CN107080756B - Use of probiotic bacteria of the genus streptococcus for the prevention and/or treatment of diabetes and related diseases - Google Patents
Use of probiotic bacteria of the genus streptococcus for the prevention and/or treatment of diabetes and related diseases Download PDFInfo
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- CN107080756B CN107080756B CN201610086713.3A CN201610086713A CN107080756B CN 107080756 B CN107080756 B CN 107080756B CN 201610086713 A CN201610086713 A CN 201610086713A CN 107080756 B CN107080756 B CN 107080756B
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Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/66—Microorganisms or materials therefrom
- A61K35/74—Bacteria
- A61K35/741—Probiotics
- A61K35/744—Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
Abstract
The invention discloses application of streptococcus probiotics in preventing and treating diabetes and related diseases, and particularly relates to the streptococcus 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 streptococcus probiotic disclosed by the invention can obviously inhibit weight gain, reduce serum glucose level, reduce blood fat 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 streptococcus probiotics in preventing and/or treating diabetes and related diseases, and also relates to a composition containing streptococcus 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 probiotic bacteria of the genus streptococcus for the prevention and/or treatment of diabetes and diseases related thereto.
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 a probiotic bacterium of the genus Streptococcus (Streptococcus) 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,
in another preferred embodiment, the streptococcus probiotic is selected from the group consisting of: streptococcus infantis (Streptococcus indumentis), Streptococcus vestibuli (Streptococcus vesicularis), or a combination thereof.
In another preferred embodiment, said Streptococcus infantis (Streptococcus infantis) is selected from the group consisting of: streptococcus infantis DSM12492, Streptococcus infantis ATCC BAA-208, Streptococcus infantis ATCC 700780, or a combination thereof.
In another preferred embodiment, the Streptococcus vestibuli (Streptococcus vesicularis) is selected from the group consisting of: streptococcus vascularis DSM 5636, Streptococcus vascularis ATCC 49126, Streptococcus vascularis ATCC 20125, or combinations 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 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 a probiotic of the genus streptococcus 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; (ii) improving insulin resistance in a mammal; and/or (iii) reducing glycated hemoglobin (HbA1c) levels in the mammal.
In another preferred embodiment, the streptococcus probiotic is selected from the group consisting of: streptococcus infantis (Streptococcus indumentis), Streptococcus vestibuli (Streptococcus vesicularis), or a combination 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 of the genus streptococcus; and (ii) a food-or pharmaceutically acceptable carrier; wherein the streptococcus probiotic is selected from the group consisting of: streptococcus infantis (Streptococcus infantis), Streptococcus vestibuli (Streptococcus vesicularis), or a combination thereof.
In another preferred embodiment, the streptococcus probiotic is selected from the group consisting of: streptococcus infantis (Streptococcus indumentis), Streptococcus vestibuli (Streptococcus vesicularis), or a combination thereof.
In another preferred embodiment, said Streptococcus infantis (Streptococcus infantis) is selected from the group consisting of: streptococcus infantis DSM12492, Streptococcus infantis ATCC BAA-208, Streptococcus infantis ATCC 700780, or a combination thereof.
In another preferred embodiment, the Streptococcus vestibuli (Streptococcus vesicularis) is selected from the group consisting of: streptococcus vascularis DSM 5636, Streptococcus vascularis ATCC 49126, Streptococcus vascularis ATCC 20125, or combinations 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.
At another placeIn a preferred embodiment, the composition comprises 1 × 10-1 × 1020cfu/mL or cfu/g of Streptococcus probiotic, preferably 1 × 104-1×1015cfu/mL or cfu/g of streptococcus probiotic, 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 streptococcus species probiotic bacteria, 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 probiotics and/or prebiotics.
In another preferred embodiment, the other probiotic is 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:
admixing (i) a streptococcus probiotic, wherein the streptococcus probiotic is selected from the group consisting of: streptococcus infantis (Streptococcus infantis), Streptococcus vestibuli (Streptococcus vesicularis), or a combination thereof.
In another preferred embodiment, the composition is an oral preparation.
In a fifth aspect, the present invention provides a method of reducing serum glucose, blood lipids and/or glycated hemoglobin levels by administering to said subject (i) a probiotic of the genus streptococcus selected from the group consisting of: streptococcus infantis (Streptococcus infantis), Streptococcus vestibuli (Streptococcus vesicularis), or a combination 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 the groups of mice after S.infringens gavage.
FIG. 2 shows the weight gain of the groups of mice after gastric lavage of S.vestibuli.
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 Streptococcus infusate on serum glucose levels in mice fed high fat diet.
FIG. 5 shows the effect of intragastric Streptococcus vestibuli 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 Streptococcus infusate on serum glucose levels in mice of the diabetic model.
FIG. 8 shows the effect of intragastric Streptococcus vestibuli on serum glucose levels in mice from a 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 Streptococcus infusate on serum triglyceride, insulin and glycated hemoglobin (HbA1c) levels in mice fed a high fat diet.
FIG. 11 shows the effect of intragastric vestibular streptococci 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 S.infundibulum on serum triglyceride, insulin and glycated hemoglobin (HbA1c) levels in mice from a diabetic model.
FIG. 14 shows the effect of intragastric vestibular streptococci on serum triglyceride, insulin and glycated hemoglobin (HbA1c) levels in diabetic model mice.
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 have unexpectedly found that streptococcus species probiotic bacteria have an effect of preventing and/or treating diabetes and related diseases, and that feeding an active composition containing streptococcus species probiotic bacteria to a subject results in the composition being capable of inhibiting weight gain, lowering serum glucose levels, lowering blood lipid levels, improving insulin resistance and/or lowering glycated hemoglobin levels, and effectively alleviating conditions of diabetes and related diseases (e.g., cardiovascular diseases, 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.
The streptococcus probiotics of the present invention and the application thereof
As used herein, the "streptococcus probiotic of the present invention" refers to one or more mixtures of multiple bacteria in streptococcus probiotic.
In a preferred embodiment of the invention, the probiotic bacteria of the genus streptococcus are selected from the group consisting of: streptococcus infantis (Streptococcus infantis), Streptococcus vestibuli (Streptococcus vesicularis), or a combination thereof.
Streptococcus (Streptococcus) is 1 genus of Streptococcus (Streptococcus), a group of coccoid gram-positive bacteria. These bacterial cells divide along one axis at all times, and are therefore usually paired or chained. Because of these characteristics, they are called "streptococci", distinguished from "staphylococci" (Staphylococcus) which can divide along multiple axes to form a mass of cells.
Streptococcus infantis is a facultative anaerobe, gram-positive, produces no spores, is immotile, and produces no catalase. The cells are spherical, have a diameter of about 0.6-1.0mm, and grow in a single dispersed form or a chain form.
The streptococcus vestibuli is microaerophilic bacterium, gram staining is positive, and no catalase is produced. The cells were spherical, about 1 μm in diameter, and grew in a chain form.
The invention provides application of streptococcus probiotic bacteria in preventing and/or treating diabetes and related diseases. The streptococcus probiotic has: a) inhibiting 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, which are gazed with streptococcus probiotic bacteria and fed with high-fat foods, have a reduced increase in body weight, an increased increase in various indices related to diabetes and related diseases (e.g., cardiovascular disease, obesity) such as serum glucose level, blood lipid level and glycated hemoglobin level, and a significant improvement in insulin resistance, compared to a control group that has not received gavage.
According to another preferred embodiment of the present invention, the diabetes model C57BL/6J male mice treated with streptococcus probiotic have significantly reduced indices associated with diabetes and its associated 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 streptococcus probiotic 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 a probiotic of the genus streptococcus, in a preferred embodiment the composition further comprises a probiotic 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 streptococcus probiotic.
When used in the preparation of a pharmaceutical composition, an effective amount of a probiotic of the genus Streptococcus (e.g., Streptococcus infantis, Streptococcus vestibuli, or combinations thereof), and/or metabolites thereof is usedSuitable dosage forms 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 active streptococcus species, or active ingredients produced by fermentation 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 probiotic bacteria of the streptococcus genus can be administered by oral administration or 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 probiotic properties of Streptococcus 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 of the genus streptococcus 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 streptococcus probiotic; 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 streptococcus probiotic; 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 streptococcus probiotic of the present invention is capable of significantly inhibiting weight gain.
(b) The streptococcus probiotic bacteria can obviously inhibit the rise of serum glucose level, blood fat level and/or glycosylated hemoglobin level, improve insulin resistance, and prevent diabetes and related diseases (such as cardiovascular diseases and obesity).
(c) The streptococcus probiotic bacteria can obviously reduce the raised serum glucose level, the blood fat level and/or the glycosylated hemoglobin level and improve the insulin resistance, thereby treating diabetes and 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 of the genus Streptococcus (e.g., Streptococcus infantis, Streptococcus vestibuli, or combinations thereof)
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 fractions in formulas 1-6 are single bacterial fractions containing Streptococcus inflatais DSM12492, Streptococcus inflatais ATCC BAA-208, Streptococcus inflatais ATCC 700780, Streptococcus vascularis DSM 5636, Streptococcus vascularis ATCC 49126, and Streptococcus vascularis ATCC 20125, respectively.
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, namely making into food composition containing bacteria component (such as Streptococcus infantis, Streptococcus vestibuli, or their combination).
Example 2
Pharmaceutical composition containing Streptococcus probiotic (such as Streptococcus infantis, Streptococcus vestibuli, or combinations thereof)
The raw material ratio is shown in table 2.
TABLE 2 pharmaceutical composition formulations
| Raw materials | Mass percent (%) |
| Bacterial composition | 1.0％ |
| Lactose | 2.0％ |
| Yeast powder | 2.0％ |
| Peptone | 1.0％ |
| Purified water | 94.0％ |
The bacterial fractions in formulas 1-6 are single bacterial fractions containing Streptococcus inflatais DSM12492, Streptococcus inflatais ATCC BAA-208, Streptococcus inflatais ATCC 700780, Streptococcus vascularis DSM 5636, Streptococcus vascularis ATCC 49126, and Streptococcus vascularis ATCC 20125, respectively.
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 lyophilized product containing bacteria component, mixing with maltodextrin, and encapsulating to obtain medicinal composition containing bacteria component (such as Streptococcus infantis, Streptococcus vestibuli, 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 streptococcus from the depository and saves the 6 strains in Shenzhen Hua Dageneva research institute. Meanwhile, Lactobacillus reuteri GMNL-89, which is purchased from China Center for Type Culture Collection (CCTCC) with the preservation number of CCTCC NO: M207154, is selected as a control group (LR group) to be cultured in MRS culture solution for 24-48h at 37 ℃.
The information on the origin of the 6 streptococci is shown in Table 3. All strains were anaerobically cultured in trypticase soy yeast extract broth (DSMZ Medium 92) for 24-48h at 37 ℃. 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 6 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 (results are shown in FIGS. 1-3 and tables 4-6).
Experiment two:
to verify the effect of the strains on diabetes model mice, normal male C57BL/6J mice (4 weeks old, purchased from the Experimental animals center of Zhongshan university) were housed in mouse cages placed in controlled positionsIn the 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 6 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. Baseline serum glucose 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 presented as mean ± standard deviation. Significance analysis was performed after analysis of variance (ANOVA) using the Tuckey multiple comparison method (GraphPad Software, San Diego, CA, USA), and p <0.05 was considered statistically significant.
The experimental results are as follows:
(1) effect of streptococcus infantis, streptococcus vestibuli, or a combination thereof on body weight in mice.
TABLE 4 weight gain in mice of each group after intragastric Streptococcus infringes (FIG. 1)
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 5-18.
TABLE 5 weight gain following gastric lavage of vestibular streptococci in groups of mice (FIG. 2)
TABLE 6 weight gain of mice in each group after gavage of the combination bacteria (FIG. 3)
Obesity is a major risk Factor for Insulin Resistance (Seamus Crowe, et al, PigmentEpithelium-Derived Factor controls to Insulin Resistance in Obesistance. CellMetabolim, Volume 10, Issue 1,40-47, doi:10.1016/j. cmet al, 2009.06.001, incorporated herein by reference) and can induce type II diabetes, and thus, control of obesity helps prevent type II diabetes.
The results are shown in tables 4 to 6 and FIGS. 1 to 3. The results show that in the growth curve of the mice, the body weight of the mice fed only high fat diet is significantly higher than the body weight of the mice fed the normal maintenance diet (p <0.05) by 8 weeks of feeding; mice fed a probiotic of the streptococcus genus of the invention (streptococcus infantis, streptococcus vestibuli, or a combination thereof) and a high fat diet at the same time were significantly less heavy than mice fed a high fat diet alone (p < 0.05); also, the body weight of mice fed with the inventive streptococcus probiotic was significantly lower (p <0.05) than the body weight of mice fed with Lactobacillus reuteri GMNL-89.
The results show that the streptococcus infantis, the streptococcus vestibuli or the combination thereof can effectively control the obesity incidence of mice and help to prevent type II diabetes, and the effect is obviously better than that of lactobacillus reuteri.
(2) Effect of streptococcus infantis, streptococcus vestibuli, or a combination thereof on serum glucose levels in mice fed a high fat diet.
TABLE 7 Effect of Streptococcus gasseris infusate on serum glucose levels in mice fed high fat diet (FIG. 4)
TABLE 8 Effect of intragastric Streptococcus vestibuli 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. Prior to the first experiment, the serum glucose levels of the groups of mice (6 weeks of age) were all non-different (p > 0.05). The results show that after 8 weeks of experimental treatment, the serum glucose content of CK mice fed with the ordinary maintenance feed is not obviously changed; the content of the glucose in the serum of the HF group mice fed with high-fat food is greatly increased; the serum glucose levels of mice treated with streptococcus infantis, streptococcus vestibuli, or a combination thereof, while higher than normal fed CK mice, were significantly lower than HF mice fed a high fat diet only (p < 0.05); also, serum glucose levels were significantly lower in mice treated with Streptococcus infantis, Streptococcus vestibuli, or a combination thereof than in mice treated with Lactobacillus reuteri (p < 0.05).
The results show that the streptococcus infantis, the streptococcus vestibuli or the combination thereof can obviously reduce the serum glucose level of mice fed with high-fat food, and the effect is obviously better than that of the lactobacillus reuteri.
(3) Effects of Streptococcus infantis, Streptococcus vestibuli, or a combination thereof on serum glucose levels in a diabetic model mouse.
TABLE 10 Effect of intragastric Streptococcus infantis on serum glucose levels in diabetic model mice (FIG. 7)
TABLE 11 influence of Pestichopus bartholinicus on serum glucose levels in diabetic model mice (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 (experiment two) was performed. The results show that after 4 weeks of experimental treatment, the serum glucose content of the mice of the diabetes model group (DM group) is obviously increased, while the serum glucose content of the mice added with the microbial inoculum is lower than that of the control group. After 8 weeks, serum glucose levels of mice fed simultaneously with the inoculum were significantly lower than in the DM group (p < 0.05); also, serum glucose levels were significantly lower in mice treated with Streptococcus infantis, Streptococcus vestibuli, or a combination thereof than in mice treated with Lactobacillus reuteri (p < 0.05).
The result shows that the streptococcus infantis, the streptococcus vestibuli or the combination thereof can obviously reduce the serum glucose content of a mouse model with diabetes, and the effect is obviously better than that of lactobacillus reuteri.
(4) Effect of streptococcus infantis, streptococcus vestibuli, or a combination thereof on serum triglyceride, insulin, and glycated hemoglobin (HbA1c) levels in mice fed a high fat diet.
TABLE 13 Effect of intragastric Streptococcus infantis on serum triglyceride, insulin and glycated hemoglobin (HbA1c) levels fed to mice fed a high fat diet (FIG. 10)
TABLE 14 Effect of intragastric vestibular Streptococcus on serum triglyceride, insulin and glycated hemoglobin (HbA1c) levels in mice fed a high fat diet (see FIG. 11)
TABLE 15 Effect of gastric lavage combination bacteria on serum triglyceride, insulin and glycated hemoglobin (HbA1c) levels in mice fed a high fat diet (see 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, the blood parameters remained unchanged for mice fed with the normal maintenance feed, while serum triglyceride, insulin and HbA1c levels were significantly increased in mice fed with high fat diet (HF group), with serum triglyceride, insulin and HbA1c levels significantly lower in mice treated with streptococcus infantis, streptococcus vestibuli, or a combination thereof than in mice fed with high fat diet alone; also, serum triglyceride, insulin, and glycated hemoglobin (HbA1c) levels of mice in the Streptococcus infantis, Streptococcus vestibuli, or combinations thereof treated group were significantly lower than those in the Lactobacillus reuteri treated group (p < 0.05).
The results show that the streptococcus infantis, the streptococcus vestibuli or the combination thereof can obviously reduce the serum triglyceride and HbA1c level of mice fed with high-fat food, can obviously improve the insulin resistance and has the effect which is obviously better than that of the lactobacillus reuteri.
(5) Effects of streptococcus infantis, streptococcus vestibuli, or a combination thereof on serum triglyceride, insulin, and glycated hemoglobin (HbA1c) levels in a diabetic model mouse.
TABLE 16 Effect of intragastric Streptococcus infantis on serum triglyceride, insulin and HbA1c levels in diabetic model mice (FIG. 13)
TABLE 17 Effect of intragastric vestibular Streptococcus on serum triglyceride, insulin and HbA1c levels in diabetic model mice (FIG. 14)
TABLE 18 Effect of gastric lavage combination bacteria on serum triglyceride, insulin and 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 streptococcus infantis, streptococcus vestibuli, or a combination thereof for 8 weeks all had significantly lower serum triglyceride, insulin, and HbA1c levels than the DM group; also, serum triglyceride, insulin, and glycated hemoglobin (HbA1c) levels of the streptococcus infantis, streptococcus vestibuli, or a combination thereof-treated group of diabetes model mice were significantly lower than those of the lactobacillus reuteri-treated group of diabetes model mice (p < 0.05).
The result shows that the streptococcus infantis, the streptococcus vestibuli or the combination thereof can obviously reduce the content of serum triglyceride and HbA1c of a diabetes model mouse, obviously improve insulin resistance and have the effect which is obviously better than that of the lactobacillus reuteri.
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 (11)
1. Use of a probiotic bacterium of the genus Streptococcus (Streptococcus) 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; the streptococcus probiotic is selected from the group consisting of: a Streptococcus vestibuli (Streptococcus vesicularis), or a combination of a Streptococcus vestibuli (Streptococcus vesicularis) and a Streptococcus infantis (Streptococcus infanis), the cardiovascular disease is hyperlipidemia.
2. Use according to claim 1, characterized in that the Streptococcus infantis (Streptococcus infantis) is selected from the group consisting of: streptococcus infantis DSM12492, Streptococcus infantis ATCC BAA-208, Streptococcus infantis ATCC 700780, or a combination thereof.
3. Use according to claim 1, wherein the streptococcus vestibuli (streptococcus vesicularis) is selected from the group consisting of: streptococcus vesicular tissue DSM 5636, Streptococcus vesicular tissue ATCC 49126, Streptococcus vesicular tissue ATCC 20125, or a combination thereof.
4. Use of a probiotic of the genus streptococcus 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; the streptococcus probiotic is selected from the group consisting of: streptococcus vestibuli (Streptococcus vesicularis), or a combination of Streptococcus vestibuli (Streptococcus vesicularis) and Streptococcus infantis (Streptococcus infantis).
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, wherein the composition comprises: (i) a safe and effective amount of a probiotic of the genus streptococcus; and (ii) a pharmaceutically acceptable carrier; wherein the probiotic bacteria of the genus Streptococcus is a combination of Streptococcus infantis (Streptococcus infantis) and Streptococcus vestibuli (Streptococcus vestigialis).
7. The composition of claim 6, wherein said composition comprises 1 × 10-1 × 1020cfu/mL or cfu/g of streptococcus probiotic, based on the total volume or total weight of the composition.
8. The composition of claim 7, wherein said composition comprises 1 × 104-1×1015cfu/mL or cfu/g of streptococcus probiotic, 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 Streptococcus species, based on the total weight of said composition.
10. The composition of claim 9, wherein said composition comprises from 0.1 to 90 wt% of said streptococcus species probiotic, based on the total weight of said composition.
11. A method of making the composition of claim 6, comprising the steps of:
mixing (i) a Streptococcus probiotic, wherein the Streptococcus probiotic is a combination of Streptococcus infantis (Streptococcus infanis) and Streptococcus vestibuli (Streptococcus vesicularis), with (ii) a pharmaceutically acceptable carrier, thereby forming the composition of claim 6.
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