CN117343880B - Saliva host-associated lactobacillus and application thereof - Google Patents
Saliva host-associated lactobacillus and application thereof Download PDFInfo
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- CN117343880B CN117343880B CN202311651443.2A CN202311651443A CN117343880B CN 117343880 B CN117343880 B CN 117343880B CN 202311651443 A CN202311651443 A CN 202311651443A CN 117343880 B CN117343880 B CN 117343880B
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Abstract
The invention belongs to the field of microorganisms, and particularly discloses a saliva host associated lactobacillus and application thereof, wherein the preservation number of the saliva host associated lactobacillus is CCTCC NO: M20231936. The invention also provides a composition containing the saliva host-associated lactobacillus and application thereof in preparing a product for improving intestinal health. The saliva host-associated lactobacillus has good safety, can inhibit various pathogenic bacteria, inhibit the expression of pro-inflammatory factors, and remarkably improve intestinal symptoms such as diarrhea.
Description
Technical Field
The invention belongs to the technical field of microorganisms, and particularly relates to a saliva host associated lactobacillus and application thereof.
Background
Intestinal microorganisms are closely related to human health and are visually known as "microbial organs". The intestinal flora is used as an important component of the organism, keeps dynamic and stable under normal conditions, and plays an important role in promoting digestion and absorption of nutrient substances, maintaining normal physiological functions of the intestinal tract, regulating various vital activities of the organism, such as immunity and the like. However, the intestinal flora is susceptible to various factors, such as: environmental factors, eating and living habits, mental factors, disease state, tumor treatment, antibiotic use, and age.
The human intestinal flora is disturbed after being influenced by the factors, namely the disturbance of the intestinal flora, which can be manifested by the deficiency of beneficial intestinal bacteria, the excessive reproduction of pathogenic bacteria, the damage of intestinal barrier function and the occurrence of intestinal inflammation, and further causes gastrointestinal diseases of a host, such as constipation, diarrhea, abdominal pain, abdominal distention and the like, and can be seriously developed into diseases such as inflammatory bowel disease, ulcerative colitis, irritable bowel syndrome and the like, thereby greatly affecting the health and life quality of the human body.
Currently, there is increasing interest in improving intestinal health and preventing or treating intestinal diseases using intestinal probiotics. The intestinal probiotics can strengthen the barrier function of intestinal mucosa, prevent adhesion and colonization of pathogenic bacteria and strengthen immune response of a system, thereby achieving the effect of maintaining intestinal health. For example, chinese patent application CN 102711778a discloses a bifidobacterium animalis subspecies lactis DN-173010 and verifies that fermented milk can alleviate ulcerative colitis through mouse experiments and histological studies. Patent application publication No. CN107312726A discloses a Lactobacillus plantarum which can inhibit the growth of harmful bacteria such as Escherichia coli, salmonella, streptococcus suis, staphylococcus aureus and the like in the intestinal tract.
Probiotics are also used to prevent or ameliorate side effects caused by some drugs, such as antibiotics. Side effects associated with chemotherapy are also common in clinic. Digestive system reactions are one of the most common side effects such as nausea, vomiting, diarrhea, constipation, etc. Taking 5-FU as an example, after 5-FU is phosphorylated to 5-FdUMP or 5-FUMP, the 5-FU is more sensitive to the proliferated small intestine cells, and can cause damage to the small intestine mucosa and interfere with the division of the intestine cells to cause necrosis of intestinal wall cells and extensive inflammation of intestinal wall, so that unbalance of the number of absorbed and secreted cells is caused, and diarrhea is caused. In addition, chemotherapeutics can also cause cellular DNA damage and mitochondrial dysfunction, leading to ROS production and apoptosis. ROS can induce NF- κb activation, further up-regulating the expression of pro-inflammatory factors, leading to damage of epithelium, endothelium and connective tissue. Under the condition that intestinal epithelium is damaged, harmful bacteria are very easy to colonize, intestinal microecology is destroyed, pathogenic bacteria are further caused to infect, and diarrhea is promoted to develop.
Saliva host-associated lactobacillus (also known as lactobacillus salivarius) is one of the important members of the intestinal probiotics. Mingfei Yao et al (NPJ Biofilms microbiomes 2021, 7 (1): 58) found that saliva host-associated lactobacillus had a better ameliorating effect on DSS (sodium dextran sulfate) -induced intestinal inflammation in mice. In addition, patent CN114621895B discloses a saliva-associated lactobacillus capable of inhibiting clostridium nucleatum and improving breath. There has been no study reporting the role of saliva host-associated lactobacillus in chemotherapy-induced diarrhea.
Disclosure of Invention
The invention firstly provides a saliva host associated lactobacillus (Ligilactobacillus salivarius) strain which is selected from saliva host associated lactobacillus Lsali-2 with a preservation number of CCTCC NO: M20231936.
In some embodiments, the 16S rDNA sequence of the saliva host-associated Lactobacillus (Ligilactobacillus salivarius) described herein is identical to SEQ ID NO. 1.
In some embodiments, the saliva host-associated lactobacillus (Ligilactobacillus salivarius) of the present invention has a gene encoding an acetogenic related enzyme having the amino acid sequence shown in SEQ ID No. 2.
In some embodiments, the saliva host-associated lactobacillus (Ligilactobacillus salivarius) of the present invention has a gene encoding an acetogenic related enzyme having the amino acid sequence shown in SEQ ID No. 3.
In some embodiments, the saliva host-associated lactobacillus (Ligilactobacillus salivarius) of the present invention has a gene encoding a propionic acid-producing enzyme having the amino acid sequence shown in SEQ ID No. 4.
Secondly, the invention also provides a culture method of the saliva host associated lactobacillus (Ligilactobacillus salivarius) strain, which comprises the steps of inoculating the saliva host associated lactobacillus strain into a culture medium, and carrying out proliferation culture to obtain the proliferated saliva host associated lactobacillus strain.
In some embodiments, the medium contains 15-20 g of BHI broth powder, 10-15 g of MRS broth powder, 12-17 of modified GAM broth powder, g per 1L g of distilled water.
The invention further provides a composition, the active ingredient of which contains the saliva host associated lactobacillus (Ligilactobacillus salivarius) strain or the saliva host associated lactobacillus (Ligilactobacillus salivarius) strain obtained by culturing by the culture method.
In some embodiments, the saliva host-associated lactobacillus (Ligilactobacillus salivarius) strain is the sole active ingredient.
Finally, the invention also provides the use of the saliva host-associated lactobacillus (Ligilactobacillus salivarius) or the composition described above for the preparation of a product for improving intestinal health.
In some embodiments, the intestinal health condition is intestinal inflammation and/or intestinal barrier damage and/or intestinal pathogen infection.
In some embodiments, the intestinal health condition is diarrhea caused by a chemotherapeutic agent.
In some embodiments, the enteropathogenic bacteria are selected from any one or a combination of the following: pseudomonas aeruginosa, shigella, salmonella typhi B, yersinia enterocolitica, staphylococcus aureus and Vibrio parahaemolyticus.
In some embodiments, the chemotherapeutic agent is selected from one or a combination of the following: 5-fluorouracil, tegafur, 5'-2' -deoxyuridine, capecitabine, tegafur, paclitaxel, docetaxel, vinorelbine, cisplatin, carboplatin, nedaplatin, oxaliplatin, lobaplatin, cyclophosphamide, ifosfamide, melphalan, carmustine, irinotecan.
In some embodiments, the saliva host-associated lactobacillus (Ligilactobacillus salivarius) of the present invention has the following biochemical identifying characteristics:
colony morphology on anaerobic triple mixed culture medium (BHI+MRS+modified GAM) is white opaque round, middle bulge and smooth and moist surface;
Genome avirulence gene;
the genome has no drug resistance gene;
In vitro non-hemolysis (i.e., gamma hemolysis);
in some embodiments, the saliva host-associated lactobacillus (Ligilactobacillus salivarius) of the present invention has the following functional identification features:
(1) Has in vitro anti-inflammatory effect;
(2) Can prevent, improve, alleviate or mitigate diarrhea, inflammation and intestinal injury associated with chemotherapy;
(3) Has antibacterial activity against Pseudomonas aeruginosa, shigella, salmonella paratyphi B, yersinia enterocolitica, staphylococcus aureus and Vibrio parahaemolyticus.
The saliva host associated lactobacillus of the invention has the following characteristics:
(1) The drug has no virulence factor, no drug resistance gene and no hemolysis, and has good safety;
(2) Has inhibiting effect on various pathogenic bacteria, can improve intestinal barrier, inhibit expression of proinflammatory factor, and can prevent, improve, relieve or alleviate diarrhea, inflammation and intestinal injury caused by chemotherapy drugs;
(3) The effect of improving diarrhea caused by the chemotherapeutic medicine is equivalent to that of the chemical agent loperamide.
The strain preservation information of the invention is as follows:
strain name: saliva host-associated lactobacillus (Ligilactobacillus salivarius) Lsali-2
Preservation date: 2023, 10, 18 days
Preservation unit: china center for type culture collection (CHINA CENTER for Type Culture Collection, CCTCC), address: university of martial arts, hubei province, post code: 430072, telephone: 027-68754052.
Preservation number: CCTCC NO: M20231936.
Drawings
FIG. 1 is a front view of colony morphology of Lactobacillus Lsali-2 strain associated with saliva host as described in example 1.
FIG. 2 is a graph showing the results of an experiment for inhibiting Lactobacillus Lsali-2 associated with saliva host in example 4.
FIG. 3 is a graph showing the results of the test of saliva host-associated Lactobacillus Lsali-2 for inhibiting inflammatory expression of cells (A. Sup. Ply of IL-6 expression; B. Sup. Ply of TNF-. Alpha. Expression) of example 5.
FIG. 4 is a graph showing the effect of Lactobacillus Lsali-2 salivary host-related to diarrhea treatment in mice with 5-fluorouracil, according to example 6.
FIG. 5 is a graph showing the effect of Lactobacillus Lsali-2 salivary host system on treatment of body weight index of mice with 5-fluorouracil diarrhea (body weight curves for groups A, D9 body weight curves for groups B, D9 body weight change rate for groups C, and colorectal length curves for groups D) according to example 6.
FIG. 6 is a graph showing the results of the relative expression amounts of colonic factor and aquaporin genes in each group of 5-fluorouracil diarrhea mice by Lactobacillus salivarius Lsali-2 (relative expression amount of A IL-1. Beta. MRNA; relative expression amount of B TNF-. Alpha. MRNA; relative expression amount of C IL-6 mRNA; relative expression amount of D AQP8 mRNA) according to example 7.
Detailed Description
Definition and description
For the strain claimed in the present invention (saliva host-associated Lactobacillus strain with a microorganism accession number of CCTCC NO: M20231936, lsali-2 strain), passaged strains which are identical to the genome of Lsali-2 strain without mutation, or which accumulate minute mutations in passaging, but which have NO substantial changes in toxicity, immunogenicity and biological activity, should be regarded as Lsali-2 strains deposited with the microorganism. The passaged strain or mutant strain having no substantial change in toxicity, immunogenicity and biological activity mainly refers to a strain based on Lsali-2 strain passaged and accumulated minute mutations in passaged. And the strain includes live bacteria and inactivated forms, whole thalli or lysate thereof or fermentation products thereof.
The Lsali-2 strain is subjected to the transmission application to inevitably introduce tiny mutation, and the passage strain or mutant strain with no substantial change in toxicity, immunogenicity and biological activity is considered to be within the contribution scope of the invention. There is no substantial change in toxicity, immunogenicity, and biological activity, including, but not limited to, regarding toxicity, immunogenicity, and biological activity as being the same within the limitations and acceptable or unavoidable errors of detection techniques such as detection sensitivity, detection limits, and the like.
It is often desirable to determine toxicity, immunogenicity, and biological activity of Lsali-2 offspring from animals, and due to differences in animal species, age, sex, health, etc., systematic errors that can be expected or unavoidable are attributed to the strains that are passaged without substantial changes in toxicity, immunogenicity, and biological activity.
It is inevitable to introduce minute mutations after a number of passages of Lsali-2 strains, and it is reasonable to expect that these minute mutations remain within the substantial technical contribution of the present invention, while they are still in the form of insubstantial mutations, which should be regarded as mutant strains having no changes in toxicity, immunogenicity, and biological activity, when they occur in non-coding sequence regions or synonymous mutations of coding regions or mutations that do not affect strain toxicity, immunogenicity, and biological activity (e.g., residues that may be linked amino acid residues between two domains, or residues that are located within the higher structure of the protein and do not affect toxicity, immunogenicity, and biological activity by being not contacted with immune cells).
The culture medium of Lsali-2 strain of the present invention cultures passaged strains, and it is reasonable to expect that, like other bacteria, it is inevitable to introduce minute mutations, which are passaged strains or mutant strains having no substantial changes in toxicity, immunogenicity and biological activity when they have no substantial changes in toxicity, immunogenicity and biological activity.
Lsali-2 strains are derived from human faeces, and it is necessary that it is possible to isolate and identify homologous strains in different humans or in the environment, which have a common ancestor with the Lsali-2 strain and which have a significant physiological genetic difference with other known saliva host-associated Lactobacillus strains, which may have the same or may have a minor difference in their genome as the Lsali-2 strain, after the filing date of the present invention.
When these homologous strains differed from Lsali-2 strain to the extent corresponding to that of the passaged strain or mutant strain which had no substantial change in toxicity, immunogenicity and biological activity from Lsali-2 strain, these homologous strains were identical to Lsali-2 strain or considered to have no difference in toxicity, immunogenicity and biological activity, and these homologous strains belonged to substantially the same strain as Lsali-2 strain.
The composition of the invention contains the active ingredient saliva host associated lactobacillus and other ingredients, such as auxiliary ingredients without physiological effects or other functional ingredients. The functional components include, but are not limited to, other functional strains, or nutritional components with nutritional, dietary supplement, dietary fibers, prebiotic components, metagen components, and the like.
The composition of the present invention may be prepared in any form convenient for use, such as powder, tablet, granule, gel, capsule or liquid, which are common in clinical or food.
The compositions of the invention are administered to a subject in an amount (therapeutically effective amount) and frequency that will exert efficacy, and it is recommended that the single use dose contain 10 2~1015 CFU、104~1013 CFU or 10 5~1012 CFU of lactobacillus associated with the saliva host (Ligilactobacillus salivarius).
The diarrhea refers to a clinical symptom that the defecation frequency is obviously higher than that of usual habits (> 3 times/d), the feces are thin, the water content is increased (> 85%), and the feces are accompanied with mucus, sepsis or undigested food.
The intestinal inflammation refers to intestinal inflammatory reaction caused by various reasons such as microbial infection, ischemia, radioactive rays, organism immunity disorder and the like, and the most common symptoms are abdominal pain, diarrhea, bloody stool, fever and the like. Can be accompanied with the increase of inflammatory factor indexes such as IL-6, etc.
The intestinal barrier damage refers to the damage of the barrier function of intestinal mucosa, which leads to the change of intestinal permeability, and intestinal endotoxin, bacteria and other harmful substances enter the blood circulation system to cause a series of inflammatory reactions and related diseases. The increased intestinal permeability may reflect damage to the intestinal mucosa and is an important indicator for evaluating the intestinal barrier function.
The specific temperature parameters in the present invention, unless specified otherwise, are understood to be constant temperature treatments and allow for variations within a certain temperature interval. Such as within a range of + -5 ℃, + -4 ℃, + -3 ℃, + -2 ℃, + -1 ℃.
The auxiliary materials comprise a drug carrier and an excipient. A pharmaceutical carrier refers to a pharmaceutical carrier that does not cause significant irritation to a subject and does not abrogate the biological activity and properties of the administered probiotic. The pharmaceutically acceptable carrier may enhance or stabilize the composition or may be used to facilitate the preparation of the composition. Pharmaceutically acceptable carriers can include solvents, dispersion media, coatings, surfactants, antioxidants, isotonic agents, absorption delaying agents, salts, pharmaceutical stabilizers, binders, excipients, disintegrants, lubricants, sweeteners, flavoring agents, dyes, and the like, and combinations thereof, as known to those skilled in the art (see, e.g., remington's Pharmaceutical Sciences, 18 th edition MACKPRINTING COMPANY,1990, pages 1289-1329). Unless the conventional carrier is incompatible with the active ingredient, it is contemplated that it will be used in a therapeutic or pharmaceutical composition. The carrier may be selected to minimize adverse side effects in the subject and/or minimize inactivation of the active ingredient.
An excipient refers to a substance that is added to a pharmaceutical composition to give the drug a certain shape or a certain concentration. Such as sterile water, physiological saline, polyalkylene glycols (such as polyethylene glycol), vegetable oils or hydrogenated naphthalenes, calcium bicarbonate, calcium phosphate, various sugars, various types of starch, cellulose derivatives, gelatin, and the like.
The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. It is apparent that the described embodiments are only some embodiments of the present invention, not all embodiments, and that all other embodiments obtained by a person skilled in the art without making creative efforts based on the embodiments in the present invention shall fall within the protection scope of the present invention.
The preparation method of the culture medium used in the following examples is as follows:
Preparation of YCFA liquid culture medium: casein 10.0 g g, yeast extract 2.5 g, mgSO 4·7H2 O0.45 mL (10% mother liquor), 10 mg/mL CaCl 2 solution 0.45 mL,TE141 10 mL,K 2HPO4 0.45 g,KH2PO4 0.45 g,NaCl 0.90 g were weighed, dissolved in appropriate amount of distilled water, heated to boil, and then stopped heating. In the cooling process of the culture medium, naOH is firstly added into the VFA-mix of 3.2 mL in batches to adjust the pH value to be neutral, the culture medium is added into the culture medium after being cooled to the room temperature, then 0.5 g of cysteine hydrochloride monohydrate and 0.1% of resazurin 1 mL are added to be uniformly stirred, the pH value is adjusted to be neutral by NaOH, the mixture is heated and boiled for the second time, the heating is stopped about 20 min in a micro-boiling state, N 2 is replaced and cooled and split-packed, the mixture is sterilized at the high temperature of 121 ℃ by wet heat for 30min, and the mixture is stored in a shade and dried place for standby.
Preparation of TE 141: 1.50 g of nitrilotriacetic acid is weighed and added into 200mL of pure water, a proper amount of NaOH is added until the solution becomes clear, then 800 and mL of water is added, the pH value is regulated to 5.5 by 50% of HCl, then 0.03 mL of MgSO4·7H2O 3.00 g,MnSO4·H2O 0.50 g,NaCl 1.00 g,FeSO4·7H2O 0.10 g,CoSO4·7H2O 0.18 g,CaCl2·2H2O 0.10 g,ZnSO4·7H2O 0.18 g,CuSO4·5H2O 0.006 g,KAl(SO4)2·12H2O 0.02 g,H3BO3 0.01 g,Na2MoO4·2H2O 0.01 g,NiCl2·6H2O 0.03 g,10 mg/mL of Na 2SeO3·5H2 O solution and 0.03 and mL of 10 mg/mL of Na 2WO4·2H2 O solution are sequentially weighed and added into the test solution, and the solution is kept clear and is kept for standby in the adding process.
Preparation of VFA-mix: the acetic acid 90 mL, the propionic acid 30 mL, the n-valeric acid 10 mL, the isobutyric acid 10 mL and the butyric acid 10 mL are measured and mixed uniformly for standby, and the pH is adjusted to be neutral by using a NaOH solution with the concentration of 5M before use.
Original sample protectant formulation (1L): weighing Na 2HPO4·12H2O 3.85g,KH2PO4 0.27 g,NaCl 8.00 g, adding a proper amount of distilled water for full dissolution, adding 200 mL glycerol, heating and boiling, and then introducing N 2 for cooling to room temperature. Then adding 1.00 g cysteine salt and 0.1% resazurin 1 mL, fully dissolving, regulating pH to neutrality by using 5M concentration NaOH solution, boiling again until the color of the protective agent is recovered to colorless state, continuously maintaining heating for 20-min, cooling to room temperature by N 2, packaging, sterilizing at 121deg.C under humid heat for 30 min, and storing in shade and dry place.
Preparation of triple mixed liquid medium (bhi+mrs+modified GAM): 19.25 g of BHI broth powder (Qingdao sea Bo Biotechnology Co., ltd., HB 8297-5) and 13.5 g of MRS broth powder (Guangdong CycloKai Biotechnology Co., ltd., 027312) were weighed, 15 g of modified GAM broth powder (Qingdao sea Bo Biotechnology Co., ltd., HB 8518-3) was dissolved in 1L of distilled water, and N 2 was substituted for deoxidization and split charging, and subjected to high temperature wet heat sterilization at 121℃for 30 min, and stored in a cool and dry place. If a solid culture medium is prepared, agar powder 12 g is also required to be added.
Preparation of MRS broth: MRS broth powder 54.0 g, cysteine hydrochloride monohydrate (omeienshan, lozenges biotechnology limited) 0.5. 0.5 g was weighed, dissolved in distilled water 1L, deoxygenated with N 2 substitution, and sterilized 15 min at 121 ℃.
Preparation of a two-mixed culture medium (bhi+mrs): 19.25 g of BHI broth powder (Qingdao sea Bo Biotechnology Co., ltd., HB 8297-5) and 27.0 g of MRS broth powder (Guangdong CycloKai Biotechnology Co., ltd., 027312) were weighed, and cysteine hydrochloride monohydrate (Emeishan Longtong Biotechnology Co., ltd.) was dissolved in 0.5. 0.5 g of distilled water of 1L, deoxygenated and packaged, sterilized at 121℃under moist heat and 15 min, and stored in a cool and dry place.
Preparing a bacterial powder preparation culture medium: 30 g of anhydrous glucose, 15 g of soybean peptone, 10 g of yeast extract powder, 5g of sodium acetate, 2g of monopotassium phosphate, 2g of disodium hydrogen phosphate, 0.1 g of magnesium sulfate, 0.045 g of manganese sulfate, 80 g of tween 80 and 0.5 g of cysteine hydrochloride monohydrate are weighed, dissolved in distilled water of 1L, and N 2 is substituted for deoxidization, split charging and sterilizing at 121 ℃ for 15 min. Stored in a cool and dry place.
EXAMPLE 1 isolation and identification of Lactobacillus Lsali-2 associated with saliva host
Collecting a fresh fecal sample of a healthy volunteer, weighing 1-2 g of the sample into a 50mL centrifuge tube, adding an original sample protecting agent according to a ratio of 1:10, sufficiently shaking, and re-suspending the sample. Under the protection of N 2, filtering the resuspension bacterial liquid by using a warp cloth, putting the resuspension bacterial liquid into a 50mL centrifuge tube, and then transferring the resuspension bacterial liquid into a glove box for sub-packaging. During sub-packaging, using 2 mL screw cap tubes, each 1 mL screw cap tubes, sub-packaging, labeling, bagging, vacuumizing, and storing in a refrigerator at-80deg.C for use.
During separation, 1 frozen sample tube is taken and transferred into a glove box for thawing. After the sample is thawed, 0.5 mL bacterial suspension is taken by a liquid transfer device, and is evenly mixed in 4.5 mL anaerobic PBS in an oscillating way, the mixture is diluted to 10 -6 in a gradient way, a proper gradient bacterial liquid is taken, evenly mixed with YCFA culture medium, distributed in 384-well plates, and subjected to anaerobic culture at 37 ℃ for 9 days. OD monitoring is provided, the bacterial liquid of the growing hole site is selected and transferred into a new 384-well plate, after the bacterial liquid is cultured in duplicate, 48h parts are cultured, one part is detected by MALDI-TOF-MS, the separated bacterial strains are initially classified, the other part is transferred into a 96-well plate again according to the mass spectrum result, after 48h parts are cultured, 16S rDNA gene amplification is carried out on one plate and is sent to Beijing biological science and technology division company for sequencing, 50% glycerol is added into the other plate according to the ratio of 1:1, and the mixture is uniformly and temporarily preserved, and the mixture is used after the PCR result is confirmed.
The sequencing result of the 16S rDNA gene is analyzed, the sequence is compared with the NCBI nucleic acid database, the result shows that the sequence similarity with one saliva host associated lactobacillus (Ligilactobacillus salivarius) is highest (100%), thus the isolated strain is primarily identified as the saliva host associated lactobacillus (Ligilactobacillus salivarius), and the isolated strain is named as saliva host associated lactobacillus Lsali-2. After culturing by adopting an anaerobic three-mixed solid culture medium (BHI+MRS+modified GAM), the colony form of the strain is a white opaque circular colony, the middle part is convex, the surface is smooth and moist, the front photograph is shown in figure 1, the strain is preserved in China center for type culture collection (CCTCC, university of Wuhan collection) for 10 months and 18 days in 2023, and the strain has the preservation number of: CCTCC NO: M20231936.
EXAMPLE 2 Whole genome analysis of saliva host-associated Lactobacillus Lsali-2
Saliva host-associated lactobacillus Lsali-2 was inoculated into 5 mL anaerobic triple mixed liquid medium (bhi+mrs+modified GAM) at an inoculum size of 2%, cultured to late log growth, strain whole genome DNA was extracted, and whole genome sequencing was performed using Illumina high throughput sequencing platform NovaSeq 6000. After assembly and annotation, the protein sequences were entered into virulence gene library Virulence Factor Databases (VFDB) for virulence factor analysis and CARD (The Comprehensive Antibiotic Resistance Database) database for alignment of developing virulence factors and drug resistance gene analysis. The result shows that the bacterium does not have virulence factors and drug resistance genes.
The novel analysis of the strain was performed using the average nucleotide similarity (Average Nucleotide Identity, ANI). By searching in Genbank, 215 published Ligilactobacillus salivarius complete genomes were found, and by fastANI (v 1.33) comparison, it was found that only 1 strain was closest to the saliva host associated lactobacillus Lsali-2 complete genome and not less than 99.9%, gca_009863605.1 (ani=99.94%). By Snippy (v4.6.0) analysis, 366 SNPs (Single Nucleotide Polymorphism ) between two strains, 16 INS (Insertion) and 22 DEL (Deletion) were found, which indicated that the genome difference was large, so that the saliva host-associated lactobacillus Lsali-2 was considered to be a new strain, and the 16S rDNA sequence thereof was shown as SEQ ID NO. 1.
The whole genome sequence is annotated by emapper-2.1.9, and it is further found that the saliva host-associated lactobacillus Lsali-2 has genes encoding acetogenic related enzymes with amino acid sequences shown as SEQ ID NO.2 and SEQ ID NO.3 and propionic acid-producing related enzymes shown as SEQ ID NO. 4.
EXAMPLE 3 hemolysis experiment of Lactobacillus Lsali-2 with saliva host
The preserved saliva host-associated lactobacillus Lsali-2 was inoculated into 5mL anaerobic triple mixed liquid medium at an inoculum size of 2% with enterococcus faecalis (beta hemolysis, cic 23658, purchased from the chinese industrial microbiological bacterial deposit management center) as a positive control and a blank medium as a negative control. All strains are anaerobically cultured in an anaerobic triple mixed liquid culture medium at 37 ℃ until the later phase of logarithmic growth, and activated strains are obtained. 2.5. Mu.L of each activated strain was inoculated onto Columbia blood plates (Shanghai family, majia biotechnology Co., ltd.) and 3 replicates were set per group. Observing after anaerobic culture at 37 ℃ for 48 h, forming a completely transparent hemolytic ring with obvious limit around the colony of the positive strain, which is beta hemolysis; the culture medium surrounding the colony of the saliva host-associated lactobacillus Lsali-2 was unchanged and was gamma-hemolyzed, i.e., not hemolyzed, and therefore, there was no risk of hemolysis in human administration.
Example 4 bacteriostatic Capacity of saliva host-associated Lactobacillus Lsali-2 against pathogenic bacteria
In this example, 6 common pathogenic bacteria causing diarrhea were selected for bacteriostasis, and pathogenic strain source information is shown in table 1.
TABLE 1 pathogenic strain Source information
| Strain name | Strain deposit number | Strain preservation unit |
| Pseudomonas aeruginosa | CMCC(B)10104 | Chinese food and drug testing institute |
| Shigella bacteria | CMCC(B)51252 | Chinese food and drug testing institute |
| Salmonella paratyphi B | CMCC(B)50094 | Chinese food and drug testing institute |
| Staphylococcus aureus | CMCC(B)26003 | Chinese food and drug testing institute |
| Yersinia enterocolitica | CMCC(B)52204 | Chinese food and drug testing institute |
| Vibrio parahaemolyticus | ATCC 17802 | American collection of microbial strains |
Preparation of saliva host-associated lactobacillus Lsali-2 fermentation broth: after the saliva host-associated lactobacillus Lsali-2 was activated, it was inoculated in an anaerobic triple mixed liquid medium (bhi+mrs+modified GAM) at an inoculum size of 2%, and subjected to anaerobic culture at 37 ℃ for 48: 48 h to obtain a fermentation broth. Preparation and coating of pathogenic bacteria: after pseudomonas aeruginosa, shigella, salmonella paratyphi b, yersinia enterocolitica, staphylococcus aureus and vibrio parahaemolyticus are activated by a TSB broth culture medium, the pseudomonas aeruginosa, shigella parahaemolytica, the salmonella paratyphi, the yersinia enterocolitica, the staphylococcus aureus and the vibrio parahaemolyticus are diluted 50 times in the TSB broth culture medium to reach proper concentration, and 0.2 mL diluted bacterial liquid is taken and coated on a TSA solid culture medium.
Lsali-2 co-cultivation with pathogenic bacteria: 3 sterilized oxford cups are placed on a coated pathogenic bacteria plate, and 0.2 mL Lsali-2 fermentation liquor is added into the oxford cups. Placing the bacteria inhibition zone into a culture box, vertically placing the bacteria inhibition zone into a plate for culture 24 h, measuring the size of the bacteria inhibition zone by using a vernier caliper, and calculating the average value of the bacteria inhibition zone. Experimental results: as shown in FIG. 2, the saliva host-associated Lactobacillus Lsali-2 has inhibitory activity against Pseudomonas aeruginosa, shigella, salmonella paratyphi B, yersinia enterocolitica, staphylococcus aureus and Vibrio parahaemolyticus.
Example 5 in vitro cell inflammation inhibition assay of saliva host-associated Lactobacillus Lsali-2
THP-1 cell polarization: THP-1 cells were plated into 96-well plates at a plating density of 1X 10 5 cells/well using RPMI-1640 (Thermo Fisher, C11875500 BT) medium containing 10% FBS and a final concentration of 100 ng/mL PMA (phorbol 12-tetradecanoate 13-acetate, sigma-Aldrich Company, P1585) in a 5% CO 2 incubator at 37℃for 24 h polarization into mature macrophages.
Strain culture: the saliva host-related lactobacillus Lsali-2 bacterial liquid is inoculated from bacterial custody into 200 mu L to 5mL mixed liquid culture medium (BHI+MRS), and is subjected to anaerobic culture in a 37 ℃ electrothermal constant temperature incubator for 24 h. After one transfer, anaerobic culture is performed for 8 h. Taking 1mL bacterial liquid, and centrifuging at 5000 rpm/min for 15 min. Diluted to 2X 10 6 CFU/mL with RPMI-1640 medium containing 10% FBS for use.
Effects of saliva host-associated Lactobacillus Lsali-2 on THP-1 cell expression of TNF- α and IL-6: after THP-1 cells become mature macrophages, the normal control group replaces RPMI-1640 medium containing 10% FBS; the model group, the positive control dexamethasone group and Lsali-2 test group were each subjected to modeling of inflammatory macrophages by exchanging RPMI-1640 medium containing 10% FBS, 100: 100 ng/mL LPS (Sigma-Aldrich Company, L3024) and 20: 20 ng/mL IFN-. Gamma.s (PeproTech, AF-300-02). Each group was placed in a 5% CO 2 incubator and incubated at 37℃for 24: 24 h. The medium was aspirated, and 100. Mu.L of RPMI-1640 medium containing 10% FBS was added to the normal control and model groups, respectively; the positive control group was supplemented with 100. Mu.L of RPMI-1640 medium containing 10% FBS and dexamethasone (purchased from Sigma-Aldrich Company, D4902-25) at a final concentration of 25. Mu.g/mL; lsali-2 test group 100. Mu.L of a pre-diluted Lactobacillus salivarius Lsali-2 strain solution was added to the test group. After incubation at 37℃in a 5% CO 2 incubator for 24H, 80. Mu.L of each cell culture broth was aspirated, at 4℃for 5000 rpm/min, centrifuged for 15 min, the supernatant was collected, and the TNF- α content was detected using a Human TNF- α (Tumor Necrosis Factor Alpha) ELISA kit (available from Wuhan Irite Biotechnology Co., ltd., E-EL-H0109 c) and the IL-6 content was detected using a Human IL-6 (Interlukin 6) ELISA kit (available from Wuhan Irite Biotechnology Co., ltd., E-EL-H6156).
Experimental results: as shown in fig. 3, the expression of IL-6, TNF- α was significantly higher in the model control group than in the normal control group (< 0.001 by P); positive control dexamethasone was able to significantly inhibit the expression of pro-inflammatory factors IL-6, TNF- α in THP-1 cells (< 0.001) P; compared with the model group, the saliva host-associated lactobacillus Lsali-2 can also significantly reduce the expression of pro-inflammatory factors IL-6 and TNF-alpha (P < 0.001), which indicates that the strain has a certain anti-inflammatory effect.
EXAMPLE 6 therapeutic Effect of saliva host-associated Lactobacillus Lsali-2 on 5-FU diarrhea mice
And (3) preparing a freeze-drying protective agent:
and (3) solution A: sucrose 8g, trehalose 8g, purified water 44 g; sterilizing at 115deg.C for 20 min.
And (2) liquid B: sodium glutamate 2g, arginine hydrochloride 2g, purified water 16 g; sterilizing at 115deg.C for 20 min.
And C, liquid: vitamin C sodium 4 g, purified water 16 g. Filtering and sterilizing for standby.
When in use, the components are mixed according to the volume ratio A, B and C=6:2:2.
Preparing bacterial powder: inoculating the preserved saliva host associated lactobacillus Lsali-2 to a bacterial powder preparation culture medium according to 10% of inoculation amount, and performing anaerobic culture at 37 ℃ for 5-8 h at 90 rpm to obtain a first-stage seed solution (OD 600 value is more than or equal to 1.5). Then, transferring the strain to a bacterial powder preparation culture medium according to the inoculation amount of 1.5%, and performing anaerobic culture at 37 ℃ for 8-12 hours at 90 rpm to obtain a secondary seed solution (OD 600 value is more than or equal to 1.8). The secondary seed liquid was pumped into the fermenter with peristaltic pump at 1.5% inoculation amount, and fermentation parameters (37 ℃, pH 5.1, 100 rpm, 0.06 MPa) were set for fermentation culture. Stopping fermentation when the OD 600 value of the fermentation broth is more than or equal to 2.2 or the OD 600 value is increased to be less than or equal to 0.1, setting the fermentation temperature to be 20 ℃, and centrifugally collecting thalli. Adding a freeze-drying protective agent according to the weight ratio of the bacterial mud to the freeze-drying protective agent of 1:1-1:2, and uniformly mixing to emulsify the bacterial mud. And (3) putting the emulsified bacterial suspension into a plate layer of a freeze dryer cooled to-40 ℃ for freeze drying, and crushing to obtain bacterial powder. 1X 10 9 CFU of the bacterial powder was formulated into a bacterial suspension using 0.2 mL physiological saline prior to animal administration.
Test animals: 20 SPF-class male Balb/c mice weighing 18-22 g, purchased from Experimental animal technology Co., ltd., beijing, and fed to SPF-class animal houses.
And (3) test design: the mice were induced with a 5-FU (available from Tianjin JinYao pharmaceutical Co., ltd., specification 10mL per branch, 0.25 g/10 mL) solution for chemotherapy-associated diarrhea model. The mice were randomly divided into 4 groups according to their initial body weight, 5 mice each, and 4 groups were a normal control group, a model control group, a positive control loperamide group, and Lsali-2 groups, respectively.
The overall test period was 9D, designated D1-D9. And D3, performing single molding treatment of the 5-FU, wherein the molding dose of the other groups is 350 mg/kg, except normal control groups, in which physiological saline is injected into the abdominal cavity.
All groups are administrated by gastric lavage, normal control group and model control group are perfused with the freeze-dried protectant, and the gastric lavage is continued for 5 days (D1-D5); the positive control group was continuously gavaged with loperamide (purchased from the western amprensen pharmaceutical company, LFJ 8684) for 9 days (D1-D9, 20 mg/kg); group Lsali-2A 1X 10 9 CFU/dose of Lactobacillus Lsali-2 strain suspension (D1-D5) was continuously fed to the gastric saliva host. After the end of D5 administration, observations were continued for 4 days. The specific experimental groupings and dosing regimens are shown in table 2.
TABLE 2 saliva host associated Lactobacillus Lsali-2 experimental grouping and dosing regimen for treating 5-FU diarrhea mice
| Group of | Quantity of | Molding agent | Amount of modeling agent | Test article | Administration volume | Dosage for administration | Days of administration |
| Normal control group | 5 | Physiological saline | / | Freeze-drying protective agent | 0.2 ML/only | / | 5 d |
| Model control group | 5 | 5-FU | 350mg/kg | Freeze-drying protective agent | 0.2 ML/only | / | 5 d |
| Loperamide group | 5 | 5-FU | 350mg/kg | Loperamide | 10 mL/kg | 20 mg/kg | 9 d |
| Lsali-2 group | 5 | 5-FU | 350mg/kg | Lsali-2 | 0.2 ML/only | 1X 10 9 CFU/min | 5 d |
Note that: 5-FU 5-fluorouracil; CFU colony forming unit colony forming units; d, tiantian
Diarrhea observations and scoring: mice were placed in 1 mouse cage with clean filter paper placed in each cage. Hard feces, normally considered 0 minutes; mild, slightly wet or soft stool was considered 1 minute; moderately, wet feces, fecal matter are not formed and anus Zhou Bujie is considered as 2 minutes; severe, thin stool and severe anus Zhou Bujie were regarded as 3 minutes. During the experimental period, mice faeces were observed and scored daily, and the total diarrhea score was the sum of the daily diarrhea scores.
The experimental results are shown in fig. 4, and the total diarrhea score of Lsali-2 groups is significantly reduced (P < 0.01) compared with the model control group, and an effect equivalent to loperamide is achieved, which shows that Lsali-2 has a significant improvement effect on diarrhea caused by 5-FU.
Lsali-2 not only significantly improved diarrhea, but also significantly improved weight loss and intestinal damage caused by 5-FU, as shown in fig. 5, lsali-2 group tested endpoint significantly increased body weight (< 0.05) (fig. 5B), significantly decreased body weight change rate (absolute value) (fig. 5C), significantly increased colorectal length (< 0.05) (fig. 5D) compared to the model control group.
In conclusion, the saliva host-associated lactobacillus Lsali-2 of the present invention can significantly improve diarrhea symptoms, weight loss and intestinal damage caused by the chemotherapeutic drug 5-FU.
EXAMPLE 7 saliva host-associated Lactobacillus Lsali-2 improvement of relative transcriptional levels of mRNA for IL-1 beta, TNF-alpha, IL-6 and AQP8 in colon of 5-FU diarrhea mice
After the animal experiment in example 6 was completed, the mid-section colon of the mouse was collected and stored in a-80 ℃ refrigerator. Total RNA from colon tissue of each group of mice was extracted according to the reagent instructions (ThermoFisherScientific, cat. No. 15596026) and reverse transcribed into cDNA, stored at-20℃for further use. The relative transcription levels of mRNA genes of the colon inflammatory factors TNF-alpha, IL-1 beta and IL-6 and the relative transcription levels of mRNA genes of aquaporin AQP-8 of each group of mice were detected by qRT-PCR (primer sequences are shown in Table 3). The reaction procedure: 95. at 3 min,95℃for 20s, 60℃for 45 s,72℃for 20s, 39 cycles total. Analysis was performed using the 2 -ΔΔCT method and data were analyzed for significance by SPSS 24.0 statistical software.
TABLE 3 qRT-PCR primer information
| Gene | Primer(s) |
| Tumor necrosis factor （TNF-α） | Forward: 5’-CTGTAGCCCACGTCGTAGC-3’Reverse: 5’-TTGAGATCCATGCCGTTG-3’ |
| Interleukin 1 beta (IL-1β) | Forward: 5’- AGTTGACGGACCCCAAAAG -3’Reverse: 5’- AGCTGGATGCTCTCATCAGG -3’ |
| Interleukin 6（IL-6） | Forward: 5'- CGCTATGAAGTTCCTCTCTGC-3'Reverse: 5'- TTGGGAGTGGTATCCTCTGTG-3' |
| Aquaporins8 (AQP8) | Forward: 5’-GGAACATCAGCGGTGGACACTTC-3’Reverse: 5’-GGGAATTAGCATGGTCTTGAGG-3’ |
As shown in fig. 6A, lsali-2 significantly reduced the relative mRNA transcription level of IL-1β compared to the model control group (< 0.05 by P);
As shown in fig. 6B, the relative mRNA transcription level of TNF- α was significantly increased in the model control group compared to the normal control group (< 0.01); lsali-2 can significantly reduce the relative mRNA transcription level of TNF- α (< 0.05 by P);
as shown in fig. 6C, the relative mRNA transcription level of model control IL-6 was significantly increased compared to the normal control group (< 0.05, < P); lsali-2 can significantly reduce the relative mRNA transcription level of IL-6 (< 0.05 with P);
as shown in fig. 6D, the relative mRNA transcription level of the model control group AQP-8 was significantly reduced compared to the normal control group (< 0.05); lsali-2 can significantly increase the relative mRNA transcript levels of AQP-8 (< 0.01).
Therefore, the saliva host-associated lactobacillus Lsali-2 can improve intestinal health symptoms by reducing the expression of inflammatory factors TNF-alpha, IL-1 beta and IL-6 and increasing the expression of aquaporin AQP-8, and has obvious treatment effect on more serious chemotherapy-associated diarrhea.
Claims (8)
1. A saliva host associated lactobacillus (Ligilactobacillus salivarius) strain is a saliva host associated lactobacillus Lsali-2 with a collection number of CCTCC NO: M20231936.
2. The method for culturing a salivary host-associated lactobacillus (Ligilactobacillus salivarius) strain as claimed in claim 1, wherein the salivary host-associated lactobacillus strain is inoculated to a culture medium and subjected to proliferation culture to obtain a proliferated salivary host-associated lactobacillus strain.
3. The culture method of claim 2, wherein the culture medium contains 15-20 g of BHI broth powder, 10-15 g of mrs broth powder, and 12-17 g of modified GAM broth powder per 1L g of distilled water.
4. A food or pharmaceutical composition comprising the saliva host-associated lactobacillus (Ligilactobacillus salivarius) strain of claim 1 or the saliva host-associated lactobacillus (Ligilactobacillus salivarius) strain obtained by the culture method of claim 2 or 3 as an active ingredient.
5. A health food composition comprising the saliva host-associated lactobacillus (Ligilactobacillus salivarius) strain of claim 1 or the saliva host-associated lactobacillus (Ligilactobacillus salivarius) strain obtained by the culture method of claim 2 or 3 as an active ingredient.
6. Use of a pharmaceutical composition according to claim 4 for the preparation of a product for improving the intestinal health, wherein the intestinal health is intestinal inflammation and/or intestinal barrier damage and/or diarrhea caused by chemotherapeutics.
7. Use of a pharmaceutical composition according to claim 4 for the preparation of a product for improving the intestinal health, characterized in that the intestinal health is an intestinal pathogenic bacterial infection caused by any one or a combination of the following: pseudomonas aeruginosa (Pseudomonas aeruginosa), shigella (SHIGELLA CASTELLANI), salmonella typhi B (Salmonella paratyphi B), yersinia enterocolitica (Yersinia enterocolitica), staphylococcus aureus (Staphylococcus aureus), vibrio parahaemolyticus (Vibrio parahaemolyticus).
8. The use according to claim 6, wherein the chemotherapeutic agent is selected from one or a combination of the following: 5-fluorouracil, tegafur, 5'-2' -deoxyuridine, capecitabine, tegafur, paclitaxel, docetaxel, vinorelbine, cisplatin, carboplatin, nedaplatin, oxaliplatin, lobaplatin, cyclophosphamide, ifosfamide, melphalan, carmustine, irinotecan.
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