WO2021045138A1 - Composition for improving irritable bowel syndrome - Google Patents

Abstract

The present invention provides a novel composition for improving stool abnormalities or gastrointestinal diseases associated therewith such as irritable bowel syndrome. More specifically, a composition for improving stool abnormalities or gastrointestinal diseases associated therewith such as irritable bowel syndrome is used, the composition comprising at least one carotenoid including adonixanthin or a pharmaceutically acceptable salt thereof.

Description

Composition for amelioration of irritable bowel syndrome Reference of related application

This patent application is accompanied by a priority claim based on Japanese Patent Application No. 2019-161387 filed on September 4, 2019, and all the disclosures in the previous patent application are by citation. It is a part of this specification.

The present invention relates to a composition for improving bowel movement abnormalities or gastrointestinal diseases associated therewith, such as irritable bowel syndrome.

Symptoms such as diarrhea, constipation and other bowel movements, and abdominal pain are organically associated with various organic changes in the digestive tract such as the intestinal tract such as inflammation and tumors, as well as endoscopy and examinations using contrast agents. It is a symptom that is also seen in many diseases that are completely normal. Irritable bowel syndrome (IBS) is known as a disease exhibiting these symptoms. Irritable bowel syndrome causes abdominal symptoms such as abdominal pain and abdominal discomfort, and / or abnormal bowel movements such as constipation and diarrhea, even though no organic lesions such as inflammation and tumors are observed. It is a functional disease of the intestinal tract. Irritable bowel syndrome can be classified into constipation type, diarrhea type, mixed type and unclassified type based on the difference in the number of defecations and stool properties.

Currently, as treatment methods for irritable bowel syndrome, lifestyle-related improvement, diet therapy, and drug therapy are being performed. As the drug, an anticholinergic drug or the like is used. However, there is still a need for something that can effectively improve irritable bowel syndrome.

On the other hand, adonixanthin and astaxanthin are a kind of carotenoids and are widely distributed in animals, plants and microorganisms. In addition, it has been reported that adonixanthin and astaxanthin have various effects. For example, Patent Document 1 describes that a carotenoid mixture containing astaxanthin as a main component may be useful for preventing retinal damage.

However, no relationship between adonixanthin and / or astaxanthin and irritable bowel syndrome or other gastrointestinal disorders associated with bowel movements has been reported.

JP-A-2015-140346

The present invention provides new technical means for effectively ameliorating bowel movement abnormalities or gastrointestinal disorders associated therewith, such as irritable bowel syndrome.

We have now found that one or more carotenoids, including adonixanthine or a pharmaceutically acceptable salt thereof, effectively relieve bowel disorders or associated gastrointestinal disorders such as irritable bowel syndrome. Found to improve. The present invention is based on such findings.

The present invention includes the following inventions.
[1] A composition for ameliorating irritable bowel syndrome, which comprises one or more carotenoids containing adonixanthine or a pharmaceutically acceptable salt thereof.
[2] The composition according to [1], wherein the carotenoid further comprises astaxanthin or a pharmaceutically acceptable salt thereof.
[3] The composition according to [1] or [2], wherein the carotenoid is a microbial, animal or plant-derived product or a chemically synthesized product.
[4] The composition according to [3], wherein the microorganism is Paracoccus carotinifaciens.
[5] The composition according to any one of [1] to [4], wherein the irritable bowel syndrome has at least one symptom selected from the group consisting of abnormal bowel movements, abdominal pain, and abdominal discomfort. Stuff.
[6] Containing one or more carotenoids, including adonixanthine or a pharmaceutically acceptable salt thereof, for ameliorating at least one symptom selected from the group consisting of abnormal bowel movements, abdominal pain, and abdominal discomfort. Composition consisting of.
[7] The composition according to [6], wherein the carotenoid further comprises astaxanthin or a pharmaceutically acceptable salt thereof.
[8] The composition according to [6] or [7], wherein the abnormal bowel movement is diarrhea, constipation or a combination thereof.
[9] The composition according to any one of [1] to [8] for humans.
[10] The composition according to any one of [1] to [9], wherein the composition is a food or drink or a food additive.
[11] The composition according to any one of [1] to [10], wherein the composition is a functional food.
[12] The composition according to any one of [1] to [9], wherein the composition is a pharmaceutical product.
[13] Use of one or more carotenoids, including adonixanthine or a pharmaceutically acceptable salt thereof, in the manufacture of compositions for the amelioration of irritable bowel syndrome.
[14] A method of ameliorating irritable bowel syndrome in a subject, in which an effective amount of one or more carotenoids, including adonixanthine or a pharmaceutically acceptable salt thereof, is administered to the subject in need thereof. Or a method that involves feeding.
[15] Use of one or more carotenoids, including adonixanthine or a pharmaceutically acceptable salt thereof, for the amelioration of irritable bowel syndrome.
[16] One or more carotenoids containing adonixanthine or a pharmaceutically acceptable salt thereof for the amelioration of irritable bowel syndrome.
[17] Rn4.5s, C1qbp, Cbl, Prlr, Gene6430527G18Rik, Tuba1a, Gja1, Serpini1, 6530418L21Rik, Slit3, Slc1a1, Zfp605, Usp22, Eif3e, Stac3, Ccdc144b, Rpl31, Zfp101, Ccdc144b, Rpl31, Zfp101 , 5930436O19Rik, Chm, A230057D06Rik, Dclk1, Cdc123, Hmgb1, Zbtb11, Hp, Hsph1, IgG2akappa, VP7-specific Ab, Ig (lambda, constant), Ig (lambda, variable), Dbp, Nrg1, Faim3, and Serpine1 The composition according to any one of [1] to [12] for suppressing the expression of at least one gene selected from the group.
[18] Jph4, Tshz3, Gmppa, Lmtk2, Scyl3, Dcaf8, Tnfrsf1a, Mast3, Uba52, Commd5, Wdr3, Arhgap44, Metap1, Terf2, Evi5, Dcun1d4, Rrm1, skiv2l2, HistMf2 , Cox6b2, Fxyd6, Nckap1l, Brdt, Hnrnph3, Rpl7a, Rps3, Оnecut2, Pоlr1c, Srsf5, Pts, Chchd5, Echdc2, Fuca1, Anks1, Ap1s1, Kcnq2, Bcan, Rap2b, 1 Rpl17, Secisbp2, Pla2g6, Aig1, Reg3a, Reg2, Reg3d, Prss2, Ctrc, Pla2g1b, Pdia2, Erp27, Ctrb1, Saa3, Idh2, Dyrk1b, Rnase1, Reg3g, Mrps35, Bfar, Expi, Rb1 Ctrl, Cpa2, Cpb1, Try5, Cpa1, Gp2, Ceacam12, Zfp362, Lepr, Tff2, Tmed6, Bpgm, Amy2a5, Cela2a, Cela3b, Pnliprp1, Cel, Pnlip, Clps, Try4, Akr1c18, Psmb4, Polr2 Any one of [1] to [12] and [17] for promoting the expression of at least one gene selected from the group consisting of Rbpjl, Atp2b4, Cnih2, Lage3, Rab5a, Pigyl, Rpl17 and Akr1c18. The composition according to one.

According to the present invention, it is possible to effectively improve a subject's bowel movement abnormality or a gastrointestinal disease associated therewith, for example, irritable bowel syndrome.

Graph showing the difference between the number of defecations on the 11th day (1st day of water avoidance stress load) and the number of defecations on the 14th day (4th day of water avoidance stress load) in the control group, astaxanthin group, or adonixanthin group. Is. It shows a gene whose expression was upregulated in the frontal lobe by water avoidance stress and whose upregulation was suppressed by both astaxanthin and adonixanthin. _{In the Fold change (log 2} ) in the figure, the Fold change of the fluorescence intensity of the gene in the control group with WAS, the astaxanthin administration group, or the adonixanthin administration group was converted by _{log 2 with respect to the fluorescence intensity of the gene in the control group without WAS.} Indicates a value. It shows a gene whose expression was upregulated in the frontal lobe by water avoidance stress and whose upregulation was suppressed by astaxanthin. The Folder change (log ₂ ) in the figure is the same as that in FIG. It shows a gene whose expression was upregulated in the frontal lobe by water avoidance stress and whose upregulation was suppressed by adonixanthin. The Folder change (log ₂ ) in the figure is the same as that in FIG. A gene whose expression was suppressed in the frontal lobe by water avoidance stress and whose expression suppression was alleviated by both astaxanthin and adonixanthin is shown. The Folder change (log ₂ ) in the figure is the same as that in FIG. It shows a gene whose expression was suppressed in the frontal lobe by water avoidance stress and whose expression was alleviated by astaxanthin. The Folder change (log ₂ ) in the figure is the same as that in FIG. It shows a gene whose expression was suppressed in the frontal lobe by water avoidance stress and whose expression was alleviated by adonixanthine. The Folder change (log ₂ ) in the figure is the same as that in FIG. A gene whose expression was upregulated in the large intestine by water avoidance stress and whose upregulation was suppressed by both astaxanthin and adonixanthin is shown. The Folder change (log ₂ ) in the figure is the same as that in FIG. It shows a gene whose expression was upregulated in the large intestine by water avoidance stress and whose upregulation was suppressed by astaxanthin. The Folder change (log ₂ ) in the figure is the same as that in FIG. It shows a gene whose expression was upregulated in the large intestine by water avoidance stress and whose upregulation was suppressed by adonixanthine. The Folder change (log ₂ ) in the figure is the same as that in FIG. A gene whose expression was suppressed in the large intestine by water avoidance stress and whose expression was alleviated by both astaxanthin and adonixanthin is shown. The Folder change (log ₂ ) in the figure is the same as that in FIG. It shows a gene whose expression was suppressed in the large intestine by water avoidance stress and whose expression was alleviated by astaxanthin. The Folder change (log ₂ ) in the figure is the same as that in FIG. It shows a gene whose expression was suppressed in the large intestine by water avoidance stress and whose expression was alleviated by adonixanthine. The Folder change (log ₂ ) in the figure is the same as that in FIG.

Specific description of the invention

The composition of the present invention for ameliorating bowel movements or gastrointestinal disorders associated therewith, such as irritable bowel syndrome, comprises one or more carotenoids comprising adonixanthine or a pharmaceutically acceptable salt thereof. It is characterized by becoming. It is a surprising fact that the above-mentioned carotenoids can remarkably suppress bowel movement abnormalities as shown in Test Example 1 described later.

Carotenoids According to one aspect, carotenoids of the invention include one or more carotenoids, including adonixanthine or a pharmaceutically acceptable salt thereof.

The chemical formula of adonixanthin is 3,3'-dihydroxy-β, β- carotene-4-one (C 40 H 54 0 3, molecular weight 582.869) and the structural formula is represented by the following formula.

According to a preferred embodiment, the carotenoids of the present invention include combinations or mixtures of two or more carotenoids containing astaxanthin or a pharmaceutically acceptable salt thereof as well as adonixanthin or a pharmaceutically acceptable salt thereof. ..

Astaxanthin belongs to the kind xanthophyll carotenoid red pigment, its chemical formula is 3,3'-dihydroxy-β, β- carotene-4,4'-dione (C 40 H 52 0 4, molecular weight 596.852) Yes, the structural formula is represented by the following formula.

According to another aspect, the carotenoids of the present invention include one or more carotenoids selected from adonixanthin, astaxanthin, and pharmaceutically acceptable salts thereof.

According to still another aspect, the carotenoid of the present invention includes one or more carotenoids containing astaxanthin or a pharmaceutically acceptable salt thereof.

Further, the carotenoid of the present invention may be a free form or a fatty acid ester form. From the viewpoint of absorbability, it is preferable to use a free carotenoid.

Further, the carotenoid of the present invention may be a stereoisomer such as an optical isomer or a cis-trans isomer.
The optical isomer of adonixanthine is at least one selected from the group consisting of 3S, 3'R-form, 3S, 3'S-form, 3R, 3'S-form and 3R, 3'R-form. It can be mentioned, preferably 3S, 3'R-form. The cis-trans isomer of adonixanthin may be a cis isomer, a trans isomer or a combination thereof. The cis-trans isomer of adonixanthine is preferably a combination of cis and trans isomers.
Examples of the optical isomer of astaxanthin include at least one selected from the group consisting of 3S, 3'S-form, 3S, 3'R-form (meso-form), and 3R, 3'R-form. It is preferably a 3S, 3'S-form. In addition, astaxanthin may be a conjugated double bond cis form in the center of the molecule, an isomer of a trans form, or a combination thereof. Examples of the cis form include a 9-cis form, a 13-cis form, a 15-cis form, a Zisis form, or a combination thereof. Astaxanthin is preferably a combination of cis and trans isomers.

Further, it is preferable to use the carotenoid of the present invention as an active ingredient.

In the present invention, the carotenoid may be in the form of pharmaceutically acceptable salts, and these salts are also included in the carotenoid in the present invention. In the present invention, carotenoids may also form salts with acids or bases. In the present invention, the pharmaceutically acceptable salt is not particularly limited as long as it forms a pharmaceutically acceptable salt with adonixanthin and / or astaxanthin. Specifically, for example, hydrohalogenate (for example, hydrofluoride salt, hydrochloride, hydrobromide, hydroiodide, etc.), inorganic acid salt (for example, sulfate, nitrate, excess). Chlorates, phosphates, carbonates, bicarbonates, etc.), organic carboxylates (eg, acetates, oxalates, maleates, tartrates, fumarates, citrates, etc.), organic sulfone Acid salts (eg, methane sulfonate, trifluoromethane sulfonate, ethane sulfonate, benzene sulfonate, toluene sulfonate, camphor sulfonate, etc.), amino acid salts (eg, asparaginate, glutamate, etc.) ), Tertiary amine salts, alkali metal salts (eg, sodium salts, potassium salts, etc.), alkaline earth metal salts (eg, magnesium salts, calcium salts, etc.), etc., but are not limited thereto.

The carotenoid of the present invention may be a commercially available product, or is produced by a chemically synthesized product produced by a conventional chemical synthesis method, a fermentation method using a microorganism, or extraction and purification from a microorganism, an animal, a plant, or the like. Microbial, animal or plant-derived products (naturally-derived) can be used. Such microorganisms include bacteria, algae and yeast. Here, the microorganism, animal or plant-derived product is a product obtained from the microorganism, animal or plant, and is preferably a product derived from a Paracoccus genus microorganism. Here, examples of the Paracoccus genus microorganisms include Paracoccus carotinifaciens, Paracoccus marcusii, Paracoccus haeundaensis and Paracoccus haeundaensis and Paracoccus zeaxianthis. Is preferably used, and more preferably Paracoccus carotinifaciens. Examples of specific strains of Paracoccus microorganisms include Paracoccus carotinifaciens E-396 strain and Paracoccus bacterium A581-1 strain (FERM BP-4671), and these mutant strains are also preferably used in the present invention. Be done.

For example, the following methods can be mentioned as methods for extracting and purifying astaxanthin and adonixanthin from microorganisms. The dried cells of Paracoccus carotinifaciens are subjected to room temperature extraction using acetone, and the extract is concentrated to dryness with an evaporator. The concentrated dry matter is dissolved in chloroform, and each carotenoid is separated on a silica gel column (using the product name "silica gel 60" (Nacalai Tesque, Inc.) as silica gel). For example, the fraction eluted with acetone from the silica gel column is further purified by HPLC (Shim-pack PRC-SIL, 15 μm, 25 cm × 20 mm ID (Shimadzu Corporation), acetone: hexane (4: 6)). , Adonixanthin free form can be obtained. Further, the astaxanthin free form can be obtained as crystals by concentrating the fraction eluted with acetone: hexane (5: 5) from the silica gel column and leaving it at 4 ° C.

Furthermore, in the composition of the present invention, a carotenoid mixture containing adonixanthin and astaxanthin may be used. Such a carotenoid mixture preferably further comprises at least one selected from the group consisting of adonylbin, canthaxanthin, asteroidenone, β-carotene, echinenone and 3-hydroxyechinenone. Further, it is more preferable that the carotenoid mixture further contains adonylvin, canthaxanthin, asteroidenone, β-carotene, echinenone and 3-hydroxyechinenone. For example, the carotenoid mixture extracted from the dried cells of Paracoccus carotinifaciens according to the methods described in JP-A-2007-261972 and JP-A-2009-50237 preferably contains astaxanthin and adonixanthin. Further comprises at least one selected from the group consisting of adonylvin, canthaxanthin, asteroidenone, β-carotene, echinenone, and 3-hydroxyechinenone.

The content of the carotenoid in the composition of the present invention is not particularly limited as long as it does not interfere with the effect of the present invention, but is, for example, 0.001 to 99% by mass, preferably 0.003 to 0.003 to the whole composition. It is 98% by mass, more preferably 0.005 to 97% by mass, still more preferably 0.01 to 96% by mass. The content of the carotenoid is, for example, the content of adonixanthin when the carotenoid is only adonixanthin, and the carotenoid is a mixture of a plurality of types of carotenoids (for example, adonixanthin and astaxanthin). If so, it is the total content of multiple carotenoids. The content of astaxanthin and adonixanthin in the composition of the present invention can be measured by the HPLC method according to the procedure described in Toxicol Rep. 2014 Aug 25; 1: 582-588.

The composition of the present invention can be provided as a composition containing the above carotenoids and optionally an orally acceptable or pharmaceutically acceptable additive. As the above additives, solvents, solubilizers, solubilizers, lubricants, emulsifiers, isotonic agents, stabilizers, preservatives, preservatives, surfactants, adjusters, chelating agents, pH adjusters, buffers. Examples include agents, excipients, thickeners, colorants, fragrances or fragrances.

The composition of the present invention can be prepared by a known method such as mixing, dissolving, dispersing and suspending the above carotenoid and optionally an orally acceptable or pharmaceutically acceptable additive. Further, in the preparation of the composition of the present invention, the mixture, solution, dispersion, suspension and the like prepared by the above method are subjected to homogenization treatment and sterilization treatment as long as the effects of the present invention are not impaired. May be good.

The form of the composition of the present invention is not particularly limited as long as it does not interfere with the effect of the present invention, and may be solid, semi-solid (including paste and gel) or liquid (including oil and slurry). It may be solid or liquid.

The dosage form of the composition of the present invention is not particularly limited as long as it does not interfere with the effects of the present invention, but is an injection, a tablet (for example, a naked tablet, a sugar-coated tablet, a film-coated tablet, an enteric coated tablet, a sustained-release tablet, an oral cavity). Internally disintegrating tablets, sublingual tablets, chewable tablets, etc.), capsules (eg, hard capsules, soft capsules), elixirs, pills, powders, powders, granules, liquids, troches, syrups, dry syrups, Emulsions, suspensions, liquids, jellies, inhalants, aerosols, powder inhalants, suppositories, ointments, creams, gels, patches, bops, lotions, drops, eye ointments, eye drops , Nasal drops and the like. The dosage form of the composition of the present invention is preferably a dosage form for oral ingestion or administration, and is a tablet, capsule, pill, powder, powder, granule, syrup, dry syrup, emulsion, liquid, suspension. Examples include turbid agents, liquid agents, troche agents, jelly agents and the like.

The method of administration or ingestion of the composition of the present invention is not particularly limited, but is limited to injection such as infusion, intravenous injection, intramuscular injection, subcutaneous injection, intradermal injection, oral, transmucosal, transdermal, intranasal, oral. Intra- and intraperitoneal administration or ingestion is mentioned, and oral ingestion or administration is preferable.

Examples of the composition of the present invention include foods and drinks such as foods and beverages, food additives, feeds, pharmaceuticals, quasi-drugs, and cosmetics, and foods and drinks are preferable from the viewpoint of convenience of ingestion.

The food or drink of the present invention is prepared by preparing the composition of the present invention as a food or drink as it is, various proteins, sugars, fats, trace elements, vitamins, plant extracts, and other active ingredients (for example, lactic acid bacteria, Bacillus spp.) Bacteria such as Bacillus), fungi such as yeast, dietary fiber, DHA or EPA) and the like may be further blended, and the composition of the present invention may be liquid, semi-solid or solid such as a solution. , The composition of the present invention may be added to general foods and drinks.

Specific examples of the above-mentioned foods and drinks include instant foods such as instant noodles, retort foods, canned foods, microwave foods, instant soups / miso juices, and freeze-dried foods; soft drinks, fruit juice drinks, vegetable drinks, and soy milk. Beverages, coffee beverages, tea beverages, powdered beverages, concentrated beverages, alcoholic beverages, jelly beverages and other beverages; nutritional drinks; bread, pasta, noodles, cake mixes, bread flour and other wheat flour products; candy, gummy, jelly, caramel, Chewing gum, chocolate, cookies, biscuits, cakes, pies, snacks, crackers, Japanese sweets, desserts and other sweets; nutrition bar; sports bar; sauces, tomato processing seasonings, flavor seasonings, cooking mixes, sauces, dressings , Soups, curry and stew ingredients, etc .; processed fats and oils, butter, margarine, mayonnaise and other fats and oils; dairy beverages, yogurts, lactic acid bacteria beverages, ice creams, creams and other dairy products; canned agricultural products , Jam, marmalades, processed agricultural products such as cereals; processed livestock foods such as ham, bacon, sausage, and roasted pork: frozen foods and the like can be exemplified, but not limited thereto.

The foods and drinks of the present invention include health foods, supplements, functional foods (including, for example, foods for specified health use, foods with nutritional function or foods with functional claims), special-purpose foods (for example, foods for the sick, preparations for infants). It also includes powdered milk, pregnant women, powdered milk for lactating women or foods for people who have difficulty swallowing or chewing) or liquid prepared milk for infants (also referred to as liquid milk for infants). As will be described later, the composition of the present invention has an effect of improving irritable bowel syndrome or an effect of improving at least one symptom selected from the group consisting of abnormal bowel movements, abdominal pain, and abdominal discomfort. Food and drink are provided for improving irritable bowel syndrome, or for improving at least one symptom selected from the group consisting of abnormal bowel movements, abdominal pain, and abdominal discomfort. That is, the food and drink of the present invention can be provided as a food and drink for a person with abdominal pain, for a person with abdominal discomfort, or for a person with abnormal bowel movements. Furthermore, in foods and drinks such as functional foods, indications such as "for those who have a stomachache", "for those who have a stomach discomfort", and "for those who have problems with bowel movements (for example, diarrhea, constipation, etc.)" May be provided with.

The intake or dose of the composition of the present invention is not particularly limited, and the formulation of the composition, the type and purity of the carotenoid, the type of the subject, the age or body weight of the subject, the symptoms, the intake or administration time, and the form of the composition. It can be determined depending on the ingestion or administration method, the combination of carotenoids or drugs other than the carotenoid of the present invention, and the like. In addition, the composition of the present invention is an effective amount for improving irritable bowel syndrome or at least one symptom selected from the group consisting of abnormal bowel movements, abdominal pain, and abdominal discomfort. It is preferably composed of the form of daily intake units. For example, when the composition of the present invention is orally ingested, the carotenoid of the present invention is in the range of 0.01 to 1000 mg, preferably 0.05 to 100 mg, more preferably 0.1 to 50 mg per day for an adult weighing 60 kg. The carotenoid can be added to the composition to the intake or dose of. Carotenoids or drugs other than the carotenoids of the present invention used in combination with the carotenoids of the present invention can also be appropriately determined based on the clinically used intake or dose, respectively.

Further, the daily intake or dose of the composition of the present invention is appropriately selected according to the formulation of the composition and the like, similarly to the intake or dose of the composition described above. The daily intake or dose of the composition of the present invention may be, for example, one or more times ingested or administered to the subject, but it is preferable that the subject is ingested or administered once. .. Therefore, the number of times of ingestion or administration of the composition of the present invention per day may be 1 to 5 times a day, preferably 1 to 3 times a day, and more preferably once a day. Is.

According to one aspect of the present invention, the subject to which the composition of the present invention is applied is not particularly limited as long as it does not interfere with the effects of the present invention, but is preferably a mammal, more preferably a primate such as a human. Dogs and cats. The subject may be a healthy person (healthy animal) or a patient (patient animal).

According to the composition of the present invention, the number of defecations in a subject with irritable bowel syndrome can be effectively suppressed. Therefore, according to the composition of the present invention, it is possible to improve irritable bowel syndrome. Therefore, according to one aspect of the invention, the composition of the invention is provided as a composition for ameliorating irritable bowel syndrome. Here, the term "improvement" of a disease or "improvement" of a symptom in the present specification merely includes the meaning of "treatment" of stopping, alleviating or delaying the progression or aggravation of a disease or symptom by medical practice. It also includes stopping, alleviating or delaying the development or exacerbation of the disease or symptoms by non-medical practice. Furthermore, "improvement" includes the meaning of "prevention" in which the occurrence or recurrence of a disease or symptom is prevented by non-medical or medical practice in advance in preparation for the expected deterioration of the disease or symptom.

The irritable bowel syndrome is not particularly limited, and examples thereof include constipation type, diarrhea type, mixed type, and unclassified type irritable bowel syndrome, and preferably constipation type, diarrhea type, or mixed type irritable bowel syndrome. It is a syndrome. The classification of such irritable bowel syndrome is based on the Rome III diagnostic criteria (Longstreth et al., Gastroenterology, 2006; 130: 1480-1491). The irritable bowel syndrome is selected from the group consisting of abnormal bowel movements (eg, constipation, diarrhea, or a combination thereof, etc.) and abdominal symptoms (eg, abdominal pain, abdominal bloating, abdominal discomfort, or a combination thereof, etc.). May have at least one symptom.

Also, according to another aspect of the invention, the compositions of the invention have abnormal bowel movements (eg, constipation, diarrhea, or a combination thereof, etc.) and abdominal symptoms (eg, abdominal pain, bloating, abdominal discomfort or a combination thereof). It is possible to improve at least one symptom selected from the group consisting of combinations, etc.). Such a symptom may be a symptom of a gastrointestinal disease such as an intestinal disease or a symptom caused by the symptom. Therefore, the composition of the present invention is provided as a composition for improving at least one symptom selected from the group consisting of abnormal bowel movements and abdominal symptoms or gastrointestinal diseases associated therewith. Examples of the gastrointestinal tract disease include functional gastrointestinal tract diseases such as diseases caused by the environment and functional bowel diseases. Specific examples of functional bowel disease include functional abdominal distension, functional constipation, functional diarrhea, irritable bowel syndrome, and unspecified functional bowel disease.

According to one aspect of the present invention, the composition of the present invention can effectively suppress the expression of a gene whose expression is enhanced in the frontal lobe or the large intestine. Here, suppression of gene expression may include suppression or relaxation of gene expression enhancement. Such genes are preferably genes whose expression is upregulated in the frontal lobe or large intestine due to stress, the frontal lobe of subjects with irritable bowel syndrome and / or subjects with at least one symptom selected from bowel movement abnormalities and abdominal symptoms. Genes whose expression is upregulated in the large intestine are more preferred. The stress is not particularly limited, and includes psychological and / or physical stress. Specific examples thereof include water avoidance stress, restraint stress, colonic extension stimulation using a balloon, water immersion stress, and low temperature stress. , Chronic stress of mother-infant separation in early childhood, TNBS (2,4,6-trinitrobenzene sulfonic acid) administration inflammation, mouse Trichinella spiralis infection, and water avoidance stress is preferable.

The genes whose expression is upregulated in the frontal lobe as described above include genes related to stress, inflammation and / or obesity (eg, Rn4.5s, C1qbp, Cbl, Prlr, Dclk1, etc.), genes related to nerve cell development and / or disorders (eg, genes related to nerve cell development and / or disorders). For example, Gene6430527G18Rik, Tuba1a, Gja1, Serpini1, 6530418L21Rik, Slit3, Slc1a1, Zbtb11, etc., genes related to DNA repair (eg Zfp605, Hmgb1, etc.), genes related to cell proliferation, cell cycle and / or tumor (eg Usp22, etc.) , Genes related to cell cycle, cell proliferation, diabetes, inflammation (Cdc123 etc.), genes related to apoptosis and / or cell aging (eg Eif3e etc.), genes related to cell motility (eg Stac3 etc.), genes related to pain (eg Stac3 etc.) Ccdc144b, etc.), transcription genes (eg, Rpl31, Zfp101, Zfp605, etc.), NAD metabolism genes (eg, Nadk, etc.), uric acid metabolism genes (eg, 1190003J15Rik, etc.), lncRNA genes (eg, 4833447P13Rik, etc.), Genes related to retinal disorders (eg, Chm, etc.), E130309D02Rik, 5930436O19Rik, A230057D06Rik, etc. can be mentioned.

The genes whose expression is upregulated in the large intestine include genes related to stress and / or inflammation (eg, Hp, etc.), genes related to cell proliferation, cell cycle and / or tumor (eg, Hsph1 etc.), and genes related to immune response. (For example, IgG2akappa, VP7-specific Ab, Ig (lambda, constant), Ig (lambda, variable), etc.), genes related to circadianism and / or hypertension (eg, Dbp, etc.), genes related to nerve cell development and / or protection Examples include genes for anti-apoptosis and / or tumors (eg, Faim3, etc.), genes for coagulation / fibrinolytic systems and / or apoptosis (eg, Serpine1 etc.), and the like.

According to a preferred embodiment of the present invention, the composition of the present invention comprises a gene whose expression is enhanced in the frontal lobe, preferably a gene whose expression is enhanced in the frontal lobe due to stress, specifically, Rn4.5s, C1qbp, Cbl, Prlr, Gene6430527G18Rik, Tuba1a, Gja1, Serpini1, 6530418L21Rik, Slit3, Slc1a1, Zfp605, Usp22, Eif3e, Stac3, Ccdc144b, Rpl31, Zfp101, Zfp605, Nadk, E130309D02Rik It is possible to suppress the expression of at least one gene selected from the group consisting of Cdc123, Hmgb1 and Zbtb11.

According to another preferred embodiment of the invention, the composition of the invention comprises a gene whose expression is upregulated in the large intestine, preferably a gene whose expression is upregulated in the large intestine due to stress, specifically Hp, Hsph1,. It is possible to suppress the expression of at least one gene selected from the group consisting of IgG2akappa, VP7-specific Ab, Ig (lambda, constant), Ig (lambda, variable), Dbp, Nrg1, Faim3, and Serpine1. is there.

According to one aspect of the present invention, the composition of the present invention can effectively promote the expression of a gene whose expression is suppressed in the frontal lobe or the large intestine. Here, promotion of gene expression may include relaxation of suppression of gene expression. Such genes are preferably genes whose expression is suppressed in the frontal lobe or large intestine by stress, and are the frontal lobe or the frontal lobe of subjects with irritable bowel syndrome and / or subjects with at least one symptom selected from abnormal bowel movements and abdominal symptoms. Genes whose expression is suppressed in the large intestine are more preferred.

The genes whose expression is suppressed in the frontal lobe as described above include genes related to nerve cell development and / or disorders (eg, Jph4, Tshz3, Gmppa, Lmtk2, Scyl3, Dcaf8, Anks1, Ap1s1, Kcnq2, Bcan, etc.), stress and / Or genes related to inflammatory response (eg, Tnfrsf1a, Mast3, Uba52, etc.), genes related to cell proliferation, cell cycle and / or tumor (eg, Commd5, Wdr3, Arhgap44, Metap1, Terf2, Evi5, Dcun1d4, Rrm1, skiv2l2, Hist2h2ac , Etc.), genes related to mitochondria and / or energy production (eg, Pmpcb, Mtrf1, Atp11b, Mfn1, Mrps35, etc.), genes related to cell motility (eg, Cox6b2, etc.), genes related to cell membrane (eg, Fxyd6, Nckap1l, etc.), Genes related to transcription and / or translation (eg Brdt, Hnrnph3, Rpl7a, Rps3, Оnecut2, Pоlr1c, Srsf5, etc.), genes related to diabetes, obesity and / or lipid metabolism (eg, Pts, Chchd5, Echdc2, Fuca1, etc.), cells Examples include genes related to the skeleton (eg, Rap2b, etc.), genes related to the possibility of prostaglandin E production (eg, 1700113I22Rik (Ptges3l), etc.), and the like.

The above-mentioned genes whose expression is suppressed in the colon include genes related to stress, oxidation, inflammatory response, digestive enzymes and / or microbial defense (for example, Reg1, Prss1, Pnliprp2, Rpl17, Secisbp2, Pla2g6, Aig1 etc.) and stress. , Oxidation, inflammatory response, digestive enzymes and / or genes for microbial defense (eg, Reg3a, Reg2, Reg3d, Prss2, Ctrc, Pla2g1b, Pdia2, Erp27, etc.), Antioxidant and / or anti-inflammatory genes (eg, Ctrb1, Saa3, Idh2, Dyrk1b, etc.), genes for anti-inflammatory and / or microbial defense (eg, Rnase1, etc.), genes for anti-apoptosis, tumor and / or mitochondria (eg, Reg3g, Mrps35, Bfar, etc.), apoptosis, autophagy and / Or genes for antitumor (eg, Expi, Rb1cc1, Eaf1, etc.), genes for apoptosis and / or antitumor (eg, Serpini2, etc.), genes for anti-apulosis, tumor and / or Crohn's disease (eg, Cuzd1, Ctrl, Cpa2, Cpb1, Try5, Cpa1, Gp2, etc., genes related to immune response (eg, Ceacam12, Zfp362, etc.), genes related to immune response and / or anti-inflammatory (eg, Lepr, Tff2, etc.), glucose metabolism and / or diabetes Genes (eg, Tmed6, Bpgm, etc.), lipid metabolism, obesity and / or tumor genes (eg, Amy2a5, Cela2a, Cela3b, Pnliprp1, Cel, Pnlip, Clps, Try4, etc.), steroid metabolism genes (eg, Akr1c18, etc.) ), Genes related to cell proliferation and / or tumor (eg, Psmb4, Polr2c, etc.), Genes related to cell development (eg, Osr2, Eml1, etc.), Genes related to cell development, homeostasis and / or digestive enzymes (eg, Rbpjl, etc.), Genes for nerve cell protection (eg, Atp2b4, etc.), genes for gout (eg, Cnih2, etc.), genes for translation and / or metabolism (eg, Lage3, Rab5a, Pigyl, etc.), genes for cell proliferation control and / or anti-atherome (For example, Rpl17, etc.).

Therefore, according to a preferred embodiment of the present invention, the composition of the present invention comprises a gene whose expression is suppressed in the frontal lobe, preferably a gene whose expression is suppressed in the frontal lobe due to stress, specifically, Jph4, Tshz3, and the like. Gmppa, Lmtk2, Scyl3, Dcaf8, Tnfrsf1a, Mast3, Uba52, Commd5, Wdr3, Arhgap44, Metap1, Terf2, Evi5, Dcun1d4, Rrm1, skiv2l2, Hist2h2ac, Pmpcb, Mtrf1 Selected from a group consisting of at least one gene from Brdt, Hnrnph3, Rpl7a, Rps3, Оnecut2, Pоlr1c, Srsf5, Pts, Chchd5, Echdc2, Fuca1, Anks1, Ap1s1, Kcnq2, Bcan, and Rap2b, 1700113I22Rik (Ptges3l). It is possible to promote expression.

According to another preferred embodiment of the present invention, the composition of the present invention comprises a gene whose expression is suppressed in the large intestine, preferably a gene whose expression is suppressed in the large intestine due to stress, specifically, Reg1, Prss1, etc. Pnliprp2, Rpl17, Sexisbp2, Pla2g6, Aig1, Reg3a, Reg2, Reg3d, Prss2, Ctrc, Pla2g1b, Pdia2, Erp27, Ctrb1, Saa3, Idh2, Dyrk1b, Rnase1, Reg3g, Mrps35, Bfar Cuzd1, Ctrl, Cpa2, Cpb1, Try5, Cpa1, Gp2, Ceacam12, Zfp362, Lepr, Tff2, Tmed6, Bpgm, Amy2a5, Cela2a, Cela3b, Pnliprp1, Cel, Pnlip, Clps, Try4, Akr1c18, Psmb4 It is possible to promote the expression of at least one gene selected from the group consisting of Eml1, Rbpjl, Atp2b4, Cnih2, Lage3, Rab5a, Pigyl, Rpl17 and Akr1c18.

According to another aspect of the invention, a method of ameliorating a subject's irritable bowel syndrome, comprising administering or ingesting a composition comprising an effective amount of the carotenoid of the invention to the subject, or. A method of improving at least one symptom selected from the group consisting of abnormal bowel movements, abdominal pain, and abdominal discomfort of a subject is provided. According to yet another aspect of the invention, a method of ameliorating a subject's irritable bowel syndrome or ameliorating at least one symptom selected from the group consisting of a subject's bowel movements, abdominal pain, and abdominal discomfort. A method is provided that comprises administering or ingesting an effective amount of the carotenoid of the invention to a subject in need thereof. According to yet another aspect of the invention, a gene whose expression is upregulated in the frontal lobe or large intestine of the subject, comprising administering or ingesting a composition comprising an effective amount of the carotenoid of the invention to the subject. A method of suppressing the expression of a gene, or a method of promoting the expression of a gene whose expression is suppressed in the frontal lobe or the large intestine of a subject is provided. According to still another aspect of the present invention, a method for suppressing the expression of a gene whose expression is enhanced in the frontal lobe or the large intestine of the subject, or a method for promoting the expression of a gene whose expression is suppressed in the frontal lobe or the large intestine of the subject. Provided is a method comprising administering or ingesting an effective amount of the carotenoid of the present invention to a subject in need thereof. Here, the "effective amount" can be set in the same manner as the content of the carotenoid of the present invention in the daily intake unit. Symptoms of the irritable bowel syndrome include abnormal bowel movements, abdominal symptoms (for example, abdominal pain, abdominal discomfort, etc.), or a combination thereof, and abnormal bowel movements and abdominal symptoms are preferable. The above method can also be applied to the subject only by non-medical practice. Accordingly, according to another aspect, a method of ameliorating a subject's irritable bowel syndrome, which comprises administering or ingesting a composition comprising an effective amount of the carotenoid of the present invention to the subject, or subject. A method (excluding medical practice) for improving at least one symptom selected from the group consisting of abnormal bowel movements, abdominal pain, and abdominal discomfort is provided. According to yet another aspect, a method for improving the irritable bowel syndrome of the subject, or a method for improving at least one symptom selected from the group consisting of abnormal bowel movement, abdominal pain, and abdominal discomfort of the subject. Provided is a method (excluding medical practice) comprising administering or ingesting an effective amount of the carotenoid of the present invention to a subject in need thereof. The above method of the present invention can be carried out according to the contents described in the present specification in the composition of the present invention.

Also, according to another aspect of the invention, for the improvement of irritable bowel syndrome, or for the improvement of at least one symptom selected from the group consisting of abnormal bowel movements, abdominal pain, and abdominal discomfort. , The use of the carotenoids of the present invention is provided. According to yet another aspect of the present invention, the present invention is used to suppress the expression of a gene whose expression is enhanced in the frontal lobe or the large intestine, or to promote the expression of a gene whose expression is suppressed in the frontal lobe or the large intestine. The use of the carotenoids of the invention is provided.

Also, according to another aspect of the invention, for the improvement of irritable bowel syndrome, or for the improvement of at least one symptom selected from the group consisting of abnormal bowel movements, abdominal pain, and abdominal discomfort. The use of the carotenoids of the present invention in the manufacture of compositions is provided. According to yet another aspect of the present invention, a composition for suppressing the expression of a gene whose expression is enhanced in the frontal lobe or the large intestine, or for promoting the expression of a gene whose expression is suppressed in the frontal lobe or the large intestine. The use of the carotenoids of the present invention in the manufacture of the above is provided.

Also, according to another aspect of the invention, for the improvement of irritable bowel syndrome, or for the improvement of at least one symptom selected from the group consisting of abnormal bowel movements, abdominal pain, and abdominal discomfort. , The carotenoids of the present invention are provided. According to yet another aspect of the present invention, the present invention is used to suppress the expression of a gene whose expression is enhanced in the frontal lobe or the large intestine, or to promote the expression of a gene whose expression is suppressed in the frontal lobe or the large intestine. The carotenoids of the invention are provided.

Any of the above-mentioned uses and aspects of the compound (carotenoid) can be carried out according to the description regarding the composition or method of the present invention.

According to another aspect of the invention, a composition comprising one or more carotenoids selected from astaxanthin, adonixanthin and pharmaceutically acceptable salts thereof is upregulated in the frontal lobe or colon. It is possible to effectively suppress the expression of a gene and / or effectively promote the expression of a gene whose expression is suppressed in the frontal lobe or the colon. Therefore, the present invention further effectively suppresses the expression of genes whose expression is enhanced in the frontal lobe or large intestine, and / or effectively promotes the expression of genes whose expression is suppressed in the frontal lobe or large intestine. It also provides new technical means for this.

The present invention also includes the following inventions.
(I) A composition for suppressing the expression of a gene whose expression is enhanced in the frontal lobe or the large intestine, which comprises one or more carotenoids selected from astaxanthin, adonixanthin and pharmaceutically acceptable salts thereof. ..
(Ii) A composition for promoting the expression of a gene whose expression is suppressed in the frontal lobe or the large intestine, which comprises one or more carotenoids selected from astaxanthin, adonixanthin and pharmaceutically acceptable salts thereof. ..
(Iii) The composition according to (i) or (ii), wherein the gene is a gene whose expression is enhanced or suppressed by stress.
(Iv) The composition according to any one of (i) to (iii), wherein the carotenoid is a microbial, animal or plant-derived product or a chemically synthesized product.
(V) The composition according to (iv), wherein the microorganism is Paracoccus carotinifaciens.
(Vi) Any one of (i) to (v) for improving a disease or symptom associated with the expression of a gene whose expression is upregulated in the frontal lobe or the large intestine, or a gene whose expression is suppressed in the frontal lobe or the large intestine. The composition according to one.
(Vii) It comprises administering or ingesting an effective amount of one or more carotenoids selected from astaxanthin, adonixanthin, and pharmaceutically acceptable salts thereof to the subject. A method of suppressing the expression of a gene whose expression is upregulated in the frontal lobe or the large intestine in a subject.
(Viii) It comprises administering or ingesting an effective amount of one or more carotenoids selected from astaxanthin, adonixanthin, and pharmaceutically acceptable salts thereof to the subject. A method of promoting the expression of a gene whose expression is suppressed in the frontal lobe or the large intestine in a subject.
(Ix) One or more carotenoids selected from astaxanthin, adonixanthin, and pharmaceutically acceptable salts thereof in the manufacture of compositions for suppressing the expression of genes whose expression is upregulated in the frontal lobe or large intestine. Use of.
(X) Of one or more carotenoids selected from astaxanthin, adonixanthin and pharmaceutically acceptable salts thereof in the manufacture of compositions for promoting expression of genes whose expression is suppressed in the frontal lobe or large intestine. use.
(Xi) One or more carotenoids selected from astaxanthin, adonixanthin, and pharmaceutically acceptable salts thereof for suppressing the expression of genes whose expression is upregulated in the frontal lobe or large intestine.
(Xii) One or more carotenoids selected from astaxanthin, adonixanthin, and pharmaceutically acceptable salts thereof for promoting the expression of genes whose expression is suppressed in the frontal lobe or large intestine.

According to one embodiment of the present invention, the expression of a gene whose expression is enhanced in the frontal lobe or the large intestine is effectively suppressed, and / or the expression of a gene whose expression is suppressed in the frontal lobe or the large intestine is effectively suppressed. Can be promoted.

According to one aspect of the invention, a composition comprising one or more carotenoids selected from astaxanthin, adonixanthin and pharmaceutically acceptable salts thereof of the invention can be expressed in the frontal lobe or large intestine. The expression of a gene that is enhanced, preferably a gene whose expression is enhanced in the frontal lobe or the large intestine due to stress, can be effectively suppressed. Here, suppression of gene expression may include suppression of enhanced expression of a gene whose expression has been enhanced.

According to one aspect of the invention, for example, when the carotenoid of the invention contains adonixanthin, the genes whose expression is upregulated in the frontal lobe include genes related to stress, inflammation and / or obesity (eg, Rn4. 5s, C1qbp, Cbl, Prlr, Dclk1, etc.), genes related to nerve cell development and / or disorders (eg Gene6430527G18Rik, Tuba1a, Gja1, Serpini1, 6530418L21Rik, Slit3, Slc1a1, Zbtb11, etc.), genes related to DNA repair (eg Zfp605) , Hmgb1 etc.), genes related to cell proliferation, cell cycle and / or tumor (eg Usp22 etc.), genes related to cell cycle, cell proliferation, diabetes, inflammation (eg Cdc123 etc.), genes related to apoptosis and / or cell aging (eg Usp22 etc.) Genes related to cell motility (eg Stac3 etc.), genes related to pain (eg Ccdc144b etc.), genes related to transcription (eg Rpl31, Zfp101, Zfp605 etc.), genes related to NAD metabolism (eg Nadk etc.) , Genes related to uric acid metabolism (eg, 1190003J15Rik, etc.), genes related to lncRNA (eg, 4833447P13Rik, etc.), genes related to retinal disorders (eg, Chm, etc.), E130309D02Rik, 5930436O19Rik, A230057D06Rik, etc. According to another aspect of the present invention, for example, when the carotenoid of the present invention contains astaxanthin, the genes whose expression is upregulated in the frontal lobe include genes related to stress and / or inflammation (for example, Nr3c1 etc.) and nerve cells. Genes for development and / or disorders (eg Zic1, Adam10, Gtf2ird1, Epha5, Fxr2, Thra, etc.), genes for immune response (eg, Arhgef26, etc.), genes for DNA repair (eg, Mest, etc.), cell proliferation, cells Cycle and / or tumor genes (eg, Dhx30, Paqr4, Xpo1, etc.), apoptosis and / or cell aging genes (eg, Prickle1, Gng11, Bcl2l13, etc.), spasm genes (eg, Scn2a1, etc.), mitochondria and / Or genes related to energy production (eg Ak2, Fxn, etc.), genes related to cell membrane (eg Tmem145, etc.), genes related to cell skeleton (eg Epb4.9, etc.), genes related to cell motility (eg 4933411K20Rik, Acta2, etc.) , Genes related to transcription and / or translation (eg, Naca, Anapc13, Btf3l4, Cst6, Celf3, Snx3, Fdx1l, Rnf40, etc.), genes related to diabetes, obesity and / or lipid metabolism (eg, Aoc2, Elovl6, Akap7, Ip6k1, etc.) Acaca, etc.) and the like.

According to one aspect of the present invention, for example, when the carotenoid of the present invention contains adonixanthin, the genes whose expression is upregulated in the colon include genes related to stress and / or inflammation (eg, Hp, etc.). Genes related to cell proliferation, cell cycle and / or tumor (eg, Hsph1 etc.), genes related to immune response (eg IgG2akappa, VP7-specific Ab, Ig (lambda, constant), Ig (lambda, variable), etc.), circadianism And / or genes for hypertension (eg, Dbp, etc.), genes for nerve cell development and / or protection (eg, Nrg1, etc.), genes for anti-apoptosis and / or tumors (eg, Faim3, etc.), coagulation / fibrinolytic system and / or Genes related to apoptosis (for example, Serpine1 etc.) and the like can be mentioned. According to another aspect of the present invention, for example, when the carotenoid contains astaxanthin, the genes whose expression is upregulated in the colon include genes related to stress, inflammatory response and / or microbial defense (eg, Defb50, etc.), and anti. Genes related to apoptosis, tumor and / or stress (eg, Hspa1a, Tspan4, Pdk4, etc.) and the like.

According to a preferred embodiment of the present invention, the genes whose expression is upregulated in the frontal lobe include, specifically, when the carotenoid of the present invention contains astaxanthin, Rn4.5s, C1qbp, Cbl, Prlr, Gene6430527G18Rik, Tuba1a, Gja1, Serpini1, 6530418L21Rik, Slit3, Slc1a1, Zfp605, Usp22, Eif3e, Stac3, Ccdc144b, Rpl31, Zfp101, Zfp605, Nadk, E130309D02Rik, 1190003J15Rik, 4833447P13Rik, 4833447P13Rik When at least one gene selected from the group consisting of is included, and the carotenoid of the present invention contains astaxanthin, Nr3c1, Zic1, Adam10, Gtf2ird1, Epha5, Fxr2, Thra, Arhgef26, Mest, Dhx30, Paqr4, Xpo1 , Prickle1, Gng11, Bcl2l13, Scn2a1, Ak2, Fxn, Tmem145, Epb4.9, 4933411K20Rik, Acta2, Naca, Anapc13, Btf3l4, Cst6, Celf3, Snx3, Fdx1l, Celf3, Snx3, Fdx1l, Rnf40, Aoc6 Included are at least one gene selected from the group.

According to another preferred embodiment of the present invention, as the gene whose expression is enhanced in the large intestine, specifically, when the carotenoid of the present invention contains astaxanthin, Hp, Hsph1, IgG2akappa, VP7-specific Ab. , Ig (lambda, constant), Ig (lambda, variable), Dbp, Nrg1, Faim3, and Serpine1. Included are at least one gene selected from the group consisting of Hspa1a, Tspan4, and Pdk4, such as Defb50.

According to one aspect of the invention, a composition comprising one or more carotenoids selected from astaxanthin, adonixanthin and pharmaceutically acceptable salts thereof of the invention can be expressed in the frontal lobe or large intestine. It is possible to promote the expression of a gene that is suppressed, preferably a gene whose expression is suppressed in the frontal lobe or large intestine by stress. Here, promotion of gene expression may include relaxation of suppression of expression of a gene whose expression has been suppressed.

According to one aspect of the present invention, for example, when the carotenoid of the present invention contains adonixanthin, the gene whose expression is suppressed in the frontal lobe includes a gene related to nerve cell development and / or disorder (for example, Jph4, Genes for Tshz3, Gmppa, Lmtk2, Scyl3, Dcaf8, etc., stress and / or inflammatory response (eg, Tnfrsf1a, Mast3, Uba52, etc.), cell proliferation, cell cycle and / or tumor genes (eg, Commd5, Wdr3, Arhgap44) , Metap1, Terf2, Evi5, Dcun1d4, Rrm1, skiv2l2, Hist2h2ac, etc., genes related to mitochondria and / or energy production (eg, Pmpcb, Mtrf1, Atp11b, Mfn1, Mrps35, etc.), genes related to cell motility (eg, Cox6b2, etc.) ), Genes related to cell membrane (eg Fxyd6, Nckap1l, etc.), Genes related to transcription and / or translation (eg Brdt, Hnrnph3, Rpl7a, Rps3, Оnecut2, Pоlr1c, Srsf5, etc.), Genes related to diabetes, obesity and / or lipid metabolism (Eg, Pts, Chchd5, Echdc2, Fuca1, etc.), genes related to nerve cell development and / or disorders (eg, Anks1, Ap1s1, Kcnq2, Bcan, etc.), genes related to cytoskeleton (eg, Rap2b, etc.), prostaglandin E Examples include genes related to the possibility of production (for example, 1700113I22Rik (Ptges3l), etc.). According to another aspect of the invention, for example, when the carotenoid contains astaxanthin, the genes whose expression is suppressed in the frontal lobe include genes related to stress, antioxidant and / or inflammatory response (eg, 5730469M10Rik, etc.), nerves, etc. Genes for cell development and / or protection (eg Adnp, etc.), genes for DNA repair (eg, Rad52, Rnaseh2b, etc.), genes for immune response (eg, Tfrc, Dnase1l1, etc.), cell proliferation, cell cycle and / or tumor Genes related to (eg, Tpd52l1, Ift122, Haus4, Nasp, Polr2e, etc.), genes related to cell motility and / or adhesion (eg, Kcnk6, Cdkl4, etc.), genes related to transcription and / or proteolysis (eg, 2210012G02Rik, Zfp39, etc.) Golga5, Fam76b, etc.), genes related to diabetes, obesity and / or lipid metabolism (eg, Echdc2, etc.).

According to one aspect of the invention, for example, when the carotenoid of the invention contains adonixanthin, the genes whose expression is suppressed in the colon include stress, oxidation, inflammatory response, digestive enzymes and / or microbial protection. Genes related to (eg Reg1, Prss1, Pnliprp2, Rpl17, Secisbp2, Pla2g6, Aig1, etc.), genes related to stress, oxidation, inflammatory response, digestive enzymes and / or microbial defense (eg Reg3a, Reg2, Reg3d, Prss2, Ctrc, Pla2g1b, Pdia2, Erp27, etc.), genes for antioxidant and / or anti-inflammatory (eg, Ctrb1, Saa3, Idh2, Dyrk1b, etc.), genes for anti-inflammatory and / or microbial defense (eg, Rnase1, etc.), anti-apoptosis, tumor And / or genes for mitochondria (eg, Reg3g, Mrps35, Bfar, etc.), genes for apoptosis, autophagy and / or antitumor (eg, Expi, Rb1cc1, Eaf1, etc.), genes for apoptosis and / or antitumor (eg, eg) Genes for Serpini2, etc.), anti-apoptosis, tumor and / or Crohn's disease (eg, Cuzd1, Ctrl, Cpa2, Cpb1, Try5, Cpa1, Gp2, etc.), genes for immune response (eg, Ceacam12, Zfp362, etc.), immune response and / Or genes for anti-inflammatory (eg Lepr, Tff2, etc.), genes for glucose metabolism and / or diabetes (eg, Tmed6, Bpgm, etc.), genes for lipid metabolism, obesity and / or tumors (eg, Amy2a5, Cela2a, Cela3b) , Pnliprp1, Cel, Pnlip, Clps, Try4, etc., genes related to steroid metabolism (eg, Akr1c18, etc.), genes related to cell proliferation and / or tumor (eg, Psmb4, Polr2c, etc.), genes related to cell development (eg Osr2, etc.) Eml1 etc.), genes related to cell development, homeostasis and / or digestive enzymes (eg Rbpjl etc.), genes related to nerve cell protection (eg Atp2b4 etc.), genes related to gout (eg Cnih2 etc.), translation and / or metabolism Genes (eg, Lage3, Rab5a, Pigyl, etc.), cell proliferation control and / or inheritance for anti-atherome Examples include children (eg, Rpl17, etc.). According to another aspect of the invention, for example, when the carotenoid contains astaxanthin, the genes whose expression is suppressed in the colon include genes related to stress, inflammatory response and / or tumor (eg, Sumo3, Egfr, Eif2ak1, Genes for Nat2, Ppip5k2, etc.), genes for antioxidant, mitochondrial and / or anti-inflammatory (eg, Otc, Cyp2d9, etc.), genes for anti-apoptosis, cell proliferation and / or tumor (eg, Birc3, Egf, etc.), genes for immune response Genes for circadianism and / or hypertension (eg, Edn1, Mettl14, etc.), genes for cell development and / or homeostasis (eg, Ear2, Cnih4, Yipf6, Hoxb3, AA415398, etc.), transcription and / Alternatively, genes related to translation (for example, Zfp512, B630005N14Rik, E330013P08Rik, Prpf19, 2610035D17Rik, Gm14207, Ddx10, Slc7a9, etc.) can be mentioned.

According to a preferred embodiment of the present invention, as genes whose expression is suppressed in the frontal lobe, for example, when the carotenoid of the present invention contains astaxanthin, specifically, Jph4, Tshz3, Gmppa, Lmtk2, Scyl3, Dcaf8, Tnfrsf1a, Mast3, Uba52, Commd5, Wdr3, Arhgap44, Metap1, Terf2, Evi5, Dcun1d4, Rrm1, skiv2l2, Hist2h2ac, Pmpcb, Mtrf1, Atp11b, Pmpcb, Mtrf1, Atp11b, Mfn1, At least one gene selected from the group consisting of Rps3, Оnecut2, Pоlr1c, Srsf5, Pts, Chchd5, Echdc2, Fuca1, Anks1, Ap1s1, Kcnq2, Bcan, and Rap2b, 1700113I22Rik (Ptges3l) can be mentioned. When the carotenoid contains astaxanthin, for example, when the carotenoid of the present invention contains astaxanthin, specifically, 5730469M10Rik, Adnp, Rad52, Rnaseh2b, Tfrc, Dnase1l1, Tpd52l1, Ift122, Haus4, Nasp, Polr2e, Kcnk6, Included are at least one gene selected from the group consisting of Cdkl4, 2210012G02Rik, Zfp39, Golga5, Fam76b, and Echdc2.

According to another preferred embodiment of the present invention, the genes whose expression is suppressed in the colon include, for example, when the carotenoid contains astaxanthin, specifically, Reg1, Prss1, Pnliprp2, Rpl17, Secisbp2, Pla2g6. , Aig1, Reg3a, Reg2, Reg3d, Prss2, Ctrc, Pla2g1b, Pdia2, Erp27, Ctrb1, Saa3, Idh2, Dyrk1b, Rnase1, Reg3g, Mrps35, Bfar, Expi, Rb1cc1, Eaf1, Serpini2, , Try5, Cpa1, Gp2, Ceacam12, Zfp362, Lepr, Tff2, Tmed6, Bpgm, Amy2a5, Cela2a, Cela3b, Pnliprp1, Cel, Pnlip, Clps, Try4, Akr1c18, Psmb4, Polr2c, Osr2 , Lage3, Rab5a, Pigyl, Rpl17 and Akr1c18 include at least one gene selected from the group, for example, if the carotenoid contains astaxanthin, Sumo3, Egfr, Eif2ak1, Nat2, Ppip5k2, Otc, Cyp2d9, Birc3, Egf, Trr2, Edn1, Mettl14, Ear2, Cnih4, Yipf6, Hoxb3, AA415398, Zfp512, B630005N14Rik, E330013P08Rik, Prpf19, 2610035D17Rik, Gm14207, Ddx10, and Slc7a9, etc. Can be mentioned.

According to one aspect of the invention, a composition comprising one or more carotenoids selected from astaxanthin, adonixanthin and pharmaceutically acceptable salts thereof of the invention can be expressed in the frontal lobe or large intestine. It may be provided as a composition for ameliorating a disease or symptom associated with or resulting from the expression of an enhanced gene. Preferable examples of diseases or symptoms associated with or caused by the expression of a gene whose expression is upregulated in the frontal lobe or colon include inflammation, obesity, tumors, etc. when the gene is C1qbp, and the gene is Cbl. In some cases, obesity, diabetes and the like can be mentioned, when the gene is Gene6430527G18Rik, nerve damage and the like can be mentioned, and when the gene is Chm, retinal disorders and the like can be mentioned.

According to another aspect of the invention, a composition comprising one or more carotenoids selected from astaxanthin, adonixanthin and pharmaceutically acceptable salts thereof of the invention can be expressed in the frontal lobe or large intestine. It may be provided as a composition for ameliorating a disease or symptom associated with or caused by expression of a suppressed gene. Preferable examples of diseases or symptoms associated with or caused by the expression of a gene whose expression is suppressed in the frontal lobe or colon include neuropathy when the gene is Gmppa or Dcaf8, and the gene is Pts. In some cases, obesity and the like can be mentioned, and when the gene is Chchd5, hypertension, obesity and the like can be mentioned, and when the gene is 5730469M10Rik, Tnfrsf1 or Mast3, inflammation and the like can be mentioned.

According to another aspect of the present invention, a method of suppressing the expression of a gene whose expression is enhanced in the frontal lobe or the large intestine of the subject, or a method of promoting the expression of a gene whose expression is suppressed in the frontal lobe or the large intestine of the subject. It comprises administering or ingesting an effective amount of one or more carotenoids selected from astaxanthin, adonixanthin and pharmaceutically acceptable salts thereof to subjects in need thereof. The method is provided. According to yet another aspect of the invention, administration or ingestion of a composition comprising an effective amount of one or more carotenoids selected from astaxanthin, adonixanthin and pharmaceutically acceptable salts thereof. Provided are a method of suppressing the expression of a gene whose expression is enhanced in the frontal lobe or the large intestine of a subject, or a method of promoting the expression of a gene whose expression is suppressed in the frontal lobe or the large intestine of the subject. ..

According to another aspect of the present invention, astaxanthin, for suppressing the expression of a gene whose expression is enhanced in the frontal lobe or the large intestine, or for promoting the expression of a gene whose expression is suppressed in the frontal lobe or the large intestine, The use of one or more carotenoids selected from adonixanthins and their pharmaceutically acceptable salts is provided.

According to another aspect of the present invention, a composition for suppressing the expression of a gene whose expression is enhanced in the frontal lobe or the large intestine, or for promoting the expression of a gene whose expression is suppressed in the frontal lobe or the large intestine. The use of one or more carotenoids selected from astaxanthin, adonixanthin and pharmaceutically acceptable salts thereof in production is provided.

According to another aspect of the present invention, astaxanthin, for suppressing the expression of a gene whose expression is enhanced in the frontal lobe or the large intestine, or for promoting the expression of a gene whose expression is suppressed in the frontal lobe or the large intestine, One or more carotenoids selected from adonixanthins and their pharmaceutically acceptable salts are provided.

The embodiments (i) to (xii) above, the embodiments, and the compounds (carotenoids) all comprise one or more carotenoids of the present invention, including adonixanthine or a pharmaceutically acceptable salt thereof. It can be carried out according to the description regarding the composition.

Hereinafter, the present invention will be described in more detail with reference to Preparation Examples and Test Examples, but the technical scope of the present invention is not limited to these examples. Unless otherwise specified, all percentages and ratios used in the present invention depend on mass. Unless otherwise specified, the units and measurement methods described in this specification are in accordance with JIS standards.

Preparation Example 1: Preparation of adonixanthin and astaxanthin The dried cells of Paracoccus carotinifaciens were subjected to room temperature extraction using acetone. The obtained extract was concentrated to dryness with an evaporator. The concentrated dry matter was dissolved in chloroform, and each carotenoid was separated by a silica gel column (product name "silica gel 60", # 30721-85 (Nacalai Tesque, Inc.) was used as silica gel). Specifically, the fraction eluted with acetone from the silica gel column is further purified by HPLC (Shim-pack PRC-SIL, 15 μm, 25 cm × 20 mm ID (Shimadzu Corporation), acetone: hexane (4: 6)). Then, an adonixanthin free form (hereinafter, also simply referred to as adonixanthin) was obtained. Further, the fraction eluted with acetone: hexane (5: 5) was concentrated from the silica gel column and left at 4 ° C. to obtain astaxanthin free as crystals (hereinafter, also simply referred to as astaxanthin).

Preparation Example 2: Preparation of Astaxanthin-Containing Composition (Administration Solution) and Adonixanthin-Containing Composition (Administration Solution) Weigh the required amount of astaxanthin obtained in Preparation Example 1 and grind it on a milk bowl while olive oil (Fuji Film Wako Pure Chemical Industries, Ltd.). It was mixed with Yakuhin Co., Ltd.) and prepared so that 300 mg of astaxanthin was contained in 10 mL of olive oil to obtain an astaxanthin administration solution. The adonixanthin administration solution was also obtained in the same manner as the astaxanthin administration solution. That is, the required amount of adonixanthin obtained in Preparation Example 1 is weighed, mixed with olive oil while mashing on a mortar, and prepared so that 300 mg of adonixanthine is contained in 10 mL of olive oil to obtain an adonixanthine administration solution. It was.

Test Example 1: Test of suppressing the number of defecations of astaxanthin or adonixanthin using a water avoidance stress (WAS) model mouse An increase in the number of defecations was observed by applying water avoidance stress to rodents, and this phenomenon occurred. Rodent water avoidance stress is widely used as a model for irritable bowel syndrome because it resembles defecation symptoms in patients with irritable bowel syndrome. Therefore, the symptom-improving effect of the composition of the present invention on irritable bowel syndrome was examined using the number of defecations in the mouse water avoidance stress model as an index.
As the experimental animal, a mouse (Slc: C57BL / 6NCr, SPF, male) (Nippon SLC Co., Ltd.) was used. A 4-day quarantine and 5-day habituation period were set after arrival. After acclimation, body weight was measured and 10 animals were grouped by a completely random sampling method so that the mean values of each group were equal.
After grouping, the test substance was administered for 14 days in each experimental group (here, the administration start date was calculated as the first day). As the test substance, the astaxanthin administration solution or the adonixanthin administration solution obtained in Preparation Example 2 was used, and olive oil was used as the control solution. Table 1 shows the test substance in each experimental group, and the dose and solution amount per administration. Administration was performed once a day by oral administration using a disposable oral sonde and a syringe. During the test, each mouse was allowed to freely ingest solid feed and tap water, and was bred at a 12-hour light-dark cycle, 18-28 ° C., and a relative humidity of 30-80%.

A WAS load test was performed for 60 minutes 30 minutes after administration of the test substance on the 11th to 14th days, and the number of feces excreted during that period was measured as the number of defecations.
Specifically, the WAS load test was conducted as follows. First, a platform (height 6 cm x top surface [3 cm x 3 cm]) was installed in the center of the water tank (30 cm x 30 cm x 30 cm), and water was added so that the water level was about 0.5 to 1 cm below the top surface of the platform. .. For 4 days on the 11th to 14th days after the administration of the test substance, 30 minutes after the administration of the test substance, the mice were placed in a water tank for 60 minutes to apply a load, and the number of defecations during that period was measured.

In the WAS load test, the number of defecations varied widely among the experimental groups, and some individuals did not defecate during the 4-day water avoidance stress load. Therefore, the top 6 animals with the total number of defecations during the 4-day load were selected as individuals susceptible to water avoidance stress, and the amount of change in the number of defecations between the 11th and 14th days was evaluated. The difference between the number of defecations on the 14th day and the number of defecations on the 11th day (the number of defecations on the 14th day-11 the number of defecations on the 11th day) of the test substance is shown in FIG. The measured values are expressed as average values. As shown in FIG. 1, the adonixanthin-administered group significantly suppressed the number of defecations as compared with the control group (*: p <0.05 vs control group (Student's t-test)).
It was confirmed that the astaxanthin-administered group also suppressed the number of defecations as compared with the control group.

Test Example 2: Microarray analysis of water avoidance stress (WAS) model mice for astaxanthin or adonixanthin A WAS loading test was performed in the same manner as in Test Example 1 except that a control group without WAS was added. The control group without WAS was a group to which the control solution was administered and the WAS load test was not performed, and 4 animals were used in the group. The control group with WAS in Test Example 2 is the same as the control group in Test Example 1.

After loading on the final day of WAS loading, total blood sampling (heparin treatment) was performed from the abdominal aorta of each animal under anesthesia. After total blood sampling, the frontal lobe and large intestine of the brain were removed, washed with physiological saline, and weighed. Each organ was treated with RNA later (Sigma-Aldrich) and cryopreserved.

<RNA preparation / quality control>
The frontal lobe and large intestine of mice treated with RNAlater and cryopreserved were quickly thawed before the start of extraction. The frontal lobe or large intestine of each individual was extracted with RNAiso plus (Takara Bio Inc.) as usual, and further treated with DNase in the liquid phase, and purified with RNeasy MinElute Cleanup Kit (QIAGEN). Then, RNA was quantified. Specifically, the obtained RNA was measured for absorbance (260 nm, 280 nm and 320 nm), concentration was calculated and purity was confirmed (2.0 or more at a ratio of 260 nm / 280 nm). The extracted RNA was stored frozen (-70 ° C or lower). The obtained RNA was electrophoresed using a microchip electrophoresis device (Agilent 2100 Bioanalyzer, Agilent Technologies, Inc.) equipped with chips (RNA Nano Chips, Agilent Technologies, Ltd.), and RIN (RNA Integrity). Number) was calculated. Only RNA having a RIN value of the reference value (6.5) or more was used. RNA above the reference value was stored frozen (-70 ° C or lower) until the next step.

<Labeled cRNA preparation / hybridization>
The above RNA samples were pooled for each group, and Cy3-labeled cRNA synthesis and purification were performed using the Low Input Quick Amp Labeling Kit (Agilent Technologies, Inc.). The concentration of the obtained labeled cRNA and Cy3 corporation were calculated from the absorbances at 260 nm, 280 nm, 550 nm and 320 nm, and it was confirmed that the reference value (Cy3-CTP isolation> 6 pmol / μg) was satisfied. After that, each labeled cRNA was fragmented using Gene Expression Hybridization Kit (Agilent Technology Co., Ltd.), applied to Whole Mouse Geneme Microarray Ver2.0 (Agilent Technology Co., Ltd.), and hybridized at 65 ° C. for 17 hours. did. The array slides were then washed using Gene Expression Wash Buffers 1 and 2 (Agilent Technologies, Inc.).

<Scan / Fluorescence intensity quantification / analysis>
The array image scanned by the microarray scanner was quantified by the array analysis software GenePix Pro 6.0 (Molecular Devices). The fluorescence intensity values were normalized, and the Fold change of the control group with WAS, the astaxanthin-administered group, and the adonixanthin-administered group was calculated with respect to the control group without WAS (Tables 3 to 14). A gene that showed a variation greater than 2-fold or less than 0.5-fold in the control group with WAS with respect to the control group without WAS, and with respect to the control group with WAS and astaxanthine-administered group or ad. Genes in which a variation of less than 0.75 times or greater than 1.5 times was observed in the nexanthine-administered group were defined as expression-variable genes. Using the database of the National Center for Biotechnology Information (NCBI) (https://www.ncbi.nlm.nih.gov/), among the above expression-variable genes, the functions of the top 30 genes with the largest variation were displayed. Genome informatics analysis was performed.

Specifically, the control group with WAS and the control group without WAS were compared, and a gene of Fold change (vs vs. control group without WAS) <0.5 was extracted as a gene suppressed by WAS (hereinafter, WAS suppression). A gene of 2 <Fold change (vs vs. control group without WAS) was extracted as a gene enhanced by WAS (hereinafter, also referred to as a WAS-enhanced gene). Here, the Fold change (vs vs. control group without WAS) is indicated by the fluorescence intensity value of the control group with WAS / the fluorescence intensity value of the control group without WAS. Then, among the WAS-enhancing genes, a gene in which the expression-enhanced by WAS was suppressed by administration of astaxanthin and adonixanthin, astaxanthin, or adonixanthin was extracted (Fold change (with WAS) <0.5). In addition, among the WAS suppressor genes, genes whose expression suppression by WAS was alleviated by administration of astaxanthin and adonixanthin, astaxanthin, or adonixanthin were extracted (2 <Fold change (vs with WAS)). However, if the number of extracted genes is less than 30, the Fold change width is widened (Fold change (vs WAS control group) <0.75 or 1.5 <Fold change (vs WAS control group)). Extracted. Here, Fold change (vs vs. control group with WAS) is shown as (astaxanthin-administered group or adonixanthin-administered group) / control group with WAS.

The results are shown in Tables 3-14 and FIGS. 2-13. The gene name is indicated by NCBI Gene Symbol. FIGS. 2 to 13 show the values obtained by converting the Fold change of the fluorescence intensity of the genes of the control group with WAS, the astaxanthin administration group, and the adonixanthin administration group with respect to the genes of the control group without WAS by log _2.

Table 3 and FIG. 2 show genes whose expression was upregulated in the frontal lobe by WAS and whose upregulation was suppressed by both astaxanthin and adonixanthin.

From Table 3 and FIG. 2, genes related to stress and / or inflammation (Rn4.5s, C1qbp, Cbl, Prlr), nerve cell development / disorder (6430527G18Rik, Tuba1a, Gja1,) in both astaxanthin administration and adonixanthin administration. It was confirmed that the expression of genes related to Serpini1, 6530418L21Rik, Slit3, Slc1a1) and apoptosis (Eif3e) was suppressed.

Tables 4 and 3 show genes whose expression was upregulated in the frontal lobe by WAS and whose expression was suppressed by astaxanthin.

From Table 4 and FIG. 3, the stress and inflammation and glucocorticoid response genes (Nr3c1) are the genes whose expression was suppressed by astaxanthin, similar to the genes whose expression was suppressed by both astaxanthin and adonixantin. , Nerve cell development / disorder (Zic1, Adam10, Gtf2ird1, Epha5, Fxr2, Thra), apoptotic gene (Prickle1, Gng11, Bcl2l13), and other genes were confirmed. In addition, genes related to mitochondria-related genes (Ak2, Fxn) and convulsions (Scn2a1) were also extracted. Among the above genes, Nr3c1, Zic1, Adam10, Epha5, Arhgef26, Mest, Dhx30, Prickle1, Gng11, Bcl2l13, Scn2a1, Tmem145, 4933411K20Rik, Naca, Anapc13, Cst6, Snx3, Elovl6, Acaca The value of the nikanthine-administered group / control group without WAS) was lower than that of the Fold change (control group with WAS / control group without WAS). Therefore, it is considered that the upregulation of such a gene is also suppressed by adonixanthin.

Tables 5 and 4 show genes whose expression was upregulated in the frontal lobe by WAS and whose upregulation was suppressed by adonixanthine.

From Table 5 and FIG. 4, as genes whose expression was suppressed by adonixanthin, genes related to chronic inflammation (Dclk1), genes related to intellectual impairment (Zbtb11), DNA repair-related genes (Hmgb1), and cell cycle genes A gene related to diabetes and inflammation (Cdc123) was confirmed in. All of the above genes had lower values in the Fold change (astaxanthin administration group / control group without WAS) than in the Fold change (control group with WAS / control group without WAS). Therefore, it is considered that the upregulation of such a gene is also suppressed by astaxanthin.

Table 6 and FIG. 5 show genes whose expression was suppressed in the frontal lobe by WAS and whose suppression was alleviated by both astaxanthin and adonixanthin.

From Table 6 and FIG. 5, both astaxanthin administration and adonixanthin administration resulted in nerve cell development / disorder (Jph4, Tshz3, Gmppa, Lmtk2, Scyl3, Dcaf8), and tumor marker genes involved in cell proliferation / cycle (Commd5, Wdr3). , Arhgap44, Metap1, Terf2, Evi5, Dcun1d4), genes related to diabetes and obesity (Pts, Chchd5), etc. were confirmed to be suppressed and relaxed.

Tables 7 and 6 show genes whose expression was suppressed in the frontal lobe by WAS and whose expression was alleviated by astaxanthin.

From Table 7 and FIG. 6, by administration of astaxanthin, stress / inflammation-related (5730469M10Rik), nerve cell development / protection (Adnp), DNA repair (Rad52, Rnaseh2b), immune response (Tfrc, Dnase1l1), cell proliferation / cycle, Involved in tumors (Tpd52l1, Ift122, Haus4, Nasp, Polr2e), cell motility / adhesion (Kcnk6, Cdkl4), transcription / proteolysis (2210012G02Rik, Zfp39, Golga5, Fam76b), and lipid metabolism / diabetes (Echdc2) It was confirmed that the suppression of expression was alleviated. In addition, all the above-mentioned genes had higher values in Fold change (control group with Adonixanthin / control group without WAS) than those in Fold change (control group with WAS / control group without WAS). Therefore, it is considered that the expression suppression of such a gene is alleviated by adonixanthine.

Tables 8 and 7 show genes whose expression was suppressed in the frontal lobe by WAS and whose expression was alleviated by adonixanthine.

From Table 8 and FIG. 7, as the above genes, stress / inflammation-related (Tnfrsf1a, Mast3, Uba52), nerve cell development / disorder (Anks1, Ap1s1, Kcnq2, Bcan), mitochondrial energy production (Atp11b, Mfn1, Mrps35), Cell proliferation / cycle / tumor (Rrm1, Skiv2l2, Hist2h2ac), cytoskeleton (Rap2b), transcription / translation (Rpl7a, Rps3, Onecut2, Polr1c, Srsf5), and genes involved in diabetes / obesity / lipid metabolism (Echdc2, Fuca1) Was confirmed. Among the above genes, Tnfrsf1a, Mast3, Uba52, Anks1, Ap1s1, Kcnq2, Bcan, Atp11b, Mfn1, Mrps35, Rrm1, Hist2h2ac, Rap2b, Rps3, Onecut2, Polr1c, Srsf5, Echdc2, and Fuc The astaxanthin-administered group / control group without WAS) had a higher value than the Fold change (control group with WAS / control group without WAS). Therefore, it is considered that the expression suppression of such a gene is alleviated by astaxanthin.

Table 9 and FIG. 8 show genes whose expression was enhanced in the large intestine by WAS and whose expression was suppressed by both astaxanthin and adonixanthin.

From Table 9 and FIG. 8, genes involved in stress and inflammation (Hp), cell proliferation / tumor (Hsph1), immune response (IgG2akappa, VP7-specific Ab), and nerve cell development were obtained by both astaxanthin administration and adonixanthin administration.・ It was confirmed that the upregulation of the gene (Nrg1) involved in protection was alleviated. In addition, the enhancement of the gene (Dbp) involved in diurnal rhythm and hypertension was also suppressed.

Tables 10 and 9 show genes whose expression was upregulated in the large intestine by WAS and whose expression was suppressed by astaxanthin.

From Table 10 and FIG. 9, it was confirmed that astaxanthin administration suppressed the upregulation of stress / inflammation, protection against microorganisms (Defb50), and anti-apoptosis / tumor-related genes (Hspa1a, Tspan4, Pdk4). Among the above genes, Defb50, Hspa1a, and Tspan4 had lower values in Fold change (adonixanthin-administered group / control group without WAS) than in Fold change (control group with WAS / control group without WAS). Therefore, it is considered that the upregulation of such a gene is also suppressed by adonixanthin.

Table 11 and FIG. 10 show genes whose expression was enhanced in the large intestine by WAS and whose expression was suppressed by adonixanthine.

From Table 11 and FIG. 10, the anti-apoptosis / tumor marker gene (Faim3), the fibrinolytic gene PAI-1 (Serpine1), the immune gene (Ig (lambda, constant), and Ig (lambda)) that are involved in apoptosis by administration of adonixanthin. , Variable))) was confirmed to suppress the upregulation of expression. All of the above genes had lower values in the Fold change (astaxanthin administration group / control group without WAS) than in the Fold change (control group with WAS / control group without WAS). Therefore, it is considered that the upregulation of such a gene is also suppressed by astaxanthin.

Table 12 and FIG. 11 show genes whose expression was suppressed in the large intestine by WAS and whose expression suppression was alleviated by both astaxanthin and adonixanthin.

From Table 12 and FIG. 11, a group of genes involved in stress and inflammation with digestive enzymes that are highly expressed in the pancreas by both astaxanthin administration and adonixanthin administration (Reg1, Prss1, Pnliprp2, Rpl17, Secisbp2, Pla2g6, Aig1), Antioxidant / anti-inflammatory (Ctrb1, Saa3, Idh2, Dyrk1b), anti-apoptosis / tumor / mitochondria (Reg3g, Mrps35, Bfar), immune response (Ceacam12, Zfp362), and genes related to glucose metabolism / diabetes (Tmed6, Bpgm) It was confirmed that the suppression of the expression of such substances was alleviated.

Tables 13 and 12 show genes whose expression was suppressed in the large intestine by WAS and whose expression was alleviated by astaxanthin.

From Table 13 and FIG. 12, genes related to stress / inflammation / tumor (umo3, Egfr, Eif2ak1, Nat2, Ppip5k2), antioxidant / mitochondria / anti-inflammatory (Otc, Cyp2d9), anti-apoptosis / cell proliferation / It was confirmed that the suppression of the expression of tumors (Birc3, Egf), immune response (Tlr2), and genes related to blood pressure and diurnal rhythm (Edn1, Mettl14) was alleviated. Of the above genes, Sumo3, Egfr, Eif2ak1, Nat2, Ppip5k2, Otc, Cyp2d9, Birc3, Egf, Trr2, Edn1, Mettl14, Ear2, Cnih4, Yipf6, Hoxb3, Zfp512, B630005N14Rik, Zfp512, B630005N14Rik , Ddx10, and Slc7a9 had higher values in the Fold change (adonixanthin-administered group / control group without WAS) than in the Fold change (control group with WAS / control group without WAS). Therefore, it is considered that the expression suppression of such a gene is alleviated by adonixanthine.

Tables 14 and 13 show genes whose expression was suppressed in the large intestine by WAS and whose expression was alleviated by adonixanthine.

From Table 14 and FIG. 13, it was confirmed that administration of adonixanthine alleviated the suppression of expression of many stress / inflammation-related digestive enzyme genes (Reg3a, Reg2, Reg3d, Prss2, Ctrc, Pla2g1b, Pdia2, Erp27). In addition, anti-inflammatory / microbial protection (Rnase1), apoptosis / antitumor (Serpini2), immune response / anti-inflammatory (Lepr, Tff2), anti-apoptosis / tumor / Crohn's disease (Cuzd1, Ctrl, Cpa2, Cpb1, Try5, Cpa1) , Gp2), and genes related to lipid metabolism, obesity, and tumors (Amy2a5, Cela2a, Cela3b, Pnliprp1, Cel, Pnlip, Clps, Try4), etc. were alleviated. Of the above genes, Reg3a, Prss2, Ctrc, Pla2g1b, Pdia2, Erp27, Rnase1, Serpini2, Lepr, Ctrl, Cpa2, Cpb1, Try5, Cpa1, Rbpjl, Gp2, Amy2a5, Cela2a, Cela3b, Pnlip , Clps, Try4, ARpl17 and Akr1c18 had higher values in the Fold change (astaxanthin administration group / control group without WAS) than in the Fold change (control group with WAS / control group without WAS). Therefore, it is considered that the expression suppression of such a gene is alleviated by astaxanthin.

Claims (18)

1. A composition for ameliorating irritable bowel syndrome, which comprises one or more carotenoids containing adonixanthine or a pharmaceutically acceptable salt thereof.
2. The composition according to claim 1, wherein the carotenoid further comprises astaxanthin or a pharmaceutically acceptable salt thereof.
3. The composition according to claim 1 or 2, wherein the carotenoid is a microbial, animal or plant-derived product or a chemically synthesized product.
4. The composition according to claim 3, wherein the microorganism is Paracoccus carotinifaciens.
5. The composition according to any one of claims 1 to 4, wherein the irritable bowel syndrome has at least one symptom selected from the group consisting of abnormal bowel movements, abdominal pain, and abdominal discomfort.
6. A composition comprising one or more carotenoids, including adonixanthine or a pharmaceutically acceptable salt thereof, for ameliorating at least one symptom selected from the group consisting of abnormal bowel movements, abdominal pain, and abdominal discomfort. Stuff.
7. The composition according to claim 6, wherein the carotenoid further comprises astaxanthin or a pharmaceutically acceptable salt thereof.
8. The composition according to claim 6 or 7, wherein the bowel movement abnormality is diarrhea, constipation or a combination thereof.
9. The composition according to any one of claims 1 to 8 for humans.
10. The composition according to any one of claims 1 to 9, wherein the composition is a food or drink or a food additive.
11. The composition according to any one of claims 1 to 10, wherein the composition is a functional food.
12. The composition according to any one of claims 1 to 9, wherein the composition is a pharmaceutical product.
13. Use of one or more carotenoids, including adonixanthine or a pharmaceutically acceptable salt thereof, in the manufacture of compositions for the amelioration of irritable bowel syndrome.
14. A method of improving irritable bowel syndrome in a subject, in which an effective amount of one or more carotenoids, including adonixanthine or a pharmaceutically acceptable salt thereof, is administered or ingested to the subject in need. A method that includes that.
15. Use of one or more carotenoids containing adonixanthine or a pharmaceutically acceptable salt thereof for the improvement of irritable bowel syndrome.
16. One or more carotenoids containing adonixanthine or a pharmaceutically acceptable salt thereof for the improvement of irritable bowel syndrome.
17. Rn4.5s, C1qbp, Cbl, Prrl, Gene6430527G18Rik, Tuba1a, Gja1, Serpini1, 6530418L21Rik, Slit3, Slc1a1, Zfp605, Usp22, Eif3e, Stac3, Ccdc144b, Rpl31, Zfp101, Zfp605, Nk Select from the group consisting of Chm, A230057D06Rik, Dclk1, Cdc123, Hmgb1, Zbtb11, Hp, Hsph1, IgG2akappa, VP7-specificAb, Ig (lambda, constant), Ig (lambda, variable), Dbp, Nrg1, Faim3, and Serpine1. The composition according to any one of claims 1 to 12, for suppressing the expression of at least one gene.
18. Jph4, Tshz3, Gmppa, Lmtk2, Scyl3, Dcaf8, Tnfrsf1a, Mast3, Uba52, Commd5, Wdr3, Arhgap44, Metap1, Terf2, Evi5, Dcun1d4, Rrm1, skiv2l2, Hist2h2ac Fxyd6, Nckap1l, Brdt, Hnrnph3, Rpl7a, Rps3, Оnecut2, Pоlr1c, Srsf5, Pts, Chchd5, Echdc2, Fuca1, Anks1, Ap1s1, Kcnq2, Bcan, Rap2b, 1700113I22Rik , Pla2g6, Aig1, Reg3a, Reg2, Reg3d, Prss2, Ctrc, Pla2g1b, Pdia2, Erp27, Ctrb1, Saa3, Idh2, Dyrk1b, Rnase1, Reg3g, Mrps35, Bfar, Expi, Rb1cc1, Eaf1 , Cpb1, Try5, Cpa1, Gp2, Ceacam12, Zfp362, Lepr, Tff2, Tmed6, Bpgm, Amy2a5, Cela2a, Cela3b, Pnliprp1, Cel, Pnlip, Clps, Try4, Akr1c18, Psmb4, Polr2c, Os , Cnih2, Lage3, Rab5a, Pigyl, Rpl17 and Akr1c18. The composition according to any one of claims 1 to 12 and 17, for promoting the expression of at least one gene selected from the group.

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