JP2016193895A - Composition for preventing or improving leaky gut - Google Patents
Composition for preventing or improving leaky gut Download PDFInfo
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- JP2016193895A JP2016193895A JP2016067297A JP2016067297A JP2016193895A JP 2016193895 A JP2016193895 A JP 2016193895A JP 2016067297 A JP2016067297 A JP 2016067297A JP 2016067297 A JP2016067297 A JP 2016067297A JP 2016193895 A JP2016193895 A JP 2016193895A
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Abstract
Description
本発明は、リーキーガットの予防又は改善用組成物に関する。 The present invention relates to a composition for preventing or improving leaky gut.
腸管は栄養吸収と生体防衛との衝突の場である。すなわち、腸管は外来因子を消化し栄養素として体内に吸収する機能を持つ一方で、外来因子が自由拡散により体内（血中）へ移行することのないように防御する機能を持つ。このような防御機構は、タイトジャンクションと呼ばれる細胞間接着構造が隣接する腸管粘膜上皮細胞同士をシールすることにより成立している。タイトジャンクションは、上皮細胞側底膜の刷子縁膜近傍に局在する巨大なタンパク質複合体であり、occludinやclaudinなどの膜貫通型タンパク質とzonula occludensなどの細胞内裏打ちタンパク質から構成される（非特許文献１）。 The intestinal tract is a place of collision between nutrient absorption and biological defense. That is, the intestinal tract has the function of digesting foreign factors and absorbing them as nutrients in the body, while protecting the foreign factors from being transferred to the body (in the blood) by free diffusion. Such a defense mechanism is established by sealing adjacent intestinal mucosal epithelial cells with an intercellular adhesion structure called tight junction. Tight junctions are large protein complexes that are located near the brush border membrane of the epithelial cell basolateral membrane and are composed of transmembrane proteins such as occludin and claudin and intracellular lining proteins such as zonula occludens (non- Patent Document 1).
腸管腔内には腸内細菌由来のエンドトキシンを始めとする有害な外来因子が存在するが、タイトジャンクションはこのような有害な物質の血中移行を防御している。しかしながら、非ステロイド性抗炎症剤（NSAIDs）の服用、炎症性腸疾患、飲酒、メタボリックシンドローム、ストレス等様々な疾患や生活場面においてタイトジャンクションの機能に異常が生じ、これに伴って腸管腔内の有害物質が血中移行している可能性を示唆する報告もある。このような状態はリーキーガット（腸管壁浸漏症候群）とも呼ばれている（非特許文献２〜５）。 In the intestinal lumen, harmful foreign factors such as endotoxin derived from intestinal bacteria exist, but tight junctions prevent the transfer of such harmful substances into the blood. However, abnormalities occur in the function of tight junctions in various diseases and life situations such as taking non-steroidal anti-inflammatory drugs (NSAIDs), inflammatory bowel disease, drinking, metabolic syndrome, stress, etc. Some reports suggest that toxic substances may be circulating in the blood. Such a state is also called leaky gut (intestinal wall leakage syndrome) (Non-Patent Documents 2 to 5).
したがって、リーキーガットを予防又は改善する食品や薬剤は、上に記載したような様々な疾患や生活場面におけるリーキーガットに関係する不健康・疾患の予防又は改善にも有効であることが期待される。また、タイトジャンクションを構成するタンパク質、及びこれらの発現を制御するサイトカインの発現を調節することによりリーキーガットを改善できる可能性についても考えられている（非特許文献１）ため、タイトジャンクション関連遺伝子の発現を調節する食品や薬剤は、リーキーガットに関係する不健康・疾患の予防又は改善にも有効であることが期待される。 Accordingly, foods and drugs that prevent or improve leaky gut are expected to be effective in preventing or improving unhealthy / disease related to leaky gut in various diseases and life situations as described above. In addition, the possibility of improving leaky gut by regulating the expression of proteins that constitute tight junctions and cytokines that control their expression is also considered (Non-Patent Document 1). Foods and drugs that regulate expression are expected to be effective in preventing or improving unhealthy / disease related to leaky gut.
既報ではグルタミン（非特許文献６）や、プロバイオティクス（非特許文献７）にリーキーガット改善作用が報告されているが、現在に至るまでリーキーガットを予防又は改善させる食品や薬剤は開発されていない。同様にタイトジャンクション関連遺伝子の発現を調節する食品や薬剤も開発されていない。 In the previous reports, glutamine (Non-patent Document 6) and probiotics (Non-patent Document 7) have been reported to improve leaky gut, but to date, foods and drugs that prevent or improve leaky gut have been developed. Absent. Similarly, foods and drugs that regulate the expression of tight junction-related genes have not been developed.
一方、グアーガム等が健常な腸管の透過性に影響を与えうるとの報告がある（非特許文献８）。しかしながら、健常な腸管の透過性の状態とタイトジャンクション機能の異常に伴うリーキーガットと称される腸管透過性が過剰に亢進した状態とでは腸管から血中への物質輸送の機構は全く異なると考えられ、グアーガム等がリーキーガットに対し予防又は改善作用を示すか否かは上記報告からは推定できない。 On the other hand, there is a report that guar gum or the like can affect the permeability of a healthy intestinal tract (Non-patent Document 8). However, the mechanism of substance transport from the intestine to the blood is completely different between the state of permeability of the healthy intestine and the state of excessive intestinal permeability called leaky gut associated with abnormal tight junction function. Therefore, it cannot be estimated from the above report whether guar gum or the like shows a preventive or ameliorating action against leaky gut.
本発明の目的は、新規のリーキーガットの予防又は改善用組成物を提供することにある。 An object of the present invention is to provide a novel composition for preventing or improving leaky gut.
本発明者らは、前記課題を解決すべく鋭意検討した結果、グアーガム分解物、難消化性デキストリン及びアルギン酸の塩等の食物繊維にリーキーガットを予防又は改善する作用を見出し、本発明を完成するに至った。 As a result of intensive studies to solve the above-mentioned problems, the present inventors have found an action to prevent or improve leaky gut in dietary fibers such as guar gum degradation products, indigestible dextrins and alginic acid salts, and complete the present invention. It came to.
すなわち本発明は、次の通りである。
（１）ガラクトマンナン、難消化性デキストリン及びアルギン酸の塩からなる群の少なくとも一つを含有することを特徴とするリーキーガットの予防又は改善用組成物。
（２）ガラクトマンナン、難消化性デキストリン及びアルギン酸の塩からなる群の少なくとも一つを含有することを特徴とする腸管透過性亢進抑制用組成物。
（３）ガラクトマンナン、難消化性デキストリン及びアルギン酸の塩からなる群の少なくとも一つを含有することを特徴とするタイトジャンクション調節用組成物。
（４）ガラクトマンナンがグアーガム分解物である（１）〜（３）のいずれか１項に記載の組成物。
（５）飲食品組成物である（１）〜（４）のいずれかに記載の組成物。
That is, the present invention is as follows.
(1) A composition for preventing or improving leaky gut comprising at least one of the group consisting of a salt of galactomannan, indigestible dextrin and alginic acid.
(2) A composition for suppressing intestinal permeability enhancement, comprising at least one of the group consisting of a salt of galactomannan, indigestible dextrin and alginic acid.
(3) A composition for adjusting a tight junction, comprising at least one of the group consisting of a salt of galactomannan, an indigestible dextrin and alginic acid.
(4) The composition according to any one of (1) to (3), wherein the galactomannan is a guar gum degradation product.
(5) The composition according to any one of (1) to (4), which is a food and drink composition.
グアーガム分解物、難消化性デキストリン、及びアルギン酸ナトリウムにNSAIDs又は炎症性腸疾患に起因するリーキーガットを予防又は改善する作用が見出された。 It has been found that guar gum degradation products, indigestible dextrin, and sodium alginate prevent or ameliorate leaky gut caused by NSAIDs or inflammatory bowel disease.
本発明のリーキーガットの予防又は改善用組成物はガラクトマンナン、難消化性デキストリン及びアルギン酸の塩からなる群の少なくとも一つを含有し、これらの１種を単独又は２種以上を組み合わせて使用することができる。 The composition for preventing or improving leaky gut of the present invention contains at least one of the group consisting of galactomannan, indigestible dextrin and alginic acid salt, and one of these is used alone or in combination of two or more. be able to.
ガラクトマンナンは多糖類の一群であり、マンノースにガラクトースが結合したものをいう。例えば、ローカストビーンガム、グアーガム、フェヌグリークガムがあり、より好ましくはグアーガムであり、特に好ましくはグアーガム分解物であり、製剤化しやすい利点がある。グアーガム分解物とは、グアーガムを熱、酸、酵素等で分解したものであり、平均分子量が約２，０００〜約５０，０００のものが好ましい。グアーガムは豆科植物グアー（Cyamopsis tetragonoloba）の種子グアー豆由来の食経験が豊かな食品成分であるため、グアーガム分解物にリーキーガット改善作用が示されれば非常に利用価値が高いと考えられる。 Galactomannan is a group of polysaccharides, and refers to galactose bound to mannose. For example, there are locust bean gum, guar gum, and fenugreek gum, more preferably guar gum, and particularly preferably a guar gum degradation product, which has the advantage of being easily formulated. The guar gum decomposition product is a product obtained by degrading guar gum with heat, acid, enzyme or the like, and preferably has an average molecular weight of about 2,000 to about 50,000. Since guar gum is a food ingredient rich in dietary experience derived from seed guar beans of the leguminous plant guar (Cyamopsis tetragonoloba), it is considered that the use value is very high if the guar gum degradation product shows an action to improve leaky gut.
難消化性デキストリンは加熱処理したデンプンをアミラーゼで加水分解し、未分解物より難消化性成分を分取し、調製される水溶性食物繊維である。難消化性デキストリンは、安全性のみでなく、低粘性、低甘味、熱および酸に対する安定性、保存性などの物性にも優れているために広範囲の食品への応用が可能であることから、難消化性デキストリンにリーキーガット改善作用が示されれば非常に利用価値が高いと考えられる。 Indigestible dextrin is a water-soluble dietary fiber prepared by hydrolyzing heat-treated starch with amylase and separating the indigestible components from the undegraded product. Since indigestible dextrin is not only safe, but also has excellent properties such as low viscosity, low sweetness, stability to heat and acid, and storage stability, it can be applied to a wide range of foods. If the indigestible dextrin has an action to improve leaky gut, it is considered highly useful.
アルギン酸は多糖類の一種であり、α−Ｌ−グルロン酸、β−Ｄ−マンヌロン酸がピラノース型で１，４−グリコシド結合で結合した構造を持っている。アルギン酸は主に褐藻に含まれる食経験が豊かな食品成分であるため、アルギン酸にリーキーガット改善作用が示されれば非常に利用価値が高いと考えられる。アルギン酸の塩とは例えば、アルギン酸ナトリウム、アルギン酸カリウム、アルギン酸カルシウム、アルギン酸アンモニウムがあり、より好ましくはアルギン酸ナトリウム、アルギン酸カリウムであり、水溶性のために製剤化しやすい利点がある。 Alginic acid is a kind of polysaccharide and has a structure in which α-L-guluronic acid and β-D-mannuronic acid are linked by a 1,4-glycoside bond in a pyranose type. Since alginic acid is a food ingredient with a rich dietary experience mainly contained in brown algae, if alginic acid shows a leaky gut improving action, it is considered to be very useful. Examples of the salt of alginic acid include sodium alginate, potassium alginate, calcium alginate, and ammonium alginate, and more preferably sodium alginate and potassium alginate, which have the advantage of being easily formulated due to water solubility.
リーキーガットとは、非ステロイド性抗炎症剤（NSAIDs）の服用、炎症性腸疾患、飲酒、メタボリックシンドローム、ストレス等様々な刺激が原因となって腸管と血管の透過性が異常に亢進し、通常は腸管内に留まり便等を通して排出されるような有害物質が腸管から血中移行してしまうような状態を意味し、腸管壁浸漏症候群とも称される。したがって、リーキーガットの予防又は治療用組成物は、腸管透過性亢進抑制用組成物にもなり得る。ここで腸管とは、好ましくは小腸の腸管である。 Leaky gut is an abnormal increase in intestinal and vascular permeability caused by various stimuli such as non-steroidal anti-inflammatory drugs (NSAIDs), inflammatory bowel disease, drinking, metabolic syndrome, and stress. Means a state in which harmful substances that remain in the intestine and are discharged through stool and the like are transferred into the blood from the intestine and are also called intestinal wall infiltration syndrome. Therefore, the composition for preventing or treating leaky gut can also be a composition for suppressing intestinal permeability enhancement. Here, the intestinal tract is preferably an intestinal tract of the small intestine.
タイトジャンクションは、上皮細胞側底膜の刷子縁膜近傍に局在する巨大なタンパク質複合体であり、腸管粘膜上皮細胞同士をシールすることにより腸管の透過性を適切に制御している。しかし、上記のような腸管の異常な透過性亢進が生じる際には、タイトジャンクションの機能にも異常が生じていると考えられる。タイトジャンクションの構成に関連する因子（タイトジャンクション関連因子）としては、タイトジャンクション構成タンパク質、及びこれらタイトジャンクション構成タンパク質の発現を制御するサイトカイン等があげられる。タイトジャンクション構成タンパク質としては、例えばclaudinファミリー、zonula occludens（ZO）ファミリー、occludinが挙げられ、好ましくはclaudin １、claudin２、claudin４、及びZO−１である。タイトジャンクションタンパク質の発現を制御するサイトカインとしてはinterleukin（IL）が挙げられ、好ましくはIL−１３である。 The tight junction is a huge protein complex localized near the brush border membrane of the epithelial cell side bottom membrane, and appropriately controls the permeability of the intestinal tract by sealing the intestinal mucosal epithelial cells. However, when abnormal permeability enhancement of the intestinal tract as described above occurs, it is considered that the function of the tight junction is also abnormal. Examples of factors related to the structure of tight junctions (tight junction-related factors) include tight junction constituent proteins and cytokines that control the expression of these tight junction constituent proteins. Examples of the tight junction constituent protein include claudin family, zonula occludens (ZO) family, and occludin, and preferably claudin 1, claudin 2, claudin 4, and ZO-1. Examples of cytokines that control the expression of tight junction proteins include interleukin (IL), preferably IL-13.
本願発明のリーキーガットの予防又は改善用組成物は、タイトジャンクション調節用組成物にもなり得る。タイトジャンクション調節用組成物とは、上記のタイトジャンクション関連因子の発現や機能を調節する機能を有する組成物を意味する。例えば、タイトジャンクション関連遺伝子の発現の異常な亢進や減弱を抑制したり、また、タンパク質の機能を調節したりする作用（酵素活性の調節、タンパク質どうしの結合の調節など）を有する組成物も含まれる。 The composition for preventing or improving leaky gut of the present invention can also be a composition for adjusting tight junctions. The composition for adjusting the tight junction means a composition having a function of adjusting the expression and function of the above-mentioned tight junction-related factor. For example, it includes compositions that have an action (such as regulation of enzyme activity or regulation of protein binding) that suppresses abnormal enhancement or attenuation of expression of tight junction-related genes and regulates protein functions. It is.
本発明のリーキーガットの予防又は改善用組成物は、腸管透過性亢進に密接に関連した疾患であるクローン病、過敏性腸症候群（ＩＢＳ）、花粉症、食物アレルギー、アトピー性皮膚炎、下痢、便秘、肝機能低下、疲労等の疾患の予防又は改善用組成物として利用可能である。これらの予防又は改善用組成物は、例えば医薬品や食品等の有効成分として使用することが可能である。また、本発明の組成物を機能性表示食品、特定保健用食品等の飲食品組成物として用いる場合、「傷んだ腸管からの有害物質の侵入を抑える」、「ダメージを受けた腸管からの有害物質の侵入を抑える」、「荒れた腸管からの有害物質の侵入を抑える」、「すかすかになった腸管からの有害物質の侵入を抑える」、「不健康な腸管を、健康に、丈夫に、元気にする」等の表示をして提供することが可能である。 The composition for preventing or ameliorating leaky gut of the present invention comprises Crohn's disease, irritable bowel syndrome (IBS), hay fever, food allergy, atopic dermatitis, diarrhea, It can be used as a composition for preventing or ameliorating diseases such as constipation, decreased liver function, and fatigue. These preventive or ameliorating compositions can be used as active ingredients such as pharmaceuticals and foods. In addition, when the composition of the present invention is used as a food or beverage composition such as a functional labeling food or a food for specified health use, “suppress the invasion of harmful substances from damaged intestinal tract”, “harmful from damaged intestinal tract. `` Suppress the invasion of substances '', `` Suppress the invasion of harmful substances from the rough intestinal tract '', `` Suppress the invasion of harmful substances from the faint intestinal tract '', `` Healthy, durable, healthy It is possible to provide it with a display such as
本発明における組成物は、公知の製剤学的方法により製剤化することができる。例えば、錠剤、顆粒剤、散剤、カプセル剤、丸剤、細粒剤、フィルムコーティング剤、ペレット剤、トローチ剤、舌下剤、咀嚼剤、バッカル剤、液剤、シロップ剤、懸濁剤、エリキシル剤、乳剤、ペースト剤、エアゾール剤、注射剤、坐剤などとして、経口的又は非経口的に使用することができる。 The composition in the present invention can be formulated by a known pharmaceutical method. For example, tablets, granules, powders, capsules, pills, fine granules, film coating agents, pellets, troches, sublingual agents, chewing agents, buccal agents, solutions, syrups, suspensions, elixirs, It can be used orally or parenterally as an emulsion, paste, aerosol, injection, suppository and the like.
これら製剤化においては、薬理学上もしくは飲食品として許容される担体、具体的には、滅菌水や生理食塩水、植物油、溶剤、基剤、乳化剤、懸濁剤、界面活性剤、安定剤、香味剤、芳香剤、賦形剤、ベヒクル、防腐剤、結合剤、希釈剤、等張化剤、増量剤、崩壊剤、緩衝剤、コーティング剤、滑沢剤、着色剤、甘味剤、粘稠剤、矯味矯臭剤、溶解補助剤あるいはその他の添加剤と適宜組み合わせることができる。 In these preparations, carriers that are acceptable pharmacologically or as foods and beverages, specifically, sterile water and physiological saline, vegetable oils, solvents, bases, emulsifiers, suspensions, surfactants, stabilizers, Flavor, fragrance, excipient, vehicle, preservative, binder, diluent, tonicity agent, extender, disintegrant, buffer, coating agent, lubricant, colorant, sweetener, viscous It can be appropriately combined with agents, flavoring agents, solubilizing agents or other additives.
本発明の組成物を医薬組成物として用いる場合には、内服用固形剤や内服用液剤などの経口用製剤として提供することが好ましい。本発明の組成物を飲食品組成物として用いる場合、当該飲食品組成物は、例えば、健康食品、機能性食品、特定保健用食品、栄養補助食品、病者用食品、あるいは食品添加物であり得る。飲食品組成物の具体例としては、ドリンク類、スープ類、乳飲料、清涼飲料水、茶飲料、アルコール飲料、ゼリー状飲料、機能性飲料等の液状食品；食用油、ドレッシング、マヨネーズ、マーガリンなどの油分を含む製品；飯類、麺類、パン類等の炭水化物含有食品；ハム、ソーセージ等の畜産加工食品；かまぼこ、干物、塩辛等の水産加工食品；漬物等の野菜加工食品；ゼリー、ヨーグルト等の半固形状食品；みそ、発酵飲料等の発酵食品；洋菓子類、和菓子類、キャンディー類、ガム類、グミ、冷菓、氷菓等の各種菓子類；カレー、あんかけ、中華スープ等のレトルト製品；インスタントスープ、インスタントみそ汁等のインスタント食品や電子レンジ対応食品等が挙げられる。さらには、粉末、穎粒、錠剤、カプセル剤、液状、ペースト状またはゼリー状に調製された健康飲食品も挙げられる。本発明における飲食品組成物の製造は、当該技術分野に公知の製造技術により実施することができる。 When the composition of the present invention is used as a pharmaceutical composition, it is preferably provided as an oral preparation such as a solid preparation for internal use or a liquid for internal use. When the composition of the present invention is used as a food / beverage product composition, the food / beverage product composition is, for example, a health food, a functional food, a food for specified health use, a dietary supplement, a food for a sick person, or a food additive. obtain. Specific examples of the food and beverage composition include liquid foods such as drinks, soups, milk beverages, soft drinks, tea beverages, alcoholic beverages, jelly-like beverages, functional beverages; edible oils, dressings, mayonnaise, margarines, etc. Products containing carbohydrates; Foods containing carbohydrates such as rice, noodles and bread; Livestock processed foods such as ham and sausage; Fish processed foods such as kamaboko, dried fish and salted fish; Vegetable processed foods such as pickles; Jelly, yogurt, etc. Semi-solid foods; fermented foods such as miso and fermented beverages; various confectioneries such as Western confectionery, Japanese confectionery, candy, gums, gummi, frozen confectionery, ice confectionery; retort products such as curry, ankake, Chinese soup; instant Examples include instant foods such as soup and instant miso soup, and foods compatible with microwave ovens. Furthermore, health foods and drinks prepared in the form of powder, granules, tablets, capsules, liquid, paste or jelly are also included. Manufacture of the food-drinks composition in this invention can be implemented with a manufacturing technique well-known in the said technical field.
本発明の組成物摂取量は、医薬品や食品等の形態、摂取する人の年齢、体重、性別、摂取の目的等に応じて適宜決定でき、特に限定されるものではないが、通常、食物繊維の量が１日成人１人当たり０．０１〜５０グラム程度、好ましくは０．０５〜１０グラム程度となるような量を、１回又は数回に分けて摂取することができる。 The amount of intake of the composition of the present invention can be appropriately determined according to the form of pharmaceuticals, foods, etc., the age, weight, gender, purpose of ingestion, etc. of the ingested person, and is not particularly limited. In an amount of about 0.01 to 50 grams, preferably about 0.05 to 10 grams per adult per day.
以下に試験例を挙げ、本発明について具体的に説明する。我々はリーキーガットモデルを用い、食物繊維についてリーキーガットの予防又は改善作用、及びタイトジャンクション関連遺伝子発現調節作用を検討することとした。リーキーガットモデルとしては、マウスアスピリン惹起性リーキーガットモデル及びマウスデキストラン硫酸ナトリウム誘発性（炎症性腸疾患惹起性）リーキーガットモデルを用いた。 Hereinafter, the present invention will be specifically described with reference to test examples. We decided to use the leaky gut model to examine the preventive or ameliorating effect of leaky gut on dietary fiber and the regulation of tight junction-related gene expression. As the leaky gut model, a mouse aspirin-induced leaky gut model and a mouse dextran sulfate sodium-induced (inflammatory bowel disease-induced) leaky gut model were used.
試験例１ アスピリン（ASA）惹起性リーキーガットに対するグアーガム分解物（PHGG）の影響
マウスに１７時間絶食を施した後、Normal群には５%アラビアゴム溶液を１０mL/kgの容量で経口投与した。Control群には５%アラビアゴム溶液にて調製したASA懸濁液を３００mg/kgの用量で経口投与した。PHGG群には２０%PHGG溶液にて調製したASA懸濁液を３００mg/kgの用量で経口投与した。５%アラビアゴム溶液又はASA懸濁液投与４時間後にリーキーガット評価を行った。リーキーガットは、経口投与したフルオレセインイソチオシアネートデキストラン（FITC-D）が腸を透過し血中に移行する量を指標に評価することとした。すなわち、FITC-Dを６００mg/kgの用量で経口投与し、その１時間後に麻酔下にて腹大静脈より血液を採取し、ヘパリンを添加したエッペンチューブに移し転倒混和後に氷冷する。採血終了後、遠心分離（１２０００rpm、４℃、３分間）によりサンプルから血漿を採取し、血漿中FITC-Dの蛍光強度を蛍光分光光度計を用いて測定した。
Test Example 1 Effect of guar gum degradation product (PHGG) on aspirin (ASA) -induced leaky gut After mice were fasted for 17 hours, a 5% gum arabic solution was orally administered to the Normal group in a volume of 10 mL / kg. In the Control group, an ASA suspension prepared with a 5% gum arabic solution was orally administered at a dose of 300 mg / kg. In the PHGG group, an ASA suspension prepared in a 20% PHGG solution was orally administered at a dose of 300 mg / kg. Leaky gut evaluation was performed 4 hours after administration of 5% gum arabic solution or ASA suspension. Leekeygut decided to evaluate the amount of orally administered fluorescein isothiocyanate dextran (FITC-D) permeating the intestine and moving into the blood. That is, FITC-D is orally administered at a dose of 600 mg / kg, and after 1 hour, blood is collected from the abdominal vena cava under anesthesia, transferred to an Eppendorf tube to which heparin has been added, and mixed by inversion, followed by ice cooling. After completion of blood collection, plasma was collected from the sample by centrifugation (12000 rpm, 4 ° C., 3 minutes), and the fluorescence intensity of FITC-D in plasma was measured using a fluorescence spectrophotometer.
＜試験結果＞
Normal群と比較し、Control群にて血中FITC-D濃度が高く（図１）、ASAによりリーキーガットが生じていることが確認された。Control群と比較し、PHGG群にて血中FITC-D濃度が低く、PHGGによりASA惹起性リーキーガットが改善していることが示された。
<Test results>
Compared with the Normal group, the blood FITC-D concentration was higher in the Control group (FIG. 1), and it was confirmed that leaky gut was generated by ASA. Compared to the control group, the FIGG-D concentration in the PHGG group was lower, indicating that PHGG improved ASA-induced leaky gut.
試験例２ アスピリン（ASA）惹起性リーキーガットに対する難消化性デキストリンの影響
マウスに１７時間絶食を施した後、Normal群には５%アラビアゴム溶液を１０mL/kgの容量で経口投与した。Control群には５%アラビアゴム溶液にて調製したASA懸濁液を３００mg/kgの用量で経口投与した。難消化性デキストリン群には２０%難消化性デキストリン溶液にて調製したASA懸濁液を３００mg/kgの用量で経口投与した。５%アラビアゴム溶液又はASA懸濁液投与４時間後にリーキーガット評価を行った。リーキーガットは、経口投与したフルオレセインイソチオシアネートデキストラン（FITC-D）が腸を透過し血中に移行する量を指標に評価することとした。すなわち、FITC-Dを６００mg/kgの用量で経口投与し、その１時間後に麻酔下にて腹大静脈より血液を採取し、ヘパリンを添加したエッペンチューブに移し転倒混和後に氷冷する。採血終了後、遠心分離（１２０００rpm、４℃、３分間）によりサンプルから血漿を採取し、血漿中FITC-Dの蛍光強度を蛍光分光光度計を用いて測定した。
Test Example 2 Effect of indigestible dextrin on aspirin (ASA) -induced leaky gut After mice were fasted for 17 hours, the Normal group was orally administered with a 5% gum arabic solution in a volume of 10 mL / kg. In the Control group, an ASA suspension prepared with a 5% gum arabic solution was orally administered at a dose of 300 mg / kg. To the indigestible dextrin group, an ASA suspension prepared with a 20% indigestible dextrin solution was orally administered at a dose of 300 mg / kg. Leaky gut evaluation was performed 4 hours after administration of 5% gum arabic solution or ASA suspension. Leekeygut decided to evaluate the amount of orally administered fluorescein isothiocyanate dextran (FITC-D) permeating the intestine and moving into the blood. That is, FITC-D is orally administered at a dose of 600 mg / kg, and after 1 hour, blood is collected from the abdominal vena cava under anesthesia, transferred to an Eppendorf tube to which heparin has been added, and mixed by inversion, followed by ice cooling. After completion of blood collection, plasma was collected from the sample by centrifugation (12000 rpm, 4 ° C., 3 minutes), and the fluorescence intensity of FITC-D in plasma was measured using a fluorescence spectrophotometer.
＜試験結果＞
Normal群と比較し、Control群にて血中FITC-D濃度が高く（図２）、ASAによりリーキーガットが生じていることが確認された。Control群と比較し、難消化性デキストリン群にて血中FITC-D濃度が低く、難消化性デキストリンによりASA惹起性リーキーガットが改善していることが示された。
<Test results>
Compared with the Normal group, the blood FITC-D concentration was higher in the Control group (FIG. 2), and it was confirmed that leaky gut was generated by ASA. Compared with the Control group, the blood FITC-D concentration was lower in the indigestible dextrin group, indicating that the ASA-inducible leaky gut was improved by the indigestible dextrin.
試験例３ デキストラン硫酸ナトリウム（DSS）惹起性リーキーガットに対するPHGGの影響
DSS惹起性リーキーガットモデルはマウスに５% DSS水溶液を４日間飲水投与することにより作製した。PHGGは５%混餌にて投与した。Normal群は通常の飼料及び飲料水にて１８日間飼育した後にリーキーガットを評価した。Control群は通常の飼料及び飲料水にて１４日間飼育した後、通常飼料及びDSS水にて４日間飼育した後にリーキーガットを評価した。PHGG投与群はPHGG混餌飼料及び通常飲料水にて１４日間飼育した後、PHGG混餌飼料及びDSS水で４日間飼育した後にリーキーガットを評価した。リーキーガットの評価は次のように行った。動物に一定期間の絶食を施した後、FITC-Dを６００mg/kgの用量で経口投与し、その１時間後に麻酔下にて腹大静脈より血液を採取し、ヘパリンを添加したエッペンチューブに移し撹拌後に氷冷した後、遠心分離（１２０００rpm、４℃、３分間）によりサンプルから血漿を採取し、血漿中FITC-Dの蛍光強度を蛍光分光光度計を用いて測定した。
Test Example 3 Effect of PHGG on dextran sulfate sodium (DSS) -induced leaky gut
The DSS-induced leaky gut model was prepared by administering 5% DSS aqueous solution to mice for 4 days. PHGG was administered with a 5% diet. The normal group was evaluated for leaky gut after being fed with normal feed and drinking water for 18 days. The Control group was bred for 14 days with normal feed and drinking water, then bred for 4 days with normal feed and DSS water, and then evaluated for leaky gut. The PHGG administration group was reared for 14 days in a PHGG mixed feed and normal drinking water, and then was reared for 4 days in a PHGG mixed feed and DSS water, and then evaluated for leaky gut. The evaluation of leaky gut was performed as follows. After fasting animals for a certain period of time, FITC-D was orally administered at a dose of 600 mg / kg. One hour later, blood was collected from the abdominal vena cava under anesthesia and transferred to an Eppendorf tube supplemented with heparin. After stirring and cooling with ice, plasma was collected from the sample by centrifugation (12000 rpm, 4 ° C., 3 minutes), and the fluorescence intensity of FITC-D in the plasma was measured using a fluorescence spectrophotometer.
＜試験結果＞
Normal群と比較し、Control群にて血中FITC-D濃度が高く（図３）、DSSの飲水投与によりリーキーガットが生じていることが確認された。Control群と比較し、PHGG投与群にて血中FITC-D濃度が低く、PHGG投与によりDSS惹起性リーキーガットが改善していることが示された。
<Test results>
Compared with the Normal group, the FITC-D concentration in the blood was higher in the Control group (Fig. 3), and it was confirmed that leaky gut was caused by drinking DSS. Compared with the control group, the FIGG-D concentration in the PHGG administration group was low, indicating that the PHGG administration improved DSS-induced leaky gut.
試験例４ デキストラン硫酸ナトリウム（DSS）惹起性リーキーガットに対するアルギン酸ナトリウムの影響
DSS惹起性リーキーガットモデルはマウスに５% DSS水溶液を４日間飲水投与することにより作製した。アルギン酸ナトリウムは５%混餌にて投与した。Normal群は通常の飼料及び飲料水にて１８日間飼育した後にリーキーガットを評価した。Control群は通常の飼料及び飲料水にて１４日間飼育した後、通常飼料及びDSS水にて４日間飼育した後にリーキーガットを評価した。アルギン酸ナトリウム投与群は、アルギン酸ナトリウム混餌飼料及び通常飲料水にて１４日間飼育した後、アルギン酸ナトリウム混餌飼料及びDSS水で４日間飼育した後にリーキーガットを評価した。リーキーガットの評価は次のように行った。動物に一定期間の絶食を施した後、FITC-Dを６００mg/kgの用量で経口投与し、その１時間後に麻酔下にて腹大静脈より血液を採取し、ヘパリンを添加したエッペンチューブに移し撹拌後に氷冷した後、遠心分離（１２０００rpm、４℃、３分間）によりサンプルから血漿を採取し、血漿中FITC-Dの蛍光強度を蛍光分光光度計を用いて測定した。
Test Example 4 Effect of sodium alginate on dextran sulfate sodium (DSS) -induced leaky gut
The DSS-induced leaky gut model was prepared by administering 5% DSS aqueous solution to mice for 4 days. Sodium alginate was administered with a 5% diet. The normal group was evaluated for leaky gut after being fed with normal feed and drinking water for 18 days. The Control group was bred for 14 days with normal feed and drinking water, then bred for 4 days with normal feed and DSS water, and then evaluated for leaky gut. The sodium alginate administration group was bred with sodium alginate mixed feed and normal drinking water for 14 days, then bred with sodium alginate mixed feed and DSS water for 4 days, and then evaluated for leaky gut. The evaluation of leaky gut was performed as follows. After fasting animals for a certain period of time, FITC-D was orally administered at a dose of 600 mg / kg. One hour later, blood was collected from the abdominal vena cava under anesthesia and transferred to an Eppendorf tube supplemented with heparin. After stirring and cooling with ice, plasma was collected from the sample by centrifugation (12000 rpm, 4 ° C., 3 minutes), and the fluorescence intensity of FITC-D in the plasma was measured using a fluorescence spectrophotometer.
＜試験結果＞
Normal群と比較し、Control群にて血中FITC-D濃度が高く（図４）、DSSの飲水投与によりリーキーガットが生じていることが確認された。Control群と比較し、アルギン酸ナトリウム投与群にて血中FITC-D濃度が低く、アルギン酸ナトリウムによりDSS惹起性リーキーガットが改善していることが示された。
<Test results>
Compared with the Normal group, the FITC-D concentration in the blood was higher in the Control group (FIG. 4), and it was confirmed that leaky gut was caused by administration of DSS drinking water. Compared with the Control group, the blood FITC-D concentration was lower in the sodium alginate administration group, and it was shown that DSS-induced leaky gut was improved by sodium alginate.
試験例５ ASA惹起性タイトジャンクション関連遺伝子発現変化に対するグアーガム分解物投与の影響
マウスに１７時間絶食を施した後、Normal群はMilliQ水（PHGG投与液の媒体）を１０mL/kgの容量で経口投与し、その直後に５%アラビアゴム溶液（ASA懸濁液の媒体）を１０mL/kgの容量で経口投与した。Control群はMilliQ水を１０mL/kgの容量で経口投与し、ASA懸濁液を３００mg/kgの用量で経口投与した。PHGG群は２０%PHGG溶液を１０mL/kgの容量で経口投与し、ASA懸濁液を３００mg/kgの用量で経口投与した。媒体又はASA投与４時間後にタイトジャンクション関連遺伝子発現量測定を行った。すなわち、麻酔下にて動物から小腸を採取した後にそれらサンプルよりRNAを抽出し、得られたトータルRNAからcDNAを合成し、得られたcDNAを定量Real-time PCR（RT-PCR）に用いた。ZO-１、claudin２、claudin４、interleukin−１３（IL−１３）、及びGapdh mRNA発現を定量RT-PCR法にて測定した。各遺伝子発現量は、それぞれ内因性コントロールであるGapdhで補正し、Normal群を１とした場合の相対値として算出した。
Test Example 5 Effect of Guar Gum Degradation Administration on ASA-Induced Tight Junction Related Gene Expression Changes After mice were fasted for 17 hours, the Normal group was orally administered MilliQ water (PHGG administration medium) at a volume of 10 mL / kg. Immediately thereafter, 5% gum arabic solution (ASA suspension medium) was orally administered in a volume of 10 mL / kg. In the Control group, MilliQ water was orally administered at a volume of 10 mL / kg, and the ASA suspension was orally administered at a dose of 300 mg / kg. In the PHGG group, 20% PHGG solution was orally administered at a volume of 10 mL / kg, and ASA suspension was orally administered at a dose of 300 mg / kg. The expression level of tight junction-related genes was measured 4 hours after administration of the vehicle or ASA. That is, after collecting the small intestine from an animal under anesthesia, RNA was extracted from these samples, cDNA was synthesized from the obtained total RNA, and the obtained cDNA was used for quantitative Real-time PCR (RT-PCR). . ZO-1, claudin 2, claudin 4, interleukin-13 (IL-13), and Gapdh mRNA expression were measured by quantitative RT-PCR. Each gene expression level was corrected by Gapdh, which is an endogenous control, and calculated as a relative value when the Normal group was 1.
＜試験結果＞
Normal群と比較し、Control群にてZO−１、claudin２、claudin４、及びIL−１３発現量が多く（図５）、アスピリンによりこれらタイトジャンクション関連遺伝子発現が変化していることが確認された。Control群と比較し、PHGG群にてZO−１、claudin２、claudin４、及びIL−１３発現量が少なく、PHGGによりアスピリン惹起性タイトジャンクション関連遺伝子発現変化が抑制されていることが示された。
<Test results>
Compared with the Normal group, the ZO-1, claudin 2, claudin 4 and IL-13 expression levels were higher in the Control group (FIG. 5), and it was confirmed that the expression of these tight junction-related genes was changed by aspirin. Compared with the Control group, the expression levels of ZO-1, claudin2, claudin4, and IL-13 were lower in the PHGG group, indicating that the aspirin-induced tight junction-related gene expression change was suppressed by PHGG.
試験例６ DSS惹起性タイトジャンクション関連遺伝子発現変化に対するPHGG投与の影響
DSS惹起性リーキーガットモデルはマウスに５% DSS水溶液を５日間飲水投与することにより作製した。PHGGは５%混餌にて投与した。Normal群は通常の飼料及び飲料水にて１９日間飼育した後にタイトジャンクション関連遺伝子発現量を測定した。Control群は通常の飼料及び飲料水にて１４日間飼育した後，通常飼料及びDSS水にて５日間飼育した後にタイトジャンクション関連遺伝子発現量を測定した。PHGGプレ投与群はPHGG混餌飼料及び通常飲料水にて１４日間飼育した後、PHGG混餌飼料及びDSS水で５日間飼育した後にタイトジャンクション関連遺伝子発現量を測定した。PHGG同時投与群は通常飼料及び飲料水にて１４日間飼育した後、PHGG混餌飼料及びDSS水にて５日間飼育した後にタイトジャンクション関連遺伝子発現測定を行った。すなわち、麻酔下にて動物から小腸を採取した後にそれらサンプルよりRNAを抽出し、得られたトータルRNAからcDNAを合成し、得られたcDNAを定量RT- PCRに用いた。claudin１及びB２m mRNA発現を定量RT-PCR法にて測定した。遺伝子発現量は、内因性コントロールであるB２mとの相対値として算出した。
Test Example 6 Effects of PHGG administration on DSS-induced tight junction-related gene expression changes
The DSS-induced leaky gut model was prepared by administering 5% DSS aqueous solution to mice for 5 days. PHGG was administered with a 5% diet. In the Normal group, the expression level of tight junction-related genes was measured after rearing in normal feed and drinking water for 19 days. The control group was bred for 14 days with normal feed and drinking water, then bred for 5 days with normal feed and DSS water, and then the expression level of tight junction-related genes was measured. The PHGG pre-administered group was bred for 14 days with PHGG mixed feed and normal drinking water, and then cultivated for 5 days with PHGG mixed feed and DSS water, and then the expression level of tight junction-related genes was measured. The PHGG co-administration group was bred for 14 days with normal feed and drinking water, then bred with PHGG mixed feed and DSS water for 5 days, and then measured for tight junction-related gene expression. That is, after collecting the small intestine from an animal under anesthesia, RNA was extracted from these samples, cDNA was synthesized from the obtained total RNA, and the obtained cDNA was used for quantitative RT-PCR. claudin1 and B2m mRNA expression was measured by quantitative RT-PCR. The gene expression level was calculated as a relative value to B2m which is an endogenous control.
＜試験結果＞
Normal群と比較し、Control群にてclaudin１ mRNA発現量が多く、DSS飲水によりタイトジャンクション関連遺伝子発現が変化していることが確認された。Control群と比較し、PHGGプレ投与群及びPHGG同時投与群にてclaudin１発現量が少なく、PHGGによりDSS惹起性タイトジャンクション関連遺伝子発現変化が抑制されていることが示された。（図６）。
<Test results>
Compared with the Normal group, the claudin1 mRNA expression level was higher in the Control group, and it was confirmed that tight junction-related gene expression was changed by drinking DSS. Compared with the Control group, the expression level of claudin 1 was lower in the PHGG pre-administered group and the PHGG co-administered group, and it was shown that DSGG-induced tight junction-related gene expression changes were suppressed by PHGG. (FIG. 6).
本発明により、新規のリーキーガットの予防又は改善用組成物を提供することが可能となった。さらには、新規の腸管透過性亢進抑制用組成物やタイトジャンクション調節用組成物の提供が可能になった。本発明の組成物は、腸管透過性亢進に密接に関連した疾患であるクローン病、過敏性腸症候群（ＩＢＳ）、花粉症、食物アレルギー、アトピー性皮膚炎、下痢、便秘、肝機能低下、疲労の疾患の予防又は治療用組成物として利用可能であり、例えば医薬品や食品等の有効成分として使用することが可能である。 According to the present invention, it has become possible to provide a novel composition for preventing or improving leaky gut. Further, it has become possible to provide a novel composition for suppressing intestinal permeability enhancement and a composition for adjusting tight junctions. The composition of the present invention comprises Crohn's disease, irritable bowel syndrome (IBS), hay fever, food allergy, atopic dermatitis, diarrhea, constipation, decreased liver function, fatigue, which are closely related to increased intestinal permeability. It can be used as a composition for the prevention or treatment of other diseases. For example, it can be used as an active ingredient of pharmaceuticals and foods.
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| CN111820419A (en) * | 2020-07-24 | 2020-10-27 | 中国海洋大学 | Composition for targeted regulation and control of enteron-bacterium and short-chain fatty acid producing bacterium |
| IT202100010412A1 (en) | 2021-04-26 | 2022-10-26 | Anseris Farma S R L | COMPOSITION FOR THE TREATMENT OF IRRITABLE BOWEL AND METABOLIC SYNDROME RELATED TO INTESTINAL PERMEABILITY ALTERATIONS. |
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| CN111820419A (en) * | 2020-07-24 | 2020-10-27 | 中国海洋大学 | Composition for targeted regulation and control of enteron-bacterium and short-chain fatty acid producing bacterium |
| CN111820419B (en) * | 2020-07-24 | 2022-05-27 | 中国海洋大学 | Composition for targeted regulation and control of enteron-bacterium and short-chain fatty acid producing bacterium |
| IT202100010412A1 (en) | 2021-04-26 | 2022-10-26 | Anseris Farma S R L | COMPOSITION FOR THE TREATMENT OF IRRITABLE BOWEL AND METABOLIC SYNDROME RELATED TO INTESTINAL PERMEABILITY ALTERATIONS. |
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