JPS63280027A - Antihyperlipemic - Google Patents
AntihyperlipemicInfo
- Publication number
- JPS63280027A JPS63280027A JP62115537A JP11553787A JPS63280027A JP S63280027 A JPS63280027 A JP S63280027A JP 62115537 A JP62115537 A JP 62115537A JP 11553787 A JP11553787 A JP 11553787A JP S63280027 A JPS63280027 A JP S63280027A
- Authority
- JP
- Japan
- Prior art keywords
- enterococcus
- antihyperlipemic
- cholesterol
- rats
- cell bodies
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 241000194033 Enterococcus Species 0.000 claims abstract description 33
- 244000005700 microbiome Species 0.000 claims abstract description 26
- 241000194032 Enterococcus faecalis Species 0.000 claims abstract description 14
- 229940032049 enterococcus faecalis Drugs 0.000 claims abstract description 14
- 241000194031 Enterococcus faecium Species 0.000 claims abstract description 6
- 239000004480 active ingredient Substances 0.000 claims abstract description 4
- 239000003524 antilipemic agent Substances 0.000 claims description 8
- 230000001315 anti-hyperlipaemic effect Effects 0.000 claims description 6
- 241000520130 Enterococcus durans Species 0.000 claims 1
- 241000894006 Bacteria Species 0.000 abstract description 11
- 230000000694 effects Effects 0.000 abstract description 10
- 239000003814 drug Substances 0.000 abstract description 8
- 238000002360 preparation method Methods 0.000 abstract description 8
- 229940079593 drug Drugs 0.000 abstract description 6
- 230000009471 action Effects 0.000 abstract description 4
- 239000000203 mixture Substances 0.000 abstract description 4
- 208000018522 Gastrointestinal disease Diseases 0.000 abstract description 3
- 230000008859 change Effects 0.000 abstract description 3
- 210000005056 cell body Anatomy 0.000 abstract 4
- 208000019423 liver disease Diseases 0.000 abstract 1
- 230000003068 static effect Effects 0.000 abstract 1
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 43
- 241000700159 Rattus Species 0.000 description 26
- 241000699670 Mus sp. Species 0.000 description 16
- 235000012000 cholesterol Nutrition 0.000 description 15
- 230000009467 reduction Effects 0.000 description 14
- 230000001580 bacterial effect Effects 0.000 description 13
- 210000002966 serum Anatomy 0.000 description 12
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 11
- 206010003210 Arteriosclerosis Diseases 0.000 description 10
- 208000011775 arteriosclerosis disease Diseases 0.000 description 10
- 230000003247 decreasing effect Effects 0.000 description 8
- 208000031226 Hyperlipidaemia Diseases 0.000 description 6
- 210000004369 blood Anatomy 0.000 description 6
- 239000008280 blood Substances 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- 239000002612 dispersion medium Substances 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 229930091371 Fructose Natural products 0.000 description 4
- 239000005715 Fructose Substances 0.000 description 4
- 108010062497 VLDL Lipoproteins Proteins 0.000 description 4
- 230000006872 improvement Effects 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 239000002609 medium Substances 0.000 description 4
- 239000002504 physiological saline solution Substances 0.000 description 4
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 3
- 210000000709 aorta Anatomy 0.000 description 3
- 230000000968 intestinal effect Effects 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 206010007269 Carcinogenicity Diseases 0.000 description 2
- 206010067125 Liver injury Diseases 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 210000001367 artery Anatomy 0.000 description 2
- 230000007670 carcinogenicity Effects 0.000 description 2
- 231100000260 carcinogenicity Toxicity 0.000 description 2
- 238000012136 culture method Methods 0.000 description 2
- 238000012258 culturing Methods 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- PXEDJBXQKAGXNJ-QTNFYWBSSA-L disodium L-glutamate Chemical compound [Na+].[Na+].[O-]C(=O)[C@@H](N)CCC([O-])=O PXEDJBXQKAGXNJ-QTNFYWBSSA-L 0.000 description 2
- 235000013305 food Nutrition 0.000 description 2
- 231100000234 hepatic damage Toxicity 0.000 description 2
- 230000008818 liver damage Effects 0.000 description 2
- 235000013923 monosodium glutamate Nutrition 0.000 description 2
- 230000003449 preventive effect Effects 0.000 description 2
- 239000012266 salt solution Substances 0.000 description 2
- 235000020183 skimmed milk Nutrition 0.000 description 2
- 229940073490 sodium glutamate Drugs 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- BHQCQFFYRZLCQQ-UHFFFAOYSA-N (3alpha,5alpha,7alpha,12alpha)-3,7,12-trihydroxy-cholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 BHQCQFFYRZLCQQ-UHFFFAOYSA-N 0.000 description 1
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 239000004380 Cholic acid Substances 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 108010028554 LDL Cholesterol Proteins 0.000 description 1
- 108010007622 LDL Lipoproteins Proteins 0.000 description 1
- 102000007330 LDL Lipoproteins Human genes 0.000 description 1
- 108010013563 Lipoprotein Lipase Proteins 0.000 description 1
- 102100022119 Lipoprotein lipase Human genes 0.000 description 1
- VRAHPESAMYMDQI-UHFFFAOYSA-N Nicomol Chemical compound C1CCC(COC(=O)C=2C=NC=CC=2)(COC(=O)C=2C=NC=CC=2)C(O)C1(COC(=O)C=1C=NC=CC=1)COC(=O)C1=CC=CN=C1 VRAHPESAMYMDQI-UHFFFAOYSA-N 0.000 description 1
- 108010011964 Phosphatidylcholine-sterol O-acyltransferase Proteins 0.000 description 1
- 102100031538 Phosphatidylcholine-sterol acyltransferase Human genes 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 239000003263 anabolic agent Substances 0.000 description 1
- 229940070021 anabolic steroids Drugs 0.000 description 1
- 229940041514 candida albicans extract Drugs 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- BHQCQFFYRZLCQQ-OELDTZBJSA-N cholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 BHQCQFFYRZLCQQ-OELDTZBJSA-N 0.000 description 1
- 235000019416 cholic acid Nutrition 0.000 description 1
- 229960002471 cholic acid Drugs 0.000 description 1
- KNHUKKLJHYUCFP-UHFFFAOYSA-N clofibrate Chemical compound CCOC(=O)C(C)(C)OC1=CC=C(Cl)C=C1 KNHUKKLJHYUCFP-UHFFFAOYSA-N 0.000 description 1
- 229960001214 clofibrate Drugs 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 231100000517 death Toxicity 0.000 description 1
- KXGVEGMKQFWNSR-UHFFFAOYSA-N deoxycholic acid Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 KXGVEGMKQFWNSR-UHFFFAOYSA-N 0.000 description 1
- 229960000633 dextran sulfate Drugs 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- BJHIKXHVCXFQLS-UYFOZJQFSA-N fructose group Chemical group OCC(=O)[C@@H](O)[C@H](O)[C@H](O)CO BJHIKXHVCXFQLS-UYFOZJQFSA-N 0.000 description 1
- 235000015203 fruit juice Nutrition 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 229950001071 nicomol Drugs 0.000 description 1
- 231100000956 nontoxicity Toxicity 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 235000008476 powdered milk Nutrition 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 235000013322 soy milk Nutrition 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- YWYZEGXAUVWDED-UHFFFAOYSA-N triammonium citrate Chemical compound [NH4+].[NH4+].[NH4+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O YWYZEGXAUVWDED-UHFFFAOYSA-N 0.000 description 1
- 235000021122 unsaturated fatty acids Nutrition 0.000 description 1
- 150000004670 unsaturated fatty acids Chemical class 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 229940100445 wheat starch Drugs 0.000 description 1
- 239000012138 yeast extract Substances 0.000 description 1
Landscapes
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Abstract
Description
【発明の詳細な説明】 〔産業上の利用分野〕 この発明は抗高脂血症剤に関するものである。[Detailed description of the invention] [Industrial application field] This invention relates to antihyperlipidemic agents.
高脂血症は、従来成人病として増加の一途をたどりつつ
ある動脈硬化の最も重要な危険因子と考えられ、遺伝性
、非遺伝性のものも含まれるが血清コレステロール値ま
たは血清トリグリセライド値が上昇する病気であり、特
に低比重リポ蛋白コレステロールは、動脈内膜細胞に取
り込まれ沈着し、動脈粥状硬化の主因になると考えられ
ている。Hyperlipidemia is considered to be the most important risk factor for arteriosclerosis, which is an increasingly common adult disease, and increases serum cholesterol or triglyceride levels, including hereditary and non-hereditary ones. In particular, low-density lipoprotein cholesterol is taken up and deposited in arterial intimal cells, and is thought to be the main cause of arterial atherosclerosis.
また、超低比重リポ蛋白（以下、ＶＬＤＬと略記する）
は、生体内において、リポプロティンリパーゼの作用に
より容易に低比重リポ蛋白（以下、ＬＤＬと略記する）
に変換する。一方高比重リボ蛋白（以下、ＨＤＬと略記
する）は、組繊細胞の表面膜から遊離コレステロールを
除去し、レシチン・コレステロール−アシル転移酵素の
作用でこれをエステル化し肝臓に運搬する作用を持つと
され、一般的にはＶＬＤＬ、ＬＤＬが増加すると高脂血
症は悪化し、ＨＤＬが増加すると逆に高脂血症は改善さ
れるといわれている。Also, very low density lipoprotein (hereinafter abbreviated as VLDL)
is easily converted into low-density lipoprotein (hereinafter abbreviated as LDL) in vivo by the action of lipoprotein lipase.
Convert to On the other hand, high-density riboprotein (hereinafter abbreviated as HDL) has the function of removing free cholesterol from the surface membrane of tissue cells, esterifying it with the action of lecithin-cholesterol-acyltransferase, and transporting it to the liver. It is generally said that an increase in VLDL and LDL worsens hyperlipidemia, and an increase in HDL conversely improves hyperlipidemia.
そして高脂血症に対しては、次式
％式％）
で表される動脈硬化指数の低下が、その症状の改善に必
要であるといわれている。For hyperlipidemia, it is said that a reduction in the arteriosclerotic index expressed by the following formula (%) is necessary to improve the symptoms.
これまでに、抗高脂血症剤としては、ニコモール、クロ
フィブレートイオン交換樹脂、タンパク同化ステロイド
、ビタミン類、不飽和脂肪酸、リン脂質、デキストラン
硫酸等が治療薬として使用されているが、なかには胃腸
障害、発癌性、肝障害などの副作用を示すものがあり、
また、副作用が少ないものでも動脈硬化指数に変化が見
られないものがあり、いずれも満足すべきものではない
。So far, antihyperlipidemic agents such as nicomol, clofibrate ion exchange resin, anabolic steroids, vitamins, unsaturated fatty acids, phospholipids, and dextran sulfate have been used as therapeutic agents; Some drugs have side effects such as gastrointestinal disorders, carcinogenicity, and liver damage.
In addition, even if there are some drugs that have few side effects, there are some that show no change in the arteriosclerosis index, and none of them are satisfactory.
最近、腸内細菌と宿主生理との関係についての研究は著
しい進歩を示し、腸内最近叢が宿主の血清コレステロー
ル値の低下に強く関与していることが明らかになってき
ている。Recently, research on the relationship between intestinal bacteria and host physiology has made remarkable progress, and it has become clear that the intestinal flora is strongly involved in lowering host serum cholesterol levels.
このように従来の技術においては胃腸障害、発癌性、肝
障害などの副作用が現われたり、副作用が少ないもので
も動脈硬化指数に変化が見られないなど満足すべき抗高
脂血症剤は得られていないという問題点があった。As described above, with conventional techniques, satisfactory antihyperlipidemic agents have not been obtained, such as side effects such as gastrointestinal disorders, carcinogenicity, and liver damage, and even with few side effects, no change in arteriosclerosis index has been observed. The problem was that it was not.
上記の問題点を解決するために、この発明は抗高脂血症
作用を有するエンテロコツカス属に属する微生物の生菌
体もしくは死菌体を主有効成分として含有した抗高脂血
症剤とする手段を採用したものである。以下その詳細を
述べる。In order to solve the above problems, the present invention provides an antihyperlipidemic agent containing as a main active ingredient live or dead microorganisms belonging to the genus Enterococcus having antihyperlipidemic action. This method adopted a method to do so. The details will be described below.
まず、この発明のエンテロコツカス属に属する微生物は
、この発明の発明者が腸内細菌の中から毒性が全く存在
しない抗高脂血症効果を有する微生物の検索を進めた結
果見出したもので、この属の各種微生物中特に好適なも
のとして、エンテロコツカス・フェカリス、エンテロコ
ツカス・フェシウム、エンテロコツカス・エビラム、エ
ンテロコツカス・デユランス、エンテロコツカス・ボオ
ヴイス等を例示することができる。First, the microorganism belonging to the genus Enterococcus of the present invention was discovered by the inventor of the present invention as a result of searching for microorganisms among intestinal bacteria that have no toxicity and have an antihyperlipidemic effect. Among the various microorganisms of this genus, particularly preferred ones include Enterococcus faecalis, Enterococcus faecium, Enterococcus evirum, Enterococcus duulans, Enterococcus boovis, and the like.
つぎに、この発明のエンテロコツカス属に属する微生物
の菌学的性質、培養条件等は「Ｂｅｒｇａｙ’ ｓＭａ
ｎｕａｌ ｏｆ Ｄｅｔｅｒｍｉｎａｔｉｖｅ Ｂａｃ
ｔｅｒｉｏｌｏｇｙ Ｊ第８版第４９０頁以降に記載さ
れているが、−例を示すとつぎのとおりである。Next, the mycological properties, culture conditions, etc. of the microorganism belonging to the genus Enterococcus of this invention are described in "Bergay's Ma
nual of Determinative Bac
It is described in teriology J 8th edition, page 490 onwards, and examples are as follows.
エンテロコツカス属の微生物は以下に示す組成からなる
ロゴサ液体培地によって３７°Ｃ・、１６時間好気的に
静置培養し、培養後培養液を遠心分離して菌体を集めた
。Microorganisms of the genus Enterococcus were aerobically cultured for 16 hours at 37°C in a Rogosa liquid medium having the composition shown below, and after the culture, the culture solution was centrifuged to collect bacterial cells.
ロゴサ液体培地の組成（精留水１リットル中）ニ
トリブチケース １０（ｇ）酵母エキス
５ 〃
トリプトース ３ 〃
ＫｔＨＰＯａ ３ ’Ｋｌ（ｔＰｏ
、 ３ ＃クエン酸アンモニウム
２ 〃
ツイーン８０ ｌ 〃グルコース
２０〃
システイン ０．２〃
塩類溶液＊ ５ （ｍｌ）ここで、得
られるロゴサ液体培地はｐＨ値６．８であり、これを１
２１℃、１５分加熱滅菌した。（なお、＊印を付けた塩
類溶液は精留水１００ｍ１中に、Ｍｇ５Ｏａ・７１（！
Ｏを１１．５ｇ、 Ｐｅ５ｏｓ ・７ＨｔＯ０，６８
ｇ、、ＭｎＳＯ４・２Ｈ，０２，４ｇを含有したもので
ある。）上記のようにして集められた菌体を、生理食塩
水によって２回洗浄した後、生理食塩水（０，８５％Ｎ
ａｃｌ水溶液）または分散媒（１％グルタミン酸ナトリ
ウム１０％脱脂粉乳を含む水溶液）に懸濁させてこれを
生菌体試料とし、これに対して生理食塩水に懸濁させた
生菌体を１１０℃、１０分間高圧下（１０ｌｂ）で加熱
滅菌したもの、加熱滅菌後凍結燥したもの、もしくは凍
結乾燥後菌体を分散媒に懸濁させたものを死菌体試料と
した。Composition of Rogosa liquid medium (in 1 liter of rectified water) Nitributicase 10 (g) Yeast extract
5 〃 Tryptose 3 〃 KtHPOa 3 'Kl(tPo
, 3 #ammonium citrate
2 Tween 80 l Glucose
20〃 Cysteine 0.2〃 Salt solution * 5 (ml) Here, the obtained Rogosa liquid medium has a pH value of 6.8, and this is
It was heat sterilized at 21°C for 15 minutes. (In addition, the salt solutions marked with * are Mg5Oa・71(!) in 100ml of rectified water.
11.5g of O, Pe5os ・7HtO0,68
g., MnSO4.2H,02.4g. ) The bacterial cells collected as described above were washed twice with physiological saline, and then washed with physiological saline (0.85% N
acl aqueous solution) or a dispersion medium (an aqueous solution containing 1% sodium glutamate and 10% skimmed milk powder) to prepare a live bacterial sample, whereas live bacterial cells suspended in physiological saline were incubated at 110°C. The dead cell samples were those that were heat sterilized under high pressure (10 lb) for 10 minutes, those that were freeze-dried after heat sterilization, or those that were freeze-dried and suspended in a dispersion medium.
また、この発明の抗高脂血症剤の効果判定に使用したコ
レステロール負荷ラット調製法として、通常Ｒｔ４に１
．５％コレステロール、０．５％コール酸を添加して配
合飼料を作製し、この配合飼料を６週齢のラットに連続
２週間８週齢まで投与し、また果糖負荷ラット調製法と
して、通常飼料中の小麦デンプンの全量を果糖で置換し
た配合飼料を６週齢のラットに連続２週間８週齢まで投
与するという方法を採用した。In addition, as a method for preparing cholesterol-loaded rats used to evaluate the effect of the antihyperlipidemic agent of this invention,
．． A compounded feed was prepared by adding 5% cholesterol and 0.5% cholic acid, and this compounded feed was administered to 6-week-old rats for 2 consecutive weeks until they were 8 weeks old. A method was adopted in which a compounded feed in which all of the wheat starch in the feed was replaced with fructose was administered to 6-week-old rats for two consecutive weeks until the age of 8 weeks.
実験例１：
この発明の死菌体投与の抗高脂血症効果を試験した、前
記の培養法および菌体調製法によって作製した各種のエ
ンテロコツカス属微生物の死菌体を各８週齢の雄の通常
マウス（１群１０匹）、通常ラット（１群５匹）および
前記ラット調製法によって作製したコレステロール負荷
ラット（１群５匹）、果糖負荷ラット（１群５匹）の４
種類の実験動物に１０１０個（６０ｍｇ） ／頭／日に
なるように経口的に４週間連続投与した。ついで、これ
らのマウスは新聞し、ラットは工大動脈からそれぞれ採
血し血清コレステロール値と血清トリグリセライド値を
測定し、得られた結果を第１表および第２表にそれぞれ
まとめた。第１表の結果から、マウスでは最高４４％の
コレステロール低下率を示し、最低でも約１９％の低下
率を示し、また、ラットに対しても最低でも約１９％の
コレステロール低下率を示し、最高では約３７％もの著
しいコレステロール低下率を示している。したがって、
いずれのエンテロコツカス属微生物もコレステロールを
著しく低下させる作用を有することがわかる。その中で
も特に有効と考えられる微生物は、エンテロコウム、エ
ンテロコツカス・デユランスであった。Experimental Example 1: The antihyperlipidemic effect of administration of killed microorganisms of the present invention was tested. Killed microorganisms of various Enterococcus microorganisms produced by the above-mentioned culture method and microbial cell preparation method were administered to 8-week-old microorganisms. 4 normal male mice (10 mice per group), normal rats (5 mice per group), cholesterol-loaded rats (5 mice per group), and fructose-loaded rats (5 mice per group) prepared by the above rat preparation method.
The drug was orally administered to various experimental animals at a dose of 1010 pieces (60 mg)/head/day for 4 consecutive weeks. Next, blood was collected from newspapers from these mice and from the arterial artery from the rats, and serum cholesterol levels and serum triglyceride levels were measured, and the obtained results are summarized in Tables 1 and 2, respectively. From the results in Table 1, mice showed a maximum cholesterol reduction rate of 44%, a minimum cholesterol reduction rate of about 19%, and rats also showed a minimum cholesterol reduction rate of about 19%, and a maximum shows a remarkable cholesterol reduction rate of about 37%. therefore,
It can be seen that all Enterococcus microorganisms have an effect of significantly lowering cholesterol. Among them, the microorganisms considered to be particularly effective were Enterococcus duurans.
なお、低下率（％）の数値は無投与群を対照とした値で
ある。In addition, the numerical value of the reduction rate (%) is a value with the non-administration group as a control.
第 １ 表 死菌体投与の血清コレステロール低
下率（％）第 ２ 表 死菌体投与の血清トリグリセ
ライド低下率（％）また第２表の結果から、血清トリグ
リセライド値もマウスに対しては最低でも約２５％、最
高では約７５％も低下していた。さらにラットに対して
も最低でも約２３％、最高では約６９％も低下しており
、各種エンテロコツカス属微生物が血清トリグリセライ
ドの低下に顕著な作用を示すことがわかるが、中でも特
に有効と思われる微生物はエンテロコツカス・フェカリ
スであった。Table 1: Serum cholesterol reduction rate (%) after administration of killed cells Table 2: Reduction rate of serum triglyceride (%) after administration of killed cells Also, from the results in Table 2, serum triglyceride levels for mice are at least approximately It dropped by 25%, and at its peak it dropped by about 75%. Furthermore, the reduction in rats was as low as about 23% and as high as about 69%, indicating that various Enterococcus microorganisms have a remarkable effect on lowering serum triglycerides, but this seems to be particularly effective. The microorganism found was Enterococcus faecalis.
実験例２；
この発明の生菌体投与の抗高脂血症効果を試験した。前
記の培養法および菌体調製法によって作製した各種のエ
ンテロコツカス属微生物の生菌体を実験例１におけると
同様の各８週齢の雄の通常マウス（１群１０匹）、通常
ラット（１群５匹）および前記ラット調製法に基づいて
作製したコレステロール負荷ラット（１群５匹）、果糖
負荷ラット（１群５匹）の４種類の実験動物に１０”個
／頭／日になるように経口的に４週間連続投与した。Experimental Example 2: The antihyperlipidemic effect of administering the live bacterial cells of this invention was tested. Live cells of various Enterococcus microorganisms prepared by the above-mentioned culture method and cell preparation method were incubated with 8-week-old male normal mice (10 mice per group) and normal rats (1 group) as in Experimental Example 1. 10"/head/day to four types of experimental animals: cholesterol-loaded rats (5 rats per group) and fructose-loaded rats (5 rats per group) prepared based on the rat preparation method described above. The drug was administered orally for 4 consecutive weeks.
これらマウスおよびラットから実施例１と同じ方法で採
血し、血清コレステロール値と血清トリグリセライド値
とを求めたが結果は第３表および第４表に示した。第３
表から、マウスでは最低で約１９％、最高では約３７％
のコレステロール低下率を示し、一方ラットでも最低的
１６％から最高的４１％のコレステロール低下率を示す
ことがわかる。Blood was collected from these mice and rats in the same manner as in Example 1, and serum cholesterol levels and serum triglyceride levels were determined, and the results are shown in Tables 3 and 4. Third
From the table, the lowest for mice is about 19% and the highest is about 37%.
It can be seen that rats also showed a cholesterol reduction rate ranging from a minimum of 16% to a maximum of 41%.
第 ３ 表 生菌体投与の血清コレステロール低下率
（％）第 ４ 表 生菌体投与の血清トリグリセライ
ド低下率Ｏ０＊２ 果糖負荷ラット
また第４表からはマウスで最低的１３％、最高約６７％
の血清トリグリセライド値の低下率を示し、ラットでは
最低的１５％から最高約６７％の血清トリグリセライド
値の低下率を示すことがわかる。これら微生物の中、特
に有効と考えられるものはエンテロコツカス・フェカリ
ス、エンテロコツカス・エビラム、エンテロコツカス・
デユランスであった。Table 3 Reduction rate of serum cholesterol (%) after administration of live bacteria Table 4 Reduction rate of serum triglyceride due to administration of live bacteria O0*2 Fructose-loaded rats and from Table 4, the lowest is 13% and the highest is about 67% in mice.
In rats, the rate of decrease in serum triglyceride values ranged from a minimum of 15% to a maximum of about 67%. Among these microorganisms, those considered to be particularly effective are Enterococcus faecalis, Enterococcus evirum, and Enterococcus faecalis.
It was durance.
実験例３：
エンテロコツカス属の安全性を試験するために、前記培
養条件および生菌体調製法によって得られた生理食塩水
？Ａ濁化生菌体 、５ｍｌをＩＣＲ系雄マウス（１群１
０頭）に９ ｘｌＯ” 、９ ＸＩＯ” 、９ ｘｌＯ
’個の３段階で腹腔内に投与し、１４日間マウスの生死
を試験しＢｅｈｒｅｎｓ−Ｋａｒｂｅｒ法に従ってＬＤ
ｓｏを算出した。結果を第５表にまとめたが、この試験
に使用したエンテロコツカス属の微生物はいづれもＬＤ
、。が１０１＠から１０１というような高い安全性を示
し、きわめて毒性が低いことがわかった。いずれのエン
テロコツカス属微生物の経口投与の場合も、最大投与量
３．２Ｘ１０′３個（約３２ｇ／ｋｇ）でも死亡例は見
られず安全であった。Experimental Example 3: In order to test the safety of Enterococcus spp., physiological saline obtained by the above-mentioned culture conditions and viable cell preparation method was used. Add 5 ml of A-turbid viable bacterial cells to ICR male mice (1 group 1
0 head) to 9 xlO", 9 XIO", 9 xlO
The mice were administered intraperitoneally in 3 stages, and the mice were tested for survival for 14 days. According to the Behrens-Karber method, LD
So was calculated. The results are summarized in Table 5, and all of the Enterococcus microorganisms used in this test were LD.
,. It was found to be highly safe with a rate of 101 to 101, indicating extremely low toxicity. In the case of oral administration of any of the Enterococcus microorganisms, no deaths were observed even at the maximum dose of 3.2 x 10'3 microorganisms (approximately 32 g/kg), indicating safety.
第５表 安全性
実験例４：
エンテロコツカス・フェカリスに−２３の抗高脂無効果
を調べるために、前記の培養条件および菌体！ｌＪ！！
！法を用いて得られたエンテロコツカス・フェカリスに
−２３の死菌体６０ｍｇ （１０＋ｏ個／頭／日）を８
週齢の通常ラットの雄に経口的に４週間連続投与し、ラ
ットの工大動脈より採血して、リボ蛋白コレステロール
を測定し、動脈硬化指数を算出した。得られた結果を第
６表にまとめたが、この表から、エンテロコツカス・フ
ェカリスに一２３無投与の対照群に比べてエンテロコツ
カス・フェカリスに一２３投与群の超低比重リボ蛋白−
コレスチロール（ＶＬＤＬ）は約５０％減少し、低比重
リボ蛋白−コレスチロール（ＬＤＬ）は約５２％も減少
し、動脈硬化指数も０．１１と顕著な改善が見られた。Table 5 Safety Experiment Example 4: To investigate the anti-hyperlipidemic effect of -23 on Enterococcus faecalis, the above culture conditions and bacterial cells were used. lJ! !
! 60 mg (10 + o cells/head/day) of -23 dead bacteria was added to Enterococcus faecalis obtained using the method.
The drug was orally administered to male rats of normal age for 4 weeks, and blood was collected from the aorta of the rats, riboprotein cholesterol was measured, and arteriosclerosis index was calculated. The obtained results are summarized in Table 6. From this table, it can be seen that the very low density riboprotein in the Enterococcus faecalis -123 administration group was significantly lower than that in the control group in which Enterococcus faecalis -123 was not administered.
Cholesterol (VLDL) decreased by about 50%, low-density riboprotein-cholestyol (LDL) decreased by about 52%, and the arteriosclerosis index also showed a remarkable improvement of 0.11.
第 ６ 表 抗高脂無効果
実験例５：
各種エンテロコツカス属微生物死菌体投与による血清コ
レステロール低下率と動脈硬化指数とを調べるために、
前記培養条件および菌体調製法により作製したエンテロ
コツカス・フェカリスに−２３、エンテロコツカス・フ
ェシウムに−５８、エンテロコツカス・エビラムＮ−５
６、エンテロコツカス・デユランス５−６６、エンテロ
コツカス・ボオヴイスＤ−７６の死菌体６０■（１０Ｉ
＠個／頭／日）を前記ラット調製法にて作製した８週齢
の雄コレステロール負荷ラットに経口的に４週間連続投
与し、工大動脈より採血し血清コレステロールを測定し
た。得られた結果を第７表に示したが、この表からエン
テロコツカス・フェカリスに−２３では約４５％、エン
テロコツカス・フェシウムに−５８では約４３％、エン
テロコツカス・エビラムＮ−５６では約３９％、エンテ
ロコツカス・デユランス５−６６では約３３％、エンテ
ロコツカス・ボオヴイスＤ−７６では約３５％の顕著な
コレステロール低下率が見られる。一方、動脈硬化指数
もすべての工・ンテロコッカス属微生物で顕著な低下を
示し、その中でも特にエンテロコツカス・フェカリスに
−２３では０．３２とほぼ正常対照群に近い値を示し動
脈硬化指数の顕著な改善が見られた。Table 6 Experimental example 5 of no anti-hyperlipid effect: In order to investigate the serum cholesterol reduction rate and arteriosclerosis index by administration of various killed microorganisms of the genus Enterococcus.
-23 for Enterococcus faecalis, -58 for Enterococcus faecium, and Enterococcus evirum N-5 produced using the above culture conditions and cell preparation method.
6. 60 dead bacterial bodies of Enterococcus duurans 5-66 and Enterococcus boovis D-76 (10I
＠pcs/head/day) was orally administered continuously for 4 weeks to 8-week-old male cholesterol-loaded rats produced by the rat preparation method described above, and blood was collected from the arterial aorta to measure serum cholesterol. The obtained results are shown in Table 7, and from this table it can be seen that Enterococcus faecalis -23 was about 45%, Enterococcus faecium -58 was about 43%, Enterococcus faecium -58 was about 43%, Enterococcus evirum N-56 A remarkable cholesterol reduction rate of about 39% is observed for Enterococcus duurans 5-66, about 33% for Enterococcus duurans 5-66, and about 35% for Enterococcus boovis D-76. On the other hand, the arteriosclerosis index also showed a remarkable decrease in all microorganisms of the genus Enterococcus, and among them, Enterococcus faecalis -23 had a value of 0.32, which is almost close to the normal control group, and the arteriosclerosis index was remarkable. A significant improvement was seen.
実施例１：
エンテロコツカス・フェカリスに−２３を前記のロゴサ
液体培地５リツトルに菌数が５Ｘ１０’／ｍｌになるよ
うに接種し、３７°Ｃ１１６時間静置培養した後、菌体
を冷凍遠心機で分離し、０．８％生理食塩水によって２
回洗浄し、得られた菌体をオートクレーブに入れ、１０
ｌｂに加圧下、１２１°Ｃ５１０分間加熱加圧して滅
菌し、さらに凍結乾燥して、乾燥死菌体粉末約４０ｇを
得た。この菌末を６力月間５℃に保った後、通常飼料に
６０■７１５ｇ飼料の割合で配合し、８週齢の雄ラット
に経口的に４週間連続投与し、工大動脈より採血して血
清コレステロール値と血清トリグリセライド値を測定し
たところ、血清コレステロール値は約４３％低下し、血
清トリグリセライド値は約６７％低下した。動脈硬化指
数も約６５％低下し、顕著な改善が見られた。Example 1: Enterococcus faecalis -23 was inoculated into 5 liters of the above-mentioned Rogosa liquid medium so that the number of bacteria was 5 x 10'/ml, and after statically culturing at 37°C for 116 hours, the bacterial cells were frozen and centrifuged. Separated in a machine and washed with 0.8% saline for 2 hours.
After washing twice, the resulting bacterial cells were placed in an autoclave for 10
The mixture was sterilized by heating and pressurizing at 121° C. for 510 minutes under pressure, and then freeze-dried to obtain about 40 g of dried dead bacterial cell powder. After keeping this bacterial powder at 5°C for 6 months, it was mixed with normal feed at a ratio of 60 to 715 g feed, and administered orally to 8-week-old male rats for 4 consecutive weeks. Blood was collected from the aorta and serum When the cholesterol level and serum triglyceride level were measured, the serum cholesterol level decreased by about 43%, and the serum triglyceride level decreased by about 67%. The arteriosclerosis index also decreased by about 65%, a remarkable improvement.
実施例２：
実施例１と同様の条件で接種、培養、集菌洗浄後、生菌
体２．０Ｘ１０”個を得たこの菌体を１％グルタミン酸
ソーダを含む１０％脱脂粉乳分散媒に懸濁し、生菌数３
．０Ｘ１０”個／１に調製し、容１５１のアンプルに１
＋ｓｌずつ分注し、凍結乾燥後アンプルを密封して５°
Ｃで保存した。６ケ月後にこの分散媒を含む凍結乾燥生
菌末を蒸留水に懸濁溶解し、８週齢の雄ラットに１日１
頭当り０．５＋ｌ（１゜５Ｘ１０”個）ずつ４週間経口
的に連続投与した後、工大動脈より採血し、血清コレス
テロール値と血清トリグリセライド値とを測定したとこ
ろ、血清コレステロール値は約３９％低下し、血清トリ
グリセライド値は約３８％低下した。動脈硬化指数も約
５２％低下し、顕著な改善が見られた。Example 2: After inoculation, culturing, and collection washing under the same conditions as in Example 1, 2.0 x 10" viable bacteria were obtained. The bacteria were suspended in a 10% skim milk powder dispersion medium containing 1% sodium glutamate. Cloudy, viable bacteria count 3
．． 0x10" pieces/1, 1 in an ampoule with a volume of 151
Dispense into +sl portions, freeze-dry, seal the ampoules, and incubate at 5°.
Saved in C. After 6 months, the freeze-dried live bacterial powder containing the dispersion medium was suspended and dissolved in distilled water and administered to 8-week-old male rats once a day.
After continuous oral administration of 0.5+l (1°5 x 10" per head) for 4 weeks, blood was collected from the arterial artery and serum cholesterol and serum triglyceride levels were measured. Serum cholesterol levels decreased by approximately 39%. However, the serum triglyceride level decreased by approximately 38%.The arteriosclerosis index also decreased by approximately 52%, indicating a significant improvement.
前記の実験例および実施例に準じて人間に対する投与も
同じように行なうことが出来る。その際の投与量は実施
例３の安全性を考慮して１日６０■から６ｇまでの範囲
が適当であり、投与形態としては死菌体の場合はアミノ
酸、コンスターチ、大豆蛋白、乳糖、脱脂粉乳等の生理
学的に許容し得る経口投与可能な分散媒を、また生菌体
の場合、牛乳、豆乳、果汁等による経口投与可能な懸濁
液を推奨することが出来、この発明の抗高脂血症剤は医
薬品としてきわめて有用であるばかりでなく、上記のよ
うな実施形態を使用して、高脂血症を予防する新しい予
防医学的食品としても提供することが出来る。高脂血症
は、サイレントディシーズと言われ、気が付いたときに
は手遅れの場合が多いので、この発明が予防医学的食品
としての抗高脂血症剤を提供出来ることはきわめて意義
深いことである。Administration to humans can be carried out in the same manner as in the experimental examples and examples described above. In consideration of the safety of Example 3, the appropriate dosage range is from 60 to 6 g per day. A physiologically acceptable orally administrable dispersion medium such as powdered milk or, in the case of viable bacteria, an orally administrable suspension using milk, soy milk, fruit juice, etc., is recommended. Lipidemia agents are not only extremely useful as pharmaceuticals, but also can be provided as new preventive medical foods for preventing hyperlipidemia using the above-described embodiments. Hyperlipidemia is said to be a silent disease, and by the time it is noticed it is often too late, so it is extremely significant that the present invention can provide an antihyperlipidemic agent as a preventive medical food.
Claims (1)
る微生物の生菌体もしくは死菌体を主有効成分として含
有することを特徴とする抗高脂血症剤。 ２）エンテロコッカス属に属する微生物がエンテロコッ
カス・フェカリス、エンテロコッカス・フェシウム、エ
ンテロコッカス・エビウム、エンテロコッカス・デュラ
ンス、エンテロコッカス・ボオヴィスである特許請求の
範囲第１項記載の抗高脂血症剤。[Scope of Claims] 1) An antihyperlipidemic agent characterized by containing as a main active ingredient live or dead microorganisms belonging to the genus Enterococcus having an antihyperlipidemic effect. 2) The antihyperlipidemic agent according to claim 1, wherein the microorganism belonging to the genus Enterococcus is Enterococcus faecalis, Enterococcus faecium, Enterococcus evium, Enterococcus durans, or Enterococcus boovis.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP62115537A JPS63280027A (en) | 1987-05-11 | 1987-05-11 | Antihyperlipemic |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP62115537A JPS63280027A (en) | 1987-05-11 | 1987-05-11 | Antihyperlipemic |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPS63280027A true JPS63280027A (en) | 1988-11-17 |
Family
ID=14664986
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP62115537A Pending JPS63280027A (en) | 1987-05-11 | 1987-05-11 | Antihyperlipemic |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS63280027A (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NL1015933C2 (en) * | 1999-03-04 | 2002-02-18 | Bhph Company Ltd | Lactic acid bacteria formulation for improving bowel movement, e.g. for treating diarrhea, comprising live microbes of Lactobacillus clearans and Enterococcus faecalis |
| EP1477555A3 (en) * | 2003-05-15 | 2004-12-15 | Yasuo Kawai | Method for culturing bacterial cells belonging to the enterococcus genus and method of producing killed bacterial cells belonging to the enterococcus genus |
| JP2004357703A (en) * | 2003-05-15 | 2004-12-24 | Yasuo Kawai | Method for culturing lactobacillus belonging to genus enterococcus and method for producing killed lactobacillus belonging to genus enterococcus |
| JP2019535828A (en) * | 2016-11-21 | 2019-12-12 | コリア フード リサーチ インスティチュートＫｏｒｅａ Ｆｏｏｄ Ｒｅｓｅａｒｃｈ Ｉｎｓｔｉｔｕｔｅ | A composition for preventing or treating obesity or metabolic syndrome caused by obesity, comprising a strain having an excellent formic acid-producing ability as an active ingredient |
| JP2020511434A (en) * | 2016-11-21 | 2020-04-16 | コリア フード リサーチ インスティチュートＫｏｒｅａ Ｆｏｏｄ Ｒｅｓｅａｒｃｈ Ｉｎｓｔｉｔｕｔｅ | Composition for preventing or treating obesity or metabolic syndrome caused by obesity, comprising formic acid or a pharmaceutically acceptable salt thereof as an active ingredient |
-
1987
- 1987-05-11 JP JP62115537A patent/JPS63280027A/en active Pending
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NL1015933C2 (en) * | 1999-03-04 | 2002-02-18 | Bhph Company Ltd | Lactic acid bacteria formulation for improving bowel movement, e.g. for treating diarrhea, comprising live microbes of Lactobacillus clearans and Enterococcus faecalis |
| ES2168076A1 (en) * | 1999-03-04 | 2002-05-16 | Bhph Company Ltd | Lactic acid bacteria preparation having biopurification activity |
| EP1477555A3 (en) * | 2003-05-15 | 2004-12-15 | Yasuo Kawai | Method for culturing bacterial cells belonging to the enterococcus genus and method of producing killed bacterial cells belonging to the enterococcus genus |
| JP2004357703A (en) * | 2003-05-15 | 2004-12-24 | Yasuo Kawai | Method for culturing lactobacillus belonging to genus enterococcus and method for producing killed lactobacillus belonging to genus enterococcus |
| JP2019535828A (en) * | 2016-11-21 | 2019-12-12 | コリア フード リサーチ インスティチュートＫｏｒｅａ Ｆｏｏｄ Ｒｅｓｅａｒｃｈ Ｉｎｓｔｉｔｕｔｅ | A composition for preventing or treating obesity or metabolic syndrome caused by obesity, comprising a strain having an excellent formic acid-producing ability as an active ingredient |
| JP2020511434A (en) * | 2016-11-21 | 2020-04-16 | コリア フード リサーチ インスティチュートＫｏｒｅａ Ｆｏｏｄ Ｒｅｓｅａｒｃｈ Ｉｎｓｔｉｔｕｔｅ | Composition for preventing or treating obesity or metabolic syndrome caused by obesity, comprising formic acid or a pharmaceutically acceptable salt thereof as an active ingredient |
| US11564955B2 (en) | 2016-11-21 | 2023-01-31 | Korea Food Research Institute | Composition including, as active ingredient, strain having ability to produce formic acid for preventing or treating obesity or metabolic syndromes caused by obesity |
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