CN116855397A - Ackermansia muciniphila and application thereof in preparing antitumor drugs - Google Patents
Ackermansia muciniphila and application thereof in preparing antitumor drugs Download PDFInfo
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- CN116855397A CN116855397A CN202210416273.9A CN202210416273A CN116855397A CN 116855397 A CN116855397 A CN 116855397A CN 202210416273 A CN202210416273 A CN 202210416273A CN 116855397 A CN116855397 A CN 116855397A
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- Prior art keywords
- akkermansia muciniphila
- strain
- mucin
- muciniphila
- philin
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- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical class OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
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- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
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- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
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- 150000003890 succinate salts Chemical class 0.000 description 1
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- IIACRCGMVDHOTQ-UHFFFAOYSA-M sulfamate Chemical compound NS([O-])(=O)=O IIACRCGMVDHOTQ-UHFFFAOYSA-M 0.000 description 1
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- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical class CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
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- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/135—Bacteria or derivatives thereof, e.g. probiotics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/66—Microorganisms or materials therefrom
- A61K35/74—Bacteria
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/195—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria
-
- C—CHEMISTRY; METALLURGY
- 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
- C12N1/20—Bacteria; Culture media therefor
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12R—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES C12C - C12Q, RELATING TO MICROORGANISMS
- C12R2001/00—Microorganisms ; Processes using microorganisms
- C12R2001/01—Bacteria or Actinomycetales ; using bacteria or Actinomycetales
Abstract
The invention discloses a mucin-philin Acremonium (Akkermansia muciniphila), which has a preservation number of CGMCC No.23185. The invention also discloses application of the mucin-philin ackermannin bacterium in preparing a medicament for preventing and/or treating pancreatic tumors. The invention also discloses a composition which comprises the akkermansia muciniphila as an active ingredient. The invention also discloses application of the akkermansia muciniphila in preparing a pharmaceutical composition for enhancing the efficacy of an anti-tumor drug. The invention also discloses a culture or a processed product thereof containing the akkermansia muciniphila. The mucin-philin Acremonium provided by the invention has better growth and proliferation capability, can secrete more key immunoregulatory substances such as palmitoleic acid, can inhibit the number of CD8+T cells more effectively so as to inhibit the growth of pancreatic tumor cells, and can also obviously increase the concentration of chemotherapeutic drugs in the pancreatic tumor microenvironment, thereby enhancing the efficacy of antitumor drugs.
Description
Technical Field
The invention belongs to the field of biological medicine, and particularly relates to mucin-philin ackermannin bacterium (Akkermansia muciniphila) and application of the mucin-philin ackermannin bacterium in preparation of a medicine for preventing and/or treating pancreatic tumors.
Background
Pancreatic cancer is one of the common malignant tumors of the digestive system, and has high malignant degree and extremely poor prognosis. The annual incidence of pancreatic cancer in China is about 12 ten thousand, and the annual incidence of developed economy such as the United states is about 6 ten thousand. In 2015 to 2020, the new occurrence of pancreatic cancer in China is increased by about 31.6%, the death cases are increased by about 43.5%, the new occurrence of the patient is almost equal to the death cases, and the diagnosis of the patient is mostly advanced. Pancreatic Ductal Adenocarcinoma (PDAC) is the most common and very fatal, with survival rates below 2-5% after one year of diagnosis, and a need for effective treatment regimens.
Pancreas is surrounded by stomach and artery, the risk of surgery is great, resection is only applicable to early tumors (about 15%), and cancer is still a great chance of recurrence after resection. At present, guidelines at home and abroad mainly recommend albumin paclitaxel and gemcitabine to be used as first-line treatment of PDAC, but the curative effect is limited and the chemotherapy drug resistance is difficult to avoid. Another possible new direction of pancreatic cancer treatment is the synergy of immune checkpoint inhibitors in combination with chemotherapy, however, in fact immune checkpoint therapy is still not clinically efficacious enough, which simultaneously suggests that the pathological mechanisms of pancreatic cancer are very different from other solid malignancies. Furthermore, new pancreatic tumor therapy clinical trials targeting extracellular matrix (ECM) also end up failing. Therefore, there is a need to develop new therapies against pancreatic cancer.
To develop a novel therapy for pancreatic cancer, the pathogenesis of pancreatic cancer must be re-recognized, and new therapies must be developed starting from the new mechanism. There is growing evidence that intestinal microecology, particularly the composition, abundance, structure and function of intestinal bacteria, are key factors that determine human immune homeostasis and influence tumorigenesis, development. For example, recent advances in research have shown that supplementation with a preferred enteric bacterium or enterobacteria can effectively enhance the ability to perturb the tumor microenvironment and enhance the efficacy of anti-tumor immunotherapy. However, no report has been made on what intestinal microorganisms can effectively suppress the occurrence and development of pancreatic tumors.
Recent progress in pancreatic cancer research has shown that serum from patients with pancreatic cancer contains antibodies against certain digestive tract bacteria, and pancreatic tumor tissue contains abundant and disordered bacterial or fungal composition, abundance, structure and function. These scientific advances suggest that microorganisms, particularly gut bacteria, may be key pathophysiological factors affecting the development of pancreatic tumors, revealing whether and how gut or intestinal bacteria affect the development of pancreatic tumors, thus providing a new powerful weapon for developing anti-pancreatic tumors.
However, no report on pancreatic tumor prevention or treatment by intervention in digestive tract or intestinal microecology has been found.
Disclosure of Invention
An object of the present invention is to provide an intestinal bacterium capable of effectively preventing and/or treating pancreatic tumor, aiming at the technical problems to be solved.
In order to achieve the aim, the invention provides a mucin-philin Acremonium (Akkermansia muciniphila) with a preservation number of CGMCC No.23185.
The akkermansia muciniphila (Akkermansia muciniphila) provided by the invention is a strain with tumor microenvironment or systemic CD8+ T cell immune function regulation activity. The akkermansia muciniphila can inhibit the number of tumor microenvironment or system CD8+ T cells and/or express the effector functions of inflammatory effector factors such as IFN-gamma, and the like, so the invention provides the application of the akkermansia muciniphila in preparing medicaments for preventing and/or treating inflammation and diseases caused, accompanied, related, induced and fed back by the inflammation. Meanwhile, the akkermansia muciniphila provided by the invention can also effectively enhance the infiltration of other antitumor drugs (such as small molecule chemotherapeutics) in the pancreatic tumor microenvironment so as to enhance the tumor killing capability of the antitumor drugs.
Preferably, the akkermansia muciniphila of the invention is any one of the following: a clinically isolated strain of akkermansia muciniphila; live bacteria, dead bacteria, bacterial lysates, metabolites, engineered bacteria, mutant bacteria and/or mutagenized bacteria of the species akkermansia muciniphila. The inventors have found that these above mucin-philins have cd8+ T cell immune function modulating activity and thus affect the expression and secretion of pro-inflammatory or anti-inflammatory factors in the host, thereby affecting inflammation and/or the outcome of the development of related pancreatic tumorigenesis caused by inflammation. The research of the inventor also discovers that the above mucin-philin ackermannin bacteria have the function of influencing the infiltration amount and half-life of anti-tumor drugs (such as small molecule chemotherapeutics) to the tumor microenvironment.
On the other hand, the invention also provides application of the akkermansia muciniphila in preparing medicaments for preventing and/or treating pancreatic tumors.
In another aspect, the present invention also provides a composition comprising the akkermansia muciniphila of the present invention as an active ingredient. Preferably, the composition may also include other kinds of enterobacteria. Preferably, the composition may further comprise a pharmaceutically acceptable carrier.
Preferably, the composition may be a food, a health product, an additive or a pharmaceutical composition, but is not limited thereto.
Preferably, the composition is a pharmaceutical composition comprising a pharmaceutically effective dose of akkermansia muciniphila and a pharmaceutically acceptable carrier.
In another aspect, the invention also provides a pharmaceutical composition comprising a pharmaceutically effective dose of akkermansia muciniphila (Akkermansia muciniphila) or a metabolite thereof, and a pharmaceutically acceptable carrier.
Preferably, the pharmaceutically acceptable carrier includes, but is not limited to, any one or more of milk powder, lactose, glucose, sucrose, maltose, sorbitol, mannose, trehalose, galactose, cyclodextrin, starch, acacia, calcium phosphate, alginate, glycerol, sodium glutamate, vitamin C, gelatin, calcium silicate, fine crystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methylcellulose, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, or mineral oil.
The invention relates to a mucin-philin Acremonium which can be any one or more of the following: live bacteria, dead bacteria, bacterial lysates, metabolites, engineered bacteria, mutant bacteria, mutagenic bacteria, and/or pharmaceutically acceptable salts of akkermansia muciniphila.
The salt comprises an acidic or basic inorganic or organic salt.
The acidic inorganic salts include hydrochloride, sulfate, phosphate, nitrate, carbonate, borate, sulfamate, or hydrobromide. The basic salt includes sodium salt, potassium salt, lithium salt, magnesium salt, calcium salt or ammonium salt.
The organic salts include acetates, propionates, butyrates, tartrates, maleates, hydroxymaleates, fumarates, citrates, lactates, mucinates, gluconates, benzoates, succinates, oxalates, phenylacetates, methylsulfonates, p-toluenesulfonates, benzenesulfonates, p-aminosalicylates, asparaginates, glutamates, edetate, stearates, palmitates, oleates, laurates, tannates, ascorbates, valerates or alkylammonium salts.
In addition, the akkermansia muciniphila (Akkermansia muciniphila) and/or metabolites thereof of the present invention can modulate the number and function of T cells including, but not limited to, cd8+ T cell subsets.
In addition, the akkermansia muciniphila (Akkermansia muciniphila) and/or the metabolites thereof can regulate the quantity and the functions of T cells including but not limited to CD8+T cell subsets and the like so as to tune the micro-environment of organisms, especially tumors and the immune homeostasis, and help the organisms to resist tumors including but not limited to pancreatic tumors.
In addition, the akkermansia muciniphila (Akkermansia muciniphila) and/or the metabolites thereof can regulate and control the infiltration and half-life of medicines including but not limited to gemcitabine and the like into tumor microenvironment, thereby enhancing the tumor killing function of the antitumor medicines.
Preferably, the pharmaceutical composition of the present invention is formulated in a form including, but not limited to, tablets, capsules, solutions, emulsions, suspensions, powders or granules.
Preferably, the mode of administration of the pharmaceutical composition of the present invention includes, but is not limited to, oral administration, rectal administration or delivery to the colon.
Preferably, the pharmaceutical composition according to the present invention further comprises a pH sensitive composition (a composition exhibiting pH dependent swelling/dissolution properties) comprising one or more enteric polymers.
On the other hand, the invention also provides application of the akkermansia muciniphila in preparing a pharmaceutical composition for enhancing the efficacy of the antitumor drug.
Preferably, the anti-tumor drug is a chemotherapeutic drug, including a small molecule chemotherapeutic drug, such as, but not limited to, any one of gemcitabine, paclitaxel, or a combination thereof.
In another aspect, the invention also provides a culture (e.g., culture supernatant) or processed product thereof comprising the akkermansia muciniphila described herein.
Compared with the existing common Acremonium, the Alternaria muciniphila (Akkermansia muciniphila) CGMCC No.23185 has better growth and proliferation capacity than ATCC strains, can secrete more key immunoregulatory substances such as palmitoleic acid and the like, can inhibit the number of CD8+ T cells more effectively so as to inhibit the growth of pancreatic tumor cells, and can also obviously increase the concentration of chemotherapeutic drugs in the pancreatic tumor microenvironment, thereby enhancing the efficacy of anti-tumor drugs.
Drawings
FIG. 1 shows a comparative statistical plot of bacterial density (OD 600) of RV02 strain of the present invention after 24 hours of culture under anaerobic culture conditions compared to ATCC strain of Alkermansia muciniphila;
FIG. 2 is a graph showing comparative statistics of the amounts of palmitic acid in culture supernatants of the strain RV02 of the present invention compared with the strain ATCC strain Alkermansia muciniphila, after culturing for 24 hours, 48 hours, 72 hours under anaerobic culture conditions;
FIG. 3 is a photograph of a typical tumor showing the inhibitory effect of RV02 strain of the present invention on pancreatic tumors as compared to ATCC strain of Acremodelling protein, and physiological saline treatment;
FIG. 4 is a graph showing typical tumor statistics of the inhibition effect of RV02 strain of the present invention on pancreatic tumors compared to ATCC strain of Alkermansia muciniphila and physiological saline treatment;
FIG. 5 shows a typical tumor statistics of the inhibition effect of the RV02 strain of Acremonium muciniphilum of the present invention on pancreatic tumors compared to the RV02 strain of Acremonium muciniphilum;
FIG. 6 shows a representative flow cytometry plot of the inhibition of CD8+ T cells in pancreatic tumor animals by the strain RV02 of the present invention, ackermansia muciniphila; the ratio of cd8+ T cells relative to total spleen cells is noted above each flow cell plot, saline set is: 9.99%, ATCC strain: 7.45%; RV02 strain is: 6.05%;
FIG. 7 is a statistical graph showing the effect of the RV02 strain of the present invention on inhibiting the number of CD8+ T cells in pancreatic tumor animals;
FIG. 8 shows a statistical plot of the inhibition of IFN-gamma secretion levels by the strain RV02 of the present invention in pancreatic tumor animals by Ackermansia muciniphila;
FIG. 9 shows a statistical graph of the effect of the RV02 strain of the present invention on increasing the inhibition of pancreatic tumors by Gemcitabine (GEM) or Paclitaxel (PTX);
FIG. 10 shows the effect of the RV02 strain of the present invention on significantly increasing the amount of gemcitabine in the tumor microenvironment by Ackermansia muciniphila;
fig. 11 shows the effect of the RV02 strain of the present invention, akkermansia muciniphila, on significantly enhancing the half-life of gemcitabine in tumor microenvironment.
The mucin-philin Acremonium (Akkermansia muciniphila) RV02 of the invention is preserved in China general microbiological culture Collection center (CGMCC) for a period of 24 and 8 months in 2021, and the preservation number is CGMCC No.23185.
Detailed Description
The invention will be further illustrated with reference to specific examples. It should be understood that the following examples are illustrative of the present invention and are not intended to limit the scope of the present invention. For simplicity, specific steps of conventional techniques well known to those skilled in the art (e.g., flow cytometry, mass spectrometry, non-targeted metabolome detection, etc.) are not described in detail in the examples below, but it is understood that such operations are known to those skilled in the art and are achievable.
Example 1: screening, isolation and identification of Alkermansia muciniphila (Akkermansia muciniphila) RV02
Pancreatic ductal carcinoma patients were recruited for experiments and compared with healthy persons, and mucin-philin ackermanni with higher abundance in faecal specimens of healthy people was found by means of 16S rRNA sequencing and the like.
Further analysis, screening and identification of intestinal bacteria are carried out by utilizing the technology of culture histology, and a mucin-philin Acremonium (Akkermansia muciniphila, named RV02 strain) is discovered and isolated from healthy human bodies.
Ackermanna mucin (Akkermansia muciniphila) is a mucin-degrading bacterium colonizing the mucous layer of the human gut, isolated from human faeces by Derrien in 2004, present in the human gut at about 3-5% and representative of the phylum Verrucomicron, belonging to the genus Akkermansia, being a gram-negative strictly anaerobic plasmid-free. Low levels of akkermansia muciniphila in the gut can lead to thinning of the mucosal lining, thereby leading to reduced gut barrier function and easier invasion of toxins in the gut into the human body. As bacteria which are preferentially planted in the intestinal mucus layer, the akkermansia muciniphila can degrade mucin to maintain the abundance of the akkermansia muciniphila, and also stimulate the thickening of the mucus layer of the organism to maintain the health condition of the organism.
The invention discloses a novel mucin-philin Acremonium RV02 screened from a large number of mucin-philin Acremonium strains, which is discovered by anaerobic culture, growth curve verification, staining microscopy and animal experiments: compared with the existing published standard strain of the mucin-philin Ackermansis, RV02 has stronger growth capacity, stronger functions of inhibiting the occurrence and development of tumors such as pancreas and the like, and more outstanding capacity of regulating the secretion of inflammatory factors INF-gamma and the number and functions of CD8+ T cells.
Colony characteristics: the Mucin-philin Acremonium RV02 of the invention is coated on a Mucin solid culture medium for culture, and the colony is white and slightly convex, and the diameter is about 1-2mm.
Morphology under microscope: after gram staining, the mucin-philin Achroman RV02 is subjected to microscopic examination, and the mucin-philin Achroman RV is oval and flagellum-free under the microscope, and is a gram negative bacterium.
The screening and isolation method of RV02 is as follows:
1. culture medium configuration
The preparation method of the Mucin culture medium comprises the following steps: 3.85g of brain heart infusion medium (BHI), 0.4g of Mucin (Mucin) and 0.05g L-cysteine were weighed out and dissolved in 100mL of water, and autoclaved at 121℃for 20 minutes.
2. Separation and screening
(1) A healthy fresh fecal sample of the tested person is collected by 0.5g, placed in a beaker containing 4.5ml of physiological saline, and diluted after the feces and the physiological saline are mixed uniformly to obtain a diluent. 1ml of the diluted solution is inoculated into 9ml of Mucin liquid culture medium, and anaerobic culture is carried out for 5 days at 37 ℃ to obtain bacterial liquid.
(2) PCR identification
The specific PCR primer sequence of the Alkermansia muciniphila is as follows
Forward primer: 5'-GCGTAGGCTGTTTCGTAAGTCGTGTGTGAAAG-3' (SEQ ID NO: 1)
Reverse primer: 5'-GAGTGTTCCCGATATCTACGCATTTCA-3' (SEQ ID NO: 2)
PCR amplification step:
bacterial liquid is taken and diluted in PBS, bacterial DNA is extracted and used as template DNA of PCR, and the specific PCR primer is used for amplification.
Amplification system (20 μl): PCR premix solutionMaster Mix (With Dye)) 7. Mu.L, 1. Mu.L of template DNA, 1. Mu.L of forward primer, 1. Mu.L of reverse primer, and 10. Mu.L of sterile deionized water.
The PCR reaction procedure was as follows:
the PCR products were run on a 2% w/v agarose gel at 100 volts for 20 minutes.
Nucleotide sequencing identification is carried out on the PCR product, BLAST comparison is carried out on the sequence result in Genbank, and a sample positive to the mucin-philin Ackermans is selected for the next operation.
And (3) selecting a bacterial liquid sample positive to the PCR reaction, streaking and inoculating the bacterial liquid sample to a Mucin solid culture medium plate, scraping all single colonies grown out, carrying out PCR identification on the whole length of the 16S rDNA gene, carrying out NCBI BLAST on a sequencing result of an amplified product, and finally screening to obtain a strain of Mucin-philin Ackermans, and naming the strain as RV02.
Comparing the main microorganism indexes such as 16S rDNA sequences, growth dynamics curves and the like of the mucin-philin Acremonium (named RV 02) and ATCC Acremonium mucin Acremonium (ATCCBAA-835 (Akkermansia muciniphila Derrien et al)), which are purchased from North Nanopsis, and analyzing the metabolic small molecules (such as palmitoleic acid) in culture supernatants of the Acremonium mucin Acremonium by utilizing mass spectrometry and non-targeted metabolome detection technology.
As shown in fig. 1, RV02 strain had higher bacterial density (OD 600) than ATCC strain akkermansia muciniphila at the same liquid medium culture time point (< 0.05; p <0.01 and p <0.001, the following results are the same), which indicates that the RV02 strain of the present invention has greater growth activity and capacity than ATCC strain of akkermansia muciniphila.
As shown in FIG. 2, the palmitoleic acid content in the culture supernatant of RV02 strain was significantly higher than that in the culture supernatant of ATCC strain, indicating that RV02 strain has stronger ability to express or produce immunoregulatory substances such as palmitoleic acid than ATCC strain Alkermansia muciniphila. This demonstrates that the RV02 strain of Acremonium muciniphilum found in the invention may have a stronger immunoregulatory function obtained in the dominant growth and body environment.
Example 2: pancreatic tumor growth experiment
1. Tumor inhibition experiment of active strain of Acremonium muciniphilum of RV02 strain
24C 57BL/6 mice were purchased from the laboratory animal center in Guangdong province at 1 month of age. Mice were randomly divided into 3 groups of 8 mice, and ampicillin (1 mg/ml), streptomycin (5 mg/ml) and colistin (1 mg/ml) were administered to the mice for one week in the drinking water, after which the same number of Panc02 pancreatic tumor cells (purchased from northna, cat No. BNCC 338) were subcutaneously injected into each group of mice one week later034 Group 1 lavage saline as control, group 2 lavage ATCC strain Acremonium muciniphilum viable bacteria (1X 10) 9 CFU/time/mouse), group 3 gastric lavage equivalent RV02 strain Ackermansia muciniphila viable bacteria (1×10) 9 CFU/time/mouse), the stomach was irrigated once every two days for 4 weeks. The volume and weight of each group of pancreatic tumors, the level of inflammatory factors such as IFN-gamma in and around the tumors of mice, and the function and status of T cell subsets such as CD4+ T cells and CD8+ T cell immunity were then analyzed.
As shown in fig. 3 and 4, the tumor volume of the mice administered with ATCC strain akkermansia muciniphila was significantly smaller than that of the normal saline control group, but the tumor volume of the mice perfused with RV02 strain akkermansia muciniphila viable bacteria was smaller than that of the ATCC strain akkermansia muciniphila. This demonstrates that oral administration of the active strain of Acremonium muciniphilum of RV02 of the present invention is effective in inhibiting pancreatic tumor growth.
2. Tumor inhibition experiment of comparison of live bacteria and dead bacteria of RV02 strain mucin-philic Acremonium
24C 57BL/6 mice were purchased from the laboratory animal center in Guangdong province at 1 month of age. Mice were randomly divided into 3 groups of 8 mice, each group was given ampicillin (1 mg/ml), streptomycin (5 mg/ml) and colistin (1 mg/ml) in each group of drinking water for one week, after one week, the same number of Panc02 pancreatic tumor cells (purchased from northlasis, cat No. BNCC 338034) were subcutaneously injected into each group of mice, and the same amount of active strain RV02 strain of Alkermania muciniphila (1×10) was perfused into group 1 9 CFU/time/mouse), group 2 gastric lavage equivalent RV02 strain of Alkermansia muciniphila dead bacteria (1×10) 9 CFU/time/mouse), the stomach was irrigated once every two days for 4 weeks. Normal saline lavage was used as a control. The volume and weight of each group of pancreatic tumors was then analyzed.
The preparation method of the RV02 strain of mucin-philin Acremonium comprises the following steps: and (3) placing the live strain of the Acremonium muciniphilum RV02 in a water bath at the temperature of 75 ℃ for 10min for pasteurization, so as to obtain the dead strain of the Acremonium muciniphilum RV02.
As shown in fig. 5, the tumor volumes of the mice in which the gastric lavage RV02 strain of active mucin-philin akkermansia and the RV02 strain of dead mucin-philin akkermansia were significantly reduced, but the tumor volumes of the mice in which the RV02 strain of active mucin-philin akkermansia was lavaged were slightly smaller than the tumor volumes of the mice in which the RV02 strain of active mucin-philin akkermansia was dead, indicating that the dead bacteria had a tumor suppression effect similar to that of the active bacteria. This demonstrates that oral administration of both live and dead Acremonium muciniphilum of RV02 strain of the present invention is effective in inhibiting pancreatic tumor growth.
As shown in fig. 6, 7 and 8, the active strain of the Acremonium muciniphilum provided by the invention can more effectively inhibit the number of CD8+ T cells and secretion of inflammatory factor IFN-gamma so as to inhibit growth of pancreatic tumor cells, and the discovery provides a new thought for treating pancreatic tumors.
Example 3: drug combination experiment
36C 57BL/6 mice were purchased from the laboratory animal center in Guangdong province at 1 month of age. Mice were randomly divided into 6 groups of 6 mice each, and after one week of administration of ampicillin (1 mg/ml), streptomycin (5 mg/ml) and colistin (1 mg/ml) in drinking water, the same number of Panc02 pancreatic tumor cells were inoculated subcutaneously into each group of mice, group 1 gastric lavage saline was used as a control, group 2 gastric lavage RV02 strain of active mucin-like akkermansia bacteria (1×10) 9 CFU/time/mouse), group 3 gavage RV02 strain Acremodelling protein Acremodelling bacteria (1×10) 9 CFU/time/mouse) and were intraperitoneally injected with Gemcitabine (Gemcitabine, GEM,50 mg/Kg/time/week), group 4 was intraperitoneally injected with Gemcitabine (Gemcitabine, GEM,50 mg/Kg/time/week), group 5 was gavaged with RV02 strain of Achroman mucin (1X 10) 9 CFU/time/mouse) and injecting Paclitaxel (PTX) intraperitoneally, group 6 intraperitoneally, the intestinal bacteria were perfused every two days for 4 weeks, and then the volume and weight of pancreatic tumor, and cd4+ T cells, cd8+ T cells immune function and status in and around the tumor of the mouse were analyzed.
Meanwhile, as shown in fig. 9, when the active strain of the RV02 strain of the present invention is applied in combination with gemcitabine or paclitaxel, the tumor volume is significantly suppressed compared with the case of singly applying the active strain of the RV02 strain of the present invention, which means that the active strain of the RV02 strain of the present invention can effectively enhance and promote the therapeutic effect of an antitumor drug (e.g., an antitumor pancreatic tumor drug).
Example 4: influence of Alkermansia muciniphila on tumor microenvironment
In general, it is difficult for chemotherapeutic agents to target the pancreatic tumor microenvironment and thereby kill tumor cells, which is a major challenge in current pancreatic tumor therapies. In this example, it was analyzed whether gastric lavage treatment of mucin-philic ackermannin helped increase the concentration of gemcitabine drug and the half-life of gemcitabine drug in the tumor microenvironment.
64C 57BL/6 mice of 1 month old were purchased from the laboratory animal center in Guangdong province. Mice were randomly divided into 4 groups of 16 mice, and after one week of administration of ampicillin (1 mg/ml), streptomycin (5 mg/ml) and colistin (1 mg/ml) in drinking water, the same number of Panc02 pancreatic tumor cells were inoculated subcutaneously into each group of mice, group 1 gastric lavage saline was used as a control, group 2 gastric lavage RV02 strain of active mucin-like akkermansia bacteria (1×10) 9 CFU/time/mouse), group 3 gavage RV02 strain Acremodelling protein Acremodelling bacteria (1×10) 9 CFU/time/mouse) and was given by intraperitoneal injection of Gemcitabine (Gemcitabine, GEM,50 mg/Kg/time), group 4 was given by intraperitoneal injection of Gemcitabine (Gemcitabine, GEM,50 mg/Kg/time). The active strain of the mucin-philin Acremonium RV02 is subjected to gastric lavage once every two days for 4 weeks. Before the live strain of the gastric lavage RV02 strain of the mucin-philin Achroman bacteria is filled, 4 mice are taken out each time after 1 week, 2 weeks, 3 weeks and 4 weeks of the live strain of the gastric lavage RV02 strain of the mucin-philin Achroman bacteria are filled, tissues such as tumors, peripheral blood, spleen, intestinal tracts and the like of the mice are taken out, and the content and half lives of gemcitabine medicines at different parts (particularly in tumor tissues) in the mice are analyzed and compared.
As shown in fig. 10, the drug concentration of gemcitabine, a chemotherapeutic drug in the microenvironment of pancreatic tumors, was significantly increased 4 weeks after administration of the RV02 strain of the present invention, akkermansia muciniphila.
Furthermore, as shown in fig. 11, the half-life of chemotherapeutic drugs within the tumor microenvironment is significantly prolonged.
Therefore, the RV02 strain mucin-philin Ackermansia can not only effectively inhibit the occurrence and development of pancreatic tumors, but also enhance the infiltration of antitumor drugs (such as chemotherapeutic drugs) into the microenvironment of the pancreatic tumors, thereby solving the problem that the pancreatic tumor chemotherapeutic drugs are difficult to reach and further kill tumor cells.
Sequence listing
<110> Rayleigh (Shenzhen) Biotech Co., ltd
<120> Ackermansia muciniphila and application thereof in preparing antitumor drugs
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gcgtaggctg tttcgtaagt cgtgtgtgaa ag 32
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<212> DNA
<213> Artificial sequence (Artificial Sequence)
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gagtgttccc gatatctacg catttca 27
Claims (10)
1. Acremonium muciniphilum (Akkermansia muciniphila) is characterized by having a preservation number of CGMCC No.23185.
2. Use of akkermansia muciniphila according to claim 1 for the manufacture of a medicament for the prevention and/or treatment of pancreatic tumours.
3. Use of akkermansia muciniphila according to claim 1 for the manufacture of a medicament for the prevention and/or treatment of inflammation and its related, concomitant, induced, feedback diseases.
4. A composition comprising the living bacterium, dead bacterium, cell lysate, metabolite, engineered bacterium, mutant bacterium, and/or mutagenic bacterium of akkermansia muciniphila of claim 1 as an active ingredient.
5. The composition of claim 4, further comprising other species of enterobacteria.
6. The composition of claim 4 or 5, further comprising a pharmaceutically acceptable carrier.
7. The composition of claim 4 or 5, wherein the pharmaceutical composition is a capsule, solution, suspension, bagged powder, or granule.
8. Use of akkermansia muciniphila according to claim 1 for the preparation of a pharmaceutical composition for enhancing the efficacy of an antitumor drug.
9. The use according to claim 8, wherein the antineoplastic agent is a chemotherapeutic agent, in particular any one of gemcitabine, paclitaxel or a combination thereof.
10. A culture or processed product thereof comprising the akkermansia muciniphila of claim 1.
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