WO2016049826A1 - Utilisation de bacteroides dans la prévention et le traitement de la coronaropathie - Google Patents

Utilisation de bacteroides dans la prévention et le traitement de la coronaropathie Download PDF

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WO2016049826A1
WO2016049826A1 PCT/CN2014/087849 CN2014087849W WO2016049826A1 WO 2016049826 A1 WO2016049826 A1 WO 2016049826A1 CN 2014087849 W CN2014087849 W CN 2014087849W WO 2016049826 A1 WO2016049826 A1 WO 2016049826A1
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bacteroides
cfu
bacteroides uniformis
uniformis
formulation
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PCT/CN2014/087849
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English (en)
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Qiang FENG
Zhuye JIE
Chuan Liu
Liang Xiao
Huihua XIA
Jun Wang
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Bgi Shenzhen Co., Limited
Bgi Shenzhen
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Priority to PCT/CN2014/087849 priority Critical patent/WO2016049826A1/fr
Priority to CN201480082402.9A priority patent/CN107073046A/zh
Publication of WO2016049826A1 publication Critical patent/WO2016049826A1/fr

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    • 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
    • A—HUMAN NECESSITIES
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the invention relates to microbiology. Specifically, the invention relates to use of Bacteroides bacterial strains in the preparation of a formulation for the treatment and/or prevention of coronary artery disease, or for decreasing the level of blood glucose or lipids, or for ameliorating coronary atherosclerotic lesions, in a subject.
  • the invention also relates to a formulation (such as a pharmaceutical composition, a nutraceutical composition or a food composition) comprising Bacteroides bacteria.
  • the invention also relates to a method for the treatment and/or prevention of coronary artery disease, or for decreasing the level of blood glucose or lipids, or for ameliorating coronary atherosclerotic lesions, in a subject, comprising the step of administrating an effective amount of Bacteroides bacterial strains to a subject in need thereof.
  • Coronary artery disease refers to any abnormal condition of the coronary arteries that interferes with the delivery of an adequate supply of blood to the cardiac (i.e., heart) muscle or any portion thereof.
  • CAD is caused by the accumulation of plaque on the arterial walls (i.e., atherosclerosis), particularly in the large and medium-sized arteries serving the heart. These conditions have similar causes, mechanisms, and treatments. CAD represents the leading cause of death and morbidity worldwide.
  • the present disclosure aims to solve at least one of the problems existing in the prior art to at least some extent.
  • the present invention is at least partially based on the following findings by the inventors.
  • CAD coronary artery disease
  • MWAS Metagenome-Wide Association Study
  • the inventors identified 2 Bacteroides probiotic bacteria. Then the inventors validated the effect of the Bacteroides probiotic bacteria on CAD in an animal experiment, respectively. Results from the animal experiment demonstrated the ability of Bacteroides uniformis and Bacteroides vulgatus to prevent and treat CAD effectively.
  • the present invention provides use of Bacteroides uniformis and/or Bacteroides vulgatus in the preparation of a formulation for the treatment and/or prevention of coronary artery disease, or for decreasing the level of blood glucose or lipids, or for ameliorating coronary atherosclerotic lesions, in a subject.
  • the present invention provides a formulation for the treatment and/or prevention of coronary artery disease, or for decreasing the level of blood glucose or lipids, or for ameliorating coronary atherosclerotic lesions, in a subject, comprising an effective amount of Bacteroides uniformis and/or Bacteroides vulgatus.
  • the present invention provides a method for the treatment and/or prevention of coronary artery disease, or for decreasing the level of blood glucose or lipids, or for ameliorating coronary atherosclerotic lesions, in a subject, comprising the step of administrating an effective amount of Bacteroides uniformis and/or Bacteroides vulgatus to a subject in need thereof.
  • the present invention provides Bacteroides uniformis and/or Bacteroides vulgatus, for use in the method for the treatment and/or prevention of coronary artery disease, or for decreasing the level of blood glucose or lipids, or for ameliorating coronary atherosclerotic lesions, in a subject.
  • Fig.1 The 65 most discriminant MLG species in the Random Forest model using 126 MLG markers.
  • the bar length indicated the importance of variable (MLG species).
  • Fig.2 The effects of administration of Bacteroides strain (Bacteroides uniformis ATCC 8492, Bacteroides uniformis CECT 7771, Bacteroides uniformis 0061, Bacteroides vulgatus ATCC 8482, Bacteroides vulgatus PC510 or Bacteroides vulgatus mpk) on OGTT curve at cholesterol-rich HF diet condition.
  • Fig.2A Results obtained before administration of Bacteroides strain (on the 16th week);
  • Fig.2B Results obtained after administration of Bacteroides strain (on the 24th week). On the 16th week, no significant differences were observed at the level of serum glucose in all HF-fed groups (Fig.2A).
  • the atherosclerotic lesion analysis demonstrated that there was no significant difference between the mice administered with different Bacteroides strains for 8 weeks.
  • the mean coronary atherosclerotic lesion area of the 6 groups administered with Bacteroides strains was significant reduced.
  • Fig.4 The histologic features (Oil red-O stained) of atherosclerotic lesions in the aortic root.
  • A NC group
  • B-D Bacteroides uniformis groups (Bacteroides uniformis ATCC 8492, Bacteroides uniformis CECT 7771, and Bacteroides uniformis 0061, respectively);
  • E-G Bacteroides vulgatus groups (Bacteroides vulgatus ATCC 8482, Bacteroides vulgatus PC510, and Bacteroides vulgatus mpk, respectively);
  • H AS group.
  • mice in AS group developed lipid-rich atherosclerotic lesions in the aortic root after fed with cholesterol-rich HF diet and placebo on the 24th week (Fig.4H, AS group); however, as compared with AS group, the mice administered with Bacteroides strains for 8 weeks displayed substantially decrease of foam cells and lipid deposition in the subintimal area (Fig.4B ⁇ 4G).
  • Fig.5 Characterization of atherosclerotic lesion composition by oil red O staining for neutral lipids. Values are shown as the mean ⁇ SEM. Difference between values from groups marked with the same letter is not statistically significant, according to analysis of variance followed by Tukey post hoc test (p> 0.05). The results showed a significant decrease in lipid accumulation in Bacteroides-treated mice, as compared with AS group, suggesting that the Bacteroides treatment improved the efflux of cholesterol from the lesional macrophages and inhibited the progress of atherosclerosis.
  • CAD Coronary artery disease
  • IHD ischemic heart disease
  • the terms “prevent”, “preventing” and “prevention” refer to preventing, suppressing, or delaying the occurrence of a disease (such as CAD).
  • the terms “treat”, “treating” and “treatment” refer to treating or curing a disease (such as CAD), delaying the onset of a symptom of a disease (such as CAD), and/or retarding the progress of a disease (such as CAD).
  • an effective amount refers to an amount that can effectively achieve the intended purpose.
  • a prophylactically effective amount may be an amount effective or sufficient for preventing, suppressing, or delaying the occurrence of a disease (such as CAD);
  • a therapeutically effective amount may be an amount effective or sufficient for treating or curing a disease (such as CAD), delaying the onset of a symptom of a disease (such as CAD), and/or retarding the progress of a disease (such as CAD).
  • Such an effective amount can be readily determined by a person skilled in the art or a physician, and may be in relevant to the intended purpose (preventing or treating), the general health, age, sex, body weight of a subject, the severity of the disease to be treated, the accompanied disease, the routine of administration and so on. The determination of such an effective amount is well within the ability of a person skilled in the art.
  • the present invention provides use of Bacteroides uniformis and/or Bacteroides vulgatus in the preparation of a formulation for the treatment and/or prevention of coronary artery disease, or for decreasing the level of blood glucose or lipids, or for ameliorating coronary atherosclerotic lesions, in a subject.
  • the formulation may comprise any strain from Bacteroides uniformis or any combination thereof.
  • the formulation may comprise one or more strains of Bacteroides uniformis, such as at least 2, 3, 4, 5, or more strains.
  • Bacteroides uniformis is selected from the group consisting of Bacteroides uniformis ATCC 8492, Bacteroides uniformis CECT 7771, Bacteroides uniformis 0061, and any combination thereof.
  • the formulation may comprise any strain from Bacteroides vulgatus or any combination thereof.
  • the formulation may comprise one or more strains of Bacteroides vulgatus, such as at least 2, 3, 4, 5, or more strains.
  • Bacteroides vulgatus is selected from the group consisting of Bacteroides vulgatus ATCC 8482, Bacteroides vulgatus PC510, Bacteroides vulgatus mpk, and any combination thereof.
  • Bacteroides uniformis and Bacteroides vulgatus as described above may be used in combination. Therefore, the formulation may comprise one or more strains from Bacteroides uniformis as well as one or more strains from Bacteroides vulgatus.
  • the formulation is a pharmaceutical composition.
  • a pharmaceutical composition may comprise a therapeutically or prophylactically effective amount of Bacteroides uniformis and/or Bacteroides vulgatus.
  • the pharmaceutical composition may be in any form known in the art of medicine.
  • the pharmaceutical composition may be in the form of a tablet, a pill, a suspension, an emulsion, a solution, a gel, a capsule, a powder, or a granule.
  • the formulation is a nutraceutical composition or a food composition.
  • a composition may be in the form of solid, semi-solid, or liquid.
  • the formulation is a dairy product, such as milk, milk powder, or yogurt.
  • the formulation further comprises an additional agent for treatment and/or prevention of coronary artery disease, or decreasing the level of blood glucose or lipids, or ameliorating coronary atherosclerotic lesions.
  • an additional agent may be selected from the group consisting of cholesterol lowering medications, beta-blockers, nitroglycerin, calcium antagonists, statins, nitroglycerin, ACE inhibitors, calcium channel blockers, aspirin, and any combination thereof.
  • the additional agent may comprise any strain(s) of Bacteroides vulgatus, such as Bacteroides vulgatus ATCC 8482, Bacteroides vulgatus PC510, Bacteroides vulgatus mpk, or any combination thereof.
  • the additional agent may comprise any strain(s) of Bacteroides uniformis, such as Bacteroides uniformis ATCC 8492, Bacteroides uniformis CECT 7771, Bacteroides uniformis 0061, or any combination thereof.
  • the formulation comprises Bacteroides uniformis and/or Bacteroides vulgatus at a unit dosage, for example, at a concentration of at least 1x10 6 cfu/g, such as at least 1x10 7 cfu/g, at least 1x10 8 cfu/g, at least 1x10 9 cfu/g, at least 1x10 10 cfu/g, at least 1x10 11 cfu/g, or at least 1x10 12 cfu/g.
  • Bacteroides uniformis and/or Bacteroides vulgatus at a unit dosage, for example, at a concentration of at least 1x10 6 cfu/g, such as at least 1x10 7 cfu/g, at least 1x10 8 cfu/g, at least 1x10 9 cfu/g, at least 1x10 10 cfu/g, at least 1x10 11 cfu/g, or at least 1x10 12 cfu/g
  • the formulation is in the form of liquid (for example, a solution, a suspension, an emulsion), it may comprise Bacteroides uniformis and/or Bacteroides vulgatus at a concentration of at least 1x10 6 cfu/ml, such as at least 1x10 7 cfu/ml, at least 1x10 8 cfu/ml, at least 1x10 9 cfu/ml, at least 1x10 10 cfu/ml, at least 1x10 11 cfu/ml, or at least 1x10 12 cfu/ml.
  • Bacteroides uniformis and/or Bacteroides vulgatus at a concentration of at least 1x10 6 cfu/ml, such as at least 1x10 7 cfu/ml, at least 1x10 8 cfu/ml, at least 1x10 9 cfu/ml, at least 1x10 10 cfu/ml, at least 1x10 11
  • the formulation may be administrated with additional therapy.
  • additional therapy may be any known for coronary artery disease, such as Coronary interventions as angioplasty, and Coronary artery bypass grafting.
  • the subject is a mammalian, such as a human.
  • the present invention provides a formulation for the treatment and/or prevention of coronary artery disease, or for decreasing the level of blood glucose or lipids, or for ameliorating coronary atherosclerotic lesions, in a subject, comprising an effective amount of Bacteroides uniformis and/or Bacteroides vulgatus.
  • the formulation may comprise any strain from Bacteroides uniformis or any combination thereof.
  • the formulation may comprise one or more strains of Bacteroides uniformis, such as at least 2, 3, 4, 5, or more strains.
  • Bacteroides uniformis is selected from the group consisting of Bacteroides uniformis ATCC 8492, Bacteroides uniformis CECT 7771, Bacteroides uniformis 0061, and any combination thereof.
  • the formulation may comprise any strain from Bacteroides vulgatus or any combination thereof.
  • the formulation may comprise one or more strains of Bacteroides vulgatus, such as at least 2, 3, 4, 5, or more strains.
  • Bacteroides vulgatus is selected from the group consisting of Bacteroides vulgatus ATCC 8482, Bacteroides vulgatus PC510, Bacteroides vulgatus mpk, and any combination thereof.
  • Bacteroides uniformis and Bacteroides vulgatus as described above may be used in combination. Therefore, the formulation may comprise one or more strains from Bacteroides uniformis as well as one or more strains from Bacteroides vulgatus.
  • the formulation is a pharmaceutical composition.
  • a pharmaceutical composition may comprise a therapeutically or prophylactically effective amount of Bacteroides uniformis and/or Bacteroides vulgatus.
  • the pharmaceutical composition may be in any form known in the art of medicine.
  • the pharmaceutical composition may be in the form of a tablet, a pill, a suspension, an emulsion, a solution, a gel, a capsule, a powder, or a granule.
  • the formulation is a nutraceutical composition or a food composition.
  • a composition may be in the form of solid, semi-solid, or liquid.
  • the formulation is a dairy product, such as milk, milk powder, or yogurt.
  • the formulation further comprises an additional agent for treatment and/or prevention of coronary artery disease, or decreasing the level of blood glucose or lipids, or ameliorating coronary atherosclerotic lesions.
  • an additional agent may be selected from the group consisting of cholesterol lowering medications, beta-blockers, nitroglycerin, calcium antagonists, statins, nitroglycerin, ACE inhibitors, calcium channel blockers, aspirin, and any combination thereof.
  • the additional agent may comprise any strain(s) of Bacteroides vulgatus, such as Bacteroides vulgatus ATCC 8482, Bacteroides vulgatus PC510, Bacteroides vulgatus mpk, or any combination thereof.
  • the additional agent may comprise any strain(s) of Bacteroides uniformis, such as Bacteroides uniformis ATCC 8492, Bacteroides uniformis CECT 7771, Bacteroides uniformis 0061, or any combination thereof.
  • the formulation comprises Bacteroides uniformis and/or Bacteroides vulgatus at a unit dosage, for example, at a concentration of at least 1x10 6 cfu/g, such as at least 1x10 7 cfu/g, at least 1x10 8 cfu/g, at least 1x10 9 cfu/g, at least 1x10 10 cfu/g, at least 1x10 11 cfu/g, or at least 1x10 12 cfu/g.
  • Bacteroides uniformis and/or Bacteroides vulgatus at a unit dosage, for example, at a concentration of at least 1x10 6 cfu/g, such as at least 1x10 7 cfu/g, at least 1x10 8 cfu/g, at least 1x10 9 cfu/g, at least 1x10 10 cfu/g, at least 1x10 11 cfu/g, or at least 1x10 12 cfu/g
  • the formulation is in the form of liquid (for example, a solution, a suspension, an emulsion), it may comprise Bacteroides uniformis and/or Bacteroides vulgatus at a concentration of at least 1x10 6 cfu/ml, such as at least 1x10 7 cfu/ml, at least 1x10 8 cfu/ml, at least 1x10 9 cfu/ml, at least 1x10 10 cfu/ml, at least 1x10 11 cfu/ml, or at least 1x10 12 cfu/ml.
  • Bacteroides uniformis and/or Bacteroides vulgatus at a concentration of at least 1x10 6 cfu/ml, such as at least 1x10 7 cfu/ml, at least 1x10 8 cfu/ml, at least 1x10 9 cfu/ml, at least 1x10 10 cfu/ml, at least 1x10 11
  • the formulation may be administrated with additional therapy.
  • additional therapy may be any known for coronary artery disease, such as Coronary interventions as angioplasty, and Coronary artery bypass grafting.
  • the subject is a mammalian, such as a human.
  • the present invention provides a method for the treatment and/or prevention of coronary artery disease, or for decreasing the level of blood glucose or lipids, or for ameliorating coronary atherosclerotic lesions, in a subject, comprising the step of administrating an effective amount of Bacteroides uniformis and/or Bacteroides vulgatus to a subject in need thereof.
  • any strain from Bacteroides uniformis or any combination thereof may be administrated to the subject.
  • one or more strains of Bacteroides uniformis such as at least 2, 3, 4, 5, or more strains may be administrated to the subject.
  • Bacteroides uniformis is selected from the group consisting of Bacteroides uniformis ATCC 8492, Bacteroides uniformis CECT 7771, Bacteroides uniformis 0061, and any combination thereof.
  • any strain from Bacteroides vulgatus or any combination thereof may be administrated to the subject.
  • one or more strains of Bacteroides vulgatus such as at least 2, 3, 4, 5, or more strains may be administrated to the subject.
  • Bacteroides vulgatus is selected from the group consisting of Bacteroides vulgatus ATCC 8482, Bacteroides vulgatus PC510, Bacteroides vulgatus mpk, and any combination thereof.
  • Bacteroides uniformis and Bacteroides vulgatus as described above may be used in combination. Therefore, one or more strains from Bacteroides uniformis as well as one or more strains from Bacteroides vulgatus may be administrated to the subject.
  • Bacteroides uniformis and/or Bacteroides vulgatus may be formulated and administrated as a pharmaceutical composition.
  • a pharmaceutical composition may comprise a therapeutically or prophylactically effective amount of Bacteroides uniformis and/or Bacteroides vulgatus.
  • the pharmaceutical composition may be in any form known in the art of medicine.
  • the pharmaceutical composition may be in the form of a tablet, a pill, a suspension, an emulsion, a solution, a gel, a capsule, a powder, or a granule.
  • Bacteroides uniformis and/or Bacteroides vulgatus may be formulated and administrated as a nutraceutical composition or a food composition.
  • a nutraceutical composition may be in the form of solid, semi-solid, or liquid.
  • such a composition is a dairy product, such as milk, milk powder, or yogurt.
  • the method further comprises administrating additional agent for treatment and/or prevention of coronary artery disease, or decreasing the level of blood glucose or lipids, or ameliorating coronary atherosclerotic lesions.
  • additional agent may be administrated before, accompanied with, or after the administration of Bacteroides uniformis and/or Bacteroides vulgatus.
  • such an additional agent may be selected from the group consisting of cholesterol lowering medications, beta-blockers, nitroglycerin, calcium antagonists, statins, nitroglycerin, ACE inhibitors, calcium channel blockers, aspirin, and any combination thereof.
  • the additional agent may comprise any strain(s) of Bacteroides vulgatus, such as Bacteroides vulgatus ATCC 8482, Bacteroides vulgatus PC510, Bacteroides vulgatus mpk, or any combination thereof.
  • the additional agent may comprise any strain(s) of Bacteroides uniformis, such as Bacteroides uniformis ATCC 8492, Bacteroides uniformis CECT 7771, Bacteroides uniformis 0061, or any combination thereof.
  • Bacteroides uniformis and/or Bacteroides vulgatus may be administrated at an amount of at least 1x10 5 cfu/kg, such as at least 1x10 6 cfu/kg, at least 1x10 7 cfu/kg, at least 1x10 8 cfu/kg, at least 1x10 9 cfu/kg, at least 1x10 10 cfu/kg, at least 1x10 11 cfu/kg, or at least 1x10 12 cfu/kg of the body weight of the subject.
  • Bacteroides uniformis and/or Bacteroides vulgatus may be administrated three times a day, twice a day, once a day, once two days, or once a week.
  • the method further comprises administration of additional therapy.
  • additional therapy may be any known for coronary artery disease, such as Coronary interventions as angioplasty, and Coronary artery bypass grafting.
  • the subject is a mammalian, such as a human.
  • the present invention provides Bacteroides uniformis and/or Bacteroides vulgatus, for use in the method for the treatment and/or prevention of coronary artery disease, or for decreasing the level of blood glucose or lipids, or for ameliorating coronary atherosclerotic lesions, in a subject.
  • any strain from Bacteroides uniformis or any combination thereof may be used for the method.
  • one or more strains of Bacteroides uniformis such as at least 2, 3, 4, 5, or more strains may be used for the method.
  • Bacteroides uniformis is selected from the group consisting of Bacteroides uniformis ATCC 8492, Bacteroides uniformis CECT 7771, Bacteroides uniformis 0061, and any combination thereof.
  • any strain from Bacteroides vulgatus or any combination thereof may be used for the method.
  • one or more strains of Bacteroides vulgatus such as at least 2, 3, 4, 5, or more strains may be used for the method.
  • Bacteroides vulgatus is selected from the group consisting of Bacteroides vulgatus ATCC 8482, Bacteroides vulgatus PC510, Bacteroides vulgatus mpk, and any combination thereof.
  • Bacteroides uniformis and Bacteroides vulgatus as described above may be used in combination. Therefore, one or more strains from Bacteroides uniformis as well as one or more strains from Bacteroides vulgatus may be used for the method.
  • Bacteroides uniformis and/or Bacteroides vulgatus may be formulated and administrated as a pharmaceutical composition.
  • a pharmaceutical composition may comprise a therapeutically or prophylactically effective amount of Bacteroides uniformis and/or Bacteroides vulgatus.
  • the pharmaceutical composition may be in any form known in the art of medicine.
  • the pharmaceutical composition may be in the form of a tablet, a pill, a suspension, an emulsion, a solution, a gel, a capsule, a powder, or a granule.
  • Bacteroides uniformis and/or Bacteroides vulgatus may be formulated and administrated as a nutraceutical composition or a food composition.
  • a nutraceutical composition may be in the form of solid, semi-solid, or liquid.
  • such a composition is a dairy product, such as milk, milk powder, or yogurt.
  • Bacteroides uniformis and/or Bacteroides vulgatus may be administrated in combination with additional agent for treatment and/or prevention of coronary artery disease, or decreasing the level of blood glucose or lipids, or ameliorating coronary atherosclerotic lesions.
  • additional agent may be administrated before, accompanied with, or after the administration of Bacteroides uniformis and/or Bacteroides vulgatus.
  • such an additional agent may be selected from the group consisting of cholesterol lowering medications, beta-blockers, nitroglycerin, calcium antagonists, statins, nitroglycerin, ACE inhibitors, calcium channel blockers, aspirin, and any combination thereof.
  • the additional agent may comprise any strain(s) of Bacteroides vulgatus, such as Bacteroides vulgatus ATCC 8482, Bacteroides vulgatus PC510, Bacteroides vulgatus mpk, or any combination thereof.
  • the additional agent may comprise any strain(s) of Bacteroides uniformis, such as Bacteroides uniformis ATCC 8492, Bacteroides uniformis CECT 7771, Bacteroides uniformis 0061, or any combination thereof.
  • Bacteroides uniformis and/or Bacteroides vulgatus may be administrated at an amount of at least 1x10 5 cfu/kg, such as at least 1x10 6 cfu/kg, at least 1x10 7 cfu/kg, at least 1x10 8 cfu/kg, at least 1x10 9 cfu/kg, at least 1x10 10 cfu/kg, at least 1x10 11 cfu/kg, or at least 1x10 12 cfu/kg of the body weight of the subject.
  • Bacteroides uniformis and/or Bacteroides vulgatus may be administrated three times a day, twice a day, once a day, once two days, or once a week.
  • Bacteroides uniformis and/or Bacteroides vulgatus may be administrated in combination with additional therapy.
  • additional therapy may be any known for coronary artery disease, such as Coronary interventions as angioplasty, and Coronary artery bypass grafting.
  • the subject is a mammalian, such as a human.
  • Example 1 Identifying biomarkers relevant to risk of coronary artery disease
  • Fecal samples from 165 south Chinese subjects including 88 patients with atherosclerotic cardiovascular disease (ACVD) and 77 control subjects (training set, Table 1), were collected by Guangdong Provincial People's Hospital in 2011. ACVD patients were diagnosed and categorized according to pathological features. Subjects were asked to collect fresh fecal samples at hospital. Collected samples were put in sterile tubes and stored at -80 ⁇ C immediately until further analysis.
  • ACVD atherosclerotic cardiovascular disease
  • Table 1 Baseline characteristics of ACVD patients and controls. The fourth column reports results from Wilcoxon rank-sum tests.
  • DNA library construction was performed following the manufacturer ⁇ s instruction (Illumina).
  • the inventors used the routine workflow to perform cluster generation, template hybridization, isothermal amplification, linearization, blocking and denaturation, and hybridization of the sequencing primers.
  • the inventors constructed one paired-end (PE) library with insert size of 350 bp for each sample, followed by a high-throughput sequencing to obtain around 30 million PE reads with length of 2x100bp.
  • High-quality reads were obtained by filtering low-quality reads with ambiguous 'N' bases, adapter contamination and human DNA contamination from the Illumina raw reads, and trimming low-quality terminal bases of reads simultaneously.
  • the inventors totally output about 4.77 Gb of fecal micbiota sequencing data (high quality clean data) per sample (Table 2) for 165 samples (88 patients and 77 controls) on Illumina HiSeq 2000 platform.
  • Table 2 Summary of metagenomic data. The fourth column reports results from Wilcoxon rank-sum tests.
  • Taxonomic assignment of genes was performed using an in-house pipeline which had described in the published T2D paper (Qin et al. 2012, supra).
  • IMG species and mOTU species profiles were aligned to the 4,653 reference genomes from IMG v400 (Markowitz, V. M. et al. IMG: the integrated microbial genomes database and comparative analysis system. Nucleic acids research 40, D115-D122 (2012), incorporated herein by reference) and to the 79,268 sequences of mOTU reference (Sunagawa, S. et al. Metagenomic species profiling using universal phylogenetic marker genes. Nature methods 10, 1196-1199 (2013), incorporated herein by reference) with default parameters, respectively. 1290 IMG species (species that were shared among at least 10 subjects) and 560 mOTU species were identified.
  • the inventors used the permutational multivariate analysis of variance (PERMANOVA) to assess the effect of 25 different characteristics, including CAD status, HDLC, CHOL, Gender, FBG, hypertension, APOB, Age, CREA, LDLC, HbA1c, APOA, TP, diabetes, ALB, TRIG, BMI, WHR, Lpa, HBDH, CKMB, AST, CK, ProBNP_E_, and ALT, on gene profiles of 4.5M reference gene catalogue.
  • the inventors performed the analysis using the method implemented in package ′′vegan′′ in R, and the permuted p-value was obtained by 10,000 times permutations.
  • PERMANOA identified two significant factors associated with gut microbe (based on gene profiles) (q ⁇ 0.05, Table 3). The analysis indicated that CAD and HDLC status were the most significantly associated markers, supporting that the disease status was the major determinant influencing the composition of gut microbiota. Gender, age and some CAD clinical indices like CHOL, FGB, hypertension and APOB, were also significant factors.
  • Table 3 PERMANOVA based on euclidean distance analysis of gene profile. The analysis was conducted to test whether clinical parameters and ACVD status have significant impact on the gut microbiota with q-value ⁇ 0.05.
  • FDR false discovery rate
  • Receiver Operator Characteristic (ROC) analysis The inventors applied the ROC analysis to assess the performance of the ACVD classification based on metagenomic markers. The inventors then used the “pROC” package in R to draw the ROC curve.
  • ROC Receiver Operator Characteristic
  • MLG metagenomic linkage group
  • the inventors performed Wilcoxon rank-sum test to the 127 MLGs species with Benjamini-Hochberg adjustment, and 126 MLGs were selected as ACVD-associated MLGs with q ⁇ 0.05. To estimate the relative abundance of an MLG species, the inventors estimated the average abundance of the genes of the MLG species, after removing the 5% lowest and 5% highest abundant genes (Qin et al. 2012, supra).
  • MLG metagenomic linkage groups
  • Qin et al. 2012, supra the distribution and the occurrence rate (Qin et al. 2012, supra) of 438,750 genes.
  • 94.8% of the significant genes (P-value ⁇ 0.01) were included into MLGs.
  • 136 MLGs (each with >550 genes, >50% coverage and q ⁇ 0.05) were annotated to NCBI database, and MLGs from the same species were grouped, resulting in 126 MLG species.
  • MLG species marker To identify MLG species makers, the inventors used “randomForest 4.5-36” package in R vision 2.10 for the 126 ACVD associated MLG species. Firstly, the inventors sorted all the 126 MLG species based on the importance given by the “randomForest” method (Liaw, Andy & Wiener, Matthew. Classification and Regression by randomForest, R News (2002), Vol. 2/3 p. 18, incorporated herein by reference). MLG marker sets were constructed by creating incremental subsets of the top ranked MLG species, starting from 5 MLG species and ending at all 126 MLG species. For each MLG maker set, the inventors calculated the false predication ratio in our cohort of 165 persons.
  • the MLG maker set (comprising 65 MLG species) with the lowest false prediction ratio were selected as MLG species makers (Fig.1), with false negative (FN) rate of 6.8% and false positive (FP) rate of 3.89%. Furthermore, the inventors drew the ROC curve using the OOB (out of bag) prediction probability of illness from randomForest model based on the selected MLG species markers, and the area under the ROC curve was calculated as 98.17% using R package “pROC” .
  • IMG species and mOTU species markers were identified based on the IMG species and mOTU species profiles, The inventors identified the ACVD associated IMG species and mOTU species with q ⁇ 0.05 (Wilcoxon rank-sum test with Benjamini-Hochberg adjustment). Subsequently, IMG species markers and mOTU species markers were selected using the randomForest approach as in MLG species markers selection.
  • 65 IMG species with ROC of 98.52% and 15 mOTU species with ROC of 96.16% also clearly distinguished CAD patients from healthy subjects (q ⁇ 0.05; see Tables 5 and 6), according to Wilcoxon rank-sum test and random forest selection.
  • 65 MLG species markers in the 65 IMG species markers and 15 mOTU species markers, the inventors found that Bacteroides uniformis was significantly enriched in controls.
  • mice were fed with high fat diets for 16 weeks to build the model of atherosclerosis, and then Bacteroides uniformis and Bacteroides vulgatus were given from the 16th week, and the effect on blood glucose and OGTT (oral glucose tolerance test), serum lipids and atherosclerotic plaque area were observed.
  • OGTT oral glucose tolerance test
  • mice 64 male specific pathogen-free (SPF) C57BL/6J mice (10-week-old), with a weight between 22.5 ⁇ 25.9g, were purchased from Laboratory Animal Center of Southern Medical University, China. Mice that used for diet-induced atherosclerosis study have ad libitum access to drinking water and chow diet for 2 weeks acclimatization. Then they were randomly divided into 2 parts: one part (8 mice) was fed with a normal chow diet (NC group, containing 10% kcal from fat, 3.85 total kcal g -1 from Research Diets, Inc., New Brunswick, NJ, USA) as healthy controls.
  • NC group containing 10% kcal from fat, 3.85 total kcal g -1 from Research Diets, Inc., New Brunswick, NJ, USA
  • mice The other part (56 mice) was fed with a high fat diet (containing 60% kcal from fat, 5.24 total kcal g -1 , from Research Diets, Inc.) with 2% cholesterol for induction of atherosclerosis, and 16 weeks later, these 56 mice were randomly divided into 7 groups (8 mice per group).
  • One group was given the same cholesterol-rich HF diet as atherosclerosis control group (AS group), receiving 200 ⁇ l columbia blood medium (DSMZ Medium 693) as placebo.
  • the other six groups also received the cholesterol-rich HF diet and were administrated with 200 ⁇ l bacterial suspension containing one of the six candidate probiotic strains, namely Bacteroides uniformis ATCC 8492, Bacteroides uniformis CECT 7771, Bacteroides uniformis 0061, Bacteroides vulgatus ATCC 8482, Bacteroides vulgatus PC510 and Bacteroides vulgatus mpk in columbia blood medium by gavage at a dose of 10 9 -10 10 cfu/ml (freshly prepared weekly). The mice were fed for further 8 weeks.
  • Bacteroides uniformis ATCC 8492 and Bacteroides vulgatus ATCC 8482 were purchased from American Type Culture Collection (ATCC).
  • Bacteroides uniformis CECT 7771 was purchased from Spanish Type Culture Collection.
  • Bacteroides uniformis 0061 was obtained from Virginia Polytechnic Institute and State University, Anaerobic Laboratory Culture Collection (Shoemaker, N. B., & Salyers, A. A. (1988). Tetracycline-dependent appearance of plasmid like forms in Bacteroides uniformis 0061 mediated by conjugal Bacteroides tetracycline resistance elements. Journal of bacteriology, 170(4), 1651-1657).
  • Bacteroides vulgatus PC510 was obtained from CSIRO Preventative Health Flagship Research Program and Division of Livestock Industries (Páraic O Cu ⁇ v, et al. Draft genome sequence of Bacteroides vulgatus PC510, a strain isolated from human feces. Journal of bacteriology, 2011, 193(15): 4025-6).
  • Bacteroides vulgatus mpk was obtained from Institute of Medical Microbiology and Hygiene, University of Tubingen (Waidmann M, et al. Bacteroides vulgatus protects against Escherichia coli-induced colitis in gnotobiotic interleukin-2-deficient mice. Gastroenterology. 2003 Jul; 125(1): 162-77).
  • the anaerobic culture technique was used to purify and incubate the strains.
  • the composition of columbia blood medium for incubating was described in DSMZ (Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH, German Collection of Microorganisms and Cell Cultures) Medium 693.
  • DSMZ Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH, German Collection of Microorganisms and Cell Cultures
  • strains were anaerobically propagated at 37 °C for 48 hours.
  • glucose was administered orally to the mice at a dose of 2.0 g/kg body weight.
  • Blood samples were taken from the tail before and 15, 30, 60, and 120 min after glucose administration, and blood glucose levels were measured with a blood glucose meter (Roche Diagnostics, Mannheim, Germany). The blood glucose level before glucose administration represented fasting glucose level.
  • TG Plasma triglycerides
  • TC plasma total cholesterol
  • heparin was injected into inferior caval vein, and the aorta were removed from the aortic root under the microscope, fixed in paraformaldehyde, then embedded in 10% phosphate buffered formalin, sectioned at 6 ⁇ m. Light microscopy was performed to evaluate the atherosclerotic changes. Histological sections on the glass slides were scanned to create virtual slides for quantitative evaluation using iVision Software (BioVision Technologies, Exton, PA, USA). For detection of neutral lipid, histological sections were stained with Oil Red-O stain. After capturing images of the sections, we determined the red area by computer-assisted color-gated measurement on the total section area (SigmaScanPro 5; SPSS Inc., Chicago, IL, USA).
  • Table 7 AUC value of OGTT curve of each group. Each value is shown as mean ⁇ SEM. Difference between values from groups marked with the same letter is not statistically significant, according to analysis of variance followed by Tukey post hoc test. Among the groups, the same letter marked represents that values were not significantly different, as determined by the Tukey's Test (p> 0.05).
  • Table 8 The effects of administration of Bacteroides strains on plasma triglycerides (TG) and plasma total cholesterol (TC). Each value is shown as mean ⁇ SEM. Difference between values from groups marked with the same letter is not statistically significant, according to analysis of variance followed by Tukey post hoc test. Among the groups, the same letter marked represents that values were not significantly different, as determined by the Tukey's Test (p> 0.05).
  • mice in AS group developed lipid-rich atherosclerotic lesions in the aortic root after fed with cholesterol-rich HF diet and placebo on the 24th week (Fig.4H, AS group).
  • Fig.4H AS group
  • mice administered with Bacteroides strains for 8 weeks displayed substantially decrease of foam cells and lipid deposition in the subintimal area (Fig.4B ⁇ 4G).

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Abstract

L'invention concerne l'utilisation de Bacteroides uniformis dans la préparation d'une formulation destinée au traitement et/ou à la prévention de la coronaropathie, ou à la réduction du niveau du glucose ou des lipides dans le sang, ou encore à l'atténuation de lésions athéroscléreuses coronariennes. Et le Bacteroides uniformis est choisi parmi Bacteroides uniformis ATCC 8492, Bacteroides uniformis CECT 7771, Bacteroides uniformis 0061.
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EP3692813A4 (fr) * 2017-10-03 2021-01-27 Keio University Composition présentant un effet d'amélioration de la résistance physique et/ou un effet anti-fatigue
EP3677273A4 (fr) * 2017-08-29 2021-04-14 BGI Shenzhen Application de bacteroides cellulosityticus dans l'élaboration d'une préparation pour la prévention et/ou le traitement de maladies associées au métabolisme lipidique

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Cited By (3)

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EP3677273A4 (fr) * 2017-08-29 2021-04-14 BGI Shenzhen Application de bacteroides cellulosityticus dans l'élaboration d'une préparation pour la prévention et/ou le traitement de maladies associées au métabolisme lipidique
US11273186B2 (en) 2017-08-29 2022-03-15 Bgi Shenzhen Application of bacteroides cellulosityticus in preparing a preparation for preventing and/or treating lipid metabolism related diseases
EP3692813A4 (fr) * 2017-10-03 2021-01-27 Keio University Composition présentant un effet d'amélioration de la résistance physique et/ou un effet anti-fatigue

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