WO2021020209A1 - Agent for promoting generation of short-chain fatty acids within intestinal duct - Google Patents
Agent for promoting generation of short-chain fatty acids within intestinal duct Download PDFInfo
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Abstract
The purpose of the present invention is to provide a short-chain fatty acid generation promoting agent for efficiently promoting generation of short-chain fatty acids within the intestinal duct. A compound having an iridoid skeleton is able to effectively promote generation of short-chain fatty acids within the intestinal duct and can be used as an agent for promoting generation of short-chain fatty acids within the intestinal duct.
Description
本発明は、腸管内において短鎖脂肪酸の生成を効果的に促進させる短鎖脂肪酸生成促進剤に関する。
The present invention relates to a short-chain fatty acid production promoter that effectively promotes the production of short-chain fatty acids in the intestinal tract.
食事由来の難消化性食物や多糖類等が腸内細菌によって資化されることにより、代謝産物として短鎖脂肪酸が生成する。腸内細菌の代謝産物として生成する短鎖脂肪酸は、主に、酢酸、プロピオン酸、酪酸、コハク酸等である。
Short-chain fatty acids are produced as metabolites by assimilating diet-derived indigestible foods and polysaccharides by intestinal bacteria. The short-chain fatty acids produced as metabolites of intestinal bacteria are mainly acetic acid, propionic acid, butyric acid, succinic acid and the like.
従来、腸管内で生成した短鎖脂肪酸は、宿主のエネルギー源として利用されると考えられてきたが、近年、腸管バリア機能の増強による病原菌の感染予防、アレルギー性炎症の改善等にも寄与していることが明らかにされている。更に、最近では、腸管内で生成した短鎖脂肪酸は、Ｇタンパク質共役型受容体（ＧＰＣＲ）を介したシグナル分子としても作用していることが解明されており、ＧＰＲ４１、ＧＰＲ４３、ＧＰＲ９１、ＧＰＲ１０９ａ、及びＯｌｆｒ７８が短鎖脂肪酸受容体として同定されている（非特許文献１～３参照）。
Conventionally, short-chain fatty acids produced in the intestinal tract have been considered to be used as an energy source for the host, but in recent years, they have contributed to prevention of pathogen infection and improvement of allergic inflammation by enhancing the intestinal barrier function. It has been clarified that Furthermore, recently, it has been elucidated that short-chain fatty acids produced in the intestinal tract also act as signal molecules via G protein-coupled receptors (GPCRs), and GPR41, GPR43, GPR91, GPR109a, And Olfr78 have been identified as short-chain fatty acid receptors (see Non-Patent Documents 1-3).
また、短鎖脂肪酸受容体が担っている生体調節機能についても種々解明されている。ＧＰＲ４１及びＧＰＲ４３は、短鎖脂肪酸受容体の中でも、短鎖脂肪酸に対する親和性が非常に高く、低濃度でもシグナル伝達作用が発現されることが知られており、腸でのＰＹＹ（ペプチドＹＹ）やＧＬＰ－１（グルカゴン様ペプチド－１）の分泌促進、膵臓でのインスリン分泌制御等に関与していることが報告されている。また、短鎖脂肪酸が交感神経節で発現しているＧＰＲ４３は、交感神経を賦活化し、ノルアドレナリンの分泌促進することも報告されている（非特許文献４）。
In addition, various bioregulatory functions of short-chain fatty acid receptors have been elucidated. Among the short-chain fatty acid receptors, GPR41 and GPR43 have a very high affinity for short-chain fatty acids, and are known to exhibit a signal-transmitting effect even at low concentrations, such as PYY (peptide YY) in the intestine. It has been reported that it is involved in the promotion of GLP-1 (glucagon-like peptide-1) secretion and the regulation of insulin secretion in the pancreas. It has also been reported that GPR43, in which short-chain fatty acids are expressed in the sympathetic ganglion, activates the sympathetic nerve and promotes the secretion of noradrenaline (Non-Patent Document 4).
このように短鎖脂肪酸受容体は様々な生体調節機能を担っており、短鎖脂肪酸受容体を介したシグナル伝達を亢進させることは、健康維持だけでなく、短鎖脂肪酸受容体を介したシグナル伝達の亢進によって予防、治療、又は改善が期待できる症状や疾患に対して有効になる。
In this way, short-chain fatty acid receptors are responsible for various bioregulatory functions, and enhancing signal transduction via short-chain fatty acid receptors not only maintains health, but also signals via short-chain fatty acid receptors. It is effective for symptoms and diseases that can be prevented, treated, or improved by enhancing transmission.
腸管内における短鎖脂肪酸の生成量の増大は、腸管内での短鎖脂肪酸受容体を介したシグナル伝達の亢進だけでなく、血中に移行する短鎖脂肪酸量を増加させ、ひいては全身での鎖脂肪酸受容体を介したシグナル伝達の亢進をもたらし得る。そこで、本発明は、腸管内において短鎖脂肪酸の生成を効果的に促進させる短鎖脂肪酸生成促進剤を提供することを目的とする。
Increased production of short-chain fatty acids in the intestine not only enhances signal transduction via short-chain fatty acid receptors in the intestine, but also increases the amount of short-chain fatty acids transferred to the blood, which in turn increases systemic. It can result in enhanced signal transduction via chain fatty acid receptors. Therefore, an object of the present invention is to provide a short-chain fatty acid production promoter that effectively promotes the production of short-chain fatty acids in the intestinal tract.
本発明者等は、前記課題を解決すべく鋭意検討を行ったところ、イリドイド骨格を有する化合物には、腸管内における短鎖脂肪酸の生成を効果的に促進する作用があることを見出した。本発明は、かかる知見に基づいて更なる検討を重ねることにより完成したものである。
The present inventors conducted diligent studies to solve the above problems, and found that a compound having an iridoid skeleton has an effect of effectively promoting the production of short-chain fatty acids in the intestinal tract. The present invention has been completed by conducting further studies based on such findings.
即ち、本発明は、下記に掲げる態様の発明を提供する。
項１． イリドイド骨格を有する化合物を含有する、腸管内における短鎖脂肪酸の生成促進剤。
項２． 前記イリドイド骨格を有する化合物が、アスペルロシド、ゲニポシド酸、オイコミオール、1-デオキシオイコミオール、エピオイコミオール、アスペルロシド酸、デアセチルアスペルロシド酸、スキャンデシド１０－Ｏ－アセテート、オークビン、オイコミシドＡ、オイコミシドＢ、及びオイコミシドＣよりなる群から選択される少なくとも１種である、項１に記載の短鎖脂肪酸の生成促進剤。
項３． 飲食品、又は内服用医薬品である、項１又は２に記載の短鎖脂肪酸の生成促進剤。
項４． 腸管内におけるプロピオン酸及び／又はコハク酸の生成促進のために用いられる、項１～３のいずれかに記載の短鎖脂肪酸の生成促進剤。
項５． イリドイド骨格を有する化合物の、腸管内における短鎖脂肪酸の生成促進剤の製造のための使用。
項６． 前記イリドイド骨格を有する化合物が、アスペルロシド、ゲニポシド酸、オイコミオール、1-デオキシオイコミオール、エピオイコミオール、アスペルロシド酸、デアセチルアスペルロシド酸、スキャンデシド１０－Ｏ－アセテート、オークビン、オイコミシドＡ、オイコミシドＢ、及びオイコミシドＣよりなる群から選択される少なくとも１種である、項５に記載の使用。
項７． 飲食品、又は内服用医薬品である、項５又は６に記載の使用。
項８． 前記生成促進剤が、腸管内におけるプロピオン酸及び／又はコハク酸の生成促進のために用いられる、項５～７のいずれかに記載の使用。
項９． イリドイド骨格を有する化合物を、腸管内における短鎖脂肪酸の生成促進が必要とされる者に投与又は摂取させる、腸管内における短鎖脂肪酸の生成促進方法。
項１０． 前記イリドイド骨格を有する化合物が、アスペルロシド、ゲニポシド酸、オイコミオール、1-デオキシオイコミオール、エピオイコミオール、アスペルロシド酸、デアセチルアスペルロシド酸、スキャンデシド１０－Ｏ－アセテート、オークビン、オイコミシドＡ、オイコミシドＢ、及びオイコミシドＣよりなる群から選択される少なくとも１種である、項９に記載の生成促進方法。
項１１． 飲食品、又は内服用医薬品である、項９又は１０に記載の生成促進方法。
項１２． 腸管内におけるプロピオン酸及び／又はコハク酸の生成を促進させる、項９～１１のいずれかに記載の生成促進方法。
項１３． イリドイド骨格を有する化合物の、腸管内における短鎖脂肪酸の生成促進のための非治療的使用。
項１４． 前記イリドイド骨格を有する化合物が、アスペルロシド、ゲニポシド酸、オイコミオール、1-デオキシオイコミオール、エピオイコミオール、アスペルロシド酸、デアセチルアスペルロシド酸、スキャンデシド１０－Ｏ－アセテート、オークビン、オイコミシドＡ、オイコミシドＢ、及びオイコミシドＣよりなる群から選択される少なくとも１種である、項１３に記載の非治療的使用。
項１５． 腸管内におけるプロピオン酸及び／又はコハク酸の生成促進のために用いられる、項１３又は１４に記載の非治療的使用。
項１６． 腸管内における短鎖脂肪酸の生成促進の処置のために使用される、イリドイド骨格を有する化合物。
項１７． 前記イリドイド骨格を有する化合物が、アスペルロシド、ゲニポシド酸、オイコミオール、1-デオキシオイコミオール、エピオイコミオール、アスペルロシド酸、デアセチルアスペルロシド酸、スキャンデシド１０－Ｏ－アセテート、オークビン、オイコミシドＡ、オイコミシドＢ、及びオイコミシドＣよりなる群から選択される少なくとも１種である、項１６に記載の化合物。
項１８． 腸管内におけるプロピオン酸及び／又はコハク酸の生成促進のために用いられる、項１６又は１７に記載の化合物。 That is, the present invention provides the inventions of the following aspects.
Item 1. An agent for promoting the production of short-chain fatty acids in the intestinal tract, which contains a compound having an iridoid skeleton.
Item 2. The compounds having an iridoid skeleton are asperuloside, geniposidic acid, eucomiol, 1-deoxyoicomiol, epioicomiol, asperuloside acid, deacetylasperuloside acid, scandecid 10-O-acetate, oakbin, eucomicide A, eucomicide. Item 2. The short-chain fatty acid production-promoting agent according to Item 1, which is at least one selected from the group consisting of B and iridoid C.
Item 3. Item 2. The short-chain fatty acid production promoter according to Item 1 or 2, which is a food or drink or an orally taken drug.
Item 4. Item 2. The short-chain fatty acid production promoter according to any one of Items 1 to 3, which is used for promoting the production of propionic acid and / or succinic acid in the intestinal tract.
Item 5. Use of compounds with an iridoid skeleton for the production of short-chain fatty acid production promoters in the intestinal tract.
Item 6. The compounds having an iridoid skeleton are asperuloside, geniposidic acid, eucomiol, 1-deoxyoicomiol, epioicomiol, asperuloside acid, deacetylasperuloside acid, scandecid 10-O-acetate, oakbin, eucomicid A, eucomicide. Item 5. The use according to Item 5, which is at least one selected from the group consisting of B and eucomicid C.
Item 7. Item 5. Use according to Item 5 or 6, which is a food or drink or an internal medicine.
Item 8. Item 6. The use according to any one of Items 5 to 7, wherein the production promoter is used for promoting the production of propionic acid and / or succinic acid in the intestinal tract.
Item 9. A method for promoting the production of short-chain fatty acids in the intestinal tract, in which a compound having an iridoid skeleton is administered or ingested by a person who needs to promote the production of short-chain fatty acids in the intestinal tract.
Item 10. The compounds having an iridoid skeleton are asperuloside, geniposidic acid, eucomiol, 1-deoxyoicomiol, epioicomiol, asperuloside acid, deacetylasperuloside acid, scandecid 10-O-acetate, oakbin, eucomicid A, eucomicide. Item 9. The method for promoting production, which is at least one selected from the group consisting of B and eucomicid C.
Item 11. Item 9. The production promoting method according to Item 9 or 10, which is a food or drink or an orally taken drug.
Item 12. Item 8. The method for promoting production according to any one of Items 9 to 11, which promotes the production of propionic acid and / or succinic acid in the intestinal tract.
Item 13. Non-therapeutic use of compounds with an iridoid skeleton to promote the production of short chain fatty acids in the intestinal tract.
Item 14. The compounds having an iridoid skeleton are asperuloside, geniposidic acid, eucomiol, 1-deoxyoicomiol, epioicomiol, asperuloside acid, deacetylasperuloside acid, scandecid 10-O-acetate, oakbin, eucomicide A, eucomicide. Item 3. The non-therapeutic use according to Item 13, which is at least one selected from the group consisting of B and eucomicid C.
Item 15. Item 3. The non-therapeutic use according to Item 13 or 14, which is used for promoting the production of propionic acid and / or succinic acid in the intestinal tract.
Item 16. A compound having an iridoid skeleton used for the treatment of promoting the production of short-chain fatty acids in the intestinal tract.
Item 17. The compounds having an iridoid skeleton are asperuloside, geniposidic acid, eucomiol, 1-deoxyoicomiol, epioicomiol, asperuloside acid, deacetylasperuloside acid, scandecid 10-O-acetate, oakbin, eucomicide A, eucomicide. Item 6. The compound according to Item 16, which is at least one selected from the group consisting of B and eucomicid C.
Item 18. Item 6. The compound according to Item 16 or 17, which is used for promoting the production of propionic acid and / or succinic acid in the intestinal tract.
項１． イリドイド骨格を有する化合物を含有する、腸管内における短鎖脂肪酸の生成促進剤。
項２． 前記イリドイド骨格を有する化合物が、アスペルロシド、ゲニポシド酸、オイコミオール、1-デオキシオイコミオール、エピオイコミオール、アスペルロシド酸、デアセチルアスペルロシド酸、スキャンデシド１０－Ｏ－アセテート、オークビン、オイコミシドＡ、オイコミシドＢ、及びオイコミシドＣよりなる群から選択される少なくとも１種である、項１に記載の短鎖脂肪酸の生成促進剤。
項３． 飲食品、又は内服用医薬品である、項１又は２に記載の短鎖脂肪酸の生成促進剤。
項４． 腸管内におけるプロピオン酸及び／又はコハク酸の生成促進のために用いられる、項１～３のいずれかに記載の短鎖脂肪酸の生成促進剤。
項５． イリドイド骨格を有する化合物の、腸管内における短鎖脂肪酸の生成促進剤の製造のための使用。
項６． 前記イリドイド骨格を有する化合物が、アスペルロシド、ゲニポシド酸、オイコミオール、1-デオキシオイコミオール、エピオイコミオール、アスペルロシド酸、デアセチルアスペルロシド酸、スキャンデシド１０－Ｏ－アセテート、オークビン、オイコミシドＡ、オイコミシドＢ、及びオイコミシドＣよりなる群から選択される少なくとも１種である、項５に記載の使用。
項７． 飲食品、又は内服用医薬品である、項５又は６に記載の使用。
項８． 前記生成促進剤が、腸管内におけるプロピオン酸及び／又はコハク酸の生成促進のために用いられる、項５～７のいずれかに記載の使用。
項９． イリドイド骨格を有する化合物を、腸管内における短鎖脂肪酸の生成促進が必要とされる者に投与又は摂取させる、腸管内における短鎖脂肪酸の生成促進方法。
項１０． 前記イリドイド骨格を有する化合物が、アスペルロシド、ゲニポシド酸、オイコミオール、1-デオキシオイコミオール、エピオイコミオール、アスペルロシド酸、デアセチルアスペルロシド酸、スキャンデシド１０－Ｏ－アセテート、オークビン、オイコミシドＡ、オイコミシドＢ、及びオイコミシドＣよりなる群から選択される少なくとも１種である、項９に記載の生成促進方法。
項１１． 飲食品、又は内服用医薬品である、項９又は１０に記載の生成促進方法。
項１２． 腸管内におけるプロピオン酸及び／又はコハク酸の生成を促進させる、項９～１１のいずれかに記載の生成促進方法。
項１３． イリドイド骨格を有する化合物の、腸管内における短鎖脂肪酸の生成促進のための非治療的使用。
項１４． 前記イリドイド骨格を有する化合物が、アスペルロシド、ゲニポシド酸、オイコミオール、1-デオキシオイコミオール、エピオイコミオール、アスペルロシド酸、デアセチルアスペルロシド酸、スキャンデシド１０－Ｏ－アセテート、オークビン、オイコミシドＡ、オイコミシドＢ、及びオイコミシドＣよりなる群から選択される少なくとも１種である、項１３に記載の非治療的使用。
項１５． 腸管内におけるプロピオン酸及び／又はコハク酸の生成促進のために用いられる、項１３又は１４に記載の非治療的使用。
項１６． 腸管内における短鎖脂肪酸の生成促進の処置のために使用される、イリドイド骨格を有する化合物。
項１７． 前記イリドイド骨格を有する化合物が、アスペルロシド、ゲニポシド酸、オイコミオール、1-デオキシオイコミオール、エピオイコミオール、アスペルロシド酸、デアセチルアスペルロシド酸、スキャンデシド１０－Ｏ－アセテート、オークビン、オイコミシドＡ、オイコミシドＢ、及びオイコミシドＣよりなる群から選択される少なくとも１種である、項１６に記載の化合物。
項１８． 腸管内におけるプロピオン酸及び／又はコハク酸の生成促進のために用いられる、項１６又は１７に記載の化合物。 That is, the present invention provides the inventions of the following aspects.
Item 1. An agent for promoting the production of short-chain fatty acids in the intestinal tract, which contains a compound having an iridoid skeleton.
Item 2. The compounds having an iridoid skeleton are asperuloside, geniposidic acid, eucomiol, 1-deoxyoicomiol, epioicomiol, asperuloside acid, deacetylasperuloside acid, scandecid 10-O-acetate, oakbin, eucomicide A, eucomicide. Item 2. The short-chain fatty acid production-promoting agent according to Item 1, which is at least one selected from the group consisting of B and iridoid C.
Item 3. Item 2. The short-chain fatty acid production promoter according to Item 1 or 2, which is a food or drink or an orally taken drug.
Item 4. Item 2. The short-chain fatty acid production promoter according to any one of Items 1 to 3, which is used for promoting the production of propionic acid and / or succinic acid in the intestinal tract.
Item 5. Use of compounds with an iridoid skeleton for the production of short-chain fatty acid production promoters in the intestinal tract.
Item 6. The compounds having an iridoid skeleton are asperuloside, geniposidic acid, eucomiol, 1-deoxyoicomiol, epioicomiol, asperuloside acid, deacetylasperuloside acid, scandecid 10-O-acetate, oakbin, eucomicid A, eucomicide. Item 5. The use according to Item 5, which is at least one selected from the group consisting of B and eucomicid C.
Item 7. Item 5. Use according to Item 5 or 6, which is a food or drink or an internal medicine.
Item 8. Item 6. The use according to any one of Items 5 to 7, wherein the production promoter is used for promoting the production of propionic acid and / or succinic acid in the intestinal tract.
Item 9. A method for promoting the production of short-chain fatty acids in the intestinal tract, in which a compound having an iridoid skeleton is administered or ingested by a person who needs to promote the production of short-chain fatty acids in the intestinal tract.
Item 10. The compounds having an iridoid skeleton are asperuloside, geniposidic acid, eucomiol, 1-deoxyoicomiol, epioicomiol, asperuloside acid, deacetylasperuloside acid, scandecid 10-O-acetate, oakbin, eucomicid A, eucomicide. Item 9. The method for promoting production, which is at least one selected from the group consisting of B and eucomicid C.
Item 11. Item 9. The production promoting method according to Item 9 or 10, which is a food or drink or an orally taken drug.
Item 12. Item 8. The method for promoting production according to any one of Items 9 to 11, which promotes the production of propionic acid and / or succinic acid in the intestinal tract.
Item 13. Non-therapeutic use of compounds with an iridoid skeleton to promote the production of short chain fatty acids in the intestinal tract.
Item 14. The compounds having an iridoid skeleton are asperuloside, geniposidic acid, eucomiol, 1-deoxyoicomiol, epioicomiol, asperuloside acid, deacetylasperuloside acid, scandecid 10-O-acetate, oakbin, eucomicide A, eucomicide. Item 3. The non-therapeutic use according to Item 13, which is at least one selected from the group consisting of B and eucomicid C.
Item 15. Item 3. The non-therapeutic use according to Item 13 or 14, which is used for promoting the production of propionic acid and / or succinic acid in the intestinal tract.
Item 16. A compound having an iridoid skeleton used for the treatment of promoting the production of short-chain fatty acids in the intestinal tract.
Item 17. The compounds having an iridoid skeleton are asperuloside, geniposidic acid, eucomiol, 1-deoxyoicomiol, epioicomiol, asperuloside acid, deacetylasperuloside acid, scandecid 10-O-acetate, oakbin, eucomicide A, eucomicide. Item 6. The compound according to Item 16, which is at least one selected from the group consisting of B and eucomicid C.
Item 18. Item 6. The compound according to Item 16 or 17, which is used for promoting the production of propionic acid and / or succinic acid in the intestinal tract.
本発明の短鎖脂肪酸生成促進剤は、腸管内で腸内細菌の代謝産物である短鎖脂肪酸の生成を促進することができる。本発明の短鎖脂肪酸生成促進剤によれば、腸管内での短鎖脂肪酸の生成量を増大させることにより、腸管バリア機能の増強による病原菌の感染予防、アレルギー性炎症の改善等の効果が期待できる。また、本発明の短鎖脂肪酸生成促進剤によれば、腸管内での短鎖脂肪酸の生成量を増大させることにより短鎖脂肪酸受容体を介したシグナル伝達を亢進できるので、生体恒常性機能の改善、ＰＹＹやＧＬＰ－１の分泌促進、インスリン分泌調節、交感神経の賦活化、短鎖脂肪酸受容体を介したシグナル伝達の低下が生じている症状や疾患に対する予防、治療又は改善等の効果が期待できる。
The short-chain fatty acid production promoter of the present invention can promote the production of short-chain fatty acids, which are metabolites of intestinal bacteria, in the intestinal tract. According to the short-chain fatty acid production promoter of the present invention, by increasing the amount of short-chain fatty acid produced in the intestinal tract, it is expected to have effects such as prevention of pathogen infection and improvement of allergic inflammation by enhancing the intestinal barrier function. it can. Further, according to the short-chain fatty acid production promoter of the present invention, signal transduction via the short-chain fatty acid receptor can be enhanced by increasing the amount of short-chain fatty acid produced in the intestinal tract, so that the homeostatic function can be enhanced. Effects such as improvement, promotion of PYY and GLP-1 secretion, regulation of insulin secretion, activation of sympathetic nerves, prevention, treatment or improvement of symptoms and diseases in which signal transduction via short-chain fatty acid receptors is reduced You can expect it.
本発明の短鎖脂肪酸生成促進剤は、腸管内における短鎖脂肪酸の生成促進用途に使用されるものであって、イリドイド骨格を有する化合物を含有することを特徴とする。以下、本発明の短鎖脂肪酸生成促進剤について詳述する。
The short-chain fatty acid production-promoting agent of the present invention is used for promoting the production of short-chain fatty acids in the intestinal tract, and is characterized by containing a compound having an iridoid skeleton. Hereinafter, the short-chain fatty acid production promoter of the present invention will be described in detail.
［イリドイド骨格を有する化合物］
本発明の短鎖脂肪酸生成促進剤は、有効成分として、イリドイド骨格を有する化合物（以下、「イリドイド化合物」と表記することもある）を含有する。 [Compound with iridoid skeleton]
The short-chain fatty acid production promoter of the present invention contains a compound having an iridoid skeleton (hereinafter, may be referred to as "iridoid compound") as an active ingredient.
本発明の短鎖脂肪酸生成促進剤は、有効成分として、イリドイド骨格を有する化合物（以下、「イリドイド化合物」と表記することもある）を含有する。 [Compound with iridoid skeleton]
The short-chain fatty acid production promoter of the present invention contains a compound having an iridoid skeleton (hereinafter, may be referred to as "iridoid compound") as an active ingredient.
イリドイド化合物としては、可食性であるもの又は薬学的に許容されるものであることを限度として、その種類については特に制限されないが、例えば、アスペルロシド、ゲニポシド酸、オイコミオール、1-デオキシオイコミオール、エピオイコミオール、アスペルロシド酸、デアセチルアスペルロシド酸、スキャンデシド１０－Ｏ－アセテート、オークビン、オイコミシドＡ、オイコミシドＢ、オイコミシドＣ等が挙げられる。これらのイリドイド化合物は、１種単独で使用してもよく、また２種以上を組み合わせて使用してもよい。
The type of iridoid compound is not particularly limited as long as it is edible or pharmaceutically acceptable, but for example, asperuloside, geniposidic acid, eucomiol, 1-deoxyoicomiol, Examples thereof include epioicomiol, asperuloside acid, deacetylasperuloside acid, scandecid 10-O-acetate, oakbin, eucomicide A, eucomicide B, and eucomicid C. These iridoid compounds may be used alone or in combination of two or more.
これらのイリドイド化合物の中でも、より一層優れた短鎖脂肪酸生成促進を奏させるという観点から、好ましくはアスペルロシド、ゲニポシド酸、より好ましくはアスペルロシドが挙げられる。
Among these iridoid compounds, asperuloside, geniposidic acid, and more preferably asperuloside are preferable from the viewpoint of promoting even more excellent short-chain fatty acid production.
本発明で使用するイリドイド化合物は、天然物由来のものであってもよく、また化学的に合成されたものであってもよい。更に、本発明で使用するイリドイド化合物は、精製品又は粗精製品のいずれであってもよい。
The iridoid compound used in the present invention may be derived from a natural product or may be chemically synthesized. Furthermore, the iridoid compound used in the present invention may be either a refined product or a crude product.
本発明で使用するイリドイド化合物の好適な例として、天然物由来のイリドイド化合物の精製品又は粗精製品、及びイリドイド化合物を含む天然物の加工処理物が挙げられる。
Preferable examples of the iridoid compound used in the present invention include refined or crude products of iridoid compounds derived from natural products, and processed products of natural products containing iridoid compounds.
アスペルロシド等のイリドイド化合物を含む天然物としては、例えば、杜仲（Eucommia ulmoides）、オオバコ（Plantago lanceolata）、ノニ（Morinda citrifolia）等の植物が挙げられる。当該植物は、栽培により生産されたものであっても天然より採取されたものであってもよい。使用する植物の部位は、イリドイド化合物を含む部位であれば制限されず、全草、花、果実、葉、枝、樹皮、根茎、種子のいずれも使用できる。杜仲の場合は、好ましくは葉が例示され、オオバコの場合は、好ましくは種子が挙げられ、ノニの場合は、好ましくは葉が挙げられる。
Examples of natural products containing iridoid compounds such as asperuloside include plants such as Eucommia ulmoides, Plantago lanceolata, and Noni (Morinda citrifolia). The plant may be cultivated or naturally harvested. The part of the plant to be used is not limited as long as it contains an iridoid compound, and any of whole plant, flower, fruit, leaf, branch, bark, rhizome, and seed can be used. In the case of Eucommia ulmoides, leaves are preferably exemplified, in the case of plantain, seeds are preferably mentioned, and in the case of noni, leaves are preferably mentioned.
イリドイド化合物を含む天然物の加工処理物としては、具体的には、前記天然物の乾燥物、粉砕物（生及び乾燥物を含む）、エキス等が挙げられる。これら加工処理物の中でも、好ましくはエキスが挙げられる。また、エキスは、非濃縮エキス（濃縮処理されていないもの）、軟エキス（つまり液状濃縮物）、エキス末（つまり乾燥物）等のいずれであってもよい。
Specific examples of the processed product of a natural product containing an iridoid compound include a dried product of the natural product, a crushed product (including raw and dried products), and an extract. Among these processed products, an extract is preferable. Further, the extract may be any of non-concentrated extract (not concentrated), soft extract (that is, liquid concentrate), extract powder (that is, dried product) and the like.
イリドイド化合物を含む天然物の加工処理物の中でも、イリドイド化合物を所定量で含ませることが容易な点で、好ましくは杜仲葉エキスが挙げられる。杜仲葉エキスは、例えば、杜仲葉をそのままの生の状態で、又は、必要に応じて、粉砕、切断、蒸熱、揉捻、乾燥、焙煎等の前処理を行った後に、抽出処理を行うことによって得ることができる。抽出処理については、植物抽出物の製造に使用される一般的な抽出手法であればよく、例えば、溶媒抽出処理、超臨界抽出処理、水蒸気蒸留処理等が挙げられる。これらの中でも、好ましくは溶媒抽出処理が挙げられる。
Among the processed natural products containing the iridoid compound, the eucommia leaf extract is preferable because it is easy to contain the iridoid compound in a predetermined amount. Tochu leaf extract is extracted, for example, in the raw state of Tochu leaf, or after pretreatment such as crushing, cutting, steaming, kneading, drying, and roasting, if necessary. Can be obtained by. The extraction treatment may be any general extraction method used for producing plant extracts, and examples thereof include solvent extraction treatment, supercritical extraction treatment, and steam distillation treatment. Among these, solvent extraction treatment is preferable.
杜仲葉エキスの溶媒抽出処理に使用される抽出溶媒としては、水（温水及び熱水を含む）、有機溶媒（メタノール、エタノール、ｎ－プロパノール、イソプロパノール、ｎ－ブタノール等の炭素数１～４の低級アルコール；プロピレングリコール、１，３－ブチレングリコール等の多価アルコール；アセトン等のケトン類；ジエチルエーテル、ジオキサン、アセトニトリル、酢酸エチルエステル等のエステル類；キシレン、ベンゼン、クロロホルム等）、これらの混合液が挙げられ、好ましくは、水、低級アルコール、これらの混合液が挙げられ、より好ましくは、温水、熱水等の加熱水が挙げられ、更に好ましくは熱水が挙げられる。これらの溶媒は１種単独で用いてもよく、２種以上を組み合わせて用いてもよい。
The extraction solvent used for the solvent extraction treatment of Tochu leaf extract includes water (including hot water and hot water), organic solvent (methanol, ethanol, n-propanol, isopropanol, n-butanol, etc.) having 1 to 4 carbon atoms. Lower alcohols; polyhydric alcohols such as propylene glycol, 1,3-butylene glycol; ketones such as acetone; esters such as diethyl ether, dioxane, acetonitrile, ethyl acetate ester; xylene, benzene, chloroform, etc.), a mixture thereof Examples thereof include water, lower alcohol, and a mixed solution thereof, more preferably heated water such as hot water and hot water, and further preferably hot water. These solvents may be used alone or in combination of two or more.
杜仲葉エキスの溶媒抽出処理における具体的な抽出条件は、イリドイド化合物を抽出できる条件であれば特に制限されない。例えば、抽出溶媒として水を用いる場合、水に浸漬させる方法が挙げられる。浸漬中、必要に応じて攪拌を行ってもよい。水の量は、例えば杜仲葉１重量部（乾燥重量基準）に対して、１０～８００重量部、好ましくは１０～７００重量部、より好ましくは１０～５００重量部の割合になるように調整することができる。抽出時の水の温度としては、例えば２０～１００℃程度、好ましくは７０～９８℃程度が挙げられ、抽出時間としては、１～６０分、好ましくは５～４０分、より好ましくは１０～４０分が挙げられる。その後、固液分離を行うことで固形物を取り除き、抽出物を取得することができる。固液分離法としては常法を用いることができ、例えば濾過や遠心分離法等が挙げられる。また、一度抽出処理に供した杜仲葉は、再度抽出処理に供してもよい。
The specific extraction conditions in the solvent extraction treatment of Eucommia leaf extract are not particularly limited as long as the iridoid compound can be extracted. For example, when water is used as the extraction solvent, a method of immersing it in water can be mentioned. If necessary, stirring may be performed during the immersion. The amount of water is adjusted to be, for example, 10 to 800 parts by weight, preferably 10 to 700 parts by weight, and more preferably 10 to 500 parts by weight with respect to 1 part by weight of Tochu leaf (based on dry weight). be able to. The temperature of water at the time of extraction is, for example, about 20 to 100 ° C., preferably about 70 to 98 ° C., and the extraction time is 1 to 60 minutes, preferably 5 to 40 minutes, more preferably 10 to 40 minutes. Minutes can be mentioned. After that, the solid matter can be removed and the extract can be obtained by performing solid-liquid separation. As the solid-liquid separation method, a conventional method can be used, and examples thereof include a filtration method and a centrifugation method. In addition, the Tochu leaf that has been subjected to the extraction treatment once may be subjected to the extraction treatment again.
抽出処理により得られた抽出物は、必要に応じて、濾過処理；ポリスチレンゲル（ポリスチレン・ジビニルベンゼン共重合体等）、イオン交換樹脂、活性炭等の担体を充填したカラムを用いた各種クロマトグラフィー等の吸着処理に供してイリドイド化合物の精製度を高めてもよい。抽出処理により得られた抽出物は、濃縮工程を経ずにそのまま非濃縮エキスとして使用してもよく、また濃縮工程に供して軟エキスとして使用したり、更に乾燥工程に供してエキス末として使用したりしてもよい。
The extract obtained by the extraction treatment is filtered as necessary; various chromatographies using a column packed with a carrier such as polystyrene gel (polystyrene / divinylbenzene copolymer, etc.), ion exchange resin, activated charcoal, etc. The degree of purification of the iridoid compound may be increased by subjecting it to the adsorption treatment of. The extract obtained by the extraction treatment may be used as a non-concentrated extract as it is without undergoing the concentration step, may be used as a soft extract in the concentration step, or may be used as an extract powder in the drying step. You may do it.
［剤型・形態・用途］
本発明の短鎖脂肪酸生成促進剤の剤型については、特に限定されず、固体状、半固体状、又は液体状のいずれであってもよい。 [Dosage form / form / use]
The dosage form of the short-chain fatty acid production promoter of the present invention is not particularly limited, and may be solid, semi-solid, or liquid.
本発明の短鎖脂肪酸生成促進剤の剤型については、特に限定されず、固体状、半固体状、又は液体状のいずれであってもよい。 [Dosage form / form / use]
The dosage form of the short-chain fatty acid production promoter of the present invention is not particularly limited, and may be solid, semi-solid, or liquid.
本発明の短鎖脂肪酸生成促進剤は、腸内に移行される形態であればよく、経口摂取又は経口投与される形態であることが好ましいが、経腸投与される形態のものであってもよい。
The short-chain fatty acid production promoter of the present invention may be in the form of being transferred into the intestine, preferably in the form of oral ingestion or oral administration, but may be in the form of enteral administration. Good.
本発明の短鎖脂肪酸生成促進剤の形態として、具体的には、飲食品及び内服用医薬品（内服用の医薬部外品を含む）が挙げられる。
Specific examples of the form of the short-chain fatty acid production promoter of the present invention include foods and drinks and pharmaceutical products for internal use (including quasi-drugs for internal use).
本発明の短鎖脂肪酸生成促進剤を飲食品の形態にする場合（即ち、アルツハイマー病の予防用の飲食品として提供する場合）、イリドイド化合物を、そのまま又は他の食品素材や添加成分と組み合わせて所望の形態に調製すればよい。このような飲食品としては、一般の飲食品の他、保健機能食品（特定保健用食品、栄養機能食品、サプリメント等を含む）、病者用食品等の食品等が挙げられる。これらの飲食品の形態として、特に限定されないが、具体的には、茶飲料、栄養ドリンク、果汁飲料、炭酸飲料、乳酸飲料等の飲料；カプセル剤（ソフトカプセル剤、ハードカプセル剤）、錠剤、顆粒剤、粉剤、ゼリー剤、リポソーム製剤等のサプリメント；グミ、キャンディー、ゼリー等の嗜好品等が挙げられる。これらの飲食品の中でも、好ましくは飲料、より好ましくは杜仲茶エキスを含む茶飲料が挙げられる。
When the short-chain fatty acid production promoter of the present invention is formed into a food or drink form (that is, when it is provided as a food or drink for the prevention of Alzheimer's disease), the iridoid compound is used as it is or in combination with other food materials or additive components. It may be prepared in a desired form. Examples of such foods and drinks include general foods and drinks, foods with health claims (including foods for specified health use, foods with nutritional claims, supplements, etc.), foods for the sick, and the like. The form of these foods and drinks is not particularly limited, but specifically, beverages such as tea beverages, energy drinks, fruit juice beverages, carbonated beverages, and lactic acid beverages; capsules (soft capsules, hard capsules), tablets, granules. , Supplements such as powders, jellies, and liposome preparations; and luxury products such as gummies, candies, and jellies. Among these foods and drinks, a beverage is preferable, and a tea beverage containing Tochu tea extract is more preferable.
本発明の短鎖脂肪酸生成促進剤を内服用医薬品（内服用の医薬部外品を含む）の製剤形態にする場合、イリドイド化合物を、そのまま又は他の添加剤等と組み合わせて所望の形態に調製すればよい。このような内服用医薬品としては、具体的には、ドリンク剤、錠剤、丸剤、散剤、細粒剤、顆粒剤、カプセル剤（ハードカプセル及びソフトカプセルを含む）、トローチ剤、チュアブル剤、エキス剤（軟エキス剤、乾燥エキス剤等を含む）、ゼリー剤、シロップ剤、酒精剤、エリキシル剤、リポソーム製剤等が挙げられる。
When the short-chain fatty acid production promoter of the present invention is used as a formulation form of an internal drug (including a quasi-drug for internal use), the iridoid compound is prepared as it is or in combination with other additives to a desired form. do it. Specific examples of such internal medicines include drinks, tablets, pills, powders, fine granules, granules, capsules (including hard capsules and soft capsules), troches, chewables, and extracts (extracts). (Including soft extracts, dry extracts, etc.), jelly agents, syrup agents, alcoholic agents, elixir agents, liposome preparations, and the like.
本発明の短鎖脂肪酸生成促進剤において、イリドイド化合物の含有量は、対象者の体格、年齢、症状、腸管内での短鎖脂肪酸の生成の程度、短鎖脂肪酸生成促進剤の形態等を勘案して、１日当たりのイリドイド化合物の摂取・投与量を踏まえて適宜設定すればよい。１日当たりのイリドイド化合物の摂取・投与量としては、イリドイド化合物の総量で１５～５００ｍｇ程度、好ましくは３０～３００ｍｇ程度、より好ましくは５０～１５０ｍｇ程度となるように設定すればよい。本発明の短鎖脂肪酸生成促進剤は、１日当たり１回、又は１日当たり複数回に分けて摂取又は投与すればよいが、好ましくは、１日当たり１～３回である。
In the short-chain fatty acid production promoter of the present invention, the content of the iridoid compound takes into consideration the physique, age, symptoms of the subject, the degree of production of short-chain fatty acids in the intestinal tract, the form of the short-chain fatty acid production promoter, and the like. Then, it may be appropriately set based on the daily intake / dose of the iridoid compound. The daily intake / dose of the iridoid compound may be set so that the total amount of the iridoid compound is about 15 to 500 mg, preferably about 30 to 300 mg, and more preferably about 50 to 150 mg. The short-chain fatty acid production promoter of the present invention may be ingested or administered once a day or in a plurality of times a day, preferably 1 to 3 times a day.
より具体的には、本発明の短鎖脂肪酸生成促進剤を飲料の製剤形態にする場合であれば、イリドイド化合物の含有量として、例えば、イリドイド化合物の総量で０．０００７５～１％程度、好ましくは０．００１５～０．６重量％程度、より好ましくは０．００２５～０．３重量％程度が挙げられる。
More specifically, when the short-chain fatty acid production promoter of the present invention is used as a beverage formulation, the content of the iridoid compound is preferably, for example, about 0.00075 to 1% in total amount of the iridoid compound. Is about 0.0015 to 0.6% by weight, more preferably about 0.0025 to 0.3% by weight.
また、本発明の短鎖脂肪酸生成促進剤を錠剤、丸剤、散剤、細粒剤、顆粒剤、カプセル剤、トローチ剤、チュアブル剤等の固形状製剤にする場合であれば、イリドイド化合物の含有量として、例えば、イリドイド化合物の総量で５～９５重量％程度、好ましくは１０～８０重量％程度、より好ましくは１５～６５重量％程度が挙げられる。
In addition, when the short-chain fatty acid production promoter of the present invention is made into a solid preparation such as tablets, pills, powders, fine granules, granules, capsules, troches, chewables, etc., it contains an iridoid compound. As the amount, for example, the total amount of the iridoid compound is about 5 to 95% by weight, preferably about 10 to 80% by weight, and more preferably about 15 to 65% by weight.
本発明の短鎖脂肪酸生成促進剤は、腸管内の短鎖脂肪酸の生成を促進する用途に使用される。即ち、本発明の短鎖脂肪酸生成促進剤は、腸管内の短鎖脂肪酸の生成促進が必要とされる対象者に対して使用される。本発明において、短鎖脂肪酸とは、腸内細菌の代謝産物として生じる短鎖脂肪酸であり、具体的には、酢酸、プロピオン酸、酪酸、コハク酸等の炭素数が１～６の短鎖脂肪酸である。本発明の短鎖脂肪酸生成促進剤は、短鎖脂肪酸の中でも、特にプロピオン酸及びコハク酸の生成促進効果に優れているので、腸管内におけるプロピオン酸の生成促進用途、及び／又は腸管内におけるコハク酸の生成促進用途に特に好適である。
The short-chain fatty acid production promoter of the present invention is used for promoting the production of short-chain fatty acids in the intestinal tract. That is, the short-chain fatty acid production promoter of the present invention is used for a subject who needs to promote the production of short-chain fatty acids in the intestinal tract. In the present invention, the short-chain fatty acid is a short-chain fatty acid produced as a metabolite of intestinal bacteria, and specifically, a short-chain fatty acid having 1 to 6 carbon atoms such as acetic acid, propionic acid, butyric acid, and succinic acid. Is. The short-chain fatty acid production-promoting agent of the present invention is particularly excellent in promoting the production of propionic acid and succinic acid among short-chain fatty acids, and therefore is used for promoting the production of propionic acid in the intestinal tract and / or succinic acid in the intestinal tract. It is particularly suitable for applications that promote the production of acids.
また、腸管内における短鎖脂肪酸の生成量の増大は、腸管バリア機能を増強させ、病原菌の感染予防や、腸管におけるアレルギー性炎症の改善に有効であるので、本発明の短鎖脂肪酸生成促進剤は、腸管バリア機能の増強用途；腸管を介した病原菌の感染予防用途；腸管におけるアレルギー性炎症の改善用途等に使用することができる。即ち、本発明の短鎖脂肪酸生成促進剤の一態様では、例えば、腸管バリア機能の増強が求められる者、腸管バリア機能が低下している者、病原菌が腸管に感染している者、腸管におけるアレルギー性炎症がある者等を対象者とすることができる。
Further, an increase in the amount of short-chain fatty acid produced in the intestinal tract enhances the intestinal barrier function, is effective in preventing infection with pathogens and improving allergic inflammation in the intestinal tract. Therefore, the short-chain fatty acid production promoter of the present invention is effective. Can be used for enhancing the intestinal barrier function; for preventing infection of pathogens via the intestinal tract; for improving allergic inflammation in the intestinal tract, and the like. That is, in one aspect of the short-chain fatty acid production promoter of the present invention, for example, in a person who is required to enhance the intestinal barrier function, a person who has a deteriorated intestinal barrier function, a person who is infected with a pathogen in the intestinal tract, and a person in the intestinal tract. Persons with allergic inflammation can be targeted.
また、高脂肪食は、腸管内における短鎖脂肪酸の生成量の低下を招くため、本発明の短鎖脂肪酸生成促進剤は、高脂肪食摂取による短鎖脂肪酸生成量の低下抑制の用途にも使用することができる。ここで、高脂肪食とは、総摂取エネルギーの内、脂肪が占める割合（脂肪重量比率）が３０％以上である食品である。即ち、本発明の短鎖脂肪酸生成促進剤の一形態では、例えば、高脂肪食の摂取の２時間前以内及び／又は脂肪食の摂取から２時間後以内に、投与又は摂取される。
Further, since a high-fat diet causes a decrease in the amount of short-chain fatty acid produced in the intestinal tract, the short-chain fatty acid production promoter of the present invention is also used for suppressing a decrease in the amount of short-chain fatty acid produced by ingesting a high-fat diet. Can be used. Here, the high-fat diet is a food in which fat accounts for 30% or more of the total energy intake (fat weight ratio). That is, in one form of the short-chain fatty acid production promoter of the present invention, for example, it is administered or ingested within 2 hours before ingestion of a high-fat diet and / or within 2 hours after ingestion of a fat diet.
また、腸管内における短鎖脂肪酸の生成量の増大は、腸管内での短鎖脂肪酸受容体を介したシグナル伝達の亢進だけでなく、血中に移行する短鎖脂肪酸量を増加させ、その結果、全身での鎖脂肪酸受容体を介したシグナル伝達の亢進をもたらし得る。そのため、本発明の短鎖脂肪酸生成促進剤は、腸管だけでなく生体全体における短鎖脂肪酸受容体を介したシグナル伝達の亢進に基づく効果を享受させることができる。即ち、本発明の短鎖脂肪酸生成促進剤の一形態では、例えば、短鎖脂肪酸受容体を介したシグナル伝達の亢進が必要とされている者を対象者とすることもできる。
In addition, an increase in the amount of short-chain fatty acids produced in the intestinal tract not only enhances signal transduction via short-chain fatty acid receptors in the intestinal tract, but also increases the amount of short-chain fatty acids transferred into the blood, resulting in an increase. , Can result in enhanced signal transduction via chain fatty acid receptors throughout the body. Therefore, the short-chain fatty acid production promoter of the present invention can enjoy the effect based on the enhancement of signal transduction via the short-chain fatty acid receptor not only in the intestinal tract but also in the whole body. That is, in one form of the short-chain fatty acid production promoter of the present invention, for example, a person who is required to enhance signal transduction via a short-chain fatty acid receptor can be targeted.
例えば、短鎖脂肪酸受容体（ＧＰＲ４１、ＧＰＲ４３、ＧＰＲ９１、ＧＰＲ１０９ａ、及びＯｌｆｒ７８）を介したシグナル伝達の亢進は、生体恒常性機能の亢進をもたらし得るので、本発明の短鎖脂肪酸生成促進剤は、生体恒常性機能の亢進用途；短鎖脂肪酸受容体を介したシグナル伝達の低下が生じている症状や疾患に対する予防、治療又は改善用途等に使用することができる。即ち、本発明の短鎖脂肪酸生成促進剤の一形態では、例えば、生体恒常性機能の亢進が必要とされる者、生体恒常性機能が低下している者、短鎖脂肪酸受容体を介したシグナル伝達の低下が生じている症状や疾患を有する者等を対象者とすることもできる。
For example, enhanced signal transduction via short-chain fatty acid receptors (GPR41, GPR43, GPR91, GPR109a, and Olfr78) can result in enhanced homeostatic function, so the short-chain fatty acid production promoter of the present invention is: Applications for enhancing homeostatic function; It can be used for prevention, treatment or improvement of symptoms and diseases in which signal transduction via short-chain fatty acid receptors is reduced. That is, in one form of the short-chain fatty acid production promoter of the present invention, for example, a person who is required to enhance the homeostatic function, a person who has a decreased homeostatic function, or a short-chain fatty acid receptor is mediated. It is also possible to target persons with symptoms or diseases in which signal transmission is reduced.
ＧＰＲ４１及びＧＰＲ４３を介したシグナル伝達の亢進は、腸管内でのＰＹＹやＧＬＰ－１の分泌促進をもたらすので、本発明の短鎖脂肪酸生成促進剤は、腸管内でのＰＹＹの分泌促進用途；ＰＹＹの分泌能低下が生じている症状や疾患に対する予防、治療又は改善用途；腸管内でのＧＬＰ－１の分泌促進用途；ＧＬＰ－１の分泌能低下が生じている症状や疾患に対する予防、治療又は改善用途等に使用することもできる。即ち、本発明の短鎖脂肪酸生成促進剤の一形態では、例えば、腸管内でのＰＹＹの分泌促進が必要とされる者、腸管内でのＰＹＹの分泌能が低下している者、腸管内でのＰＹＹの分泌低下が生じている症状や疾患を有する者等を対象者とすることもできる。
Since the enhancement of signal transduction via GPR41 and GPR43 leads to the promotion of PYY and GLP-1 secretion in the intestinal tract, the short-chain fatty acid production promoter of the present invention is used for promoting the secretion of PYY in the intestinal tract; Preventive, therapeutic or ameliorating use for symptoms or diseases with decreased secretory capacity; use for promoting GLP-1 secretion in the intestinal tract; prevention, treatment or improvement for symptoms or diseases with decreased secretory capacity of GLP-1 It can also be used for improvement purposes. That is, in one form of the short-chain fatty acid production promoter of the present invention, for example, a person who needs to promote the secretion of PYY in the intestinal tract, a person who has a decreased secretory ability of PYY in the intestinal tract, and a person in the intestinal tract. It is also possible to target a person having a symptom or a disease in which the secretion of PYY is decreased in the above.
また、ＧＰＲ４１及びＧＰＲ４３を介したシグナル伝達は、膵臓でのインスリン分泌調節にも関与しているので、本発明の短鎖脂肪酸生成促進剤は、インスリン分泌調節用途；２型糖尿病の予防、治療又は改善用途等に使用することもできる。即ち、本発明の短鎖脂肪酸生成促進剤の一形態では、例えば、インスリン分泌調節が必要とされる者、２型糖尿病を罹患している者等を対象者とすることもできる。
In addition, since signal transduction via GPR41 and GPR43 is also involved in the regulation of insulin secretion in the pancreas, the short-chain fatty acid production promoter of the present invention is used for insulin secretion regulation; prevention, treatment or treatment of type 2 diabetes. It can also be used for improvement purposes. That is, in one form of the short-chain fatty acid production promoter of the present invention, for example, a person who is required to regulate insulin secretion, a person suffering from type 2 diabetes, or the like can be targeted.
更に、交感神経節で発現しているＧＰＲ４３を介したシグナル伝達の亢進は、交感神経を賦活化し、ノルアドレナリンの分泌促進をもたらすので、本発明の短鎖脂肪酸生成促進剤は、交感神経を賦活化用途；ノルアドレナリンの分泌促進用途等にも使用することができる。即ち、本発明の短鎖脂肪酸生成促進剤の一形態では、例えば、交感神経を賦活化が求められる者、交感神経の機能が低下している者、ノルアドレナリンの分泌促進が求められる者、ノルアドレナリンの分泌能が低下している者等を対象者とすることもできる。
Furthermore, the enhancement of signal transduction mediated by GPR43 expressed in the sympathetic ganglion activates the sympathetic nerve and promotes the secretion of noradrenaline. Therefore, the short-chain fatty acid production promoter of the present invention activates the sympathetic nerve. Applications: It can also be used for promoting the secretion of noradrenaline. That is, in one form of the short-chain fatty acid production promoter of the present invention, for example, a person who is required to activate the sympathetic nerve, a person whose sympathetic nerve function is deteriorated, a person who is required to promote the secretion of noradrenaline, and a noradrenaline. It is also possible to target persons with reduced secretory capacity.
以下に実施例を示して本発明をより具体的に説明するが、本発明はこれらに限定されるものではない。
The present invention will be described in more detail with reference to Examples below, but the present invention is not limited thereto.
試験例１
５週齢の雄マウス（Ｃ５７／６Ｊ、日本チャールス・リバー株式会社）を３群に分け、各群のマウスに対して表１に示す組成の飼料を給餌して１2週間飼育した。 Test Example 1
Five-week-old male mice (C57 / 6J, Charles River Co., Ltd., Japan) were divided into three groups, and the mice in each group were fed the feed having the composition shown in Table 1 and bred for 12 weeks.
５週齢の雄マウス（Ｃ５７／６Ｊ、日本チャールス・リバー株式会社）を３群に分け、各群のマウスに対して表１に示す組成の飼料を給餌して１2週間飼育した。 Test Example 1
Five-week-old male mice (C57 / 6J, Charles River Co., Ltd., Japan) were divided into three groups, and the mice in each group were fed the feed having the composition shown in Table 1 and bred for 12 weeks.
１１日間飼育後に各マウスを解剖して盲腸内容物を採取し、以下の方法でメタボローム解析によりコハク酸及びプロピオン酸量を測定した。先ず、採取した盲腸内容物を凍結乾燥し、凍結乾燥物に対して、３ｍｍジルコニアビーズ３個を入れ、破砕機で破砕した。破砕後のサンプルを１０ｍｇ量りとった後、０．１mmジルコニアビーズ１００mgを入れ、更に５００μＬの内部標準物質（methionine sulfone、D-camphor-10-sulfonic acid）を添加し、破砕機にて１５００ｒｐｍ、５分間破砕した。その後、サンプルに５００μＬのクロロホルム、及び超純水２００μＬを添加し、破砕機にて１５００ｒｐｍ、５分間処理した。得られたサンプルを遠心機にて４℃、４６００ｇ、３０分間遠心分離し、分離された上清を分画分子量５ｋＤａの限外濾過フィルターチューブへ移し、遠心機にて４℃、９１００ｇ、３～７時間遠心分離し、タンパク質の除去を行なった。回収した濾液は、真空乾燥機で４０℃、３時間乾固させたのち、５０μＬの超純水に再溶解し、代謝産物抽出液を得た。得られた代謝産物抽出液はＣＥ－ＴＯＦＭＳ（ａｇｉｌｅｎｔ Ｔｅｃｈｎｏｌｏｇｉｅｓ社）の陽イオンモードで分析を行った。分析条件は文献［Hirayama, A. et al., Cancer Res.69, 4918 LP - 4925. 2009］に記載の条件に基づいて測定を行なった。また、測定後のデータは、解析ソフトウェア（Master Hands、Human Metabolome. Technologies, Inc.; Sugimoto et al., 2010）を用いて、代謝物質であるコハク酸及びプロピオン酸の同定及び濃度（盲腸内容物の乾燥重量１ｇ当たりのモル数）の算出を行なった。
After breeding for 11 days, each mouse was dissected and the contents of the cecum were collected, and the amounts of succinic acid and propionic acid were measured by metabolome analysis by the following method. First, the collected cecal contents were freeze-dried, three 3 mm zirconia beads were added to the freeze-dried material, and the contents were crushed by a crusher. After weighing 10 mg of the crushed sample, add 100 mg of 0.1 mm zirconia beads, add 500 μL of internal standard substances (methionine sulfone, D-camphor-10-sulfonic acid), and use a crusher at 1500 rpm, 5 Crushed for minutes. Then, 500 μL of chloroform and 200 μL of ultrapure water were added to the sample, and the sample was treated with a crusher at 1500 rpm for 5 minutes. The obtained sample is centrifuged at 4 ° C., 4600 g for 30 minutes in a centrifuge, the separated supernatant is transferred to an ultrafiltration filter tube having a molecular weight cut off of 5 kDa, and the separated supernatant is transferred to an ultrafiltration filter tube at 4 ° C., 9100 g, 3 to 3 to Centrifuge for 7 hours to remove protein. The recovered filtrate was dried at 40 ° C. for 3 hours in a vacuum dryer and then redissolved in 50 μL of ultrapure water to obtain a metabolite extract. The obtained metabolite extract was analyzed in the cation mode of CE-TOFMS (agilent Technologies). The analysis conditions were measured based on the conditions described in the literature [Hirayama, A. et al., Cancer Res. 69, 4918 LP-4925. 2009]. In addition, the data after measurement is the identification and concentration of metabolites succinic acid and propionic acid (cecal contents) using analysis software (MasterHands, HumanMetabolome. Technologies, Inc .; Sugimoto et al., 2010). The number of moles per 1 g of dry weight) was calculated.
得られた結果を表２及び３に示す。高脂肪食群では、コントロール食群に比べて、コハク酸及びプロピオン酸の生成量が低下していた。これに対して、高脂肪食＋アスペルロシド群では、コントロール食群に比べて、コハク酸及びプロピオン酸の生成量が増加していた。これらの結果から、アスペルロシドには、腸管内で短鎖脂肪酸の生成を促進する作用があることが明らかとなった。
The results obtained are shown in Tables 2 and 3. In the high-fat diet group, the amounts of succinic acid and propionic acid produced were lower than those in the control diet group. On the other hand, in the high-fat diet + asperuloside group, the amounts of succinic acid and propionic acid produced were increased as compared with the control diet group. From these results, it was clarified that asperuloside has an action of promoting the production of short-chain fatty acids in the intestinal tract.
試験例２
５週齢の雄マウス（Ｃ５７／６Ｊ、日本チャールス・リバー株式会社）を４群に分け、各群のマウスに対して表４に示す組成の飼料を給餌して９週間飼育した。 Test Example 2
Five-week-old male mice (C57 / 6J, Nippon Charles River Co., Ltd.) were divided into four groups, and the mice in each group were fed the feed having the composition shown in Table 4 and bred for 9 weeks.
５週齢の雄マウス（Ｃ５７／６Ｊ、日本チャールス・リバー株式会社）を４群に分け、各群のマウスに対して表４に示す組成の飼料を給餌して９週間飼育した。 Test Example 2
Five-week-old male mice (C57 / 6J, Nippon Charles River Co., Ltd.) were divided into four groups, and the mice in each group were fed the feed having the composition shown in Table 4 and bred for 9 weeks.
９週間飼育後の各マウスを６時間絶食させた後にグルコースを１．５ｇ／Ｋｇ体重で経口投与し、その１０分後に血液を採取して、血中の活性型ＧＬＰ－１濃度を、ELIZAキット(「GLP-1, Active form Assay Kit-IBL」、株式会社免疫生物研究所)を用いて測定を行った。
After each mouse after 9 weeks of breeding was fasted for 6 hours, glucose was orally administered at a body weight of 1.5 g / Kg, and 10 minutes later, blood was collected to obtain the active GLP-1 concentration in the blood by using the ELIZA kit. Measurements were performed using (“GLP-1, Activeform Assay Kit-IBL”, Immuno-Biological Laboratory Co., Ltd.).
得られた結果を表５に示す。この結果、コントロール食群及び高脂肪食群では、ＧＬＰ－１の分泌量に殆ど変化はなかったが、高脂肪食＋アスペルロシド0.125％群、及び高脂肪食＋アスペルロシド0.5％群では、コントロール食群及び高脂肪食群に比べて、ＧＬＰ－１の分泌量が増加していた。即ち、高脂肪食＋アスペルロシド0.125％群、及び高脂肪食＋アスペルロシド0.5％群では、腸管内における短鎖脂肪酸の生成量の増大により、ＧＰＲ４１及びＧＰＲ４３が刺激され、その結果、ＧＬＰ－１の分泌量が増加したと考えられる。
The results obtained are shown in Table 5. As a result, there was almost no change in the amount of GLP-1 secreted in the control diet group and the high-fat diet group, but in the high-fat diet + asperuloside 0.125% group and the high-fat diet + asperloside 0.5% group, the control diet group. And, the amount of GLP-1 secreted was increased as compared with the high-fat diet group. That is, in the high-fat diet + asperuloside 0.125% group and the high-fat diet + asperuloside 0.5% group, GPR41 and GPR43 were stimulated by the increase in the amount of short-chain fatty acids produced in the intestinal tract, and as a result, GLP-1 was secreted. It is believed that the amount has increased.
試験例３
９名の被験者（ＢＭＩ値２５～３０、４０歳以上の男女）に、１日１回の頻度で４週間、表６に示す組成の錠剤を摂取させた。
Test Example 3
Nine subjects (BMI values 25 to 30, men and women over 40 years old) were allowed to ingest tablets having the composition shown in Table 6 once a day for 4 weeks.
９名の被験者（ＢＭＩ値２５～３０、４０歳以上の男女）に、１日１回の頻度で４週間、表６に示す組成の錠剤を摂取させた。
Nine subjects (BMI values 25 to 30, men and women over 40 years old) were allowed to ingest tablets having the composition shown in Table 6 once a day for 4 weeks.
錠剤の摂取前と摂取開始から８週間後に、表７に示す自覚症状について問診を行い、１～５点の５段階（１全くなし, ２ほとんどなし, ３少しあり, ４中等度あり, ５高度にあり）で評点化した。この基準では、評点１及び２は問題なし、評点３は症状傾向があるが観察指導、評点４及び５は治療が必要、と判断できる。また、表７に示す自覚症状は、いずれも、腸管内での短鎖脂肪酸生成促進作用の副次効果によって改善が期待できるものである。
Before taking the tablets and 8 weeks after the start of taking the tablets, we asked about the subjective symptoms shown in Table 7 and asked 5 grades of 1 to 5 points (1 none, 2 almost none, 3 a little, 4 moderate, 5 advanced. It was scored in). According to this criterion, it can be judged that the scores 1 and 2 have no problem, the scores 3 tend to be symptomatic, but observation guidance is required, and the scores 4 and 5 require treatment. In addition, all of the subjective symptoms shown in Table 7 can be expected to be improved by the side effect of the short-chain fatty acid production promoting action in the intestinal tract.
被験者の各自覚症状の点数を平均した値を表７に示す。この結果から、アスペルロシド及びゲニポシド酸を摂取することにより、腸管内での短鎖脂肪酸の生成量が増大したことが示唆された。
Table 7 shows the average value of the scores of each subjective symptom of the subject. From this result, it was suggested that the amount of short-chain fatty acids produced in the intestinal tract was increased by ingesting asperuloside and geniposidic acid.
処方例
表８～１０に示す１日摂取量となるようにイリドイド化合物が含有させた飲食品又は内服用医薬品は、腸管内の短鎖脂肪酸の生成を促進する効果が期待できる。 Prescription Examples Foods and drinks or oral medicines containing iridoid compounds so as to have a daily intake shown in Tables 8 to 10 can be expected to have an effect of promoting the production of short-chain fatty acids in the intestinal tract.
表８～１０に示す１日摂取量となるようにイリドイド化合物が含有させた飲食品又は内服用医薬品は、腸管内の短鎖脂肪酸の生成を促進する効果が期待できる。 Prescription Examples Foods and drinks or oral medicines containing iridoid compounds so as to have a daily intake shown in Tables 8 to 10 can be expected to have an effect of promoting the production of short-chain fatty acids in the intestinal tract.
Claims (7)
- イリドイド骨格を有する化合物の、腸管内における短鎖脂肪酸の生成促進剤の製造のための使用。 Use of a compound having an iridoid skeleton for the production of a short-chain fatty acid production promoter in the intestinal tract.
- 前記イリドイド骨格を有する化合物が、アスペルロシド、ゲニポシド酸、オイコミオール、1-デオキシオイコミオール、エピオイコミオール、アスペルロシド酸、デアセチルアスペルロシド酸、スキャンデシド１０－Ｏ－アセテート、オークビン、オイコミシドＡ、オイコミシドＢ、及びオイコミシドＣよりなる群から選択される少なくとも１種である、請求項１に記載の使用。 The compounds having an iridoid skeleton are asperuloside, geniposidic acid, eucomiol, 1-deoxyoicomiol, epioicomiol, asperuloside acid, deacetylasperuloside acid, scandecid 10-O-acetate, oakbin, eucomicide A, eucomicide The use according to claim 1, which is at least one selected from the group consisting of B and eucomicid C.
- 飲食品、又は内服用医薬品である、請求項１又は２に記載の使用。 Use according to claim 1 or 2, which is a food or drink or an internal medicine.
- 前記生成促進剤が、腸管内におけるプロピオン酸及び／又はコハク酸の生成促進のために用いられる、請求項１又は２に記載の使用。 The use according to claim 1 or 2, wherein the production promoter is used for promoting the production of propionic acid and / or succinic acid in the intestinal tract.
- イリドイド骨格を有する化合物を、腸管内における短鎖脂肪酸の生成促進が必要とされる者に投与又は摂取させる、腸管内における短鎖脂肪酸の生成促進方法。 A method for promoting the production of short-chain fatty acids in the intestinal tract, in which a compound having an iridoid skeleton is administered or ingested by a person who needs to promote the production of short-chain fatty acids in the intestinal tract.
- イリドイド骨格を有する化合物の、腸管内における短鎖脂肪酸の生成促進のための非治療的使用。 Non-therapeutic use of compounds with an iridoid skeleton to promote the production of short-chain fatty acids in the intestinal tract.
- 腸管内における短鎖脂肪酸の生成促進の処置のために使用されるイリドイド骨格を有する化合物。 A compound with an iridoid skeleton used for the treatment of promoting the production of short-chain fatty acids in the intestinal tract.
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| JP2012077012A (en) * | 2010-09-30 | 2012-04-19 | Kobayashi Pharmaceutical Co Ltd | Bone density increasing agent and agent for anti-menopausal syndrome |
| JP2018050526A (en) * | 2016-09-28 | 2018-04-05 | 帝人株式会社 | Intestinal environment improving composition |
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| JP2012077012A (en) * | 2010-09-30 | 2012-04-19 | Kobayashi Pharmaceutical Co Ltd | Bone density increasing agent and agent for anti-menopausal syndrome |
| JP2018050526A (en) * | 2016-09-28 | 2018-04-05 | 帝人株式会社 | Intestinal environment improving composition |
Non-Patent Citations (3)
| Title |
|---|
| FUJIKAWA TAKAHIKO, HIRATA TETSUYA, HOSOO SHINGO, NAKAJIMA KENJI, WADA ATSUNORI, YURUGI YUTAKA, SOYA HIDEAKI, MATSUI TAKASHI, YAMAG: "Asperuloside stimulates metabolic function in rats across several organs under high-fat diet conditions, acting like the major ingredient of Eucommia leaves with anti-obesity activity", JOURNAL OF NUTRITIONAL SCIENCE, vol. 1, no. e10, 5 September 2012 (2012-09-05), pages 1 - 11, XP055788171, ISSN: 2048-6790 * |
| GONG NIAN, FAN HUI, MA AI-NIU, XIAO QI, WANG YONG-XIANG: "Geniposide and its iridoid analogs exhibit antinociception by acting at the spinal GLP-1 receptors", NEUROPHARMACOLOGY, vol. 84, September 2014 (2014-09-01), pages 31 - 45, XP055788178, ISSN: 0028-3908 * |
| OKU, H. ET AL.: "Allergy-Preventive Effects of Chlorogenic Acid and Iridoid Derivatives from Flower Buds of Lonicera japonica", BIOLOGICAL AND PHARMACEUTICAL BULLETIN, vol. 34, no. 8, 2011, pages 1330 - 1333, XP055224403, ISSN: 1347-5215, DOI: 10.1248/bpb.34.1330 * |
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| JP2021020871A (en) | 2021-02-18 |
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