CN113637606A - Microorganism combined preparation compounded by metazoan and phage, preparation method and application thereof - Google Patents
Microorganism combined preparation compounded by metazoan and phage, preparation method and application thereof Download PDFInfo
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- CN113637606A CN113637606A CN202110912517.8A CN202110912517A CN113637606A CN 113637606 A CN113637606 A CN 113637606A CN 202110912517 A CN202110912517 A CN 202110912517A CN 113637606 A CN113637606 A CN 113637606A
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- phage
- lactobacillus
- bacteriophage
- metazoan
- bifidobacterium
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Abstract
The invention provides a microorganism combined preparation compounded by metazoan and bacteriophage, which comprises metazoan and bacteriophage; the metazoan can effectively inhibit the growth capacity and activity of the harmful bacteria biofilm, and removes the protection of the biofilm on the harmful bacteria, thereby opening a rapid channel for the bacteriophage to infect the harmful bacteria. After the harmful bacteria are eliminated, the beneficial bacteria restore the occupation of focus epithelial cells and realize rapid colonization and proliferation under the action of metazoan, thereby achieving the balance of microecological flora. In addition, according to further research of the applicant, after the probiotics are compounded, the metabolite of the probiotics can further inhibit the formation of a biological film. Therefore, the speed of infecting the harmful bacteria by the phage is faster and the effect is better.
Description
Technical Field
The invention provides a microbial combined preparation, a preparation method and application thereof, and belongs to the technical field of microbial application.
Background
The body surface skin of the human body, the mucous membranes of the oral cavity, the upper respiratory tract, the intestinal tract, the genitourinary tract and the like which are communicated with the outside and the cavity thereof host microorganisms with different types and quantities, the parasites are safe and adaptive to the host under normal conditions, and various microorganisms are mutually restricted to keep a mutual coexistence state. Micro-ecological flora exists in the digestive tract, upper respiratory tract, skin, urethra, external genitalia, conjunctiva of the eye and external auditory canal of the human body.
In recent years, more and more people have recognized the importance of the human flora. Taking the micro-ecology of the intestinal flora as an example, the health of the gastrointestinal tract is related to various chronic diseases of human body. The health of the intestine is further complemented by the balance of intestinal flora. The balance of the intestinal flora depends on various factors, such as dietary preferences, stress levels, antibiotic usage, and other lifestyle and environmental factors. If intestinal problems occur, the main method for solving the problems is to use antibiotics and take probiotics. In case of serious intestinal diseases, operations are likely to be performed, but during the operation, doctors usually pay attention to the health status of the intestinal flora of patients, and sometimes perform fecal strain transplantation or the like to ensure the intestinal flora of patients to be in a balanced state. It follows that human health is closely related to intestinal health, and that the balance of intestinal flora is an important determinant of intestinal health.
Probiotic formulations are common treatments for infectious enteritis, or for intestinal flora imbalance due to foreign bacterial invasion. The Transparency Market Research study showed that the Market for probiotics, prebiotics and other digestive acid products in the united states reached $68.8billion, and even $83.5billion in 2022. Common probiotic preparations include live bifidobacterium preparations, live bacillus subtilis preparations and the like. A product named as a probiotic preparation is available on the market, and the probiotic preparation comprises NCFM, bifidobacterium lactis BI-04, rhamnosus LR-32 and the like, and has the effect of protecting intestinal tracts. The probiotic preparation can regulate intestinal microecology and promote intestinal balance recovery. However, it takes a long time and it is impossible to relieve the discomfort caused by the symptoms such as vomiting and diarrhea. Nor as a means of routine bowel health maintenance.
The administration of antibiotics (bacterial antibiotics) is also a common treatment for relieving gastrointestinal discomfort, but the administration of antibiotics may cause an imbalance in the microecology of multiple bacterial flora in the human body, and the application of such treatment is gradually reduced.
Since it has a strong bactericidal activity, phages are used as an anti-bacterial infection agent. Chinese patent CN106754751A discloses enterohemorrhagic Escherichia coli bacteriophage and application thereof, which has high-efficiency sterilization capability on EHEC; chinese patent CN106754751A is enterohemorrhagic Escherichia coli bacteriophage and application thereof, the preservation number of the bacteriophage strain is CCTCC NO: m2016539, deposited at the China center for type culture Collection, university of Wuhan, China, at 29.9.2016, and classified and named as enterohemorrhagic Escherichia coli phage vB _ ECM _ MIE, Entero-hemorrhagic Escherichia coli O157, H7 phase vB _ ECM _ MIE; has high-efficiency sterilization capability on EHEC. Although the bacteriophage can play a good role in cracking harmful bacteria, the bacteriophage cannot quickly restore the balance of microecological flora of the focus.
Disclosure of Invention
The invention provides a microbial combined preparation, a preparation method and application thereof, aiming at solving the defects and shortcomings in the prior art, and the composition not only can quickly and effectively solve the problem of bacterial infection, but also can help to restore the balance of primary microecological flora.
In order to solve the technical problems, the invention provides the following technical scheme: a microorganism combined preparation compounded by metazoan and bacteriophage comprises metazoan and bacteriophage; the metazoan comprises inactivated probiotics and metabolites of the probiotics; the bacteriophage has substantial lytic capacity to pathogenic bacteria and is non-toxic, and the bacteriophage is a single strain bacteriophage or a mixture of multiple strains of bacteriophage. By adopting the technical scheme, the postbiotic phage and the phage have synergistic effect, and have better bacteriostatic or bactericidal effect. Meanwhile, the metazoan can promote the growth of the primary flora and help the micro-ecology in the organism to restore balance.
Further, the phage is Escherichia phage, Salmonella phage, Edwardsiella phage, Citrobacter phage, Shigella phage, Klebsiella phage, Serratia phage, Proteus phage, Pseudomonas phage, Klebsiella phage, Comamonas phage, Brevundimonas phage, Acinetobacter phage, Flavobacterium phage, Weeksella phage, aureomonas phage, Xanthomonas phage, Vibrio phage, Aeromonas phage, Staphylococcus phage, viridogrisein phage, beta hemolytic Streptococcus phage, angina Streptococcus phage, pneumococcus phage, Listeria phage, Campylobacter phage, Salmonella phage, Edwardsiella phage, Salmonella phage, or Salmonella, or a phage, or Salmonella, or a phage, or a vaccine, one or more of Malassezia phage, Propionibacterium phage, Arthrobacter phage, gonococcus phage, Streptococcus anaerobically digested phage, and Gardnerella phage;
further, the bacteriophage is Escherichia coli bacteriophage, Enterobacter sakazakii bacteriophage, Escherichia coli bacteriophage, Klebsiella pneumoniae bacteriophage, Salmonella bacteriophage, heterotypic Citrobacter, Shigella bacteriophage, Pseudomonas aeruginosa bacteriophage, Acinetobacter hemolyticus bacteriophage, Flavobacterium meningitidis bacteriophage, animal ulcer Weeksella bacteriophage, P.xanthans bacteriophage, Vibrio cholerae bacteriophage, one or more of vibrio parahaemolyticus phage, vibrio alginolyticus phage, vibrio vulnificus phage, staphylococcus aureus phage, streptococcus pyogenes phage, streptococcus angiitis phage, streptococcus pneumoniae, listeria phage, campylobacter phage, malassezia symptomatica phage, propionibacterium acnes phage, campylobacter bacteriophages, gonococcal phage, and gardnerella bacteriophages.
Wherein, the coliphage can be selected from Esc-COP-4(KCTC 12663BP), Esc-CHP-1(KCTC 12660BP), Esc-CHP-2(KCTC 12661BP), Esc-COP-1(KCTC 12662B), Esc-COP-9(KCTC 13131BP), Esc-COP-7(KCTC 13130BP), CCTCC NO: m2016539, LL5, LH01, T4D, LL 12; the bacteriophage of Enterobacter sakazakii can be selected from SK1(CGMCC No.3741), SK 2(CGMCC No.3742), SK3(CGMCC No.3743), SK4(CGMCC No.3744), SK5(CGMCC No.3745), EspYZU05(CCTCC NO: M2016716); the Escherichia phage can be selected from BP539, BP700, BP753, BP814, BP953, BP954, BP970, BP1002, BP1151, BP1155, BP1168, BP1176, BP1197, BP1226, BP 1229; the Klebsiella pneumoniae phage can be selected from RDP-KP-20004(CGMCC No.21407), RDP-KP-20005(CGMCC No.21408), vB _ KpMM _ hel (CCTCC No: M2015760); the Salmonella bacteriophage can be selected from CCTCC NO: M2014429, STP4-a (CCTCC NO: M2014145); the shigella bacteriophage may be selected from CCTCC NO: m209029, SGF3(CGMCC No.20294), SSE1(CGMCC No. 18853); the pseudomonas aeruginosa bacteriophage can be selected from Pse-AEP-3(KCTC13165BP), Pse-AEP-4(KCTC13166BP), vB _ PaeM _ QKL1(CGMCC No.13381) and RDP-PA-20001(CGMCC No. 21410); the Vibrio cholerae bacteriophage may be selected from vB-Vchs-PR02(CGMCC NO. 18861); the Vibrio parahaemolyticus phage may be selected from VppYZU84(CCTCC M2020242), Vib-PAP-5(KCTC 13029BP), Vib-PAP-2(KCTC 12910BP), Vib-PAP-4(KCTC 13168BP), Vib-PAP-7(KCTC 13247 BP); the Vibrio alginolyticus phage may be selected from ValB1 MD (CCTCC M2019290), ValB1 HC (CCTCC M2019291), VAP7(CCTCC NO: M2018767), VAP21(CCTCC NO: M2018768), VAP9(CCTCC NO: M2018766); the Staphylococcus aureus phage may be selected from qdsa002(CCTCC M2015554), BP-13(CCTCC NO: M2015142), BP-13A (CCTCC M2016535), BP-14(CCTCC NO: M2015143), BP-39(CCTCC NO: M2015144), CCTCC M2011409; the listeria phage can be selected from LipG2-5(CCTCC M2010003), CCTCC NO: m2018644, CCTCC NO: m2018645; propionibacterium acnes phages may be selected from PA6 (NCIMB: 41332), 1874 (NCIMB: 41334), 1878 (NCIMB: 41333), 1905 (NCIMB: 41335), 1894 (NCIMB: 41349), 103609 (NCIMB: 41350), 103672 (NCIMB: 41351).
Further, the mode of inactivating the probiotics can be any mode in the prior art, such as heating, ultraviolet irradiation, chemical treatment and the like; the inactivated probiotics may be treated, such as grinding, crushing or freeze drying; the metazoan is a mixture of inactivated probiotics and its metabolites. In the technical scheme, the metazoan is one or a combination of more than two of lactobacillus, bifidobacterium, streptococcus, lactococcus, leuconostoc, propionibacterium, pediococcus, staphylococcus, bacillus and kluyveromyces; preferably, the postnatal element is one or a combination of more of lactobacillus casei, lactobacillus crispatus, lactobacillus delbrueckii, lactobacillus fermentum, lactobacillus gasseri, lactobacillus helveticus, lactobacillus johnsonii, lactobacillus paracasei, lactobacillus plantarum, lactobacillus reuteri, lactobacillus rhamnosus, lactobacillus salivarius, lactobacillus sake, lactobacillus curvatus, lactobacillus gasseri, streptococcus thermophilus, lactococcus lactis subsp lactis, lactococcus lactis cremoris, lactococcus lactis diacetylactis, leuconostoc mesenteroides, propionibacterium freudenreichii, propionibacterium, pediococcus acidilactici, pediococcus pentosaceus, staphylococcus xylosus, staphylococcus carnosus, bacillus coagulans and bacillus subtilis; more preferably, the metazoan is one or a combination of more than two of lactobacillus helveticus, lactobacillus casei, lactobacillus gasseri, lactobacillus paracasei, lactobacillus plantarum, lactobacillus rhamnosus, lactobacillus crispatus, lactobacillus salivarius, lactobacillus acidophilus, lactobacillus brevis, lactobacillus bulgaricus, lactobacillus fermentum, lactobacillus reuteri, bifidobacterium lactis, bifidobacterium breve, bifidobacterium bifidum, bifidobacterium infantis, bifidobacterium longum, streptococcus thermophilus, pediococcus pentosaceus and bacillus coagulans.
Wherein the Lactobacillus helveticus strain can be selected from Lactobacillus helveticus HA-122; the Lactobacillus paracasei can be selected from Lactobacillus paracasei HA-108, Lactobacillus paracasei MCC 1849; the Lactobacillus plantarum can be selected from Lactobacillus plantarum HA-119, Lactobacillus plantarum L-137, Lactobacillus plantarum K-1, Lactobacillus plantarum K-2, Lactobacillus plantarum SNK, Lactobacillus plantarum LP 226; the Lactobacillus rhamnosus can be selected from Lactobacillus rhamnosus HA-111; streptococcus thermophilus may be selected from str. thermophilus HA-110; lactobacillus crispatus can be selected from KT-11; the Lactobacillus casei may be selected from Lactobacillus casei 327; bacillus coagulans may be selected from b.coagulans GBI-30; pediococcus pentosaceus can be selected from Pediococcus pentosaceus NB 17; the Bifidobacterium longum may be selected from Bifidobacterium longum 108. In the case where not indicated herein:
"Lactobacillus plantarum HA-119" means Lactobacillus plantarum HA-119 metazoa;
"Lactobacillus plantarum L-137" refers to Lactobacillus plantarum L-137 metazoa;
"Lactobacillus plantarum K-1" means Lactobacillus plantarum K-1 metazoan;
"Lactobacillus plantarum K-2" means Lactobacillus plantarum K-2 metazoan;
"Lactobacillus plantarum SNK" means Lactobacillus plantarum SNK metazoa;
"Lactobacillus plantarum LP 226" means Lactobacillus plantarum LP226 metazoa;
bifidobacterium lactis
"means Bifidobacterium lactis
Postnatal vitality;
"Lactobacillus helveticus HA-122" means Lactobacillus helveticus HA-122 metazoan;
"Lactobacillus paracasei HA-108" refers to Lactobacillus paracasei HA-108 metazoa;
"Lactobacillus paracasei MCC 1849" refers to a metazoan after Lactobacillus paracasei MCC 1849;
"Lactobacillus rhamnosus HA-111" refers to Lactobacillus rhamnosus HA-111 metazoan;
"Streptococcus thermophilus HA-110" means Streptococcus thermophilus HA-110 metazoan;
"Lactobacillus crispatus KT-11" is expressed as Lactobacillus crispatus KT-11 metagen;
"Lactobacillus casei 327" refers to Lactobacillus casei 327 metazoan;
"Bacillus coagulans GBI-30" refers to Bacillus coagulans GBI-30 metazoan;
"Pediococcus pentosaceus NB 17" refers to Pediococcus pentosaceus NB17 metazoan;
"Bifidobacterium longum 108" is denoted as Bifidobacterium longum 108 metazoa.
The consumption of metazoan and phage was: the ratio of the number of inactivated probiotic bacteria to the number of phage bacteria in the metazoan is 1:100-100:1, preferably 1:99, 5:95, 10:90, 20:80, 30:70, 40:60, 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, or 99: 1.
Alternatively, the ratio of postbiotic to phage is 0.25 mg: 108pfu (pfu is plaque forming unit) phage to 1000 mg: 108pfu phage; further, 0.5 mg: 108pfu phage, 1 mg: 108pfu phage, 5 mg: 108pfu phage, 10 mg: 108pfu phage, 50 mg: 108pfu phage, 100 mg: 108pfu phage, 200 mg: 108pfu phage, 500 mg: 108pfu phage, 800 mg: 108pfu phage, or 1000 mg: 108pfu phage.
Or the dosage of the metazoan and the phage is as follows: the amount of the postnatal element is 0.25-1000mg, and the amount of the bacteriophage is 0.1-1000 mg; further, the amount of the metazoan is 0.5-800mg, and the amount of the phage is 0.5-800 mg; further, the amount of the metazoan is 1-500mg, and the amount of the phage is 1-500 mg; further, the amount of the metazoan is 5-200mg, and the amount of the phage is 5-200 mg; furthermore, the amount of the metazoan is 10-100mg, and the amount of the phage is 10-100 mg; further, the amount of metazoan is 50-80mg, and the amount of phage is 50-80 mg.
Alternatively, the ratio of postbiotic to phage is 0.1 hundred million: 108pfu phage to 1000 hundred million: 108pfu phage. Further, 1 hundred million: 108pfu phage, 5 hundred million: 108pfu phage, 10 hundred million: 108pfu phage, 50 hundred million: 108pfu phage, 100 hundred million: 108pfu phage, 200 hundred million: 108pfu phage, 500 hundred million: 108pfu phage, 800 hundred million: 108pfu phage, or 1000 hundred million: 108pfu phage. The number of the post-biotics is the number of dead bacteria of inactivated probiotics, and the number of the dead bacteria is determined by detecting and calculating the number of the viable bacteria of the probiotics for producing the post-biotics and the viable bacteria density.
As a more preferable technical scheme, the composition also comprises probiotics or/and prebiotics. The probiotics are used as the supplement of the exogenous bacteria, and can assist in quickly restoring the microecological flora balance in the organism; prebiotics provide nutrition to both exogenous and endogenous probiotics and also aim to rapidly restore the microecological balance of the beneficial flora.
Further, the probiotic bacteria is one or more of Lactobacillus, Bifidobacterium, Streptococcus, lactococcus, Leuconostoc, Propionibacterium, Pediococcus, Staphylococcus, Bacillus, and Kluyveromyces; preferably, the probiotics are one or more of lactobacillus casei, lactobacillus crispatus, lactobacillus delbrueckii, lactobacillus fermentum, lactobacillus gasseri, lactobacillus helveticus, lactobacillus johnsonii, lactobacillus paracasei, lactobacillus plantarum, lactobacillus reuteri, lactobacillus rhamnosus, lactobacillus salivarius, lactobacillus sake, lactobacillus curvatus, lactobacillus gasseri, streptococcus thermophilus, lactococcus lactis subsp lactis, lactococcus lactis cremoris, lactococcus lactis diacetyl subsp lactis, leuconostoc mesenteroides, propionibacterium freudenreichigera subsp, propionibacterium, pediococcus acidilactici, pediococcus pentosaceus, staphylococcus parvum, staphylococcus xylosus, staphylococcus carnosus, bacillus coagulans and bacillus subtilis; more preferably, the probiotic bacteria are one or more of lactobacillus helveticus, lactobacillus casei, lactobacillus gasseri, lactobacillus paracasei, lactobacillus plantarum, lactobacillus rhamnosus, lactobacillus crispatus, lactobacillus salivarius, lactobacillus acidophilus, lactobacillus brevis, lactobacillus bulgaricus, lactobacillus fermentum, lactobacillus reuteri, bifidobacterium lactis, bifidobacterium breve, bifidobacterium bifidum, bifidobacterium infantis, bifidobacterium longum, streptococcus thermophilus, pediococcus pentosaceus and bacillus coagulans; or/and the prebiotics are one or more of short chain fatty acids, lactoferrin, fructo-oligosaccharide, xylo-oligosaccharide, lacto-oligosaccharide, inulin, lactulose, artichoke, chicory, oat, barley, leguminous plants, garlic, olive dish, beans or herbs.
The dosage of the probiotics is as follows: the ratio of the number of inactivated probiotic bacteria to the number of probiotic bacteria in metazoan is 1:100-100:1, preferably 1:99, 5:95, 10:90, 20:80, 30:70, 40:60, 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, or 99: 1.
Or the dosage ratio of the metazoan to the probiotics is 0.25 mg: 100 hundred million to 1000 mg: 100 hundred million; further, 0.5 mg: 100 hundred million probiotics, 1 mg: 100 hundred million probiotics, 5 mg: 100 hundred million probiotics, 10 mg: 100 hundred million probiotics, 50 mg: 100 hundred million probiotics, 100 mg: 100 hundred million probiotics, 200 mg: 100 hundred million probiotics, 500: 100 hundred million probiotics, 800 mg: 100 hundred million probiotics, or 1000 mg: 100 hundred million probiotics.
Or the dosage ratio of the metazoan to the probiotics is 0.1 hundred million: 100 to 1000 billion probiotics: 100 hundred million probiotics. Further, 1 hundred million: 100 hundred million probiotics, 5 hundred million: 100 hundred million probiotics, 10 hundred million: 100 hundred million probiotics, 50 hundred million: 100 hundred million probiotics, 100 hundred million: 100 hundred million probiotics, 200 hundred million: 100 hundred million probiotics, 500 hundred million: 100 hundred million probiotics, 800 hundred million: 100 hundred million probiotics, or 1000 hundred million: 100 hundred million probiotics.
The invention also provides a product which comprises the microbial combined preparation and auxiliary materials. The product has 0.1-1000 hundred million/g of metazoan and 10% of bacteriophage4pfu/g-1010pfu/g; further, the amount of metazoan is 10 to 800 hundred million/g, and the amount of phage is 106pfu/g-109pfu/g; further, the amount of metazoan is 50 to 200 hundred million/g and the amount of phage is 107pfu/g-109pfu/g; further, the amount of metazoan is 100 to 150 hundred million/g and the amount of phage is 107pfu/g-108pfu/g。
Alternatively, the product contains 0.1-1000 hundred million/ml of postnatal and 10% of bacteriophage4pfu/ml-1010pfu/ml; further, the amount of metazoan is 10 to 800 hundred million/ml, and the amount of phage is 106pfu/ml-109pfu/ml; further, the amount of metazoan is 50 to 200 hundred million/ml and the amount of phage is 107pfu/ml-109pfu/ml; further, the amount of metazoan is 100 to 150 hundred million/ml and the amount of phage is 107pfu/ml-108pfu/ml。
In the present invention, the product can be in various dosage forms, including but not limited to powder, suppository, solid beverage, hard capsule, soft beverage, multi-layer hard capsule, bean-dissolving powder, freeze-dried powder, milk bean, chocolate, soft sweets with filling, chocolate sandwich, tea beverage, cold-extracted coffee, wet tissue, ointment, cream, liquid, emulsion, gel, and solid.
The invention also provides the application of the product or the microorganism combined preparation in preparing medicaments, foods or animal foods, nourishments, health products or supplements, daily chemical products, cosmetics, cleaning products and disinfection products for treating bacterial infectious diseases.
Among them, bacterial infections include, but are not limited to, gastrointestinal diseases, urinary system diseases, reproductive system diseases, respiratory diseases and skin-like diseases caused by bacterial infections in humans or animals.
The invention also provides a preparation method of the product, which comprises the following specific steps: mixing the metagen suspension with phage liquid, adding or not adding auxiliary materials, molding and packaging to obtain a finished product; wherein, the mixing of the metazoan suspension and the phage liquid and the addition of the auxiliary materials are sequentially carried out, or the mixing and the addition of the auxiliary materials are simultaneously carried out;
preferably, the auxiliary materials are pretreated, so that the auxiliary materials meet the requirements of the preparation formulation and then are mixed with the mixture of the metazoan suspension and the phage liquid to obtain the preparation formulation and then are packaged into a finished product; or mixing the auxiliary materials with the mixture of the metazoan suspension and the phage liquid, processing to obtain a product meeting the requirement of the dosage form, and then forming and packaging the product.
The microbial composition preparation provided by the invention can quickly relieve bacterial infection in a body, recover occupation of beneficial bacteria on focus epithelial cells, and realize quick colonization and proliferation under the action of metazoan, so that the balance of microecological flora is achieved, and the recovery of microecological balance in the body is facilitated.
Drawings
FIG. 1 shows the inhibition of E.coli in the initial colonization phase by a composition preparation of the present invention;
FIG. 2 shows the inhibition of Escherichia coli in the mature stage by the composition preparation of the present invention;
FIG. 3 the effect of different metagens of the present invention on the growth capacity of E.coli biofilms;
FIG. 4 the effect of different metazoans of the invention on the biofilm growth capacity of Staphylococcus aureus;
FIG. 5 the effect of different metazoans of the present invention on the growth capacity of Candida albicans biofilms;
FIG. 6 the effect of a prebiotic on Candida albicans on initial regular biofilm activity after a variation of the present invention;
FIG. 7 the effect of different metagens of the present invention on the biofilm activity of Candida albicans in the maturation stage.
Detailed Description
The invention is further described with reference to specific examples. The following examples are only for illustrating the technical solutions of the present invention more clearly, and the protection scope of the present invention is not limited thereby.
The following examples are provided to further illustrate the present invention.
Bacteriophage is a virus that infects microorganisms such as bacteria (viruses that feed bacteria), fungi, actinomycetes, spirochetes, etc., and has high specificity for a host. Bacteriophages are generally divided into two categories: one is a bacterium that replicates and multiplies in a host bacterium, thereby producing a plurality of progeny phages, which are then lysed, called virulent or virulent phages; the bacteriophage can kill bacteria after infecting the bacteria, but has no toxicity to organisms. Thus, bacteriophages have also become medically accepted as alternatives to antibiotics. Patent US5688501 discloses a method for treating diseases of bacterial infection using bacteriophages with specific lytic or non-lytic properties; patent US4957686 also discloses the use of bacteriophages to improve the conditions of bacterial infections in the oral cavity. Although the above reports can alleviate bacterial infection in a short time, the dysbiosis of the body caused by bacterial infection cannot be well controlled. Moreover, infected bacteria are planted in the organism, and the removal effect of the bacteriophage on the bacteria can be seriously influenced due to the existence of a biological film on the surface of bacterial colonies.
Long-term results of research by the applicant show that: 1. the postnatal can promote the growth of the probiotics, the research result has already filed an invention patent (application number: 202110026795.3) to the national intellectual property office, and the application is not repeated. Therefore, the problem can be well solved by compounding the metazoan and the phage. 2. The metazoan can effectively inhibit the growth capacity and activity of the harmful bacteria biofilm. The biofilm is a stable complex three-dimensional network structure formed by microorganisms, which are adapted to the surrounding environment, adhere to the surfaces of living or non-living media and are wrapped by extracellular matrix secreted by the microorganisms. It has been reported that bacterial biofilms are the causative mechanism responsible for persistent bacterial infections, and that the majority of clinical infection cases are associated with biofilm formation. During the bacterial infection process of the bacteriophage, the bacterial biofilm can obstruct the infection process. Therefore, the metazoan can inhibit the growth capacity and activity of the biological membrane and open a channel for the bacteriophage to infect the bacteria. The following description will specifically explain the above developments with specific examples.
Experimental example:
1. experimental material and experimental equipment
1.1 Main reagents: LB medium, sterile water, broth medium and the like
1.2 Main equipment: electronic balance (mettler-toledo instruments (shanghai) limited), steam sterilization pot (Shandong Boke scientific instruments limited), Mingmei microscope + computer (Mingmei photoelectric technology limited, Guangzhou), ultrasonic cleaner (Kunshan ultrasonic instruments limited), pH meter (mettler-toledo instruments (shanghai) limited), high-speed centrifuge (Shanghai Luxiang instruments centrifugal machine limited), constant temperature cradle (Shandong Boke scientific instruments limited), medical refrigerator freezer (Haier), heating magnetic stirrer (Shanghai Hengyi scientific instruments limited), electric heating constant temperature incubator (Shanghai Hengyi scientific instruments limited), micropipeter (eppendorf and other experimental devices.
2. The experimental method comprises the following steps:
in the following examples, the test strains are commercially available, are in an open state, and can be requested by a researcher from a relevant institution.
2.1 recovery and culture of probiotics/harmful bacteria: taking a proper amount of sample, diluting with sterile water by 10 times, and homogenizing at 8000rpm for 2 min. And (3) coating the prepared sample bacterial liquid on a proper culture medium, and culturing for 48-72h at a proper temperature. The activated plate was stored in a refrigerator for subsequent experiments. Wherein the culture conditions of different genera of probiotics are as follows:
bifidobacteria: the common culture medium is PYG and MRS, the culture temperature is 36 ℃, and anaerobic culture is carried out;
lactic acid bacteria: the common culture medium is MRS and improved MC, the culture temperature is 36 ℃, and anaerobic culture is carried out;
streptococcus thermophilus: the common culture medium is MRS and modified MC, the culture temperature is 36 ℃, and aerobic culture is carried out;
2.2 cultivation of phages: the host cells corresponding to the phage were cultured overnight in liquid. The phage samples were diluted 10-fold with sterile water. 1ml of host cell sap and 100ul of phage liquid were mixed well and left for 15min to infect. The mixture was added to 5ml of 0.7% agar medium cooled to 45 ℃, mixed well, immediately poured onto the surface of a plate containing 2% medium and plated flat. And (5) after the band plate is solidified, moving the band plate into an incubator for culturing for 8-24 h.
Control plates containing no phage were also prepared according to the procedure described above.
Placing the plate containing the phage at-20 deg.C for 4-5h, freezing, and thawing. The liquid produced after thawing was transferred to a centrifuge tube and centrifuged at 10000rpm for 10 minutes to pellet the host bacteria. Transferring the supernatant to a new tube, and removing residual bacteria with a filter (0.22 μm pore size) to obtain phage stock solution without host bacteria.
2.3 microbial combination agent colonization test for inhibiting harmful bacteria
Grouping escherichia coli: taking out the activated escherichia coli plate, selecting an escherichia coli single colony, inoculating the escherichia coli single colony in an LB liquid culture medium plate, and culturing at 37 ℃: culturing for 24 hours to obtain the Escherichia coli with the biomembrane as the initial planting stage; and culturing the group B for 48 hours to obtain the Escherichia coli with a mature biofilm.
Grouping treatment liquids: adding the treated solution into 5ml of 0.7% agar medium cooled to 45 deg.C, mixing, pouring onto the surface of Escherichia coli plates of group A and group B, and spreading. After coagulation, the plate was transferred to an incubator and cultured overnight, and the number of coliphage plaques on the plate was counted (the larger the number of coliphage plaques, the better the inhibition effect on colibacillus), with the results shown in fig. 1-2. Wherein, the grouping condition of the treatment liquid is as follows:
experimental group 1: 50ul of E.coli phage Esc-COP-4 phage fluid (10)9cpu)
Experimental group 2: 1ml later suspension (1mg/ml) +50ul of E.coli phage Esc-COP-4 phage liquid (10)9cpu)
Experimental group 3: 1ml postbiotic suspension (1mg/ml) +1ml probiotic (OD 0.6) +50ul coliphage Esc-COP-4 phage fluid (10 ul)5cpu)
Experimental group 4: 1ml postbiotic suspension (1mg/ml) +1ml probiotic (OD 0.6) +50ul coliphage Esc-COP-4 phage fluid (10 ul)9cpu)
Blank control: 2.5mL of PBS solution.
In the above, the probiotic bacteria are viable bacteria strains corresponding to metazoan.
As shown in the figure 1-2, in different growth stages of the escherichia coli, post-biotic suspensions of different strains and the escherichia coli phage are compounded to treat the escherichia coli, the bacterial plaque number of the escherichia coli phage is remarkably improved, and the bacterial plaque number of the escherichia coli phage is proved to show good inhibition effect on the escherichia coli. The specific analysis is as follows:
1. coli in the initial colonization phase: the experimental group 1 and the experimental group 2 both show good inhibition effect on escherichia coli, but the inhibition effect of the experimental group 2 is obvious compared with that of the experimental group 1, namely, the inhibition effect of the postbiotic suspensions of different strains on escherichia coli after being compounded with the escherichia coli phage respectively has obvious difference compared with that of the escherichia coli by the escherichia coli phage alone. Wherein, the inhibiting effect of the lactobacillus plantarum HA-119 and the Escherichia coli bacteriophage after being compounded on Escherichia coli is most obvious in difference compared with the inhibiting effect of the Escherichia coli by the Escherichia coli bacteriophage acting alone, and the Lactobacillus crispatus KT-11 and the Lactobacillus rhamnosus HA-111 are also obvious in difference.
2. Maturation period of Escherichia coli: the experimental group 1 and the experimental group 2 both show good inhibition effect on escherichia coli, but the inhibition effect of the experimental group 2 is obvious compared with that of the experimental group 1, namely, the inhibition effect of the postbiotic suspensions of different strains on escherichia coli after being compounded with the escherichia coli phage respectively has obvious difference compared with that of the escherichia coli by the escherichia coli phage alone. Wherein, the inhibiting effect of the lactobacillus plantarum HA-119 compounded with the coliphage on the escherichia coli is most obvious in difference compared with the inhibiting effect of the coliphage on the escherichia coli alone, and the lactobacillus crispatus KT-11, the lactobacillus rhamnosus HA-111 and the lactobacillus paracasei HA-108 also have obvious difference.
The inhibition effect of the post-growth element and the phage compound on the escherichia coli is better than that of the phage acting alone, and the post-growth element probably breaks the protection of an escherichia coli biological membrane firstly, so that the phage can act on the escherichia coli quickly, and more plaques are formed. The components contained in the metazoan, such as teichoic acid, extracellular polysaccharide protein and the like can inhibit the formation and activity of the escherichia coli biofilm, so that a path is opened for the bacteriophage to exert the effect of infecting escherichia coli, the protection effect of the biofilm on the escherichia coli is relieved, and the bacteriophage is favorable for exerting the effect.
According to further research of the applicant, the probiotic is added into the microbial combined preparation, so that the effect of inhibiting escherichia coli is better. Therefore, the applicant formulated live bacterial strains corresponding to metazoan and metazoan together with phage and examined the inhibition of escherichia coli, and the results are shown in experimental group 3 and experimental group 4 in fig. 1. As can be seen from fig. 1, after the probiotics were added, the inhibition effect of the experimental group 3 and the experimental group 4 on escherichia coli was significantly improved compared to the experimental group 1 and the experimental group 2. The lactobacillus plantarum and the lactobacillus crispatus have good inhibition effect in the initial colonization period and the maturation period of the escherichia coli biomembrane; lactobacillus helveticus and streptococcus thermophilus have good inhibition effect on escherichia coli in a biomembrane maturation stage. The applicant believes that the metabolites may further inhibit biofilm formation upon the addition of probiotics. Therefore, the bacteriophage can infect the escherichia coli more quickly and show the maximum phage plaque number, namely, the best inhibition effect on the escherichia coli.
In order to verify the influence of metazoa on the biofilm of harmful bacteria, the applicant utilizes metazoa of different strains to examine the influence of metazoa on the growth capability of the biofilm of harmful bacteria and the activity of the biofilm in different growth periods of the harmful bacteria, as described in experiments 2.4 and 2.5.
2.4 post-biotic inhibition of growth of biofilm of harmful bacteria
Taking out the activated harmful bacteria plate, selecting single colony of the harmful bacteria, inoculating the single colony in LB liquid culture medium, and culturing at 37 ℃ overnight. Centrifuging at 8000rpm and 4 deg.C for 5min, collecting thallus, washing with PBS twice, and adjusting bacterial liquid concentration to 10 with RPMI-1640 liquid culture medium6CFU/mL. mu.L of the inoculum and 100. mu.L of the metazoan suspension (1mg/mL) were added to a 96-well plate, and MRS medium was used as a blank. The plates were incubated at 37 ℃ for 48 h. After incubation, the cells were gently washed 3 times with PBS, 100. mu.L of 0.1% crystal violet was added to each well, stained for 20min, the crystal violet was discarded, washed 3 times with PBS, 100. mu.L of 95% ethanol was added to each well, and the absorbance at 570nm was measured with a microplate reader. The results are shown in FIGS. 3-5.
As can be seen from the results of FIGS. 3-5, the metazoan of different strains have certain inhibition effects on the growth of the harmful bacteria biofilm against the harmful bacteria Escherichia coli, Staphylococcus aureus and Candida albicans, but the inhibition degrees are different. Among them, the inhibitory effect on Escherichia coli is the best, and the inhibitory effect on Candida albicans is inferior to that of Escherichia coli. This may be related to the pathogenic ability of different harmful bacteria. Because the biofilm is formed after the microorganisms contact the surface of a host or an object, the bacteria in the biofilm have stronger drug resistance, virulence and pathogenicity than the suspended bacteria due to the existence of the biofilm. Therefore, the inhibitory effect on the growth ability of Candida albicans biofilm was inferior to that of Escherichia coli and Staphylococcus aureus. The inhibitory effect of different metazoans on the same harmful bacterium is also different: 1. for Escherichia coli, 10 metazoans have good inhibitory effect, wherein the inhibitory effect of Lactobacillus crispatus KT-11 is the best. 2. HAs better inhibiting effect on staphylococcus aureus, lactobacillus paracasei HA-108, lactobacillus plantarum L-137 and HA-119 and lactobacillus crispatus KT-11. Streptococcus thermophilus HA-110, Bacillus coagulans GBI-30, Pediococcus pentosaceus NB17 and Bifidobacterium longum 108 are less effective in inhibiting. 3. The lactobacillus paracasei HA-108, the lactobacillus plantarum L-137 and HA-119 and the lactobacillus rhamnosus HA-111 all show good inhibition effect on the growth capacity of the biological membrane for the candida albicans.
2.5 post-suspension test for inhibiting the Activity of harmful bacteria biofilm
Taking out the activated Candida albicans plate, selecting a Candida albicans single colony, inoculating the Candida albicans single colony in a YPD liquid culture medium, and culturing at 37 ℃ overnight. 100 μ L of Candida albicans suspension was put into a 96-well plate, shake-cultured at 37 ℃ and 80rpm for 3 hours, the culture solution in the well was discarded, and washed gently 3 times with PBS. Each set was provided in parallel with 3.
a. In the initial planting stage: a96-well plate washed 3 times gently with PBS was incubated at 37 ℃ for 24 hours with 200. mu.L of RPMI-1640 liquid medium and 100. mu.L of metazoan suspension (1mg/mL) per well, and the blank was filled with 200. mu.L of RPMI-1640 liquid medium.
b. In the maturation stage: the 96-well plate was washed 3 times with PBS and 200. mu.L of RPMI-1640 liquid medium was added to each well, and the culture was continued for 24 hours. After completion of the incubation, the cells were washed 3 times with PBS. 100 μ L of metazoan suspension (1mg/mL) was added to each well and incubated at 37 ℃ for 24h, with 200 μ L of RPMI-1640 liquid medium added as a blank.
The treated 96-well plate was washed 3 times with PBS after discarding the supernatant, 90. mu.L of LXTT (difenoconazole yellow) (concentration: 0.75mg/mL) and 10. mu.L of PMS (N-methylphenazinium methyl sulfate) (concentration: 0.32mg/mL) were added to each well, incubated for 3 hours in the dark, and the absorbance at 492nm was measured with a microplate reader, the results are shown in FIGS. 6-7.
As can be seen from FIGS. 6-7, the postbiotic suspension has inhibitory effects on the biofilm activity of Candida albicans, both in the initial colonization phase and in the maturation phase. Wherein, the Lactobacillus plantarum L-137 and the HA-199 have good inhibition effect on the activity of the biomembrane of Candida albicans in the initial colonization period and the maturation period. Lactobacillus crispatus KT-11 also showed good inhibitory effect during the initial colonization period.
In conclusion, the research of the applicant finds that the metazoan can effectively inhibit the growth capacity and activity of the harmful bacteria biofilm, and removes the protection of the biofilm on the harmful bacteria, thereby opening a rapid channel for the bacteriophage to infect the harmful bacteria. After the harmful bacteria are eliminated, the beneficial bacteria restore the occupation of focus epithelial cells and realize rapid colonization and proliferation under the action of metazoan, thereby achieving the balance of microecological flora. In addition, according to further research of the applicant, after the probiotics are compounded, the metabolite of the probiotics can further inhibit the formation of a biological film. Therefore, the speed of infecting the harmful bacteria by the phage is faster and the effect is better.
The present invention has been disclosed in terms of the preferred embodiment, but is not intended to be limited to the embodiment, and all technical solutions obtained by substituting or converting equivalents thereof fall within the scope of the present invention.
Claims (10)
1. A microorganism combined preparation compounded by metazoan and bacteriophage is characterized in that: including metazoan and phage; the metazoan comprises inactivated probiotics; the bacteriophage has substantial lytic capacity to pathogenic bacteria, and the bacteriophage is a single-strain bacteriophage or a mixture of multiple-strain bacteriophages.
2. The metazoan and phage-recompounded microbial combined preparation of claim 1, characterized in that: the phage is Escherichia phage, Salmonella phage, Edwardsiella phage, Citrobacter phage, Shigella phage, Klebsiella phage, Serratia phage, Proteus phage, Pseudomonas phage, Klebsiella phage, Comamonas phage, Brevundimonas phage, Acinetobacter phage, Flavobacterium phage, Weeksella phage, aureomonas phage, Xanthomonas phage, Vibrio phage, Aeromonas phage, Staphylococcus phage, viridogrisella phage, beta hemolytic streptococcus phage, pharyngeal streptococci phage, pneumococcus phage, Listeria phage, Campylobacter phage, Salmonella phage, Edwardsiella phage, Salmonella phage, Bacillus phage, Klebsiella phage, Comamonas phage, Salmonella phage, and phage, and phage, one or more of Malassezia phage, Propionibacterium phage, Arthrobacter phage, gonococcus phage, Streptococcus anaerobically digested phage, and Gardnerella phage;
or/and
the metazoan is one or more of Lactobacillus, Bifidobacterium, Streptococcus, lactococcus, Leuconostoc, Propionibacterium, Pediococcus, Staphylococcus, Bacillus, and Kluyveromyces; preferably, the postnatal element is one or a combination of more of lactobacillus casei, lactobacillus crispatus, lactobacillus delbrueckii, lactobacillus fermentum, lactobacillus gasseri, lactobacillus helveticus, lactobacillus johnsonii, lactobacillus paracasei, lactobacillus plantarum, lactobacillus reuteri, lactobacillus rhamnosus, lactobacillus salivarius, lactobacillus sake, lactobacillus curvatus, lactobacillus gasseri, streptococcus thermophilus, lactococcus lactis subsp lactis, lactococcus lactis cremoris, lactococcus lactis diacetylactis, leuconostoc mesenteroides, propionibacterium freudenreichii, propionibacterium, pediococcus acidilactici, pediococcus pentosaceus, staphylococcus xylosus, staphylococcus carnosus, bacillus coagulans and bacillus subtilis; more preferably, the metazoan is one or a combination of more than two of lactobacillus helveticus, lactobacillus casei, lactobacillus gasseri, lactobacillus paracasei, lactobacillus plantarum, lactobacillus rhamnosus, lactobacillus crispatus, lactobacillus salivarius, lactobacillus acidophilus, lactobacillus brevis, lactobacillus bulgaricus, lactobacillus fermentum, lactobacillus reuteri, bifidobacterium lactis, bifidobacterium breve, bifidobacterium bifidum, bifidobacterium infantis, bifidobacterium longum, streptococcus thermophilus, pediococcus pentosaceus and bacillus coagulans.
3. The metazoan and phage-recompounded microbial combined preparation of claim 2, characterized in that: the bacteriophage is Escherichia coli bacteriophage, Enterobacter sakazakii bacteriophage, Escherichia coli bacteriophage, Klebsiella pneumoniae bacteriophage, Salmonella bacteriophage, heterotypic Citrobacter, Shigella bacteriophage, Pseudomonas aeruginosa bacteriophage, Acinetobacter hemolyticus bacteriophage, Flavobacterium meningitidis bacteriophage, animal ulcer Weissex bacteriophage, P.flavus bacteriophage, Vibrio cholerae bacteriophage, one or more of vibrio parahaemolyticus phage, vibrio alginolyticus phage, vibrio vulnificus phage, staphylococcus aureus phage, streptococcus pyogenes phage, streptococcus angiitis phage, streptococcus pneumoniae, listeria phage, campylobacter phage, malassezia symptomatica phage, propionibacterium acnes phage, campylobacter bacteriophages, gonococcal phage, and gardnerella bacteriophages.
4. The metazoan and phage-recompounded microbial combined preparation of claim 1, characterized in that: the composition further comprises probiotics or/and prebiotics.
5. The metazoan and phage-recompounded microbial combined preparation of claim 4, characterized in that: the probiotic bacteria is one or more of Lactobacillus, Bifidobacterium, Streptococcus, lactococcus, Leuconostoc, Propionibacterium, Pediococcus, Staphylococcus, Bacillus, and Kluyveromyces;
preferably, the probiotics are one or more of lactobacillus casei, lactobacillus crispatus, lactobacillus delbrueckii, lactobacillus fermentum, lactobacillus gasseri, lactobacillus helveticus, lactobacillus johnsonii, lactobacillus paracasei, lactobacillus plantarum, lactobacillus reuteri, lactobacillus rhamnosus, lactobacillus salivarius, lactobacillus sake, lactobacillus curvatus, lactobacillus gasseri, streptococcus thermophilus, lactococcus lactis subsp lactis, lactococcus lactis cremoris, lactococcus lactis diacetyl subsp lactis, leuconostoc mesenteroides, propionibacterium freudenreichigera subsp, propionibacterium, pediococcus acidilactici, pediococcus pentosaceus, staphylococcus parvum, staphylococcus xylosus, staphylococcus carnosus, bacillus coagulans and bacillus subtilis;
more preferably, the metazoan is one or a combination of more than two of lactobacillus helveticus, lactobacillus casei, lactobacillus gasseri, lactobacillus paracasei, lactobacillus plantarum, lactobacillus rhamnosus, lactobacillus crispatus, lactobacillus salivarius, lactobacillus acidophilus, lactobacillus brevis, lactobacillus bulgaricus, lactobacillus fermentum, lactobacillus reuteri, bifidobacterium lactis, bifidobacterium breve, bifidobacterium bifidum, bifidobacterium infantis, bifidobacterium longum, streptococcus thermophilus, pediococcus pentosaceus and bacillus coagulans;
or/and
the prebiotics is one or more of short chain fatty acid, lactoferrin, fructo-oligosaccharide, xylo-oligosaccharide, lacto-oligosaccharide, inulin, lactulose, artichoke, herba Cichorii, herba Avenae Fatuae, fructus Hordei vulgaris, Leguminosae, Bulbus Allii, herba Canarii albi, beans or herbs.
6. A product characterized by: comprising a microbial combination according to any one of claims 1 to 5 and an adjuvant.
7. The product of claim 6, wherein: the product is in the form of powder, suppository, solid beverage, hard capsule, soft beverage, multi-layer hard capsule, dissolved bean, lyophilized powder, milk bean, chocolate, soft sweets with filling, chocolate with filling, tea beverage, cold-extracted coffee, wet towel, ointment, cream, liquid, emulsion, gel, or solid.
8. Use of the product according to claim 6 and the microbial composition according to any one of claims 1 to 5 for the preparation of a medicament, food or animal food, nutraceutical or supplement, daily chemical, cosmetic, cleaning, disinfecting product for the treatment of bacterial infectious diseases.
9. Use according to claim 8, characterized in that: the bacterial infectious diseases include gastrointestinal system diseases, urinary system diseases, reproductive system diseases, respiratory diseases and skin diseases caused by bacterial infection in human or animals.
10. A method for preparing a product, which is characterized by comprising the following steps: mixing the metagen suspension with phage liquid, adding or not adding auxiliary materials, molding and packaging to obtain a finished product; wherein, the mixing of the metazoan suspension and the phage liquid and the addition of the auxiliary materials are sequentially carried out, or the mixing and the addition of the auxiliary materials are simultaneously carried out;
preferably, the auxiliary materials are pretreated, so that the auxiliary materials meet the requirements of the preparation formulation and then are mixed with the mixture of the metazoan suspension and the phage liquid to obtain the preparation formulation and then are packaged into a finished product; or mixing the auxiliary materials with the mixture of the metazoan suspension and the phage liquid, processing to obtain a product meeting the requirement of the dosage form, and then forming and packaging the product.
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