CN108624520B - Lactobacillus plantarum strain GMNL-662 for promoting bone regeneration and composition thereof - Google Patents
Lactobacillus plantarum strain GMNL-662 for promoting bone regeneration and composition thereof Download PDFInfo
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- 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
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- C12R2001/25—Lactobacillus plantarum
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Abstract
The invention discloses a lactobacillus plantarum GMNL-662 capable of promoting bone regeneration and a composition thereof. The lactobacillus plantarum strain GMNL-662 has the capacity of improving osteogenesis gene expression, inhibiting bone erosion related gene expression and improving the expression of a cell hormone TGF-beta related to bone formation, so that bone loss can be delayed.
Description
Technical Field
The invention relates to a lactobacillus plantarum GMNL-662 capable of promoting bone regeneration and a composition thereof, in particular to the lactobacillus plantarum GMNL-662 capable of improving osteogenic gene expression and the composition thereof.
Background
Osteoporosis is a systemic skeletal disease characterized by a decrease in bone mass, a deterioration in the microstructure of the bone tissue, resulting in a fragile skeleton and an increased risk of fracture.
In the bone remodeling process, including the bone formation of osteoblasts and the bone resorption of osteocytes, the dynamic balance of bone tissues is maintained, and once the bone resorption exceeds the bone formation, bone loss is caused, and finally osteoporosis is caused. Generally, osteoporosis is further classified into postmenopausal osteoporosis and senile osteoporosis. Osteoporosis after menopause is common in women after menopause, and because the estrogen amount in the body of the women after menopause is suddenly reduced, the activity of osteocyte is enhanced to absorb the trabecula, the trabecula is thinned, broken, reduced in number and discontinuous, and the bone strength is weakened; and senile osteoporosis is characterized by that the function of osteoblast is declined, the intake of calcium and vitamin D is insufficient, and the intestinal absorption function is worsened, so that the bone synthesis is reduced, the cortex lycii radicis is becomes coarse and large pores, the trabecula bone is disappeared, and the bone strength is obviously reduced.
The existing medicines for preventing and treating osteoporosis and fracture can be divided into three types of medicines for resisting bone erosion or losing, medicines for promoting bone formation or osteogenesis and mixed type according to the action mechanism. The bone corrosion resisting medicine comprises calcium agent, vitamin D, calcitonin, bisphosphate, estrogen receptor regulator, sex hormone, osteoclast enzyme inhibitor, RANKL monoclonal antibody and the like, and the mixed type is only one of strontium salts at present. Drugs that prevent osteoporosis themselves are associated with several side effects. Clinical trial results show that the drugs used in combination have no additive effect, but can mutually resist or increase the incidence or strength of side effects, so that two anti-loss agents or an anti-loss agent and an osteogenesis promoting agent are not suggested to be used together in various osteoporosis prevention and treatment guidelines of various countries at present.
Osteoporosis medicines commonly used for the aged and climacteric women clinically, such as bisphosphonates medicines like Fujinmei tablet, Kegusong tablet, Keguhua tablet, etc., if the patients take the osteoporosis medicines for a long time without paying attention to oral hygiene or performing tooth extraction and tooth implantation operations, serious jaw bone joint necrosis is feared to occur; recent studies have also found that it may cause adverse reactions of atypical femoral fractures.
In the past, some documents have suggested that certain probiotic strains have the ability to reduce bone loss in mice with ovariectomized, for example: reuteri ATCC PTA 6475; paracasei DSM 13434; l. plantarum DSM 15312, DSM 15313, b.longum, etc., are all tested in the form of viable bacteria and found to be able to delay bone loss by reducing the mechanism of the inflammatory response, but they do not have the ability to regenerate bone and are a relatively negative treatment modality.
Therefore, it is necessary to provide a lactobacillus plantarum GMNL-662 and a composition thereof for promoting bone regeneration, so as to solve the problems of the prior art.
Disclosure of Invention
The invention mainly aims to provide a Lactobacillus Plantarum GMNL-662 capable of promoting bone regeneration and a composition thereof, wherein the Lactobacillus Plantarum GMNL-662(Lactobacillus Plantarum GMNL-662) can enter a digestive system in any form, increase the expression of cell hormones TGF-beta and Osteocalcin (osteopalcin), and simultaneously inhibit and reduce the expression of bone erosion related genes (such as TRAP-5), thereby achieving the purpose of improving bone loss.
In order to achieve the above objects, one embodiment of the present invention provides a Lactobacillus Plantarum (Lactobacillus Plantarum) strain promoting bone regeneration, which is Lactobacillus Plantarum GMNL-662 deposited at the chinese typical culture collection (CCTCC) with the collection number M2016571.
In one embodiment of the invention, the Lactobacillus plantarum strain GMNL-662 is a viable or a dead strain.
In one embodiment of the invention, the Lactobacillus plantarum strain GMNL-662 has the ability to increase osteogenic gene expression.
The osteogenic gene is Osteocalcin (Osteocalcin) gene.
In order to achieve the above objects, another embodiment of the present invention provides a composition for promoting bone regeneration, which comprises the lactobacillus plantarum strain for promoting bone regeneration as described above.
In one embodiment of the present invention, the composition for promoting bone regeneration is a pharmaceutical composition, a nutritional supplement, a health food, a medical food or a combination thereof.
Drawings
FIG. 1 shows a bar graph of the expression amount of the cytokine TGF-. beta.in each group in experiment 2.
FIG. 2 is a bar graph showing the expression amount of the osteogenic gene Osteocalcin in each group in experiment 2.
FIG. 3 is a bar graph showing the expression level of the bone erosion-related gene TRAP-5 in each group in experiment 2.
Detailed Description
In order to make the aforementioned and other objects, features and advantages of the present invention comprehensible, preferred embodiments accompanied with figures are described in detail below. In addition, as used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Numerical ranges (e.g., 10% to 11% A) include upper and lower limits (i.e., 10% to 11%) unless otherwise specified; numerical ranges without lower limits (e.g., less than 0.2% B, or less than 0.2% B) are all meant to indicate that the lower limit may be 0 (i.e., 0% to 0.2%). The words used above are words of description and understanding, rather than words of limitation.
One embodiment of the invention provides a Lactobacillus Plantarum strain promoting bone regeneration, which is Lactobacillus Plantarum GMNL-662(Lactobacillus Plantarum GMNL-662) and is deposited in the chinese culture collection center (CCTCC) with the deposit number M2016571.
An embodiment of the present invention provides a composition for promoting bone regeneration, comprising lactobacillus plantarum strain GMNL-662 as described above. Preferably, the composition for promoting bone regeneration may also be presented in the form of a pharmaceutical composition, a nutritional supplement, a health food, a medical food or a combination thereof, i.e., the composition for promoting bone regeneration may be designed in various forms in consideration of effectiveness or convenience. In addition, the composition for promoting bone regeneration preferably enters the digestive system in an edible way, so as to promote the expression of osteogenic genes, inhibit the expression of bone erosion genes and increase the expression of a cell hormone TGF-beta for protecting bone loss, thereby delaying the bone loss.
The lactobacillus plantarum strain GMNL-662 in the above examples is mainly one of a plurality of isolates obtained by screening and isolating from human intestinal tracts. PCR was performed using the primers of Table 1 (SEQ ID NO:1 and SEQ ID NO:2) to replicate the 16S rDNA fragments of each of the multiple isolates, which were then sequenced to obtain one of the 16S rDNA gene sequences as follows (SEQ ID NO: 3); subsequently, as shown in table 2 below, the results of the alignment at the NCBI website revealed that the 16S rDNA sequence of the isolate was similar to the 16S rDNA sequence of Lactobacillus Plantarum (Lactobacillus Plantarum), and the similarity was 99% or more, so that it was confirmed that the strain GMNL-662 indeed belongs to Lactobacillus Plantarum.
TABLE 1 primer sequence alignment
| Primer | Sequence numbering | Sequence of |
| PAF | SEQ ID NO:1 | AGA GTT TGA TCC TGG CTC AG |
| 536R | SEQ ID NO:2 | GTA TTA CCG CGG CTG CTG |
TABLE 2 strain sequence alignment table
| NCBI accession number | Bacterial strainsName of scholars | Degree of similarity |
| KT236093.1 | Lactobacillus plantarum KLB 410 | 99％ |
| KT962240.1 | Lactobacillus plantarum USIM03 | 99％ |
| KT025848.1 | Lactobacillus plantarum KF | 99％ |
| KR816164.1 | Lactobacillus plantarum KF9 | 99％ |
The complete 16S rDNA sequence (SEQ ID NO:3) of Lactobacillus plantarum GMNL-662 is as follows:
GCCGTTGGCGTCGGATACATGCATGTCGTACGAACTCTGGTATTGATTGGTGCTTGCATCATGATTTACATTTGAGTGAGTGGCGAACTGGTGAGTAACACGTGGGAAACCTGCCCAGAAGCGGGGGATAACACCTGGAAACAGATGCTAATACCGCATAACAACTTGGACCGCATGGTCCGAGCTTGAAAGATGGCTTCGGCTATCACTTTTGGATGGTCCCGCGGCGTATTAGCTAGATGGTGGGGTAACGGCTCACCATGGCAATGATACGTAGCCGACCTGAGAGGGTAATCGGCCACATTGGGACTGAGACACGGCCCAAACTCCTACGGGAGGCAGCAGTAGGGAATCTTCCACAATGACGAAAGTCTGATGGAGCAACGCCGCGTGAGTGAAGAAGGGTTTCGGCTCGTAAAACTCTGTTGTTAAAGAAGAACATATCTGAGAGTAACTGTTCAGGTATTGACGGTATTTAACCAGAAAGCCACGGCTAACTACGTGCCAGCAGCCGCGGGTAAACAC
fermentation test was performed on the lactobacillus plantarum strain GMNL-662, and the results shown in table 3 were obtained.
TABLE 3 fermentation Enhance test results
In order to verify that the lactobacillus plantarum GMNL-662 provided by the present invention has the property of promoting bone regeneration and can improve the symptoms of bone loss, the following experiments were performed.
Experiment 1: bone tissue analysis
The strain is as follows: lactobacillus plantarum (Lactobacillus plantarum; GMNL-662)
Strain treatment:
(1) preparation of viable bacteria: lactobacillus plantarum strain (Lactobacillus plantarum GMNL-662) was inoculated from a frozen tube to 1ml of MRS broth and cultured at 37 ℃ for 20 hours under aerobic conditions. The following day, 15. mu.l of overnight culture broth to 1.5ml of MRS broth (1% secondary activation) was taken, followed by static culture at 37 ℃ under aerobic conditions for 20 hours, estimating the number of viable bacteria by OD 600nm, and adjusting the viable bacteria dose to 8X 107cfu/ml for use.
(2) Preparing dead bacteria: lactobacillus plantarum GMNL-662(Lactobacillus plantarum) was inoculated from a frozen tube to 1ml of MRS broth and cultured aerobically at 37 ℃ for 20 hours. The next day, 15. mu.l of overnight culture broth was taken to 1.5ml of MRS broth (1% secondary activation), followed by static culture at 37 ℃ under aerobic conditions for 20 hours, and the number of cells was estimated at OD 600nm and adjusted to 4.1X 108cfu/ml, and autoclaved at 121 ℃ for 15 minutes for later use.
Osteoporosis mouse model:
female ICR mice, 8 weeks old, were purchased from leschen technologies and ovariectomy was performed at 9 weeks of age. Under anesthesia, the mouse is cut at the ovary positions on the two sides of the back, and the ovary removing operation is carried out; all groups began tube feeding with test substance 4 days after surgery. Mice were divided into sham-operated groups (Control group, only abdominal cavity was opened, ovaries were not removed); and 4 Ovariectomy (OVX). Mouse sacrificeWhen animals are killed, the ovary tissues are checked, whether the ovary removing operation is successful or not is confirmed, the animals which fail the operation are confirmed, and experimental results are not adopted. Of 4 groups of mice in the ovariectomized group, 1 group was selected as the vehicle group (H)2Group O), group 1 is a positive control drug (anti-osteoporosis drug Alendronate). Alendronate was suspended in deionized water at a concentration of 0.25mg/ml, and mice were administered 0.1ml per 10 g of body weight 4 times a week. The other 2 groups are respectively tube-fed with 0.2ml of GMNL-662 viable bacteria (viable bacteria concentration is 8 x 10)7cfu/ml; conversion of daily dose of mice to 1.6X 107cfu/mouse, human dose 4X 109cfu/60kg adult), and 0.2ml of dead bacteria (dead bacteria concentration of 4.1X 10)8cfu/ml; reduced mouse dose of 8.2X 107cells/mouse, converted human dose: 2X 1010cells/60kg adult), two groups were fed one tube per day, and 28 consecutive days later, mice were anesthetized and sacrificed by collecting blood from the abdominal veins, and femurs were removed for analysis.
The analysis method comprises the following steps:
the right femoral distal stem was computed tomography with a micro-computed tomography (SkyScan 1076, Kontizh, Belgium, 18 μm resolution) and the ratio of trabecular bone area, i.e. bone volume to tissue volume, was analyzed with analytical software. The location of the analysis selects the area 100 slices below the growth plate (toward the proximal end) that does not contain cortical bone. Analysis of bone mineral Density the same area was selected for analysis of bone mineral density without cortical bone. The data obtained by the experiment are analyzed by two-tail variation number (two-way analysis of variance) and are subjected to T-test statistical analysis, and all the data are expressed by mean plus or minus standard deviation (mean plus or minus SD); each group and OVX + H2The groups of O were compared and statistically significantly different in different symbols (p < 0.05; p < 0.01). The results of experiment 1 are shown in tables 4 and 5.
TABLE 4 ratio of trabecular bone regions (BV/TV)
From Table 4 can be seenAfter ovariectomy, mice were in the onset group (OVX + H)2O), i.e. the ratio of bone volume to tissue volume, was significantly lower than in the sham operated group (Control), indicating success of the osteoporosis model. Comparing the live and dead groups fed with GMNL-662, it was found that the BV/TV analysis was significantly higher than the symptomatic group, indicating that GMNL-662 indeed slowed the extent of bone loss after ovarian ablation. Alendronate is a positive control group and also has the function of protecting the degree of bone loss after the ovary is removed; the protective effect of the tube-fed two groups of GMNL-662 strain is even slightly better than that of the anti-osteoporosis drug Alendronate.
TABLE 5 femoral bone mineral Density (without cortical bone, BMD)
As can be seen from Table 5, the group of the onset symptoms (OVX + H)2O) both have significantly lower mineral density than the prosthetic hand group (Control); the bone density of the group fed with GMNL-662 live bacteria and dead bacteria is obviously superior to that of the group with the disease (OVX + H)2O), indicating that tube-feeding both groups of GMNL-662 can slow the extent of bone loss following ovarian ablation.
Experiment 2: effect of GMNL-662 on osteogenic, cytokine and osteolytic genes
Extracting tibial RNA: after the experiment is finished, the left femur of the mouse is taken down, the tibia is cut into small pieces by scissors, and a proper amount of liquid nitrogen is added to rapidly grind the bone; adding ground bone meal into 0.5ml
Reagent carries out RNA extraction, 0.1ml of chloroform (chloroform) is added, the mixture is turned up and down for 15 times, the mixture is placed at room temperature for 5 minutes to react, then centrifugation is carried out, the upper layer is extracted into a new microcentrifuge tube eppendorf, 0.25ml of isopropanol is added, and centrifugation is carried out after the mixture is placed at room temperature for 10 minutes; the supernatant was removed and the centrifuged pellet was washed with 0.5ml of 75% ethanol; after the centrifuged precipitate was dried, 20 to 50. mu.l of DEPC water (diethyl pyrocarbonate treated water) was added thereto and redissolved, and the RNA concentration was measured.
RNA-inverted cDNA: taking 1-5 μ g RNA and supplementing RNase-free water (RNase-free water) to 10 μ l; in addition, 10 × Ramdon primer (2 μ l), 10mM dNTP (1 μ l), 65 ℃ for 5 minutes, ice for 2-3 minutes; after the first stage of action, 5 XTT buffer (4. mu.l), 0.1M DTT (1. mu.l), RNase inhibitor (RNase inhibitor, Invitrogen, RNaseOUTTM, 1. mu.l), RT enzyme ((Invitrogen,
1 μ l), Mix RT min and 50 ℃ for 60 min and 70 ℃ for 15 min, were subjected to the action of reverse transcriptase.
Tibial cDNA for real-time PCR analysis: mu.l of tibial cDNA was added with 4. mu.l of 1. mu.M F + R primers (forward/reverse primer sequence shown below) and 5. mu.l of 2x Rotor-Gene SYBR Green PCR Master Mix (Qiagen, Cat.204076) and reacted in a Q-PCR machine, with the relative expression amounts of TGF-. beta.and RANKL being obtained by subtracting GAPDH from the original expression amount.
TABLE 5 primer sequences
The analysis method comprises the following steps: the data obtained from the experiments were analyzed as two-tailed variabilities (two-way analysis of variance) and subjected to T-test. Statistical analysis of each group with OVX + H2Compared with group O, p is less than 0.05; p < 0.01.
As shown in FIG. 1, both viable and dead forms of GMNL-662 increased the expression of the cytokine TGF-. beta.that protected bone loss. After the ovary of the mouse is removed, compared with a sham operation group, the expression level of the bone generation related cytokine gene TGF-beta is obviously reduced; TGF-beta expression and ovarian ablation groups (OVX + H) fed with GMNL-662 groups (GMNL-662 dead and live bacteria)2O) was significantly increased, indicating that GMNL-662 had the effect of promoting TGF- β expression and thereby delaying bone loss.
Next, as shown in FIG. 2, the expression level of osteogenic gene Osteocalcin was measured in groups of GMNL-662 (live and dead bacteria) after ovariectomyAre all higher than those in the group with symptoms (OVX + H)2O), which shows that GMNL-662 has the effect of promoting the expression of osteogenic genes, and both live and dead forms of GMNL-662 can improve the expression of osteogenic genes Osteocalcin, thereby delaying bone loss.
With continued reference to FIG. 3, it is evident that the disease group (OVX + H) was established after ovariectomy in mice2O) the expression level of TRAP-5, a bone erosion-related gene, was increased as compared with that of the sham operated group (Control); the expression level of the bone erosion gene TRAP-5 of the group fed with GMNL-662 live bacteria and dead bacteria is obviously lower than that of the group with the disease (OVX + H)2O), indicating that GMNL-662 has the effect of inhibiting the expression of the eroding bone gene and thereby delaying bone loss.
According to the results, the lactobacillus plantarum GMNL-662 provided by the invention can be determined, no matter in a live bacterium or heat killed bacterium type, the bone loss phenomenon of an ovary enucleated mouse can be remarkably reduced in bone tissue analysis (ratio of trabecular bone region, BV/TV) and femoral Bone Mineral Density (BMD) of an animal experiment; and the GMNL-662 is found to have the capacity of promoting the expression of osteogenic gene (osteopecalin) and inhibiting the expression of bone erosion gene (TRAP-5) and increasing the expression of cell hormone TGF-beta for protecting bone loss, thereby achieving the purpose of inhibiting the bone loss.
In addition, the experimental result also finds that the effect of GMNL-653 on protecting bone loss is better than that of Alendronate which is an osteoporosis medicine. However, it has been found that Alendronate has many side effects in clinical practice, including heart disease, stubborn pain, jaw necrosis, bone fracture, esophageal cancer, etc.; therefore, the safe lactobacillus plantarum GMNL-662 without side effects applied to the aspect of delaying bone loss can be a better choice for preventing and improving the osteoporosis of postmenopausal women in the future.
The present invention has been described in relation to the above embodiments, which are only exemplary of the implementation of the present invention. It must be noted that the disclosed embodiments do not limit the scope of the invention. Rather, modifications and equivalent arrangements included within the spirit and scope of the claims are included within the scope of the invention.
SEQUENCE LISTING
<110> Jingyue Biotechnology Ltd
<120> Lactobacillus plantarum Strain GMNL-662 promoting bone regeneration and composition thereof
<130> TP161062-TW
<160> 11
<170> PatentIn version 3.5
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<212> DNA
<213> Artificial sequence
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<223> PAF primer
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agagtttgat cctggctcag 20
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<223> 536R primer
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gtattaccgc ggctgctg 18
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<213> Artificial sequence
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<223> GMNL-66216S rDNA sequence primer
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gccgttggcg tcggatacat gcatgtcgta cgaactctgg tattgattgg tgcttgcatc 60
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gcgggggata acacctggaa acagatgcta ataccgcata acaacttgga ccgcatggtc 180
cgagcttgaa agatggcttc ggctatcact tttggatggt cccgcggcgt attagctaga 240
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acattgggac tgagacacgg cccaaactcc tacgggaggc agcagtaggg aatcttccac 360
aatgacgaaa gtctgatgga gcaacgccgc gtgagtgaag aagggtttcg gctcgtaaaa 420
ctctgttgtt aaagaagaac atatctgaga gtaactgttc aggtattgac ggtatttaac 480
cagaaagcca cggctaacta cgtgccagca gccgcgggta aacac 525
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<213> Artificial sequence
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acagtcacca gcatctcagc 20
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<220>
<223> Osteocalcin forward primer
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<213> Artificial sequence
<220>
<223> Osteocalcin reverse primer
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actttatttt ggagctgctg tgac 24
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gacgatgggc gctgacttca 20
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<213> Artificial sequence
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Claims (4)
1. Lactobacillus plantarum (A) for promoting bone regenerationLactobacillus plantarum) The strain is characterized in that the Lactobacillus plantarum strain is Lactobacillus plantarum GMNL-662, and the Lactobacillus plantarum GMNL-662 is preserved in China center for type culture Collection with the preservation number of CCTCC NO: M2016571.
2. A composition for promoting bone regeneration, comprising the lactobacillus plantarum strain having the ability to increase osteocalcin gene expression according to claim 1, GMNL-662.
3. The composition for promoting bone regeneration according to claim 2, wherein: the composition for promoting bone regeneration is a pharmaceutical composition.
4. The composition for promoting bone regeneration according to claim 2, wherein: the lactobacillus plantarum strain GMNL-662 is a live strain or a dead strain.
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| CN110628660B (en) * | 2018-06-22 | 2021-06-22 | 景岳生物科技(中国)有限公司 | Lactobacillus composition for inhibiting gastritis caused by gastric helicobacter pylori and application thereof |
| CN109172613B (en) * | 2018-08-14 | 2022-04-22 | 景岳生物科技(中国)有限公司 | Skin external composition containing lactobacillus dead bacteria culture and its use for promoting wound healing and reducing scar generation |
| US20220072070A1 (en) * | 2019-06-25 | 2022-03-10 | Synbio Tech Inc. | Method for improving walking capacity of elderly subjects |
| CN115806898A (en) * | 2022-08-10 | 2023-03-17 | 重庆第二师范学院 | Lactobacillus plantarum KSFY04 and application thereof |
| CN115948296B (en) * | 2022-12-23 | 2024-02-27 | 四川高福记生物科技有限公司 | Lactobacillus plantarum for improving musculoskeletal health and/or improving exercise capacity, and composition and application thereof |
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