CN107208037A - Purposes of the Bacteroides in prevention and treatment coronary artery disease - Google Patents
Purposes of the Bacteroides in prevention and treatment coronary artery disease Download PDFInfo
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- CN107208037A CN107208037A CN201480082329.5A CN201480082329A CN107208037A CN 107208037 A CN107208037 A CN 107208037A CN 201480082329 A CN201480082329 A CN 201480082329A CN 107208037 A CN107208037 A CN 107208037A
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- bacteroides vulgatus
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- 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
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- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/135—Bacteria or derivatives thereof, e.g. probiotics
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- A61K31/60—Salicylic acid; Derivatives thereof
- A61K31/612—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid
- A61K31/616—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid by carboxylic acids, e.g. acetylsalicylic acid
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Abstract
Bacteroides bacterium bacterial strain is preparing the coronary artery disease for treating and/or preventing subject, or for reducing the blood glucose or blood lipid level of subject or for the purposes in the preparation for the coronary atherosclerosis for improving subject.A kind of preparation (such as pharmaceutical composition, nutraceutical composition or food composition) comprising Bacteroides bacterium.A kind of coronary artery disease for being used to treating and/or preventing subject, or reduction subject blood glucose blood lipid level or improve subject coronary atherosclerosis method, this method include to subject in need apply effective dose Bacteroides bacterium bacterial strain the step of.
Description
The cross reference of related application
Nothing
Field
The present invention relates to microbiology.In particular it relates to which Bacteroides bacterium bacterial strain is being prepared for tested
Treated in person and/or prevent coronary artery disease or for reducing blood glucose or blood lipid level or athero- hard for improving coronary artery
Change the purposes in the preparation of lesion.The invention further relates to the preparation comprising Bacteroides bacterium (such as pharmaceutical composition, nutritional drugs
Physical property composition or food composition).The invention further relates to in subject treat and/or prevent coronary artery disease or
Reduce blood glucose or blood lipid level or improve the method for coronary atherosclerosis, this method includes tested to have that this needs
The step of person applies the Bacteroides bacterium bacterial strain of effective dose.
Background
Coronary artery disease (CAD) refers to any unusual condition coronarius, centripetal (i.e. heart) flesh of its interference or its
Any part delivers enough blood supplies.Generally, CAD is the accumulation (that is, atherosclerosis) on arterial wall by patch
It is caused, particularly in the large-scale and medium-sized artery of heart is served.The reason for these patient's condition have similar, mechanism and control
Treat.CAD represents global dead and morbidity main cause.
Current knowledge shows h and E factor and its interaction co-induction complicated phenotype and many diseases.
Coronary artery disease (CAD) passes through GWAS (full-length genome associations point in recent years as one of complex disease with strongest influence power
Analysis) studied more and more, and have revealed that 10.6% inherent cause represents (Ehret, G.B. by 46 common variations
Deng Genetic variants in novel pathways influence blood pressure and
Cardiovascular disease risk.Nature 478,103-109, are incorporated herein by reference).However, still needing
Will more influence on environmental factor such as enteric microorganism and genes and microorganism to the knowledge of the contribution of disease.
Our " organ passed into silence ", intestinal microbiota is played most important to our health in many aspects
Effect, such as from food intake energy, produce important metabolin, promote development and the maturation of immune system, and protection
Host is from pathogenic infection etc..It has recently been demonstrated that flora ecological disturbance, chronic inflammation and metabolic disorder be present in it is some
In metabolic disease such as the enteron aisle of diabetes and obesity.Coronary artery disease is characterized in inflammation, oxidation and lipid-metabolism, this
May be potentially relevant with enteric microorganism and its metabolin.One recent studies have indicated that, enteric microorganism can be by red meat composition
(such as VBT, phosphatidyl choline, cholesterol) is metabolized to TMA, and it will be further oxided into TMAO in liver, so that
Cause oxidation reaction in blood vessel, and then cause inflammation and lipidosis, ultimately cause atherosclerosis and coronary heart disease.Meanwhile,
Compared with health volunteer, the intestinal microbiota of the patient with symptomatic atherosclerotic shows obvious exception
(Intestinal microbiota metabolism of L-carnitine, a nutrient such as Koeth, R.A. in
Red meat, promotes atherosclerosis.Nature medicine 19,576-585, are incorporated by reference into this
Text).These researchs show that the ecological disturbance of enteric microorganism can be by inducing mankind's metabolic disorder to significantly affect coronary artery disease
The pathogenesis of disease.However, intestinal bacilli illness is in the pathogenesis of the coronary artery disease induced by atherosclerosis
Effect and its influence to metabolic system still make us puzzled.
Summary
The disclosure is intended at least solve at least one problem present in prior art to a certain extent.
The present invention is based at least partially on the following discovery of the present inventor.
The assessment of intestinal microbiota and sign have turned into the main of human diseases (including coronary artery disease (CAD)) and ground
Study carefully field.In order to analyze the enteric microorganism content in CAD patient, the present inventor is based on to individual from 165
The depth shotgun sequencing of intestinal microbial DNA sample, has carried out scheme (Qin, the J. of grand genome association analysis (MGWAS)
Deng A metagenome-wide association study of gut microbiota in type
2diabetes.Nature 490,55-60 (2012), are incorporated herein by reference).
The present inventor identifies 2 kinds of Bacteroides probiotics.Then, the present inventor has separately verified above-mentioned 2 kinds of bacteroids
Belong to influence of the probiotics in zoopery to CAD.The result of zoopery demonstrates bacteroides uniformis (Bacteroides
Uniformis) and bacteroides vulgatus (Bacteroides vulgatus) effective prevention and treatment CAD ability.
Therefore, in one aspect, prepared the invention provides bacteroides uniformis and/or bacteroides vulgatus for treating
And/or the coronary artery disease of prevention subject, or for reducing the blood glucose or blood lipid level of subject, or it is tested for improving
Purposes in the preparation of the coronary atherosclerosis of person.
In second aspect, the invention provides in the coronary artery disease for treating and/or preventing subject, or use
In the blood glucose or blood lipid level of reduction subject or for the preparation for the coronary atherosclerosis for improving subject, it is wrapped
Bacteroides uniformis and/or bacteroides vulgatus containing effective dose.
At the 3rd aspect, the invention provides for treating and/or prevent the coronary artery disease of subject, or it is used for
Reduce the blood glucose or blood lipid level of subject or for the method for the coronary atherosclerosis for improving subject, it includes
The step of bacteroides uniformis and/or bacteroides vulgatus of effective dose being applied to subject in need.
At the 4th aspect, the invention provides bacteroides uniformis and/or bacteroides vulgatus, it is used to treat and/or pre-
The coronary artery disease of anti-subject, or the blood glucose or blood lipid level of subject is reduced, or improve the coronary artery congee of subject
In the method for sample hardening lesion.
Brief description
According to the following description with reference to accompanying drawing, these and other aspects of the invention and favourable aspect will be clear and more
It is readily appreciated that, wherein：
Fig. 1：The MLG species of 65 in Random Forest model based on 126 MLG marks most identifications.Bar is long
Spend the importance of indicator variable (MLG species).
Fig. 2：Under the HF eating conditions rich in cholesterol, Bacteroides bacterial strain (bacteroides uniformis ATCC 8492, simple form
Bacteroid CECT 7771, bacteroides uniformis 0061, bacteroides vulgatus ATCC 8482, bacteroides vulgatus PC510 or commonly intend bar
Bacterium mpk) influence of the administration to OGTT curves.Fig. 2A：Using the result obtained before Bacteroides bacterial strain (at the 16th week)；Figure
2B：Using the result obtained after Bacteroides bacterial strain (at the 24th week).At the 16th week, blood sugar level was not in all HF nursings groups
It was observed that significant difference (Fig. 2A).However, (at the 24th week) after gavage is handled 8 weeks, compared with AS groups, bacteroides uniformis group
Substantially reduced (Fig. 2 B) with the AUC (TG-AUC) of the blood glucose (mmol/l) in bacteroides vulgatus group.
Fig. 3：Using Bacteroides bacterial strain, (bacteroides uniformis ATCC 8492, bacteroides uniformis CECT7771, simple form intend bar
Bacterium 0061, bacteroides vulgatus ATCC 8482, bacteroides vulgatus PC510 or bacteroides vulgatus mpk) after, mouse coronary artery is athero-
Harden the quantitative result (n=8/ groups) of lesion area.Value is shown as average value ± SEM.According to variance analysis and then carry out
Tukey post-hoc tests (p>0.05), the difference of the value between the group of same letter mark is not statistically significant.Such as Fig. 3
Shown, atherosclerotic lesion analysis shows are not significantly different between the mouse of 8 weeks is applied with different Bacteroides bacterial strains.
By contrast, compared with AS groups, 6 groups of the average coronary atherosclerosis area that application of Bacteroides bacterial strain is notable
Reduce.
Fig. 4：The histological characteristic of aortic root atherosclerotic lesion (through oil red O stain).A：NC groups, B-D：It is single
Shape bacteroid group (being respectively bacteroides uniformis ATCC 8492, bacteroides uniformis CECT 7771 and bacteroides uniformis 0061)；E-G
Bacteroides vulgatus group (being respectively bacteroides vulgatus ATCC 8482, bacteroides vulgatus PC510 and bacteroides vulgatus mpk)；H：AS
Group.As a result show, compared with healthy control group (Fig. 4 A, NC group), at the 24th week, through HF diet of the feeding rich in cholesterol and peace
Console the mouse in the AS groups after agent, atherosclerotic lesion (Fig. 4 H, AS to be formed rich in lipid are developed in aortic root
Group)；However, compared with AS groups, application of foam cells and lipid in region under the inner membrance of the Bacteroides bacterial strain mouse of 8 weeks
Deposition display is greatly decreased (Fig. 4 B~4G).
Fig. 5：The sign of the atherosclerotic lesion constituent carried out by the dyeing of oil red O centering lipids.Value
It is shown as average value ± SEM.Tukey post-hoc tests (the p according to variance analysis and then carried out>0.05), same letter is marked
Group value between difference be not statistically significant.As a result show, compared with AS groups, in the mouse of Bacteroides processing
Lipid accumulation significantly reduce, this shows that Bacteroides processing promotes the outflow of cholesterol in lesion macrophage, and suppresses
The development of atherosclerosis.
It is described in detail
Terms used herein has the implication that the those of ordinary skill such as relevant art is generally understood that.However,
For a better understanding of the present invention, the definition and explanation of relational language is provided below.
According to the present invention, it is athero- that term " coronary artery disease (CAD) " is also referred to as atherosclerotic heart disease, artery
Hardening angiocardiopathy, coronary heart disease or ischemic heart disease (IHD), and be most common heart disease type and heart disease
The reason for breaking-out.The disease is that as caused by the patch gathered along heart arter inwall, the patch makes artery narrow simultaneously
Reduce the blood flow for flowing to heart.
According to the present invention, term " prevention " (prevent, preventing or prevention) refers to prevent, suppress or
Delay disease (such as CAD) generation.
According to the present invention, term " treatment " (treat, treating or treatment) refers to treat or to cure disease (all
Such as CAD), delay the breaking-out of the symptom of disease (such as CAD), and/or delay disease (such as CAD) development.
According to the present invention, term " effective dose " refers to effectively realize the amount of expected purpose.For example, prevention effective dose can
To be effectively or be enough to prevent, suppress or delay the amount of disease (such as CAD) generation；Therapeutically effective amount can be effectively or
It is enough to treat or cures disease (such as CAD), delays the breaking-out of disease (such as CAD) symptom and/or delay disease (such as CAD)
The amount of development.Such effective dose can be readily determined by those skilled in the art or doctor, and can be with expected purpose
It is (prevention or treat), the general health of subject, the age, sex, body weight, the order of severity of disease to be treated, concurrent
The correlations such as disease, daily administration.The determination of such effective dose is completely in the limit of power of those skilled in the art.
Term such as "/kind (a) ", "/kind (an) " and " being somebody's turn to do (the) " are not only intended to refer to singular entity, and
Also include the species that specific example can be used to illustrate.Unless pointed out in the claims, otherwise term herein
For describing the specific embodiment of the present invention, but it is not intended to be limiting the present invention.
In one aspect, bar is intended the invention provides bacteroides uniformis (Bacteroides uniformis) and/or commonly
Bacterium (Bacteroides vulgatus) is preparing the coronary artery disease for treating and/or preventing subject, or for dropping
The blood glucose or blood lipid level of low subject or for the purposes in the preparation for the coronary atherosclerosis for improving subject.
In preferred embodiments, the preparation can any bacterial strain comprising bacteroides uniformis or its any combination.For example,
The preparation can include one or more bacterial strains of bacteroides uniformis, such as at least 2,3,4,5 kind or more kind bacterial strain.Preferred
In embodiment, bacteroides uniformis is selected from bacteroides uniformis ATCC 8492, bacteroides uniformis CECT 7771, bacteroides uniformis
0061 and its any combination.
In preferred embodiments, the preparation can any bacterial strain comprising bacteroides vulgatus or its any combination.Example
Such as, the preparation can include one or more bacterial strains of bacteroides vulgatus, for example, at least 2,3,4,5 kind or more kind bacterial strain.
In preferred embodiments, bacteroides vulgatus is selected from bacteroides vulgatus ATCC 8482, bacteroides vulgatus PC510, bacteroides vulgatus
Mpk and its any combination.
In preferred embodiments, bacteroides uniformis as described above and bacteroides vulgatus can be applied in combination.Therefore, institute
One or more bacterial strains of bacteroides uniformis and one or more bacterial strains of bacteroides vulgatus can be included by stating preparation.
In preferred embodiments, the preparation is pharmaceutical composition.Such pharmaceutical composition can include treatment or pre-
The bacteroides uniformis and/or bacteroides vulgatus of anti-effective dose.In preferred embodiments, described pharmaceutical composition can be medical science
Any form known to field.For example, described pharmaceutical composition can be tablet, pill, supensoid agent, emulsion, solution, gel
Agent, capsule, the form of pulvis or granule.
In preferred embodiments, the preparation is nutraceutical composition or food composition.Such composition
Can be solid, the form of semi-solid or liquid.In preferred embodiments, the preparation is dairy products, such as milk, milk powder or
Yoghourt.
In preferred embodiments, the preparation, which is also included, is used to treat and/or prevent coronary artery disease, or reduction blood
Sugar or blood lipid level or the other medicament for improving coronary atherosclerosis.This other medicament may be selected from drop courage and consolidate
Alcohol medicine, beta-Blocking agent, nitroglycerin, calcium antagonist, Statins, nitroglycerin, Vel-Tyr-Pro-Trp-Thr-Gln-Arg-Phe, calcium channel blocker, A Si
Woods and its any combination.
In addition, in the case where the preparation includes bacteroides uniformis, the other medicament can include bacteroides vulgatus
Any bacterial strain, such as bacteroides vulgatus ATCC 8482, bacteroides vulgatus PC510, bacteroides vulgatus mpk or its any combination.
Similarly, in the case where the preparation includes bacteroides vulgatus, the other medicament may include any of bacteroides uniformis
Bacterial strain, such as bacteroides uniformis ATCC 8492, bacteroides uniformis CECT 7771, bacteroides uniformis 0061 or its any combination.
In preferred embodiments, the preparation includes the bacteroides uniformis and/or bacteroides vulgatus of unit dose, example
Such as, concentration is at least 1x106Cfu/g, at least such as 1x107Cfu/g, at least 1x108Cfu/g, at least 1x109Cfu/g, at least
1x1010Cfu/g, at least 1x1011Cfu/g or at least 1x1012Cfu/g bacteroides uniformis and/or bacteroides vulgatus.Described
In the case that preparation is liquid (for example, solution, supensoid agent, emulsion) form, it can be at least 1x10 comprising concentration6cfu/
Ml, at least such as 1x107Cfu/ml, at least 1x108Cfu/ml, at least 1x109Cfu/ml, at least 1x1010Cfu/ml, at least
1x1011Cfu/ml or at least 1x1012Cfu/ml bacteroides uniformis and/or bacteroides vulgatus.
In preferred embodiments, the preparation can be applied together with extra therapy.This extra therapy can be with
It is any therapy for becoming known for coronary artery disease, such as intervention of coronary artery (such as angioplasty), and coronary artery
Bypass grafting.
In preferred embodiments, the subject is mammal, such as people.
In second aspect, the invention provides for treating and/or prevent the coronary artery disease of subject, or it is used for
Reduce the blood glucose or blood lipid level of subject or for the preparation for the coronary atherosclerosis for improving subject, it is included
The bacteroides uniformis and/or bacteroides vulgatus of effective dose.
In preferred embodiments, the preparation can any bacterial strain comprising bacteroides uniformis or its any combination.Example
Such as, the preparation can include one or more bacterial strains of bacteroides uniformis, for example, at least 2,3,4,5 kind or more kind bacterial strain.
In preferred embodiment, bacteroides uniformis, which is selected from bacteroides uniformis ATCC 8492, bacteroides uniformis CECT 7771, simple form, to be intended
Bacillus 0061 and its any combination.
In preferred embodiments, the preparation can any bacterial strain comprising bacteroides vulgatus or its any combination.For example,
The preparation can include one or more bacterial strains of bacteroides vulgatus, for example, at least 2,3,4,5 kind or more kind bacterial strain.Preferred
In embodiment, bacteroides vulgatus be selected from bacteroides vulgatus ATCC 8482, bacteroides vulgatus PC510, bacteroides vulgatus mpk and
It is combined.
In preferred embodiments, it can be combined and use bacteroides uniformis as described above and bacteroides vulgatus.Therefore, it is described
Preparation can include one or more bacterial strains of bacteroides uniformis and one or more bacterial strains of bacteroides vulgatus.
In preferred embodiments, the preparation is pharmaceutical composition.Such pharmaceutical composition can include treatment or pre-
The bacteroides uniformis and/or bacteroides vulgatus of anti-effective dose.In preferred embodiments, described pharmaceutical composition can be medical science
Any form known to field.For example, described pharmaceutical composition can be tablet, pill, supensoid agent, emulsion, solution, gel
Agent, capsule, the form of pulvis or granule.
In preferred embodiments, the preparation is nutraceutical composition or food composition.Such composition
Can be solid, the form of semi-solid or liquid.In preferred embodiments, the preparation is dairy products, such as milk, milk powder or
Yoghourt.
In preferred embodiments, the preparation, which is also included, is used to treat and/or prevent coronary artery disease, or reduction blood
Sugar or blood lipid level or the other medicament for improving coronary atherosclerosis.This other medicament may be selected from drop courage and consolidate
Alcohol medicine, beta-Blocking agent, nitroglycerin, calcium antagonist, Statins, nitroglycerin, Vel-Tyr-Pro-Trp-Thr-Gln-Arg-Phe, calcium channel blocker, A Si
Woods and its any combination.
In addition, in the case where the preparation includes bacteroides uniformis, the other medicament can include bacteroides vulgatus
Any bacterial strain, such as bacteroides vulgatus ATCC 8482, bacteroides vulgatus PC510, bacteroides vulgatus mpk or its any combination.
Similarly, in the case where the preparation includes bacteroides vulgatus, the other medicament may include any of bacteroides uniformis
Bacterial strain, such as bacteroides uniformis ATCC 8492, bacteroides uniformis CECT 7771, bacteroides uniformis 0061 or its any combination.
In preferred embodiments, the preparation includes the bacteroides uniformis and/or bacteroides vulgatus of unit dose, example
Such as, concentration is at least 1x106Cfu/g, at least such as 1x107Cfu/g, at least 1x108Cfu/g, at least 1x109Cfu/g, at least
1x1010Cfu/g, at least 1x1011Cfu/g or at least 1x1012Cfu/g bacteroides uniformis and/or bacteroides vulgatus.Described
In the case that preparation is liquid (for example, solution, supensoid agent, emulsion) form, it can be at least 1x10 comprising concentration6cfu/
Ml, at least such as 1x107Cfu/ml, at least 1x108Cfu/ml, at least 1x109Cfu/ml, at least 1x1010Cfu/ml, at least
1x1011Cfu/ml or at least 1x1012Cfu/ml bacteroides uniformis and/or bacteroides vulgatus.
In preferred embodiments, the preparation can be applied together with extra therapy.This extra therapy can be with
It is any therapy for becoming known for coronary artery disease, such as intervention of coronary artery (such as angioplasty), and coronary artery
Bypass grafting.
In preferred embodiments, the subject is mammal, such as people.
At the 3rd aspect, the invention provides for treating and/or prevent the coronary artery disease of subject, or it is used for
Reduce the blood glucose or blood lipid level of subject or for the method for the coronary atherosclerosis for improving subject, it includes
The step of bacteroides uniformis and/or bacteroides vulgatus of effective dose being applied to subject in need.
In preferred embodiments, any bacterial strain or its any combination of bacteroides uniformis can be applied to subject.For example,
Can to subject apply bacteroides uniformis one or more bacterial strains, for example, at least 2,3,4,5 kind or more kind bacterial strain.Preferred
Embodiment in, bacteroides uniformis be selected from bacteroides uniformis ATCC 8492, bacteroides uniformis CECT 7771, bacteroides uniformis
0061 and its any combination.
In preferred embodiments, any bacterial strain or its any combination of bacteroides vulgatus can be applied to subject.For example,
Can to subject apply bacteroides vulgatus one or more bacterial strains, for example, at least 2,3,4,5 kind or more kind bacterial strain.Preferred
In embodiment, bacteroides vulgatus be selected from bacteroides vulgatus ATCC 8482, bacteroides vulgatus PC510, bacteroides vulgatus mpk and
It is combined.
In preferred embodiments, bacteroides uniformis as described above and bacteroides vulgatus can be applied in combination.Therefore, may be used
One or more bacterial strains of bacteroides uniformis and one or more bacterial strains of bacteroides vulgatus are applied to subject.
In preferred embodiments, bacteroides uniformis and/or bacteroides vulgatus can be prepared as pharmaceutical composition
And administration.Such pharmaceutical composition can include the bacteroides uniformis and/or bacteroides vulgatus for treating or preventing effective dose.Excellent
Select in embodiment, described pharmaceutical composition can be any form known to medical domain.For example, described pharmaceutical composition can
In the form of being tablet, pill, supensoid agent, emulsion, solution, gel, capsule, pulvis or granule.
In preferred embodiments, can using bacteroides uniformis and/or bacteroides vulgatus as nutraceutical composition or
Food composition is prepared and applied.Such composition can be solid, the form of semi-solid or liquid.Preferred real
Apply in scheme, such composition is dairy products, such as milk, milk powder or Yoghourt.
In preferred embodiments, methods described also includes applying and is used to treat and/or prevent coronary artery disease, or drop
Hypoglycemia or blood lipid level, or improve the other medicament of coronary atherosclerosis.This other medicament can be
Using being applied prior to, concurrently with, or after bacteroides uniformis and/or bacteroides vulgatus.
In preferred embodiments, this other medicament may be selected from cholesterol-lowering drug, beta-Blocking agent, nitroglycerin,
Calcium antagonist, Statins, nitroglycerin, Vel-Tyr-Pro-Trp-Thr-Gln-Arg-Phe, calcium channel blocker, aspirin and its any combination.
In addition, in the case where applying bacteroides uniformis to subject, the other medicament may include bacteroides vulgatus
Any bacterial strain, such as bacteroides vulgatus ATCC 8482, bacteroides vulgatus PC510, bacteroides vulgatus mpk or its any combination.
Similarly, in the case where applying bacteroides vulgatus to subject, the other medicament may include any of bacteroides uniformis
Bacterial strain, such as bacteroides uniformis ATCC 8492, bacteroides uniformis CECT 7771, bacteroides uniformis 0061 or its any combination.
In preferred embodiments, can be with least 1x105Cfu/kg, at least such as 1x106Cfu/kg, at least
1x107Cfu/kg, at least 1x108Cfu/kg, at least 1x109Cfu/kg, at least 1x1010Cfu/kg, at least 1x1011Cfu/kg or
At least 1x1012The amount of cfu/kg subject's body weight applies bacteroides uniformis and/or bacteroides vulgatus.In preferred embodiments,
Can so that 3 times a day, 2 times a day, one time a day, every 1 time on the two or 1 times a week in the way of apply bacteroides uniformis and/or common
Bacteroid.
In preferred embodiments, methods described also includes applying extra therapy.This extra therapy can be
Know any therapy for coronary artery disease, such as intervention of coronary artery (such as angioplasty), and coronary artery bypass
Transplantation.
In preferred embodiments, the subject is mammal, such as people.
At the 4th aspect, the invention provides bacteroides uniformis and/or bacteroides vulgatus, it is used to treat and/or pre-
The coronary artery disease of anti-subject, or the blood glucose or blood lipid level of subject is reduced, or improve the coronary artery congee of subject
In the method for sample hardening lesion.
In preferred embodiments, any bacterial strain of bacteroides uniformis or its any combination can be used for this method.For example, single
One or more bacterial strains of shape bacteroid, for example, at least 2,3,4,5 kind or more plant bacterial strain can be used for this method.It is being preferable to carry out
In scheme, bacteroides uniformis be selected from bacteroides uniformis ATCC 8492, bacteroides uniformis CECT 7771, bacteroides uniformis 0061 and
It is combined.
In preferred embodiments, any bacterial strain of bacteroides vulgatus or its any combination can be used for this method.For example, general
One or more bacterial strains of logical bacteroid, such as at least 2,3,4,5 kind or more plant bacterial strain and can be used for this method.It is being preferable to carry out
In scheme, bacteroides vulgatus is selected from bacteroides vulgatus ATCC 8482, bacteroides vulgatus PC510, bacteroides vulgatus mpk and its appointed
Meaning combination.
In preferred embodiments, it can be combined and use bacteroides uniformis as described above and bacteroides vulgatus.Therefore, simple form
One or more bacterial strains of bacteroid and one or more bacterial strains of bacteroides vulgatus can be used for this method.
In preferred embodiments, bacteroides uniformis and/or bacteroides vulgatus can be formulated and apply as pharmaceutical composition
With.Such pharmaceutical composition can include the bacteroides uniformis and/or bacteroides vulgatus for treating or preventing effective dose.Preferred real
Apply in scheme, described pharmaceutical composition can be any form known to medical domain.For example, described pharmaceutical composition can be
Tablet, pill, supensoid agent, emulsion, solution, gel, capsule, the form of pulvis or granule.
In preferred embodiments, bacteroides uniformis and/or bacteroides vulgatus can be used as nutraceutical composition or food
Compositions are formulated and applied.Such composition can be solid, the form of semi-solid or liquid.In preferred embodiment
In, such composition is dairy products, such as milk, milk powder or Yoghourt.
In preferred embodiments, can be by bacteroides uniformis and/or bacteroides vulgatus with being used to treat and/or preventing coronal
Arterial disease, or the other pharmaceutical agent combinations of reduction blood glucose or blood lipid level or improvement coronary atherosclerosis are applied.
This other medicament can be applied prior to, concurrently with, or after bacteroides uniformis and/or bacteroides vulgatus is applied.
In preferred embodiments, this other medicament can be sweet selected from cholesterol-lowering drug, beta-Blocking agent, nitric acid
Oil, calcium antagonist, Statins, nitroglycerin, Vel-Tyr-Pro-Trp-Thr-Gln-Arg-Phe, calcium channel blocker, aspirin and its any combination.
In addition, in the case where applying bacteroides uniformis to subject, the other medicament may include bacteroides vulgatus
Any bacterial strain, such as bacteroides vulgatus ATCC 8482, bacteroides vulgatus PC510, bacteroides vulgatus mpk or its any combination.
Similarly, in the case where applying bacteroides vulgatus to subject, the other medicament can include appointing for bacteroides uniformis
What bacterial strain, such as bacteroides uniformis ATCC 8492, bacteroides uniformis CECT 7771, bacteroides uniformis 0061 or its any group
Close.
In preferred embodiments, bacteroides uniformis and/or bacteroides vulgatus can be with least 1x105Cfu/kg, such as
At least 1x106Cfu/kg, at least 1x107Cfu/kg, at least 1x108Cfu/kg, at least 1x109Cfu/kg, at least 1x1010cfu/
Kg, at least 1x1011Cfu/kg or at least 1x1012The amount of cfu/kg subject's body weight is applied.In preferred embodiments, simple form
Bacteroid and/or bacteroides vulgatus can so that 3 times a day, 2 times a day, one time a day, every 1 time on the two or 1 times a week in the way of apply
With.
In preferred embodiments, bacteroides uniformis and/or bacteroides vulgatus can be applied together with extra therapy.This
Kind extra therapy can be any therapy for becoming known for coronary artery disease, such as intervention of coronary artery (such as blood vessel into
Shape art), and CABG.
In preferred embodiments, the subject is mammal, such as people.
The present invention is further illustrated in the following non-limiting examples.Unless otherwise stated, part and percentage
Than by weight, the number of degrees for degree Celsius.Used reagent is all obtained commercially.For those of ordinary skill in the art it is aobvious and
It is clear to, although these embodiments indicate the preferred embodiments of the invention, only provides by way of illustration.
Embodiment
Embodiment 1：The identification biomarker related to coronary artery disease risk
1.1：Sample collection
Guangdong People's Hospital in 2011 have collected the fecal specimens from 165 southern china subjects, described tested
Person includes 88 atherosclerotic cardiovascular disease (ACVD) patients and 77 control subjects's (training group, table 1).According to
Pathological characters are diagnosed and classified to ACVD patient.Subject is required to collect fresh excreta sample in hospital.By collection
Sample is placed in sterile tube and is stored in -80 DEG C immediately until further analysis.
This research has been obtained for complete ethics approval, and all patients give Written informed consent.Should
Research is ratified by hospital general of Guangdong Province institutional review board.
Table 1：ACVD patient and the baseline characteristic of control subject.4th row report the knot of Wilcoxon rank tests
Really.
Annotation：For the information of sex, one in 88 patients is unknown, and two in 77 control subjects are
Unknown.
1.2：DNA is extracted
Fecal specimens are thawed on ice, and use Qiagen QIAamp DNA Stool Mini kits (Qiagen)
DNA is extracted according to the specification of manufacturer.Extract is handled to eliminate RNA pollutions with the RNase without DNA enzymatic.Use
NanoDrop spectrophotometers, Qubit fluorescence photometers (with Quant-iTTM dsDNA BR Assay kits) and gel electrophoresis are surveyed
Determine DNA amount.
1.3：DNA library builds and is sequenced
According to specification (Illumina) the constructed dna library of manufacturer.The present inventor is carried out using routine workflow
DNA clusters, template hybridization, isothermal duplication, single stranded, blocking and denaturation and the hybridization of sequencing primer.The present inventor constructs
Insert Fragment size in a kind of pair of end (PE) sequencing library, the library in each sample is 350bp, then carries out high pass
Sequence is measured to obtain PE reading (reads) of about 30,000,000 length as 2 × 100bp.By from the original reading mistakes of Illumina
Filter off remove with it is uncertain ' N' bases, the low quality reading of joint pollution and the pollution of people's source DNA and simultaneously by trimming reading
In low quality terminal bases obtain high-quality reading.
To 165 samples, (88 patients and 77 controls are tested on the platforms of Illumina HiSeq 2000 by the present inventor
Person) in each sample output altogether about 4.77Gb fecal microorganism group sequencing data (high-quality valid data) (table 2).
Table 2：The general introduction of grand genomic data.4th row report the result of Wilcoxon rank tests.
1.4：The processing and analysis of grand genomic data
1.4.1：Gene catalogue (gene catalogue) is built
Gene catalogue is built.By using with for building the diabetes B gene catalogue identical parameter (A such as Qin, J.
metagenome-wide association study of gut microbiota in type 2diabetes.Nature
490,55-60 (2012), are incorporated herein by reference), the present inventor uses the SOAPdenovo v1.06 (De such as Li, R. novo
assembly of human genomes with massively parallel short read
sequencing.Genome Research 20,265-272,doi:10.1101/gr.097261.109 (2009), by drawing
With being incorporated herein) and GeneMark v2.7 (Zhu, W., Lomsadze, A.＆Borodovsky, M.Ab initio gene
identification in metagenomic sequences.Nucleic acids research 38,e132,doi:
10.1093/nar/gkq275 (2010), is incorporated herein by reference) the high-quality readings of 165 samples has been carried out respectively from
Head (de novo) assembling and predictive genes.Using BLAT the genes of all predictions is carried out in contrast with right, and such gene
It will be removed as redundancy, the gene has after being compared more than the sequence of its length 90% with another gene to be higher than
95% homogeneity (being not allow for breach), so as to obtain including nonredundancy gene catalogue (the 4.5M bases of 4,537,046 genes
Because of catalogue).
The taxology distribution (taxonomic assignment) of gene.Using published T2D papers (Qin et al.,
Internal process described in 2012, ibid) is predicted the taxology distribution of gene.
1.4.2：The structure of data set (data profile)
Gene profile (gene profile).Using above-mentioned 4,537,046 genes and they are relative in 165 samples
The amount of abundance come build for associate Journal of Sex Research gene profile (the present inventor use with disclosed T2D papers (Qin etc. 2012, together
On) described in identical method calculate Relative gene abundance.
IMG species and mOTU species spectrum.Using default parameters respectively by total excrement valid reading and from IMG v400's
4,653 reference gene groups (Markowitz, V.M. etc., IMG：the integrated microbial genomes
Database and comparative analysis system.Nucleic acids research 40, D115-D122
(2012), be incorporated herein by reference) and mOTU reference 79,268 sequence (Metagenomic such as Sunagawa, S.
species profiling using universal phylogenetic marker genes.Nature methods
10,1196-1199 (2013), are incorporated herein by reference) it is compared.Identify 1290 IMG species (at least ten by
The species shared in examination person) and 560 mOTU species.
1.4.3：Influence the factor analysis of intestinal microbiota gene profile.The present inventor uses displacement multivariate analysis of variance
(permutational multivariate analysis of variance, PERMANOVA) assesses 25 kinds of different characteristics
(including CAD states, HDLC, CHOL, sex, FBG, hypertension, APOB, age, CREA, LDLC, HbA1c, APOA, TP, glycosuria
Disease, ALB, TRIG, BMI, WHR, Lpa, HBDH, CKMB, AST, CK, ProBNP_E_ and ALT) to 4.5M reference gene catalogues
The influence of gene profile.The present inventor is analyzed using the method implemented in the software kit " vegan " in R softwares, and is led to
Cross the p value that 10,000 displacements obtain displacement.The present inventor also uses " p.adjust " and Benjamini- in R softwares
Hochberg methods correct multiple check, to obtain the q values each examined.PERMANOA identifies related to enteric microorganism
Two key factors (be based on gene profile) (q<0.05, table 3).Analysis shows, CAD and HDLC states are most significantly correlated marks
Will thing, this explanation morbid state is to influence the main determining factor of intestinal microbiota composition.Sex, age and some CAD face
Bed index such as CHOL, FGB, hypertension and APOB are also key factor.
Table 3：The PERMANOVA of Euclidean distance analysis based on gene profile.The analysis is used to examine clinical parameter and ACVD
Whether state has on intestinal microbiota significantly affects (that is, q values<0.05).
1.4.4：The identification of ACVD Research of predicting markers
The identification of ACVD related genes.In order to identify grand genome spectrum and associating between ACVD, in 2.1M Gao Fashengji
Because carrying out double tail Wilcoxon sums of ranks in (be present in all 165 samples and be removed less than the gene in 10 samples) spectrum
Examine.438,750 gene markers (account for 2.1M genes 20.48%) are obtained altogether, and it is rich in patient or control subject
Collection, p value<0.01, FDR=2.23%.
Estimate false discovery rate (FDR).Inventor applies " q values " method (Storey, the J.D.A proposed in previous research
direct approach to false discovery rates.Journal of the Royal Statistical
Society 64,479-498 (2002), are incorporated herein by reference) replace order p value rejection method (sequential p-
Value rejection method) estimate FDR.
Receiver Operating Characteristics (ROC) analyze.The present inventor analyzes to assess based on grand genomic marker thing using ROC
The performance of ACVD classification.Then, inventor draws ROC curve using " pROC " software kit in R softwares.
1.4.5：The identification for building the MLG species mark related to ACVD of MLG species
126 MLG species of the gene profile based on 438,750 ACVD Research of predicting markers.The present inventor by with openly
T2D papers (Qin etc., 2012, ibid) described in same procedure, construct grand base using 438,750 gene markers
Because of a group linkage group (MLG).It is all to annotate by the way that these genes and 4,653 reference gene groups in IMG v400 are compared
438,750 genes.If the constitutive gene that 50% is had more than in a MLG is annotated into a genome, the MLG quilts
Distribution to the genome, otherwise its is referred to as non-classified.Having 136, there is the MLG genomes more than 550 genes to be chosen
Select out.The MLG genomes for belonging to same species are divided into one group to build MLG species.Finally, the present inventor obtains 127
Individual MLG species.The present inventor has carried out Wilcoxon orders using Benjamini-Hochberg adjusting methods to 127 kinds of MLG species
And inspection, wherein 126 MLG are chosen as ACVD correlations MLG, q<0.05.In order to estimate the relative abundance of a MLG species, this
Inventor remove that 5% is minimum and 5% highest abundance gene after estimate the MLG species gene average abundance (Qin etc.,
2012, ibid).
Inventor constructs the 136 of distribution based on 438,750 genes and incidence (Qin etc., 2012, ibid) altogether
Individual grand genome linkage group (has>The MLG of 550 genes).Include in MLG 94.8% notable gene (P- values<0.01).
136 MLG are annotated in ncbi database, and (each MLG has>550 genes,>50% coverage rate and q<0.05), and
And be one group by the MLG from same species points, obtain 126 MLG species.
The identification of MLG species marks.For identification of M LG species marks, the present inventor is used in R softwares 2.10 editions
" randomForest 4.5-36 " software kits analyze 126 ACVD correlation MLG species.First, the present inventor be based on by
The importance that " randomForest " method is provided all 126 kinds of MLG species are sorted (Liaw, Andy＆Wiener,
Matthew.Classification and Regression by randomForest, R News (2002), volume 2/3,
P.18, it is incorporated herein by reference).MLG mark collection is built by creating the increment subset of the MLG species ranked the first,
It terminates since 5 MLG species and to all 126 MLG species.For each MLG marks collection, the present inventor calculates
False prediction rate in the group of 165 people.Finally, MLG mark collection (including 65 MLG things of the selection with minimum false prediction rate
Kind) as MLG species mark (Fig. 1), wherein false negative (FN) rate is 6.8%, and false positive (FP) rate is 3.89%.In addition,
Inventor is pre- using OOB (the outer data of bag) disease from randomForest models based on selected MLG species mark
Probability is surveyed to draw ROC curve, and it is 98.17% to calculate area under ROC curve using R software kits " pROC ".
In 65 MLG species, the MLG species bacteroides uniformis (q=4.21E-11) that is enriched with control group and common
Bacteroid (q=1.80E-09), the SCFA that is known as produces bacterium.
1.4.6：The identification of ACVD correlation IMG species and mOTU species.Identified based on IMG species and mOTU species spectrum
IMG species and mOTU species marks.The present inventor identifies the related IMG species and mOTU species (q of ACVD<0.05) (profit
With the Wilcoxon rank tests of Benjamini-Hochberg adjusting methods).Then, using randomForest methods (such as in MLG
It is the same in the selection of species mark) select IMG species mark and mOTU species marks.
Selected according to Wilcoxon rank tests and random forest, the 65 IMG species and ROC that ROC is 98.52% are
CAD patient and health volunteer are distinguished (q with will also recognize that by 96.16% 15 mOTU species<0.05；Referring to the He of table 5
6).Similar to 65 MLG species marks, in 65 IMG species marks and 15 mOTU species marks, the present inventor
It was found that bacteroides uniformis significant enrichment in control group.
Embodiment 2：Checking in the zoopery related to CAD
In order to verify the ability of probiotics bacteroides uniformis and bacteroides vulgatus in prevention and treatment CAD relevant diseases,
Present inventor has performed zoopery.
2.1：Method
Suppression for research bacteroides uniformis and bacteroides vulgatus to the Aortic Plaque area of mouse atherosclerosis is made
With to mouse feeding high fat diet 16 weeks, to set up Atherosclerosis Model, then giving bacteroides uniformis from the 16th week
And bacteroides vulgatus, and observe to blood glucose and OGTT (oral glucose tolerance test), blood fat and atherosclerotic plaque face
Long-pending influence.
2.1.1：Animal and treatment
The C57BL/6J of 64 male no-special pathogens (SPF) is bought from Chinese Nanfang Medical Univ's Experimental Animal Center
Mouse (10 week old), 22.5~25.9g of body weight.The mouse for being used in the atherosclerosis study of diet induced is arbitrarily drunk
With water and feed diet, the adaptation for continuing 2 weeks.Then they are randomly divided into 2 parts：A part of (8 mouse) feeding is normal
(10% calorie comes from fat to feed diet in NC groups, the diet, and every gram of diet contains 3.85 total kcal, and it is purchased from
Research Diets, Inc., New Brunswick, NJ, USA) it is used as normal healthy controls.Another part (56 mouse) feeding
For it is atherosclerosis-inducing with 2% cholesterol high fat diet (in the diet 60% calorie from fat,
And every gram of diet contains 5.24 total kcal, it is purchased from Research Diets, Inc.), after 16 weeks, this 56 mouse are divided at random
Into 7 groups (every group of 8 mouse).One group, as atherosclerosis control group (AS groups), is given same as described above solid rich in courage
The HF diet of alcohol, and 200 μ l Colombia blood culture medium (DSMZ Medium 693) of receiving are used as placebo.Other 6 groups
(B1~B6 groups) also receives the HF diet rich in cholesterol, and contains 6 using 200 μ l respectively to mouse in each group by gavage
Kind of candidate probiotic strain (i.e. bacteroides uniformis ATCC 8492, bacteroides uniformis CECT 7771, bacteroides uniformis 0061, commonly
Bacteroid ATCC 8482, bacteroides vulgatus PC510 and bacteroides vulgatus mpk) one of bacterial suspension, above-mentioned bacterial strains be suspended
In Colombia's blood culture medium, concentration is 109-1010Cfu/ml (freshly prepared weekly).Above-mentioned mouse is further fed
Support 8 weeks.
Bacteroides uniformis ATCC 8492 and bacteroides vulgatus ATCC 8482 is purchased from American type culture collection
(ATCC)。
Bacteroides uniformis CECT 7771 is purchased from Spain's common micro-organisms collection.
Bacteroides uniformis 0061 is obtained from Virginia Polytechnic Institute and State University's anaerobic bacteria laboratory cultures thing collection
(Shoemaker,N.B.,&Salyers,A.A.(1988).Tetracycline-dependent appearance of
plasmid like forms in Bacteroides uniformis 0061mediated by conjugal
Bacteroides tetracycline resistance elements.Journal of bacteriology,170(4),
1651-1657)。
Bacteroides vulgatus PC510 is obtained from CSIR O and prevents sex-health flagship project and animal husbandry branch of industry (P á raic
Draft genome sequence of Bacteroides vulgatus PC510, a strain such as O Cu í v isolated
from human feces.Journal of bacteriology,2011,193(15):4025-6)。
Bacteroides vulgatus mpk is obtained from Univ Eberhard Karls's medical microbial and hygiene research institute (Waidmann M etc.
Bacteroides vulgatus protects against Escherichia coli-induced colitis in
gnotobiotic interleukin-2-deficient mice.Gastroenterology.2003Jul；125(1):162-
77)。
The bacterial strain is purified and cultivated using technique of anaerobic incubation.Group for Colombia's blood culture medium of culture
Into be described in DSMZ (Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH,
German Collection of Microorganisms and Cell Cultures) in Medium 693.In order to test mesh
, by bacterial strain, anaerobism is bred 48 hours at 37 DEG C.
2.1.2：Oral glucose tolerance test (OGTT)
After fasting 8 hours, with the dosage of 2.0g/kg body weight to Mouse oral glucose administration.Glucose apply it is preceding and
15 after, 30,60 and 120 minutes from afterbody blood sampling, and with blood-glucose meter (Roche Diagnostics, Mannheim,
Germany blood sugar level) is measured.Blood sugar level before glucose is applied represents fasting blood glucose level.
2.1.3：The collection of blood and sustainer
At the end of the 24th week, after fasting 12 hours, whole blood is collected from Orbital Vessels clump, by 4 DEG C with
5000rpm centrifuges separation in 15 minutes and obtains serum, and is stored in -80 DEG C for subsequent biochemical test.All animals
Put to death by cervical dislocation.Use the kit of the spectrophotomelric assay of the whole last plasma products of joint enzymatic reaction and reaction
(Nanjing Jiancheng Bio-engineering Institute, China) measures plasma triglyceride (TG) and blood
Starch T-CHOL (TC).Collect and handle sustainer for the cross-sectional analysis of the plaque area in aortic root.
2.1.4：The assessment of atherosclerotic plaque
Collect after blood, heparin is injected into inferior caval vein, take out sustainer from aortic root under the microscope, and in poly
It is fixed in formaldehyde, then embedded in the formalin of 10% phosphate-buffered, be cut into 6 μm of slabs.Carry out optical microphotograph
Spectroscopy is to evaluate the change of atherosclerosis.Histotomy on scanning slide is used for iVision softwares to produce
(BioVision Technologies, Exton, PA, USA) carries out the virtual slide of qualitative assessment.In order to detect neutral fats
Matter, by histotomy oil red O stain.After the image of capture section, we are gated by computer assisted color and surveyed
Amount determines red area (SigmaScanPro 5 on always section area；SPSS Inc.,Chicago,IL,USA).
2.2：As a result
2.2.1：Influence to blood glucose and OGTT
At the 16th week, significant difference (Fig. 2A) is not observed in blood sugar level in all HF nursings groups.However, in pipe
After feeding is handled 8 weeks (the 24th week), compared with AS groups, bacteroides uniformis group is observed in oral glucose tolerance test and general
The AUC (TG-AUC) of blood glucose (mmol/l) in logical bacteroid group is significantly reduced (Fig. 2 B), in each group AUC data such as table 7
It is shown.
Table 7：The AUC of every group of OGTT curves.Each value is shown as average value ± SEM.According to variance analysis and then
Difference between the Tukey post-hoc tests of progress, the value of the group of same letter mark is not statistically significant.In each group
Between, the same letter of mark represents that the value of labeled group is examined by Tukey and is defined as no significant difference (p>0.05).
2.2.2：Influence to serum lipids
Bacteroides uniformis ATCC 8492, CECT 7771 and 0061 and bacteroides vulgatus ATCC8482, PC510 and mpk
Administration the result of serum lipids is shown in Table 8.Compared with NC groups, the place of the HF diet rich in cholesterol and tube feed placebo
Reason significantly increases plasma triglyceride and total plasma cholesterol.However, compared with AS groups, bacteroides uniformis and bacteroides vulgatus
The serum lipid level of tube feed group is significantly reduced.
Table 8：Influence of the administration of Bacteroides bacterial strain to plasma triglyceride (TG) and total plasma cholesterol (TC).Each
Value is shown as average value ± SEM.The Tukey post-hoc tests according to variance analysis and then carried out, the group of same letter mark
Difference between value is not statistically significant.Between each group, the same letter of mark represents the value of labeled group
Examined by Tukey and be defined as no significant difference (p>0.05).
2.2.3：The effect of mouse coronary atherosclerosis is treated using Bacteroides bacterial strain
Fig. 3 show apply Bacteroides bacterial strain (bacteroides uniformis ATCC 8492, bacteroides uniformis CECT 7771,
Bacteroides uniformis 0061, bacteroides vulgatus ATCC 8482, bacteroides vulgatus PC510 or bacteroides vulgatus mpk) after mouse hat
The quantitative result (n=8/ groups) of shape atherosclerotic lesion area.Value is shown as average value ± SEM.According to variance analysis and
Tukey post-hoc tests (the p then carried out>0.05), the difference between the group of same letter mark is not statistically significant.
As shown in figure 3, atherosclerotic lesion analysis shows are using between mouse of the different Bacteroides bacterial strains after 8 weeks
Without significant difference.By contrast, compared with AS groups, it application of 6 groups of average coronary atherosclerosis of Bacteroides bacterial strain
Lesion area is substantially reduced (Fig. 3, table 9).
As shown in the histologic characteristics of aortic root vertical section, compared to healthy control group (Fig. 4 A, NC group), in AS groups
Mouse feeding rich in cholesterol HF diet and placebo after, the 24th week in aortic root formed rich in lipid move
Pulse atherosclerosis lesion (Fig. 4 H, AS group).By contrast, compared with AS groups, it application of the interior of the Bacteroides bacterial strain mouse of 8 weeks
Foam cells and lipidosis under film in region are substantially reduced (Fig. 4 B~4G).
The difference of lipid accumulation shows bacteroides uniformis ATCC 8492, bacteroides uniformis CECT7771, bacteroides uniformis
0061st, bacteroides vulgatus ATCC 8482, bacteroides vulgatus PC510 and bacteroides vulgatus mpk drink to the HF rich in cholesterol respectively
The progression of atherosclerosis eaten in the mouse atherosclerosis model of induction has mitigation.Compared with AS groups, pass through
Quantitative detection of the oil red O stain to the lipid accumulation in atherosclerotic lesion shows the fat in the mouse of Bacteroides processing
Matter accumulation is substantially reduced (Fig. 5, table 9).These results show that Bacteroides treatment promotes the stream of lesion Macrophage cholesterol
Go out, and inhibit the development of atherosclerosis.
Table 9：Lesion area (%) and oil red O (lesion area %) in all groups
In a word, result of this study demonstrate that bacteroides uniformis ATCC 8492, bacteroides uniformis CECT 7771, simple form are intended
Bacillus 0061, bacteroides vulgatus ATCC 8482, bacteroides vulgatus PC510 and bacteroides vulgatus mpk are used to improve coronary artery disease
Disease and relevant disease, the level for reducing blood glucose or blood fat or the ability for improving coronary atherosclerosis.
Although being shown in detail and having described illustrative embodiment, those skilled in the art should manage
Solution, the embodiment above is illustrative, and is not intended to be limiting in any manner the disclosure, and can be without departing substantially from the disclosure
Spirit, principle and scope in the case of the embodiment is changed, substitutions and modifications.
Claims (40)
1. bacteroides vulgatus (Bacteroides vulgatus) is preparing the coronary artery for treating and/or preventing subject
Disease, or for reducing the blood glucose or blood lipid level of subject or coronary atherosclerosis for improving subject
Purposes in preparation.
2. purposes according to claim 1, wherein the bacteroides vulgatus be selected from bacteroides vulgatus ATCC 8482, it is common
Bacteroid PC510, bacteroides vulgatus mpk and its any combination.
3. purposes according to claim 1 or 2, wherein the preparation is pharmaceutical composition, preferably comprises treatment or prevention
The bacteroides vulgatus of effective dose, and it is optionally tablet, pill, supensoid agent, emulsion, solution, gel, capsule, pulvis
Or the form of granule.
4. purposes according to claim 1 or 2, wherein the preparation is nutraceutical composition or food composition,
And it is optionally solid, the form of semi-solid or liquid, and preferably dairy products, such as milk, milk powder or Yoghourt.
5. the purposes according to any one of claim 1-4, is used to treating and/or preventing hat wherein the preparation is also included
Coronary disease, or reduce blood glucose or blood lipid level or improve the other medicament of coronary atherosclerosis.
6. purposes according to claim 5, wherein the other medicament be selected from bacteroides uniformis, cholesterol-lowering drug,
Beta-Blocking agent, nitroglycerin, calcium antagonist, Statins, nitroglycerin, Vel-Tyr-Pro-Trp-Thr-Gln-Arg-Phe, calcium channel blocker, aspirin and
It is combined.
7. purposes according to claim 6, wherein the bacteroides uniformis is selected from bacteroides uniformis ATCC 8492, simple form
Bacteroid CECT 7771, bacteroides uniformis 0061 and its any combination.
8. the purposes according to any one of claim 1-7, wherein the preparation is at least 1x10 comprising concentration6Cfu/g,
Such as at least 1x107Cfu/g, at least 1x108Cfu/g, at least 1x109Cfu/g, at least 1x1010Cfu/g, at least 1x1011cfu/
G or at least 1x1012Cfu/g bacteroides vulgatus, or wherein described preparation are liquid form, and are at least comprising concentration
1x106Cfu/ml, at least such as 1x107Cfu/ml, at least 1x108Cfu/ml, at least 1x109Cfu/ml, at least 1x1010cfu/
Ml, at least 1x1011Cfu/ml or at least 1x1012Cfu/ml bacteroides vulgatus.
9. the purposes according to any one of claim 1-8, wherein the preparation is applied together with extra therapy, such as
Intervention of coronary artery (such as angioplasty) and CABG.
10. the purposes according to any one of claim 1-9, wherein the subject is mammal such as people.
11. a kind of preparation, it is used to treat and/or prevents the coronary artery disease of subject, or for reducing the blood of subject
Sugar or blood lipid level, or for improving the coronary atherosclerosis of subject, the preparation is common comprising effective dose
Bacteroid.
12. preparation according to claim 11, wherein the bacteroides vulgatus be selected from bacteroides vulgatus ATCC 8482, it is general
Logical bacteroid PC510, bacteroides vulgatus mpk and its any combination.
13. the preparation according to claim 11 or 12, wherein the preparation is pharmaceutical composition, preferably comprises treatment or pre-
The bacteroides vulgatus of anti-effective dose, and it is optionally tablet, pill, supensoid agent, emulsion, solution, gel, capsule, powder
Agent or the form of granule.
14. the preparation according to claim 11 or 12, wherein the preparation is nutraceutical composition or combinations of foods
Thing, and it is optionally solid, the form of semi-solid or liquid, and preferably dairy products, such as milk, milk powder or Yoghourt.
15. the preparation according to any one of claim 11-14, is used to treat and/or pre- wherein the preparation is also included
Anti- coronary artery disease, or reduce blood glucose or blood lipid level or improve the other medicament of coronary atherosclerosis.
16. preparation according to claim 15, wherein the other medicament is selected from bacteroides uniformis, gemfibrozil
Thing, beta-Blocking agent, nitroglycerin, calcium antagonist, Statins, nitroglycerin, Vel-Tyr-Pro-Trp-Thr-Gln-Arg-Phe, calcium channel blocker, aspirin
And its any combination.
17. preparation according to claim 16, wherein the bacteroides uniformis is selected from bacteroides uniformis ATCC 8492, list
Shape bacteroid CECT 7771, bacteroides uniformis 0061 and its any combination.
18. the preparation according to any one of claim 11-17, wherein the preparation is at least 1x10 comprising concentration6cfu/
G, at least such as 1x107Cfu/g, at least 1x108Cfu/g, at least 1x109Cfu/g, at least 1x1010Cfu/g, at least
1x1011Cfu/g or at least 1x1012Cfu/g bacteroides vulgatus, or wherein described preparation are liquid form and include concentration
It is at least 1x106Cfu/ml such as at least 1x107Cfu/ml, at least 1x108Cfu/ml, at least 1x109Cfu/ml, at least
1x1010Cfu/ml, at least 1x1011Cfu/ml or at least 1x1012Cfu/ml bacteroides vulgatus.
19. the preparation according to any one of claim 11-18, wherein the preparation is applied together with extra therapy,
The extra therapy such as intervention of coronary artery (such as angioplasty) and CABG.
20. the preparation according to any one of claim 11-19, wherein the subject is mammal such as people.
21. a kind of method, it is used to treat and/or prevents the coronary artery disease of subject, or for reducing the blood of subject
Sugar or blood lipid level, or for improving the coronary atherosclerosis of subject, it is included to subject in need
Using effective dose bacteroides vulgatus the step of.
22. method according to claim 21, wherein the bacteroides vulgatus be selected from bacteroides vulgatus ATCC 8482, it is general
Logical bacteroid PC510, bacteroides vulgatus mpk and its any combination.
23. the method according to claim 21 or 22, wherein the bacteroides vulgatus is matched somebody with somebody as pharmaceutical composition
System and administration, described pharmaceutical composition are optionally tablet, pill, supensoid agent, emulsion, solution, gel, capsule, pulvis
Or the form of granule.
24. the method according to claim 21 or 22, wherein regarding the bacteroides vulgatus as nutraceutical composition
Or food composition is prepared and applied, the composition is optionally solid, semi-solid or liquid form, and is preferably
Dairy products, such as milk, milk powder or Yoghourt.
25. the method according to any one of claim 21-24, wherein methods described also include apply be used for treat and/
Or prevention coronary artery disease, or reduction blood glucose or blood lipid level, or improve the other medicine of coronary atherosclerosis
Agent, wherein preferably, the other medicament is applied prior to, concurrently with, or after the bacteroides vulgatus is applied.
26. method according to claim 25, wherein the other medicament is selected from bacteroides uniformis, gemfibrozil
Thing, beta-Blocking agent, nitroglycerin, calcium antagonist, Statins, nitroglycerin, Vel-Tyr-Pro-Trp-Thr-Gln-Arg-Phe, calcium channel blocker, aspirin
And its any combination.
27. method according to claim 26, wherein the bacteroides uniformis is selected from bacteroides uniformis ATCC 8492, list
Shape bacteroid CECT 7771, bacteroides uniformis 0061 and its any combination.
28. the method according to any one of claim 21-27, wherein with least 1x105Cfu/kg, such as at least
1x106Cfu/kg, at least 1x107Cfu/kg, at least 1x108Cfu/kg, at least 1x109Cfu/kg, at least 1x1010Cfu/kg, extremely
Few 1x1011Cfu/kg or at least 1x1012The amount of subject's body weight described in cfu/kg applies the bacteroides vulgatus, and preferably
Ground is so that 3 times a day, 2 times a day, one time a day, every 1 time on the two or 1 times a week in the way of apply the bacteroides vulgatus.
29. the method according to any one of claim 21-28, wherein methods described also include applying extra therapy,
Such as intervention of coronary artery (such as angioplasty) and CABG.
30. the method according to any one of claim 21-29, wherein the subject is mammal such as people.
31. a kind of bacteroides vulgatus, it is used to treat and/or prevents the coronary artery disease of subject, or tested for reducing
In the method for the blood glucose or blood lipid level of person or the coronary atherosclerosis of improvement subject.
32. bacteroides vulgatus according to claim 31, wherein the bacteroides vulgatus is selected from bacteroides vulgatus ATCC
8482nd, bacteroides vulgatus PC510, bacteroides vulgatus mpk and its any combination.
33. the bacteroides vulgatus according to claim 31 or 32, wherein the bacteroides vulgatus is used as pharmaceutical composition quilt
Prepare and apply, described pharmaceutical composition is optionally tablet, pill, supensoid agent, emulsion, solution, gel, capsule, powder
Agent or the form of granule.
34. the bacteroides vulgatus according to claim 31 or 32, wherein the bacteroides vulgatus is used as nutraceutical group
Compound or food composition are formulated and applied, and the composition is optionally solid, semi-solid or liquid form, and preferably
Ground is dairy products, such as milk, milk powder or Yoghourt.
35. the bacteroides vulgatus according to any one of claim 31-34, wherein the bacteroides vulgatus and other medicine
Agent be administered in combination, the other medicament be used for treat and/or prevent coronary artery disease, reduction blood glucose or blood lipid level or
Improve coronary atherosclerosis, wherein preferably, institute is applied prior to, concurrently with, or after the bacteroides vulgatus is applied
State other medicament.
36. bacteroides vulgatus according to claim 35, consolidates wherein the other medicament is selected from bacteroides uniformis, drop courage
Alcohol medicine, beta-Blocking agent, nitroglycerin, calcium antagonist, Statins, nitroglycerin, Vel-Tyr-Pro-Trp-Thr-Gln-Arg-Phe, calcium channel blocker, A Si
Woods and its any combination.
37. bacteroides vulgatus according to claim 36, wherein the bacteroides uniformis is selected from bacteroides uniformis ATCC
8492nd, bacteroides uniformis CECT 7771, bacteroides uniformis 0061 and its any combination.
38. the bacteroides vulgatus according to any one of claim 31-37, wherein the bacteroides vulgatus is with least
1x105Cfu/kg, at least such as 1x106Cfu/kg, at least 1x107Cfu/kg, at least 1x108Cfu/kg, at least 1x109cfu/
Kg, at least 1x1010Cfu/kg, at least 1x1011Cfu/kg or at least 1x1012The amount of subject's body weight described in cfu/kg is applied, and
And preferably described bacteroides vulgatus is so that 3 times a day, 2 times a day, one time a day, every 1 time on the two or 1 times a week in the way of apply.
39. the bacteroides vulgatus according to any one of claim 31-38, wherein the bacteroides vulgatus and extra treatment
Method is applied together, the extra therapy such as intervention of coronary artery (such as angioplasty) and coronary artery bypass grafting
Art.
40. the bacteroides vulgatus according to any one of claim 31-39, wherein the subject be mammal such as
People.
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| PCT/CN2014/087850 WO2016049827A1 (en) | 2014-09-30 | 2014-09-30 | Use of bacteroides in prevention and treatment for coronary artery disease |
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| CN111638324A (en) * | 2020-05-28 | 2020-09-08 | 长沙都正生物科技有限责任公司 | Coronary heart disease diagnosis biomarker combination and application thereof |
| CN111714522A (en) * | 2019-03-04 | 2020-09-29 | 中国科学院微生物研究所 | Bacteroides and application thereof |
| CN114053310A (en) * | 2022-01-17 | 2022-02-18 | 中国疾病预防控制中心传染病预防控制所 | Application of bacteroides vulgatus probiotics CGMCC NO.17140 in preparation of lipid-lowering drugs |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2020055193A1 (en) * | 2018-09-14 | 2020-03-19 | Industry-Academic Cooperation Foundation, Yonsei University | Microorganism with antibacterial activity for enteric pathogenic bacteria and pharmaceutical composition for preventing and treating enteric pathogenic bacteria induced disease using the same |
| CN114949002B (en) * | 2022-06-08 | 2024-03-19 | 广州知易生物科技有限公司 | Application of akkermansia muciniphila in preparation of composition for preventing and treating atherosclerosis |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN111714522A (en) * | 2019-03-04 | 2020-09-29 | 中国科学院微生物研究所 | Bacteroides and application thereof |
| CN111714522B (en) * | 2019-03-04 | 2022-07-15 | 中国科学院微生物研究所 | Bacteroides and application thereof |
| CN111638324A (en) * | 2020-05-28 | 2020-09-08 | 长沙都正生物科技有限责任公司 | Coronary heart disease diagnosis biomarker combination and application thereof |
| CN111638324B (en) * | 2020-05-28 | 2023-08-11 | 长沙都正生物科技有限责任公司 | Coronary heart disease diagnosis biomarker composition and application thereof |
| CN114053310A (en) * | 2022-01-17 | 2022-02-18 | 中国疾病预防控制中心传染病预防控制所 | Application of bacteroides vulgatus probiotics CGMCC NO.17140 in preparation of lipid-lowering drugs |
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