JP2015139424A - Method for producing equol-containing composition - Google Patents
Method for producing equol-containing composition Download PDFInfo
- Publication number
- JP2015139424A JP2015139424A JP2014015367A JP2014015367A JP2015139424A JP 2015139424 A JP2015139424 A JP 2015139424A JP 2014015367 A JP2014015367 A JP 2014015367A JP 2014015367 A JP2014015367 A JP 2014015367A JP 2015139424 A JP2015139424 A JP 2015139424A
- Authority
- JP
- Japan
- Prior art keywords
- equol
- containing composition
- present
- isoflavones
- aglycone
- 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
- ADFCQWZHKCXPAJ-GFCCVEGCSA-N equol Chemical compound C1=CC(O)=CC=C1[C@@H]1CC2=CC=C(O)C=C2OC1 ADFCQWZHKCXPAJ-GFCCVEGCSA-N 0.000 title claims abstract description 93
- 235000019126 equol Nutrition 0.000 title claims abstract description 93
- ADFCQWZHKCXPAJ-UHFFFAOYSA-N indofine Natural products C1=CC(O)=CC=C1C1CC2=CC=C(O)C=C2OC1 ADFCQWZHKCXPAJ-UHFFFAOYSA-N 0.000 title claims abstract description 93
- 239000000203 mixture Substances 0.000 title claims abstract description 53
- 238000004519 manufacturing process Methods 0.000 title abstract description 20
- 244000005700 microbiome Species 0.000 claims abstract description 68
- 108090000790 Enzymes Proteins 0.000 claims abstract description 65
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- CJWQYWQDLBZGPD-UHFFFAOYSA-N isoflavone Natural products C1=C(OC)C(OC)=CC(OC)=C1C1=COC2=C(C=CC(C)(C)O3)C3=C(OC)C=C2C1=O CJWQYWQDLBZGPD-UHFFFAOYSA-N 0.000 claims abstract description 40
- 235000008696 isoflavones Nutrition 0.000 claims abstract description 40
- 150000002515 isoflavone derivatives Chemical class 0.000 claims abstract description 37
- TWCMVXMQHSVIOJ-UHFFFAOYSA-N Aglycone of yadanzioside D Natural products COC(=O)C12OCC34C(CC5C(=CC(O)C(O)C5(C)C3C(O)C1O)C)OC(=O)C(OC(=O)C)C24 TWCMVXMQHSVIOJ-UHFFFAOYSA-N 0.000 claims abstract description 36
- PLMKQQMDOMTZGG-UHFFFAOYSA-N Astrantiagenin E-methylester Natural products CC12CCC(O)C(C)(CO)C1CCC1(C)C2CC=C2C3CC(C)(C)CCC3(C(=O)OC)CCC21C PLMKQQMDOMTZGG-UHFFFAOYSA-N 0.000 claims abstract description 36
- PFOARMALXZGCHY-UHFFFAOYSA-N homoegonol Natural products C1=C(OC)C(OC)=CC=C1C1=CC2=CC(CCCO)=CC(OC)=C2O1 PFOARMALXZGCHY-UHFFFAOYSA-N 0.000 claims abstract description 36
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- DKVBOUDTNWVDEP-NJCHZNEYSA-N teicoplanin aglycone Chemical compound N([C@H](C(N[C@@H](C1=CC(O)=CC(O)=C1C=1C(O)=CC=C2C=1)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)OC=1C=C3C=C(C=1O)OC1=CC=C(C=C1Cl)C[C@H](C(=O)N1)NC([C@H](N)C=4C=C(O5)C(O)=CC=4)=O)C(=O)[C@@H]2NC(=O)[C@@H]3NC(=O)[C@@H]1C1=CC5=CC(O)=C1 DKVBOUDTNWVDEP-NJCHZNEYSA-N 0.000 claims description 7
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- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 5
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- GHOKWGTUZJEAQD-ZETCQYMHSA-N (D)-(+)-Pantothenic acid Chemical compound OCC(C)(C)[C@@H](O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-ZETCQYMHSA-N 0.000 description 4
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- JHYXBPPMXZIHKG-UHFFFAOYSA-N dihydrodaidzein Chemical compound C1=CC(O)=CC=C1C1C(=O)C2=CC=C(O)C=C2OC1 JHYXBPPMXZIHKG-UHFFFAOYSA-N 0.000 description 4
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- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- GMTUGPYJRUMVTC-UHFFFAOYSA-N Daidzin Natural products OC(COc1ccc2C(=O)C(=COc2c1)c3ccc(O)cc3)C(O)C(O)C(O)C=O GMTUGPYJRUMVTC-UHFFFAOYSA-N 0.000 description 3
- KYQZWONCHDNPDP-UHFFFAOYSA-N Daidzoside Natural products OC1C(O)C(O)C(CO)OC1OC1=CC=C2C(=O)C(C=3C=CC(O)=CC=3)=COC2=C1 KYQZWONCHDNPDP-UHFFFAOYSA-N 0.000 description 3
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- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000006071 cream Substances 0.000 description 3
- KYQZWONCHDNPDP-QNDFHXLGSA-N daidzein 7-O-beta-D-glucoside Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=CC=C2C(=O)C(C=3C=CC(O)=CC=3)=COC2=C1 KYQZWONCHDNPDP-QNDFHXLGSA-N 0.000 description 3
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- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical group OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 2
- KWTQSFXGGICVPE-UHFFFAOYSA-N 2-amino-5-(diaminomethylideneamino)pentanoic acid;hydron;chloride Chemical compound Cl.OC(=O)C(N)CCCN=C(N)N KWTQSFXGGICVPE-UHFFFAOYSA-N 0.000 description 2
- GYLUFQJZYAJQDI-UHFFFAOYSA-N 4',6,7-trihydroxyisoflavone Chemical compound C1=CC(O)=CC=C1C1=COC2=CC(O)=C(O)C=C2C1=O GYLUFQJZYAJQDI-UHFFFAOYSA-N 0.000 description 2
- ALYNCZNDIQEVRV-UHFFFAOYSA-N 4-aminobenzoic acid Chemical compound NC1=CC=C(C(O)=O)C=C1 ALYNCZNDIQEVRV-UHFFFAOYSA-N 0.000 description 2
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- 241000290152 Adlercreutzia equolifaciens DSM 19450 Species 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical group OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
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Abstract
Description
本発明は、エクオール含有組成物の製造方法に関する。 The present invention relates to a method for producing an equol-containing composition.
大豆には多くの大豆イソフラボン類が含まれており、これらイソフラボン類は、女性ホルモン作用(エストロゲン)や抗酸化作用を有し、イソフラボン類を摂取することにより、乳癌、前立腺癌、骨粗しょう症、高コレステロール血症、心疾患、更年期障害などに対して予防効果があることが明らかにされている(非特許文献1〜6)。 Soy contains many soy isoflavones. These isoflavones have female hormone action (estrogens) and antioxidant action. By taking isoflavones, breast cancer, prostate cancer, osteoporosis, It has been clarified that there is a preventive effect against hypercholesterolemia, heart disease, climacteric disorder and the like (Non-Patent Documents 1 to 6).
ところが一方で、大豆は日本の5大アレルギー食品の一つに挙げられており、大豆アレルギーは、大豆に含まれる貯蔵タンパク質中のアレルゲンタンパク質が原因で起こることが分かっている。1992年時点で、16種類の大豆アレルゲンタンパク質が同定されているが、アレルギーの出現頻度の高い主要アレルゲンは、Gly m Bd 30K、Gly m Bd 60K(7Sグロブリンα-サブユニット)およびGly m Bd 28Kであるとみられている。(非特許
文献7)。そのため、大豆アレルゲンを低減化した大豆加工食品などの開発がなされている(特許文献1〜3)。
On the other hand, soybeans are listed as one of the five major allergic foods in Japan, and it is known that soybean allergy is caused by allergen proteins in storage proteins contained in soybeans. As of 1992, 16 types of soybean allergen proteins have been identified, but the major allergens with high frequency of allergy are Gly m Bd 30K, Gly m Bd 60K (7S globulin α-subunit) and Gly m Bd 28K. It is considered to be. (Non-patent document 7). Therefore, development of soybean processed food etc. which reduced soybean allergen is made (patent documents 1-3).
近年の研究で、大豆をそのまま粉末化してイソフラボン類を測定すると、表1に示す12種類のイソフラボン類が存在し、そのうちダイジン、マロニルダイジン、ゲニスチン、マロニルゲニスチンが大部分を占めることが明らかにされた(非特許文献8)。 In recent studies, when soybeans are powdered as they are and isoflavones are measured, it is clarified that there are 12 types of isoflavones shown in Table 1, of which daidzin, malonyl daidzin, genistin and malonylgenistin account for the majority. (Non-patent document 8).
更に、この大豆イソフラボン類における、上記女性ホルモン作用や抗酸化作用を発揮す
るための重要な活性本体は、ダイジンが体内で代謝されて、下記のように、ダイゼインからジヒドロダイゼインを経て生成するエクオールに主に由来することが分かってきた。すなわち、大豆内の主なイソフラボン類であるダイジンは、大豆中では糖と結合した配糖体の形で存在するが、この配糖体は、ヒトや動物の体内に入ると消化酵素又は腸内細菌の産生する酵素であるβ−グルコシダーゼ等の働きにより、ジヒドロダイゼインを経て、O−デスメチルアンゴレンシン又はエクオールへと酵素的に変換され、特に、エクオールはエストロゲン活性が高いことが知られている(非特許文献9及び10)。
Furthermore, in the soy isoflavones, the important active body for exerting the above-mentioned female hormone action and antioxidant action is equol produced from daidzein through dihydrodaidzein as shown below. It has been found to come from the Lord. That is, Daidine, the main isoflavones in soybean, exists in the form of glycosides bound to sugars in soybeans, but these glycosides enter digestive enzymes or intestines when they enter the human or animal body. It is known that β-glucosidase, which is an enzyme produced by bacteria, is enzymatically converted to O-desmethylangolensin or equol via dihydrodaidzein. In particular, equol is known to have high estrogenic activity. (Non-patent documents 9 and 10).
ところが、人が大豆を食べても、その中に含まれるダイゼインを有効なエクオールにまで代謝する能力には個人差があり、日本人で約5割、欧米人で約3割程度の人しか代謝できないことも明らかとなっている(非特許文献11及び12)。そのため、代謝のできない人が、有効成分であるエクオールを直接摂取することができるように、エクオールを含有する大豆発酵物などが開発されており、そのうち大豆アレルゲンが低減されているものも開発されている(特許文献4〜6)。 However, even if a person eats soybeans, the ability to metabolize daidzein contained therein to effective equol varies from person to person. Only about 50% of Japanese people and about 30% of Westerners can metabolize. It is also clear that this is not possible (Non-Patent Documents 11 and 12). For this reason, fermented soy products containing equol have been developed so that people who cannot metabolize can directly take equol, an active ingredient, and some of them also have reduced soy allergens. (Patent Documents 4 to 6).
ダイゼインを有効なエクオールにまで代謝できない人は、有効成分であるエクオールを直接摂取することが望ましい。しかしながら、アレルゲンを低減したエクオール含有発酵物等は開発されているものの、アレルギーを惹起しない、実質的にアレルゲンをフリーにしたものは未だ開発されていない。
本発明は、実質的にアレルゲンを含まないエクオール含有組成物の製造方法の提供を課題とする。
Those who are unable to metabolize daidzein to effective equol should take equol, the active ingredient, directly. However, although equol-containing fermented products with reduced allergens have been developed, no allergen free product that does not cause allergies has been developed yet.
This invention makes it a subject to provide the manufacturing method of the equol containing composition which does not contain an allergen substantially.
本発明者らは、上記知見に基づき更に検討を進め、実質的にアレルゲンを含まないエクオール含有組成物を得る方法を検討したところ、イソフラボン類を特定の酵素で処理し、その後に特定の微生物で発酵させることにより、これを達成できることに想到し、本発明を完成させた。すなわち、本発明は以下に示すとおりである。 Based on the above findings, the present inventors have further studied and studied a method for obtaining an equol-containing composition that is substantially free of allergens. As a result, isoflavones were treated with a specific enzyme, and then treated with a specific microorganism. It was conceived that this can be achieved by fermentation, and the present invention was completed. That is, the present invention is as follows.
〔1〕(1)イソフラボン類を、前記イソフラボン類をアグリコンに変換する酵素で処理する工程、(2)前記工程(1)で得られた前記アグリコンを含有する培地で嫌気性微生物を培養し、前記嫌気性微生物により、前記アグリコンをエクオールに変換する工程、及び、(3)前記工程(2)で産生された前記エクオールを含有するエクオール含有組成物を、前記培地から回収する工程、を含む、エクオール含有組成物の製造方法。
〔2〕前記嫌気性微生物が、アサッカロバクター・セラツス(Asaccharobacter celatus
)DSM 18785の16S rDNAと95%以上の同一性を有する16S rDNAを保有
する微生物である、〔1〕に記載の方法。
〔3〕前記嫌気性微生物が、アサッカロバクター(Asaccharobacter)属、スラッキア(Slackia)属、またはアドレクラウチア(Adlercreutzia)属に分類される微生物である、
〔1〕または〔2〕に記載の方法。
〔4〕前記酵素がβ−グルコシダーゼ又はペクチナーゼである、〔1〕〜〔3〕のいずれかに記載の方法。
〔5〕〔1〕〜〔4〕のいずれかに記載の方法により製造されたエクオール含有組成物を含む化粧料。
〔6〕〔1〕〜〔4〕のいずれかに記載の方法により製造されたエクオール含有組成物を含む医薬。
〔7〕〔1〕〜〔4〕のいずれかに記載の方法により製造されたエクオール含有組成物を含む食品。
[1] (1) a step of treating isoflavones with an enzyme that converts the isoflavones to an aglycone; (2) culturing an anaerobic microorganism in a medium containing the aglycone obtained in the step (1); Converting the aglycone into equol by the anaerobic microorganism, and (3) recovering the equol-containing composition containing the equol produced in the step (2) from the medium. A method for producing an equol-containing composition.
[2] The anaerobic microorganism is Asaccharobacter celatus.
) The method according to [1], wherein the microorganism possesses 16S rDNA having 95% or more identity with DSM 18785 16S rDNA.
[3] The anaerobic microorganism is a microorganism classified into the genus Asaccharobacter, the genus Slackia, or the genus Adlercreutzia.
The method according to [1] or [2].
[4] The method according to any one of [1] to [3], wherein the enzyme is β-glucosidase or pectinase.
[5] A cosmetic comprising the equol-containing composition produced by the method according to any one of [1] to [4].
[6] A medicament comprising the equol-containing composition produced by the method according to any one of [1] to [4].
[7] A food containing the equol-containing composition produced by the method according to any one of [1] to [4].
本発明によれば、実質的にアレルゲンを含まないエクオール含有組成物の製造方法を提供することができる。 ADVANTAGE OF THE INVENTION According to this invention, the manufacturing method of the equol containing composition substantially free of allergen can be provided.
以下、本発明について、具体的な態様を示しながら詳細に説明するが、本発明は例示する具体的態様に限定されないことはいうまでもない。 Hereinafter, the present invention will be described in detail while showing specific embodiments, but it is needless to say that the present invention is not limited to the illustrated specific embodiments.
本発明は、
(1)イソフラボン類を、前記イソフラボン類をアグリコンに変換する酵素で処理する工程、
(2)前記工程(1)で得られた前記アグリコンを含有する培地で嫌気性微生物を培養し、前記嫌気性微生物により、前記アグリコンをエクオールに変換する工程、及び、
(3)前記工程(2)で産生された前記エクオールを含有するエクオール含有組成物を、前記培地から回収する工程、
を含む、エクオール含有組成物の製造方法、に関する。
The present invention
(1) A process of treating isoflavones with an enzyme that converts the isoflavones to aglycone,
(2) culturing an anaerobic microorganism in the medium containing the aglycone obtained in the step (1), converting the aglycon into equol by the anaerobic microorganism, and
(3) recovering the equol-containing composition containing the equol produced in the step (2) from the medium;
The manufacturing method of the equol containing composition containing this.
本発明に係るエクオール含有組成物の製造方法は、(1)イソフラボン類を、前記イソフラボン類をアグリコンに変換する酵素で処理する「酵素処理工程」、(2)前記工程(1)で得られた前記アグリコンを含有する培地で嫌気性微生物を培養し、前記嫌気性微生物により、前記アグリコンをエクオールに変換する「発酵工程」、及び、(3)前記工程(2)で産生された前記エクオールを含有するエクオール含有組成物を、前記培地から回収する「回収工程」を含む。 The method for producing an equol-containing composition according to the present invention includes (1) an “enzyme treatment step” in which isoflavones are treated with an enzyme that converts the isoflavones to aglycone, and (2) obtained in the step (1). An anaerobic microorganism is cultured in a medium containing the aglycone, and a “fermentation step” for converting the aglycon into equol by the anaerobic microorganism, and (3) containing the equol produced in the step (2) And a “recovery step” of recovering the equol-containing composition from the medium.
なお、本発明に係るエクオール含有組成物の製造方法は、上記(1)〜(3)の工程を有するものであるが、その他の工程を有していてもよい。
その他の工程としては、例えば、後述する酵素処理工程において酵素処理の基質となるイソフラボン類を調製するに際し、大豆、クズ、レッドクローバー、カンゾウなどのマメ科植物を粉砕、抽出、樹脂精製などにより調製する工程が挙げられる。例えば、特開平11−263786号公報に開示されている大豆胚芽を原料としたイソフラボン化合物の製造方法のように、従来の方法により行うことができる。該工程は後述する酵素処理工程の前に行うことができる。
In addition, although the manufacturing method of the equol containing composition which concerns on this invention has the process of said (1)-(3), it may have another process.
Other steps include, for example, preparing legumes such as soybeans, kudzu, red clover and licorice by pulverization, extraction, resin purification, etc., when preparing isoflavones as substrates for enzyme treatment in the enzyme treatment step described below. The process to do is mentioned. For example, it can be performed by a conventional method such as the method for producing an isoflavone compound using soybean germ as a raw material disclosed in JP-A-11-263786. This step can be performed before the enzyme treatment step described later.
<1.酵素処理工程>
本発明の酵素処理工程は、イソフラボン類を、該イソフラボン類をアグリコンに変換する酵素で処理する工程である。
<1. Enzyme treatment process>
The enzyme treatment step of the present invention is a step of treating isoflavones with an enzyme that converts the isoflavones to aglycone.
<1−1.イソフラボン類>
本発明のイソフラボン類は、イソフラボンを基本骨格とするフラボノイドの配糖体である。その原料に特に制限はないが、例えば、大豆、クズ、レッドクローバー、カンゾウなどマメ科植物から得ることができる。これらの中でも、アグリコンとしてダイゼインの含有量の多い大豆が好ましく、その中でも大豆胚軸がより好ましい。
<1-1. Isoflavones>
The isoflavones of the present invention are flavonoid glycosides having isoflavone as a basic skeleton. Although there is no restriction | limiting in particular in the raw material, For example, it can obtain from legumes, such as a soybean, kuzu, red clover, and a daylily. Among these, soybean having a large content of daidzein is preferable as the aglycone, and among them, soybean hypocotyl is more preferable.
本発明のイソフラボン類は、特段限定されないが、アグリコンのアセチル化配糖体、アグリコンのマロニル化配糖体、及びアグリコンのスクシニル化配糖体等の任意の誘導体を挙げることができる。
アグリコンの配糖体としては、例えば、ダイジンなどを挙げることができる。アグリコンのアセチル化配糖体としては、アセチルダイジンなどを挙げることができる。アグリコンのマロニル化配糖体としては、マロニルダイジンなどを挙げることができる。アグリコンのスクシニル化配糖体としては、スクシニルダイジンなどを挙げることができる。
本発明のイソフラボン類には、これらの一種が含まれていてもよく、複数種含まれていてもよい。これらの中でも、ダイジンが好ましい。
なお、本明細書において、イソフラボン類とは、アグリコンに糖が結合した上記配糖体等の任意の誘導体を指すものとし、糖が結合していない、すなわちアグリコン自体は含まれないものとする。
The isoflavones of the present invention are not particularly limited, and may include arbitrary derivatives such as an acetylated glycoside of aglycone, a malonylated glycoside of aglycone, and a succinylated glycoside of aglycone.
Examples of aglycone glycosides include daidzin. Examples of the acetylated glycoside of aglycone include acetyldaidine. Examples of malonylated glycosides of aglycone include malonyl daidzine. Examples of succinylated glycosides of aglycone include succinyl daidine.
One kind of these may be contained in the isoflavones of the present invention, and a plurality of kinds may be contained. Among these, daidzin is preferable.
In the present specification, isoflavones refer to any derivative such as the above-mentioned glycoside in which sugar is bound to aglycone, and sugar is not bound, that is, aglycone itself is not included.
本発明の酵素処理工程で用いるイソフラボン類は精製されていても、精製されていなくてもよい。大豆胚軸をそのまま用いることもでき、精製されておらず他の成分が含まれていてもよい。市販されているものであれば、例えば、粉砕大豆胚軸(不二製油製)、イソ
フラボン高含有エキス粉末(タマ生化学株式会社製)などが挙げられる。
The isoflavones used in the enzyme treatment step of the present invention may or may not be purified. Soybean hypocotyls can be used as they are, and other components may be contained without being purified. Examples of commercially available products include ground soybean hypocotyl (Fuji Oil), isoflavone-rich extract powder (Tama Seikagaku Co., Ltd.), and the like.
<1−2.アグリコン>
本発明のアグリコンは、特段限定されないが、例えば、ダイゼイン、6−ヒドロキシダイゼイン、ジヒドロダイゼインなどを挙げることができる。
本発明のアグリコンには、これらの一種が含まれていてもよく、複数種含まれていてもよい。これらの中でも、ダイゼインが好ましい。
<1-2. Aglycon>
The aglycone of the present invention is not particularly limited, and examples thereof include daidzein, 6-hydroxy daidzein, dihydrodaidzein and the like.
One kind of these may be contained in the aglycon of the present invention, and a plurality of kinds may be contained. Among these, daidzein is preferable.
<1−3.酵素の種類>
本発明の酵素処理工程におけるイソフラボン類に対して、該イソフラボン類をアグリコンに変換するために作用させる酵素は、上述したアグリコン配糖体等の任意の誘導体において、アグリコンと糖との結合を切断する活性を有していれば、特段限定されないが、エクオール生産の観点から、好ましくは酵素番号がEC3に含まれる酵素、より好ましくはEC3.2に含まれる酵素、さらに好ましくはEC3.2.1に含まれる酵素であり、特に好ましくはβ−グルコシダーゼ(EC 3.2.1.21)、ペクチナーゼ(EC 3.2.1.15)であり、生産性の観点から、最も好ましくはペクチナーゼである。
<1-3. Types of enzymes>
The enzyme that acts on the isoflavones in the enzyme treatment step of the present invention to convert the isoflavones to aglycone cleaves the bond between the aglycone and the sugar in any derivative such as the above-mentioned aglycone glycosides. Although it is not particularly limited as long as it has activity, from the viewpoint of equol production, it is preferable that the enzyme number is preferably an enzyme included in EC3, more preferably an enzyme included in EC3.2, more preferably EC3.2.1. Among them, β-glucosidase (EC 3.2.1.21) and pectinase (EC 3.2.1.15) are particularly preferable, and pectinase is most preferable from the viewpoint of productivity.
<1−4.酵素処理>
<1−4−1.イソフラボン類の含有量>
本発明の酵素処理工程において、酵素処理溶液全量に対するイソフラボン類の含有量は、特段限定されないが、エクオールの生産濃度の観点からイソフラボン類として、0.1g/L以上であることが好ましく、0.5g/L以上であることがより好ましく、1.0g/L以上であることがさらに好ましい。一方、酵素活性の観点から、10g/L以下であることが好ましく、5g/L以下であることがより好ましく、3g/L以下であることがさらに好ましい。
<1-4. Enzyme treatment>
<1-4-1. Content of isoflavones>
In the enzyme treatment step of the present invention, the content of isoflavones relative to the total amount of the enzyme treatment solution is not particularly limited, but is preferably 0.1 g / L or more as isoflavones from the viewpoint of equol production concentration. More preferably, it is 5 g / L or more, and further preferably 1.0 g / L or more. On the other hand, from the viewpoint of enzyme activity, it is preferably 10 g / L or less, more preferably 5 g / L or less, and even more preferably 3 g / L or less.
<1−4−2.酵素の濃度>
本発明の酵素処理工程において、酵素処理溶液全量に対する酵素の含有量は、酵素処理が効率良く進行すれば特段限定されないが、酵素として、0.01質量%以上10質量%以下であることが好ましく、0.05質量%以上5%質量以下であることがより好ましく、0.1質量%以上1%質量以下であることがさらに好ましい。
<1-4-2. Enzyme concentration>
In the enzyme treatment step of the present invention, the content of the enzyme relative to the total amount of the enzyme treatment solution is not particularly limited as long as the enzyme treatment proceeds efficiently, but the enzyme is preferably 0.01% by mass or more and 10% by mass or less. It is more preferably 0.05% by mass or more and 5% by mass or less, and further preferably 0.1% by mass or more and 1% by mass or less.
<1−4−3.酵素処理温度>
本発明の酵素処理工程において、酵素処理溶液の温度は、酵素活性を保ち、酵素処理が効率良く進行すれば特段限定されないが、酵素を活性化し、迅速な酵素処理を行うために、10℃以上であることが好ましく、30℃以上であることがより好ましく、40℃以上であることがさらに好ましい。一方、酵素活性の保持の観点から、80℃以下であることが好ましく、70℃以下であることがより好ましく、60℃以下であることがさらに好ましい。
<1-4-3. Enzyme treatment temperature>
In the enzyme treatment step of the present invention, the temperature of the enzyme treatment solution is not particularly limited as long as the enzyme activity is maintained and the enzyme treatment proceeds efficiently, but in order to activate the enzyme and perform rapid enzyme treatment, it is 10 ° C. or higher. It is preferable that it is 30 degreeC or more, and it is further more preferable that it is 40 degreeC or more. On the other hand, from the viewpoint of maintaining enzyme activity, it is preferably 80 ° C. or lower, more preferably 70 ° C. or lower, and further preferably 60 ° C. or lower.
<1−4−4.酵素処理時のpH>
本発明の酵素処理工程において、酵素処理溶液のpHは、酵素活性を保ち、酵素処理が効率良く進行すれば特段限定されないが、2以上10以下であることが好ましく、3以上8以下であることがより好ましく、4以上7以下であることがさらに好ましい。
<1-4-4. PH during enzyme treatment>
In the enzyme treatment step of the present invention, the pH of the enzyme treatment solution is not particularly limited as long as the enzyme activity is maintained and the enzyme treatment proceeds efficiently, but it is preferably 2 or more and 10 or less, preferably 3 or more and 8 or less. Is more preferably 4 or more and 7 or less.
<1−4−5.酵素処理時間>
本発明の酵素処理工程において、酵素処理の時間は、酵素活性を保ち、酵素処理が効率良く進行すれば特段限定されないが、酵素活性の観点から、1時間以上であることが好ましく、4時間以上であることがより好ましく、15時間以上であることがさらに好ましい。一方、生産性の観点から、72時間以下であることが好ましく、48時間以下であるこ
とがより好ましく、36時間以下であることがさらに好ましい。
<1-4-5. Enzyme treatment time>
In the enzyme treatment step of the present invention, the enzyme treatment time is not particularly limited as long as the enzyme activity is maintained and the enzyme treatment proceeds efficiently, but from the viewpoint of enzyme activity, it is preferably 1 hour or more, and 4 hours or more. It is more preferable that it is 15 hours or more. On the other hand, from the viewpoint of productivity, it is preferably 72 hours or shorter, more preferably 48 hours or shorter, and further preferably 36 hours or shorter.
<2.発酵工程>
本発明の発酵工程は、前記酵素処理工程で得られた前記アグリコンを含有する培地で嫌気性微生物を培養し、前記嫌気性微生物により、前記アグリコンをエクオールに変換する工程である。
なお、上記嫌気性微生物を培養する培地においては、上記酵素処理工程においてイソフラボン類からアグリコンに変化されなかったイソフラボン類をはじめ、その他の成分が含まれていてもよい。
<2. Fermentation process>
The fermentation step of the present invention is a step of culturing an anaerobic microorganism in a medium containing the aglycone obtained in the enzyme treatment step, and converting the aglycone into equol by the anaerobic microorganism.
In addition, in the culture medium which culture | cultivates the said anaerobic microorganism, other components may be contained including the isoflavones which were not changed from isoflavones to aglycone in the said enzyme treatment process.
<2−1.アグリコン濃度>
本発明の発酵工程におけるアグリコンは、前記酵素処理工程において、イソフラボン類から酵素によって変換されたアグリコンである。
本発明の発酵工程において、該アグリコンの濃度は、特段限定されないが、生産されるエクオールの濃度をより大きくするために、イソフラボン類として、0.1g/L以上であることが好ましく、0.5g/L以上であることがより好ましく、1.0g/L以上であることがさらに好ましい。一方、酵素活性の観点から、10g/L以下であることが好ましく、5g/L以下であることがより好ましく、3g/L以下であることがさらに好ましい。
<2-1. Aglycon concentration>
The aglycone in the fermentation process of the present invention is an aglycon converted from isoflavones by an enzyme in the enzyme treatment process.
In the fermentation process of the present invention, the concentration of the aglycone is not particularly limited, but in order to increase the concentration of equol produced, it is preferably 0.1 g / L or more as isoflavones, 0.5 g / L or more is more preferable, and 1.0 g / L or more is more preferable. On the other hand, from the viewpoint of enzyme activity, it is preferably 10 g / L or less, more preferably 5 g / L or less, and even more preferably 3 g / L or less.
<2−2.嫌気性微生物>
本発明で用いる嫌気性微生物は、前記アグリコンを含有する培地で培養でき、前記アグリコンからエクオールを発酵できる微生物であれば、特段限定されないが、コーリオバクテリアセアエ(Coriobacteriaceae)科に分類される菌、ストレプトコッカセアエ(Streptococcaceae)科に分類される菌、又はこれらの類縁菌を、エクオール生産能を有するも
のとして例示することができる。
<2-2. Anaerobic microorganism>
The anaerobic microorganism used in the present invention is not particularly limited as long as it can be cultured in a medium containing the aglycone and can ferment equol from the aglycone, but is classified into the family Coriobacteriaceae The bacteria classified into the family Streptococcaceae, or their related bacteria, can be exemplified as having equol-producing ability.
また、以下の群から選択される属に分類される嫌気性微生物を、エクオール生産能を有するものとして例示することができる。
・コーリオバクテリウム(Coriobacterium)属
・アドレクラウチア(Adlercreutzia)属
・アサッカロバクター(Asaccharobacter)属
・アトポビウム(Atopobium)属
・コリンゼラ(Collinsella)属
・クリプトバクテリウム(Cryptobacterium)属
・デニトロバクテリウム(Denitrobacterium)属
・エガセラ(Eggerthella)属
・エンテロハブダス(Enterorhabdus)属
・ゴードニバクター(Gordonibacter)属
・オルセネラ(Olsenella)属
・パラエゲセエラ(Paraeggerthella)属
・スラッキア(Slackia)属
・ラクトコッカス(Lactococcus)属
Moreover, the anaerobic microorganism classified into the genus selected from the following groups can be illustrated as what has an equol production ability.
-Coriobacterium genus-Adlercreutzia genus-Asaccharobacter genus-Atopobium genus-Collinsella genus-Cryptobacterium genus-Denitrobacteria The genus Denitrobacterium ・ Eggerthella ・ Enterorhabdus ・ Gordonibacter ・ Olsenella ・ Paraeggerthella ・ Slackia ・ Lactococcus Genus
これらの属に分類された微生物から選択され、アグリコンを利用して嫌気発酵によってエクオールを生成する微生物は、本発明における好ましい微生物である。 A microorganism selected from microorganisms classified into these genera and producing equol by anaerobic fermentation using aglycone is a preferable microorganism in the present invention.
中でも、上記属に分類された微生物のうち、アサッカロバクター・セラツス(Asaccharobacter celatus)DSM 18785又はそれと近縁である、アサッカロバクター・セラツス(Asaccharobacter celatus)DSM 18785の16S rDNA(16S rRNAの遺伝子配列
)と95%以上、好ましくは97%以上、より好ましくは98%以上、さらに好ましくは99%以上の同一性を有する16S rDNAを保有する微生物を使用することが好ましい。アサッカロバクター・セラツス(Asaccharobacter celatus)DSM 18785の16S rRNAの遺伝子配列は配列番号1である。
Among them, among the microorganisms classified into the above genus, Asaccharobacter celatus DSM 18785 or its closely related Asaccharobacter celatus DSM 18785 16S rDNA (16S rRNA It is preferable to use a microorganism having 16S rDNA having 95% or more, preferably 97% or more, more preferably 98% or more, and even more preferably 99% or more identity to the gene sequence). The gene sequence of 16S rRNA of Asaccharobacter celatus DSM 18785 is SEQ ID NO: 1.
さらに上記微生物のうち、アサッカロバクター(Asaccharobacter)属、スラッキア(Slackia)属、アドレクラウチア(Adlercreutzia)属に属する微生物は、本発明における
エクオール産生能を有する微生物としてより好ましい。
Further, among the above microorganisms, microorganisms belonging to the genus Asaccharobacter, Slackia, and Adlercreutzia are more preferable as microorganisms having equol-producing ability in the present invention.
微生物がエクオールを生成することは、培養物中のダイゼイン、ジヒドロダイゼイン、エクオール等を定量することにより確認することができる。これらの定量は、当業者であれば、例えば、WO2012/033150パンフレット、特開2012−135217号公報、特開2012−135218号公報、特開2012−135219号公報などの記載に基づき行うことができる。 The production of equol by a microorganism can be confirmed by quantifying daidzein, dihydrodaidzein, equol and the like in the culture. Those skilled in the art can perform these determinations based on, for example, the descriptions of WO 2012/033150 pamphlet, JP 2012-135217 A, JP 2012-135218 A, JP 2012-135219 A, and the like. .
さらに、以下の嫌気性微生物を利用することができる。
Adlercreutzia equolifaciens DSM 19450
Enterorhabdus mucosicola DSM 19490
Slackia isoflavoniconvertens HE8(DSM 22006)
Slackia sp. TM-30 FERM P-20729
Eggerthella sp. KCCM-10490
Asaccharobacter celatus DSM 18785
Lactococcus garvieae DSM 6783
Furthermore, the following anaerobic microorganisms can be used.
Adlercreutzia equolifaciens DSM 19450
Enterorhabdus mucosicola DSM 19490
Slackia isoflavoniconvertens HE8 (DSM 22006)
Slackia sp.TM-30 FERM P-20729
Eggerthella sp.KCCM-10490
Asaccharobacter celatus DSM 18785
Lactococcus garvieae DSM 6783
上記微生物のうち、アサッカロバクター・セラツス(Asaccharobacter celatus)DSM 18785株、アドレクラウチア・エクオーリファシエンス(Adlercreutzia equolifaciens)DSM 19450株、もしくは、スラッキア・イソフラボニコンバーテンス(Slackia isoflavoniconvertens)DSM 22006株、又はこれらの菌と同様の種としての性質を有する類縁の菌を
より好ましい嫌気性微生物として挙げることができる。
Among the above microorganisms, Asaccharobacter celatus DSM 18785, Adlercreutzia equolifaciens DSM 19450, or Slackia isoflavoniconvertens DSM 22006 Alternatively, related bacteria having the same species characteristics as these bacteria can be mentioned as more preferable anaerobic microorganisms.
上記嫌気性微生物は、その寄託番号に示された寄託機関から入手することができる。各受託番号は、当該嫌気性微生物が、それぞれ次の寄託機関に寄託されていることを示す。
FERM 特許生物寄託センター;International Patent Organism Depositary (IPOD)
http://unit.aist.go.jp/pod/ci/index.html
DSM German Collection of Microorganisms and Cell Cultures (DSMZ)
http://www.dsmz.de/
KCCM Korean Culture Center of Microorganisms
The anaerobic microorganisms can be obtained from the depository indicated by the deposit number. Each deposit number indicates that the anaerobic microorganism is deposited at the next depository.
FERM Patent Organism Depositary; International Patent Organism Depositary (IPOD)
http://unit.aist.go.jp/pod/ci/index.html
DSM German Collection of Microorganisms and Cell Cultures (DSMZ)
http://www.dsmz.de/
KCCM Korean Culture Center of Microorganisms
<2−3.培養・発酵条件>
本発明で用いる嫌気性微生物は、エクオールの生産に適した条件で、培地中でアグリコンと接触させられ、培養される。
本発明のエクオール含有組成物の生産に適した条件とは、エクオール生成活性を持つ嫌気性微生物の生存と活動が維持されることをいう。より具体的には、嫌気性微生物の生存が可能な気相条件(嫌気性条件)が維持され、該嫌気性微生物の活性と増殖を支持するための栄養素が与えられることをいう。嫌気性微生物の生存に適した種々の培地組成が公知である。したがって、先に示したエクオール生産能を有する嫌気性微生物について、当業者は、適切な培地組成を選択することができる。たとえば、実施例において用いた日水製薬社製のGAMブイヨン培地や、Difco社製のBHI培地等を使用することができる。
<2-3. Culture and fermentation conditions>
The anaerobic microorganism used in the present invention is contacted with aglycone in a medium and cultured under conditions suitable for equol production.
The conditions suitable for production of the equol-containing composition of the present invention mean that the survival and activity of anaerobic microorganisms having equol production activity are maintained. More specifically, it means that gas phase conditions (anaerobic conditions) that allow anaerobic microorganisms to survive are maintained, and nutrients are provided to support the activity and growth of the anaerobic microorganisms. Various medium compositions suitable for the survival of anaerobic microorganisms are known. Therefore, those skilled in the art can select an appropriate medium composition for the anaerobic microorganisms having the equol-producing ability shown above. For example, the GAM bouillon medium manufactured by Nissui Pharmaceutical Co., Ltd., the BHI medium manufactured by Difco, etc. used in the Examples can be used.
本発明で用いられる培地には、例えば、水溶性の有機物を炭素源として加えることができる。水溶性の有機物として、ソルボース、フラクトース、グルコース、並びに、吉草酸、酪酸、プロピオン酸、酢酸、及びギ酸など有機酸類等の化合物を挙げることができる。 For example, a water-soluble organic substance can be added to the medium used in the present invention as a carbon source. Examples of water-soluble organic substances include sorbose, fructose, glucose, and organic acids such as valeric acid, butyric acid, propionic acid, acetic acid, and formic acid.
炭素源としての培地に加える有機物の濃度は、効率的に培地中の嫌気性微生物を発育させるために適宜調節することができる。一般的には、0.1〜10wt/vol%の範囲から添加量を選択することによって、過不足を避けることができる。 The concentration of the organic substance added to the medium as a carbon source can be adjusted as appropriate in order to efficiently grow anaerobic microorganisms in the medium. Generally, excess and deficiency can be avoided by selecting the addition amount from the range of 0.1 to 10 wt / vol%.
上記の炭素源に加えて、培地には、窒素源を加えることができる。本発明において、窒素原としては通常の発酵に用いうる各種の窒素化合物を用いることができる。好ましい無機窒素源は、アンモニウム塩、及び硝酸塩である。好ましい有機窒素源はアミノ酸類、酵母エキス、ペプトン類、肉エキス、肝臓エキス、消化血清末などである。より好ましい無機窒素源は、硫安、塩化アンモニウム、リン酸アンモニウム、リン酸水素アンモニウム、硝酸カリウム及び硝酸ソーダである。より好ましい窒素源はアルギニン、シトルリン、オルニチン、リジン、酵母エキス、ペプトン類である。 In addition to the above carbon source, a nitrogen source can be added to the medium. In the present invention, various nitrogen compounds that can be used for normal fermentation can be used as the nitrogen source. Preferred inorganic nitrogen sources are ammonium salts and nitrates. Preferred organic nitrogen sources are amino acids, yeast extract, peptones, meat extract, liver extract, digested serum powder and the like. More preferred inorganic nitrogen sources are ammonium sulfate, ammonium chloride, ammonium phosphate, ammonium hydrogen phosphate, potassium nitrate and sodium nitrate. More preferred nitrogen sources are arginine, citrulline, ornithine, lysine, yeast extract, and peptones.
更に、炭素源や窒素源に加えて、偏性嫌気性微生物の培養に適した他の有機物あるいは無機物を培地に加えることもできる。例えば、ビタミンなどの補因子や各種の塩類等の無機化合物を培地に加えることによって、偏性嫌気性微生物の増殖や活性を増強できる場合もある。例えば、無機化合物、ビタミン類、動植物由来の微生物増殖補助因子として以下のものを挙げることができる。 Furthermore, in addition to a carbon source and a nitrogen source, other organic substances or inorganic substances suitable for cultivation of obligate anaerobic microorganisms can also be added to the medium. For example, the growth and activity of obligate anaerobic microorganisms may be enhanced by adding inorganic compounds such as vitamins and other cofactors and various salts to the medium. For example, the following can be mentioned as microbial growth cofactors derived from inorganic compounds, vitamins and animals and plants.
無機化合物として、例えば、リン酸二水素カリウム、硫酸マグネシウム、硫酸マンガン、塩化ナトリウム、塩化コバルト、塩化カルシウム、硫酸亜鉛、硫酸銅、明ばん、モリブデン酸ソーダ、塩化カリウム、ホウ酸等、塩化ニッケル、タングステン酸ナトリウム、セレン酸ナトリウム、硫酸第一鉄アンモニウムが挙げられる。 Examples of inorganic compounds include potassium dihydrogen phosphate, magnesium sulfate, manganese sulfate, sodium chloride, cobalt chloride, calcium chloride, zinc sulfate, copper sulfate, alum, sodium molybdate, potassium chloride, boric acid, nickel chloride, Examples include sodium tungstate, sodium selenate, and ferrous ammonium sulfate.
また、ビタミン類として、例えば、ビオチン、葉酸、ピリドキシン、チアミン、リボフラビン、ニコチン酸、パントテン酸、ビタミンB12、チオオクト酸、p−アミノ安息香酸が挙げられる。さらに、ポルフィリン化合物であるヘミンを添加するとよい場合がある。 Examples of vitamins include biotin, folic acid, pyridoxine, thiamine, riboflavin, nicotinic acid, pantothenic acid, vitamin B12, thiooctoic acid, and p-aminobenzoic acid. Furthermore, it may be good to add hemin which is a porphyrin compound.
これらの無機化合物やビタミン類、あるいは増殖補助因子を添加して培養液を製造する方法は公知である。培地は、液体、半固体、あるいは固体とすることができる。本発明のエクオールの製造方法において、好ましい培地の形態は、液体培地である。 Methods for producing a culture solution by adding these inorganic compounds, vitamins, or growth cofactors are known. The medium can be liquid, semi-solid, or solid. In the equol production method of the present invention, a preferred medium form is a liquid medium.
本発明で用いる嫌気性微生物は、公知の微生物の培養方法にしたがって培養することができる。工業的な製造には、培地や基質ガスを連続的に供給することができ、かつ培養物を回収するための機構を備えた連続培養システム(continuous fermentation system)が好適である。 The anaerobic microorganism used in the present invention can be cultured according to a known microorganism culture method. For industrial production, a continuous culture system capable of continuously supplying a medium and a substrate gas and equipped with a mechanism for recovering the culture is suitable.
本発明で用いる嫌気性微生物の培養においては、連続培養システム内への酸素の混入を防ぐことが必要である。培養器は通常用いられる培養槽がそのまま利用できる。嫌気性微生物の培養にも利用することができる培養タンクは市販されている。培養槽内に混入する酸素を、窒素などの不活性気体あるいは水素ガスなどで置換することにより、嫌気的な雰囲気を作ることができる。 In the culture of anaerobic microorganisms used in the present invention, it is necessary to prevent oxygen from being mixed into the continuous culture system. As the incubator, a commonly used culture tank can be used as it is. Culture tanks that can also be used for culturing anaerobic microorganisms are commercially available. An anaerobic atmosphere can be created by replacing oxygen mixed in the culture tank with an inert gas such as nitrogen or hydrogen gas.
例えば、嫌気培養ジャー(anaerobic jar)を、嫌気性微生物を培養するためのバイオリアクターとすることができる。嫌気培養ジャーは、金属、ガラス、あるいは合成樹脂製の気密容器で構成され、内部を大気中の酸素から遮断することができる。さ
らに、嫌気培養ジャーは、嫌気培養ジャー内部の空間や培養液中に含まれる分子状酸素を除去するための機構を備えることができる。たとえば、嫌気培養ジャー内部を吸引する真空ポンプを接続して吸引し、酸素以外の気体を供給することで、内部を嫌気状態に維持することができる。
For example, an anaerobic jar can be a bioreactor for culturing anaerobic microorganisms. The anaerobic culture jar is composed of an airtight container made of metal, glass, or synthetic resin, and can block the inside from oxygen in the atmosphere. Furthermore, the anaerobic culture jar can be equipped with a mechanism for removing molecular oxygen contained in the space inside the anaerobic culture jar or in the culture solution. For example, a vacuum pump that sucks the inside of the anaerobic culture jar is connected and sucked, and a gas other than oxygen is supplied, whereby the inside can be maintained in an anaerobic state.
本発明においては、培養槽に付加的な機能を与えることができる。たとえば、通常使用される撹はん混合槽のほか、気泡塔型、ドラフトチューブ型の培養槽も利用できる。液体培地に吹き込まれる混合気体によって微生物は遊離分散され、微生物と培地を十分に接触させることができる。また、バイオトリックリングフィルター(biotrickling filter)のように通気性の高いスラグ、その他セラミック系の無機充てん物、あるいはポリプロピレン等の有機合成物質の充てん層に、水分を滴らせながら微生物を生息させ、そこにガスを通気しながら培養することもできる。さらに、使用する微生物は常法によりカラギーナンゲル、アルギン酸ゲル、アクリルアミドゲル、キチン、セルロース、寒天などに固定化して用いることもできる。 In the present invention, an additional function can be given to the culture tank. For example, in addition to a commonly used stirred mixing tank, a bubble column type or draft tube type culture tank can also be used. The microorganisms are released and dispersed by the mixed gas blown into the liquid medium, and the microorganisms and the medium can be sufficiently brought into contact with each other. In addition, microorganisms inhabit while dripping moisture on a highly breathable slag such as a biotic ring filter, other ceramic-based inorganic fillers, or packed layers of organic synthetic materials such as polypropylene, It can also be cultured while aeration of gas. Furthermore, the microorganisms to be used can be used by immobilizing them on carrageenan gel, alginic acid gel, acrylamide gel, chitin, cellulose, agar, etc. by a conventional method.
本発明の発酵工程においては、上記の基質ガスからなる気相を構成する気体の組み合わせは特に制限されるものではなく、水素、二酸化炭素、窒素等から選択される1種類以上の気体を構成成分として用いることが可能である。当該気相においては、水素が構成成分として含まれていることが好ましい。 In the fermentation process of the present invention, the combination of gases constituting the gas phase composed of the substrate gas is not particularly limited, and one or more gases selected from hydrogen, carbon dioxide, nitrogen and the like are constituent components. Can be used. The gas phase preferably contains hydrogen as a constituent component.
上記の場合、当該発酵工程の気相において、水素の分圧パーセント濃度が2〜100%であることが好ましい。たとえば、2%、4%、6%、10%、20%、30%、40%、50%、80%、100%、又はこれらから選択される2点の分圧パーセント濃度を下限(「〜以上、又は、〜より高い)及び上限(〜以下、又は、〜より低い)、とする濃度範囲により示される分圧パーセント濃度であることが好ましい。 In the above case, the hydrogen partial pressure percent concentration is preferably 2 to 100% in the gas phase of the fermentation process. For example, 2%, 4%, 6%, 10%, 20%, 30%, 40%, 50%, 80%, 100%, or two points of partial pressure percent concentration selected from these lower limits (“˜ It is preferably the partial pressure percent concentration indicated by the concentration range as above, or higher, and upper limit (less than or equal to or lower).
また、効率よくエクオールを生成させるためには、気相を構成する混合気体の培養槽への通気量は0.01〜2.0 V/V/Mガス量/液量/分であることが好ましい。 Moreover, in order to produce | generate equol efficiently, the ventilation | gas_flowing amount to the culture tank of the mixed gas which comprises a gaseous phase should be 0.01-2.0 V / V / M gas amount / liquid amount / min. preferable.
本発明で用いる嫌気性微生物は、通常、37℃付近(30〜42℃)の温度でエクオール生産能を有する嫌気性微生物である。 The anaerobic microorganism used in the present invention is usually an anaerobic microorganism having an equol-producing ability at a temperature around 37 ° C. (30 to 42 ° C.).
本発明において、嫌気性微生物を培養する際の加圧条件は、当該微生物が生育できる条件であれば特に限定されるものではないが、好ましい加圧条件としては、0.02〜0.2MPaの範囲を挙げることができる。 In the present invention, the pressurizing condition for culturing the anaerobic microorganism is not particularly limited as long as the microorganism can grow, but the preferable pressurizing condition is 0.02 to 0.2 MPa. A range can be mentioned.
微生物の十分な生育のため、培養物のpHは、3.0〜8.0が好ましく、4.5〜7.5がより好ましい。また、エクオールの回収量を増加させるため、培養槽の温度は特に制限されるものではないが、37℃を好ましい温度として挙げることができる。 For sufficient growth of microorganisms, the pH of the culture is preferably 3.0 to 8.0, more preferably 4.5 to 7.5. In order to increase the amount of equol recovered, the temperature of the culture tank is not particularly limited, but 37 ° C. can be mentioned as a preferable temperature.
<3.回収工程>
本発明の回収工程は、前記発酵工程で産生された前記エクオールを含有するエクオール含有組成物を、前記培地から回収する工程である。
<3. Recovery process>
The recovery step of the present invention is a step of recovering the equol-containing composition containing the equol produced in the fermentation step from the medium.
当業者は、生成した嫌気性微生物と培養生成液を分離するために公知の任意の方法を用いることができる。好ましい分離の方法は、ろ過性能、濃縮性能を有するホローファイバー型限外ろ過あるいは精密ろ過膜を利用する方法である。また、微生物と該生成液の分離に十分なろ過速度を得るためには使用する微生物に応じて適当な分画分子量の膜を選択すればよい。生産されたエクオールは当業者に公知の任意の手段で培地から回収することができる。例えば、培養槽から限外ろ過膜を通して分離された培養液からエクオールを回収
することができる。エクオールの精製方法は公知である。たとえば、培養物を遠心分離などで菌体を除き、上清を減圧下に濃縮、乾固後、70%エタノールあるいはメタノールで抽出する。抽出液をさらにシリカゲルクロマトグラフィーや晶析などの操作を行うことで精製できる。また、アンバーライトやセパビーズなどスチレン−ジビニルベンゼンの吸着樹脂も用いることができる。
Those skilled in the art can use any known method for separating the produced anaerobic microorganisms from the culture product solution. A preferable separation method is a method using a hollow fiber type ultrafiltration or microfiltration membrane having filtration performance and concentration performance. In addition, in order to obtain a filtration rate sufficient for separating the microorganism and the product solution, a membrane having an appropriate fractional molecular weight may be selected according to the microorganism used. The produced equol can be recovered from the medium by any means known to those skilled in the art. For example, equol can be recovered from a culture solution separated from a culture tank through an ultrafiltration membrane. Methods for purifying equol are known. For example, the cells are removed by centrifuging the culture, and the supernatant is concentrated under reduced pressure, dried and then extracted with 70% ethanol or methanol. The extract can be purified by further operations such as silica gel chromatography and crystallization. Also, styrene-divinylbenzene adsorption resin such as amberlite and sepa beads can be used.
本発明の回収工程では、効率よくエクオールを回収するため、培養槽に供給される新鮮な培地の量は、培養槽内の培養物における希釈率が時間当たり0.04〜2/hrが好ましい。より好ましい希釈率は0.08〜1/hrである。 In the recovery process of the present invention, in order to efficiently recover equol, the amount of fresh medium supplied to the culture tank is preferably such that the dilution rate in the culture in the culture tank is 0.04 to 2 / hr per hour. A more preferable dilution ratio is 0.08 to 1 / hr.
<4.エクオール含有組成物>
本発明の製造方法により得られるエクオール含有組成物は、様々な用途、例えば、化粧料や医薬品、食品などとして提供することができる。飲食品又は医薬品等として摂取することにより、乳癌、前立腺癌、骨粗しょう症、高コレステロール血症、心疾患、更年期障害等を予防できる。
<4. Equol-containing composition>
The equol-containing composition obtained by the production method of the present invention can be provided for various uses such as cosmetics, pharmaceuticals, and foods. Breast cancer, prostate cancer, osteoporosis, hypercholesterolemia, heart disease, climacteric disorder, etc. can be prevented by taking it as a food or drink or medicine.
<5.化粧料>
本発明のエクオール含有組成物を化粧料の素材として用いる場合、該エクオール含有組成物を水溶液、ローション、スプレー液、懸濁液および乳化液などの液状;粉末、顆粒およびブロック状などの固体状;クリームおよびペーストなどの半固体状;ゲル状等の各種所望の剤形の化粧料に調製することができる。このような化粧料は、洗顔料、乳液、クリーム、ゲル、エッセンス(美容液)、パック・マスク等の基礎化粧料、ファンデーション、口紅等のメーキャップ化粧料、口腔化粧料、芳香化粧料、毛髪化粧料、ボディ化粧料等の各種化粧料として有用である。本発明により得られるエクオールを含有組成物を含む化粧料は、美白用化粧料、ニキビ改善用化粧料、しわ改善化粧料として使用される。
本発明のエクオール含有組成物を含有する化粧料は、常法に従って製造することができる。また、化粧料への配合量、配合方法、配合時期は適宜選択することができる。さらに、必要に応じて、瓶、袋、缶、スプレー缶、噴霧容器、箱、パック等の適宜の容器に封入することができる。
本発明のエクオール含有組成物を化粧料の素材として用いる場合、化粧料全量に対する上記エクオール含有組成物の含有量は、本発明の所望の効果が奏される限り特に限定されないが、エクオールとして、通常0.00005〜10質量%であり、好ましくは0.0001〜5質量%であり、より好ましくは0.0001〜2質量%である。
<5. Cosmetics>
When the equol-containing composition of the present invention is used as a cosmetic material, the equol-containing composition is a liquid such as an aqueous solution, lotion, spray solution, suspension and emulsion; a solid such as a powder, granule and block; It can be prepared into cosmetics in various desired dosage forms such as semi-solid forms such as creams and pastes; gels and the like. Such cosmetics include facial cleansers, milks, creams, gels, essences (beauty serums), basic cosmetics such as packs and masks, makeup cosmetics such as foundations and lipsticks, oral cosmetics, aromatic cosmetics and hair cosmetics. It is useful as various cosmetics such as cosmetics and body cosmetics. The cosmetic containing the equol-containing composition obtained by the present invention is used as a whitening cosmetic, an acne improving cosmetic, or a wrinkle improving cosmetic.
A cosmetic containing the equol-containing composition of the present invention can be produced according to a conventional method. Moreover, the compounding quantity, the compounding method, and the compounding time to cosmetics can be selected suitably. Furthermore, it can be enclosed in appropriate containers, such as a bottle, a bag, a can, a spray can, a spray container, a box, and a pack, as needed.
When the equol-containing composition of the present invention is used as a cosmetic material, the content of the equol-containing composition with respect to the total amount of the cosmetic is not particularly limited as long as the desired effect of the present invention is exhibited. It is 0.00005-10 mass%, Preferably it is 0.0001-5 mass%, More preferably, it is 0.0001-2 mass%.
<6.医薬品>
本発明のエクオール含有組成物を医薬品の素材として用いる場合、その剤形は、予防または治療しようとする疾患や医薬品の使用形態、投与経路等に応じて選択することができる。例えば、錠剤、被覆錠剤、丸剤、カプセル剤、顆粒剤、散剤、液剤、懸濁剤、乳剤、シロップ剤、注射剤、坐剤、浸剤、煎剤、チンキ剤等が挙げられる。これらの各種製剤は、常法に従って主薬に対して必要に応じて充填剤、増量剤、賦形剤、結合剤、保湿剤、崩壊剤、界面活性剤、滑沢剤、着色剤、矯味矯臭剤、溶解補助剤、懸濁剤、コーティング剤などの医薬の製剤技術分野において通常使用し得る既知の補助剤を用いて製剤化することができる。また、この医薬製剤中に着色剤、保存剤、香料、風味剤、甘味剤等や他の医薬品を含有させてもよい。
本発明のエクオール含有組成物は、乳癌、前立腺癌、骨粗しょう症、心疾患、更年期障害の予防や治療のために使用することができる。
<6. Pharmaceuticals>
When the equol-containing composition of the present invention is used as a pharmaceutical material, the dosage form can be selected depending on the disease to be prevented or treated, the usage form of the pharmaceutical, the administration route, and the like. Examples include tablets, coated tablets, pills, capsules, granules, powders, solutions, suspensions, emulsions, syrups, injections, suppositories, dip agents, decoction, tinctures and the like. These various preparations are prepared according to conventional methods as necessary with respect to the active ingredient, such as fillers, extenders, excipients, binders, humectants, disintegrants, surfactants, lubricants, coloring agents, flavoring agents. The pharmaceutical composition can be formulated using known adjuvants that can be usually used in the pharmaceutical preparation technical field, such as solubilizing agents, suspension agents, and coating agents. Moreover, you may contain a coloring agent, a preservative, a fragrance | flavor, a flavoring agent, a sweetening agent, etc. and other pharmaceuticals in this pharmaceutical formulation.
The equol-containing composition of the present invention can be used for the prevention and treatment of breast cancer, prostate cancer, osteoporosis, heart disease and menopause.
本発明のエクオール含有組成物を医薬品の素材として用いる場合、医薬品全量に対する上記エクオール含有組成物の含有量は、本発明の所望の効果が奏される限り特に限定されないが、エクオールとして、通常0.001〜30質量%であり、好ましくは0.01〜
20質量%であり、より好ましくは0.1〜10質量%である。また、上記エクオール含有組成物を含有する医薬品の投与量は、患者の年齢、体重、症状の程度等によって適宜設定され得る。
When the equol-containing composition of the present invention is used as a pharmaceutical material, the content of the equol-containing composition with respect to the total amount of the pharmaceutical is not particularly limited as long as the desired effect of the present invention is exhibited. 001-30 mass%, preferably 0.01-
It is 20 mass%, More preferably, it is 0.1-10 mass%. In addition, the dose of the pharmaceutical agent containing the equol-containing composition can be appropriately set depending on the age, weight, symptom level, etc. of the patient.
<7.食品>
本発明のエクオール含有組成物を食品の素材として用いる場合、一般の食品の他、特定保健用食品、栄養補助食品、機能性食品、病者用食品、食品添加物等として使用できる。食品の形態としては、本発明に係るエクオール含有組成物を含む清涼飲料、ミルク、プリン、ゼリー、飴、ガム、グミ、ヨーグルト、チョコレート、スープ、クッキー、スナック菓子、アイスクリーム、アイスキャンデー、パン、ケーキ、シュークリーム、ハム、ミートソース、カレー、シチュー、チーズ、バター、ドレッシング等を例示することができる。
<7. Food>
When the equol-containing composition of the present invention is used as a food material, it can be used as a food for specified health use, a dietary supplement, a functional food, a food for a sick person, a food additive, etc. in addition to a general food. As a form of food, soft drinks, milk, pudding, jelly, rice cake, gum, gummy, yogurt, chocolate, soup, cookies, snack confectionery, ice cream, popsicle, bread, cake including the equol-containing composition according to the present invention , Cream puffs, ham, meat sauce, curry, stew, cheese, butter, dressing and the like.
本発明のエクオール含有組成物は、水、タンパク質、糖質、脂質、ビタミン類、ミネラル類、有機酸、有機塩基、果汁、フレーバー類等を主成分として使用することができる。タンパク質としては、例えば、全脂粉乳、脱脂粉乳、部分脱脂粉乳、カゼイン、大豆タンパク質、鶏卵タンパク質、肉タンパク質等の動植物性タンパク質、及びこれらの加水分解物、バターなどが挙げられる。糖質としては、糖類、加工澱粉(デキストリンのほか、可溶性澱粉、ブリティッシュスターチ、酸化澱粉、澱粉エステル、澱粉エーテル等)、食物繊維などが挙げられる。脂質としては、例えば、ラード、サフラワー油、コーン油、ナタネ油、ヤシ油、これらの分別油、水素添加油、エステル交換油等の植物性油脂などが挙げられる。ビタミン類としては、例えば、ビタミンA、カロチン類、ビタミンB群、ビタミンC、ビタミンD群、ビタミンE、ビタミンK群、ビタミンP、ビタミンQ、ナイアシン、ニコチン酸、パントテン酸、ビオチン、イノシトール、コリン、葉酸などが挙げられ、ミネラル類としては、例えば、カルシウム、カリウム、マグネシウム、ナトリウム、銅、鉄、マンガン、亜鉛、セレン、乳清ミネラルなどが挙げられる。有機酸としては、例えば、リンゴ酸、クエン酸、乳酸、酒石酸などが挙げられる。これらの成分は、2種以上を組み合わせて使用してもよく、合成品及び/又はこれらを多く含む食品を用いてもよい。 The equol-containing composition of the present invention can use water, protein, carbohydrates, lipids, vitamins, minerals, organic acids, organic bases, fruit juices, flavors and the like as main components. Examples of the protein include whole milk powder, skim milk powder, partially skim milk powder, casein, soybean protein, chicken egg protein, meat protein, and other animal and vegetable proteins, and their hydrolysates and butter. Examples of the saccharide include saccharides, processed starch (in addition to dextrin, soluble starch, British starch, oxidized starch, starch ester, starch ether, etc.), dietary fiber, and the like. Examples of lipids include lard, safflower oil, corn oil, rapeseed oil, coconut oil, fractionated oils thereof, hydrogenated oil, and vegetable oils such as transesterified oil. Examples of vitamins include vitamin A, carotene, vitamin B group, vitamin C, vitamin D group, vitamin E, vitamin K group, vitamin P, vitamin Q, niacin, nicotinic acid, pantothenic acid, biotin, inositol, choline. And minerals include, for example, calcium, potassium, magnesium, sodium, copper, iron, manganese, zinc, selenium, and whey minerals. Examples of the organic acid include malic acid, citric acid, lactic acid, and tartaric acid. Two or more of these components may be used in combination, or a synthetic product and / or a food containing a large amount thereof may be used.
本発明のエクオール含有組成物を含有する食品は、常法に従って製造することができる。また、食品への配合量、配合方法、配合時期は適宜選択することができる。さらに、必要に応じて、瓶、袋、缶、箱、パック等の適宜の容器に封入することができる。
本発明のエクオール含有組成物を食品の素材として用いる場合、食品全量に対する上記エクオール含有組成物の含有量は、本発明の所望の効果が奏される限り特に限定されないが、エクオールとして、通常0.01〜10質量%であり、好ましくは0.05〜5質量%であり、より好ましくは0.1〜2質量%である。
The food containing the equol-containing composition of the present invention can be produced according to a conventional method. Moreover, the compounding quantity to a foodstuff, a compounding method, and a compounding time can be selected suitably. Furthermore, it can be enclosed in appropriate containers, such as a bottle, a bag, a can, a box, and a pack, as needed.
When the equol-containing composition of the present invention is used as a food material, the content of the equol-containing composition with respect to the total amount of food is not particularly limited as long as the desired effect of the present invention is exhibited. It is 01-10 mass%, Preferably it is 0.05-5 mass%, More preferably, it is 0.1-2 mass%.
以下、具体的な実施例により本発明をさらに詳細に説明するが、本発明はこれらの実施例に限定されるものではない。 Hereinafter, the present invention will be described in more detail with reference to specific examples, but the present invention is not limited to these examples.
[実施例1]
<1.イソフラボン類の調製>
本実施例では、イソフラボン類として、大豆胚軸(不二製油製)をワーリングブレンダーを用いて、1分間×3回(計3分間)、粉砕したものを用いた。
[Example 1]
<1. Preparation of isoflavones>
In this example, soybean hypocotyls (produced by Fuji Oil Co., Ltd.) were crushed for 1 minute × 3 times (3 minutes in total) using a Waring blender as isoflavones.
<2.酵素処理>
酵素処理溶液としては、イソフラボン類として270gの大豆胚軸(不二製油製)、酵素として2.7gのペクチナーゼGアマノ、および1180gの脱イオン水を用いて、計1450gとし、pHを4〜7に調整して調製した。酵素処理は、50℃で20〜24時
間、撹拌しながら行った。
<2. Enzyme treatment>
As the enzyme treatment solution, 270 g of soybean hypocotyl (produced by Fuji Oil Co., Ltd.) as isoflavones, 2.7 g of pectinase G Amano as an enzyme, and 1180 g of deionized water, a total of 1450 g, with a pH of 4-7 And prepared. The enzyme treatment was carried out at 50 ° C. for 20-24 hours with stirring.
<3.嫌気性微生物による発酵>
(種培養)
GAMブイヨン培地(日水製薬製)5.9gとL−アルギニン塩酸塩1.2gを純水100mLに溶かし、窒素ガスを通じながら20mLずつ嫌気性菌培養用18mm試験管(三紳工業製)に分注し、ブチルゴム栓、プラスチックキャップをして115℃、15分間滅菌した。
この培地に−80℃で凍結保存していたアサッカロバクター・セラツス(Asaccharobacter celatus) DSM 18785株を植菌し、無菌フィルターを通した水素ガスで気相を2分間
以上置換した後、37℃、250spmで16時間振とう培養を行った。
<3. Fermentation by anaerobic microorganisms>
(Seed culture)
Dissolve 5.9 g of GAM bouillon medium (manufactured by Nissui Pharmaceutical) and 1.2 g of L-arginine hydrochloride in 100 mL of pure water, and dispense 20 mL each into an 18 mm test tube for anaerobic bacterial culture (manufactured by Sangen Industrial) through nitrogen gas. Poured, butyl rubber stopper and plastic cap, and sterilized at 115 ° C. for 15 minutes.
This medium was inoculated with Asaccharobacter celatus strain DSM 18785, which had been stored frozen at -80 ° C, and the gas phase was replaced with hydrogen gas passed through a sterile filter for 2 minutes or more. And shaking culture at 250 spm for 16 hours.
(発酵)
上記種培養液と同様に、L−アルギニン塩酸塩を添加したGAMブイヨン培地を、115℃、15分間オートクレーブ滅菌し、室温まで冷却後、上述した種培養液を植菌し、気相を水素ガスで無菌的に2分間以上置換した後、37℃、250spmの条件で振とう培養し、発酵を行った。
(fermentation)
Similar to the above seed culture, GAM bouillon medium supplemented with L-arginine hydrochloride was autoclaved at 115 ° C. for 15 minutes, cooled to room temperature, inoculated with the above seed culture, and the gas phase was transferred to hydrogen gas. And aseptically replaced for 2 minutes or more, and then cultured under shaking at 37 ° C. and 250 spm for fermentation.
<4.エクオール含有組成物の回収>
上記発酵後の培養液を3000rpmで10分遠心し、0.45μmのMF膜でろ過し、不溶物を除去して、エクオール含有組成液を回収した。組成液を乾燥処理(スプレード
ライ処理)することによりエクオール含有物(EQ−N)を得た。
<4. Recovery of equol-containing composition>
The culture solution after fermentation was centrifuged at 3000 rpm for 10 minutes, filtered through a 0.45 μm MF membrane, insolubles were removed, and an equol-containing composition solution was recovered. The composition liquid was dried (spray-dried) to obtain an equol-containing product (EQ-N).
<5.アレルゲンの検出>
得られたエクオール含有組成物について、FASTKITスリム大豆(日本ハム中央研究所製
)を用いてアレルゲンの検出を行った。
具体的な方法は、FATKITスリムのマニュアルに従った。サンプルとしてEQ−N 2gを使用し、キット中の抽出用緩衝液38mLを加え、30〜60分混合後、3回抽出し、その後、3000×g、4℃、20分で遠心分離後し、上清をろ紙でろ過し、キット内の希釈用緩衝液で10倍に希釈し測定サンプルとした。測定は、テストストリップに100μLを滴下し、15分展開後目視判定をした。
<5. Allergen detection>
About the obtained equol containing composition, allergen was detected using FASTKIT slim soybean (made by Nippon Ham Central Research Laboratory).
The specific method followed the FATKIT Slim manual. Using 2 g of EQ-N as a sample, add 38 mL of extraction buffer in the kit, mix for 30 to 60 minutes, extract 3 times, and then centrifuge at 3000 xg, 4 ° C, 20 minutes, The supernatant was filtered with a filter paper and diluted 10-fold with a dilution buffer in the kit to obtain a measurement sample. In the measurement, 100 μL was dropped on the test strip, and visually developed after 15 minutes of development.
[比較例1]
上記酵素処理および発酵を行わず、粉砕した大豆胚軸について、上記と同様にしてアレルゲンの検出を行った。
[Comparative Example 1]
Allergens were detected in the same manner as described above for the ground soybean hypocotyl without performing the enzyme treatment and fermentation.
<6.結果>
アレルゲンが存在する場合には、図1に示すテストストリップにおいて、矢印で示す位置にバンドが出現するところ、酵素処理および発酵を経てエクオール含有組成物が回収された実施例1においてはアレルゲンの存在を示すバンドは検出されなかった。一方、酵素処理および発酵を経なかった比較例1においてはアレルゲンの存在を示すバンドが検出された。
以上より、本発明上記酵素処理および発酵を行うことで、実質的にアレルゲンを含まないエクオール含有組成物が得られることがわかった。
<6. Result>
When the allergen is present, a band appears at the position indicated by the arrow in the test strip shown in FIG. 1. In Example 1, where the equol-containing composition was recovered through enzyme treatment and fermentation, the presence of the allergen was confirmed. The indicated band was not detected. On the other hand, a band indicating the presence of allergen was detected in Comparative Example 1 which did not undergo enzyme treatment and fermentation.
As mentioned above, it turned out that the equol containing composition which does not contain an allergen substantially is obtained by performing the said enzyme treatment and fermentation of this invention.
本発明の方法により製造されたエクオール含有組成物を、飲食品又は医薬品等として摂取することにより、乳癌、前立腺癌、骨粗しょう症、高コレステロール血症、心疾患、更年期障害等を予防できる。 Breast cancer, prostate cancer, osteoporosis, hypercholesterolemia, heart disease, climacteric disorder and the like can be prevented by ingesting the equol-containing composition produced by the method of the present invention as a food or drink or a pharmaceutical product.
Claims (7)
(2)前記工程(1)で得られた前記アグリコンを含有する培地で嫌気性微生物を培養し、前記嫌気性微生物により、前記アグリコンをエクオールに変換する工程、及び、
(3)前記工程(2)で産生された前記エクオールを含有するエクオール含有組成物を、前記培地から回収する工程、
を含む、エクオール含有組成物の製造方法。 (1) A process of treating isoflavones with an enzyme that converts the isoflavones to aglycone,
(2) culturing an anaerobic microorganism in the medium containing the aglycone obtained in the step (1), converting the aglycon into equol by the anaerobic microorganism, and
(3) recovering the equol-containing composition containing the equol produced in the step (2) from the medium;
A process for producing an equol-containing composition.
18785の16S rDNAと95%以上の同一性を有する16S rDNAを保有する微生物である、請求項1に記載の方法。 The anaerobic microorganism is an Asaccharobacter celatus DSM
The method of claim 1, wherein the microorganism possesses 16S rDNA having 95% or more identity with 18785 16S rDNA.
項1または2に記載の方法。 The method according to claim 1 or 2, wherein the anaerobic microorganism is a microorganism classified into the genus Asaccharobacter, the genus Slackia, or the genus Adlercreutzia.
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