CN117085045A - Lactobacillus paracasei for preventing and/or treating hyperuricemia and application thereof - Google Patents
Lactobacillus paracasei for preventing and/or treating hyperuricemia and application thereof Download PDFInfo
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- CN117085045A CN117085045A CN202311293657.7A CN202311293657A CN117085045A CN 117085045 A CN117085045 A CN 117085045A CN 202311293657 A CN202311293657 A CN 202311293657A CN 117085045 A CN117085045 A CN 117085045A
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- lactobacillus paracasei
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
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Abstract
The invention discloses lactobacillus paracasei for preventing and/or treating hyperuricemia and application thereof, and relates to the technical field of microorganisms. The lactobacillus paracasei provided by the invention still has higher activity in the alimentary canal nutrition environment, and has better development and utilization prospects for preventing or treating hyperuricemia, gout or other hyperuricemia complications or kidney injury.
Description
Technical Field
The invention relates to the technical field of microorganisms, in particular to lactobacillus paracasei for preventing and/or treating hyperuricemia and application thereof.
Background
Hyperuricemia (HUA) is currently the "fourth highest" following hypertension, hyperlipidemia, hyperglycemia, and is a disease caused by excessive uric acid generation or insufficient excretion in the human body, and persistent Hyperuricemia can lead to gout, a series of complications. The medicine for treating hyperuricemia is the most commonly used means in clinic, has the advantages of quick response and short period, but has side effects, is easy to cause anaphylactic reaction and can increase the physical burden of patients to different degrees, so a product which is safe and effective for treating hyperuricemia and has no toxic or side effects is urgently needed.
In recent years, probiotics play a remarkable role in regulating intestinal health of a human body, about 30% of uric acid in the human body is directly discharged from the intestinal tract, and intestinal probiotics play an important role in uric acid reduction, and some probiotics have been demonstrated to be capable of relieving hyperuricemia by producing metabolites affecting purine decomposition and uric acid production, and have the potential of becoming a new method for clinically treating hyperuricemia.
Chinese patent 202011066042.7 discloses a probiotic strain for reducing purine and uric acid, a composition and application thereof, and lactobacillus plantarum KLpl-3 shows obvious effect of reducing blood uric acid in a murine model of hyperuricemia. However, the screening conditions of the test method are only purine precursor substrates, and the purine precursor substrates can synthesize purine nucleosides, nucleotides and other substances, and the screening mode is that a reaction system only contains the purine precursor substrates, and no other nutrition conditions exist; since other nutrients such as carbon source amino acids and the like are contained in the intestinal tract, the strain may preferably utilize these nutrients rather than the purine precursor, and thus may not have an effect in a practically rich intestinal nutrient environment.
In view of this, the present invention has been made.
Disclosure of Invention
The invention aims to provide lactobacillus paracasei for preventing and/or treating hyperuricemia and application thereof, so as to solve the technical problems.
The invention is realized in the following way:
in a first aspect, the invention provides an application of lactobacillus paracasei (Lacticaseibacillus paracasei) or a culture thereof in preparing a medicament for preventing and/or treating hyperuricemia and gout, gout complications or kidney injury caused by the hyperuricemia,
lactobacillus paracasei is selected from at least one of the following bacterial strains:
(1) The 16S rDNA sequence of lactobacillus paracasei has at least 99.5 percent sequence identity with the 16S rDNA sequence existing in a strain with the preservation number of CCTCC NO: M2023443, which is preserved in the CCTCC at 3-month 31 of 2023;
(2) The whole genome sequence of lactobacillus paracasei has at least 95% of genome-average genetic similarity (Average Nucleotide Identity, ANI) with the sequence shown in NCBI sequence number JAVVNQ000000000, or the whole genome sequence of lactobacillus paracasei has at least 95% of genome-average genetic similarity (ANI) with a strain with the accession number cctccc No. M2023443, which is preserved in CCTCC for 3 months of 2023;
the culture is dead bacteria, cell broken material, fermentation supernatant and/or fermentation precipitate of Lactobacillus paracasei.
The inventor separates, screens and purifies a strain from the feces of healthy people, the 16s rDNA sequence of the strain is SEQ ID NO.1, and the comparison and analysis of the strain and NCBI database show that the comparison similarity of the strain and Lactobacillus paracasei 3534 strain reaches 99.86 percent. The strain PRS-22 is identified as a strain of Lactobacillus paracasei (Lacticaseibacillus paracasei) by combining with physiological and biochemical identification results, and is named as the Lactobacillus paracasei PRS-22.
The study shows that the lactobacillus paracasei PRS-22 has remarkable effect on reducing the uric acid content in blood, and a person skilled in the art can expect that the lactobacillus paracasei with the 16s rDNA sequence having at least 99.5 percent of sequence identity with the sequence shown by SEQ ID NO.1 also has the same or similar effect and can reduce the uric acid content in blood.
Further, and as would be expected by those skilled in the art, lactobacillus paracasei having a sequence identity of at least 99.9% with the sequence set forth in SEQ ID NO.1 would also have the same or similar efficacy, and would be able to reduce blood uric acid levels.
Further, analysis of the whole genome sequencing data of the strain using GTDBTK software gave a Lacticaseibacillus paracasei (gcf_ 000829035.1) for its nearest reference strain, an ANI value of 98.19, by FASTANI algorithm. When the ANI value is greater than 95, then 2 are considered to be the same species, and thus the strain is identified as Lactobacillus paracasei (Lacticaseibacillus paracasei).
It was found that Lactobacillus paracasei, which has at least 95% sequence identity with the sequence shown by NCBI sequence No. JAVVNQ00000, also has the same or similar efficacy and is capable of reducing blood uric acid content, as would be expected by those skilled in the art.
The whole genome sequence of Lactobacillus paracasei has a genome-average genetic similarity (Average Nucleotide Identity, ANI) of at least 97.5% to the sequence shown in NCBI sequence No. JAVVNQ000000000, or the whole genome sequence of Lactobacillus paracasei has a genome-average genetic similarity (ANI) of at least 97.5% to a strain with a preservation number of CCTCC NO: M2023443, which is preserved in CCTCC at 3 months of 2023.
In a preferred embodiment of the invention, the whole genome sequence of Lactobacillus paracasei has at least 99% genomic average genetic similarity (Average Nucleotide Identity, ANI) to the sequence shown in NCBI sequence No. JAVVNQ000000000, or the whole genome sequence of Lactobacillus paracasei has at least 99% genomic average genetic similarity (ANI) to the strain deposited with CCTCC at 3.3.31, under accession number CCTCC NO: M2023443.
In a preferred embodiment of the invention, the whole genome sequence of Lactobacillus paracasei has a genome-average genetic similarity (Average Nucleotide Identity, ANI) of at least 99.5% to the sequence shown in NCBI sequence No. JAVVNQ000000000, or the whole genome sequence of Lactobacillus paracasei has a genome-average genetic similarity (ANI) of at least 99.5% to the strain deposited on CCTCC at 3/31 of 2023 under the accession number CCTCC NO: M2023443.
In a preferred embodiment of the use of the invention, the 16S rDNA sequence of Lactobacillus paracasei has at least 99.5% sequence identity with the sequence shown in SEQ ID NO.1.
Lactobacillus paracasei is a gram positive bacterium.
The experiment of simulating artificial gastric juice and artificial intestinal juice shows that the lactobacillus paracasei provided by the invention still has higher bacterial strain survival rate in the alimentary canal nutrition environment, and the viable count is not obviously reduced. The result indicates that the lactobacillus paracasei provided by the invention still has higher activity in the alimentary canal nutrition environment, and has better development and utilization prospects for treating or preventing and improving hyperuricemia-induced gout, gout complications or kidney injury.
The sequence shown in SEQ ID NO.1 is as follows:
CCTAATACATGCAGTCGAACGAGTTCTCGTTGATGATCGGTGCTTGCACCGAGATTCAACATGGAACGAGTGGCGGACGGGTGAGTAACACGTGGGTAACCTGCCCTTAAGTGGGGGATAACATTTGGAAACAGATGCTAATACCGCATAGATCCAAGAACCGCATGGTTCTTGGCTGAAAGATGGCGTAAGCTATCGCTTTTGGATGGACCCGCGGCGTATTAGCTAGTTGGTGAGGTAATGGCTCACCAAGGCGATGATACGTAGCCGAACTGAGAGGTTGATCGGCCACATTGGGACTGAGACACGGCCCAAACTCCTACGGGAGGCAGCAGTAGGGAATCTTCCACAATGGACGCAAGTCTGATGGAGCAACGCCGCGTGAGTGAAGAAGGCTTTCGGGTCGTAAAACTCTGTTGTTGGAGAAGAATGGTCGGCAGAGTAACTGTTGTCGGCGTGACGGTATCCAACCAGAAAGCCACGGCTAACTACGTGCCAGCAGCCGCGGTAATACGTAGGTGGCAAGCGTTATCCGGATTTATTGGGCGTAAAGCGAGCGCAGGCGGTTTTTTAAGTCTGATGTGAAAGCCCTCGGCTTAACCGAGGAAGCGCATCGGAAACTGGGAAACTTGAGTGCAGAAGAGGACAGTGGAACTCCATGTGTAGCGGTGAAATGCGTAGATATATGGAAGAACACCAGTGGCGAAGGCGGCTGTCTGGTCTGTAACTGACGCTGAGGCTCGAAAGCATGGGTAGCGAACAGGATTAGATACCCTGGTAGTCCATGCCGTAAACGATGAATGCTAGGTGTTGGAGGGTTTCCGCCCTTCAGTGCCGCAGCTAACGCATTAAGCATTCCGCCTGGGGAGTACGACCGCAAGGTTGAAACTCAAAGGAATTGACGGGGGCCCGCACAAGCGGTGGAGCATGTGGTTTAATTCGAAGCAACGCGAAGAACCTTACCAGGTCTTGACATCTTTTGATCACCTGAGAGATCAGGTTTCCCCTTCGGGGGCAAAATGACAGGTGGTGCATGGTTGTCGTCAGCTCGTGTCGTGAGATGTTGGGTTAAGTCCCGCAACGAGCGCAACCCTTATGACTAGTTGCCAGCATTTAGTTGGGCACTCTAGTAAGACTGCCGGTGACAAACCGGAGGAAGGTGGGGATGACGTCAAATCATCATGCCCCTTATGACCTGGGCTACACACGTGCTACAATGGATGGTACAACGAGTTGCGAGACCGCGAGGTCAAGCTAATCTCTTAAAGCCATTCTCAGTTCGGACTGTAGGCTGCAACTCGCCTACACGAAGTCGGAATCGCTAGTAATCGCGGATCAGCACGCCGCGGTGAATACGTTCCCGGGCCTTGTACACACCGCCCGTCACACCATGAGAGTTTGTAACACCCGAAGCCGGTGGCGTAACCCTTTAGGGAGCGAGCCGTCTAAGGGGACCT。
the cell disruption product includes, but is not limited to, a cell disruption product obtained by at least one of the following means: ultrasonic, mechanical disruption, enzymatic, physical or chemical treatment.
The fermentation supernatant is prepared by the following preparation method: inoculating Lactobacillus paracasei, culturing, and removing thallus.
The fermentation sediment is prepared by the following preparation method: inoculating lactobacillus paracasei, culturing, centrifuging or naturally settling, and removing supernatant to obtain fermented precipitate.
In a preferred embodiment of the invention, the lactobacillus paracasei is a gram positive bacterium.
In a preferred embodiment of the invention, the Lactobacillus paracasei has a preservation number of CCTCC NO: M2023443, and is preserved in China center for type culture Collection with a preservation date of 2023, 3 and 31 days.
In a preferred embodiment of the application of the present invention, the complications of gout include at least one of gouty arthritis, tophus, joint deformity, urinary tract stones, gouty kidney disease, gouty kidney failure and cardiovascular disease without limitation.
In a preferred embodiment of the use of the invention, the kidney injury is acute kidney injury or chronic kidney injury.
Renal injury includes, but is not limited to: tubular epithelial cells undergo vacuolation, apoptosis and shedding.
In a preferred embodiment of the use of the invention, the medicament is formulated for oral administration or injection administration. Injection administration includes, but is not limited to, subcutaneous injection, intramuscular injection, intravenous injection, and intradermal injection.
In a preferred embodiment of the invention, the medicament further comprises pharmaceutically acceptable excipients.
In a preferred embodiment of the present invention, the pharmaceutically acceptable excipients are selected from at least one of fillers, disintegrants, lubricants, flavoring agents, binders, suspending agents and fragrances.
Pharmaceutically acceptable excipients include, but are not limited to: pharmaceutically acceptable carriers, auxiliary substances or solvents. Pharmaceutically acceptable excipients include various organic or inorganic carriers and/or auxiliary materials, as they are commonly used for pharmaceutical purposes, in particular for solid pharmaceutical formulations. Examples include: excipients, for example sucrose, starch, mannitol, sorbitol, lactose, glucose, cellulose, talc, calcium phosphate, calcium carbonate; binders, such as cellulose, methylcellulose, hydroxypropyl cellulose, polypropylene pyrrolidone, gelatin, acacia, polyethylene glycol, sucrose, starch; disintegrants, for example starch, hydrolyzed starch, carboxymethyl cellulose calcium salt, hydroxypropyl starch, sodium starch glycolate, sodium bicarbonate, calcium phosphate, calcium citrate; lubricants, such as magnesium stearate, talc, sodium lauryl sulfate; perfumes such as citric acid, menthol, glycine, orange powder; preservatives, such as sodium benzoate, sodium bisulphite, parabens (e.g. methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, butyl parahydroxybenzoate); stabilizers such as citric acid, sodium citrate, acetic acid and polycarboxylic acids from the titrilex series, such as diethylenetriamine pentaacetic acid (DTPA); suspending agents, such as methylcellulose, polyvinylpyrrolidone, aluminum stearate; a dispersing agent; diluents, such as water, organic solvents; waxes, fats and oils, such as beeswax, cocoa butter; polyethylene glycol; white vaseline, etc.
In a preferred embodiment of the invention, the pharmaceutical dosage form is a tablet, pill, powder, suspension, gel, emulsion, cream, granule, nanoparticle, capsule, suppository, injection or spray.
In an alternative embodiment, the medicament is a liquid pharmaceutical formulation (e.g., as one of an injection), such as a solution, suspension, and gel, typically containing a liquid carrier, such as water and/or a pharmaceutically acceptable organic solvent. In addition, such liquid formulations may also contain pH adjusting agents, emulsifying or dispersing agents, buffering agents, preservatives, wetting agents, gelling agents (e.g., methylcellulose), dyes, and/or flavoring agents, e.g., as defined above. The drugs may be isotonic, i.e. they may have the same osmotic pressure as blood. The isotonicity of the drug may be adjusted by using sodium chloride and other pharmaceutically acceptable agents such as dextrose, maltose, boric acid, sodium tartrate, propylene glycol and other inorganic or organic soluble materials. The viscosity of the liquid composition may be adjusted by a pharmaceutically acceptable thickener such as methyl cellulose. Other suitable thickening agents include, for example, xanthan gum, carboxymethyl cellulose, hydroxypropyl cellulose, carbomers, and the like. The preferred concentration of thickener depends on the agent selected.
In an alternative embodiment, the medicament is a solid pharmaceutical formulation, such as a lyophilized bacterial powder, a granular formulation, or the like.
In a second aspect, the invention also provides lactobacillus paracasei with a preservation number of CCTCC NO: M2023443, which is preserved in China center for type culture Collection, and the preservation date is 2023 and 31 days of 3 months.
The lactobacillus paracasei PRS-22 can still ensure 99.16 percent of survival rate after being incubated for 3 hours in an artificial gastric juice environment with the pH value of 3.0, and has the advantage of strong acid resistance. In simulated intestinal juice with pH of 6.8, PRS-22 has good survival in 3 hours, no obvious reduction of viable bacteria number, and good intestinal juice tolerance.
In a third aspect, the invention also provides a microbial inoculum or culture comprising lactobacillus paracasei as described above;
in an alternative implementation, the form of the microbial agent or culture is liquid, solid or semi-solid.
In an alternative embodiment, the amount of Lactobacillus paracasei in the solid microbial agent or culture is at least 5X 10 9 CFU/g; the amount of Lactobacillus paracasei in the liquid microbial inoculum or culture is at least 5×10 9 CFU/mL。
In a fourth aspect, the invention also provides a composition comprising lactobacillus paracasei as described above.
In an alternative embodiment, the composition is a pharmaceutical composition.
In an alternative embodiment, the composition is a vaccine composition. The vaccine composition further comprises an adjuvant.
The term "adjuvant" refers to a substance capable of modifying or enhancing an immune response to an antigen. In other words, the immune response to an antigen may be higher or different in the presence of an adjuvant than when an adjuvant is not present (including when the response is modified, e.g., a subset of T cells activated in the presence of an adjuvant is different than a subset activated in the absence of an adjuvant).
The adjuvant is for example selected from lipid adjuvants.
In a fifth aspect, the present invention also provides a method for culturing lactobacillus paracasei, comprising: inoculating lactobacillus paracasei on the culture medium for culture.
In an alternative embodiment, the culturing means is at least one of anaerobic culture and facultative anaerobic culture.
The invention has the following beneficial effects:
the study of the invention shows that the lactobacillus paracasei PRS-22 has remarkable effect of reducing the uric acid content in blood, and a person skilled in the art can expect that the lactobacillus paracasei 16s rDNA sequence has the same or similar effect as that of the lactobacillus paracasei with the sequence consistency of at least 99.5 percent as shown in SEQ ID NO.1, so that the uric acid content in blood can be reduced. The experiment of simulating artificial gastric juice and artificial intestinal juice shows that the lactobacillus paracasei provided by the invention still has higher bacterial strain survival rate in the alimentary canal nutrition environment, and the viable count is not obviously reduced. The result indicates that the lactobacillus paracasei provided by the invention still has higher activity in the alimentary canal nutrition environment, and has better development and utilization prospects for treating or preventing and improving hyperuricemia-induced gout, gout complications or kidney injury.
Preservation description
Preservation address: chinese, wuhan, university of Wuhan
Preservation date: 2023, 3, 31
Strain name: lactobacillus paracasei PRS-22
Latin name: lacticaseibacillus paracasei PRS-22
Preservation mechanism: china center for type culture Collection
The preservation organization is abbreviated as: CCTCC (cctccc)
Accession numbers of the preservation center: cctccc No. M2023443.
Identification result: survival of
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings that are needed in the embodiments will be briefly described below, it being understood that the following drawings only illustrate some embodiments of the present invention and therefore should not be considered as limiting the scope, and other related drawings may be obtained according to these drawings without inventive effort for a person skilled in the art.
FIG. 1 is a PRS-22 gram;
FIG. 2 is a graph showing the statistical result of uric acid content in blood of mice after administration;
FIG. 3 is a graph showing the results of genomic analysis of 6 enzyme genes and PRS-22 associated with the xanthine synthesis pathway;
FIG. 4 is a diagram showing the gene functions of 6 enzymes involved in the xanthine synthesis pathway.
Detailed Description
Reference now will be made in detail to embodiments of the invention, one or more examples of which are described below. Each example is provided by way of explanation, not limitation, of the invention. Indeed, it will be apparent to those skilled in the art that various modifications and variations can be made to the present invention without departing from the scope or spirit of the invention. For example, features illustrated or described as part of one embodiment can be used on another embodiment to yield still a further embodiment.
Unless otherwise indicated, practice of the present invention will employ conventional techniques of cell biology, molecular biology (including recombinant techniques), microbiology, biochemistry and immunology, which are within the ability of a person skilled in the art. This technique is well explained in the literature, as is the case for molecular cloning: laboratory Manual (Molecular Cloning: A Laboratory Manual), second edition (Sambrook et al, 1989); oligonucleotide Synthesis (Oligonucleotide Synthesis) (M.J.Gait et al, 1984); animal cell culture (Animal Cell Culture) (r.i. freshney, 1987); methods of enzymology (Methods in Enzymology) (Academic Press, inc.), experimental immunology handbook (Handbook of Experimental Immunology) (D.M.Weir and C.C.Blackwell, inc.), gene transfer vectors for mammalian cells (Gene Transfer Vectors for Mammalian Cells) (J.M.Miller and M.P.calos, inc., 1987), methods of contemporary molecular biology (Current Protocols in Molecular Biology) (F.M.Ausubel et al, inc., 1987), PCR: polymerase chain reaction (PCR: the Polymerase Chain Reaction, inc., 1994), and methods of contemporary immunology (Current Protocols in Immunology) (J.E.Coligan et al, 1991), each of which is expressly incorporated herein by reference.
In order to make the objects, technical solutions and advantages of the embodiments of the present invention more clear, the technical solutions of the embodiments of the present invention will be clearly and completely described below. The specific conditions are not noted in the examples and are carried out according to conventional conditions or conditions recommended by the manufacturer. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
The features and capabilities of the present invention are described in further detail below in connection with the examples.
Example 1
The embodiment provides lactobacillus paracasei, and the separation and identification processes are as follows:
collecting feces of healthy people, performing 10-time gradient dilution by using PBS under aseptic conditions, selecting three concentration gradients, streaking and inoculating on MRS agar medium (purchased from Qingdao sea Bo biotechnology Co., ltd., product number: HB 0396), performing three repetitions of each gradient, simultaneously using PBS as a blank control, performing anaerobic culture in a constant temperature incubator at 37 ℃ for 24-72 hours, then picking colonies of different forms for gram staining microscopy, performing 2 times streaking and purification in the MRS medium, and performing staining microscopy again to observe bacterial forms and whether purification is performed.
The purified strain was designated PRS-22.
The identification method of the strain PRS-22 is as follows:
(1) Morphological characteristics: as shown in FIG. 1, the colony surface is smooth, round and milky.
(2) The result of gram staining is shown in FIG. 1, and PRS-22 is a gram positive bacterium.
(3) The PRS-22 obtained by separation is identified by 16s rDNA sequencing, and the sequence of the used primer is as follows:
27F：agagtttgatcctggctcag；
1429R：ggttaccttgttacgactt。
the 16S rDNA gene sequence of the strain PRS-22 is amplified and sequenced, and the PCR amplified product is sent to Shanghai Biotechnology engineering (Shanghai) Inc. for sequencing, and the 16S rDNA nucleotide sequence of the strain PRS-22 is shown in SEQ ID NO.1. After 16s rDNA sequences are aligned through NCBI library, the similarity rate of the strain with Lactobacillus paracasei 3534 strain is 99.86%. The invention utilizes an Illumina PE150 platform to carry out whole genome sequencing on the strain extract, and then carries out original data reading, genome assembly and further analysis. The analysis results show that: the genome consisted of 3106004 base pairs with a GC content of 46.21%, comprising 3105 genomes, 7 rrnas, 62 trnas and 1 tmRNA. The whole genome sequence of the strain PRS-22 is shown as the sequence shown in NCBI sequence No. JAVVNQ 000000000.
(4) And (5) physiological and biochemical identification.
The strain PRS-22 was subjected to physiological and biochemical tests of a plurality of indexes shown in Table 1, and the test results are shown in Table 1.
TABLE 1 PRS-22 physiological and biochemical identification results of strains
| Glycerol | — | Mannitol (mannitol) | + | D-raffinose | — |
| Erythritol | — | Sorbitol | + | Starch | v |
| D-arabinose | — | alpha-methyl-D-mannosides | — | Liver sugar (glycogen) | — |
| L-arabinose | — | alpha-methyl-D-glucoside | — | Xylitol | — |
| D-ribose | + | N-acetyl-glucosamine | + | D-gentiobiose | v |
| D-xylose | — | Amygdalin | + | D-melezitose | + |
| L-xylose | — | Arbutin | + | D-lyxose | — |
| D-ribitol/adonitol | + | Radix Schefflerae Arboricolae | + | D-tagatose | + |
| beta-methyl-D-xylosides | — | Salicin | + | D-fucose | — |
| D-galactose | + | D-cellobiose | + | L-fucose | — |
| D-glucose | + | D-maltose | + | D-arabitol | — |
| D-fructose | + | D-lactose | + | L-arabitol | — |
| D-mannose | + | D-melibiose | — | Potassium gluconate | + |
| L-sorbose | + | D-sucrose | v | 2-Keto-gluconate Potassium | — |
| L-rhamnose | — | D-trehalose | + | 5-keto-gluconate potassium salt | — |
| Dulcitol | — | Inulin | — | ||
| Inositol (inositol) | v | D-melezitose | — |
Note that: +: a positive result; -: negative results; v, weak positive.
As can be seen from the physiological and biochemical identification result, the strain PRS-22 is identified as a strain of lactobacillus paracasei.
Experimental example 1
The test example carries out drug resistance detection on the strain PRS-22.
The determination was carried out using a micro broth dilution method with reference to the standard specified in the ISO 10932 document. According to the concentration ranges and solvents of the respective antibiotics in Table 2, the corresponding antibiotic mother liquor was prepared and then filtered with a 0.22 μm filter membrane. Adopting a double dilution method to continuously dilute for nine times to obtain ten antibiotic solutions with corresponding concentration and continuous double concentration gradients, respectively adding the antibiotic solutions into 2-11 columns of sterile 96-well plates according to the sequence from low concentration to high concentration, adding 100 mu L of antibiotic solution into each well,
inoculating glycerol bacteria frozen at-80 ℃ to an MRS agar culture medium plate for streak activation, culturing at 37 ℃ for 24-48 hours, picking plate colonies, dispersing into the MRS broth culture medium, fully mixing uniformly to ensure that the OD of bacterial liquid is equal to that of the strain 600 =0.16 to 0.2, the number of corresponding viable bacteria is about 3×10 8 cfu/mL was inoculated into LSM broth medium at 2-fold concentration according to an inoculum size of 0.1% (v/v), mixed well, and 100. Mu.L of the bacterial liquid was taken into 96-well plates of plus antibiotics.
Column 1 of the 96-well plate was a positive control, containing no antibiotics, only the experimental strain and the medium, column 12 of the 96-well plate was added with 100 μl of sterile water and 100 μl of 2-fold concentration LSM medium as a negative control. And (3) placing the 96-well plate at the constant temperature of 37 ℃ for culture for 48 hours, wherein the lowest antibiotic concentration of the strain without visible growth is the MIC of the strain for antibiotics.
The results of the lactobacillus paracasei PRS-22 antibiotic resistance analysis are shown in table 2, and the resistance phenotype of the strain to antibiotics is analyzed according to the judgment of the european food safety agency (EFSA (2012)) on the threshold ECOFF of microbial susceptibility to different antibiotics. If the MIC value is greater than ECOFF, the strain is indicated as resistant to the antibiotic, and if the MIC value is less than or equal to ECOFF, the strain is indicated as sensitive to the antibiotic.
TABLE 2MIC values and drug sensitivity results
Note that: "S" means sensitivity and "R" means resistance
As shown in Table 2, the strain PRS-22 was mainly resistant to erythromycin and ampicillin; is sensitive to tetracycline, clindamycin, chloramphenicol, kanamycin, gentamicin and streptomycin.
Experimental example 2
The experimental example is subjected to experimental evaluation on the digestive tract environmental tolerance characteristics of lactobacillus paracasei PRS-22.
1. Simulated artificial gastric fluid (Simulated Gastric Fluid, SGF) experiment
(1) Artificial gastric juice: 2.0g NaCl and 3.2g pepsin (Soy bao pepsin, 1:3000, marked as 800-2500 activity units in each mg) are taken, 7.0mL of 37% diluted hydrochloric acid and pure water are added for dissolution and volume fixing to 1000mL, and the pH value of the solution is 1.2. Adjusting pH to 3.0 (simulating human postprandial intestinal juice pH and mouse fasting intestinal juice pH), filtering, and sterilizing;
(2) Collecting bacteria: the strain is statically cultivated for 8-10 h at 37 ℃ to reach logarithmic growth phase, bacterial liquid is split-packed in a 50mL sterile EP tube, centrifugated for 5min at 4000rpm at room temperature, the supernatant is discarded,the bacterial cells were resuspended with PBS and the OD of the bacterial solution was adjusted 600 The number of viable bacteria was about 2X 10 9 CFU/mL, then taking 15mL sterile EP tube, adding 6mL bacterial liquid with adjusted OD value respectively, centrifuging (the same condition as above), discarding supernatant, collecting bacterial mud for standby, and leaving 1 tube to be resuspended by PBS as control group;
(3) Incubating and culturing artificial gastric juice: 6mL of the artificial gastric juice with the pH value of 3 is added into a 15mL centrifuge tube containing bacterial mud, and the mixture is blown and evenly mixed, incubated and cultured for 3 hours, and the coating count is carried out.
(4) Calculating the gastric acid tolerance of bacteria: and (3) counting the plates, recording the colony numbers of the plates, and performing data processing to obtain gastric juice tolerance results of the strain after the artificial gastric juice with different pH values acts for different time. Calculating a survival rate formula: survival = A2/a1×100% formula: a1 is the number of viable bacteria (CFU/mL) of artificial gastric juice incubated for 0h at different pH values; a2 is the number of viable bacteria (CFU/mL) incubated for 3h in artificial gastric juice at different pH.
The results are shown in Table 3, and show that the strain PRS-22 can still ensure 99.16% survival rate and has strong acid resistance after being incubated for 3 hours in an artificial gastric juice environment with pH of 3.0.
TABLE 3PRS-22 (Lactobacillus paracasei) acid and bile salt resistance data
| Name of test solution | Incubation time | The content percentage of viable bacteria is% |
| Artificial gastric juice ph=3.0 | 3h | 99.16％ |
| Ph=6.8 of artificial intestinal juice | 3h | 96.20％ |
| 0.2% ox gall salt MRS broth | 3h | 59.56％ |
2. Simulated artificial intestinal juice (SIF) -SimulatedIntestinalFluid (SIF) experiment
(1) Artificial intestinal juice: taking 6.8g of monopotassium phosphate, adding 500mL of water to dissolve the monopotassium phosphate, and adjusting the pH value to 6.8 by using 0.1mol/L sodium hydroxide solution; another 10g of pancreatin (Soxhinbao trypsin, 1:250) was dissolved by adding water in an appropriate amount, and the two solutions were mixed, diluted to 1000mL with water, filtered and sterilized.
(2) The bacteria collecting method is the same as the artificial gastric juice (SimulatedGastricFluid, SGF) simulating experiment;
(3) Incubating and culturing artificial intestinal juice: 8mL of artificial intestinal juice is taken and respectively added into 4 15mL centrifuge tubes containing bacterial mud, and the mixture is blown and evenly mixed, incubated and cultivated for 3 hours, and the viable count is measured, and the plate counting method is the same as that of the simulated gastric juice (SGF) experiment.
As shown in Table 3, in the simulated intestinal fluid at pH6.8, PRS-22 still ensured 96.20% survival rate within 3 hours, survived well, and no significant decrease in viable count occurred.
3. Experiment for simulating human body internal bile salt environment
(1) Preparing a ox gall salt culture medium: weighing 2g/L (0.2%) of ox gall salt, inoculating to MRS liquid culture medium, and autoclaving for use;
(2) The strain was collected and tested in the artificial gastric juice (SimulatedGastricFluid, SGF) described above.
(3) Incubation and culture of ox gall salt: respectively adding into 3ml MRS broth containing 0.2% ox gall salt for incubation and culture for 3h;
(4) Plate coating count: carrying out 10-time gradient dilution on bacterial solutions of different concentration ox gall salt incubation time points, selecting three proper dilution factors, uniformly absorbing 100uL of dilution liquid, carrying out flat plate coating, setting 3 parallel concentration dilution liquids, and culturing at 37 ℃;
(5) And (3) counting the plates, recording the colony number of each plate, and performing data processing to obtain the cholate tolerance condition of the strain. The calculated survival rate formula is as follows: survival = A2/a1×100% formula: a1 is the number of viable bacteria (CFU/mL) of bacterial liquid in 0% ox gall salt culture medium solution for 0 h; a2 is the viable count (CFU/mL) of the incubation for 2 h.
As shown in Table 3, the survival rate was 59.56% when incubated for 3 hours at 0.2% ox gall salt concentration.
Experimental example 3
In this experimental example, lactobacillus paracasei in example 1 was tested in a mouse model of hyperuricemia, and its use in the treatment or prevention of hyperuricemia was verified.
The experimental method comprises the following steps:
(1) Sample preparation: centrifuging the cultured Lactobacillus paracasei PRS-22 strain suspension, discarding supernatant, and regulating bacterial concentration with sterile physiological saline to about 1×10 viable count 9 CFU/mL。
(2) Animal experiment: the mice selected in this experiment were female Balb/c mice, 6-8 weeks old, and had a weight range of 18-22g, purchased from Shanghai Ling Biotechnology Co.
The mouse hyperuricemia model is used for verifying the drug effect, and the model construction method is as follows:
mice were acclimatized for one week before the start of the experiment. Mice were weighed before molding began and randomly grouped according to body weight. Control mice were lavaged with 200. Mu.l of physiological saline daily and injected intraperitoneally with 200. Mu.l of 0.5% CMC-Na. Model and treatment mice were lavaged with 75mg/kg adenine (MCE, HY-B0152) daily, while being intraperitoneally injected with 250mg/kg Potassium oxazinate (MCE, HY-17511) daily. The molding lasts for 7 days, mice are fed intermittently for 16 hours after the molding on the 7 th day, and blood samples are collected on the 8 th day to detect uric acid content.
The experimental groupings were as follows:
| group of | Number of animals | Medicament | Dosage of | Administration mode | Time of administration |
| Control group | 10 | - | - | - | - |
| Model group | 10 | Physiological saline | 0.2mL | p.o. | QD×7 days |
| Probiotic treatment group | 10 | PRS-22 | Viable count 1×10 9 CFU/only | p.o. | QD×7 days |
Experimental results:
experimental results were analyzed using GraphPad Prism 8 software. Experimental data are expressed as mean ± SEM. P <0.05 indicates that the difference is statistically significant. Wherein P <0.05; * P <0.01; * P <0.001.
As can be seen from fig. 2, uric acid levels in blood were significantly elevated in mice of the model group (P < 0.01) compared to the control group, indicating successful modeling.
As can be seen from FIG. 2, the blood uric acid level in the experimental group was reduced by 46.72% (4.582. Mu.g/mL) as compared with the model group. Thus, lactobacillus paracasei PRS-22 of the present example can significantly improve blood uric acid levels in hyperuricemia mice.
Experimental example 4
In this experimental example, the genome of Lactobacillus paracasei PRS-22 was analyzed, and 6 enzyme genes (shown in FIG. 4) related to the xanthine synthesis pathway were compared with the genome of Lactobacillus paracasei PRS-22.
And (3) selecting and downloading the protein sequences of the swiss library related genes in uniprot by Blastp for comparison, wherein the parameter selection e-value is smaller than 1e-05, the bit-score is larger than 50, the identity is larger than 20, and the coverage is larger than 50.
As a result of the comparison, as shown in FIG. 3, PRS-22 contains EC2.4.2.1, EC2.4.2.8 two genes, and does not contain EC3.5.4.3, EC3.1.3.5, EC1.17.1.4, EC1.17.3.2 four genes, and these genes can reduce the uric acid precursor xanthine formation pathway or reduce the uric acid synthesis pathway; these genes are contained to contribute to a reduction in the uric acid precursor xanthine formation pathway, which in turn leads to a reduction in the uric acid synthesis pathway.
The above description is only of the preferred embodiments of the present invention and is not intended to limit the present invention, but various modifications and variations can be made to the present invention by those skilled in the art. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. Use of lactobacillus paracasei (Lacticaseibacillus paracasei) or a culture thereof for the manufacture of a medicament for the prevention and/or treatment of hyperuricemia, and gout, gout complications or kidney damage caused by hyperuricemia, characterized in that the lactobacillus paracasei is selected from at least one bacterial strain of the group consisting of:
(1) The 16S rDNA sequence of the lactobacillus paracasei has at least 99.5 percent sequence consistency with the 16S rDNA sequence existing in a strain with the preservation number of CCTCC NO: M2023443, which is preserved in the CCTCC at the 3 rd month of 2023;
(2) The whole genome sequence of the lactobacillus paracasei has at least 95% of genome average genetic similarity (Average Nucleotide Identity, ANI) with a sequence shown by NCBI sequence number JAVVNQ000000000, or has at least 95% of genome average genetic similarity (ANI) with a strain with a preservation number of CCTCC NO: M2023443, which is preserved in CCTCC at 3 months of 2023;
the culture is dead bacteria, cell debris, fermentation supernatant and/or fermentation sediment of the lactobacillus paracasei.
2. The use according to claim 1, wherein the lactobacillus paracasei is a gram positive bacterium;
preferably, the whole genome sequence of lactobacillus paracasei has a genome-average genetic similarity (Average Nucleotide Identity, ANI) of at least 97.5% with that shown in NCBI sequence number JAVVNQ000000000, or the whole genome sequence of lactobacillus paracasei has a genome-average genetic similarity (ANI) of at least 97.5% with a strain with a accession number cctccc No. M2023443, which is deposited with cctccc at 3 months 31 of 2023;
preferably, the whole genome sequence of lactobacillus paracasei has at least 99% genome-average genetic similarity (Average Nucleotide Identity, ANI) with the sequence shown in NCBI sequence number JAVVNQ000000000, or the whole genome sequence of lactobacillus paracasei has at least 99% genome-average genetic similarity (ANI) with a strain with the accession number cctccc No. M2023443, which is deposited with cctccc at 3 months 31 of 2023; the method comprises the steps of carrying out a first treatment on the surface of the
Preferably, the whole genome sequence of lactobacillus paracasei has a genome-average genetic similarity (Average Nucleotide Identity, ANI) of at least 99.5% to the sequence shown in NCBI sequence number JAVVNQ000000000, or the whole genome sequence of lactobacillus paracasei has a genome-average genetic similarity (ANI) of at least 99.5% to a strain with a accession number cctccc No. M2023443, which is deposited with CCTCC at 3 months 31 of 2023;
preferably, the 16S rDNA sequence of Lactobacillus paracasei has at least 99.5% sequence identity with the sequence shown in SEQ ID NO.1.
3. The use according to claim 1, wherein the lactobacillus paracasei has a preservation number of CCTCC No. M2023443, and is preserved in the chinese collection of typical cultures, with a preservation date of 2023, 3 and 31 days.
4. The use according to any one of claims 1-3, wherein the gout complication is selected from at least one of gouty arthritis, tophus, joint deformity, urinary tract stones, gouty kidney disease, gouty kidney failure, and cardiovascular disease;
preferably, the kidney injury is an acute kidney injury or a chronic kidney injury.
5. The use according to any one of claims 1-3, wherein the medicament is formulated for oral administration or injection administration.
6. The use according to any one of claims 1 to 3, wherein the medicament further comprises pharmaceutically acceptable excipients.
7. The lactobacillus paracasei is characterized in that the lactobacillus paracasei is preserved with the preservation number of CCTCC NO: M2023443, and is preserved in China center for type culture Collection with the preservation date of 2023 and 3 months and 31 days.
8. A microbial agent or culture comprising the lactobacillus paracasei of claim 7;
preferably, the bacterial agent or culture is in the form of a liquid, solid or semi-solid.
9. A composition comprising the lactobacillus paracasei of claim 7;
preferably, the composition is a pharmaceutical composition;
preferably, the composition is a vaccine composition.
10. A method of culturing lactobacillus paracasei according to claim 7, comprising: inoculating the lactobacillus paracasei on a culture medium for culture;
preferably, the means of cultivation is at least one of anaerobic cultivation and facultative anaerobic cultivation.
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