CN115429821A - Compound probiotic composition for preventing dental caries and regulating intestinal flora and immunity and preparation method and application thereof - Google Patents
Compound probiotic composition for preventing dental caries and regulating intestinal flora and immunity and preparation method and application thereof Download PDFInfo
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- CN115429821A CN115429821A CN202211388501.2A CN202211388501A CN115429821A CN 115429821 A CN115429821 A CN 115429821A CN 202211388501 A CN202211388501 A CN 202211388501A CN 115429821 A CN115429821 A CN 115429821A
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Abstract
The invention relates to the field of probiotics, and provides a post-probiotic composition of composite probiotics for preventing dental caries and regulating intestinal flora and immunity, a preparation method and application thereof, wherein the post-probiotic composition comprises inactivated thalli of the composite probiotics and metabolites of the composite probiotics; the composite probiotics comprise lactobacillus casei Zhang, bifidobacterium animalis subsp lactis V9 and lactobacillus plantarum P-8; the post-biotic composition of the compound probiotics can balance the intestinal flora, protect the intestinal epithelial barrier, improve the immunity and prevent or treat dental caries.
Description
Technical Field
The invention relates to the field of probiotics, in particular to a composite probiotic composition for preventing decayed teeth and regulating intestinal flora and immunity, and a preparation method and application thereof.
Background
Metazoans (Postbiotics) are a new means of intervention in the intestinal ecosystem that has emerged in recent years. In 2013, tsilingiiri K et al proposed that metazoan refers to a factor that is released by the metabolic activity of probiotics and that can have a beneficial effect on the host in a direct or indirect manner. Thereafter, the concept of metazoan was redefined three times after each other by different researchers. Until 2021, the international association of probiotics and prebiotics (ISAPP) issued a consensus statement of metazoan, the first time the official notion of metazoan was put forward as "preparation of inanimate microorganisms and/or their components beneficial to the health of the host". Due to the characteristics of 'no life' of the metazoan and the like, the metazoan has great application prospect. At present, metazoans have been considered by the industry as fourth generation microecologics following probiotics, prebiotics and synbiotic preparations.
The mechanisms of action of metazoans mainly include regulation of resident flora, enhancement of epithelial barrier function, regulation of local and systemic immunity, regulation of systemic metabolism and the emission of systemic signals through the nervous system. Although the effects of metazoans on microbiome may be temporary, they may still have important roles. Currently, the hotspot study of metazoan is mainly focused on five aspects: first, control of biofilm formation, regulation of gene expression, reduction of inflammatory cytokines, and modulation of immunity based on probiotics (e.g., lactobacilli and bifidobacteria); second, exopolysaccharides, as components of metagenes, can reduce inflammation by yet undefined signaling mechanisms to promote barrier function; thirdly, the action of the inactivated lactobacillus on treating obesity, wherein lactobacillus casei is more studied; fourthly, metazoan improves apoptosis, regulates the balance of intestinal flora, promotes interleukin production and has an effect on inflammatory bowel disease; fifthly, the health effect of metazoan on intestinal flora and allergic dermatitis is researched.
Disclosure of Invention
Therefore, the technical problem to be solved by the invention is a composite probiotic composition for preventing dental caries and regulating intestinal flora and immunity, and a preparation method and application thereof.
Therefore, the invention provides the following technical scheme:
a post-biotic composition of composite probiotics comprises inactivated thallus of composite probiotics and metabolite of composite probiotics;
the composite probiotics comprise lactobacillus casei Zhang: (A)Lactobacillus caseiZhang), bifidobacterium animalis subspecies lactis V9 (Zhang)Bifidobacteriumanimalissubsp.lactisV9) and Lactobacillus plantarum P-8 (C)Lactobacillus plantarum P-8）；
Optionally, the lactobacillus casei Zhang, the bifidobacterium animalis subspecies lactis V9 and the lactobacillus plantarum P-8 are compounded according to the ratio of the number of colony forming units of (2-3) to (2-3);
optionally, the lactobacillus casei Zhang, bifidobacterium animalis subsp lactis V9 and lactobacillus plantarum P-8 are compounded according to a ratio of the number of colony forming units of 1;
optionally, before inactivating the composite probiotics, the total viable count of the composite probiotics is more than or equal to 3.0 multiplied by 10 10 cfu/g。
Optionally, the metabolite comprises an organic acid;
optionally, the organic acid comprises at least one of lactic acid, citric acid, oxalic acid, malic acid, phenyllactic acid, succinic acid, 4-hydroxyphenyllactic acid, salicylic acid, vanillic acid, benzoic acid, phenylalanine, and short chain fatty acids;
optionally, the short chain fatty acid comprises at least one of acetic acid, propionic acid, butyric acid and valeric acid.
Optionally, the metabolite further comprises at least one of daidzin, soy isoflavones, gamma-aminobutyric acid, D-psicose, 3-indoleacrylic acid, daidzein, glycerol butyrate, (E) -9-octadecenamide, preaustinid A, an active short peptide molecule, trihydroxyflavone, irone, genistein, lauryl diethanolamine, and malonyl genistin.
Alternatively, an active short peptide molecule such as Glu-phe-trp (glutamic acid-phenylalanine-tryptophan).
The preparation method of the post-biotic composition of the compound probiotics comprises the steps of fermenting and inactivating the compound probiotics to obtain a product;
optionally, inoculating the composite probiotics into the feed liquid, adding lactase, fermenting at constant temperature of 30-38 ℃ until the pH is 4.5-4.6, stopping fermentation, adding auxiliary materials, preheating, homogenizing, and then inactivating;
optionally, the addition amount of lactase is 0.1 mL/kg-1.0 mL/kg of feed liquid;
optionally, the auxiliary material comprises maltodextrin, and the addition amount of the maltodextrin is 5-25g/kg of fermentation liquid;
optionally, preheating to 55-60 ℃, and homogenizing under the primary pressure of 18-20.0 Mpa and the secondary pressure of 4.0-5.0 Mpa;
optionally, inactivating at 75-95 deg.C for 15-30min;
optionally, the preparation method of the feed liquid comprises: weighing fermentation raw materials, dissolving materials, homogenizing, sterilizing and/or cooling;
optionally, the fermentation raw material comprises an organic nitrogen source, an organic carbon source and a pH regulator;
optionally, the organic nitrogen source comprises whole soybean powder, skimmed milk powder, whey protein powder or soybean protein isolate powder;
optionally, the organic carbon source comprises skim milk powder, whole soybean powder, skim milk powder or whey protein powder;
optionally, the pH adjusting agent comprises sodium citrate;
optionally, the fermentation raw material comprises 1.5-7 weight parts of whole soybean powder, 11-18 weight parts of skimmed milk powder, 0.05-0.5 weight part of sodium citrate and 74.5-87.45 weight parts of water;
optionally, the temperature of the material is 55-60 ℃, and the time is 10-30min;
optionally, in the preparation method of the feed liquid, the homogenization conditions are as follows: 55-60 ℃, the primary pressure is 18-20.0 Mpa, and the secondary pressure is 4.0-5.0 Mpa;
optionally, in the preparation method of the feed liquid, the sterilization conditions are as follows: 90-95 ℃ for 15-45min.
A preparation, which takes the compound post-probiotic composition or the compound post-probiotic composition prepared by the preparation method of the compound post-probiotic composition as an active ingredient;
optionally, the composition also comprises a formulation allowable excipient or carrier;
optionally, the form of the preparation comprises a liquid preparation and a solid preparation;
optionally, the preparation form comprises injection, tablet, capsule, powder, granule or paste.
The compound probiotic metazoan composition, the compound probiotic metazoan composition prepared by the preparation method of the compound probiotic metazoan composition or the preparation have the application in any one of the following items:
1) Regulating host intestinal flora;
2) Regulating the immunity of a host;
3) Inhibiting oral potential pathogenic bacteria;
4) Preventing, alleviating, adjunctively treating or treating dental caries and/or periodontal disease;
5) Modulating oral microbial diversity and/or oral flora architecture;
6) The application in preparing products for regulating host intestinal flora;
7) The application in preparing products for regulating host immunity;
8) The application in preparing products for inhibiting potential pathogenic bacteria in the oral cavity;
9) The application in preparing products for preventing, relieving, assisting in treating or treating dental caries and/or periodontal disease;
10 Use for the preparation of a product for modulating the diversity and/or structure of oral microorganisms;
11 Application in preparing products for preventing, relieving, adjunctively treating or treating colitis;
12 Use in the manufacture of a product for increasing body weight.
Optionally, the use of the preparation of a product for modulating the level of IL-1 β, TNF- α and/or IL-6 in a host; or
Use in preparing products for inhibiting Streptococcus (Streptococcus), gemelalla (Gemelalla) and Porphyromonas (Porphyromonas) in oral cavity; or
Use in the manufacture of a product for ameliorating damage to host colon tissue; or
Use for the manufacture of a product for protecting the epithelial barrier of the intestinal tract of a host.
Optionally, the product is a food, health product or medicine;
optionally, the product is a functional bakery, dairy, oral care or functional health product.
The technical scheme of the invention has the following advantages:
the post-biotic composition of the compound probiotics provided by the invention comprises inactivated thalli of the compound probiotics and metabolites of the compound probiotics;
the composite probiotics comprise lactobacillus casei Zhang: (A. Casei)Lactobacillus caseiZhang), bifidobacterium animalis subsp lactis V9 (Zhang)Bifidobacteriumanimalissubsp.lactisV9) and Lactobacillus plantarum P-8 (C)Lactobacillus plantarumP-8); the inactivated thallus of the composite probiotics has good capability of inhibiting potential oral pathogenic bacteria, can play a role in preventing, relieving, assisting in treating or treating dental caries, and effectively regulates intestinal flora, protects intestinal epithelial barrier and regulates immunity. Besides the probiotic bacteria, the metabolite of the composite probiotic bacteria is rich in bioactive substances such as organic acid, short-chain fatty acid and the like, and the bioactive substances can enter the intestinal tract of a host to be utilized to further regulate the metabolism of the organism, thereby playing an important role in maintaining the intestinal health, regulating the immune response and inhibiting the potential pathogenic bacteria in the oral cavity.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, and it is obvious that the drawings in the following description are some embodiments of the present invention, and other drawings can be obtained by those skilled in the art without creative efforts.
FIG. 1 is a design drawing of an experiment in the study of the postnatal regulation of dental caries-associated oral flora in Experimental example 1;
FIG. 2 is a graph showing the analysis of the results of the diversity of oral microorganisms associated with caries in metazoan regulation in Experimental example 1; p <0.05 indicates significant difference;
FIG. 3 is a profile of the taxonomic distribution of metazoan regulation of the major oral microbiota associated with dental caries in Experimental example 1; in the figure, a is a genus horizontal distribution, and b is a species horizontal distribution; taxa with an average relative abundance below 1% in the graph were classified as "other";
FIG. 4 is a principal coordinate analysis (PCoA; bray-Curtis distance) of the oral microbiota of different groups on days 0 and 14 in Experimental example 1;
FIG. 5 is a graph of Adonis test results in Experimental example 1 to assess the difference in beta diversity between the specific groups at day 0 and day 14; p <0.05 indicates a significant difference;
FIG. 6 is a graph showing the difference between the Bray-Curtis distances between the metazoan combination-filling treatment group and the healthy group and between the caries filling treatment group and the healthy group in Experimental example 1; p <0.05 indicates significant difference;
FIG. 7 is a graph showing the analysis of important cariogenic bacteria in the microenvironment of the mouth associated with post-natal regulation and caries in Experimental example 1; p <0.05 indicates a significant difference;
FIG. 8 is a graph showing the analysis of the relative abundance of important cariogenic bacteria in the microenvironment of the oral cavity associated with caries by metazoan regulation in Experimental example 1; p <0.05 indicates significant difference;
FIG. 9 is a graph showing the analysis of the correlation results between the metazoan combination therapy group and important cariogenic bacteria in the microenvironment of the mouth associated with dental caries in Experimental example 1;
FIG. 10 is a graph showing the analysis of the correlation results between important cariogenic bacteria in the microenvironment of the mouth associated with caries in the caries-filling treatment group in Experimental example 1;
FIG. 11 is a graph showing the analysis of the results of post-natal conditioning and caries filling treatment in Experimental example 1; in the figure, a is the relative abundance of aerobic bacteria, anaerobic bacteria and facultative anaerobic bacteria in each group of oral microbiota; b is a graph of the relative abundance of bacteria containing mobile elements, gram negative bacteria, gram positive bacteria in each group of oral microbiota; c, the relative abundance of biomembrane forming bacteria, potential pathogenic bacteria and antioxidant stress bacteria in each group of oral microbiota; p <0.05 indicates significant difference;
FIG. 12-1 is a graph of the prediction of the functional characteristics of the oral microbiota of subjects by the unobserved reconstitution of the community phylogenetic survey 2 (PICRUSt 2) in Experimental example 1, and comparing the data of each group at day 0 and day 14 by the Wilcoxon test; wherein, a represents an abundant pathway with a significant difference between C0 and D0, and B represents an abundant pathway with a significant difference between a14 and B14; p <0.05 indicates significant difference;
FIG. 12-2 is a graph of the prediction of the functional characteristics of the oral microbiota of subjects by the unobserved state reconstruction community phylogenetic survey 2 (PICRUSt 2) in Experimental example 1 and comparison of the data of each group on day 0 by the Wilcoxon test; wherein, it represents an abundant pathway with significant differences between A0, B0 and D0; p <0.05 indicates significant difference;
FIGS. 12-3 are graphs of the functional characteristics of the oral microbiota of subjects predicted by the unobserved reconstitution community phylogenetic survey 2 (PICRUSt 2) in Experimental example 1, and comparing the data of each group at day 0 and 14 by Wilcoxon test; wherein, a is Kyoto Encyclopedia of Genes and Genomes (KEGG) orthology (KO), B is predicted enzyme between A14 and B14; p <0.05 indicates significant difference;
FIG. 13 shows the HE staining result of rat colon 21 days after the prebiotics intake of the probiotic compound in the experimental example; control is normal group; DSS is a model group; DSS +0.5mg metazoan is a low-dose metazoan group; DSS +1mg metazoan is a medium-dose metazoan group; DSS +2mg metazoan is a high dose metazoan group;
FIG. 14 shows the effect of different treatment groups on the immune factor IL-1. Beta. In IBD rats 21 days after ingestion of complex probiotics in the experimental examples; the control group is a normal group; dextran sulfate sodium salt (DSS) as a model group; DSS +0.5mg metazoan is a low dose metazoan group; DSS +1mg metazoan is a medium-dose metazoan group; DSS +2mg metazoan is a high dose metazoan group;
FIG. 15 shows the effect of different treatment groups on TNF- α, an immune factor in IBD rats, 21 days after ingestion of probiotic complexes in the experimental examples; the control group is a normal group; DSS is a model group; DSS +0.5mg metazoan is a low-dose metazoan group; DSS +1mg postbiotic is a medium-dose postbiotic group; DSS +2mg metazoan is a high-dose metazoan group;
FIG. 16 shows the effect of different treatment groups on the immune factor IL-6 of IBD rats 21 days after ingestion of complex probiotics in the experimental examples; the control group is a normal group; DSS is a model group; DSS +0.5mg metazoan is a low dose metazoan group; DSS +1mg postbiotic is a medium-dose postbiotic group; DSS +2mg metazoan is a high dose metazoan group;
FIG. 17 is a graph showing the change in body weight of rats after 21 days of prebiotics after intake of probiotic compounds in the experimental examples; the control group is a normal group; DSS is a model group; DSS +0.5mg metazoan is a low-dose metazoan group; DSS +1mg postbiotic is a medium-dose postbiotic group; DSS +2mg metazoan is a high-dose metazoan group;
FIG. 18 is a graph of histological damage scores of rats 21 days after ingestion of complex probiotics in the experimental examples; the control group is a normal group; DSS is a model group; DSS +0.5mg metazoan is a low dose metazoan group; DSS +1mg metazoan is a medium-dose metazoan group; DSS +2mg metazoan is a high dose metazoan group;
in the above-mentioned figures, A _0 (or A0) represents the group A sample collected on day 0, and A _14 (or A14) represents the group A sample collected on day 14; b _0 (or B0) represents group B samples taken on day 0, B _14 (or B14) represents group B samples taken on day 14; c _0 (or C0) represents the samples collected on day 0 of group C, and C _14 (or C14) represents the samples collected on day 14 of group C; d represents the D group of samples taken on day 0.
Detailed Description
The following examples are provided to better understand the present invention, not to limit the best mode, and not to limit the content and protection scope of the present invention, and any product that is the same or similar to the present invention and is obtained by combining the present invention with other features of the prior art and the present invention falls within the protection scope of the present invention.
The examples do not show the specific experimental steps or conditions, and can be performed according to the conventional experimental steps described in the literature in the field. The reagents or instruments used are not indicated by manufacturers, and are all conventional reagent products which can be obtained commercially.
The following examples:
lactobacillus casei Zhang (Lactobacillus caseiZhang), the preservation number of which is CGMCC No.5469;
bifidobacterium animalis subsp lactis V9 (Bifidobacteriumanimalissubsp.lactisV9) with the preservation number of CGMCC No.5470;
lactobacillus plantarum P-8 (Lactobacillus plantarumP-8), the preservation number is CGMCC No.6312;
the above mentioned Lactobacillus casei Zhang, bifidobacterium animalis subsp lactis V9 and Lactobacillus plantarum P-8 are disclosed in patent document CN 114432346A.
Example 1 post-probiotic composition with Complex Probiotics
The embodiment provides a post-probiotic composition comprising inactivated thallus of composite probiotic and metabolite of composite probiotic;
the composite probiotics comprise lactobacillus casei Zhang: (A)Lactobacillus caseiZhang), bifidobacterium animalis subsp lactis V9 (Zhang)Bifidobacteriumanimalissubsp.lactisV9) and Lactobacillus plantarum P-8 (C)Lactobacillus plantarum P-8）。
The preparation method of the post-biotic composition of the composite probiotics comprises the following steps:
1) Weighing: mixing 4wt% of full-fat soybean powder, 14.5wt% of skim milk powder, 2.5wt% of sodium citrate and the balance of water according to the proportion requirement;
2) Material melting: melting at 58 deg.C for 15min to obtain feed liquid;
3) Homogenizing: 58 ℃, the primary pressure is 19 Mpa, and the secondary pressure is 5.0 Mpa;
4) And (3) sterilization: sterilizing the homogenized material liquid at 93 deg.C for 30min;
5) And (3) cooling: cooling the sterilized feed liquid to 35 ℃;
6) Adding strains and lactase: adding composite probiotics into feed liquid: lactobacillus casei Zhang, bifidobacterium animalis subsp lactis V9 and lactobacillus plantarum P-8 are added according to the ratio of the number of colony forming units of 1 6 CFU/g (feed liquid), and adding 0.5mL/kg (feed liquid) of lactase (with the enzyme activity of 5000U/g) according to production requirements;
7) Constant-temperature fermentation: fermenting at 35 deg.C until pH is 4.5-4.6 and 18-19 h (total viable count of composite probiotic is not less than 3.0 × 10) 10 cfu/g)；
8) Inactivation: mixing with maltodextrin 18g/kg (fermentation liquid) according to production requirement, preheating to 58 deg.C, homogenizing under first pressure of 19 MPa and second pressure of 5.0 MPa, sterilizing and inactivating (inactivation condition 85 deg.C, 15 min);
9) Spray drying: and (3) spray-drying the inactivated bacterial suspension to obtain postbiotic powder (namely the postbiotic powder for compound probiotics).
And detecting the metabolic substances in the post-biotic powder of the composite probiotics.
Mixing the post-biotic sample with water 1:4 (mass ratio), sucking 0.1mL into a 1.5mL tube, adding 0.4mL of the extract (methanol: acetonitrile =1:1 (V/V)), fully shaking, and placing into an ultrasonic cold water bath for 10min; placing a 1.5mL tube after water bath in a low-temperature refrigerator at-40 ℃ for incubation for 1h; taking out the sample, and centrifuging for 20min at 12000 Xg; and sucking the supernatant, passing through a membrane, transferring the supernatant into an upper sample bottle, sucking the supernatant into a quality control sample in equal amount for all samples, and detecting the quality control sample on a machine along with the test sample. The target compound was chromatographed on a Waters ACQUITY UPLC BEH Amide (2.1 mm X100 mm, 1.7 μm) liquid chromatography column using Vanqish (Thermo Fisher Scientific) ultra performance liquid chromatography. Temperature of the sample pan: 4 ℃, injection volume: 2 μ L. Converting the original data into an mzXML format by a Proteo Wizard, completing peak detection, extraction, alignment and integration processing by using an R language and an internal program based on XCMS, obtaining a final metabolite name, wherein the detection result is that the final metabolite contains organic acid, and the organic acid comprises at least one of lactic acid, citric acid, oxalic acid, malic acid, phenyllactic acid, succinic acid, 4-hydroxyphenyllactic acid, salicylic acid, vanillic acid, benzoic acid, phenylalanine and short-chain fatty acid; the short chain fatty acid comprises at least one of acetic acid, propionic acid, butyric acid and valeric acid, and further comprises at least one of soyasaponin, soy isoflavone, gamma-aminobutyric acid, D-psicose, 3-indoleacrylic acid, daidzein, glycerol butyrate, (E) -9-octadecenamide, preaustinoid A, active short peptide molecules, trihydroxyflavone, irone, genistein, lauryl diethanolamine and malonyl genistin.
Example 2 post-probiotic composition with Complex Probiotics
The embodiment provides a post-probiotic composition comprising inactivated thallus of composite probiotic and metabolite of composite probiotic;
the composite probiotics comprise lactobacillus casei Zhang: (A)Lactobacillus caseiZhang), bifidobacterium animalis subsp lactis V9 (Zhang)Bifidobacteriumanimalissubsp.lactisV9) and Lactobacillus plantarum P-8 (C)Lactobacillus plantarum P-8）。
The preparation method of the post-biotic composition of the composite probiotics comprises the following steps:
1) Weighing: mixing 1.5wt% of full-fat soybean powder, 11wt% of skim milk powder, 0.05wt% of sodium citrate and the balance of water according to the proportion requirement;
2) Material melting: melting at 55 deg.C for 30min to obtain feed liquid;
3) Homogenizing: 55 deg.C, primary pressure 18 Mpa, and secondary pressure 4.0 Mpa;
4) And (3) sterilization: sterilizing the homogenized material liquid at 90 deg.C for 45 min;
5) And (3) cooling: cooling the sterilized feed liquid to 35 ℃;
6) Adding strains and lactase: adding composite probiotics into feed liquid: the ratio of the number of colony forming units of lactobacillus casei Zhang, bifidobacterium animalis subspecies lactis V9 and lactobacillus plantarum P-8 is 2:32, the inoculation amount is 6 multiplied by 10 6 CFU/g (feed liquid), and adding 0.1mL/kg (feed liquid) of lactase (with the enzyme activity of 5000U/g) according to production requirements;
7) Constant-temperature fermentation: fermenting at 35 deg.C until pH is 4.5-4.6 and 18-19 h (total viable count of composite probiotic is not less than 3.0 × 10) 10 cfu/g)；
8) Inactivation: mixing maltodextrin 5g/kg (fermentation liquid) according to production requirements, preheating to 55 deg.C, homogenizing under first-stage pressure of 18 MPa and second-stage pressure of 4.0 MPa, sterilizing and inactivating (inactivation condition of 75 deg.C, 30 min);
9) Spray drying: and (3) spray-drying the inactivated bacterial suspension to obtain postbiotic powder (namely the postbiotic powder for compound probiotics).
And detecting the metabolic substances in the post-biotic powder of the composite probiotics.
Example 3 post-probiotic composition with Complex Probiotics
The embodiment provides a post-biotic composition of composite probiotics, which comprises inactivated thallus of the composite probiotics and metabolites of the composite probiotics;
the composite probiotics comprise lactobacillus casei Zhang (Zhang)Lactobacillus caseiZhang), bifidobacterium animalis subsp lactis V9 (Zhang)Bifidobacteriumanimalissubsp.lactisV9) and Lactobacillus plantarum P-8 (C)Lactobacillus plantarum P-8）。
The preparation method of the post-biotic composition of the composite probiotics comprises the following steps:
1) Weighing: mixing 7wt% of full-fat soybean powder, 18wt% of skim milk powder, 0.5wt% of sodium citrate and the balance of water according to the proportion requirement;
2) Material melting: melting at 60 deg.C for 10min to obtain feed liquid;
3) Homogenizing: 60 ℃, primary pressure of 20.0 MPa and secondary pressure of 5.0 MPa;
4) And (3) sterilization: sterilizing the homogenized material liquid at 95 deg.C for 15 min;
5) And (3) cooling: cooling the sterilized feed liquid to 35 ℃;
6) Adding strains and lactase: adding composite probiotics into feed liquid: lactobacillus casei Zhang, bifidobacterium animalis subsp lactis V9 and Lactobacillus plantarum P-8 by weight2.5 according to a colony forming unit number ratio of 2.5 6 CFU/g (feed liquid), and adding 1.0mL/kg (feed liquid) of lactase (with the enzyme activity of 5000U/g) according to production requirements;
7) Constant-temperature fermentation: fermenting at 35 deg.C until pH is 4.5-4.6 and 18-19 h (total viable count of composite probiotic is not less than 3.0 × 10) 10 cfu/g)；
8) Inactivation: mixing with maltodextrin 25g/kg (fermentation liquid) according to production requirement, preheating to 60 deg.C, homogenizing under primary pressure of 20.0 Mpa and secondary pressure of 5.0 Mpa, sterilizing and inactivating (inactivation condition of 95 deg.C, 15 min);
9) And (3) spray drying: and (3) spray-drying the inactivated bacterial suspension to obtain postbiotic powder (namely the postbiotic powder for compound probiotics).
And detecting the metabolic substances in the post-biotic powder of the composite probiotics.
Experimental example 1 post-biotrophic regulation dental caries-associated oral flora study
1 method of experiment
1.1 Experimental formulation: example 1 the resulting composite probiotic post-biotic powder was prepared.
1.2 test grouping
Experimental group design figure 1 shows that 98 volunteers (18-30 years old), caries-filling treatment group (40 persons, 2 persons who exited during the course of the experiment, group (B) in figure 1), metazoan combination-filling treatment group (41 persons, 3 persons who exited during the course of the experiment, group (a) in figure 1), caries group (8 persons, group (D) in figure 1) and healthy group (9 persons, group (C) in figure 1) were recruited. The postbiotic combined filling treatment group is characterized in that in the filling treatment process, the composite probiotic postbiotic powder is taken twice a day (after Chinese meal and dinner), 0.6g each time, and the composite probiotic postbiotic powder is continuously taken for 14 days. Groups of saliva samples were collected on days 0 and 14 post caries filling treatment, and 16S rRNA full length sequencing was used for follow-up analysis of the flora (Qiime 2).
1.3 results of the experiment
1.3.1 analysis of results on oral microbial diversity
In Shannon index analysis results and simpson index analysis results, the intra-sample diversity (Alpha diversity) of oral flora in carious group was significantly higher than that in healthy group (P =0.001 and P = 0.036), the filling treatment group significantly reduced the Alpha diversity (P < 0.05) of oral flora in patients, and the post-prebiotic combination filling treatment group significantly reduced the Alpha diversity in the complex probiotic post-prebiotic powder adjuvant therapy compared to filling treatment alone after 14 days of treatment, as shown in fig. 2. The metazoan intervention is more effective in regulating oral microbial diversity.
1.3.2 Analysis of results of changes in oral flora structure
As shown in fig. 3-6, on day 0 after treatment, the caries filling treatment group and the metazoan combined filling treatment group have no significant difference from the oral flora structure of the healthy group, but have significant difference from the caries group (P < 0.05), which indicates that the conversion from non-caries to caries may cause significant change of the oral flora structure; compared with the day 0, the oral cavity flora structure is obviously changed after 14 days of filling treatment (caries filling treatment group and anabiosis combined filling treatment group), while the flora structure of healthy volunteers is relatively stable; after 14 days of treatment, the Bray-Curtis distance of the metazoan combined filling treatment group is still obviously different from that of the healthy group, but is closer than that of the filling treatment group to the healthy group, which shows that the metazoan combined filling treatment is more beneficial to regulating the restoration of the oral flora structure of the carious patient.
1.3.3 Analysis of important cariogenic results in the microenvironment of the oral cavity
The relative abundance of Streptococcus (Streptococcus), gemfibrococcus (Gemella) and Porphyromonas (Porphyromonas) in the oral cavity of patients in the cariogenic group was significantly higher than that of the healthy group (P < 0.05), which may be important cariogenic bacteria in the microenvironment of the oral cavity, as shown in fig. 7.
The relative abundance of porphyromonas, streptococcus, geminicoccus, etc. in the oral cavity of the patient was significantly decreased after filling treatment compared to the carious group, and the relative abundance of Campylobacter succinogenes (Campylobacter concinnatus) and alisteris microaerophilus (dialistrinvisies) was significantly increased (P < 0.05). After 14 days of metazoan combined filling treatment, the abundance of Pseudomonas (Pseudomonas) was significantly increased and prevotella sargentii (Prevotellashahii) was significantly decreased, as shown in fig. 8.
The correlation between the metazoan combination filling therapy flora was stronger (159 vs 114) compared to the filling therapy group, suggesting that metazoan intervention may stabilize the oral flora of the patient, as shown in fig. 9-10.
1.3.4 Caries filling therapy outcome analysis
The biofilm-forming ability of the oral flora was significantly enhanced in the carious group compared to the healthy group (P = 0.005), and after filling, the biofilm-forming ability of the flora was significantly reduced, but the state of the healthy group was not restored. The pathogenic bacteria in the oral flora of the carious group are remarkably increased (P < 0.05), the relative abundance of potential pathogenic bacteria is not remarkably reduced (P > 0.05) only by filling treatment temporarily, and the abundance of the pathogenic bacteria is remarkably increased again after 14 days of treatment (P < 0.05) without postbiotic intervention; after 14 days of filling treatment, the abundance of the antioxidant stress bacteria is remarkably reduced, and the metazoan combined filling treatment group can keep the abundance of the antioxidant stress bacteria stable. Postnatal combined filling therapy significantly upregulated formaldehyde assimilation, formaldehyde oxidation pathways, and multiple energy-related enzyme abundances (P < 0.05) compared to the filling therapy group. In conclusion, the supplementation of the metazoan can effectively regulate the diversity of oral flora of the patient, promote the abundance of related energy enzymes, obviously inhibit the abundance of potential pathogenic bacteria, improve the oxidation stress resistance of the flora and further enhance the filling treatment effect of the caries. As shown in fig. 11, as well as fig. 12-1, 12-2, and 12-3.
1.4 conclusion
The biological composition after supplementing the composite probiotics can more effectively regulate the diversity of oral microorganisms, is beneficial to regulating the recovery of the oral flora structure of a patient with dental caries, remarkably inhibits the abundance of potential pathogenic bacteria, has the effect of preventing or treating dental caries, and enables the oral flora of the patient to be more stable.
Experimental example 2 clinical study of the Effect of different doses of probiotic postnatal on IBD rats
1 method of experiment
1.1 Experimental formulation: the composite probiotic postbiotic powder (called postbiotic for short) prepared in example 1.
1.2 test grouping
The experiment adopts a rat model of inflammatory enteritis (IBD) induced by dextran sulfate sodium salt (DSS), and the rat model is specifically divided into the following groups: male Wistar rats at 6 weeks of age were randomly divided into normal group (12), model group (12), low dose epigenetic group (12), medium dose epigenetic group (12), high dose epigenetic group (12). Normal group (0-21 d: normal saline, once a day, 2ml per gavage); model group (0-7d: 3% dextran sulfate sodium salt (DSS), once daily, 2ml per gavage, 7-21d: physiological saline, once daily, 2ml per gavage); low dose postbiotic group (0-7d; medium dose postbiotic group (0-7d 3% dss, once daily, 2ml per gavage, 7-21d: once daily, 1mg postbiotic/individual gavage per time); high dose postbiotic group (0-7d.
Rat stool and serum samples were collected at days 0, 7, and 21 (d), respectively, for metabolome and metagenomic assays, respectively, to analyze changes in rat colonic tissue damage levels, immune factor indicator (IL-1. Beta., TNF-. Alpha., IL-6) levels, and body weight.
1.3 results of the experiment
1.3.1 Analysis of colon HE staining results of rats of different treatment groups
After 21 days, colon tissues from each group of rats were collected and HE stained, and compared to the model group (sodium gluconate sulfate (DSS) in fig. 13), the intermediate dose postbiotic group (DSS +1mg postbiotic in fig. 13) and the high dose postbiotic group (DSS +2mg postbiotic in fig. 13), the mucosal layer, intestinal epithelial structure was substantially intact, epithelial cell exfoliation and edema of the lamina propria and submucosa were less, and no significant inflammation was seen, as shown in fig. 13.
1.3.2 Effect of different treatment groups on Inflammatory Bowel Disease (IBD) rat immune factor
Both the middle dose (DSS +1mg postnatal in FIG. 14, FIG. 15, FIG. 16) and high dose (DSS +2mg postnatal in FIG. 14, FIG. 15, FIG. 16) postnatal groups reduced IL-1 β, TNF- α and IL-6 levels in the serum of IBD rats compared to the model group. Whereas low dose metazoans (DSS +0.5mg metazoans in FIG. 16) had no effect on IL-6, as shown in FIGS. 14, 15, and 16.
1.3.3 Effect of different treatment groups on the body weight and histological score of IBD rats
After a low dose, the prebiotics have no effect on improving colon tissue damage and restoring body weight of IBD rats; after neutralizing the high dose, the survivors can improve the colon tissue damage of IBD rats and increase the body weight of the rats, as shown in figure 17 and figure 18.
1.4 conclusion
Through analysis on the change of colon tissue damage level, immune factor index (IL-1 beta, TNF-alpha and IL-6) level and body weight of the IBD rat, the metazoan can regulate intestinal flora and immune factors through a host, so that the inflammatory symptoms of the IBD rat are effectively improved, the damage of colon tissue is improved, and the body weight is increased.
Animal experiments show that the product has obvious treatment efficacy on regulating intestinal flora and immunity and improving colonic tissue injury.
It should be understood that the above examples are only for clarity of illustration and are not intended to limit the embodiments. Other variations and modifications will be apparent to persons skilled in the art in light of the above description. This need not be, nor should it be exhaustive of all embodiments. And obvious variations or modifications therefrom are within the scope of the invention.
Claims (17)
1. The post-biotic composition of the compound probiotics is characterized by comprising inactivated thalli of the compound probiotics and metabolites of the compound probiotics;
the composite probiotics comprise lactobacillus casei Zhang (Zhang)Lactobacillus caseiZhang) Bifidobacterium animalis subsp lactis V9: (A)Bifidobacteriumanimalissubsp.lactisV9) and Lactobacillus plantarum P-8 (C)Lactobacillus plantarum P-8）。
2. The post-probiotic composition according to claim 1, characterized in that,
the lactobacillus casei Zhang, the bifidobacterium animalis subspecies lactis V9 and the lactobacillus plantarum P-8 are compounded according to the ratio of the number of colony forming units of (2-3) to (2-3).
3. The post-probiotic composition of claim 1, characterized in that,
the lactobacillus casei Zhang, the bifidobacterium animalis subsp lactis V9 and the lactobacillus plantarum P-8 are compounded according to the ratio of the number of colony forming units of 1; and/or
Before the composite probiotics are inactivated, the total viable count of the composite probiotics is more than or equal to 3.0 multiplied by 10 10 cfu/g。
4. A composite probiotic prebiotic composition according to any of claims 1-3, characterized in that the metabolite comprises organic acids;
the organic acid comprises at least one of lactic acid, citric acid, oxalic acid, malic acid, phenyllactic acid, succinic acid, 4-hydroxyphenyllactic acid, salicylic acid, vanillic acid, benzoic acid, phenylalanine, and short chain fatty acids.
5. The post-probiotic composition of claim 4, characterized in that,
the short chain fatty acids comprise at least one of acetic acid, propionic acid, butyric acid and valeric acid; and/or
The metabolite further comprises at least one of daidzin, soy isoflavones, gamma-aminobutyric acid, D-psicose, 3-indoleacrylic acid, daidzein, glycerol butyrate, (E) -9-octadecenamide, preaustinol A, an active short peptide molecule, trihydroxyflavone, irilone, genistein, lauryl diethanolamine, and malonyl genistin.
6. A method for preparing a post-biotic composition of complex probiotics according to any of claims 1-5, wherein the product is obtained by fermentation and inactivation of complex probiotics.
7. The method for preparing post-biotic composition of composite probiotics according to claim 6,
inoculating composite probiotic bacteria into the feed liquid, adding lactase, fermenting at constant temperature of 30-38 deg.C until pH is 4.5-4.6, adding adjuvants, preheating, homogenizing, and inactivating.
8. The method for preparing a post-probiotic composition of claim 7, wherein,
the addition amount of lactase is 0.1mL/kg feed liquid-1.0 mL/kg feed liquid; and/or
The auxiliary material comprises maltodextrin, and the adding amount is 5-25g/kg of fermentation liquid; and/or
Preheating to 55-60 ℃, and homogenizing under the primary pressure of 18-20.0 Mpa and the secondary pressure of 4.0-5.0 Mpa; and/or
Inactivating at 75-95 deg.C for 15-30min; and/or
The preparation method of the feed liquid comprises the following steps: weighing fermentation raw materials, melting, homogenizing, sterilizing and/or cooling.
9. The method for preparing a post-probiotic composition of claim 8, wherein,
in the preparation method of the feed liquid, the fermentation raw materials comprise an organic nitrogen source, an organic carbon source and a pH regulator;
the organic nitrogen source comprises full-fat soybean powder, skim milk powder, whey protein powder or soybean protein isolate powder;
the organic carbon source comprises skim milk powder, whole soybean powder, skim milk powder or whey protein powder;
the pH regulator comprises sodium citrate.
10. The method for preparing a post-probiotic composition of claim 8 or 9, characterized in that,
the fermentation raw material comprises 1.5-7 parts by weight of full-fat soybean powder, 11-18 parts by weight of skim milk powder, 0.05-0.5 part by weight of sodium citrate and 74.5-87.45 parts by weight of water; and/or
In the preparation method of the feed liquid, the temperature of the material is 55-60 ℃, and the time is 10-30min; and/or
In the preparation method of the feed liquid, the homogenization conditions are as follows: 55-60 ℃, the primary pressure is 18-20.0 Mpa, and the secondary pressure is 4.0-5.0 Mpa; and/or
In the preparation method of the feed liquid, the sterilization conditions are as follows: 90-95 ℃ for 15-45min.
11. A preparation comprising as an active ingredient a composite probiotic post-biotic composition according to any one of claims 1 to 5 or a composite probiotic post-biotic composition produced by the method for producing a composite probiotic post-biotic composition according to any one of claims 6 to 10.
12. The formulation of claim 11, further comprising formulation-approved excipients or carriers;
the form of the preparation comprises a liquid preparation and a solid preparation.
13. The formulation of claim 12,
the preparation form comprises injection, tablet, capsule, powder, granule or paste.
14. The composite post-probiotic composition according to any one of claims 1 to 5, the composite post-probiotic composition prepared by the method for preparing the composite post-probiotic composition according to any one of claims 6 to 10, or the formulation according to any one of claims 11 to 13, for use in any one of:
1) The application in preparing products for regulating host intestinal flora;
2) The application in preparing products for regulating host immunity;
3) The application in preparing products for inhibiting potential pathogenic bacteria in the oral cavity;
4) The application in preparing products for preventing, relieving, assisting in treating or treating dental caries and/or periodontal disease;
5) The application in preparing products for regulating the diversity of oral microorganisms and/or the structure of oral flora;
6) The application in preparing products for preventing, relieving, and adjunctively treating or treating colitis;
7) Application in preparing products for increasing body weight.
15. Use according to claim 14, for the preparation of a product for modulating the level of IL-1 β, TNF- α and/or IL-6 in a host; or
Use for the preparation of a product inhibiting the bacteria genus Streptococcus (Streptococcus), gemelalla (Gemelalla) and/or Porphyromonas (Porphyromonas) in the oral cavity; or
Use in the preparation of a product for ameliorating damage to colon tissue in a host; or
Use for the manufacture of a product for protecting the epithelial barrier of the intestinal tract of a host.
16. Use according to claim 14 or 15, wherein the product is a food, health product or pharmaceutical product.
17. Use according to claim 16, wherein the product is a functional bakery, dairy, oral care or functional health product.
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