JP6255644B2 - Gastrointestinal immunity control composition - Google Patents
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Description
本発明は、消化管免疫制御活性を有する消化管免疫制御組成物に関するものであり、米麹を含有する消化管免疫抑制組成物に関する。 The present invention relates to a gastrointestinal tract immune control composition having gastrointestinal tract immune control activity, and to a gastrointestinal tract immunosuppressive composition containing rice bran.
消化管や呼吸器粘膜に分布する免疫システムは、免疫系全体の６０％以上を占め、その特徴的な免疫活動により、外来異物の認識・排除を行い、生命活動を維持するのに極めて重要な役割を担っている。 The immune system distributed in the gastrointestinal tract and respiratory mucosa occupies more than 60% of the immune system, and it is extremely important for recognizing and eliminating foreign substances and maintaining vital activities through its characteristic immune activity. Have a role.
粘膜免疫装置の中でも消化管免疫は，食物からの栄養源の取り込みを監視する他、微生物や食物由来の成分，薬物などの影響を受け、腸内環境の保全や食物アレルギー応答の制御、免疫寛容、造血などの生体応答と密接に関連している。この特徴的な消化管免疫反応は、パイエル板という腸の特殊なリンパ組織によって担われ、このリンパの機能を制御するアジュバント活性様のメカニズムが経口可能なワクチンや抗アレルギー薬開発のための新規な薬理学的作用機序として注目されている（例えば、非特許文献１を参照）。 Among mucosal immune devices, gastrointestinal immunity is monitored by the intake of nutrients from food, affected by microorganisms, food-derived components, drugs, etc., maintaining the intestinal environment, controlling food allergic responses, and immune tolerance It is closely related to biological responses such as hematopoiesis. This characteristic gastrointestinal immune response is borne by a special lymphoid tissue of the intestine called Peyer's patch, and an adjuvant-like mechanism that controls the function of this lymph is a novel novel for the development of orally available vaccines and antiallergic drugs. It attracts attention as a pharmacological mechanism of action (see, for example, Non-Patent Document 1).
本発明は、このような技術的背景の下、発酵食品及び発酵プロセスに関わる菌体が腸内環境を改善し、生体の健康維持、増進に役立つことを実証し、消化管免疫活性を制御することで健康維持に役立つ消化管免疫制御組成物を提供することを目的とする。 In the present invention, the present invention demonstrates that bacterial cells related to fermented foods and fermentation processes improve the intestinal environment and are useful for maintaining and promoting the health of living organisms, and controlling gastrointestinal immunity activity. It is an object of the present invention to provide a gastrointestinal tract immune control composition useful for maintaining health.
本発明者らは、石川県下で造られる発酵食品の免疫に対する機能性を評価する目的で、いくつかの発酵食品をマウスに投与して粘膜応答に及ぼす影響や作用機序を遺伝子レベルで明らかにすることを課題として研究を進めてきた。 In order to evaluate the immunity functionality of fermented foods produced in Ishikawa Prefecture, the present inventors have clarified the effects and mechanism of action on mucosal responses by administering several fermented foods to mice. The research has been promoted as an issue.
その結果、米麹の抽出物に特定のサイトカイン産生を制御する作用やパイエル板における特定の遺伝子発現を制御する作用があることを見出すに至った。 As a result, it has been found that the extract of rice bran has an action of controlling specific cytokine production and an action of controlling specific gene expression in Peyer's patches.
本発明は、このような知見に基づいて完成されたものである。すなわち、本発明のＴｈ１選択的サイトカイン産生抑制剤は、米麹または米麹抽出物のうちの少なくとも１種を有効成分として含有するサイトカイン産生抑制剤において、パイエル板構成細胞におけるＴｈ１及びＴｈ２のサイトカイン産生のうちＴｈ１のＩＬ−２産生およびＩＦＮ−γ産生を選択的に抑制し、パイエル板構成細胞のＴｈ１選択的なサイトカイン産生抑制用途に使用されることを特徴とする。
また本発明のパイエル板構成細胞遺伝子発現制御剤は、米麹または米麹抽出物のうちの少なくとも１種を有効成分として含有する遺伝子発現制御剤において、パイエル板構成細胞における、
１）peroxisome proliferative activated receptor, gamma, coactivator 1 alpha（Ppargc1a）の遺伝子発現増強、
２）nitric oxide synthase 2（Nos2），IgM variable region（V165-D-J-Cmu），similar to Ig heavy chain V region 93G7 precursor（LOC640614），hydrogen voltage-gated channel 1（Hvcn1）の少なくともいずれか一つの遺伝子発現抑制、
３）stearoyl-Coenzyme A desaturase 2（Scd2）の遺伝子発現抑制、
の前記１）から３）のうち少なくともいずれか一つの用途に用いられることを特徴とする。
The present invention has been completed based on such findings. That is, the Th1-selective cytokine production inhibitor of the present invention is a cytokine production inhibitor containing at least one kind of rice bran or rice bran extract as an active ingredient, and Th1 and Th2 cytokine production in Peyer's patch constituent cells. Among them, it is characterized by selectively inhibiting Th1 IL-2 production and IFN-γ production and being used for Th1 selective cytokine production suppression of Peyer's patch constituent cells.
The Peyer's patch constituent cell gene expression control agent of the present invention is a gene expression control agent containing at least one of rice bran or rice bran extract as an active ingredient.
1) Enhanced expression of peroxisome proliferative activated receptor, gamma,
2) Nitric oxide synthase 2 (Nos2), IgM variable region (V165-DJ-Cmu), similar to Ig heavy chain V region 93G7 precursor (LOC640614), at least one gene of hydrogen voltage-gated channel 1 (Hvcn1) Expression suppression,
3) Inhibition of stearoyl-Coenzyme A desaturase 2 (Scd2) gene expression,
The above-mentioned 1) to 3) are used for at least one of the applications.
本発明の消化管免疫制御組成物は、消化管疾患制御剤、アレルギー予防剤、炎症抑制剤The gastrointestinal tract immune control composition of the present invention comprises a gastrointestinal disease control agent, an allergy preventive agent, and an inflammation inhibitor.
、肥満抑制剤のうち少なくともいずれか一つの用途に用いられる消化管免疫制御組成物に, A gastrointestinal tract immune control composition used for at least one of obesity inhibitors
おいて、Leave
Ｔｈ１選択的サイトカイン産生抑制剤またはパイエル板構成細胞遺伝子制御剤を含有するContains a Th1-selective cytokine production inhibitor or Peyer's patch component cell gene regulator
ことを特徴とする。It is characterized by that.
本発明の消化管免疫制御組成物は、前記の通り、サイトカイン産生を選択的に抑制する作用や、パイエル板における特定の遺伝子の発現を上昇あるいは低下させる作用を有することから、消化管疾患やアレルギーの予防、炎症抑制、肥満抑制等の効果を得ることができる。したがって、本発明の消化管免疫制御組成物により、健康維持、増進を図ることが可能である。 The gastrointestinal tract immune control composition of the present invention, as described above, has an action of selectively suppressing cytokine production and an action of increasing or decreasing the expression of a specific gene in Peyer's patch. Effects such as prevention of inflammation, suppression of inflammation, and suppression of obesity can be obtained. Therefore, health maintenance and promotion can be achieved by the gastrointestinal tract immune control composition of the present invention.
以下、本発明を適用した消化管免疫制御組成物の実施形態について、詳細に説明する。 Hereinafter, an embodiment of a gastrointestinal tract immune control composition to which the present invention is applied will be described in detail.
本発明の米麹を含むことを特徴事項とするものであり、これにより消化管免疫活性を制御する機能を有する。米麹は、例えば清酒製造工程で使用されるもの等を用いることができる。 It is characterized by including the rice bran of the present invention, and thereby has a function of controlling gastrointestinal tract immune activity. As the rice bran, for example, those used in the sake production process can be used.
前記米麹は、米麹そのものであってもよいし、抽出物等の米麹処理物等であってもよい。例えば、米麹抽出物は、水やアルコールで抽出することにより得ることができ、特に、熱水抽出物を凍結乾燥した乾燥粉末体等の形態で用いるのが好適である。また、前記米麹を含む組成物を薬剤等の形態で供する場合には、薬理上許容し得る担体、賦活剤、各種添加物等を加えることも可能である。 The rice bran may be the rice bran itself or a processed rice bran such as an extract. For example, the rice bran extract can be obtained by extraction with water or alcohol, and is particularly preferably used in the form of a dry powder or the like obtained by freeze-drying the hot water extract. When the composition containing rice bran is provided in the form of a drug or the like, a pharmacologically acceptable carrier, an activator, various additives, and the like can be added.
本発明の消化管免疫制御組成物は、サイトカイン産生を選択的に抑制する作用や、パイエル板における特定の遺伝子の発現を上昇あるいは低下させる作用を有する米麹を含むものであるので、消化管疾患やアレルギーの予防、炎症抑制、肥満抑制等の効果を得ることができ、健康維持、増進を図る上で極めて有用である。 Since the gastrointestinal tract immune control composition of the present invention contains rice bran having an action of selectively suppressing cytokine production and an action of increasing or decreasing the expression of a specific gene in Peyer's patch, it can be used for gastrointestinal diseases and allergies. Effects such as prevention of inflammation, suppression of inflammation, suppression of obesity and the like, and is extremely useful for maintaining and improving health.
以下、本発明を適用した具体的な実施例について、実験結果を基に説明する。 Hereinafter, specific examples to which the present invention is applied will be described based on experimental results.
消化管免疫応答の評価方法Gastrointestinal immune response evaluation method
（１）サンプルの作製
酒造メーカーより提供された米麹１ｋｇを熱水で抽出し、その抽出物を濾過後に凍結乾燥に付し、乾燥粉末体を得た。これをサンプルとして以下の実験に用いた。
（２）実験動物
Ｃ５７ＢＬ／６Ｎ（雄，５ｗ，日本チャールズリバー）を実験時に適宜購入し、金沢大学自然研動物飼育施設で１週間以飼育、上馴化させてから実験に使用した。
(1) Preparation of
(2) Experimental animal C57BL / 6N (male, 5w, Charles River, Japan) was appropriately purchased at the time of the experiment, and was bred and acclimatized for 1 week or more in the Kanazawa University Nature Research Animal Breeding Facility before use in the experiment.
（３）サンプルの調製と投与
（１）の方法で得られたサンプルについて、最終投与量が３０ｍｇ／ｋｇ／ｄａｙになるよう、用時、精製水に懸濁して投与サンプルを調製した。この投与サンプルを（２）の条件で飼育したマウスに０．１ｍＬ／１０ｇで１日１回（午前１０時）、連続的に５日間、経口投与した。
(3) Preparation and administration of sample A sample obtained by the method of (1) was prepared by suspending in purified water at the time of use so that the final dose was 30 mg / kg / day. This administration sample was orally administered to mice bred under the condition (2) at 0.1 mL / 10 g once a day (10 am) for 5 consecutive days.
（４）パイエル板構成細胞の採取
初回のサンプル投与開始から７日後に、マウスを過剰のエーテルにより致死せしめ、無菌条件下に小腸を摘出して、散布するパイエル板を実体顕微鏡下に摘出した。得られたパイエル板を冷えたリン酸緩衝液に入れて洗浄後、７５０Ｕ／ｍＬのコラゲナーゼ（ｔｙｐｅＩ：シグマ・アルドリッチ社製）完全培地（ＲＰＭＩ−１６４０）に投入し、１時間インキュベートした。インキュベート終了後、分離したパイエル板構成リンパ球を２００μｍのナイロンメッシュを通してシングルセル懸濁液として細胞数を計測した。
(4) Collection of Peyer's patch constituent cells Seven days after the start of the first sample administration, the mice were killed with excess ether, the small intestine was removed under aseptic conditions, and the Peyer's patch to be sprayed was removed under a stereomicroscope. The obtained Peyer's board was washed in a cold phosphate buffer, and then placed in 750 U / mL collagenase (type I: Sigma-Aldrich) complete medium (RPMI-1640) and incubated for 1 hour. After completion of the incubation, the number of cells was counted as a single cell suspension of the separated Peyer's plate lymphocytes through a 200 μm nylon mesh.
パイエル板構成細胞を３×１０６ｃｅｌｌｓ／ｍＬの濃度となるように５％ＦＣＳ化ＲＰＭＩ−１６４０培地に再浮遊して調製し、２４ウエル培養プレートに１ｍＬずつ播種した。５％ＣＯ２雰囲気下、３７℃で１時間の安定培養を行った後に、最終濃度が５μｇ／ｍＬのConcanavalin A（ＣｏｎＡ），あるいは１μｇ／ｍＬのlipopolysaccharide（ＬＰＳ）を各ウエルに添加し、４８〜１４４時間、静置培養した。 Peyer's plate constituting cells were prepared by resuspending in 5% FCS-modified RPMI-1640 medium to a concentration of 3 × 10 6 cells / mL, and seeding 1 mL each in a 24-well culture plate. After stable culture at 37 ° C. for 1 hour in a 5% CO 2 atmosphere, Concanavalin A (ConA) with a final concentration of 5 μg / mL or lipopolysaccharide (LPS) with a final concentration of 5 μg / mL was added to each well. Static culture was performed for ˜144 hours.
（５）培養液上清中のＴｈ１およびＴｈ２関連サイトカインの測定
ＣｏｎＡによる刺激培養終了後に、培養液上清を回収し、ここに含まれるＴヘルパー細胞による免疫調節因子であるＩＬ−２とＩＦＮ−γ（Ｔｈ１），ＩＬ−４とＩＬ−５（Ｔｈ２）を市販のＥＬＩＳＡ ｋｉｔ（ｅＢｉｏｓｃｉｅｎｃｅ社製）を用いて測定した。測定方法は、ｋｉｔの添付文書に従い、形成する発色色素の吸光度を測定し、標準物質による検量線からそれぞれのサイトカイン産生量を算定した。
(5) Measurement of Th1 and Th2-related cytokines in culture supernatant After completion of stimulation culture with ConA, the culture supernatant is recovered, and IL-2 and IFN- which are immunoregulatory factors by T helper cells contained therein γ (Th1), IL-4 and IL-5 (Th2) were measured using a commercially available ELISA kit (manufactured by eBioscience). The measuring method was to measure the absorbance of the chromogenic dye to be formed according to the package insert of the kit and to calculate the amount of each cytokine produced from the calibration curve with the standard substance.
（６）パイエル板構成細胞からのＲＮＡ抽出
上記のパイエル板構成細胞の培養とは別に、（４）の操作で得られたパイエル板について、市販のＲＮＡ抽出ｋｉｔを使用して、パイエル板から直接ｔｏｔａｌ ＲＮＡを採取した。すなわち、ｋｉｔに付属する組織融解用試薬をパイエル板組織に直接添加し、以降はマニュアルに従って操作してｔｏｔａｌ ＲＮＡを得た。ＲＮＡ量は２６０および２８０ｎｍの吸光度差を測定することにより計測し、その後、ｔｏｔａｌ ＲＮＡ１μｇを１．２％アガロースゲルで電気泳動した後、ＥＢ染色し、１８Ｓおよび２８Ｓのバンドの明瞭さからＲＮＡのクオリティーを確認した。抽出したｔｏｔａｌ ＲＮＡは、以下のＤＮＡマイクロアレイによる発現遺伝子網羅解析を実施するまで−８０℃で保存した。
(6) RNA extraction from Peyer's patch constituent cells Separately from the culture of Peyer's patch constituent cells, the Peyer's board obtained by the operation of (4) is directly extracted from Peyer's board using a commercially available RNA extraction kit. Total RNA was collected. That is, the tissue melting reagent attached to the kit was directly added to Peyer's board tissue, and thereafter, total RNA was obtained by operating according to the manual. The amount of RNA was measured by measuring the difference in absorbance between 260 and 280 nm, and then 1 μg of total RNA was electrophoresed on a 1.2% agarose gel, followed by EB staining. From the clarity of the 18S and 28S bands, the RNA quality was determined. It was confirmed. The extracted total RNA was stored at −80 ° C. until the gene expression analysis using the following DNA microarray was performed.
（７）ＤＮＡマイクロアレイ
パイエル板構成細胞から抽出したｔｏｔａｌ ＲＮＡについて発現遺伝子の網羅的解析を実施した。すなわち、（６）の方法で得たＲＮＡ（７００ ｎｇ）を市販の商品名MessageAmp II-Biotin Enhanced kit（Ａｍｂｉｏｎ社製）でｃＲＮＡを作製し、遺伝子標的ハイブリダイゼーションをマウスＧｅｎｅＣｈｉｐ（商品名）（Ａｆｆｙｍｅｔｒｉｘ社製）で測定した。すなわち、ｃＲＮＡから作製した２重鎖ＤＮＡをＧｅｎｅＣｈｉｐに滴下し、４５℃、１６時間作用させた。作用終了後にチップをFluidic
Station 450で洗浄して染色し、ハイブリッド染色された遺伝子をGeneChip Operating
software（商品名）を搭載したワークステーションでイメージ化し、そのイメージのヒートマップを計算機上で数値化した。ミスマッチする発現遺伝子と完全にマッチした遺伝子との差を計算機上で演算し、その後、対象となるマウスから得た遺伝子との相対的な変動をチェックし、１．５倍以上の変動する遺伝子群を抽出した。抽出された遺伝子群で変化が認められたものについては、適宜、Ingenuity Pathway Analysis（ＩＰＡ）解析（データベースアクセスは米国）に付し、そのメカニズム解析を実施した。
(7) DNA microarray Exhaustive analysis of expressed genes was performed on total RNA extracted from Peyer's patch constituent cells. That is, RNA (700 ng) obtained by the method (6) was prepared using a commercially available product name MessageAmp II-Biotin Enhanced kit (manufactured by Ambion), and gene target hybridization was performed using mouse GeneChip (trade name) (Affymetrix). ). That is, double-stranded DNA prepared from cRNA was added dropwise to GeneChip and allowed to act at 45 ° C. for 16 hours. Fluidic tip after action
GeneChip Operating
It was imaged on a workstation equipped with software (product name), and the heat map of that image was digitized on a computer. Calculate the difference between the mismatched expression gene and the perfectly matched gene on a computer, and then check the relative variation with the gene obtained from the target mouse. Extracted. For the extracted gene group, a change was observed, and it was appropriately subjected to Ingenuity Pathway Analysis (IPA) analysis (database access in the United States), and the mechanism analysis was performed.
米麹のＴｈサイトカイン産生に及ぼす影響
米麹熱水抽出物を３０ｍｇ／ｋｇ／ｄａｙの用量で５日間、マウスに経口投与した結果、図１に示す通り、パイエル板構成細胞におけるＩＬ−２及びＩＦＮ−γ産生を有意に抑制し、その作用は４８時間目まで持続した。
Effect of rice bran on Th cytokine production As a result of oral administration of rice bran hot water extract at a dose of 30 mg / kg / day to mice for 5 days, as shown in FIG. 1, IL-2 and IFN in Peyer's patch constituent cells -Gamma production was significantly suppressed, and the effect persisted until 48 hours.
一方、図２に示す通り、パイエル板構成細胞におけるＩＬ−４及びＩＬ−５のＴｈ２サイトカイン産生に対し、米麹抽出物は全く影響しないこともわかった。 On the other hand, as shown in FIG. 2, it was also found that the rice bran extract had no influence on the production of Th2 cytokines of IL-4 and IL-5 in Peyer's patch constituent cells.
ＤＮＡマイクロアレイを用いたパイエル板構成細胞における発現遺伝子の網羅的解析
図３は、何も処置しないマウスから得たパイエル板構成細胞における発現遺伝子の変動を示すものであり、図中、左下は発現が少ない遺伝子であり、右上は頻繁に発現している遺伝子を表す。中線を軸に上下の閾線を設け、上に発現するドットは遺伝子中で上方調節（up-regulation）される遺伝子群を、閾線の下側は下方調節（down-regulation）される遺伝子群をそれぞれ表す。
Comprehensive analysis of expressed genes in Peyer's patch constituent cells using DNA microarrays Figure 3 shows the variation of expressed genes in Peyer's patch constituent cells obtained from mice not treated with anything. There are few genes, and the upper right represents genes that are frequently expressed. The upper and lower threshold lines are set with the middle line as the axis, and the dots expressed above are the genes that are up-regulated in the gene, and the genes that are down-regulated below the threshold line Each group is represented.
定常状態にある場合には、発現方向に向かう遺伝子はなく、中線を境に２倍以上の変動を示す遺伝子は１０個から１００個程度に収まる。正常マウスのパイエル板では、おおよそ８の遺伝子の調節発現が認められた（表１を参照）。 When in a steady state, there are no genes in the direction of expression, and there are only about 10 to 100 genes that exhibit more than twice the fluctuations from the middle line. In the normal mouse Peyer's patch, approximately 8 genes were regulated (see Table 1).
これに対して、表２及び表３に示す通り、米麹抽出物を投与したマウスでは、何も処置しないマウスに比べて３９個の重複しない遺伝子に変動が認められ、その変動はラクトバチルス（Lactobacillus）乳酸菌あるいはエンテロコックス（Enterococcus）乳酸菌よりも顕著である。また、変動した遺伝子群のうち半分の２０個がup-regulationされ、残りはdow-regulationすることがわかった。 On the other hand, as shown in Table 2 and Table 3, in the mice administered with the rice bran extract, 39 non-overlapping genes were observed compared to the mice not treated with any change. It is more prominent than Lactobacillus lactic acid bacteria or Enterococcus lactic acid bacteria. In addition, it was found that 20 of the half of the fluctuating gene group was up-regulated and the rest were dow-regulated.
米麹の消化管免疫制御
米麹抽出物は，パイエル板構成細胞におけるＴｈ１およびＴｈ２サイトカイン産生のうち、Ｔｈ１のＩＬ−２及びＩＦＮ−γの産生を選択的に抑制する作用が認められた。これらの一連のサイトカインは、過剰に産生された場合に、自己免疫疾患を誘発することが知られており、このことから、米麹には穏やかな摂取でクローン病など消化管系の疾患やアレルギーの予防、及び腸内悪玉菌の増殖による炎症抑制に効果があるものと考えられる。
Gastrointestinal immunity control of rice bran The rice bran extract has an action to selectively suppress the production of IL-2 and IFN-γ of Th1 among Th1 and Th2 cytokine production in Peyer's patch constituent cells. It was. These series of cytokines are known to induce autoimmune diseases when produced in excess, which suggests that rice bran is mildly ingested with gastrointestinal diseases such as Crohn's disease and allergies. It is thought to be effective in preventing inflammation and suppressing inflammation due to the growth of enteric bad bacteria.
ＤＮＡマイクロアレイの結果で、米麹の摂取はパイエル板における（１）peroxisome
proliferative activated receptor, gamma, coactivator 1 alphaの発現を上昇させた。この遺伝子にコードされるＰＰＡＲ−γは、腸組織の再構築に関連することから，、度な米麹摂取は腸環境保全に役立つものと考えられる。さらに、（２）nitric oxide synthase 2，IgM
variable region，hydrogen voltage-gated channel 1の発現を低下させたことから、米麹抽出物は、腸管の過剰な炎症反応を押さえる抗炎症効果を有するものと考えられる。また、（３）stearoyl-Coenzyme
A desaturase 2の発現を低下させることから、これにコードされる酵素によって脂質合成が抑制され（文献：PNAS, 2005 vol. 102
,12501-12506参照）、肥満抑制にも応用できるものと考えられる。
As a result of DNA microarray, rice bran intake was in Peyer's patch (1) peroxisome
Increased expression of proliferative activated receptor, gamma, coactivator 1 alpha. Since PPAR-γ encoded by this gene is related to the reconstruction of intestinal tissue, frequent intake of rice bran is considered to be useful for intestinal environment conservation. Furthermore, (2)
Since the expression of variable region and hydrogen voltage-gated
Since it reduces the expression of A
, 12501-12506), and is considered to be applicable to obesity suppression.
Claims (4)
１）peroxisome proliferative activated receptor, gamma, coactivator 1 alpha（Ppargc1a）の遺伝子発現増強、
２）nitric oxide synthase 2（Nos2），IgM variable region（V165-D-J-Cmu），similar to Ig heavy chain V region 93G7 precursor（LOC640614），hydrogen voltage-gated channel 1（Hvcn1）の少なくともいずれか一つの遺伝子発現抑制、
３）stearoyl-Coenzyme A desaturase 2（Scd2）の遺伝子発現抑制、
の前記１）から３）のうち少なくともいずれか一つの用途に用いられることを特徴とするパイエル板構成細胞遺伝子発現制御剤。 In a gene expression control agent containing at least one of rice bran or rice bran extract as an active ingredient, in Peyer's patch constituent cells,
1) Enhanced expression of peroxisome proliferative activated receptor, gamma, coactivator 1 alpha (Ppargc1a),
2) Nitric oxide synthase 2 (Nos2), IgM variable region (V165-DJ-Cmu), similar to Ig heavy chain V region 93G7 precursor (LOC640614), at least one gene of hydrogen voltage-gated channel 1 (Hvcn1) Expression suppression,
3) Inhibition of stearoyl-Coenzyme A desaturase 2 (Scd2) gene expression,
The Peyer's patch constituent cell gene expression regulator, which is used for at least one of the above 1) to 3).
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