CN118001305B - Application of bifidobacterium longum JBLC-141 in preparation of medicine for improving paraneoplastic thrombocytosis - Google Patents
Application of bifidobacterium longum JBLC-141 in preparation of medicine for improving paraneoplastic thrombocytosis Download PDFInfo
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Abstract
The invention relates to the technical field of probiotics, in particular to a novel application of bifidobacterium longum JBLC-141, and specifically relates to an application of bifidobacterium longum JBLC-141 in preparation of a medicament for improving paraneoplastic thrombocytosis, wherein bifidobacterium longum (Bifidobacterium longum) JBLC-141 is preserved in China general microbiological culture Collection center of China Committee for culture Collection of microorganisms on 7 and 8 days in 2019, and the preservation address is No. 3 of Qing Jiu No.1 in North Star West Lu in Beijing area, and the preservation number is CGMCC No.18094. Clinical experiments prove that the bifidobacterium longum JBLC-141 can regulate platelet count and maintain the stability of blood coagulation function, has potential functions in regulating key biomarkers related to ovarian cancer, and further hinders disease progression.
Description
Technical Field
The invention relates to the technical field of probiotics, in particular to a novel application of bifidobacterium longum JBLC-141, and specifically relates to an application of bifidobacterium longum JBLC-141 in preparation of a medicament for improving paraneoplastic thrombocythemia.
Background
Ovarian Cancer (OC) stands out in gynaecological malignancies, and due to its high malignancy, the highest mortality rate in this category is always maintained. Worldwide, it is estimated that 313000 women receive OC diagnosis each year, with about 207000 dying from the disease. Ovarian cancer recurrence is the leading cause of death. Unfortunately, a significant proportion of patients relapse soon after initial treatment. Studies have shown that the shorter the time interval for the first relapse, the worse the prognosis, which underscores the need for research and development of new drugs that can delay the critical period for the patient. There is increasing evidence underscores the importance of elevated platelet levels as biomarkers affecting tumor microenvironment, leading to recurrence of ovarian cancer. Thus, preventing an increase in platelet count is expected to improve the time to first relapse in patients.
In the field of tumor biology, the interaction between tumor cells and platelets is of paramount importance. Activated platelets play a key role in recruiting or differentiating immune cells by producing a large number of inflammatory factors, thereby participating in the inflammatory reaction process. The sustained inflammatory response further promotes proliferation of tumor stem cells through a variety of mechanisms, including evading apoptosis, maintaining autonomic growth and proliferation signals, promoting tumor angiogenesis and immune escape. Clinical trials aimed at modulating the thrombopoietin of ovarian cancer have shown promising therapeutic effects, which motivate the expectation of future breakthroughs. The comprehensive exploration of the complex regulatory mechanisms involved in this interaction is of profound importance in advancing cancer treatment strategies.
At present, few studies on the efficacy and safety of probiotics in improving ovarian cancer with paraneoplastic thrombocytosis are performed, and there is a lack of clinical trials for improving paraneoplastic thrombocytosis by probiotic intervention to improve prognosis of ovarian cancer patients.
Disclosure of Invention
Aiming at the technical problem that the prior art about the curative effect and safety of probiotics in improving ovarian cancer with paraneoplastic thrombocytosis is seldom studied, the invention provides an application of bifidobacterium longum JBLC-141 in preparing medicaments for improving paraneoplastic thrombocytosis, and experiments prove that bifidobacterium longum JBLC-141 has the curative effect and safety in improving ovarian cancer with paraneoplastic thrombocytosis.
The technical scheme of the invention is as follows:
The application of bifidobacterium longum JBLC-141 in preparing medicaments for improving paraneoplastic thrombocytosis is that bifidobacterium longum (Bifidobacterium longum) JBLC-141 is preserved in China general microbiological culture Collection center (China Committee for culture Collection of microorganisms) on the 7 th month 8 th year 2019, and the preservation address is North Star Xiyu No. 1, 3 in the Chaoyang district of Beijing city, and the preservation number is CGMCC No. 18094.
Further, the drugs for improving paraneoplastic thrombocythemia include bifidobacterium longum JBLC-141 powder and isomaltooligosaccharide.
Further, the preparation of bifidobacterium longum JBLC-141 bacterial powder comprises the following steps:
(a) Inoculating activated bifidobacterium longum JBLC-141 to MRS liquid culture medium, and performing anaerobic culture at 37 ℃ to obtain bacterial liquid;
(b) And (3) centrifuging the bacterial liquid to obtain bacterial cells, washing the bacterial cells with sterile physiological saline, re-suspending the bacterial cells in reconstituted skim milk to obtain bacterial suspension, and freeze-drying and crushing the bacterial suspension to obtain the microbial suspension.
Further, anaerobic culture conditions were N 2:H2:CO2 =85:10:5.
Further, the concentration of bifidobacterium longum JBLC-141 in the bacterial suspension was 1.0X10. 10 10~2.0×1010 cfu/mL.
Further, the viable count of bifidobacterium longum JBLC-141 in the drug for improving paraneoplastic thrombocythemia is 0.5X10- 9~5.0×109 cfu/g.
Further, the medicine for improving paraneoplastic thrombocytosis has the function of regulating platelet count, interleukin-6, interleukin-8, tumor necrosis factor-alpha, cancer antigen 125 and human epididymal protein 4 secretion.
Further, the medicine for improving paraneoplastic thrombocythemia has the function of maintaining the stability of the blood coagulation function.
The invention has the beneficial effects that:
Clinical experiments prove that the bifidobacterium longum JBLC-141 can regulate platelet count and maintain the stability of blood coagulation function, has potential functions in regulating key biomarkers related to ovarian cancer, and further hinders disease progression.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings that are required to be used in the description of the embodiments or the prior art will be briefly described below, and it will be obvious to those skilled in the art that other drawings can be obtained from these drawings without inventive effort.
FIG. 1 is a bar graph comparing blood clotting functions to platelet counts for each group of patients before and after intervention in the application example.
FIG. 2 is a bar graph of cytokine comparisons in plasma for each group of patients before and after intervention in the application example.
FIG. 3 is a graph showing comparison of differences in intestinal microbiota diversity between groups of patients before and after intervention in the application example.
Fig. 4 is a LEfSe differential analysis of each group of patients before and after intervention in the application example.
FIG. 5 is a graph showing comparison of differences in intestinal microbiota classification between groups of patients before and after intervention in the application example.
Fig. 6 is a comparison of post-operative stationary phase for each group of patients with dry prognosis in the application example.
In the figure, CB represents the pre-intervention control group, TB represents the pre-intervention probiotic group, CA represents the post-intervention control group, and TA represents the dry prognosis probiotic group. * P <0.05, P <0.01, P <0.001, ns, no significant.
Detailed Description
In order to make the technical solution of the present invention better understood by those skilled in the art, the technical solution of the present invention will be clearly and completely described below with reference to the accompanying drawings in the embodiments of the present invention, and it is apparent that the described embodiments are only some embodiments of the present invention, not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the present invention without making any inventive effort, shall fall within the scope of the present invention.
The bifidobacterium longum JBLC-141 of the present invention has been disclosed in chinese invention patent CN 112592872B, and the preservation information thereof is as follows:
The strain is preserved in China general microbiological culture Collection center (China general microbiological culture Collection center) in 7 and 8 days of 2019, the preservation address is North Star Xiyu No. 1 and No. 3 in the Korean region of Beijing, the preservation number is CGMCC No. 18094, and the strain is classified and named as Bifidobacterium longum Bifidobacterium longum.
Example 1
(A) Inoculating activated bifidobacterium longum JBLC-141 to an MRS liquid culture medium according to an inoculum size of 1% (w/w), and performing anaerobic culture for 24 hours at 37 ℃ under the anaerobic condition of N 2:H2:CO2 = 85:10:5 to obtain bacterial liquid;
Every liter of MRS liquid culture medium comprises:
10g of peptone, 5g of beef powder, 2g of K 2HPO4·7H2 O, 2g of tri-ammonium citrate, 5g of CH 3COONa·3H2 O, 20g of glucose, 1mL of Tween 80 and 0.05g of MgSO 4·7H2O 0.2g、MnSO4·4H2 O;
(b) Centrifuging the bacterial liquid to obtain bacterial cells, washing the bacterial cells with sterile physiological saline, and then re-suspending the bacterial cells in 15% (w/w) reconstituted skim milk to obtain bacterial suspension with the concentration of JBLC-141 of bifidobacterium longum of 1.0X10 10 cfu/mL, and performing freeze drying and crushing to obtain bacterial powder of JBLC-141 bifidobacterium longum;
(c) Freeze drying the bacterial suspension, pulverizing, mixing with isomaltooligosaccharide (available from BAO SHILIAO biological Co., ltd.) to obtain bacterial preparation with bacterial count of 0.5X10 9 cfu/g, and making into medicine for improving paraneoplastic thrombocytosis.
Example 2
(A) Inoculating activated bifidobacterium longum JBLC-141 to an MRS liquid culture medium according to an inoculum size of 1% (w/w), and performing anaerobic culture for 24 hours at 37 ℃ under the anaerobic condition of N 2:H2:CO2 = 85:10:5 to obtain bacterial liquid;
Every liter of MRS liquid culture medium comprises:
10g of peptone, 5g of beef powder, 2g of K 2HPO4·7H2 O, 2g of tri-ammonium citrate, 5g of CH 3COONa·3H2 O, 20g of glucose, 1mL of Tween 80 and 0.05g of MgSO 4·7H2O 0.2g、MnSO4·4H2 O;
(b) Centrifuging the bacterial liquid to obtain bacterial cells, washing the bacterial cells with sterile physiological saline, and then re-suspending the bacterial cells in 15% (w/w) reconstituted skim milk to obtain bacterial suspension with the concentration of bifidobacterium longum JBLC-141 of 2.0X10 10 cfu/mL, and performing freeze drying and crushing to obtain bifidobacterium longum JBLC-141 bacterial powder;
(c) Freeze drying the bacterial suspension, pulverizing, mixing with isomaltooligosaccharide (available from BAO SHILIAO biological Co., ltd.) to obtain bacterial preparation with bacterial count of 5.0X10 9 cfu/g, and making into medicine for improving paraneoplastic thrombocytosis.
Example 3
(A) Inoculating activated bifidobacterium longum JBLC-141 on MRS liquid culture medium according to an inoculum size of 1% (w/w), and performing anaerobic culture for 24 hours at 37 ℃ under the anaerobic condition of N 2：H2：CO2 = 85:10:5, obtaining bacterial liquid;
Every liter of MRS liquid culture medium comprises:
10g of peptone, 5g of beef powder, 2g of K 2HPO4·7H2 O, 2g of tri-ammonium citrate, 5g of CH 3COONa·3H2 O, 20g of glucose, 1mL of Tween 80 and 0.05g of MgSO 4·7H2O 0.2g、MnSO4·4H2 O;
(b) Centrifuging the bacterial liquid to obtain bacterial cells, washing the bacterial cells with sterile physiological saline, and then re-suspending the bacterial cells in 15% (w/w) reconstituted skim milk to obtain bacterial suspension with the concentration of JBLC-141 of bifidobacterium longum of 1.0X10 10 cfu/mL, and performing freeze drying and crushing to obtain bacterial powder of JBLC-141 bifidobacterium longum;
(c) Freeze drying the bacterial suspension, pulverizing, mixing with isomaltooligosaccharide (available from BAO SHILIAO biological Co., ltd.) to obtain bacterial preparation with bacterial count of 1.0X10 9 cfu/g, and making into medicine for improving paraneoplastic thrombocytosis.
Clinical trial with bifidobacterium longum JBLC-141 for intervention in improvement of paraneoplastic thrombocythemia
1. Test content
Test design and patient selection
Criteria for enrolled patients required that they were between 18 and 75 years of age, new pathologically diagnosed as epithelial ovarian cancer, and received a combination chemotherapy regimen of carboplatin and paclitaxel. In addition, patients were included in the study if their platelet count was greater than 300X 10 9/L at the time of initial diagnosis and no antibiotics were used for 3 months prior to group entry. Exclusion criteria include hemophilia, blood system related diseases, other immune diseases that cause platelet abnormalities, or complications with other cancers or chronic diseases.
A total of 100 eligible patients were randomly assigned to either the probiotic group (T group) or the control group (C group), with 50 patients per group. Patients in group T received treatment with bifidobacterium longum JBLC-141, taken daily 4g each in the morning and evening 2g of the example 3 bifidobacterium longum JBLC-141; patients in group C were given 4g placebo (isomaltooligosaccharide) daily, 2g each in the morning and evening. The test time lasted 90 days. Most of the time during the study allowed the patient freedom. During intervention, participants are advised to follow specific details to minimize confounding factors, including maintaining a light diet, avoiding cold or spicy foods, and avoiding strenuous exercise.
All statistical analyses were performed using SPSS 26.0 for clinical data analysis and GraphPad 9.0 for graphical representation. For clinical laboratory tests and clinical features, the measured data conforming to a normal distribution are expressed as mean ± standard deviation (m±sd). For data that does not meet the normal distribution, a conversion (such as a logarithmic conversion) is performed by a mathematical formula to meet the normal distribution standard, and then the average value ± standard deviation (m ± sd) is used. Subsequently, T-test or one-way anova was used for both types of distributions. After collection and classification, the ranking data is subjected to chi-square testing. In the analysis of microbiota sequencing data, unpaired normal distribution data was analyzed using a one-way anova, whereas the non-parametric Kruskal-Wallis test was used for data of non-normal distribution. Multiple comparisons were made using either the Tukey test or the Dunn test (two-tailed). Unless explicitly indicated, a significance threshold of P <0.05 is considered statistically significant for all analyses.
2. Analysis of results
During the clinical trial, 5 patients were out of visit, 3 of group C (6%), 2 of group T (4%).
(One) blood coagulation function and platelet evaluation
On days 0 and 90 of the test, the participants were tested for their clotting functions (prothrombin time PT, activated partial thromboplastin time APTT, thrombin time TT, fibrinogen FIB and D-dimer) and platelets. The changes in the blood clotting function test data and blood routine test data of the participants before and after the intervention are shown in FIG. 1.
Comparing the results of the clotting function tests for the groups, patients in group T did not significantly change PT, APTT, FIB and D-dimer under intervention of bifidobacterium longum JBLC-141. In contrast, group C showed statistically significant deterioration of coagulation parameters such as PT, APTT, FIB and D-dimer. This difference suggests that bifidobacterium longum JBLC-141 intervention helps maintain stability of clinical clotting functions.
At the same time, the platelet change before and after the T-group intervention was not statistically significant, while the platelet count after the placebo intervention was significantly increased for group C. Platelet counts of groups T and C showed significant differences after the trial, indicating the potential of bifidobacterium longum JBLC-141 in affecting platelet kinetics, in significant contrast to placebo. It can be seen that bifidobacterium longum JBLC-141 has a good effect on clotting functions and platelet count.
(II) cytokines and tumor markers
On days 0 and 90 of the trial, the plasma of the participants were analyzed for interleukin-6 (IL-6), interleukin-8 (IL-8), tumor necrosis factor-alpha (TNF-alpha), cancer antigen 125 (CA 125) and human epididymal protein 4 (HE 4).
As shown in FIG. 2, no statistically significant changes in IL-6, IL-8, TNF-. Alpha., CA125 and HE4 levels were observed in the plasma of patients after intervention in the T group receiving the intervention of bifidobacterium longum JBLC-141. In contrast, in group C, which received placebo intervention, IL-6, IL-8, TNF-. Alpha.CA 125 and HE4 were significantly elevated in the plasma of the patients after the intervention, and these changes were statistically significant compared to group T.
The differences in the pattern of changes in these cytokines and tumor markers observed between groups T and C indicate that bifidobacterium longum JBLC-141 may have an effect on slowing the progression of the disease. Statistically significant differences indicate a potential role for bifidobacterium longum JBLC-141 intervention in modulating key biomarkers associated with ovarian cancer, thereby impeding disease progression.
(III) analysis of intestinal microbiota diversity
The change in intestinal microbiota diversity was analyzed comprehensively for all patients 90 days after the probiotic or placebo administration. As shown in fig. 3A, analysis of the alpha diversity index showed that after the intervention with bifidobacterium longum JBLC-141, the patient's Chao1 and Faith _pd values (representing species abundance and uniformity, respectively) did not show statistically significant changes, indicating that the alpha diversity of the intestinal microbiota remained relatively stable on a microscopic scale. As shown in fig. 3B, the PCoA results demonstrate a significant separation of the TA group from the other groups, indicating a significant change in β -diversity between species following intervention by bifidobacterium longum JBLC-141. The heat map of the TA group species composition (fig. 3C) underscores the significant abundance of bifidobacteria. The Venn diagram of FIG. 3D shows that the common ASV sequences for all groups are 177 and the unique sequence numbers for the CB, CA, TB, and TA groups are 26, 22, 71, and 78, respectively.
Further analysis using LEfSe, as shown in figure 4, there were significant differences in abundance of actinomycota, actinomycetes, bifidobacteriales, bifidobacteriaceae, and bifidobacterium in the TA group compared to the other groups.
The above test results indicate that bifidobacterium longum JBLC-141 induces a significant change in the macrostructure of the intestinal microbiota of cancer patients.
The differences in the relative abundance of gut microbiota at the phylum, class and genus levels for each group were continued to be investigated. The major gates observed in each group before and after intervention were firmicutes, actinomycetes and proteus (fig. 5A). Comparative analysis showed that the relative abundance of the firmicutes was further reduced in the TA group compared to the TB and CA groups, the actinomycetes was increased, while the relative abundance of the proteus showed no significant change (fig. 5B-5D).
In the class of actinomycetes, the proportion of TA groups is significantly higher than other groups, as shown by the classification tree results of FIG. 5E.
Subsequent analysis at the genus level determined that B.Bluegum, B.bifidus, C.chrysalis, E.Zhengi, E.faecalis and Streptococcus are dominant genera (FIGS. 5F-5L). Detailed examination of the relative abundance at the genus level indicated that bifidobacteria abundance was significantly increased in the TA group compared to the TB and CA groups, consistent with findings at the actinomycota level. Furthermore, the relative abundance of eubacterium and faecalis was slightly reduced in the TA group compared to the CA group. No significant differences were observed between the b.brucellosis and kolin bacteria in all groups.
The research results show that bifidobacterium longum JBLC-141 is successfully established and proliferated in a patient, and the intestinal microenvironment is induced to be obviously changed.
(IV) postoperative stabilization period and recurrence
Patients who were involved in the present clinical trial were subjected to a full follow-up for 12 months to monitor recurrence and to finalize the analysis at the post-operative stationary phase. The results showed that the post-operative stable posture ratio for the group C and T participants was 22:18 (months). The risk ratio between the two groups was calculated to be 0.71 (95% ci, 0.43-1.16), and Log-Rank test showed no significant statistical difference in final results at the post-operative stabilization period between the two groups (p= 0.1695, fig. 6A).
At the same time, the platelet differences of all patients before and after the intervention were analyzed and classified into a non-recurrent group and a recurrent group (fig. 6B-6D), and the results showed that the platelet values of the two patients of the non-recurrent group and the recurrent group were statistically different. In addition, fig. 6E shows the non-randomness of the correlation between platelet count fluctuations and follow-up time (r=0.712, p < 0.0001). In particular, changes in platelet count reflect pre-and post-intervention changes, indicating a clear link to the time course of follow-up.
(V) safety assessment and adverse events
Safety and adverse event assessments showed that most events occurred during the first week of intervention, with all events being of a severity level 1-2. Comparative analysis showed that there were no statistically significant differences in adverse events (including diarrhea, nausea, fatigue, headache, vomiting, weight loss, abdominal pain, loss of appetite, and insomnia) between patients receiving probiotic treatment and those receiving placebo treatment.
Notably, 5 non-visit patients all were enrolled in the clinical trial during the intervention due to adverse events, with 3 patients belonging to group C and 2 belonging to group T. Diarrhea events are mainly grade 1 or grade 2, the most prominent adverse event requiring medical intervention. Management strategies include post-withdrawal observations, dose adjustments, and antidiarrheal interventions. Other adverse events, such as nausea and fatigue (both grade 1), were observed after withdrawal, or did not require clinical intervention.
Although the present invention has been described in detail by way of preferred embodiments with reference to the accompanying drawings, the present invention is not limited thereto. Various equivalent modifications and substitutions may be made in the embodiments of the present invention by those skilled in the art without departing from the spirit and scope of the present invention, and it is intended that all such modifications and substitutions be within the scope of the present invention/be within the scope of the present invention as defined by the appended claims.
Claims (8)
1. An application of bifidobacterium longum JBLC-141 in preparing a medicament for improving paraneoplastic thrombocytosis is characterized in that bifidobacterium longum (Bifidobacterium longum) JBLC-141 is preserved in China general microbiological culture Collection center (China Committee for culture Collection of microorganisms) on 7-8 th 2019, and the preservation address is No. 3 of West Highway No. 1 in North Star of the Korean area of Beijing and the preservation number is CGMCC No. 18094.
2. The use according to claim 1, wherein the agent for improving paraneoplastic thrombocythemia comprises bifidobacterium longum JBLC-141 powder and isomaltooligosaccharide.
3. The use according to claim 2, wherein the preparation of bifidobacterium longum JBLC-141 powder is:
(a) Inoculating activated bifidobacterium longum JBLC-141 to MRS liquid culture medium, and performing anaerobic culture at 37 ℃ to obtain bacterial liquid;
(b) And (3) centrifuging the bacterial liquid to obtain bacterial cells, washing the bacterial cells with sterile physiological saline, re-suspending the bacterial cells in reconstituted skim milk to obtain bacterial suspension, and freeze-drying and crushing the bacterial suspension to obtain the microbial suspension.
4. The use according to claim 3, wherein the anaerobic culture conditions are N 2:H2:CO2 = 85:10:5.
5. The use according to claim 3, wherein the concentration of bifidobacterium longum JBLC-141 in the bacterial suspension is 1.0 x 10 10~2.0×1010 cfu/mL.
6. The use according to claim 3, wherein the viable count of bifidobacterium longum JBLC-141 in the paraneoplastic thrombocythemia-ameliorating medicament is 0.5 x 10 9~5.0×109 cfu/g.
7. The use according to claim 1, wherein the agent for improving paraneoplastic thrombocythemia has the function of regulating platelet count, interleukin-6, interleukin-8, tumor necrosis factor- α, cancer antigen 125 and human epididymal protein 4 secretion.
8. The use according to claim 1, wherein the agent for improving paraneoplastic thrombocythemia has the function of maintaining the stability of the clotting function.
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