Application of Bifidobacterium longum BL21 in the preparation of agents to alleviate cisplatin-induced multi-organ damage.

Abstract

This invention relates to the application of *Bifidobacterium longum* BL21 in the preparation of formulations to alleviate multi-organ damage induced by cisplatin chemotherapy, namely, a novel microbial strategy for preventing or alleviating multi-organ damage induced by cisplatin chemotherapy. This invention creatively discovers that *Bifidobacterium longum* BL21 can alleviate kidney damage, intestinal damage, and bone marrow suppression without interfering with the antitumor activity of cisplatin. Specifically, it can reverse the increase in serum creatinine and blood urea nitrogen levels caused by cisplatin chemotherapy, reverse the increase in inflammatory factor levels in kidney tissue caused by cisplatin chemotherapy, and alleviate oxidative stress damage in kidney tissue caused by cisplatin chemotherapy; it can reverse the increase in intestinal permeability caused by cisplatin chemotherapy, reverse the downregulation of intestinal tight junction protein expression caused by cisplatin chemotherapy, reverse the increase in serum endotoxin levels caused by cisplatin chemotherapy, and reverse the decrease in beneficial intestinal bacteria caused by cisplatin chemotherapy; it can improve hematopoietic dysfunction caused by cisplatin chemotherapy and restore white blood cell count.

Description

Technical Field

[0001] This invention belongs to the field of probiotic technology and relates to a novel use of Bifidobacterium longum BL21, specifically the application of Bifidobacterium longum BL21 in the preparation of formulations that alleviate multi-organ damage caused by cisplatin chemotherapy. Background Technology

[0002] Cisplatin is a widely used first-line chemotherapy drug in clinical practice for the treatment of various solid tumors, including testicular cancer, ovarian cancer, lung cancer, and head and neck cancer. However, its severe dose-limiting toxicities greatly restrict clinical efficacy and patient tolerability. Many patients develop acute kidney injury (AKI) after receiving cisplatin treatment, characterized by significantly elevated serum creatinine (Scr) and blood urea nitrogen (BUN) levels, accompanied by pathological changes such as renal tubular epithelial cell necrosis and vacuolation. In addition, cisplatin can cause severe intestinal mucositis, disrupt the intestinal barrier function, lead to dysbiosis, and induce bone marrow suppression, manifested as leukopenia and thrombocytopenia, which seriously affects patients' quality of life and may delay subsequent treatment.

[0003] Currently used clinical protective strategies, such as adequate hydration and the use of cytoprotective agents like amifostine, have limitations in protective efficacy, potential for new side effects (such as hypotension), and high treatment costs. Other nephrotoxicity-protective drugs also have drawbacks such as insufficient efficacy or significant side effects. Furthermore, cisplatin-induced intestinal mucosal damage is difficult to repair, easily leading to dysbiosis and systemic inflammation.

[0004] Therefore, it is very meaningful to develop a protective strategy that can effectively protect normal tissues without interfering with the antitumor activity of cisplatin.

[0005] In recent years, the gut-kidney axis has played a crucial role in the cisplatin toxicity amplification mechanism. Cisplatin initially damages the intestinal epithelium, disrupting tight junctions and increasing intestinal permeability. This allows harmful substances such as endotoxins (e.g., lipopolysaccharide, LPS) and uremic toxin precursors to translocate into the bloodstream. These substances activate pattern recognition receptors (e.g., TLR4), thereby initiating the myeloid differentiation factor 88 (MyD88)-dependent nuclear factor κB (NF-κB) signaling pathway, triggering a systemic inflammatory storm. This recruits and activates immune cells such as macrophages to infiltrate the kidneys, exacerbating local oxidative stress, inflammation, and apoptosis, creating a vicious cycle. Therefore, targeting the gut microbiota and using probiotic intervention to repair the intestinal barrier and regulate immunity, thereby interrupting the toxicity transmission of the gut-kidney axis, has become a promising research direction. Summary of the Invention

[0006] In view of the shortcomings of the prior art, the purpose of this invention is to provide a novel use of Bifidobacterium longum BL21, specifically the application of Bifidobacterium longum BL21 in the preparation of a formulation to alleviate multi-organ damage caused by cisplatin chemotherapy.

[0007] To achieve this objective, the present invention adopts the following technical solution:

[0008] In a first aspect, the present invention provides the use of Bifidobacterium longum BL21 in the preparation of a formulation to alleviate multi-organ damage induced by cisplatin chemotherapy;

[0009] The Bifidobacterium longum BL21 strain is the Bifidobacterium longum BL21 strain with the preservation number CGMCC No.10452.

[0010] Preferably, the multi-organ injury includes kidney injury, intestinal injury, and bone marrow function suppression.

[0011] Preferably, the dosage form of the formulation includes lyophilized powder, tablets, capsules, microcapsules, granules, or solutions. The formulation of the present invention can be formulated into various dosage forms to meet the needs of different usage scenarios.

[0012] Preferably, the formulation further contains excipients; the excipients include any one or a combination of at least two of the following: fillers, binders, wetting agents, disintegrants, emulsifiers, solubilizers, osmotic pressure regulators, colorants, pH regulators, antioxidants, antibacterial agents, or buffers.

[0013] Preferably, the number of Bifidobacterium longum BL21 in the preparation is not less than 1×10⁻⁶. 9 CFU / mL or 1×10 9 CFU / g, for example 1×10 9 CFU / g (CFU / mL), 1×10 10 CFU / g (CFU / mL), 5×10 10 CFU / g (CFU / mL), 1×10 11 CFU / g (CFU / mL), 3×10 11 CFU / g (CFU / mL), 5×10 11 CFU / g (CFU / mL), 1×10 12 CFU / g (CFU / mL), 1×10 13 CFU / g (CFU / mL), etc., and other specific point values ​​within this range can be selected, which will not be elaborated here.

[0014] In the above applications, the formulation reverses the increase in serum creatinine and blood urea nitrogen levels caused by cisplatin chemotherapy, reverses the increase in renal inflammatory factor levels caused by cisplatin chemotherapy, and alleviates renal oxidative stress damage caused by cisplatin chemotherapy.

[0015] In the above applications, the formulation reverses the increase in intestinal permeability caused by cisplatin chemotherapy, reverses the downregulation of intestinal tight junction protein expression caused by cisplatin chemotherapy, reverses the increase in serum endotoxin levels caused by cisplatin chemotherapy, and reverses the decrease in beneficial intestinal bacteria caused by cisplatin chemotherapy.

[0016] In the above applications, the formulation improves hematopoietic dysfunction caused by cisplatin chemotherapy and restores white blood cell count.

[0017] In a second aspect, the present invention provides the use of Bifidobacterium longum BL21 in the preparation of formulations that reverse the increase in serum creatinine and blood urea nitrogen levels caused by cisplatin chemotherapy, reverse the increase in renal inflammatory factor levels caused by cisplatin chemotherapy, or alleviate oxidative stress damage to renal tissue caused by cisplatin chemotherapy.

[0018] The Bifidobacterium longum BL21 strain is the Bifidobacterium longum BL21 strain with the preservation number CGMCC No.10452.

[0019] Preferably, the dosage form of the formulation includes lyophilized powder, tablets, capsules, microcapsules, granules, or solutions. The formulation of the present invention can be formulated into various dosage forms to meet the needs of different usage scenarios.

[0020] Preferably, the formulation further contains excipients; the excipients include any one or a combination of at least two of the following: fillers, binders, wetting agents, disintegrants, emulsifiers, solubilizers, osmotic pressure regulators, colorants, pH regulators, antioxidants, antibacterial agents, or buffers.

[0021] Preferably, the number of Bifidobacterium longum BL21 in the preparation is not less than 1×10⁻⁶. 9 CFU / mL or 1×10 9 CFU / g, for example 1×10 9 CFU / g (CFU / mL), 1×10 10 CFU / g (CFU / mL), 5×10 10 CFU / g (CFU / mL), 1×10 11 CFU / g (CFU / mL), 3×10 11 CFU / g (CFU / mL), 5×10 11 CFU / g (CFU / mL), 1×10 12 CFU / g (CFU / mL), 1×10 13CFU / g (CFU / mL), etc., and other specific point values ​​within this range can be selected, which will not be elaborated here.

[0022] Thirdly, the present invention provides the use of Bifidobacterium longum BL21 in the preparation of formulations that reverse the increase in intestinal permeability caused by cisplatin chemotherapy, reverse the downregulation of intestinal tight junction protein expression caused by cisplatin chemotherapy, or reverse the increase in serum endotoxin levels caused by cisplatin chemotherapy.

[0023] The Bifidobacterium longum BL21 strain is the Bifidobacterium longum BL21 strain with the preservation number CGMCC No.10452.

[0024] Preferably, the dosage form of the formulation includes lyophilized powder, tablets, capsules, microcapsules, granules, or solutions. The formulation of the present invention can be formulated into various dosage forms to meet the needs of different usage scenarios.

[0025] Preferably, the formulation further contains excipients; the excipients include any one or a combination of at least two of the following: fillers, binders, wetting agents, disintegrants, emulsifiers, solubilizers, osmotic pressure regulators, colorants, pH regulators, antioxidants, antibacterial agents, or buffers.

[0026] Preferably, the number of Bifidobacterium longum BL21 in the preparation is not less than 1×10⁻⁶. 9 CFU / mL or 1×10 9 CFU / g, for example 1×10 9 CFU / g (CFU / mL), 1×10 10 CFU / g (CFU / mL), 5×10 10 CFU / g (CFU / mL), 1×10 11 CFU / g (CFU / mL), 3×10 11 CFU / g (CFU / mL), 5×10 11 CFU / g (CFU / mL), 1×10 12 CFU / g (CFU / mL), 1×10 13 CFU / g (CFU / mL), etc., and other specific point values ​​within this range can be selected, which will not be elaborated here.

[0027] Fourthly, this invention provides the use of Bifidobacterium longum BL21 in the preparation of formulations that improve hematopoietic dysfunction induced by cisplatin chemotherapy;

[0028] The Bifidobacterium longum BL21 strain is the Bifidobacterium longum BL21 strain with the preservation number CGMCC No.10452.

[0029] Preferably, the dosage form of the formulation includes lyophilized powder, tablets, capsules, microcapsules, granules, or solutions. The formulation of the present invention can be formulated into various dosage forms to meet the needs of different usage scenarios.

[0030] Preferably, the formulation further contains excipients; the excipients include any one or a combination of at least two of the following: fillers, binders, wetting agents, disintegrants, emulsifiers, solubilizers, osmotic pressure regulators, colorants, pH regulators, antioxidants, antibacterial agents, or buffers.

[0031] Preferably, the number of Bifidobacterium longum BL21 in the preparation is not less than 1×10⁻⁶. 9 CFU / mL or 1×10 9 CFU / g, for example 1×10 9 CFU / g (CFU / mL), 1×10 10 CFU / g (CFU / mL), 5×10 10 CFU / g (CFU / mL), 1×10 11 CFU / g (CFU / mL), 3×10 11 CFU / g (CFU / mL), 5×10 11 CFU / g (CFU / mL), 1×10 12 CFU / g (CFU / mL), 1×10 13 CFU / g (CFU / mL), etc., and other specific point values ​​within this range can be selected, which will not be elaborated here.

[0032] Compared with the prior art, the present invention has the following beneficial effects:

[0033] This invention develops a novel microbial strategy for preventing or alleviating multi-organ damage induced by cisplatin chemotherapy. Specifically, it utilizes *Bifidobacterium longum* BL21 to prepare a formulation for preventing or alleviating this damage. This invention creatively discovers that *Bifidobacterium longum* BL21 can alleviate kidney damage, intestinal damage, and bone marrow suppression without interfering with the antitumor activity of cisplatin. Specifically, it can reverse the increases in serum creatinine and blood urea nitrogen levels caused by cisplatin chemotherapy, reverse the increases in renal inflammatory factor levels caused by cisplatin chemotherapy, and alleviate oxidative stress damage to renal tissue caused by cisplatin chemotherapy; it can reverse the increased intestinal permeability caused by cisplatin chemotherapy, reverse the downregulation of intestinal tight junction protein expression caused by cisplatin chemotherapy, reverse the increase in serum endotoxin levels caused by cisplatin chemotherapy, and reverse the decrease in beneficial intestinal bacteria caused by cisplatin chemotherapy; it can improve hematopoietic dysfunction caused by cisplatin chemotherapy and restore white blood cell count. This invention also provides new ideas for the widespread application of *Bifidobacterium longum* BL21.

[0034] The BL21 strain involved in this invention is classified and named Bifidobacterium longum. It is deposited at the China General Microbiological Culture Collection Center (CGMCC) on January 27, 2015, with accession number CGMCC No. 10452. The address is No. 3, No. 1 Beichen West Road, Chaoyang District, Beijing. Attached Figure Description

[0035] Figure 1 The graph shows the results of serum creatinine and serum urea nitrogen levels in each group of mice.

[0036] Figure 2 This is a graph showing the expression levels of KIM-1 mRNA, a biomarker of kidney injury, in each group of mice.

[0037] Figure 3 This is a graph showing the pathological damage scores of the kidney tissues of mice in each group;

[0038] Figure 4 This is a graph showing the levels of oxidative stress indicators in the kidney tissue of mice in each group;

[0039] Figure 5 This is a graph showing the levels of inflammatory factors in the kidney tissue of mice in each group;

[0040] Figure 6 This is a graph showing the changes in white blood cell levels in the blood of mice in each group over time;

[0041] Figure 7 This is a graph showing the intestinal permeability of mice in each group;

[0042] Figure 8 This is a graph showing the serum endotoxin levels in each group of mice;

[0043] Figure 9 This is a graph showing the expression levels of Occludin and Claudin-1 in the colon tissue of mice in each group;

[0044] Figure 10 This is a graph showing the relative abundance of beneficial bacteria Akkermansia muciniphila in the colon contents of mice in each group;

[0045] Figure 11 This is a graph showing the effect of BL21 combined with cisplatin on tumor volume in CT26 tumor-bearing mice;

[0046] Figure 12 The figure shows the effect of BL21 combined with cisplatin on tumor weight in CT26 tumor-bearing mice. Detailed Implementation

[0047] The technical solution of the present invention will be further illustrated below through specific embodiments. Those skilled in the art should understand that the embodiments described are merely illustrative of the present invention and should not be construed as limiting the invention in any way.

[0048] The following method for preparing the Bifidobacterium longum BL21 bacterial suspension involved in the experiment is as follows: The strain was inoculated into MRS liquid medium at an inoculum of 2% (v / v) and incubated at 37°C for 24 h to obtain the seed culture; then, it was inoculated into MRS liquid medium at an inoculum of 2% (v / v) and incubated at 37°C for 24 h to obtain the bacterial suspension; the bacterial suspension was centrifuged at 4000 rpm for 5 min at 4°C, filtered, and the bacterial cells were obtained; the bacterial cells were resuspended in pure water and diluted as needed to obtain the bacterial suspension.

[0049] MRS medium: peptone 10 g / L, beef extract 10 g / L, yeast extract 5 g / L, diammonium citrate 2 g / L, glucose 20 g / L, Tween-80 1 mL / L, sodium acetate 5 g / L, dipotassium hydrogen phosphate 2 g / L, magnesium sulfate 0.58 g / L, manganese sulfate 0.25 g / L.

[0050] Example 1

[0051] Protective effect of BL21 strain against cisplatin-induced acute kidney injury:

[0052] (1) Experimental animals: 6-week-old SPF male C57BL / 6 mice were raised in a controlled environment with a room temperature maintained at 25±2°C and a humidity of 50%±5%, following a 12-hour light / dark cycle, and were allowed to eat and drink freely. All animal experiments were conducted in strict accordance with the laboratory animal use guidelines and animal ethics requirements.

[0053] (2) Animal grouping: After one week of acclimatization feeding as described above, 32 mice were randomly divided into 4 groups (n=8 per group). The intervention protocols for each group are as follows:

[0054] BL21 intervention group (BL21): Intraperitoneal injection of cisplatin (20 mg / kg), followed by daily gavage administration of BL21 live bacterial suspension (2×10⁻⁶ mg / kg) starting 3 days prior to cisplatin injection. 9 CFU / vial / day, continuing until day 3 after cisplatin injection.

[0055] Cisplatin model group (Model): Cisplatin (20 mg / kg) was injected intraperitoneally. Starting 3 days before the injection of cisplatin, sterile PBS was administered by gavage daily at the same volume as that in the BL21 intervention group until the 3rd day after the injection of cisplatin.

[0056] Positive control group: Amifostine (200 mg / kg) was injected intraperitoneally 30 minutes before the intraperitoneal injection of cisplatin.

[0057] Control group: Intraperitoneal injection of an equal volume of normal saline, followed by gavage administration of sterile PBS.

[0058] (3) Sample collection and indicator detection:

[0059] On the 3rd day after cisplatin injection, the following samples were collected and indicators were tested.

[0060] (3.1) Serum creatinine (SCr) and blood urea nitrogen (BUN) levels:

[0061] Blood was collected from the orbital sinus of mice and incubated at 25°C for 2 hours. The samples were then centrifuged at 2000×g for 10 min, and the supernatant was aliquoted and stored. Blood urea nitrogen and serum creatinine were measured using a biochemical analyzer. Blood urea nitrogen and creatinine are key clinical indicators of renal function. Elevated levels of blood urea nitrogen and creatinine are associated with deteriorating renal function, suggesting impaired filtration of nitrogenous waste products in the kidneys.

[0062] The results are as follows Figure 1 As shown, the results indicated that the levels of Scr and BUN in the model group were significantly higher than those in the blank control group, while the levels of Scr and BUN in the BL21 intervention group were reduced by 45% and 42% respectively compared with the model group (P<0.01).

[0063] (3.2) KIM-1 mRNA expression level in kidney tissue:

[0064] KIM-1 (Kidney Injury Molecule-1) is a transmembrane protein whose expression is significantly elevated when the kidneys suffer acute or chronic injury, thus it is widely regarded as a biomarker for early kidney injury. Total RNA was isolated from kidney tissues of mice in each group using a gene extraction kit. The isolated RNA was reverse transcribed into cDNA, and then processed according to the qPCR kit instructions. Gene expression was normalized to β-actin, and the relative expression level of KIM-1 mRNA was calculated using the 2-ΔΔCt method.

[0065] The results are as follows Figure 2 As shown, the results indicated that the KIM-1 expression level in the model group was significantly higher than that in the blank control group, and BL21 intervention significantly reduced the KIM-1 expression level (P<0.001).

[0066] (3.3) Kidney histopathological score:

[0067] Mouse kidneys were removed, fixed in 10% formaldehyde, and then embedded in paraffin. Kidney sections with a thickness of 5 μm were prepared, stained with hematoxylin and eosin (HE), and observed under an optical microscope. The pathological condition of each group of kidneys was scored according to a standardized Banff scoring system.

[0068] The results are as follows Figure 3 As shown, the results indicated that the BL21 intervention group had significantly reduced renal lesions compared to the model group, with a pathological score decrease of approximately 55% (P<0.001).

[0069] (3.4) Oxidative stress indicators:

[0070] The activities of SOD, GSH and MDA in the supernatant of kidney tissue homogenate were detected using an enzyme-linked immunosorbent assay kit, and the relative activities of each group and the model group were calculated.

[0071] The results are as follows Figure 4 As shown, the results indicated that the SOD and GSH activities in the BL21 group increased by 28% and 31% respectively compared with the model group (P<0.05), and the MDA level decreased by 35% (P<0.05), which means that it can significantly reverse the level of oxidative stress in kidney tissue.

[0072] (3.5) Inflammatory factor markers:

[0073] The levels of TNF-α and IL-6 in the supernatant of renal tissue homogenate were detected using an enzyme-linked immunosorbent assay kit, and the relative levels of each group and the model group were calculated.

[0074] The results are as follows Figure 5 As shown in the results, the levels of BL21 and BL21 decreased by 48% and 39% respectively (P<0.01), which means that the levels of inflammatory factors in kidney tissue were significantly reduced.

[0075] Example 2

[0076] The alleviating effect of BL21 strain on cisplatin-induced myelosuppression:

[0077] Based on the experiment in Example 1, tail vein blood was collected before cisplatin injection and on days 1, 3, 5, and 7 after injection. The levels of white blood cells and platelets in the blood of mice in the BL21 group, blank control group, and model group were detected using a fully automated blood cell analyzer.

[0078] The results are as follows Figure 6 As shown, the results indicated that the white blood cell count in the model group reached its lowest point on days 3 and 5 after cisplatin injection; the white blood cell count in the BL21 intervention group was significantly higher than that in the model group at the same time points (P<0.05), indicating that the white blood cell count recovered more quickly. Platelet count also showed a similar recovery trend.

[0079] Example 3

[0080] Protective effect of BL21 strain against cisplatin-induced intestinal injury:

[0081] (1) Experimental animals: 6-week-old SPF male C57BL / 6 mice were raised in a controlled environment with a room temperature maintained at 25±2°C and a humidity of 50%±5%, following a 12-hour light / dark cycle, and were allowed to eat and drink freely. All animal experiments were conducted in strict accordance with the laboratory animal use guidelines and animal ethics requirements.

[0082] (2) Animal grouping: After one week of acclimatization feeding as described above, 32 mice were randomly divided into 4 groups (n=8 per group). The intervention protocols for each group are as follows:

[0083] BL21 intervention group (BL21): Intraperitoneal injection of cisplatin (20 mg / kg), followed by daily gavage administration of BL21 live bacterial suspension (2×10⁻⁶ mg / kg) starting 3 days prior to cisplatin injection. 9 CFU / vial / day, continuing until day 3 after cisplatin injection.

[0084] Cisplatin model group (Model): Cisplatin (20 mg / kg) was injected intraperitoneally. Starting 3 days before the injection of cisplatin, sterile PBS was administered by gavage daily at the same volume as that in the BL21 intervention group until the 3rd day after the injection of cisplatin.

[0085] Positive control group: Amifostine (200 mg / kg) was injected intraperitoneally 30 minutes before the intraperitoneal injection of cisplatin.

[0086] Control group: Intraperitoneal injection of an equal volume of normal saline, followed by gavage administration of sterile PBS.

[0087] (3) Sample collection and indicator detection:

[0088] On the 3rd day after cisplatin injection, the following samples were collected and indicators were tested.

[0089] (3.1) Intestinal permeability test:

[0090] Mice in each group were administered an equal amount of FITC-glucan (4 kDa) by gavage. Blood was collected 4 hours later to prepare serum, and the serum fluorescence value was detected.

[0091] The results are as follows Figure 7 As shown in the results, the serum fluorescence value in the BL21 intervention group was significantly lower than that in the cisplatin model group (P<0.05), indicating that intestinal permeability was significantly improved.

[0092] (3.2) Serum endotoxin detection:

[0093] After blood was collected from the orbital cavity of mice, the samples were allowed to stand at 25°C for 2 h. The samples were then centrifuged at 2000×g for 10 min, and the supernatant was aliquoted and stored. The serum endotoxin (LPS) levels of each group of mice were detected using an endotoxin detection kit.

[0094] The results are as follows Figure 8 As shown in the results, the serum LPS level in the BL21 group decreased by about 40% compared with the model group (P<0.01), indicating that BL21 can restore the intestinal mucosal barrier function.

[0095] (3.3) Tight junction protein levels:

[0096] The expression levels of ocludin and claudin1 in the colon of mice in each group were analyzed and quantified using Western blot.

[0097] The results are as follows Figure 9 As shown, the results indicated that cisplatin-induced colonic Occludin and Claudin-1 protein expression was downregulated, while BL21 pretreatment significantly reversed this phenomenon, restoring expression levels to near normal.

[0098] (3.4) Intestinal flora analysis:

[0099] Mice were euthanized, their abdomens were disinfected, and they were dissected. Colonic contents from each group of mice were collected for microbial diversity analysis. The 16S rDNA V3-V4 hypervariable regions of all bacteria in the samples were sequenced on a sequencing platform to determine the characteristics of the gut microbiota.

[0100] The relative abundance of the beneficial bacterium Akkermansia muciniphila is as follows: Figure 10 As shown, the results indicated that BL21 intervention reshaped the bacterial community structure and significantly increased the relative abundance of beneficial bacteria Akkermansia muciniphila compared to the model group (P<0.001).

[0101] Example 4

[0102] The effect of BL21 strain on the antitumor efficacy of cisplatin:

[0103] (1) Experimental animals: 6-week-old SPF male BALB / c mice were raised in a controlled environment with a room temperature maintained at 25±2°C and a humidity of 50%±5%, following a 12-hour light / dark cycle, and were allowed to eat and drink freely. All animal experiments were conducted in strict accordance with laboratory animal use guidelines and animal ethics requirements.

[0104] (2) Establishment of tumor model: CT26 colon cancer cells were subcutaneously injected into the posterior part of the right axilla of BALB / c mice until the tumor volume reached approximately 100 mm. 3 .

[0105] (3) Animal grouping: The tumor model mice were randomly divided into 3 groups (6 mice in each group) according to the above-mentioned method. The intervention plan for each group is as follows:

[0106] Cisplatin monotherapy group: Cisplatin dosage was 5 mg / kg (once a week for a total of two weeks);

[0107] Cisplatin + BL21 combination group: Cisplatin dosage was 5 mg / kg (once a week for a total of two weeks); BL21 bacterial culture was administered orally at a dose of 2 × 10⁻⁶ mg / kg. 9 CFU / unit / day, throughout the entire experimental period;

[0108] Control group: administered physiological saline solution of the same volume as the bacterial culture via gavage daily throughout the entire experimental period.

[0109] (4) Evaluation of therapeutic effect:

[0110] The tumor volume of each group of mice was recorded every two days, such as... Figure 11 As shown.

[0111] After the experiment, the tumor weight of each group of mice was recorded, such as... Figure 12 As shown.

[0112] Depend on Figure 11 and Figure 12 The results showed that the tumor volume growth curves of the cisplatin monotherapy group and the cisplatin + BL21 combination group almost overlapped, and there was no statistically significant difference in the final tumor weight (P>0.05), indicating that the combined use of BL21 did not weaken the tumor-suppressing effect of cisplatin, and the BL21 strain had no effect on the anti-tumor efficacy of cisplatin.

[0113] The applicant declares that the technical solution of this invention is illustrated by the above embodiments, but this invention is not limited to the above embodiments, that is, it does not mean that this invention must rely on the above embodiments to be implemented. Those skilled in the art should understand that any improvements to this invention, equivalent substitutions of raw materials for the products of this invention, addition of auxiliary components, selection of specific methods, etc., all fall within the protection scope and disclosure scope of this invention.

[0114] The preferred embodiments of the present invention have been described in detail above. However, the present invention is not limited to the specific details of the above embodiments. Within the scope of the technical concept of the present invention, various simple modifications can be made to the technical solution of the present invention, and these simple modifications all fall within the protection scope of the present invention.

[0115] It should also be noted that the various specific technical features described in the above specific embodiments can be combined in any suitable manner without contradiction. In order to avoid unnecessary repetition, the present invention will not describe the various possible combinations separately.

Claims

1. Application of Bifidobacterium longum BL21 in the preparation of agents to alleviate cisplatin-induced multi-organ damage; The Bifidobacterium longum BL21 strain is the Bifidobacterium longum strain with accession number CGMCC No.10452.

2. The application according to claim 1, characterized in that, The multi-organ damage includes kidney damage, intestinal damage, and bone marrow suppression.

3. The application according to claim 1, characterized in that, The dosage forms of the preparation include lyophilized powder, tablets, capsules, microcapsules, granules, or solutions; Preferably, the formulation further contains excipients; the excipients include any one or a combination of at least two of the following: fillers, binders, wetting agents, disintegrants, emulsifiers, solubilizers, osmotic pressure regulators, colorants, pH regulators, antioxidants, antibacterial agents, or buffers.

4. The application according to claim 1, characterized in that, The number of Bifidobacterium longum BL21 in the preparation is not less than 1×10⁻⁶. 9 CFU / mL or 1×10 9 CFU / g.

5. The application according to claim 1, characterized in that, The formulation reverses the increase in serum creatinine and blood urea nitrogen levels caused by cisplatin chemotherapy, reverses the increase in renal inflammatory factor levels caused by cisplatin chemotherapy, and alleviates renal oxidative stress damage caused by cisplatin chemotherapy.

6. The application according to claim 1, characterized in that, The formulation reverses the increased intestinal permeability caused by cisplatin chemotherapy, reverses the downregulation of intestinal tight junction protein expression caused by cisplatin chemotherapy, reverses the increased serum endotoxin levels caused by cisplatin chemotherapy, and reverses the reduction of beneficial intestinal bacteria caused by cisplatin chemotherapy.

7. The application according to claim 1, characterized in that, The formulation improves hematopoietic dysfunction caused by cisplatin chemotherapy and restores white blood cell count.

8. Application of Bifidobacterium longum BL21 in the preparation of formulations that reverse the increase in serum creatinine and blood urea nitrogen levels caused by cisplatin chemotherapy, reverse the increase in renal inflammatory factor levels caused by cisplatin chemotherapy, or alleviate oxidative stress damage to renal tissue caused by cisplatin chemotherapy. The Bifidobacterium longum BL21 strain is the Bifidobacterium longum strain with accession number CGMCC No.10452.

9. Application of Bifidobacterium longum BL21 in the preparation of formulations that reverse cisplatin-induced increased intestinal permeability, reverse cisplatin-induced downregulation of intestinal tight junction protein expression, or reverse cisplatin-induced elevated serum endotoxin levels. The Bifidobacterium longum BL21 strain is the Bifidobacterium longum strain with accession number CGMCC No.10452.

10. Application of Bifidobacterium longum BL21 in the preparation of agents to improve hematopoietic dysfunction induced by cisplatin chemotherapy; The Bifidobacterium longum BL21 strain is the Bifidobacterium longum strain with accession number CGMCC No.10452.

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