WO2021020210A1 - Gut microbiota regulating agent - Google Patents

Gut microbiota regulating agent Download PDF

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Publication number
WO2021020210A1
WO2021020210A1 PCT/JP2020/028094 JP2020028094W WO2021020210A1 WO 2021020210 A1 WO2021020210 A1 WO 2021020210A1 JP 2020028094 W JP2020028094 W JP 2020028094W WO 2021020210 A1 WO2021020210 A1 WO 2021020210A1
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Prior art keywords
intestinal flora
iridoid
item
bacteria belonging
phylum
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PCT/JP2020/028094
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French (fr)
Japanese (ja)
Inventor
平田　哲也
光博 渡辺
杏菜 中村
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小林製薬株式会社
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Publication of WO2021020210A1 publication Critical patent/WO2021020210A1/en

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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/105—Plant extracts, their artificial duplicates or their derivatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/46—Eucommiaceae (Eucommia family), e.g. hardy rubber tree
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system

Definitions

  • the present invention increases the proportion of bacteria belonging to the phylum Bacteroides and Akkermansia mucinifila in the intestine, and reduces the proportion of bacteria belonging to the phylum Firmicutes, in the intestine.
  • an intestinal flora regulator that can regulate the bacterial flora to a healthy state.
  • Non-Patent Documents 1 and 2 The development of intestinal bacteriology has revealed that the balance of the intestinal flora is closely related to the maintenance of host ecological homeostasis. The intestinal flora interacts closely with mucosal immune cells, nerve cells, endocrine cells, etc., and if the balance is lost, it causes diseases in the gastrointestinal tract, autoimmune diseases, lifestyle-related diseases, etc. (Non-Patent Documents 1 and 2).
  • Lakshminarayanan B et al. Compositional dynamics of the human intestinal microbiota with aging: implications for health. J Nutr Health Aging 18: 773-86, 2014 Intestinal ecosystem and anti-aging, such as Masatsugu Fukuda: Anti-aging Medicine 9: 717-722,2014 Backhed Fet al., The gut microbiota as an environmental factor that regulates fat storage. Proc Natl Acad Sci 101: 15718-15723, 2004 Hildebrandt MA et al., High-fat diet determines the composition of the murine gut microbiome independently of obesty, Gastroenterology 137: 1716-1724. 2009. Ley RE et al., Obesity alters gut microbial ecology. Proc Natl Acad Sci 102: 11070-11075, 2005 Turnbaugh PJ et al., Anti obesity-associated gut microbiome with increased capacity for energy harvest. Nature 444; 1027-1031, 2006
  • An object of the present invention is to provide an intestinal flora regulator capable of adjusting the intestinal flora to a healthy state.
  • the present inventors have increased the ratio of bacteria belonging to the phylum Bacteroides and Akkermansia muciniphila in the intestine to the compound having an iridoid skeleton, and Pharmacu. It was found that it has the effect of reducing the proportion of bacteria belonging to the phylum Bacteroides and can maintain a healthy balance of the intestinal flora.
  • the present invention has been completed by conducting further studies based on such findings.
  • Item 1 An intestinal flora regulator containing a compound having an iridoid skeleton.
  • 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 2. The intestinal flora regulator according to Item 1, which is at least one selected from the group consisting of B and acetylid C.
  • Item 3. Item 2.
  • the intestinal flora regulator according to Item 1 or 2 which is a food or drink or an orally taken drug.
  • Item 4. Item 3. The intestine according to any one of Items 1 to 3, which is used to increase the proportion of bacteria belonging to the phylum Bacteroides and Akkermansia muciniphila and to decrease the proportion of bacteria belonging to the phylum Bacteroides in the intestine. Internal bacterial flora regulator.
  • Item 5. Use of compounds with an iridoid skeleton for the production of intestinal flora regulators.
  • 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 5 or 6 wherein the intestinal flora regulator is a food or drink or an internal medicine.
  • Item 5 The intestinal flora regulator is used to increase the proportion of bacteria belonging to the phylum Bacteroides and Akkermansia muciniphila and decrease the proportion of bacteria belonging to the phylum Bacteroides in the intestine. Use described in any of 7 to 7.
  • Item 9 A method for adjusting an intestinal flora, in which a compound having an iridoid skeleton is administered or ingested by a person who needs to adjust the intestinal flora.
  • Item 10 A method for adjusting an intestinal flora, in which a compound having an iridoid skeleton is administered or ingested by a person who needs to adjust the intestinal flora.
  • 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 11 The method for adjusting an intestinal flora according to Item 9 or 10, wherein the intestinal flora adjusting agent is a food or drink or an internal medicine.
  • Adjustment of the intestinal flora according to any one of Items 9 to 11, which increases the proportion of bacteria belonging to the phylum Bacteroides and Akkermansia muciniphila and decreases the proportion of bacteria belonging to the phylum Bacteroides in the intestine.
  • Method. Item 13.
  • 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.
  • 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 16 or 17 which is used to increase the proportion of bacteria belonging to the phylum Bacteroides and Akkermansia muciniphila and to decrease the proportion of bacteria belonging to the phylum Bacteroides.
  • the intestinal flora regulator of the present invention increases the proportion of bacteria belonging to the phylum Bacteroidetes and Akkermansia muciniphila in the intestine, and reduces the proportion of bacteria belonging to the phylum Pharmacutes, thereby causing the intestinal bacteria Since the balance of the flora can be made healthy, the intestinal environment is healthy, the intestinal environment is maintained healthy, and the prevention of symptoms and diseases caused by the unhealthy intestinal environment. , Effective for treatment or improvement.
  • the intestinal flora regulator of the present invention is characterized by containing a compound having an iridoid skeleton.
  • a compound having an iridoid skeleton a compound having an iridoid skeleton.
  • the intestinal flora regulator of the present invention contains a compound having an iridoid skeleton (hereinafter, may be referred to as “iridoid compound”) as an active ingredient.
  • 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.
  • asperuloside and geniposide are preferable from the viewpoint of increasing the ratio of bacteria belonging to the phylum Bacteroides and Akkermansia muciniphila and further enhancing the effect of reducing the ratio of bacteria belonging to the phylum Fermicutes. Acids, more preferably asperulosides.
  • 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.
  • 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.
  • 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.
  • leaves are preferably exemplified, in the case of plantain, seeds are preferably mentioned, and in the case of noni, leaves are preferably mentioned.
  • 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.
  • an extract is preferable.
  • 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.
  • 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.
  • 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 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.
  • 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.
  • 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.
  • the solid matter can be removed and the extract can be obtained by performing solid-liquid separation.
  • the solid-liquid separation method a conventional method can be used, and examples thereof include a filtration method and a centrifugation method.
  • the Tochu leaf that has been subjected to the extraction treatment once may be subjected to the extraction treatment again.
  • 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.
  • the dosage form of the intestinal flora regulator of the present invention is not particularly limited, and may be solid, semi-solid, or liquid.
  • the intestinal flora regulator 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.
  • Specific examples of the form of the intestinal flora regulator of the present invention include foods and drinks and medicines for internal use (including quasi-drugs for internal use).
  • the intestinal flora regulator of the present invention is in the form of a food or drink (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 additives. It may be prepared in a desired form.
  • 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.
  • a beverage is preferable, and a tea beverage containing Tochu tea extract is more preferable.
  • the intestinal flora regulator of the present invention When 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, tablets, capsules (including hard capsules and soft capsules), troches, chewables, and extracts. Examples thereof include agents (including soft extracts, dry extracts, etc.), jelly agents, syrup agents, alcoholic agents, elixir agents, liposome preparations, and the like.
  • the content of the iridoid compound is determined by taking into consideration the physique, age, intestinal environment, morphology of the intestinal flora regulator, etc. of the subject, and the daily intake of the iridoid compound. -It may be set appropriately based on the dosage.
  • 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 intestinal flora regulator 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.
  • 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.
  • the intestinal flora regulator of the present invention is made into a solid preparation such as tablets, pills, powders, fine granules, granules, capsules, lozenges, chewables, iridoid compounds are contained.
  • 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.
  • the intestinal flora regulator of the present invention has the effect of increasing the proportion of bacteria belonging to the phylum Bacteroidetes and Akkermansia muciniphila and reducing the proportion of bacteria belonging to the phylum Fermicutes, and regulates the intestinal flora. It is then used to adjust the balance of the gut flora to a healthy state. That is, in one form of the intestinal flora regulator of the present invention, a person having a low ratio of bacteria belonging to the phylum Bacteroidetes to bacteria belonging to the phylum Fermicutes in the intestinal flora can be targeted.
  • the ratio of bacteria belonging to the phylum Bacteroides to the bacteria belonging to the phylum Fermicutes in the intestinal flora is low means, for example, the ratio of the phylum Bacteroides to the bacteria belonging to the phylum Fermicutes in the gut flora. Is 0.6 or less, preferably 0.05 to 0.6, more preferably 0.05 to 0.5, still more preferably 0.05 to 0.3, and particularly preferably 0.05 to 0.2. There is one thing.
  • the intestinal flora regulator of the present invention can also be used for enhancing the immune function of a living body. That is, in one form of the intestinal flora regulator of the present invention, for example, a person who is required to enhance the immune function, a person who has a decreased immune function, or the like can be targeted.
  • the intestinal flora regulator of the present invention can also be used for the prevention, treatment, or improvement of diseases and symptoms caused by an unhealthy intestinal environment. That is, in one form of the intestinal flora regulator of the present invention, for example, it is necessary to treat a person whose intestinal environment is unhealthy or a disease or symptom caused by the unhealthy intestinal environment. It is also possible to target those who are said to be.
  • the intestinal flora regulator of the present invention is used. It can also be used for suppressing the phase change of the intestinal bacterial flora by ingesting a high-fat diet.
  • 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 intestinal flora regulator 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.
  • the intestinal flora regulator of the present invention optimizes the energy consumption of the ingested food. It can also be used for the purpose of.
  • the intestinal flora regulator of the present invention is an agent for improving the proportion of bacteria belonging to the phylum Bacteroides in the intestinal flora, an agent for improving the proportion of Ackermannia musiniphila in the intestinal flora, and fermicutes in the intestinal flora. It can also be used as a ratio reducing agent for bacteria belonging to the phylum.
  • 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.
  • each mouse was dissected and the contents of the cecum were collected, and the bacterial ratio of the intestinal flora was analyzed by the following method.
  • the collected cryptic contents were lyophilized, and the lyophilized product was lyophilized with 100 mg of 3 mm zirconia beads and 400 ⁇ L of Tris-EDTA buffer containing 1 wt% sodium dodecyl sulfate, and phenol / chloroform / isoamyl alcohol (volume ratio 25:24). : 1) 400 ⁇ L of the mixed solvent was added, and the mixture was shaken at 1500 rpm for 15 minutes using a shake master.
  • the obtained suspension was separated by a centrifuge at 17800 g for 5 minutes at 4 ° C., and DNA was recovered. Then, RNA was removed by RNase A. Then, the obtained DNA sample was treated with the above-mentioned mixed solvent of phenol / chloroform / isoamyl alcohol (volume ratio 25:24: 1) to purify the sample.
  • the 16S rRNA gene in the obtained DNA sample was analyzed by the method shown below. First, the V1-V2 region of the 16S rRNA gene was amplified from the obtained DNA using the primers shown in Table 2. The polymerase reaction was carried out at 98 ° C. for 1 minute for 1 cycle, and further at 98 ° C. for 10 seconds and 55 ° C. for 15 seconds, 68 ° C. for 30 seconds for 20 cycles, and then an extension reaction at 68 ° C. for 3 minutes. ..
  • the PCR product obtained was purified using the Agenvourt AMPure XP kit (Beckman Coulter Co., Ltd.). The purified sample was then amplified with a forward primer containing the P5 sequence shown in Table 3 and a reverse primer containing the P7 sequence to give a PCR product.
  • the obtained PCR product was sequenced by MiSeq (Illumina).
  • the obtained 16S rRNA sequence was first assembled into paired-end reads using software (FLASH, https://ccb.jhu.edu/software/FLASH/, Johns Hopkins University the Center for Computational Biology). Of the combined leads, those with a quality score of less than 25 were removed, and a file was output. Then, for each known bacterial sequence (reference sequence) contained in the database, reads having a sequence homologous of 97% or more were put together to create an Operational Taxonomy Unit (OTU).
  • OTU Operational Taxonomy Unit
  • Test Example 2 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.
  • Table 7 shows the average value of the scores of each subjective symptom of the subject. This result suggests that ingestion of asperuloside and geniposidic acid improved the balance of the intestinal flora and brought it into a healthy state.

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Abstract

An objective of the present invention is to provide a gut microbiota regulating agent that is capable of regulating gut microbiota to a healthy state.　In the present invention, a compound having an iridoid skeleton acts to increase the proportions of bacteria of phylum Bacteroidetes and Akkermansia muciniphila and decrease the proportion of bacteria of phylum Firmicutes in the intestinal tract, making it possible to improve the balance of the gut microbiota to a healthy state, and thus can be used as a gut microbiota regulating agent.

Description

腸内細菌叢調整剤Gut flora regulator
　本発明は、腸内で、バクテロイデス（Ｂａｃｔｅｒｏｉｄｅｓ）門に属する細菌及びアッカーマンシア・ムシニフィラ（Ａｋｋｅｒｍａｎｓｉａ　ｍｕｃｉｎｉｐｈｉｌａ）の比率を増加させ、且つファーミキューテス（Ｆｉｒｍｉｃｕｔｅｓ）門に属する細菌の比率を低減し、腸内細菌叢を健全な状態に調整できる、腸内細菌叢調整剤に関する。 The present invention increases the proportion of bacteria belonging to the phylum Bacteroides and Akkermansia mucinifila in the intestine, and reduces the proportion of bacteria belonging to the phylum Firmicutes, in the intestine. Regarding an intestinal flora regulator that can regulate the bacterial flora to a healthy state.
　腸内細菌学の発展により、腸内細菌叢のバランスが宿主の生態恒常性維持と密接な関係性があることが明らかにされている。腸内細菌叢が、粘膜免疫細胞、神経細胞、内分泌細胞等と密接に相互作用しており、そのバランスが崩れると、消化管での疾病発症、自己免疫疾患、生活習慣病等を生じさせる原因にもなっている（非特許文献１及び２）。 The development of intestinal bacteriology has revealed that the balance of the intestinal flora is closely related to the maintenance of host ecological homeostasis. The intestinal flora interacts closely with mucosal immune cells, nerve cells, endocrine cells, etc., and if the balance is lost, it causes diseases in the gastrointestinal tract, autoimmune diseases, lifestyle-related diseases, etc. (Non-Patent Documents 1 and 2).
　また、腸内細菌叢は、宿主の摂取食品からエネルギーを抽出することによってエネルギーバランスを制御するという重要な役割を担っている。最近の研究では、腸内細菌叢における組成や変化が、肝臓又は筋肉組織におけるＡＭＰＫ（ａｃｔｉｖａｔｅｄ ｐｒｏｔｅｉｎ ｋｉｎａｓｅ）活性の上昇及び空腹時誘発脂肪因子の抑制解除を伴う食事誘発肥満と関連していることが報告されている（非特許文献３及び４）。 In addition, the intestinal flora plays an important role in controlling the energy balance by extracting energy from the host's food intake. Recent studies have shown that composition and changes in the gut flora are associated with diet-induced obesity with increased AMPK (activated protein kinase) activity in liver or muscle tissue and desuppression of fasting-induced fat factors. It has been reported (Non-Patent Documents 3 and 4).
　また、健全な状態の腸内細菌叢では、バクテロイデス門に属する細菌が優勢、ファーミキューテス門に属する細菌が劣勢になっていることが知られているが、高脂肪食への食生活の変化等によって腸内細菌叢のバランスが崩れると、バクテロイデス門に属する細菌の減少と、ファーミキューテス門に属する細菌の増加を招き、その結果、インスリン抵抗性の増加等が引き起こされることが報告されている（非特許文献５及び６）。更に、腸内細菌叢中のアッカーマンシア・ムシニフィラは、抗炎症作用を発揮しており、健全な腸内環境を維持する上で重要な役割を担っていることも明らかになっている。 In addition, it is known that bacteria belonging to the phylum Bacteroidetes are dominant and bacteria belonging to the phylum Fermicutes are inferior in the healthy intestinal flora, but changes in eating habits to a high-fat diet It has been reported that when the intestinal flora is out of balance due to such factors, the number of bacteria belonging to the phylum Bacteroidetes decreases and the number of bacteria belonging to the phylum Fermicutes increases, resulting in an increase in insulin resistance. (Non-Patent Documents 5 and 6). Furthermore, Akkermansia muciniphila in the intestinal flora has an anti-inflammatory effect and has been shown to play an important role in maintaining a healthy intestinal environment.
　近年、食生活の乱れ、高脂肪食の増加等によって、腸内細菌叢のバランスが乱れ、バクテロイデス門に属する細菌及びアッカーマンシア・ムシニフィラの比率が低下し、ファーミキューテス門に属する細菌の比率が増加している人が増加傾向にあり、腸内細菌叢のバランスを改善できる素材の開発が望まれている。 In recent years, due to disordered eating habits, increase in high-fat diet, etc., the balance of the intestinal flora has been disturbed, the ratio of bacteria belonging to the phylum Bacteroides and Akkermansia muciniphila has decreased, and the ratio of bacteria belonging to the phylum Fermicutes has increased. The number of people who are increasing is increasing, and it is desired to develop a material that can improve the balance of the intestinal bacterial flora.
　本発明の目的は、腸内細菌叢を健全な状態に調整できる腸内細菌叢調整剤を提供することである。 An object of the present invention is to provide an intestinal flora regulator capable of adjusting the intestinal flora to a healthy state.
　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、腸内で、バクテロイデス門に属する細菌及びアッカーマンシア・ムシニフィラの比率を増加させ、且つファーミキューテス門に属する細菌の比率を低減させる作用があり、腸内細菌叢のバランスを健全な状態できることを見出した。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。 As a result of diligent studies to solve the above-mentioned problems, the present inventors have increased the ratio of bacteria belonging to the phylum Bacteroides and Akkermansia muciniphila in the intestine to the compound having an iridoid skeleton, and Pharmacu. It was found that it has the effect of reducing the proportion of bacteria belonging to the phylum Bacteroides and can maintain a healthy balance of the intestinal flora. 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、腸内細菌叢調整剤。
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に記載の腸内細菌叢調整剤。
項３．　飲食品、又は内服用医薬品である、項１又は２に記載の腸内細菌叢調整剤。
項４．　腸内で、バクテロイデス門に属する細菌及びアッカーマンシア・ムシニフィラの比率を増加させ、且つファーミキューテス門に属する細菌の比率を低減させるために使用される、項１～３のいずれかに記載の腸内細菌叢調整剤。
項５．　イリドイド骨格を有する化合物の、腸内細菌叢調整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．　前記腸内細菌叢調整剤が、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．　前記腸内細菌叢調整剤が、腸内で、バクテロイデス門に属する細菌及びアッカーマンシア・ムシニフィラの比率を増加させ、且つファーミキューテス門に属する細菌の比率を低減させるために使用される、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、腸内細菌叢の調整が必要とされる者に投与又は摂取させる、腸内菌叢の調整方法。
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に記載の腸内菌叢の調整方法。
項１１．　前記腸内細菌叢調整剤が、飲食品又は内服用医薬品である、項９又は１０に記載の腸内菌叢の調整方法。
項１２．　腸内で、バクテロイデス門に属する細菌及びアッカーマンシア・ムシニフィラの比率を増加させ、且つファーミキューテス門に属する細菌の比率を低減させる、項９～１１のいずれかに記載の腸内菌叢の調整方法。
項１３．　イリドイド骨格を有する化合物の、腸内細菌叢調整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．　腸内で、バクテロイデス門に属する細菌及びアッカーマンシア・ムシニフィラの比率を増加させ、且つファーミキューテス門に属する細菌の比率を低減させるために使用される、項１３又は１４に記載の非治療的使用。
項１６．　腸内細菌叢調整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．　バクテロイデス門に属する細菌及びアッカーマンシア・ムシニフィラの比率を増加させ、且つファーミキューテス門に属する細菌の比率を低減させるために使用される、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 intestinal flora regulator containing 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, eucomicid A, eucomicide. Item 2. The intestinal flora regulator according to Item 1, which is at least one selected from the group consisting of B and acetylid C.
Item 3. Item 2. The intestinal flora regulator according to Item 1 or 2, which is a food or drink or an orally taken drug.
Item 4. Item 3. The intestine according to any one of Items 1 to 3, which is used to increase the proportion of bacteria belonging to the phylum Bacteroides and Akkermansia muciniphila and to decrease the proportion of bacteria belonging to the phylum Bacteroides in the intestine. Internal bacterial flora regulator.
Item 5. Use of compounds with an iridoid skeleton for the production of intestinal flora regulators.
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. The use according to Item 5 or 6, wherein the intestinal flora regulator is a food or drink or an internal medicine.
Item 8. Item 5 The intestinal flora regulator is used to increase the proportion of bacteria belonging to the phylum Bacteroides and Akkermansia muciniphila and decrease the proportion of bacteria belonging to the phylum Bacteroides in the intestine. Use described in any of 7 to 7.
Item 9. A method for adjusting an intestinal flora, in which a compound having an iridoid skeleton is administered or ingested by a person who needs to adjust the intestinal flora.
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, eucomicide A, eucomicide. Item 9. The method for adjusting an intestinal flora according to Item 9, which is at least one selected from the group consisting of B and acetylid C.
Item 11. Item 9. The method for adjusting an intestinal flora according to Item 9 or 10, wherein the intestinal flora adjusting agent is a food or drink or an internal medicine.
Item 12. Item 4. Adjustment of the intestinal flora according to any one of Items 9 to 11, which increases the proportion of bacteria belonging to the phylum Bacteroides and Akkermansia muciniphila and decreases the proportion of bacteria belonging to the phylum Bacteroides in the intestine. Method.
Item 13. Non-therapeutic use of compounds with an iridoid skeleton for intestinal flora regulation.
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. Non-therapeutic use according to Item 13 or 14, which is used to increase the proportion of bacteria belonging to the phylum Bacteroides and Akkermansia muciniphila and to decrease the proportion of bacteria belonging to the phylum Bacteroides in the intestine. ..
Item 16. A compound having an iridoid skeleton used for the treatment of intestinal flora regulation.
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 16. The compound according to Item 16 or 17, which is used to increase the proportion of bacteria belonging to the phylum Bacteroides and Akkermansia muciniphila and to decrease the proportion of bacteria belonging to the phylum Bacteroides.
　本発明の腸内細菌叢調整剤は、腸内で、バクテロイデス門に属する細菌及びアッカーマンシア・ムシニフィラの比率を増加させ、且つファーミキューテス門に属する細菌の比率を低減させることにより、腸内細菌叢のバランスを健全な状態にすることができるので、腸内環境の健全化、健全な腸内環境の保持、腸内環境が不健全になることが一因となって生じる症状や疾患の予防、治療又は改善等に有効である。 The intestinal flora regulator of the present invention increases the proportion of bacteria belonging to the phylum Bacteroidetes and Akkermansia muciniphila in the intestine, and reduces the proportion of bacteria belonging to the phylum Pharmacutes, thereby causing the intestinal bacteria Since the balance of the flora can be made healthy, the intestinal environment is healthy, the intestinal environment is maintained healthy, and the prevention of symptoms and diseases caused by the unhealthy intestinal environment. , Effective for treatment or improvement.
　本発明の腸内細菌叢調整剤は、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、本発明の腸内細菌叢調整剤について詳述する。 The intestinal flora regulator of the present invention is characterized by containing a compound having an iridoid skeleton. Hereinafter, the intestinal flora regulator of the present invention will be described in detail.
［イリドイド骨格を有する化合物］
　本発明の腸内細菌叢調整剤は、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 intestinal flora regulator 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、バクテロイデス門に属する細菌及びアッカーマンシア・ムシニフィラの比率を増加させ、且つファーミキューテス門に属する細菌の比率を低減させる効果をより一層高めるという観点から、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 and geniposide are preferable from the viewpoint of increasing the ratio of bacteria belonging to the phylum Bacteroides and Akkermansia muciniphila and further enhancing the effect of reducing the ratio of bacteria belonging to the phylum Fermicutes. Acids, more preferably asperulosides.
　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］
　本発明の腸内細菌叢調整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 intestinal flora regulator of the present invention is not particularly limited, and may be solid, semi-solid, or liquid.
　本発明の腸内細菌叢調整剤は、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 intestinal flora regulator 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.
　本発明の腸内細菌叢調整剤の形態として、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 intestinal flora regulator of the present invention include foods and drinks and medicines for internal use (including quasi-drugs for internal use).
　本発明の腸内細菌叢調整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 intestinal flora regulator of the present invention is in the form of a food or drink (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 additives. 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.
　本発明の腸内細菌叢調整剤を内服用医薬品（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、錠剤、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 intestinal flora regulator 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, tablets, capsules (including hard capsules and soft capsules), troches, chewables, and extracts. Examples thereof include agents (including soft extracts, dry extracts, etc.), jelly agents, syrup agents, alcoholic agents, elixir agents, liposome preparations, and the like.
　本発明の腸内細菌叢調整剤において、イリドイド化合物の含有量は、対象者の体格、年齢、腸内環境、腸内細菌叢調整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。本発明の腸内細菌叢調整剤は、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 intestinal flora regulator of the present invention, the content of the iridoid compound is determined by taking into consideration the physique, age, intestinal environment, morphology of the intestinal flora regulator, etc. of the subject, and the daily intake of the iridoid compound. -It may be set appropriately based on the dosage. 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 intestinal flora regulator 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、本発明の腸内細菌叢調整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 intestinal flora regulator 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、本発明の腸内細菌叢調整剤を錠剤、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 intestinal flora regulator of the present invention is made into a solid preparation such as tablets, pills, powders, fine granules, granules, capsules, lozenges, chewables, iridoid compounds are contained. 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.
　本発明の腸内細菌叢調整剤は、バクテロイデス門に属する細菌及びアッカーマンシア・ムシニフィラの比率を増加させ、且つファーミキューテス門に属する細菌の比率を低減させる作用があり、腸内細菌叢を調整して、腸内細菌叢のバランスを健全な状態に調整するために使用される。即ち、本発明の腸内細菌叢調整剤の一形態では、腸菌叢においてファーミキューテス門に属する細菌に対するバクテロイデス門の比率に属する細菌の割合が低い者を対象者とすることができる。ここで、「腸菌叢においてファーミキューテス門に属する細菌に対するバクテロイデス門の比率に属する細菌の割合が低い」とは、例えば、腸菌叢において、ファーミキューテス門に属する細菌に対するバクテロイデス門の比率が０．６以下、好ましくは、０．０５～０．６、より好ましくは０．０５～０．５、更に好ましくは０．０５～０．３、特に好ましくは０．０５～０．２であることが挙げられる。 The intestinal flora regulator of the present invention has the effect of increasing the proportion of bacteria belonging to the phylum Bacteroidetes and Akkermansia muciniphila and reducing the proportion of bacteria belonging to the phylum Fermicutes, and regulates the intestinal flora. It is then used to adjust the balance of the gut flora to a healthy state. That is, in one form of the intestinal flora regulator of the present invention, a person having a low ratio of bacteria belonging to the phylum Bacteroidetes to bacteria belonging to the phylum Fermicutes in the intestinal flora can be targeted. Here, "the ratio of bacteria belonging to the phylum Bacteroides to the bacteria belonging to the phylum Fermicutes in the intestinal flora is low" means, for example, the ratio of the phylum Bacteroides to the bacteria belonging to the phylum Fermicutes in the gut flora. Is 0.6 or less, preferably 0.05 to 0.6, more preferably 0.05 to 0.5, still more preferably 0.05 to 0.3, and particularly preferably 0.05 to 0.2. There is one thing.
　腸内細菌叢のバランスを健全な状態にすることにより、腸内上皮細胞を覆う粘液を健康な状態に維持することができ、その結果、生体の免疫機能の亢進がもたらされ得るので、本発明の腸内細菌叢調整剤は、生体の免疫機能の亢進用途等に使用することもできる。即ち、本発明の腸内細菌叢調整剤の一形態では、例えば、免疫機能の亢進が求められる者、免疫機能が低下している者等を対象者とすることができる。また、本発明の腸内細菌叢調整剤は、腸内環境が不健全になることが一因となって生じる疾患や症状の予防、治療、又は改善用途に使用することもできる。即ち、本発明の腸内細菌叢調整剤の一形態では、例えば、腸内環境が不健全な者、腸内環境が不健全になることが一因となって生じる疾患や症状の治療が必要とされている者等を対象者とすることもできる。 By keeping the balance of the intestinal flora healthy, the mucus covering the intestinal epithelial cells can be maintained in a healthy state, and as a result, the immune function of the living body can be enhanced. The intestinal flora regulator of the present invention can also be used for enhancing the immune function of a living body. That is, in one form of the intestinal flora regulator of the present invention, for example, a person who is required to enhance the immune function, a person who has a decreased immune function, or the like can be targeted. In addition, the intestinal flora regulator of the present invention can also be used for the prevention, treatment, or improvement of diseases and symptoms caused by an unhealthy intestinal environment. That is, in one form of the intestinal flora regulator of the present invention, for example, it is necessary to treat a person whose intestinal environment is unhealthy or a disease or symptom caused by the unhealthy intestinal environment. It is also possible to target those who are said to be.
　また、高脂肪食は、バクテロイデス門に属する細菌の比率の低下且つファーミキューテス門に属する細菌の比率の増大という腸内細菌叢の変相を招くため、本発明の腸内細菌叢調整剤は、高脂肪食摂取による腸内細菌叢の変相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、本発明の腸内細菌叢調整剤の一形態では、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。 In addition, since a high-fat diet causes a change in the intestinal flora, which is a decrease in the proportion of bacteria belonging to the phylum Bacteroides and an increase in the proportion of bacteria belonging to the phylum Bacteroides, the intestinal flora regulator of the present invention is used. It can also be used for suppressing the phase change of the intestinal bacterial flora by ingesting a high-fat diet. 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 intestinal flora regulator 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、腸内細菌叢は、宿主の摂取食品からエネルギーを抽出することによってエネルギーバランスを制御する役割を担っているので、本発明の腸内細菌叢調整剤は、摂取食品のエネルギー消費の適正化の目的で使用することもできる。 Further, since the intestinal flora plays a role of controlling the energy balance by extracting energy from the ingested food of the host, the intestinal flora regulator of the present invention optimizes the energy consumption of the ingested food. It can also be used for the purpose of.
　更に、本発明の腸内細菌叢調整剤は、腸内細菌叢におけるバクテロイデス門に属する細菌の比率向上剤、腸内細菌叢におけるアッカーマンシア・ムシニフィラの比率向上剤、腸内細菌叢におけるファーミキューテス門に属する細菌の比率低減剤等として使用することもできる。 Furthermore, the intestinal flora regulator of the present invention is an agent for improving the proportion of bacteria belonging to the phylum Bacteroides in the intestinal flora, an agent for improving the proportion of Ackermannia musiniphila in the intestinal flora, and fermicutes in the intestinal flora. It can also be used as a ratio reducing agent for bacteria belonging to the phylum.
　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.
Figure JPOXMLDOC01-appb-T000001
Figure JPOXMLDOC01-appb-T000001
　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、以下の方法で腸内細菌叢の菌比率の分析を行った。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１００ｍｇ及び１重量%ドデシル硫酸ナトリウム含有Ｔｒｉｓ－ＥＤＴＡバッファー４００μL、並びにフェノール／クロロホルム／イソアミルアルコール（容量比２５:２４:１）の混合溶媒４００μL加え、シェイクマスターを用いて１５００ｒｐｍ、１５分間振とうした。得られた懸濁液を遠心分離機にて、１７８００ｇ、５分間、４℃で分離し、ＤＮＡを回収した。その後、ＲＮａｓｅ ＡよるＲＮＡ除去を行った。次いで、得られたＤＮＡサンプルを上記のフェノール／クロロホルム／イソアミルアルコール（容量比２５:２４:１）の混合溶媒で処理をすることにより サンプルを精製した。 After breeding for 11 days, each mouse was dissected and the contents of the cecum were collected, and the bacterial ratio of the intestinal flora was analyzed by the following method. First, the collected cryptic contents were lyophilized, and the lyophilized product was lyophilized with 100 mg of 3 mm zirconia beads and 400 μL of Tris-EDTA buffer containing 1 wt% sodium dodecyl sulfate, and phenol / chloroform / isoamyl alcohol (volume ratio 25:24). : 1) 400 μL of the mixed solvent was added, and the mixture was shaken at 1500 rpm for 15 minutes using a shake master. The obtained suspension was separated by a centrifuge at 17800 g for 5 minutes at 4 ° C., and DNA was recovered. Then, RNA was removed by RNase A. Then, the obtained DNA sample was treated with the above-mentioned mixed solvent of phenol / chloroform / isoamyl alcohol (volume ratio 25:24: 1) to purify the sample.
　得られたＤＮＡサンプル中の１６ＳｒＲＮＡ遺伝子について以下に示す方法で分析した。先ず、得られたＤＮＡから、表２に示すプライマーを使用して１６ＳｒＲＮＡ遺伝子のＶ１－Ｖ２領域を増幅させた。ポリメラーゼ反応は、９８℃、１分間を１サイクル行い、更に９８℃、１０秒間と５５℃、１５秒間、６８℃、３０秒間を２０サイクル行った後に、６８℃、３分間の伸長反応を行った。 The 16S rRNA gene in the obtained DNA sample was analyzed by the method shown below. First, the V1-V2 region of the 16S rRNA gene was amplified from the obtained DNA using the primers shown in Table 2. The polymerase reaction was carried out at 98 ° C. for 1 minute for 1 cycle, and further at 98 ° C. for 10 seconds and 55 ° C. for 15 seconds, 68 ° C. for 30 seconds for 20 cycles, and then an extension reaction at 68 ° C. for 3 minutes. ..
Figure JPOXMLDOC01-appb-T000002
Figure JPOXMLDOC01-appb-T000002
　次いで、Ａｇｅｎｖｏｕｒｔ ＡＭＰｕｒｅ ＸＰキット（ベックマン・コールター株式会社）を用いて得られたＰＣＲ産物を精製した。その後、精製サンプルを、表３に示すＰ５配列を含むフォワードプライマー及びＰ７配列を含むリバースプライマーを用いて増幅し、ＰＣＲ産物を得た。 Next, the PCR product obtained was purified using the Agenvourt AMPure XP kit (Beckman Coulter Co., Ltd.). The purified sample was then amplified with a forward primer containing the P5 sequence shown in Table 3 and a reverse primer containing the P7 sequence to give a PCR product.
Figure JPOXMLDOC01-appb-T000003
Figure JPOXMLDOC01-appb-T000003
　得られたＰＣＲ産物をＭｉＳｅｑ（illumina社）にてシーケンスした。得られた１６ＳｒＲＮＡ配列は最初にソフトウェア（FLASH、https://ccb.jhu.edu/software/FLASH/、Johns Hopkins University the Center for Computational Biology）を用いて、ペアエンドリードの組み立てを行なった。結合させたリードのうちクオリティースコア２５未満のものを取り除き、ファイル出力を行なった。その後、データベースに含まれる既知の細菌の配列（リファレンス配列）ごとに、９７％以上相同な配列を持つリードをまとめて、Ｏｐｅｒａｔｉｏｎａｌ Ｔａｘｏｎｏｍｉｃ Ｕｎｉｔ（ＯＴＵ)を作成した。リードはメタゲノム解析プログラム（QIIME、http://qiime.org/home_static/dataFiles.html、North Arizona University, Pathogen and Microbiome, Knight and Caporaso labs.）を用いて処理した。得られたＯＴＵデータはオンライン解析ソフト（Microbiome analyst、　https://www.microbiomeanalyst.ca/MicrobiomeAnalyst/faces/home.xhtml）を用いて統計処理した。 The obtained PCR product was sequenced by MiSeq (Illumina). The obtained 16S rRNA sequence was first assembled into paired-end reads using software (FLASH, https://ccb.jhu.edu/software/FLASH/, Johns Hopkins University the Center for Computational Biology). Of the combined leads, those with a quality score of less than 25 were removed, and a file was output. Then, for each known bacterial sequence (reference sequence) contained in the database, reads having a sequence homologous of 97% or more were put together to create an Operational Taxonomy Unit (OTU). Reads were processed using a metagenomic analysis program (QIIME, http://qiime.org/home_static/dataFiles.html, North Arizona University, Pathogen and Microbiome, Knight and Caporaso labs.). The obtained OTU data was statistically processed using online analysis software (Microbiome analyze, https://www.microbiomeanalyst.ca/MicrobiomeAnalyst/faces/home.xhtml).
　得られた結果を表４及び５に示す。高脂肪食群では、コントロール食群に比べて、バクテロイデス門に属する細菌の比率が低下し、ファーミキューテス門に属する細菌の比率が増加していた。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、バクテロイデス門に属する細菌の比率が増加し、且つファーミキューテス門に属する細菌の比率が低下していた。また、コントロール食群及び高脂肪食群では、アッカーマンシア・ムシニフィラは検出限界以下であったが、高脂肪食＋アスペルロシド群では、アッカーマンシア・ムシニフィラの存在が検出された。以上の結果から、アスペルロシドには、腸内細菌叢のバランスを健全な状態にする作用があることが確認された。 The results obtained are shown in Tables 4 and 5. In the high-fat diet group, the proportion of bacteria belonging to the phylum Bacteroides decreased and the proportion of bacteria belonging to the phylum Bacteroides increased as compared with the control diet group. On the other hand, in the high-fat diet + asperuloside group, the proportion of bacteria belonging to the phylum Bacteroides increased and the proportion of bacteria belonging to the phylum Bacteroides decreased as compared with the control diet group. In the control diet group and the high-fat diet group, Akkermansia muciniphila was below the detection limit, but in the high-fat diet + asperuloside group, the presence of Akkermansia muciniphila was detected. From the above results, it was confirmed that asperuloside has an effect of making the balance of the intestinal flora healthy.
Figure JPOXMLDOC01-appb-T000004
Figure JPOXMLDOC01-appb-T000004
Figure JPOXMLDOC01-appb-T000005
Figure JPOXMLDOC01-appb-T000005
試験例２
　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。
Figure JPOXMLDOC01-appb-T000006
 Test Example 2
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.
Figure JPOXMLDOC01-appb-T000006
　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、腸内細菌叢調整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 secondary effect of the intestinal flora regulating action.
　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、腸内細菌叢のバランスが改善されて健全な状態になっ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. This result suggests that ingestion of asperuloside and geniposidic acid improved the balance of the intestinal flora and brought it into a healthy state.
Figure JPOXMLDOC01-appb-T000007
Figure JPOXMLDOC01-appb-T000007
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、腸内細菌叢のバランスを健全な状態に改善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 improving the balance of the intestinal bacterial flora to a healthy state.
Figure JPOXMLDOC01-appb-T000008
Figure JPOXMLDOC01-appb-T000008
Figure JPOXMLDOC01-appb-T000009
Figure JPOXMLDOC01-appb-T000009
Figure JPOXMLDOC01-appb-T000010
Figure JPOXMLDOC01-appb-T000010

Claims (7)

  1. 　イリドイド骨格を有する化合物の、腸内細菌叢調整剤の製造のための使用。 Use of a compound having an iridoid skeleton for the production of an intestinal flora regulator.
  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、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.
  3. 　前記腸内細菌叢調整剤が、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。 The use according to claim 1 or 2, wherein the intestinal flora regulator is a food or drink or an internal medicine.
  4. 　前記腸内細菌叢調整剤が、腸内で、バクテロイデス門に属する細菌及びアッカーマンシア・ムシニフィラの比率を増加させ、且つファーミキューテス門に属する細菌の比率を低減させるために使用される、請求項１又は２に記載の使用。 The intestinal flora regulator is used to increase the proportion of bacteria belonging to the phylum Bacteroides and Akkermansia muciniphila in the intestine and to reduce the proportion of bacteria belonging to the phylum Bacteroides. Use according to 1 or 2.
  5. 　イリドイド骨格を有する化合物を、腸内細菌叢の調整が必要とされる者に投与又は摂取させる、腸内菌叢の調整方法。 A method for adjusting the intestinal flora, in which a compound having an iridoid skeleton is administered or ingested by a person who needs to adjust the intestinal flora.
  6. 　イリドイド骨格を有する化合物の、腸内細菌叢調整のための非治療的使用。 Non-therapeutic use of compounds with an iridoid skeleton for intestinal flora regulation.
  7. 　腸内細菌叢調整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 intestinal flora regulation.
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JP2012020945A (en) * 2010-07-13 2012-02-02 Kobayashi Pharmaceutical Co Ltd Bile acid secretion promoter
JP2015127340A (en) * 2009-05-12 2015-07-09 富士フイルム株式会社 Agent for regulating composition ratio of intestinal bacterial flora
CN109363044A (en) * 2018-12-05 2019-02-22 海南康来特生物科技有限公司 A kind of functional beverage and preparation method containing water-soluble capejasmine extract

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JP2015127340A (en) * 2009-05-12 2015-07-09 富士フイルム株式会社 Agent for regulating composition ratio of intestinal bacterial flora
JP2012020945A (en) * 2010-07-13 2012-02-02 Kobayashi Pharmaceutical Co Ltd Bile acid secretion promoter
CN109363044A (en) * 2018-12-05 2019-02-22 海南康来特生物科技有限公司 A kind of functional beverage and preparation method containing water-soluble capejasmine extract

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114681477A (en) * 2020-12-29 2022-07-01 中国科学院上海药物研究所 Application of iridoid glycoside compound in regulating intestinal flora

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