CN113583903B - Microbial composition for preventing or treating type II diabetes and preparation method and application thereof - Google Patents

Microbial composition for preventing or treating type II diabetes and preparation method and application thereof Download PDF

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CN113583903B
CN113583903B CN202110839317.4A CN202110839317A CN113583903B CN 113583903 B CN113583903 B CN 113583903B CN 202110839317 A CN202110839317 A CN 202110839317A CN 113583903 B CN113583903 B CN 113583903B
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diabetes
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microbial composition
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方曙光
盖忠辉
朱建国
王艳丽
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WeCare Probiotics Co Ltd
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Abstract

The invention relates to a microbial composition for preventing or treating type II diabetes, and a preparation method and application thereof, wherein the microbial composition for preventing or treating type II diabetes comprises a bifidobacterium longum BL21 strain and a lactobacillus rhamnosus LRa05 strain. The microbial composition can remarkably reduce the weight of a type II diabetes patient; the level of ALT, AST and the like in the serum of a type II diabetes patient is obviously reduced; reducing the levels of serum inflammatory factors TNF-alpha, IL-1 beta and the like; significantly reducing elevated fasting glucose levels and area under the curve in an oral glucose tolerance test; the plasma DX-4000-FITC level at 2.5h is obviously reduced; significantly reduced plasma LPS levels. Therefore, the microbial composition has a great application prospect in preparing medicines, foods or health products for preventing, treating and relieving type II diabetes.

Description

Microbial composition for preventing or treating type II diabetes mellitus and preparation method and application thereof
Technical Field
The invention belongs to the technical field of biological medicines, relates to a microbial composition and a preparation method and application thereof, and particularly relates to a microbial composition for preventing or treating type II diabetes and a preparation method and application thereof.
Background
Type II diabetes is the most common type of diabetes, accounting for approximately 90% of all diabetes cases. In type II diabetes, hyperglycemia is caused by insufficient insulin secretion and failure of the human body to respond adequately to insulin, defined as insulin resistance. During the insulin resistant state, insulin is poorly acting and therefore initially causes increased insulin secretion to reduce the increase in blood glucose levels, but over time, a condition of relatively insufficient insulin secretion may continue to develop.
Type II diabetes is usually slow to develop and often does not present as acute metabolic disturbances unlike type i diabetes, which means that it is difficult to determine the actual onset time. It often takes a long time to find and as many as one-third to one-half of the type II diabetes cases in the population may be undiagnosed, as they may remain asymptomatic for many years. When unrecognized for a long time, chronic hyperglycemia complications may occur. Certain type II diabetic patients are first diagnosed with this disease because they develop complications resulting from hyperglycemia (e.g., foot ulcers, vision changes, kidney failure, or infection).
Type II diabetes is most common in the elderly, but is also increasing in children, adolescents and young adults due to increased levels of obesity, lack of exercise and improper diet. The prevalence of type II diabetes has been high worldwide and is on the rise in all areas of the world. This rising trend is exacerbated by aging population, economic development and increasingly urbanization, which results in more sedentary lifestyles and more unhealthy food consumption associated with obesity.
At present, the hypoglycemic drugs for treating diabetes mainly comprise: biguanide drugs, sulfonylurea drugs, thiazolidinedione drugs, glinide drugs, alpha-glycosidase inhibitors, dipeptidyl peptidase-4 inhibitors. However, these drugs do not cure diabetes radically, and at the same time, various therapeutic drugs have adverse reactions: such as hypoglycemic events and weight gain (e.g., insulin and insulin secretagogues, etc.), gastrointestinal reactions (e.g., biguanide drugs, glycosidase inhibitors, GLP-1 receptor agonists, etc.), weight gain, edema, or adverse cardiac events (e.g., thiazolidinedione drugs TZDs), etc. In addition, chronic administration of metformin causes irritation to the gastrointestinal tract of some patients and may affect the absorption of vitamin B12 by the patients, and rosiglitazone causes impairment of liver function and edema, etc. As a result, patients have disease tolerance, so that the effect of reducing blood sugar can be effectively achieved only by taking a large amount of hypoglycemic drugs, but long-term use of insulin can cause the patients to have drug dependence, still has temporary solution and permanent solution, and the blood sugar of the patients is difficult to be effectively controlled and is easy to repeat.
Therefore, there is a need to develop more therapeutic strategies that can effectively prevent or treat type II diabetes, and the use of drugs to treat diabetes does not preclude the importance of other measures to combat this disease. Recent studies have shown that chronic inflammation caused by endotoxin entering blood due to intestinal dysbacteriosis is one of the important factors in the development of metabolic diseases such as obesity and diabetes. The imbalance of flora disturbance can trigger systemic chronic reaction inflammation, thereby causing islet beta cell injury and insulin resistance reduction, simultaneously influencing the absorption of sugar by other cells in vivo to convert energy, causing the difficulty in normal operation of human body functions, and finally triggering a series of complications.
Disclosure of Invention
In view of the defects of the prior art, the invention aims to provide a microbial composition and a preparation method and application thereof, and particularly provides a microbial composition for preventing or treating type II diabetes and a preparation method and application thereof.
In order to achieve the purpose, the invention adopts the following technical scheme:
in a first aspect, the present invention provides a microbial composition for preventing or treating type II diabetes, comprising bifidobacterium and lactobacillus;
the Bifidobacterium is named as Bifidobacterium longum (Bifidobacterium longum) BL21 strain, the preservation unit is China general microbiological culture Collection center (CGMCC), the preservation time is 2015, 1 month and 27 days, the preservation number is CGMCC 10452, and the address is as follows: xilu No. 1 Hospital No. 3, beijing, chaoyang, north;
the Lactobacillus is named as Lactobacillus rhamnosus LRa05 strain, the preservation unit is China general microbiological culture Collection center, the preservation time is 2020 years, 7 months and 20 days, the preservation number is CGMCC 1.12734, and the address is as follows: xilu No. 1 Hospital No. 3, beijing, chaoyang, north.
The invention creatively develops a new strategy for preventing or treating type II diabetes, namely, the Bifidobacterium longum and lactobacillus rhamnosus form a microbial composition, wherein the Bifidobacterium longum (Bifidobacterium longum) is a probiotic, so that the Bifidobacterium longum BL21 related to the invention is relatively healthy for human bodies and is not easy to generate adverse reactions; lactobacillus rhamnosus (Lactobacillus rhamnosus) is also one of the probiotics, so the Lactobacillus rhamnosus LRa05 related to the invention is healthy and has no toxic and side effects to human bodies.
Research shows that the microbial composition can obviously reduce the weight of a type II diabetes patient; remarkably reducing the levels of alanine Aminotransferase (ALT), aspartate Aminotransferase (AST), triglyceride (TG) and cholesterol (TC) in the serum of a type II diabetes patient; reducing the levels of serum inflammatory factors TNF-alpha, IL-1 beta, IL-6, IL-23, IP-10, and OX-40; significantly reducing elevated fasting glucose levels and area under the curve in an oral glucose tolerance test; the plasma DX-4000-FITC level at 2.5h is obviously reduced; significantly reduced plasma LPS levels. Therefore, the microbial composition has a great application prospect in preparing medicines, foods or health-care products for preventing, treating and relieving type II diabetes.
Preferably, the viable count of the Bifidobacterium longum (BL 21) strain or the Lactobacillus rhamnosus (Lactobacillus rhamnous) LRa05 strain in the microbial composition is not lower than 1 × 10 6 CFU/mL or 1X 10 6 CFU/g, e.g. 1X 10 6 CFU/mL(CFU/g)、2×10 6 CFU/mL(CFU/g)、3×10 6 CFU/mL(CFU/g)、5×10 6 CFU/mL(CFU/g)、7×10 6 CFU/mL(CFU/g)、8×10 6 CFU/mL(CFU/g)、1×10 7 CFU/mL(CFU/g)、5×10 7 CFU/mL(CFU/g)、1×10 8 CFU/mL (CFU/g), etc., and other specific values within the range can be selected, which are not described herein.
Preferably, the ratio of the viable count of the Bifidobacterium longum (Bifidobacterium longum) BL21 strain to the viable count of the Lactobacillus rhamnosus (Lactobacillus rhamnosus) LRa05 strain is 1 (0.5-2), such as 1.
In a second aspect, the present invention provides a method for preparing a microbial composition for preventing or treating type II diabetes according to the first aspect, the method comprising:
respectively inoculating the BL21 strain and the LRa05 strain into a culture medium for culturing to obtain a culture solution; centrifuging the culture solution to obtain thalli; resuspending the thalli by using a freeze-drying protective agent to obtain a resuspension solution; freeze-drying the heavy suspension to obtain a BL21 freeze-dried microbial inoculum and an LRa05 freeze-dried microbial inoculum; and mixing the BL21 freeze-dried microbial inoculum and the LRa05 freeze-dried microbial inoculum to obtain the microbial composition for preventing or treating type II diabetes.
The preparation process of the microbial composition is simple, is suitable for industrial large-scale production, and has remarkable practicability.
Preferably, the inoculation mass of the strain is 2-4% of the mass of the culture medium, such as 2%, 2.5%, 3%, 3.5%, 4%, and the like, and other specific values in the numerical range can be selected, which is not described in detail herein.
Preferably, the formulation of the medium comprises: peptone 5-15g/L, beef extract 5-15g/L, glucose 15-25g/L, sodium acetate 1-3g/L, yeast powder 3-7g/L, diammonium hydrogen citrate 1-3g/L, K 2 PO 4 ·3H 2 O1-4g/L、MgSO 4 ·7H 2 O 0.05-0.15g/L、MnSO 4 0.04-0.06g/L, tween 80 0.5-1.5mL/L, cysteine salt0.4-0.6g/L of acid salt.
Preferably, the culture is carried out for 12-24h (e.g. 12h, 14h, 15h, 17h, 18h, 20h, 22h, 24h, etc.) at 36-38 ℃ (e.g. 36 ℃, 36.5 ℃, 37 ℃, 37.5 ℃, 38 ℃, etc.), and other specific values in the above numerical range can be selected, which is not described herein again.
Preferably, the formulation of the lyoprotectant comprises: 80-120g/L (such as 80g/L, 90g/L, 100g/L, 110g/L, 120g/L and the like) of skimmed milk powder, 80-120g/L (such as 80g/L, 90g/L, 100g/L, 110g/L, 120g/L and the like) of trehalose, 8-12g/L (such as 8g/L, 9g/L, 10g/L, 11g/L, 12g/L and the like) of L-sodium glutamate, and other specific values in the value range can be selected, and are not repeated.
Preferably, the mass ratio of the lyoprotectant to the bacteria is (1-3): 1, for example, 1.
In a third aspect, the present invention provides a use of the microbial composition for preventing or treating type II diabetes according to the first aspect in the preparation of a medicament for preventing or treating type II diabetes.
Preferably, the dosage form of the medicament comprises any one of suspension, granules, capsules, powder, tablets, emulsions, solutions, dripping pills, injections, suppositories, enemas, aerosols, patches or drops.
Preferably, the medicament further comprises pharmaceutically acceptable auxiliary materials.
Preferably, the auxiliary materials comprise any one or a combination of at least two of a carrier, a diluent, an excipient, a filler, a binder, a wetting agent, a disintegrating agent, an emulsifier, a cosolvent, a solubilizer, an osmotic pressure regulator, a surfactant, a coating material, a coloring agent, a pH regulator, an antioxidant, a bacteriostatic agent or a buffering agent.
The combination of at least two of the above-mentioned components, such as the combination of diluent and excipient, the combination of binder and wetting agent, the combination of emulsifier and cosolvent, etc., can be selected in any combination manner, and will not be described in detail herein.
In a fourth aspect, the present invention provides a use of the microbial composition for preventing or treating type II diabetes according to the first aspect in the preparation of a health food for alleviating type II diabetes.
In a fifth aspect, the invention provides a use of the microbial composition for preventing or treating type II diabetes according to the first aspect in preparing a solid beverage for alleviating type II diabetes.
In a sixth aspect, the present invention also provides the use of a microbial composition for the prevention or treatment of type II diabetes according to the first aspect, in the manufacture of a medicament for the reduction of the level of alanine aminotransferase, aspartate aminotransferase, triglyceride or cholesterol for the purpose of non-diagnosis and/or treatment of the disease.
In a seventh aspect, the present invention also provides a use of the microbial composition for preventing or treating type II diabetes as described in the first aspect, in the preparation of a medicament for reducing the level of serum inflammatory factor TNF-alpha, IL-1 beta, IL-6, IL-23, IP-10 or OX-40, for the purpose of non-diagnosis and/or treatment of a disease.
In an eighth aspect, the present invention also provides the use of the microbial composition for preventing or treating type II diabetes according to the first aspect in the preparation of a medicament for lowering plasma DX-4000-FITC levels for the purpose of non-diagnosis and/or treatment of the disease.
In a ninth aspect, the present invention also provides the use of the microbial composition for preventing or treating type II diabetes according to the first aspect, in the preparation of a medicament for lowering plasma LPS levels for the purpose of non-diagnosis and/or treatment of the disease.
Compared with the prior art, the invention has the following beneficial effects:
the invention creatively develops a new strategy for preventing or treating type II diabetes, namely, the bifidobacterium longum and the lactobacillus rhamnosus form a microbial composition, and researches show that the microbial composition can obviously reduce the weight of a patient with type II diabetes; remarkably reducing the levels of alanine Aminotransferase (ALT), aspartate Aminotransferase (AST), triglyceride (TG) and cholesterol (TC) in the serum of a type II diabetes patient; reducing the levels of serum inflammatory factors TNF-alpha, IL-1 beta, IL-6, IL-23, IP-10 and OX-40; significantly reducing elevated fasting glucose levels and area under the curve in an oral glucose tolerance test; the plasma DX-4000-FITC level at 2.5h is obviously reduced; significantly reduced plasma LPS levels. Therefore, the microbial composition has a great application prospect in preparing medicines, foods or health-care products for preventing, treating and relieving type II diabetes.
Drawings
FIG. 1 is a statistical graph of the results of the ALT level measurements in the serum of rats in each group;
FIG. 2 is a statistical chart showing the measurement results of the AST level in the serum of rats of each group;
FIG. 3 is a statistical graph showing the results of measurement of TC levels in the serum of rats of each group;
FIG. 4 is a statistical graph showing the results of measurement of TG levels in the serum of rats of each group;
FIG. 5 is a statistical chart of the results of the TNF-. Alpha.level measurements in serum of rats of each group;
FIG. 6 is a statistical chart showing the results of measurement of IL-1. Beta. Level in serum of rats of each group;
FIG. 7 is a statistical chart showing the results of measurement of IL-6 levels in serum of rats of each group;
FIG. 8 is a statistical chart showing the results of measurement of IL-23 level in serum of rats of each group;
FIG. 9 is a statistical chart of the results of FITC-dextran concentration in plasma of rats of various groups;
FIG. 10 is a statistical chart of the results of LPS levels in serum of rats of each group;
in each of the figures, the symbol "indicates P <0.05, the symbol" indicates P <0.01, and the symbol "indicates P <0.001.
Detailed Description
The technical solution of the present invention is further explained by the following embodiments. It should be understood by those skilled in the art that the examples are only for the understanding of the present invention and should not be construed as the specific limitations of the present invention.
Peptone, beef extract, glucose, sodium acetate, yeast powder, diammonium hydrogen citrate and K related to the following contents 2 PO 4 ·3H 2 O、MgSO 4 ·7H 2 O、MnSO 4 Tween 80 and cysteine hydrochloride were purchased from national pharmaceutical group chemicals, ltd; SPF grade male 3-week-old SD rats, high fat and general feed were purchased from shanghai slyke; STZ was purchased from Sigma-Aldrich; the glucometer and the blood glucose test paper are purchased from Taiwan boschlon; ELISA kits for detecting insulin, TNF-alpha, IL-1 beta, IL-6, IL-17 and IL-23 are purchased from Shanghai enzyme-linked biotechnology, inc.; endotoxin LPS assay enzyme-linked immunoassay kits were purchased from wuhan Uscn Life Science.
The media formulations referred to in the following examples are as follows:
MRS medium (g/L): 10g/L of peptone, 10g/L of beef extract, 20g/L of glucose, 2g/L of sodium acetate, 5g/L of yeast powder, 2g/L of diammonium hydrogen citrate and K 2 PO 4 ·3H 2 O 2.6g/L、MgSO 4 ·7H 2 O 0.1g/L、MnSO 4 0.05g/L, tween 80 mL/L and cysteine hydrochloride 0.5g/L.
Bifidobacterium longum (Bifidobacterium longum) BL21 strain related to the following contents, the preservation unit is China general microbiological culture Collection center of culture Collection management Committee, the preservation time is 2015, 1 month and 27 days, the preservation number is CGMCC 10452, and the addresses are: xilu No. 1 Hospital No. 3, beijing, chaoyang, north;
the Lactobacillus rhamnosus (Lactobacillus rhamnous) LRa05 strain is preserved in China general microbiological culture Collection center for 7-20 days in 2020 years, the preservation time is CGMCC 1.12734, and the address is as follows: xilu No. 1 Hospital No. 3, beijing, chaoyang, north.
The following contents relate to a formula of the freeze-drying protective agent: 100g/L of skimmed milk powder, 100g/L of trehalose, 10g/L of L-sodium glutamate and sterile water as a solvent.
Preparation example 1
(1) Preparation of bifidobacterium longum BL21 freeze-dried powder:
inoculating bifidobacterium longum BL21 into a culture medium according to the inoculation amount accounting for 3% of the total mass of the culture medium, and culturing at 37 ℃ for 18 hours to obtain a culture solution; centrifuging the culture solution to obtain thalli; use of the cellsResuspending a freeze-drying protective agent (the mass ratio of the freeze-drying protective agent to thalli is 2; and freeze-drying the heavy suspension by adopting a vacuum freezing method to obtain the Bifidobacterium longum (Bifidobacterium longum) BL21 freeze-dried powder. Is prepared into 5 multiplied by 10 after being redissolved by water 9 CFU/mL of the bacterial solution was gavaged to type II diabetic rats for 12 consecutive weeks.
(2) Preparation of lactobacillus rhamnosus Ra05 freeze-dried powder:
inoculating lactobacillus rhamnosus Ra05 into a culture medium according to the inoculation amount accounting for 3% of the total mass of the culture medium, and culturing at 37 ℃ for 18h to obtain a culture solution; centrifuging the culture solution to obtain thalli; resuspending the thalli by using a freeze-drying protective agent (the mass ratio of the freeze-drying protective agent to the thalli is 2; and (3) freeze-drying the heavy suspension by adopting a vacuum freezing method to obtain the freeze-dried powder of the LRa05 of Lactobacillus rhamnosus (Lactobacillus rhamnosus). Is prepared into 5 multiplied by 10 after being redissolved by water 9 CFU/mL of the bacterial solution was gavaged to type II diabetic rats for 12 consecutive weeks.
(3) Preparation of bifidobacterium longum BL21 and lactobacillus rhamnosus LRa05 freeze-dried powder mixture I:
mixing lyophilized powder of Bifidobacterium longum BL21 with the same viable count with lyophilized powder of Lactobacillus rhamnosus LRa05, and dissolving in water to obtain 5 × 10 lyophilized powder 9 CFU/mL of the broth was gavaged to type II diabetic rats for 12 consecutive weeks.
(4) Preparation of bifidobacterium longum BL21 and lactobacillus rhamnosus LRa05 freeze-dried powder mixture II:
uniformly mixing freeze-dried powder of bifidobacterium longum BL21 with viable count of 1 9 CFU/mL of the bacterial solution was gavaged to type II diabetic rats for 12 consecutive weeks.
(5) Preparation of bifidobacterium longum BL21 and lactobacillus rhamnosus LRa05 lyophilized powder mixture III:
uniformly mixing bifidobacterium longum BL21 freeze-dried powder with viable count of 2 9 CFU/mL of the bacterial solution was gavaged to type II diabetic rats for 12 consecutive weeks.
(6) Preparation of a bifidobacterium longum BL21 and lactobacillus rhamnosus LRa05 lyophilized powder mixture IV:
uniformly mixing freeze-dried powder of bifidobacterium longum BL21 with viable count of 1 9 CFU/mL of the bacterial solution was gavaged to type II diabetic rats for 12 consecutive weeks.
(7) Preparation of bifidobacterium longum BL21 and lactobacillus rhamnosus LRa05 lyophilized powder mixture V:
uniformly mixing bifidobacterium longum BL21 freeze-dried powder with viable count of 4 9 CFU/mL of the broth was gavaged to type II diabetic rats for 12 consecutive weeks.
Example 1
Effect of microbial composition on body weight of type II diabetic rats:
(1) Grouping condition:
54 male SD rats (6 weeks old, body weight between 170g-190 g) with 3-4 per cage, feeding temperature strictly controlled at 22 + -2 deg.C, light/dark cycle for 12h, and free access to food and water. After 2 weeks of acclimatizing feeding, rats were randomized into CTL groups (n = 6) and fed regular diet; the group of high fat diet (n = 48), fed with high fat diet (88% normal diet, 10% lard, 1.5% cholesterol, 0.5% bile salts), was further divided into type II diabetes group (D2M group, n = 6) and intervention 1-7 group (BL 21+ LRa05 group, n = 6).
(2) Establishing a type II diabetes rat model:
at week 3, all rats were fasted for 12h and except for the CTL group, the rats in each group were injected with freshly prepared streptozotocin STZ (50 mmol/L) at 100mg/kg body weight. An amount of STZ was dissolved in 50mmol/L citric acid-sodium citrate buffer (pH 4.5), and the CTL group was injected with 0.85% physiological saline. After 1 week of modeling (4 th week), the fasting blood sugar of the successfully modeled diabetic rat is higher than 7.0mmol/L, and the blood sugar of the diabetic rat is higher than 11.0mmol/L after 2 hours of meal. The 48 type II diabetic rats successfully modeled were divided into eight groups: (1) 6 in the type II diabetes group (D2M group); (2) Intervention 1 group contains 6 animals, and the freeze-dried powder mixture I bacterial liquid prepared in the preparation example 1 is fed; (3) Intervention 2 groups of 6 animals are fed with the freeze-dried powder mixture II bacterial liquid prepared in the preparation example 1; (4) 3 groups of 6 animals were intervened, and the lyophilized powder mixture III prepared in preparation example 1 was fed; (5) The 4 groups of 6 animals are intervened, and the lyophilized powder mixture IV bacterial liquid prepared in the preparation example 1 is fed; (6) The 5 groups were intervened and 6 were fed with the lyophilized powder mixture V bacterial solution prepared in preparation example 1; (7) Intervention 6 groups of 6 animals in total, and feeding BL21 freeze-dried powder bacterial liquid prepared in preparation example 1; (8) A total of 6 animals in 7 groups were fed with the Ra05 lyophilized powder suspension prepared in preparation example 1.
(3) The experimental process comprises the following steps:
the experiment took 12 weeks: the adaptation period of the rat is 1-2 weeks; the molding period is 3-6 weeks; beginning gavage in 7-12 weeks until the experiment is finished, and the intervention group takes 0.2mL of bacterial liquid (the total amount of viable bacteria in single gavage is 1 × 10) 9 Gavage at doses of CFU)/one/time; all groups were free water and food intake.
Body weights of rats in the CTL group, D2M group, and intervention 1-3 groups were measured at week 12, and the results are shown in table 1: the body weight of the rats in the D2M group is obviously higher than that of the rats in the CTL group, and the difference has statistical significance (P is less than 0.05). The body weight of the rats in the intervention group is obviously reduced compared with that of the rats in the D2M group (p < 0.05).
TABLE 1
Group of Body weight (g)
CTL group 552±14
D2M group 649±39
Intervention 1 group 576±38
Intervention 2 groups 583±42
Intervention 3 groups 566±39.5
Example 2
Effect of microbial composition on fasting plasma glucose and OGTT in type II diabetic rats:
grouping, establishing type II diabetic rat models and experimental procedures were consistent with example 1.
Fasting blood glucose was measured after the rats had fasted for 12h and postprandial blood glucose was measured after 2h of feeding. When performing the Oral Glucose Tolerance Test (OGTT), all rats were fasted overnight and fasting blood glucose was collected as baseline value before glucose administration (time =0 min). Then, 2g/kg of glucose solution was orally administered by gavage. Blood samples were collected 15, 30, 60 and 120min after glucose administration. Blood glucose levels were measured and the area under the glucose curve (AUC) was calculated.
The results are shown in tables 2 and 3, and it can be seen from table 2 that: glucose levels were significantly reduced on average in the intervention groups compared to the D2M group, and were reduced to a more significant extent in the intervention 1-3 groups (p < 0.05). As can be seen from Table 3: the total area under the curve (TAUC) values were significantly reduced for the intervention groups compared to the D2M group, and the total area under the curve was reduced to a much more significant extent for the intervention groups 1-3 (p < 0.05).
TABLE 2
Group of Fasting blood glucose (mg/dL)
CTL group 121±10.5
D2M group 380±27
Intervention 1 group 190±19.8
Intervention 2 groups 186±29.8
Intervention 3 groups 192±16.8
Intervention 4 groups 197±21
Intervention 5 groups 205±28
Intervention 6 groups 229±18.9
Intervention 7 groups 238±28.5
TABLE 3
Group of Area under curve
CTL group 2555±101.5
D2M group 3910±280.8
Intervention 1 group 2988±401.6
Intervention 2 groups 2923±423.7
Intervention 3 groups 2990±455.6
Intervention 4 groups 3188±371.5
Intervention 5 groups 3158±421.4
Intervention 6 groups 3365±468.3
Intervention 7 groups 3269±431.2
Example 3
Effect of microbial composition on biochemical indicators of type II diabetic rat serum:
grouping, establishing type II diabetic rat models and experimental procedures were consistent with example 1.
At the end of the experiment of 12 weeks, after the mice are fasted for 12 hours without water prohibition, the eyeballs are taken out after anesthesia for blood sampling, the upper layer transparent liquid is carefully collected as serum after centrifugation at 4000 Xg for 10min at the low temperature of 4 ℃, and the serum is frozen and stored at the temperature of minus 80 ℃ for standby.
Determination of serum ALT, AST, TC, TG: taking out the reserved serum, thawing, and measuring the rat serum ALT, AST, TC and TG by using a biochemical automatic biochemical analyzer according to a machine and a specification. The results are shown in FIGS. 1 to 4, respectively.
As can be seen from FIG. 1, the serum ALT level of the rats in the D2M group was significantly increased compared to that in the CTL group, and the difference was statistically significant (p < 0.05). Compared with the D2M group, the serum ALT level of the rats in the intervention 1 group is reduced, and the difference has statistical significance (p is less than 0.05).
As can be seen from FIG. 2, the AST level in the serum of the rats in the D2M group was significantly increased compared to that in the CTL group, and the difference was statistically significant (p < 0.05). Compared with the D2M group, the rats in the intervention 1 group have reduced serum AST level, and the difference has statistical significance (p is less than 0.05).
As can be seen from FIG. 3, the serum TC level of the rats in the D2M group was significantly increased compared to that in the CTL group, and the difference was statistically significant (p < 0.05). Compared with the D2M group, the TC level of the serum of the rats in the intervention 1 group is reduced, and the difference is statistically significant (p is less than 0.05).
As can be seen from FIG. 4, the serum TG levels of the rats in the D2M group were significantly increased compared with those in the CTL group, and the difference was statistically significant (p < 0.05). Compared with the D2M group, the serum TG level of rats in the intervention 1 group is reduced, and the difference has statistical significance (p is less than 0.05).
Example 4
Effect of microbial composition on serum inflammatory factor indicators in type II diabetic rats:
grouping, establishing type II diabetic rat models and experimental procedures were consistent with example 1.
Detection of relevant cytokines in serum: the contents of TNF-alpha, IL-1 beta, IL-6 and IL-23 are determined by ELISA kit, the method is referred to the instruction. The results are shown in FIGS. 5-8, respectively.
As can be seen from FIG. 5, the serum TNF-. Alpha.levels of the rats in the D2M group were significantly increased compared to those in the CTL group, and the difference was statistically significant (p < 0.05). Compared with the D2M group, the level of TNF-alpha in the serum of rats in the intervention 1 group is reduced, and the difference has statistical significance (p is less than 0.05).
As shown in FIG. 6, the serum IL-1. Beta. Level of the rats in the D2M group was significantly increased compared with that in the CTL group, and the difference was statistically significant (p < 0.05). Compared with the D2M group, the level of IL-1 beta in the serum of the rats in the intervention 1 group is reduced, and the difference has statistical significance (p is less than 0.05).
As can be seen from FIG. 7, the serum IL-6 level of the rats in the D2M group was significantly increased compared to that in the CTL group, and the difference was statistically significant (p < 0.05). Compared with the D2M group, the level of IL-6 in the serum of the rats in the intervention 1 group is reduced, and the difference is statistically significant (p is less than 0.05).
As can be seen from FIG. 8, the serum IL-23 level of the rats in the D2M group was significantly increased compared to that in the CTL group, and the difference was statistically significant (p < 0.05). Compared with the D2M group, the level of IL-23 in the serum of rats in the intervention 1 group is reduced, and the difference has statistical significance (p is less than 0.05).
Example 5
Effect of microbial composition on intestinal permeability of type II diabetic rats:
grouping, establishing type II diabetic rat models and experimental procedures were consistent with example 1.
In vivo intestinal permeability test procedure: rats were fasted overnight and blood samples were taken as a negative control for the experiment to determine the background of rat plasma. Rats were then given FITC-dextran (600 mg/kg) (Sigma-Aldrich) by oral gavage and blood samples were taken after 2.5 and 5 h. Blood samples were immediately centrifuged at 6000rpm, plasma was separated and diluted with an equal volume of Phosphate Buffered Saline (PBS) (pH = 7.4). Using Synergy TM H4 fluorescent enzyme label instrument
Figure BDA0003178366340000151
Plasma concentrations of FITC-dextran were determined at an excitation wavelength of 485nm and an emission wavelength of 535nm, compared to a standard curve of FITC-dextran serially diluted. The results are shown in FIG. 9.
As can be seen from FIG. 9, the serum FITC-dextran level of the rats in the D2M group was significantly increased compared to that in the CTL group, and the difference was statistically significant (p < 0.05). Compared with the D2M group, the interference 1 group of rats has the reduced serum FITC-dextran level, and the difference has statistical significance (p is less than 0.05).
Plasma Lipopolysaccharide (LPS) assay: plasma LPS levels were determined using the LPS detection kit according to the manufacturer's instructions. Plasma was mixed with LAL reagent and incubated in a 37 ℃ heat block for 10min, then substrate solution was added and finally incubated at 37 ℃ for 6min. Thereafter, a stop reagent is added. The presence of LPS in plasma was inferred by the appearance of yellow color. The absorbance of the sample was quantitatively measured by spectrophotometry, and the results are shown in FIG. 10.
As can be seen from FIG. 10, the serum LPS levels of the rats in the D2M group were significantly increased compared to those in the CTL group, and the difference was statistically significant (p < 0.05). Compared with the D2M group, the interference 1 group rats have reduced serum LPS level, and the difference has statistical significance (p is less than 0.05).
The applicant states that the present invention is illustrated by the above examples, but the present invention is not limited to the above examples, i.e. it does not mean that the present invention must be implemented by the above examples. It should be understood by those skilled in the art that any modification of the present invention, equivalent substitutions of the raw materials of the product of the present invention, addition of auxiliary components, selection of specific modes, etc., are within the scope and disclosure of the present invention.
The preferred embodiments of the present invention have been described in detail, however, the present invention is not limited to the specific details of the above embodiments, and various simple modifications may be made to the technical solution of the present invention within the technical idea of the present invention, and these simple modifications are within the protective scope of the present invention.
It should be noted that the various technical features described in the above embodiments can be combined in any suitable manner without contradiction, and the invention is not described in any way for the possible combinations in order to avoid unnecessary repetition.

Claims (12)

1. A microbial composition for preventing or treating type II diabetes, which is characterized in that microbial strains in the microbial composition for preventing or treating type II diabetes consist of bifidobacteria and lactobacilli;
the bifidobacterium is named as bifidobacterium longum (Bifidobacterium longum) BL21 strain, the preservation unit is China general microbiological culture Collection center, the preservation time isThe preservation number is CGMCC 10452 at 27 months 1 in 2015, and the addresses are as follows: xilu No. 1 Hospital No. 3, beijing, chaoyang, north;
the lactobacillus is named as lactobacillus rhamnosus (A), (B), (C)Lactobacillus rhamnosus) The LRa05 strain is preserved in China general microbiological culture Collection center (CGMCC), the preservation time is 7 months and 20 days 2020, the preservation number is CGMCC 1.12734, and the address is as follows: xilu No. 1 Hospital No. 3, beijing, chaoyang, beicheng;
said Bifidobacterium longum: (A), (B), (C)Bifidobacterium longum) BL21 strain and Lactobacillus rhamnosus (B)Lactobacillus rhamnosus) The ratio of viable count of LRa05 strain is 1 (0.5-2).
2. The microbial composition of claim 1, wherein the bifidobacterium longum (b), (f) isBifidobacterium longum) BL21 strain or Lactobacillus rhamnosus (B)Lactobacillus rhamnosus) The viable count of the LRa05 strain in the microbial composition is not less than 1 x 10 6 CFU/mL or 1X 10 6 CFU/g。
3. The method for preparing a microbial composition for the prevention or treatment of type II diabetes according to any one of claims 1 to 2, wherein the preparation method comprises:
respectively inoculating the BL21 strain and the LRa05 strain into a culture medium for culturing to obtain a culture solution; centrifuging the culture solution to obtain thalli; resuspending the thalli by using a freeze-drying protective agent to obtain a resuspension solution; freeze-drying the heavy suspension to obtain a BL21 freeze-dried microbial inoculum and an LRa05 freeze-dried microbial inoculum; and mixing the BL21 freeze-dried microbial inoculum and the LRa05 freeze-dried microbial inoculum to obtain the microbial composition for preventing or treating the type II diabetes.
4. The method for preparing a microbial composition for the prevention or treatment of type II diabetes mellitus according to claim 3, wherein the inoculated mass of said strain is 2-4% of the mass of the culture medium.
5. As claimed in claim 3The preparation method of the microbial composition for preventing or treating type II diabetes is characterized in that the formula of the culture medium comprises: peptone 5-15g/L, beef extract 5-15g/L, glucose 15-25g/L, sodium acetate 1-3g/L, yeast powder 3-7g/L, diammonium hydrogen citrate 1-3g/L, K 2 PO 4 ·3H 2 O 1-4 g/L、MgSO 4 ·7H 2 O 0.05-0.15 g/L、MnSO 4 0.04-0.06g/L, tween 80.5-1.5 mL/L, and cysteine hydrochloride 0.4-0.6g/L.
6. The method for preparing a microbial composition for the prevention or treatment of type II diabetes according to claim 3, wherein said culturing is carried out at 36-38 ℃ for 12-24 h.
7. The method of claim 3, wherein the formulation of the lyoprotectant includes: 80-120g/L of skimmed milk powder, 80-120g/L of trehalose and 8-12g/L of L-sodium glutamate.
8. The method for producing a microbial composition for preventing or treating type II diabetes according to claim 3, wherein the mass ratio of the lyoprotectant to the microbial cell is (1-3): 1.
9. Use of the microbial composition for the prevention or treatment of type II diabetes according to any one of claims 1-2 in the manufacture of a medicament for the prevention or treatment of type II diabetes.
10. The use of claim 9, wherein the medicament is in a dosage form selected from the group consisting of a suspension, granules, capsules, powders, tablets, emulsions, solutions, drops, injections, suppositories, enemas, aerosols, patches and drops.
11. The use of claim 10, wherein the medicament further comprises a pharmaceutically acceptable excipient.
12. The use of claim 11, wherein the adjuvants comprise any one or a combination of at least two of diluents, fillers, binders, wetting agents, disintegrants, emulsifiers, co-solvents, solubilizers, osmotic pressure regulators, surfactants, coating materials, colorants, pH regulators, antioxidants, bacteriostats, or buffers.
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