dehydrogenase level was significantly decreased in the model group compared to the control group. Malondialdehyde is the end product of lipid peroxidation, and its elevated levels indicate a significant oxidative stress in the model group, affecting cell function and structure, and thus damaging testicular tissue. Nitric oxide is an important biological signaling molecule, but its overproduction may lead to inflammation and cellular injury, and elevated nitric oxide levels in the model set may reflect inflammatory states and endothelial dysfunction. Interleukin-17 and tumor necrosis factor- α are key pro-inflammatory cytokines in the inflammatory process, and elevated levels of these two cytokines indicate a significant inflammatory response in testis tissue in mice in the model group. Lactate dehydrogenase is a marker of cell damage and cell death, and a decrease in lactate dehydrogenase levels in the model set may reflect a decrease in cellular metabolic activity or impairment of cellular integrity.
After each group of probiotic interventions, especially in the S4 group, levels of testicular malondialdehyde, nitric oxide, interleukin-17 and tumor necrosis factor- α were significantly reduced and lactate dehydrogenase levels were significantly increased. This shows that the probiotic intervention according to the invention is effective in reducing the oxidative stress and inflammatory states of testicular tissue. Probiotic intervention helps to protect testicular tissue from further damage by reducing lipid peroxidation products, modulating nitric oxide production, and inhibiting the release of pro-inflammatory cytokines. The increase in lactate dehydrogenase levels may reflect a restoration of cellular metabolic activity and an improvement in cellular integrity following probiotic intervention, possibly due to the reduction of oxidative stress and inflammation by the probiotics, thereby promoting restoration of cell repair and function.
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 (8)

1. The probiotics for improving the spermatogenic disorder is characterized in that strains in the probiotics for improving the spermatogenic disorder comprise a bifidobacterium adolescentis Bifidobacterium adolescentisBAC strain with a preservation number of CGMCC No.19884 and a bacillus coagulans Bacillus coagulans BC99 strain with a preservation number of CGMCC No. 21801; the ratio of the viable count of the bifidobacterium adolescentis Bifidobacterium adolescentis BAC strain to the viable count of the bacillus coagulans Bacillus coagulans BC strain is 1:5-5:1; in the probiotic agent, the total number of viable bacteria is not less than 2X 10 9 CFU/mL or 2X 10 9 CFU/g.
2. The probiotic for ameliorating dysspermia according to claim 1, wherein the probiotic is in a dosage form comprising a lyophilized powder, capsule, tablet or granule.
3. A probiotic for ameliorating dysspermia according to claim 1, wherein said probiotic further comprises lyoprotectants and/or functional adjuvants.
4. A probiotic agent for improving a dysspermia according to claim 3, characterized in that the lyoprotectant comprises 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;
The functional auxiliary agent comprises any one or a combination of at least two of fructo-oligosaccharide, galacto-oligosaccharide, xylo-oligosaccharide, isomalto-oligosaccharide, soybean oligosaccharide, inulin, spirulina, arthrospira, coriolus versicolor polysaccharide, stachyose, polydextrose, alpha-lactalbumin or lactoferrin.
5. The probiotic for improving dysspermia according to claim 1, characterized in that it is prepared by a preparation process comprising:
Respectively inoculating BAC30 strain and BC99 strain into a culture medium for activation and fermentation culture to obtain fermentation liquor; respectively centrifuging the fermentation liquid, mixing with a freeze-drying protective agent, and freeze-drying to obtain BAC30 bacterial powder and BC99 bacterial powder; and mixing BAC30 bacterial powder and BC99 bacterial powder according to the ratio of the viable count to obtain the probiotic agent for improving the spermatogenesis disorder.
6. The probiotic for improving dysspermia according to claim 5, wherein BAC30 bacterial powder and BC99 bacterial powder are mixed according to the viable count ratio and then mixed with functional auxiliary agents.
7. Use of a probiotic for ameliorating a spermatogenic disorder according to any of claims 1-6 in the manufacture of a product for preventing, alleviating or treating oligospermia or oligospermia.
8. The use according to claim 7, wherein the product further comprises adjuvants;
The auxiliary materials comprise any one or a combination of at least two of excipient, filler, adhesive, wetting agent, disintegrating agent, emulsifying agent, cosolvent, solubilizer, osmotic pressure regulator, coating material, colorant, pH regulator, antioxidant, bacteriostat or buffer.
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Citations (2)

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CN112852679A (en) * 2021-03-17 2021-05-28 武汉微康益生菌研究院有限公司 Probiotic bacillus coagulans and application thereof
CN114774318A (en) * 2022-04-19 2022-07-22 微康益生菌(苏州)股份有限公司 Application of lactobacillus paracasei in preparation of product for relieving anxiety and depression symptoms

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112852679A (en) * 2021-03-17 2021-05-28 武汉微康益生菌研究院有限公司 Probiotic bacillus coagulans and application thereof
CN114774318A (en) * 2022-04-19 2022-07-22 微康益生菌(苏州)股份有限公司 Application of lactobacillus paracasei in preparation of product for relieving anxiety and depression symptoms

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