CN106994134B - Application of intestinal probiotics in prevention and/or treatment of diabetes and related diseases thereof - Google Patents
Application of intestinal probiotics in prevention and/or treatment of diabetes and related diseases thereof Download PDFInfo
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- CN106994134B CN106994134B CN201610051026.8A CN201610051026A CN106994134B CN 106994134 B CN106994134 B CN 106994134B CN 201610051026 A CN201610051026 A CN 201610051026A CN 106994134 B CN106994134 B CN 106994134B
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- A—HUMAN NECESSITIES
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Abstract
The invention discloses application of intestinal probiotics in preventing and treating diabetes and related diseases, and particularly relates to the intestinal probiotics for preparing a composition or a preparation, wherein the composition or the preparation is used for one or more of the following purposes: (a) preventing and/or treating diabetes; (b) preventing and/or treating cardiovascular diseases; and/or (c) preventing and/or treating obesity. The intestinal probiotics provided by the invention can obviously inhibit weight gain, reduce serum glucose level, reduce blood lipid level, improve insulin resistance and/or reduce glycosylated hemoglobin level, and effectively relieve diabetes and related diseases.
Description
Technical Field
The invention belongs to the field of microbiology, and particularly relates to application of intestinal probiotics in preventing and/or treating diabetes and related diseases, and also relates to a composition containing the intestinal probiotics and application thereof.
Background
There are a large number of commensal microorganisms in humans, most of which reside in the human intestinal tract, in amounts exceeding 1000 trillion (10 trillion)14Order of magnitude) of more than 10 times the total number of human cells. In a long evolutionary process, intestinal microorganisms and human beings achieve good cooperation and play a crucial role in nutrition, metabolism and immunity of human bodies, and many researchers regard the intestinal microflora of the human bodies as an organ of the human bodies or a second genome of the human bodies, wherein the abundant genetic information contained in the intestinal microflora is closely related to the health of the human bodies. Through research on nearly ten thousand samples of diabetes, coronary heart disease, diabetes, colon cancer and other diseases, some specific species show significant association with the diseases, and the results provide a completely new direction for clinical assessment and diagnosis of the diseases and later intervention treatment.
Diabetes has become the third chronic disease seriously threatening human health after tumor and cardiovascular and cerebrovascular diseases in the world. At the same time, it will severely affect the human cardiovascular and cerebrovascular vessels and kidneys. With the rapid development of economy and the continuous improvement of life style, the incidence of metabolic diseases such as diabetes and the like in China is rapidly increased, and the incidence of metabolic diseases becomes a main threat affecting human health. The recent data from the international diabetes union show that the incidence of diabetes patients is 2.5% in 1994, 5.5% in 2002, and 9.7% by 2008. At present, the incidence rate of diabetes in China is equivalent to that of economically developed America, and the incidence rate of diabetes in large cities reaches 9-10%. In 2005, reports issued by the world health organization indicated that, from 2005 to 2015, the national income that would be lost due to premature death from heart disease, stroke, and diabetes was approximately 3.9 trillion RMB. Therefore, researches on main causes of diabetes, establishes powerful and easily-popularized intervention measures and suppresses the rising trend of the incidence of diabetes in people become urgent scientific problems to be solved in the fields of biomedicine and nutriology in China.
More than 90% of people with diabetes are type II diabetes. Type II diabetes is a chronic complex disease that presents hyperglycemic symptoms due to dysbalance of blood glucose, and in the course of onset, disorders of carbohydrate and fat metabolism affect normal physiological activities of organs and tissues throughout the body. The pathological causes of type II diabetes are diversified, and are generally considered to be due to the combined action of innate genetic factors and acquired environmental factors. There are many studies on these aspects, but none of them can explain the onset of type II diabetes and its pathogenic mechanism well.
At present, no effective method and medicament for preventing and/or treating diabetes and related diseases with small side effect exist in the field.
Therefore, there is an urgent need in the art to develop a novel drug for preventing and/or treating diabetes and related diseases without toxic and side effects.
Disclosure of Invention
It is an object of the present invention to provide the use of intestinal probiotics in the prevention and/or treatment of diabetes and its related diseases.
It is another object of the present invention to provide a pharmaceutical, beverage, food composition, or animal feed composition for preventing and/or treating diabetes and its related diseases, which is effective without toxic and side effects.
Another object of the present invention is to provide a method for reducing serum glucose, blood lipid and/or glycated hemoglobin levels and uses thereof.
The present invention provides in a first aspect the use of an intestinal probiotic for the preparation of a composition or formulation for one or more uses selected from the group consisting of: (a) preventing and/or treating diabetes; (b) preventing and/or treating cardiovascular diseases; and/or (c) preventing and/or treating obesity, wherein the intestinal probiotic is selected from the group consisting of: fermented aminoacidococcus species, Bifidobacterium dentium species, or combinations thereof.
In another preferred embodiment, the probiotic bacteria comprise zymococcus amino acids.
In another preferred embodiment, the amino acid fermenting coccus (Acylaminococcus fermentum) is selected from the group consisting of: acylaminococcus fermentors DSM20731, Acylaminococcus fermentors ATCC25088, Acylaminococcus fermentors ATCC25086, or a combination thereof.
In another preferred example, the intestinal probiotic comprises Bifidobacterium odonta (Bifidobacterium dentium).
In another preferred embodiment, the Bifidobacterium odonta (Bifidobacterium dentist) is selected from the group consisting of: bifidobacterium genus DSM 20436, Bifidobacterium genus DSM 20084, Bifidobacterium genus DSM 20221, or a combination thereof.
In another preferred embodiment, said intestinal probiotics comprise one or more selected from table 3.
In another preferred embodiment, the intestinal probiotics are selected from table 3 and are from the same or different genera.
In another preferred embodiment, the composition is selected from the group consisting of: a food composition, a nutraceutical composition, a pharmaceutical composition, a beverage composition, a feed composition, or a combination thereof.
In another preferred embodiment, the composition is an oral preparation.
In another preferred embodiment, the composition is a liquid preparation, a solid preparation or a semi-solid preparation.
In another preferred embodiment, the dosage form of the composition is selected from the group consisting of: powders, tablets, dragees, capsules, granules, suspensions, solutions, syrups, drops, and sublingual tablets.
In another preferred embodiment, the food composition comprises an emulsion product, a solution product, a powder product, or a suspension product.
In another preferred embodiment, the food composition comprises milk, milk powder, or an emulsion.
In another preferred embodiment, the liquid formulation is selected from the group consisting of: solution preparations or suspension preparations.
In a second aspect the present invention provides the use of an intestinal probiotic for the manufacture of a composition or formulation for one or more uses selected from the group consisting of: (i) lowering serum glucose levels in a mammal; (ii) improving insulin resistance in a mammal; and/or (iii) reducing glycated hemoglobin (HbA1c) levels in a mammal, wherein the gut probiotic is selected from the group consisting of: fermentative amino acid coccus species, Bifidobacterium odonta species, or combinations thereof.
In another preferred embodiment, the composition or formulation is also used independently or additionally for one or more uses selected from the group consisting of:
(iv) inhibiting weight gain in a mammal;
(v) reducing blood lipid levels in a mammal.
In another preferred embodiment, the mammal comprises a human or non-human mammal.
In another preferred embodiment, the non-human mammal includes a rodent, such as a rat, a mouse.
In another preferred embodiment, said lowering blood lipid levels in a mammal comprises lowering serum triglyceride levels.
In a third aspect, the present invention provides a composition for the treatment and/or prevention of diabetes, said composition comprising: (i) a safe and effective amount of a probiotic; and (ii) a food-or pharmaceutically acceptable carrier; wherein the intestinal probiotic is selected from the group consisting of: fermented aminoacidococcus species, Bifidobacterium dentium species, or combinations thereof.
In another preferred embodiment, the probiotic bacteria comprise zymococcus amino acids.
In another preferred embodiment, the amino acid fermenting coccus (Acylaminococcus fermentum) is selected from the group consisting of: acylaminococcus fermentors DSM20731, Acylaminococcus fermentors ATCC25088, Acylaminococcus fermentors ATCC25086, or a combination thereof.
In another preferred example, the intestinal probiotic comprises Bifidobacterium odonta (Bifidobacterium dentium).
In another preferred embodiment, the Bifidobacterium odonta (Bifidobacterium dentist) is selected from the group consisting of: bifidobacterium genus DSM 20436, Bifidobacterium genus DSM 20084, Bifidobacterium genus DSM 20221, or a combination thereof.
In another preferred embodiment, the composition is selected from the group consisting of: a food composition, a nutraceutical composition, a pharmaceutical composition, a beverage composition, a feed composition, or a combination thereof.
In another preferred embodiment, the composition comprises 1 × 10-1 × 1020cfu/mL or cfu/g of probiotic bacteria, preferably 1 × 104-1×1015cfu/mL or cfu/g of intestinal probiotic bacteria, based on the total volume or total weight of the composition.
In another preferred embodiment, said composition comprises 0.0001-99 wt%, preferably 0.1-90 wt% of said intestinal probiotics, based on the total weight of said composition.
In another preferred embodiment, the composition is in unit dosage form (tablet, capsule or vial), and the mass of the composition in each unit dosage form is 0.05-5g, preferably 0.1-1 g.
In another preferred embodiment, the composition further comprises other intestinal probiotics and/or prebiotics.
In another preferred embodiment, said other intestinal probiotics are selected from the group consisting of: lactic acid bacteria, bifidobacteria, Lactobacillus acidophilus, or combinations thereof.
In another preferred embodiment, the prebiotic is selected from the group consisting of: fructooligosaccharides (FOS), Galactooligosaccharides (GOS), Xylooligosaccharides (XOS), Lactosucrose (LACT), Soy Oligosaccharides (SOS), Inulin (Inulin), or combinations thereof.
In a fourth aspect, the present invention provides a method for preparing a composition according to the third aspect of the present invention, comprising the steps of:
mixing (i) a probiotic gut bacteria selected from the group consisting of: fermented aminoacidococci (Acidococcusefermentors), Bifidobacterium (Bifidobacterium denum), or combinations thereof.
In another preferred embodiment, the composition is an oral preparation.
In a fifth aspect, the present invention provides a method of lowering serum glucose, blood lipids and/or glycated hemoglobin levels by administering to said subject (i) a probiotic gut selected from the group consisting of: fermented aminoacidococcus species, Bifidobacterium dentium species, or combinations thereof.
In another preferred embodiment, said administering comprises oral administration.
In another preferred embodiment, the dosage is 0.01-5g/50kg body weight/day, preferably 0.1-2g/50kg body weight/day.
In another preferred embodiment, the method is also used for improving insulin resistance.
In another preferred embodiment, the subject comprises a mammal, such as a human.
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.
Drawings
FIG. 1 shows the weight gain of various groups of mice after fermentation with M.gastrectasia.
FIG. 2 shows the weight gain of various groups of mice after administration of Bifidobacterium gastrodiae.
FIG. 3 shows the weight gain of the mice in each group after the gavage of the combination bacteria.
FIG. 4 shows the effect of Zymobacter gastrectans on serum glucose levels in mice fed high fat diet.
FIG. 5 shows the effect of Bifidobacterium gastrolavage on serum glucose levels in mice fed high fat diet.
FIG. 6 shows the effect of the gavage combination on serum glucose levels in mice fed high fat diet.
FIG. 7 shows the effect of Zymobacter gastricicola on serum glucose levels in diabetic model mice.
FIG. 8 shows the effect of Bifidobacterium gavage on serum glucose levels in mice of the diabetic model.
FIG. 9 shows the effect of COMBINATION OF GASTRIC INGREDIENTS on serum glucose levels in mice from a diabetic model.
FIG. 10 shows the effect of Zymococcus gastriculatus on serum triglyceride, insulin and glycated hemoglobin (HbA1c) levels in mice fed high fat diet.
FIG. 11 shows the effect of Bifidobacterium gastrolavage on serum triglyceride, insulin and glycated hemoglobin (HbA1c) levels in mice fed high fat diet.
FIG. 12 shows the effect of gavage combination on serum triglyceride, insulin and glycated hemoglobin (HbA1c) levels in mice fed high fat diet.
FIG. 13 shows the effect of Zymococcus gastriculatus on serum triglyceride, insulin and glycated hemoglobin (HbA1c) levels in diabetic model mice.
FIG. 14 shows the effect of Bifidobacterium gastrolavage on serum triglyceride, insulin and glycated hemoglobin (HbA1c) levels in mice of the diabetic model.
FIG. 15 shows the effect of Pegaster lavage on serum triglyceride, insulin and glycated hemoglobin (HbA1c) levels in mice from a diabetic model.
Detailed Description
The present inventors have made extensive and intensive studies and experiments, and unexpectedly found that zymococcus amino acids (Acidococci) and/or Bifidobacterium dentis (Bifidobacterium dense) have the effects of preventing and/or treating diabetes and related diseases, and when an active composition containing the above-mentioned probiotic bacteria is fed to a subject, the composition has been found to be capable of inhibiting weight gain, lowering serum glucose level, lowering blood lipid level, improving insulin resistance and/or lowering hemoglobin level, and effectively relieving the symptoms of diabetes and related diseases (such as cardiovascular disease, obesity). The present invention has been completed based on this finding.
As used herein, the term "comprising" means that the various ingredients can be applied together in a mixture or composition of the invention. Thus, the terms "consisting essentially of and" consisting of are encompassed by the term "comprising.
Intestinal probiotics and application thereof
As used herein, the "gut probiotic of the invention" refers to a mixture of one or more of two genera zymococcus amino acids, bifidobacterium odonta or a mixture of one or more of a plurality of bacteria per genus.
Wherein, the zymotic amino acid coccus is anaerobe, gram staining is negative, no spore is formed, the zymotic amino acid coccus can not move, cells are in a kidney-shaped double-sphere shape, and the diameter is between 0.6 and 1.0 mu m.
Bifidobacterium dentis is a strictly anaerobic bacterium, gram-positive, rod-shaped, branched, and present in the intestinal tract and oral cavity.
The invention provides application of intestinal probiotics in preventing and/or treating diabetes and related diseases. The zymococcus amino acid, bifidobacterium odonta, or a combination thereof has a) an inhibitory effect on weight gain; (b) lowering serum glucose levels; (c) lowering blood lipid levels; (d) improving insulin resistance; and/or (e) the ability to decrease glycated hemoglobin levels.
According to a preferred embodiment of the present invention, C57BL/6J male mice fed with high-fat food, which are gazed by intestinal probiotics (such as zymococcus amino acids, bifidobacterium bifidum, or a combination thereof), have a reduced weight gain compared to the control group that has not received gavage, and have an inhibited gain in various indicators related to diabetes and related diseases (such as cardiovascular disease, obesity), such as serum glucose level, blood lipid level, and glycated hemoglobin level, and significantly improve insulin resistance.
According to another preferred embodiment of the present invention, the diabetes model C57BL/6J male mice treated with a probiotic (e.g., zymococcus amino acid, bifidobacterium bifidum, or a combination thereof) in the intestines have significantly reduced indices associated with diabetes and related diseases (e.g., cardiovascular disease), such as serum glucose level, blood lipid level, and glycated hemoglobin level, and significantly improved insulin resistance, as compared to untreated controls.
Therefore, the intestinal probiotics (such as zymococcus amino acid, bifidobacterium odonta or the combination thereof) can be used for preventing and/or treating diabetes and related diseases (such as cardiovascular diseases and obesity).
Composition and application thereof
The invention also provides a composition, preferably a pharmaceutical composition. The composition comprises an effective amount of intestinal probiotics (such as zymococcus amino acids, bifidobacterium dentis, or a combination thereof), and in a preferred embodiment, the composition further comprises probiotics selected from the group consisting of: lactic acid bacteria, bifidobacteria, lactobacillus acidophilus, or combinations thereof; and/or a prebiotic selected from the group consisting of: fructooligosaccharides (FOS), Galactooligosaccharides (GOS), Xylooligosaccharides (XOS), Lactosucrose (LACT), Soy Oligosaccharides (SOS), Inulin (Inulin), or combinations thereof.
In a preferred embodiment, the composition is a liquid preparation, a solid preparation or a semisolid preparation.
In a preferred embodiment, the liquid formulation is selected from the group consisting of: solution preparations or suspension preparations.
In a preferred embodiment, the dosage form of the composition is selected from the group consisting of: powders, tablets, dragees, capsules, granules, suspensions, solutions, syrups, drops, and sublingual tablets.
The pharmaceutical composition of the present invention may be administered in any form of pharmaceutical tablets, injections or capsules, which includes excipients, pharmaceutically acceptable vehicles and carriers, which may be selected according to the administration route. The pharmaceutical preparation of the present invention may further comprise auxiliary active ingredients.
Lactose, glucose, sucrose, sorbitol, mannose, starch, acacia gum, calcium phosphate, alginate, gelatin, calcium silicate, fine crystalline cellulose, polyvinylpyrrolidone (PVP), cellulose, water, syrup, methyl cellulose, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, mineral oil, or the like can be used as the carrier, excipient, diluent, or the like of the pharmaceutical composition of the present invention.
In addition, the pharmaceutical composition of the present invention may further include lubricants, wetting agents, emulsifiers, suspension stabilizers, preservatives, sweeteners, flavors, and the like. The pharmaceutical compositions of the present invention may be manufactured in enteric-coated formulations by a variety of well-known methods so that the active ingredient of the pharmaceutical composition, i.e., the microorganism, passes through the stomach without being destroyed by stomach acid.
In addition, the microorganism of the present invention can be used in the form of a capsule prepared by a conventional method. For example, standard excipients are mixed with the lyophilized microorganisms of the present invention to form pellets, which are then filled into gelatin capsules. In addition, the microorganisms of the present invention and the pharmaceutically acceptable excipients such as liquid gums, celluloses, silicates or mineral oils are mixed to make a suspension or dispersion, which can be filled into soft gelatin capsules.
The pharmaceutical composition of the present invention can be made into enteric coated tablets for oral administration. The term "enteric coating" in the present application includes all coatings which are approved for use with conventional drugs, which are not degraded by gastric acid, but which are sufficiently decomposed in the small intestine to rapidly release the microorganisms of the present invention. The enteric coating of the invention is capable of being maintained at 36-38 ℃ for more than 2 hours in synthetic gastric acid, e.g. HCl solution at pH 1, and preferably disintegrates within 1.0 hour in synthetic intestinal fluid, e.g. buffer at pH 7.0.
The enteric coating of the invention is coated at about 16-30mg, preferably 16-25mg, more preferably 16-20mg per tablet. The thickness of the casing is 5-100 μm, and the ideal thickness is 20-80 μm. The enteric coating composition is selected from conventional polymers known per se.
Preferred casings for use in the present invention are prepared from cellulose acetate phthalate polymers or trimellitate polymers and copolymers of methacrylic acid (e.g., copolymers containing greater than 40% methacrylic acid and methacrylic acid containing hydroxypropyl methylcellulose phthalate or its ester derivatives).
The cellulose acetate phthalate used in the enteric coating of the present invention has a viscosity of about 45 to 90cp, an acetyl content of 17 to 26%, and a phthalic acid content of 30 to 40%. The cellulose acetate trimellitate used in the enteric coating has a viscosity of about 5-21cp and an phthalide content of 17-26%. Cellulose acetate trimellitate is manufactured by Eastman Kodak company and can be used for the casing material in the present invention.
The hydroxypropyl methyl cellulose phthalate used in the enteric coating of the invention has a molecular weight of generally 20,000-.
Hydroxypropyl methylcellulose phthalate, which is used in the casing of the present invention, was HP50, produced by Shin-etsu chemidl co.ltd. HP50 contains 6-10% hydroxypropyl, 20-24% methoxy, and 21-27% propyl, and has a molecular weight of 84,000 daltons. Another enteric material is HP55, HP55 contains 5-9% hydroxypropyl methylcellulose phthalate, 18-22% methoxyl, 27-35% phthalic acid, and has a molecular weight of 78,000 daltons.
The sausage casing of the invention is prepared as follows: the enteric coating solution is sprayed onto the core using conventional methods. All solvents in the enteric coating process are alcohols (e.g., ethanol), ketones (e.g., acetone), halogenated hydrocarbon compounds (e.g., dichloromethane), or combinations thereof. Softeners, such as di-n-butyl phthalate and glyceryl triacetate, are added to the enteric coating solution in a ratio of 1 part of the garment to about 0.05 parts or about 0.3 parts softener. The spraying process is preferably carried out continuously, the amount of material sprayed being controlled according to the conditions employed for coating. The spray pressure can be adjusted at will, and in general, the desired results are obtained at an average pressure of 1-1.5 Pa.
For example, in the present invention, a composition comprising 1 × 10-1 × 10 is prepared to provide a composition comprising a pharmaceutically effective amount of the compound of the present invention20cfu/ml or cfu/g (in particular, 1 × 10 can be contained4-1×1015cfu/ml or cfu/g, more particularly, 1 × 106-1×1011cfu/ml or cfu/g) of a probiotic (such as a fermented amino acid coccus, bifidobacterium odonta, or a combination thereof).
When used in the preparation of pharmaceutical compositions, the effective dosage of probiotic gut bacteria (e.g., S.fermentum, S.odontois, or combinations thereof), and/or metabolites thereof, may vary with the mode of administration and the severity of the condition to be treated, dosage forms suitable for oral administration comprise about 1 × 10-1 × 10 in intimate admixture with a solid or liquid pharmaceutically acceptable carrier20cfu/ml or cfu/g (in particular, 1 × 10 can be contained4-1×1015cfu/ml or cfu/g, more particularly, 1 × 106-1×1011cfu/ml or cfu/g) of a viable intestinal probiotic (such as a fermenting amino acid coccus, bifidobacterium odonta, or a combination thereof), or a fermentation-produced active ingredient thereof. This dosage regimen may be adjusted to provide the best therapeutic response. For example, divided doses may be administered several times per day, or the dose may be proportionally reduced, as may be required by the urgency of the condition being treated.
The intestinal probiotic bacteria (such as zymococcus amino acid, bifidobacterium dentis, or the combination thereof) can be administered by oral administration and the like. The solid support comprises: starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose and kaolin, and liquid carriers include: culture medium, polyethylene glycol, nonionic surfactant, and edible oil (such as corn oil, peanut oil, and sesame oil) as appropriate for the characteristics of the probiotic bacteria (such as the bacteria, bifidobacterium animalis, or combinations thereof) of the intestinal tract and the particular mode of administration desired. Adjuvants commonly used in the preparation of pharmaceutical compositions may also advantageously be included, for example flavouring agents, colouring agents, preservatives and antioxidants such as vitamin E, vitamin C, BHT and BHA.
Preferred pharmaceutical compositions are solid compositions, especially tablets and solid-filled or liquid-filled capsules, from the standpoint of ease of preparation and administration. Oral administration is preferred.
The composition of the present invention is administered to the subject 1 or more times per day. Dosage units for administration represent dosages which can be divided formally and which are suitable for human beings or all other mammalian subjects. Each unit containing a pharmaceutically acceptable carrier and a therapeutically effective amount of a microorganism of the invention. The amount administered will vary with the weight of the patient and the severity of the diabetes, the supplemental active ingredients included and the microorganism used. Furthermore, the administration can be divided, if possible, and can be continued, if desired. Therefore, the amount to be administered is not a limitation of the present invention. Further, the "composition" in the present invention means not only a pharmaceutical but also a functional food and a health supplement food. In a preferred embodiment, the composition comprises: beverages, foods, pharmaceuticals, animal feeds, and the like.
In a preferred embodiment of the present invention, there is also provided a food composition comprising an effective amount of a probiotic (e.g., a zymococcus amino acid, bifidobacterium dentis, or a combination thereof) in a form selected from the group consisting of a solid, a dairy product, a solution product, a powder product, and a suspension product, and the balance a food acceptable carrier.
In a preferred embodiment, the formulation of the composition is as follows:
1×10-1×1020cfu/mL of intestinal probiotic bacteria (such as zymococcus amino acids, bifidobacterium bifidum, or combinations thereof); and a food-acceptable or pharmaceutically acceptable carrier, and/or an excipient.
In another preferred embodiment, the formulation of the composition is as follows:
1×106-1×1011cfu/mL of intestinal probiotic bacteria (such as zymococcus amino acids, bifidobacterium bifidum, or combinations thereof); and a food-acceptable or pharmaceutically acceptable carrier, and/or an excipient.
Method for reducing serum glucose, blood lipid and/or glycated hemoglobin levels
In another preferred example, the method comprises: ingesting a pharmaceutical composition, food composition, beverage composition, or a combination thereof, of the present invention. The subject is a human.
In another preferred example, the method comprises: ingesting a pharmaceutical composition, food composition, or animal feed, or a combination thereof, of the present invention. The experimental object is an animal, preferably a mouse or a rabbit.
In another preferred embodiment, the method is also used for improving insulin resistance.
The main advantages of the invention include:
(a) the intestinal probiotics (such as zymococcus amino acid, bifidobacterium dentis or the combination thereof) can obviously inhibit the weight gain.
(b) The intestinal probiotics (such as zymococcus amino acid, bifidobacterium dentium or the combination thereof) can obviously inhibit the rise of serum glucose level, blood fat level and/or glycosylated hemoglobin level and improve insulin resistance, thereby preventing diabetes and related diseases (such as cardiovascular diseases and obesity).
(c) The intestinal probiotics (such as zymococcus amino acid, bifidobacterium dentium or the combination thereof) can remarkably reduce the raised serum glucose level, the blood fat level and/or the glycosylated hemoglobin level and improve the insulin resistance, thereby treating the diabetes and the related diseases (such as cardiovascular diseases and obesity).
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Experimental procedures without specific conditions noted in the following examples, molecular cloning is generally performed according to conventional conditions such as Sambrook et al: the conditions described in the laboratory Manual (New York: Cold Spring Harbor laboratory Press, 1989), or according to the microorganism: the conditions described in the handbook of experiments (James Cappuccino and Natalise Sherman eds., Pearson Edurion Press) or as recommended by the manufacturer.
Example 1 food composition containing probiotic bacteria (e.g., zymococcus amino acids, bifidobacterium odonta, or combinations thereof) in the gut
The raw material formulation is shown in table 1.
TABLE 1 food composition formula
| Raw materials | Mass percent (%) |
| Bacterial composition | 0.5 |
| Milk | 90.0 |
| White sugar | 9.5 |
The bacterial components in formulations 1-6 are single bacterial components, and respectively contain Acidococci microorganisms DSM20731, Acidococci microorganisms ATCC25088, Acidococci microorganisms ATCC25086, Bifidobacterium dense DSM 20436, Bifidobacterium dense DSM 20084 and Bifidobacterium dense DSM 20221.
The bacteria component in the formula 7 is a mixture of any two of the 6 bacteria (weight ratio is 1: 1).
Mixing milk and white sugar according to the above formula ratio, stirring to completely mix, preheating, homogenizing under 20Mpa, sterilizing at 90 deg.C for 5-10 min, cooling to 40-43 deg.C, inoculating 1-100 × 106cfu/g of bacteria component, and making into food composition containing bacteria component (such as fermented amino acid coccus, Bifidobacterium odonta, or their combination).
Example 2
The raw material ratio of the pharmaceutical composition containing intestinal probiotics (such as zymococcus amino acids, bifidobacterium dentis or the combination thereof) is shown in table 2.
TABLE 2 pharmaceutical composition formulations
The bacterial components in formulations 1-6 are single bacterial components, and respectively contain Acidococci microorganisms DSM20731, Acidococci microorganisms ATCC25088, Acidococci microorganisms ATCC25086, Bifidobacterium dense DSM 20436, Bifidobacterium dense DSM 20084 and Bifidobacterium dense DSM 20221.
The bacteria component in the formula 7 is a mixture of any two of the 6 bacteria (weight ratio is 1: 1).
Mixing lactose, yeast powder, and peptone with purified water at a certain proportion, preheating to 60-65 deg.C, homogenizing under 20Mpa, sterilizing at 90 deg.C for 20-30 min, cooling to 36-38 deg.C, inoculating bacteria component (1-50 × 10)6cfu/mL), fermenting at 36-38 deg.C to pH of 6.0, centrifuging, and freeze drying to water content less than 3% to obtain freeze-dried product containing bacteria. Weighing 0.5 g of lyophilized product containing bacteria component, mixing with maltodextrin in equal amount, and encapsulating to obtain medicinal composition containing bacteria component (such as fermented amino acid coccus, Bifidobacterium odonta, or their combination).
Example 3 animal Experimental validation
Experimental materials:
mice: c57BL/6J male mice (4 weeks old, purchased from the experimental animal center of university of zhongshan) were purchased, grown in the same environment, and fed the same diet.
The inventor obtains 6 strains of intestinal probiotics from a depository and saves the intestinal probiotics in Shenzhen Hua Dagene research institute. Meanwhile, selecting; lactobacillus reuteri (Lactobacillus reuteri GMNL-89) purchased from China Center for Type Culture Collection (CCTCC) with the preservation number of CCTCC NO: M207154 as a control group (LR group) was cultured in MRS culture solution at 37 ℃ for 24-48 h.
The source information of the 6 strains of intestinal probiotics is shown in table 3. The bacteria 1-3 are cultured in fermentation amino acid coccus culture fluid (DSMZ Medium 414) at 37 deg.C for 24-48 h. The bacteria 4-6 are anaerobically cultured in Bifidobacterium culture fluid (DSMZ Medium58) at 37 deg.C for 24-48 h. All strains were verified by 16S rDNA sequencing and the experiment was started.
The strain information is shown in Table 3.
TABLE 3 information on the strains
ATCC, American Type Culture Collection;
DSMZ Leibniz-Institute DSMZ-Deutsche Sammlung von Mikroorganismen undZellkulturen GmbH, Germany Collection of microorganisms.
High fat food: 60% fat, 20% carbohydrate and 20% protein, available from Research Diets, USA (D12492).
Ordinary maintenance feed: purchased from the experimental animals center of Zhongshan university.
The experimental method comprises the following steps:
experiment one:
to verify the effect of the strains on mice fed different diets, normal male C57BL/6J mice (4 weeks old, purchased from the experimental animal center at university of zhongshan) were housed in a squirrel cage placed in a controlled environment: the solution is irradiated for 12 hours every day, and the temperature is kept at 22 ℃. Mice can freely eat and drink water, and are randomly grouped after being adaptively fed for 2 weeks, namely a control group (CK), an experimental microbial inoculum group (a bacterium 1 group, a bacterium 2 group, a bacterium 3 group, a bacterium 4 group, a bacterium 5 group, a bacterium 6 group, a bacterium 2+ bacterium 3 group, a bacterium 4+ bacterium 5 group, a bacterium 1+ bacterium 4 group), a control microbial inoculum group (LR, Lactobacillus reuteri GMNL-89) and a high-fat food group (HF), wherein 10 mice are in each group. The LR group, HF group and experimental inoculum group were fed with high-fat diet, and the CK group was fed with normal maintenance diet. The experimental bacteria group and LR group were separately gavaged with 0.2ml of corresponding bacterial liquid (10)8CFU/0.2 ml); the HF group and CK group were gavaged with an equal amount of physiological saline for 8 weeks, and body weights were measured once a week (fig. 1-3 and tables 4-6).
Experiment two:
to verify the effect of the strain on diabetes model mice, normal male C57BL/6J mice (4 weeks old, purchased from Experimental animal of Zhongshan university)Center of the animal) in a squirrel cage placed in a controlled environment: the solution is irradiated for 12 hours every day, and the temperature is kept at 22 ℃. Mice can freely eat and drink water, and are adaptively fed for 2 weeks and then fed with high-fat food for 8 weeks. At 4 weeks, the mice with fasting blood sugar content higher than 10.0mmol/L are selected and randomly grouped after the next 4 weeks, and are respectively an experimental microbial inoculum group (a bacterium 1 group, a bacterium 2 group, a bacterium 3 group, a bacterium 4 group, a bacterium 5 group, a bacterium 6 group, a bacterium 2+ bacterium 3 group, a bacterium 4+ bacterium 5 group, a bacterium 1+ bacterium 4 group), a control microbial inoculum group (LR) and a diabetes model group (DM), wherein 10 mice are selected. The experimental microbial inoculum group and LR group were separately intragastrically administered with 0.2ml of corresponding bacterial strain liquid (10)6～108CFU/0.2 ml); the DM group was gavaged with an equal amount of normal saline for 8 weeks, and all mice were fed the same high fat diet and in the same living environment.
Blood parameters
After the mice had an empty stomach for 16 hours, blood was drawn from the retrobulbar capillaries and capillary vessels in the orbit, respectively, and immediately stored in a refrigerator at 4 ℃. Separating plasma, and storing at-20 deg.C. Serum glucose baseline levels were determined using a glucose meter (purchased from Roche Diagnostics); measuring the serum triglyceride level by using an enzyme reaction-spectrophotometric thermometer measuring coupling reagent kit; serum insulin levels and glycated hemoglobin (HbA1c) levels were measured using an ELISA kit (Nanjing institute of bioengineering).
Statistical analysis of data
Data results are expressed as mean ± sem. Significance analysis was performed after analysis of variance (ANOVA) using the Tuckey multiple comparison method (GraphPad Software, San Diego, CA, USA), and a p <0.05 was considered statistically significant.
The experimental results are as follows:
(1) effect of zymococcus amino acids, bifidobacterium odonta, or a combination thereof on body weight in mice.
TABLE 4 weight gain in mice of each group after fermentation with M.gastricium (FIG. 1)
TABLE 5 weight gain in mice of each group after administration of Bifidobacterium gastrodiae (FIG. 2)
TABLE 6 weight gain of mice in each group after gavage of the combination bacteria (FIG. 3)
The results are shown in FIGS. 1 to 3 and tables 4 to 6. The results show that in the growth curve of the mice, the body weight of the mice fed only high fat diet was significantly higher than the body weight of the mice fed the normal maintenance diet (p <0.05) by 8 weeks of feeding. Mice fed both bacteria (zymococcus amino acids, bifidobacterium dentis, or combinations thereof) and high fat diet were significantly lower in body weight than mice fed only high fat diet (p <0.05), and also lower in LR group. The results indicate that zymococcus amino acids, bifidobacterium dentis, or combinations thereof can effectively control the incidence of obesity in mice and contribute to the prevention of type II diabetes.
(2) Effect of zymococcus amino acids, bifidobacterium odonta, or a combination thereof on serum glucose levels in mice fed a high fat diet.
TABLE 7 Effect of Pegastrogenic Aminococcus on serum glucose levels in mice fed high fat diet (FIG. 4)
Note: the data in the tables are mean ± standard deviation, and no identical letter after the number indicates significant difference (p <0.05) for any two sets of data in each column, as is the case for tables 7-18.
TABLE 8 Effect of Bifidobacterium gastrolavage on serum glucose levels in mice fed high fat diet (FIG. 5)
TABLE 9 Effect of the gastric lavage combination on serum glucose levels in mice fed high fat diet (FIG. 6)
The results are shown in tables 7 to 9 and FIGS. 4 to 6. There were no differences in serum glucose levels in the groups of mice (6 weeks of age) before the first experiment was performed (p > 0.05). The results show that there was no significant change in serum glucose levels in CK mice fed with the normal maintenance diet after 8 weeks of experimental treatment. While HF group mice fed high fat diet had significantly increased serum glucose levels. The serum glucose levels of mice treated with s.fermentum, b.dentata, or a combination thereof were significantly lower than those of the HF group fed only high fat diet (p <0.05), although higher than those of the CK group.
The results indicate that zymococcus amino acids, bifidobacterium odonta, or a combination thereof can significantly reduce serum glucose levels in mice fed a high fat diet.
(3) Effect of zymococcus amino acid, bifidobacterium odonta, or a combination thereof on serum glucose levels in diabetic model mice.
TABLE 10 influence of Zymobacter inoculums on serum glucose levels in diabetic model mice (FIG. 7)
TABLE 11 Effect of Bifidobacterium gastrolavage on serum glucose levels in mice model with diabetes (FIG. 8)
TABLE 12 Effect of gastric lavage combination bacteria on serum glucose levels in diabetic mice (FIG. 9)
The results are shown in tables 10 to 12 and FIGS. 7 to 9. Serum glucose was not different in all groups of mice (14 weeks old) before the diabetes model mouse experiment was performed. The results show that after 4 weeks of experimental treatment, the serum glucose levels of the mice in the diabetes model group (DM group) are significantly increased, while the serum glucose levels of the mice added with the microbial inoculum are lower than those in the DM group. After 8 weeks, mice fed the inoculum(s) (zymococcus amino acid, bifidobacterium dentale, or a combination thereof) had significantly lower serum glucose levels than the DM group (p < 0.05).
The results show that the content of the serum glucose of the diabetes model mouse can be obviously reduced by the zymococcus amino acid, the bifidobacterium odonta or the combination thereof.
(4) Effect of zymococcus amino acids, bifidobacterium odonta, or a combination thereof on serum triglyceride, insulin, and glycated hemoglobin (HbA1c) levels in mice fed high fat diet.
TABLE 13 effects of Pegastrogenic Aminococcus on serum triglyceride, insulin and glycated hemoglobin (HbA1c) levels fed to mice fed high fat diet (FIG. 10)
TABLE 14 Effect of Bifidobacterium gastrolavage on serum triglyceride, insulin and glycated hemoglobin (HbA1c) levels in mice fed high fat diet (FIG. 11)
TABLE 15 Effect of gastric lavage combination bacteria on serum triglyceride, insulin and glycated hemoglobin (HbA1c) levels in mice fed high fat diet (FIG. 12)
The results are shown in tables 13 to 15 and FIGS. 10 to 12. Serum triglyceride, insulin and HbA1c levels of normal mice (6 weeks of age) were not different in all groups before experiment one was performed. The results show that after 8 weeks of experimental treatment, blood parameters remained unchanged for mice fed with maintained normal diet, while serum triglyceride, insulin and HbA1c levels were significantly increased for mice fed with high fat diet (HF group), and serum triglyceride, insulin and HbA1c levels were significantly lower on average than for mice fed with high fat diet alone (p <0.05) for mice treated with s.
The results show that the zymococcus amino acid, the bifidobacterium odonta or the combination thereof can obviously reduce the serum triglyceride and HbA1c level of mice fed with high-fat food and can obviously improve the insulin resistance.
(5) The effect of zymococcus amino acid, bifidobacterium odonta, or a combination thereof on serum triglyceride, insulin, and glycated hemoglobin (HbA1c) levels in diabetic model mice.
TABLE 16 Effect of Pestichopus acidilactici on serum triglyceride, insulin and glycated hemoglobin (HbA1c) levels in diabetic model mice (FIG. 13)
TABLE 17 Effect of Bifidobacterium gastrolavage on serum triglyceride, insulin and glycated hemoglobin (HbA1c) levels in diabetic model mice (FIG. 14)
TABLE 18 Effect of gastric lavage combination bacteria on serum triglyceride, insulin and glycated hemoglobin (HbA1c) levels in diabetic model mice (FIG. 15)
The results are shown in tables 16 to 18 and FIGS. 13 to 15. The results show that mice treated with s.fermentum, b.dentis, or a combination thereof after 8 weeks all had significantly lower serum triglyceride, insulin, and HbA1c levels than the DM group of mice.
The results show that the zymococcus amino acid, the bifidobacterium odonta or the combination thereof can obviously reduce the content of serum triglyceride and HbA1c of a diabetes model mouse and obviously improve the insulin resistance.
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.
Claims (12)
1. Use of an intestinal probiotic for the preparation of a composition or formulation for one or more uses selected from the group consisting of: (a) preventing and/or treating diabetes; and/or (b) preventing and/or treating obesity, wherein the gut probiotic is selected from the group consisting of: fermented aminoacidococci (Acidococcus fermentum), or a combination of fermented aminoacidococci and Bifidobacterium (Bifidobacterium dentistry) bacteria.
2. The use according to claim 1, wherein the Bifidobacterium odonta (Bifidobacterium) is selected from the group consisting of: bifidobacterium genus DSM 20436, Bifidobacterium genus DSM 20084, Bifidobacterium genus DSM 20221, or a combination thereof.
3. Use according to claim 1, wherein the amino acid fermenting cocci (Acylaminococcus fermentans) are selected from the group consisting of: acylaminococcus transferans DSM20731, Acylaminococcus transferans ATCC25088, Acylaminococcus transferans ATCC25086, or a combination thereof.
4. Use of an intestinal probiotic for the preparation of a composition or formulation for one or more uses selected from the group consisting of: (i) lowering serum glucose levels in a mammal; and/or (ii) improving insulin resistance in a mammal, wherein the intestinal probiotic is selected from the group consisting of: fermented aminoacidococci (Acidococcuseferments), or a combination of fermented aminoacidococci (Acidococci fermentum) with Bifidobacterium (Bifidobacterium denum).
5. The use according to claim 4, wherein the composition or formulation is also used independently or additionally for one or more uses selected from the group consisting of:
(i) inhibiting weight gain in a mammal;
(ii) Reducing blood lipid levels in a mammal.
6. A composition for the treatment and/or prevention of diabetes, said composition comprising: (i) a safe and effective amount of a probiotic; and (ii) a pharmaceutically acceptable carrier; wherein the intestinal probiotic is a combination of fermented amino acid coccus (Acidococcus fermentum) and Bifidobacterium (Bifidobacterium dentistry).
7. The composition of claim 6, wherein said composition comprises 1 × 10-1 × 1020cfu/mL or cfu/g of probiotic bacteria, in total volume of the composition orTotal weight of the composition.
8. The composition of claim 7, wherein said composition comprises 1 × 104-1×1015cfu/mL or cfu/g of intestinal probiotic bacteria, based on the total volume or total weight of the composition.
9. The composition of claim 6, wherein said composition comprises from 0.0001 to 99 wt% of said probiotic, based on the total weight of said composition.
10. The composition of claim 9, wherein said composition comprises from 0.1 wt% to 90 wt% of said intestinal probiotic, based on the total weight of said composition.
11. The composition of claim 6, wherein the composition further comprises other gut probiotics and/or prebiotics.
12. A method of making the composition of claim 6, comprising the steps of:
mixing (i) a probiotic gut bacteria in combination with (ii) a pharmaceutically acceptable carrier, thereby forming the composition of claim 6, wherein the probiotic gut bacteria is a combination of zymococcus amino acids (Acidococci) and Bifidobacterium dentis (Bifidobacterium).
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