CN111450125A - New application of lactobacillus reuteri CCFM8631 - Google Patents
New application of lactobacillus reuteri CCFM8631 Download PDFInfo
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- CN111450125A CN111450125A CN202010181916.7A CN202010181916A CN111450125A CN 111450125 A CN111450125 A CN 111450125A CN 202010181916 A CN202010181916 A CN 202010181916A CN 111450125 A CN111450125 A CN 111450125A
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- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
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Abstract
Experiments show that the lactobacillus reuteri CCFM8631 can reduce weight reduction, reduce the weight reduction of collagen-induced rheumatoid arthritis, reduce the joint swelling degree of rats, reduce the level of I L-1 β in proinflammatory factor serum, has a remarkable recovery effect on butyrate in excrement of rats with rheumatoid arthritis to reach a normal level, can regulate intestinal flora composition disorder caused by the rheumatoid arthritis, directly inhibit von pretella copri capable of aggravating the rheumatoid arthritis, and remarkably inhibit the differentiation capacity of Th17 cells at the mesentery part of rats with arthritis.
Description
Technical Field
The invention belongs to the technical field of microorganisms, and particularly relates to a new application of lactobacillus reuteri CCFM8631, in particular to an application of lactobacillus reuteri CCFM8631 in preparation of a product for preventing and/or treating rheumatoid arthritis.
Background
Rheumatoid Arthritis (RA) is a chronic, systemic autoimmune disease that manifests initially as synovitis, pannus formation, followed by articular cartilage destruction, bone tissue inflammation, late stage joint sclerosis, significant narrowing or disappearance of the joint space, and finally progresses to osteoarthrosis, narrowing or even disappearance of the joint space, and joint deformity leading to functional disability. Epidemiological investigation shows that about 0.5% -1% of people worldwide suffer from rheumatoid arthritis, the prevalence rate of China is about 0.32% -0.36%, wherein the incidence rate of men and women is about 1: 3. these data suggest that rheumatoid arthritis as a non-negligible class of autoimmune diseases has threatened public health and well-being.
The exact etiology and pathogenesis of rheumatoid arthritis are not clear, and at present, the rheumatoid arthritis is mainly considered to be autoimmune disease caused by the joint/interaction of genetic factors, environmental factors, infection factors, immunity factors and the like. Immune factors are involved in innate and adaptive immunity, where B cells and CD4+ T cells and their subpopulations play a crucial role in the development and progression of disease. The immune system of the body is stimulated by environmental factors or self-antigens to cause the response disorder of the immune system, CD4+ T cells are abnormally developed and differentiated, B cells are generated from antibodies to destroy the immune tolerance of the body, and the autoimmune reaction is initiated. CD4+ T lymphocytes have various subgroups, which are closely related to rheumatoid arthritis, namely Th17 cells and Treg cells, the balance of the ratio of Th17/Treg cells is favorable for maintaining the immune balance of the body, the over-differentiation of the Th17 cells can lead to the generation of a large amount of proinflammatory cytokines so as to further strengthen inflammatory reaction, the secretion of the proinflammatory cytokines is reduced due to the lack of Tregs, and the immune tolerance of the body is damaged. In a number of clinical studies, increased Th17 cells and decreased Treg cells in the blood of RA patients are detected, and the proportion of the cells is unbalanced, and the balance is restored after treatment. The immune response of the body is a complex and precise systemic response that affects not only local responses but also systemic immune responses. Intestinal mucosa is an important mucosal site, and intestinal immunity influences systemic immune response of organisms. The immune response at the site of the intestinal mucosa is largely shaped by intestinal bacteria. The relative abundance of Prevotella in feces of RA patients increases significantly during the early stage of onset, and the abundance of this bacterium decreases to normal levels during the later stage of disease, accompanied by the development of disease. Further exploring the immune response of different species of Prevotella, it was found that Prevotella copri has the effect of inducing arthritis in mice, while Prevotella histicola relieves the arthritis condition. Therefore, the intestinal tract can be used as a target for treating RA, and specific microorganisms are used for intervening intestinal flora to regulate intestinal immunity, so that systemic immune response is influenced, and further RA-related symptoms are relieved.
At present, rheumatoid arthritis is mainly treated clinically, and the prevention consciousness is lacked. Non-steroidal anti-inflammatory drugs, antirheumatic drugs and adrenoglucocorticoid are generally adopted to relieve the disease, but the latent period before the clinical manifestation of the disease is ignored, and a great deal of clinical research finds that some autoantibodies, such as rheumatoid factors and the like, can be detected in the blood of RA patients months or even years ago. Therefore, there is a need to find a safe, effective product which is easy to implement without side effects and which is effective in preventing and/or alleviating rheumatoid arthritis. Lactic acid bacteria, as a safe and edible food, have been widely used in the field of prevention or treatment of various diseases, such as prevention or treatment of gastrointestinal diseases, neurological diseases, alleviation of heavy metal toxicity, promotion of digestion and absorption, antagonism of infection by pathogenic bacteria, and enhancement of immunity. Therefore, the development of the probiotic preparation capable of effectively intervening the occurrence and development of the rheumatoid arthritis diseases has important social value. Although there is a related patent application (publication No. CN108165505A) for treating or relieving osteoarthritis pain by using probiotic Streptococcus thermophilus TCI633, the pathogenesis of osteoarthritis and rheumatoid arthritis is obviously different, and no report of using Lactobacillus reuteri to improve Th17 cellular immune response to relieve rheumatoid arthritis is available at present.
Disclosure of Invention
In view of the above, the present invention provides the application of lactobacillus reuteri (L Lactobacillus reuteri) CCFM8631 in the preparation of products for preventing and/or treating rheumatoid arthritis diseases, aiming at the above problems in the prior art.
In one embodiment, the invention inspects the influence of lactobacillus reuteri CCFM8631 on collagen-induced rheumatoid arthritis rats, and the result shows that the lactobacillus reuteri CCFM8631 can reduce the reduction of the weight of the collagen-induced rheumatoid arthritis rats and reduce the joint swelling degree of the rats.
In one embodiment, the invention investigates the influence of the lactobacillus reuteri CCFM8631 on the I L-1 β in the serum of rats with rheumatoid arthritis, and the result shows that the lactobacillus reuteri CCFM8631 can reduce the level of the I L-1 β in the serum of proinflammatory factors, so the invention provides the application of the lactobacillus reuteri CCFM8631 in preparing products for regulating the content of the proinflammatory cytokines I L-1 β in the serum.
In one embodiment, the regulation effect of the lactobacillus reuteri CCFM8631 on butyrate in the excrement of rats with rheumatoid arthritis is examined, and the result shows that the lactobacillus reuteri CCFM8631 has a remarkable recovery effect on the butyrate in the excrement of rats with rheumatoid arthritis so as to enable the butyrate to reach a normal level. Therefore, the invention provides the application of the lactobacillus reuteri CCFM8631 in the product for improving the content of butyrate in feces.
In one embodiment, the invention examines the regulation effect of the lactobacillus reuteri CCFM8631 on the fecal flora of rats with rheumatoid arthritis, and the result shows that the lactobacillus reuteri CCFM8631 can regulate the intestinal flora composition disorder caused by the rheumatoid arthritis.
In one embodiment, the present invention examined the effect of Lactobacillus reuteri CCFM8631 on the growth of Prevotella copri in vitro, and the results showed that Lactobacillus reuteri CCFM8631 directly inhibits Prevotella copri, which may exacerbate rheumatoid arthritis. Therefore, the invention provides the application of the lactobacillus reuteri CCFM8631 in the products for inhibiting the growth and the propagation of Prevotella copri.
In one embodiment, the present invention examined the effect of lactobacillus reuteri CCFM8631 on Th17 cells in mesenteric lymph nodes, and the results showed that lactobacillus reuteri CCFM8631 significantly inhibited the differentiation ability of Th17 cells at mesenteric in arthritic rats. Therefore, the invention provides the application of the lactobacillus reuteri CCFM8631 in the product for regulating the proportion of Th17 cells at mesenteric lymph nodes.
The invention provides application of lactobacillus reuteri CCFM8631 in preparation of products for preventing and/or treating rheumatoid arthritis diseases.
The lactobacillus reuteri (L Lactobacillus reuteri) CCFM8631 is preserved in China general microbiological culture Collection center (CGMCC) in 2017 at 07 th and 07 th, the preservation address is the microbial research institute of China academy of sciences No. 3 of North West Lu No.1 institute of North China, Chaoyang district, Beijing, and the preservation number is CGMCC NO. 14394.
In the invention, the viable count of the lactobacillus reuteri CCFM8631 in the product is not less than 1 × 109CFU/m L or 1 × 109CFU/mg。
The product of the invention includes but is not limited to drugs, microbial agents or fermented foods.
Wherein the medicament contains lactobacillus reuteri CCFM8631, a medicament carrier and/or a medicament auxiliary material.
In the present invention, the fermented food is a food produced by fermentation using the lactobacillus reuteri CCFM8631 as a starter.
In the present invention, the recommended dosage of the product is 1m L or 1 mg/day, i.e. at least 1 × 10/day of intake9CFU live bacteria.
The lactobacillus reuteri CCFM8631 can reduce weight reduction, reduce weight reduction of collagen-induced rheumatoid arthritis, reduce joint swelling degree of rats, reduce I L-1 β level in proinflammatory factor serum, has a remarkable recovery effect on butyrate in excrement of rats with the rheumatoid arthritis to enable the rat excrement to reach a normal level, can regulate intestinal flora composition disorder caused by the rheumatoid arthritis, directly inhibit Prevotella copri capable of aggravating the rheumatoid arthritis, and remarkably inhibit differentiation capacity of Th17 cells at mesentery of rats with the rheumatoid arthritis.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below.
FIG. 1 shows the effect of example 1CCFM8631 on rheumatoid arthritis rats; a: body weight; b: joint thickness clinical score; c: a clinical score;
FIG. 2 shows the effect of example 2CCFM8631 on cytokines I L-1 β in the serum of rheumatoid arthritis rats, # P <0.05, # P <0.01, # P <0.001, P <0.05, # P <0.05 and/or P <0.05 on the control group;
FIG. 3 shows the effect of example 3CCFM8631 on butyric acid in the feces of rheumatoid arthritis rats; # P <0.05, # P <0.01, # P <0.001 compared to the placebo control group; p <0.05, P <0.05 compared to model group;
FIG. 4 shows the effect of example 4CCFM8631 on levels of Rheumatoid arthritis rat fecal flora; a: bacteroides; b: tenericutes;
FIG. 5 shows the effect of example 4CCFM8631 on fecal microbiota levels in rats with rheumatoid arthritis; a: analoplataceae; b: rikenella ceae;
FIG. 6 shows the effect of example 4CCFM8631 on the level of fecal flora in rheumatoid arthritis rats; a: anaeroplastsna; b: paraprevorella; c: sarcina;
FIG. 7 shows the effect of example 5CCFM8631 on Th17 cell differentiation in mesenteric lymph nodes of rheumatoid arthritis rats;
FIG. 8 shows a representative map of Th17 cells in mesenteric lymph nodes in each group of example 5; a: a normal group; b: a model group; c: a drug group; d: group of lactobacillus reuteri.
Detailed Description
The invention discloses application of lactobacillus reuteri CCFM8631 in preparation of products for preventing and/or treating rheumatoid arthritis diseases. Those skilled in the art can modify the process parameters appropriately to achieve the desired results with reference to the disclosure herein. It is expressly intended that all such similar substitutes and modifications which would be obvious to one skilled in the art are deemed to be included in the invention. While the methods and products of the present invention have been described in terms of preferred embodiments, it will be apparent to those of ordinary skill in the art that variations and modifications of the methods described herein, as well as other suitable variations and combinations, may be made to implement and use the techniques of the present invention without departing from the spirit and scope of the invention.
In order to further understand the present invention, the technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Unless otherwise specified, the reagents involved in the examples of the present invention are all commercially available products, and all of them are commercially available.
Example 1: effect of Lactobacillus reuteri CCFM8631 on collagen-induced rheumatoid arthritis rats
SPF (specific Pathologen free) grade female Wistar rats of 7 weeks of age were kept in an SPF grade environment of 22-24 ℃, 40% -60% humidity, 12h daily exposure, and all animals were free to eat and drink water. Experimental animals were randomized 1 week after acclimation into four groups: the normal group, the model group, the drug methotrexate group and the CCFM8631 group are respectively provided with 8-9 drugs, and the specific experimental treatment is shown in the table 1.
CCFM8631 is activated for three generations in MRS culture medium, enlarged culture is carried out with 5 percent of inoculation amount, culture is centrifugally concentrated and washed three times by sterile normal saline, bacterial mud is resuspended in 30 percent sterile sucrose solution, and the concentration is adjusted to 5 × 1010CFU/m L, subpackaging, placing in a refrigerator at-80 deg.C, and diluting with sterile distilled water ten times before intragastric administration.
The modeling method comprises the steps of mixing a cattle type II collagen solution and a Freund incomplete adjuvant in equal volume and completely emulsifying, wherein the modeling adopts a method of two times of immunization, 0.15m L completely emulsified emulsion is sucked for the first immunization and injected subcutaneously at a position 1.5cm away from the root of a rat tail, and 0.15m L completely emulsified emulsion is sucked again for subcutaneous injection at a position 2.0cm away from the root of the rat tail when the immunization is strengthened after one week.
TABLE 1 grouping and treatment method of experimental animals
The whole experimental period was 7 weeks, and it can be seen from fig. 1A that the pre-gavage CCFM8631 had no effect on body weight for two weeks. Rheumatoid arthritis symptoms appeared after 1 week after the booster immunization, the body weight of the model group tended to decrease, and was significantly lower than that of the normal group from week 3 (model group: 250.98 + -7.02 g/mouse; blank group: 294.08 + -8.97 g/mouse, p < 0.001); the weight of the rats in the CCFM8631 group is close to that of the drug group and is higher than that of the model group (the CCFM8631 group is 264.66 +/-5.82 g/mouse; the drug group is 269.59 +/-4.33 g/mouse; and p is 0.93), and no side effect occurs in the drug group. As can be seen from FIGS. 1B and 1C, the model group had severe swelling and redness of the joints at week 3, the ankle thickness was about 1.7 times that of the blank group, the joint thickness was significantly increased, and the gastric perfusion CCFM8631 was able to alleviate the swollen ankle thickness of the ankle, which was only 31.3% greater than that of the blank group. Consistent with this, CCFM8631 also decreased clinical score. The lactobacillus reuteri CCFM8631 can reduce the weight reduction and reduce the joint swelling degree of rats, which indicates that the lactobacillus reuteri CCFM8631 has the function of improving rheumatoid arthritis.
Example 2 Effect of Lactobacillus reuteri CCFM8631 on the serum I L-1 β in rats with rheumatoid arthritis
Example 1 after completion of the molding experiment, rats were fasted for 12 hours without water deprivation, blood samples were collected, left to stand at room temperature for 30 minutes, centrifuged at 3000g at room temperature for 15 minutes, and the supernatant was collected and subjected to measurement using E L ISA kit (RD 1; cat # DY501) of rat I L-1 β, according to the instructions.
The results are shown in figure 2, the concentration of I L-1 β in the serum of the rats in the rheumatoid arthritis model group is 834.76 +/-223.67 ng/m L, which is obviously higher than that of the normal group (142.77 +/-49.84 ng/m L) (p is 0.012), compared with the rats in the model group, the levels of I L-1 β are obviously reduced in the drug group and the CCFM8631 group and are close to that of the normal group, which are 159.35 +/-39.84 ng/m L and 175.49 +/-42.29 ng/m L respectively, and the results indicate that the Lactobacillus reuteri CCFM8631 can reduce the level of I L-1 β in the serum of proinflammatory factors.
Example 3: regulation effect of lactobacillus reuteri CCFM8631 on butyrate in excrement of rats with rheumatoid arthritis
Example 1 after the molding experiment was completed, rats were fasted for 12 hours without water prohibition, feces were collected in liquid nitrogen, and then transferred to a-80 refrigerator, and taken out before the experiment, vacuum freeze-dried, 0.05g of the lyophilized feces sample was accurately weighed and dissolved in 0.5m L saturated sodium chloride solution, soaked for 30min, homogenized by a tissue homogenizer, 0.02m L10% sulfuric acid was added, shaken for 30s, 0.8m L ether solution was accurately added to the feces solution in a fume hood, centrifuged for 30s for 15min (8000g, 4 ℃), and the supernatant was transferred to a centrifuge tube containing 0.3g of anhydrous sodium sulfate, shaken uniformly, centrifuged for 15min (8000g, 4 ℃), and the supernatant was taken until the butyrate content in the feces was detected by GCMS.
The results are shown in FIG. 3, in which the content of butyric acid in the rats of the rheumatoid arthritis model group was decreased to 64.0% of that of the rats of the normal group. Intervention of CCFM8631 significantly increased the content of butyric acid (FIG. 3) back to the level of the normal group (normal group vsCCFM8631 group: 8.25. + -. 0.67vs 10.01. + -. 0.52. mu. mol/g). The results show that the lactobacillus reuteri CCFM8631 has a remarkable recovery effect on butyrate in the excrement of rats with rheumatoid arthritis, so that the normal level of butyrate is reached.
Example 4: regulation effect of lactobacillus reuteri CCFM8631 on rheumatoid arthritis rat fecal flora
Example 1 feces from rats were collected after completion of the molding experiment, genomic DNA was extracted from the feces, and specific PCR amplification and 16S rDNA sequencing were performed on V3-V4 region to analyze changes in fecal flora. The results are shown in fig. 4, 5 and 6.
As shown in fig. 4, the fecal microflora of rats in the rheumatoid arthritis model group was significantly changed compared to that in the normal group. At the phylum level, the relative abundance of bacteroidides (fig. 4A) was increased for the model group compared to the normal group. While tenericates (fig. 4B) decreased significantly, CCFM8631 had a restorative effect on this change, but not significantly. At the family level, the relative abundance of anaerobaplasmataceae (fig. 5A) in model group stools was significantly reduced compared to the content of normal group; and Rikenellaceae (fig. 5B) was significantly increased, and the relative abundance was increased from 0.23% in the normal group to 1.07%. After intake of CCFM8631, the relative abundance of Anaeroplasmataceae and rikennellacea restored the content of the normal group. At the genus level, the model group showed a significant decrease in anaeoplasma (fig. 6A) and an increase in pararevotella (fig. 6B) (p ═ 0.058) compared to the normal group. After CCFM8631 intervention, Anaeroplasma returned to normal levels, and the abundance of paraprevolella did not change. And the abundance of Sarcina was lower in the model group than in the blank group, which was restored and higher than in the normal group by CCFM8631 (fig. 6C). The function of lactobacillus reuteri CCFM8631 in regulating intestinal flora composition disorder caused by rheumatoid arthritis is demonstrated.
Example 5: effect of Lactobacillus reuteri CCFM8631 on Th17 cells in mesenteric lymph nodes
Example 1 after the end of the Molding experiment, IsofluorineAnesthetizing rat with alkane, collecting blood from heart, soaking in 75% ethanol for 15min, opening abdominal cavity with sterile instrument, aseptically taking mesenteric lymph node, preparing mesenteric lymph node into single cell suspension, and adjusting cell concentration to 2 × 105cells/100 mu L, adding a mixture of phorbol ester 12-myristate 13-acetate (PMA) and ionomycin, culturing and stimulating for 6h in a 37 ℃ cell culture box, carrying out surface staining and I L-17A-PE intracellular staining on stimulated cells by CD4-FITC, and detecting the proportion of Th17 cells by a flow cytometer.
As a result, as shown in fig. 7, the proportion of Th17 cells was significantly increased in the model group compared to the normal group, which was 11.83 times higher than that in the normal group. Under the drug treatment, the proportion of Th17 cells is reduced to 0.33 percent, which is 1.83 times that of the normal group; the CCFM8631 has obvious inhibition effect on Th17 cells, which is only 2 times of that of a normal group, and the inhibition effect is close to that of a medicament. FIGS. 8A-D show plots of the Th17 cell fraction (Q2) for representative samples in each group. According to the results, the differentiation capacity of Th17 cells at mesentery of arthritic rats is remarkably enhanced (11.66%), and Lactobacillus reuteri CCFM8631 is remarkably inhibited (0.38%).
Example 6: lactobacillus reuteri CCFM8631 inhibits the growth of Prevotella copri in vitro
15 tubes containing 4.8m L of BHI medium were divided into 3 groups of 5 tubes each, which were CCFM8631 control group, Prevotella copri control group, CCFM8631 and Prevotella copri co-cultured group, 100. mu. L1 × 10 was added to the control group6The corresponding bacterial liquid of CFU/m L and sterile physiological saline of 100 mu L are respectively added into the co-culture component of 100 mu L1 × 106CCFM8631 bacterial liquid of CFU/m L and 100 mu L1 × 106CFU/m L Prevotella copri, mixing, placing in anaerobic workstation, culturing at 37 deg.C for 24h, collecting 1m L, and performing colony counting by pouring, when counting colonies, using MRS agar medium for CCFM8631 control group, BHI agar medium supplemented with 5% cholate and 10% horse serum for Prevotella copri control group, and using two media for cocultivation, which are agar MRS medium (growth of CCFM8631 only), BHI agar medium supplemented with 5% cholate and 10% horse serum (growth of Prevotella copri only), the counting results are shown in Table2, respectively.
TABLE 2 in vitro Co-culture of CCFM8631 with Prevotella copri (unit: 10)9CFU/mL)
| Name of bacterium | CCFM8631 control group | Prevotella copri control group | Co-culture group |
| CCFM8631 | 6.1±4.6 | — | 6.5±9.2 |
| Prevotella copri | — | 4.2±1.9 | 1.9±8.8 |
As shown in Table 2, after CCFM8631 and Prevotella copri were co-cultured, the growth of Prevotella copri was significantly inhibited, and the inhibition rate was 54% compared to the control group, while the growth of CCFM8631 was not affected, indicating that Lactobacillus reuteri CCFM8631 directly inhibits Prevotella copri, which may aggravate rheumatoid arthritis.
Claims (6)
1. Application of Lactobacillus reuteri (L Acobacterium reuteri) CCFM8631 in preparing products for regulating content of proinflammatory cytokine I L-1 β in serum, inhibiting growth and reproduction of Prevotella copri, increasing content of butyrate in feces and regulating proportion of Th17 cells at mesenteric lymph nodes.
2. Application of Lactobacillus reuteri (L Lactobacillus reuteri) CCFM8631 in preparing products for preventing and/or treating rheumatoid arthritis diseases.
3. Use according to claim 1 or 2, wherein the viable count of lactobacillus reuteri CCFM8631 in said product is not less than 1 × 109CFU/m L or 1 × 109CFU/mg。
4. Use according to claim 1 or 2, wherein the product is a medicament, a bacterial preparation or a fermented food product.
5. The use according to claim 4, wherein the medicament comprises Lactobacillus reuteri CCFM8631, a pharmaceutical carrier and/or a pharmaceutical excipient.
6. The use according to claim 4, wherein the fermented food product is a food product produced by fermentation using the Lactobacillus reuteri CCFM8631 as a starter.
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