JP6002582B2 - Gastrin production inhibitor and food composition containing the same - Google Patents

Gastrin production inhibitor and food composition containing the same Download PDF

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JP6002582B2
JP6002582B2 JP2012554806A JP2012554806A JP6002582B2 JP 6002582 B2 JP6002582 B2 JP 6002582B2 JP 2012554806 A JP2012554806 A JP 2012554806A JP 2012554806 A JP2012554806 A JP 2012554806A JP 6002582 B2 JP6002582 B2 JP 6002582B2
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古賀 泰裕
泰裕 古賀
幸夫 浅見
幸夫 浅見
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    • AHUMAN NECESSITIES
    • A23FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23CDAIRY PRODUCTS, e.g. MILK, BUTTER OR CHEESE; MILK OR CHEESE SUBSTITUTES; MAKING THEREOF
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    • A23LFOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
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    • AHUMAN NECESSITIES
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    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • AHUMAN NECESSITIES
    • A23FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23VINDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2400/00Lactic or propionic acid bacteria
    • A23V2400/11Lactobacillus
    • A23V2400/145Gasseri

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Description

本発明は、胃炎、胃潰瘍、胃酸過多および逆流性食道炎に対する改善効果を有する乳酸菌ならびに該乳酸菌を含む医薬組成物および食品組成物に関する。   The present invention relates to a lactic acid bacterium having an improving effect on gastritis, gastric ulcer, hyperacidity and reflux esophagitis, and a pharmaceutical composition and a food composition containing the lactic acid bacterium.

腸管は、高密度の生存する細菌を含む多数の異なる細菌種からなる多様性に富んだ微生物叢を内包し、管腔内容物の1011〜1012cells/gもの濃度にまで達している。消化管の生来の微生物叢の健康や疾患における役割は、代謝活性、腸管上皮および免疫システムへの栄養的効果、および定着した宿主を外来微生物の侵入から防御することなどを含めよく知られている(非特許文献1)。The intestinal tract contains a diverse microbial flora consisting of many different bacterial species, including a high density of living bacteria, and has reached a concentration of 10 11 to 10 12 cells / g of luminal contents. The role of the digestive tract's natural microbiota in health and disease is well known, including metabolic activity, nutritional effects on the intestinal epithelium and immune system, and protecting established hosts from invasion of foreign microorganisms. (Non-Patent Document 1).

一方、胃は、Helicobacter pyloriに感染していない場合、ヒトにおいて、数種の細菌だけが存在する。絶食の間、胃液にはStreptococcus、LactobacillusおよびVeillonellaを含む少数の細菌だけが約10〜10/mlで含まれている。しかしながら、これらの細菌は、口腔や喉からの一過性のもので常在ではないと見られている(非特許文献2および3)。ヒトの胃におけるこのような細菌の欠乏は、管腔内の高い酸度が原因であると思われる。On the other hand, if the stomach is not infected with Helicobacter pylori, there are only a few bacteria in humans. During fasting, the gastric juice contains only a few bacteria, including Streptococcus, Lactobacillus, and Veillonella, at about 10 2 to 10 3 / ml. However, these bacteria are transient from the oral cavity and throat and are not considered to be resident (Non-patent Documents 2 and 3). Such bacterial deficiency in the human stomach is likely due to high intraluminal acidity.

H. pyloriは、ヒトの胃において、消化性潰瘍や癌を引き起こす病原性細菌としてよく知られている。ヘリコバクター属細菌は、当初から、ヒトの生来の胃内微生物叢に属するとも提案されてきた(非特許文献4)。この仮説は、H. pyloriが幼児期の早いうちに獲得され、その後何十年もの間、相当数において胃に定着し続けているという事実に支持されている。このことによって、胃の生理学的発達および機能において、胃の生来の微生物叢の役割について明らかにする必要が生じる。しかしながら、H. pyloriを用いた感染試験によって、その役割を明らかにすることは困難である。なぜなら、CagA、空胞化毒素、ウレアーゼおよびその代謝産物などのH. pyloriの種々の病原性因子が、慢性の病的炎症を胃組織において誘導するからであり、このことがH. pyloriの生来の細菌としての生理学的役割をあいまいにしてしまう。   H. pylori is well known as a pathogenic bacterium that causes peptic ulcer and cancer in the human stomach. From the beginning, Helicobacter bacteria have also been proposed to belong to human natural gastric microbiota (Non-patent Document 4). This hypothesis is supported by the fact that H. pylori was acquired early in childhood and continued to settle in the stomach for a number of decades thereafter. This creates a need to clarify the role of the stomach's natural microflora in the physiological development and function of the stomach. However, it is difficult to clarify its role by infection tests using H. pylori. This is because various virulence factors of H. pylori, such as CagA, vacuolating toxins, urease and its metabolites, induce chronic pathological inflammation in stomach tissue, which is the natural origin of H. pylori. It obscures the physiological role of bacteria.

先の研究において、本発明者らは、特定病原体未感染(specific pathogen-free、SPF)マウスの胃において、支配的にラクトバチルス属細菌からなる生来の微生物叢を見出した(非特許文献5)。SPFマウスの胃の酸度がより低いことによって、ラクトバチルス属細菌が胃に定着することができるものと考えられた。さらには、原因の明確でない炎症の変化が、SPFマウスの胃に生じていた。   In the previous study, the present inventors found a natural microflora consisting mainly of Lactobacillus bacteria in the stomach of specific pathogen-free (SPF) mice (Non-patent Document 5). . It was considered that Lactobacillus bacteria could settle in the stomach due to the lower acidity of the stomach of SPF mice. In addition, an unclear inflammation change occurred in the stomach of SPF mice.

このように本発明者らを含め多くの研究グループが、ラクトバチルス属細菌などの乳酸菌やピロリ菌(Helicobacter pylori)と胃との関係について着目し、研究を重ねてきた。なかでも、乳酸菌による胃炎や胃潰瘍の予防改善については、多くの検討がなされてきている(特許文献1〜5)。しかしながら、これらの多くの検討は、乳酸菌の抗ピロリ菌作用を利用したものであり、かかる作用を利用しない上部消化管疾患などの予防改善については、十分な検討がなされてこなかった現状がある。   As described above, many research groups including the present inventors have focused on the relationship between lactic acid bacteria such as Lactobacillus genus bacteria and Helicobacter pylori and the stomach, and have repeated research. In particular, many studies have been made on the prevention and improvement of gastritis and gastric ulcer caused by lactic acid bacteria (Patent Documents 1 to 5). However, many of these studies utilize the anti-H. Pylori action of lactic acid bacteria, and there are currently no sufficient studies on the prevention and improvement of upper gastrointestinal diseases that do not use such action.

特許第4509250号公報Japanese Patent No. 4509250 特許第3046303号公報Japanese Patent No. 3046303 特許第2672247号公報Japanese Patent No. 2672247 特許第3810403号公報Japanese Patent No. 3810403 特許第4021951号公報Japanese Patent No. 4021951

Guarner F, Malagelada JR. "Gut flora in health and disease." Lancet 2003; 361: 512-519.Guarner F, Malagelada JR. "Gut flora in health and disease." Lancet 2003; 361: 512-519. Lambert J, and Hull R. "Upper gastrointestinal tract disease and probiotics" Asia Pacific J Clin Nutr 1996; 5: 31-35.Lambert J, and Hull R. "Upper gastrointestinal tract disease and probiotics" Asia Pacific J Clin Nutr 1996; 5: 31-35. Ruddell WS, Axon AT, Findlay JM, Bartholomew BA, and Hill MJ. "Effect of cimetidine on the gastric bacterial flora." Lancet. 1980; Mar 29: 672-674.Ruddell WS, Axon AT, Findlay JM, Bartholomew BA, and Hill MJ. "Effect of cimetidine on the gastric bacterial flora." Lancet. 1980; Mar 29: 672-674. Blaser M J. "Helicobacters are indigenous to the human stomach: duodenal ulceration is due to changes in gastric microecology in the modern era." Gut 1998; 43: 721-727.Blaser M J. "Helicobacters are indigenous to the human stomach: duodenal ulceration is due to changes in gastric microecology in the modern era." Gut 1998; 43: 721-727. Kabir AMA, Aiba Y, Takagi A, Kamiya S, Miwa T, and Koga Y. "Prevention of Helicobacter pylori infection by lactobacilli in a gnotobiotic murine model." Gut 1997; 41: 49-55.Kabir AMA, Aiba Y, Takagi A, Kamiya S, Miwa T, and Koga Y. "Prevention of Helicobacter pylori infection by lactobacilli in a gnotobiotic murine model." Gut 1997; 41: 49-55.

本発明者らは、ラクトバチルス属細菌を生菌または死菌で無菌マウスに与えたところ、胃内のガストリン産生細胞数が有意に減少することを見出し、さらに鋭意研究を重ねた結果、本発明を完成するに至った。   The present inventors found that the number of gastrin-producing cells in the stomach was significantly reduced when the Lactobacillus genus bacteria were given to sterile mice as live or dead bacteria. It came to complete.

すなわち本発明は、以下のガストリン産生抑制剤およびそれを含有する食品組成物に関する。
[1]ラクトバチルス属細菌の死菌体を含む、ガストリン産生抑制剤。
[2]ラクトバチルス属細菌の死菌体を含み、生菌体を含まない、ガストリン産生抑制剤。
[3]ラクトバチルス属細菌が、Lactobacillus gasseriである、前記[1]または[2]に記載のガストリン産生抑制剤。
[4]ラクトバチルス属細菌が、Lactobacillus gasseri OLL2716 (受託番号:FERM BP-6999)である、前記[1]または[2]に記載のガストリン産生抑制剤。
[5]前記[1]〜[4]のいずれか一項に記載のガストリン産生抑制剤を含有する、食品組成物。
[6]乳酸菌による発酵食品である、前記[5]に記載の食品組成物。
[7]乳酸菌による発酵食品が、発酵乳である、前記[6]に記載の食品組成物。
[8]発酵乳が、ヨーグルトである、前記[7]に記載の食品組成物。
That is, this invention relates to the following gastrin production inhibitors and food compositions containing the same.
[1] A gastrin production inhibitor comprising dead cells of Lactobacillus bacteria.
[2] A gastrin production inhibitor comprising dead cells of Lactobacillus bacteria and no live cells.
[3] The gastrin production inhibitor according to [1] or [2], wherein the Lactobacillus genus bacterium is Lactobacillus gasseri.
[4] The gastrin production inhibitor according to [1] or [2] above, wherein the Lactobacillus bacterium is Lactobacillus gasseri OLL2716 (Accession Number: FERM BP-6999).
[5] A food composition comprising the gastrin production inhibitor according to any one of [1] to [4].
[6] The food composition according to the above [5], which is a fermented food by lactic acid bacteria.
[7] The food composition according to [6], wherein the fermented food by lactic acid bacteria is fermented milk.
[8] The food composition according to [7], wherein the fermented milk is yogurt.

本発明のガストリン産生抑制剤は、ラクトバチルス属細菌の死菌体を用いているため、ピロリ菌に対する除菌作用を有するものではないが(例えば、特許文献1および2)、胃組織を構成する細胞に直接働きかけ胃酸分泌を抑制することができる。さらに、例えば、ピロリ菌除菌後の胃酸過多、それに起因する逆流性食道炎、さらにピロリ菌とは関係のない胃炎、胃潰瘍や逆流性食道炎、例えば、加齢による逆流性食道炎などに対して効果が期待できる。
とくに本発明によれば、乳酸菌の抗ピロリ菌作用を利用しない胃酸過多に基づく胸焼け、胃痛等の一連の症状、逆流性食道炎、食道ガンなどの予防改善する新たな医薬または食品を提供することができる。
Since the gastrin production inhibitor of the present invention uses dead cells of Lactobacillus bacteria, it does not have a sterilizing action against H. pylori (for example, Patent Documents 1 and 2), but constitutes stomach tissue. It can work directly on cells and suppress gastric acid secretion. Furthermore, for example, for gastric hyperacidity after eradication of Helicobacter pylori, reflux esophagitis resulting therefrom, gastritis unrelated to Helicobacter pylori, gastric ulcer and reflux esophagitis, such as reflux esophagitis due to aging, etc. Can be expected.
Particularly, according to the present invention, there is provided a new medicine or food for preventing and improving a series of symptoms such as heartburn and gastric pain, reflux esophagitis, esophageal cancer and the like based on excessive acidity without utilizing the anti-pylori action of lactic acid bacteria. Can do.

さらに、例えば、非ステロイド性抗炎症薬(NSAID)服用者には胃酸に起因する胃炎や逆流性食道炎が問題となっているところ、現状では、プロトンポンプインヒビター(PPI)により胃酸分泌を抑える治療法が取られている。しかしながら、PPIの投与できる期間は最長8週間に限られている上、作用点がプロトンポンプであるために胃酸分泌促進ホルモンであるガストリンの発現が異常に上昇してしまう副作用がある。これに対して、本発明のガストリン産生抑制剤は、ガストリンの分泌を胃組織を構成する細胞に直接働きかけ抑えるためPPIの使用量を少なくしたり、PPI投与終了後のガストリン上昇の副作用を抑えたりすることができると予想され、本発明のガストリン産生抑制剤とPPIとの併用により効果的に胃酸過多に起因した胃炎、胃潰瘍、逆流性食道炎および過酸症を改善できると考えられる。   Furthermore, for example, gastritis caused by gastric acid and reflux esophagitis are a problem for nonsteroidal anti-inflammatory drug (NSAID) users. Currently, proton pump inhibitor (PPI) is used to suppress gastric acid secretion. The law is being taken. However, the period during which PPI can be administered is limited to a maximum of 8 weeks, and since the action point is a proton pump, there is a side effect that the expression of gastrin, a gastric acid secretion promoting hormone, is abnormally increased. In contrast, the gastrin production inhibitor of the present invention directly reduces the amount of PPI used to suppress the secretion of gastrin on the cells constituting the gastric tissue, and suppresses the side effect of gastrin elevation after the end of PPI administration. It is expected that the gastrin production inhibitor of the present invention and PPI can effectively improve gastritis, gastric ulcer, reflux esophagitis and peracidosis due to excessive gastric acidity.

また死菌体を用いるので、輸送時等の温度管理が不要であるため、取扱いが簡便で、品質劣化の虞がない。また、他の微生物(とくに細菌)との共生関係を考慮する必要がなく、比較的利用に制限がない。
さらに本発明のガストリン産生抑制剤を含む食品組成物は、ラクトバチルス属細菌の死菌体を積極的に含有せしめるものであり、従来の食品組成物とは全く組成の異なるものであり、ガストリンを抑制することによって、胃酸分泌を抑制することなどが可能である。
In addition, since dead cells are used, temperature management during transportation and the like is unnecessary, so handling is simple and there is no risk of quality deterioration. In addition, there is no need to consider the symbiotic relationship with other microorganisms (particularly bacteria), and there is relatively no restriction on use.
Furthermore, the food composition containing the gastrin production inhibitor of the present invention actively contains dead cells of the genus Lactobacillus, which is completely different in composition from conventional food compositions. By suppressing it, it is possible to suppress gastric acid secretion.

本発明のガストリン産生抑制剤は、ラクトバチルス(Lactobacillus)属細菌の死菌体を含む。本発明のガストリン産生抑制剤は、医薬または食品添加剤としても用いることができる。また、本発明のガストリン産生抑制剤は、ラクトバチルス(Lactobacillus)属細菌の死菌体を含み、生菌体を含まないことも可能である。また死菌体のみからなっていてもよい。   The gastrin production inhibitor of the present invention contains dead cells of bacteria belonging to the genus Lactobacillus. The gastrin production inhibitor of the present invention can also be used as a pharmaceutical or food additive. Moreover, the gastrin production inhibitor of this invention contains the dead microbial cell of Lactobacillus (Lactobacillus) genus bacteria, and it is also possible not to contain a living microbial cell. Moreover, it may consist only of dead cells.

Lactobacillus属に含まれる種の例として、Lactobacillus delbrueckii subsp. burgalicus、Lactobacillus delbrueckii subsp. lactis、Lactobacillus paracasei subsp. paracasei、Lactobacillus helveticus、Lactobacillus helveticus subsp. jugurti、Lactobacillus acidophilus、Lactobacillus crispatus、Lactobacillus amylovorus、Lactobacillus gallinarum、Lactobacillus gasseri、Lactobacillus oris、Lactobacillus casei subsp. rhamnosus、Lactobacillus johnsonii、Lactobacillus fermentum、Lactobacillus brevisを挙げることができるが、本発明におけるラクトバチルス属細菌は、死菌体でガストリン産生を抑制すれば、とくに限定されず、前記の例の1種または2種以上であってもよい。好ましくは、Lactobacillus gasseriであり、とくに好ましくは、Lactobacillus gasseri OLL2716 (受託番号:FERM BP-6999)(本菌株は、独立行政法人産業技術総合研究所特許生物寄託センター(旧通商産業省工業技術院生命工学工業技術研究所)、〒305−8566 日本国茨城県つくば市東1丁目1番地1中央第6(旧住所:〒305−8566 日本国茨城県つくば市東1丁目1番3号)に平成11年5月24日付で寄託されている)である。   Examples of species contained in the genus Lactobacillus include Lactobacillus delbrueckii subsp.burgalicus, Lactobacillus delbrueckii subsp. Lactis, Lactobacillus paracasei subsp.paracasei, Lactobacillus helveticus, Lactobacillus helveticus subsp. Examples include gasseri, Lactobacillus oris, Lactobacillus casei subsp.rhamnosus, Lactobacillus johnsonii, Lactobacillus fermentum, and Lactobacillus brevis. , One or more of the above examples may be used. Lactobacillus gasseri is preferable, and Lactobacillus gasseri OLL2716 (Accession No .: FERM BP-6999) (this strain is the National Institute of Advanced Industrial Science and Technology Patent Biodeposition Center (former Life Science Institute of Industry and Technology) Institute of Engineering and Industrial Technology), 1st Central, 1st Higashi 1-chome, Tsukuba, Ibaraki, Japan 305-8565, Japan (former address: 1-3-3 Higashi 1-chome, Tsukuba, Ibaraki 305-8586, Japan), 1999 (Deposited on May 24).

本発明のガストリン産生抑制剤を医薬として用いる場合、有効成分であるラクトバチルス属細菌の死菌体が結果的に胃に作用すれば、その投与経路はとくに限定されない。投与した個体のガストリン産生を抑制し、胃酸過多、胃炎、胃潰瘍、逆流性食道炎などに対して改善効果を奏する。
本発明のガストリン産生抑制剤の投与には、経口的または非経口的に投与することが含まれる。例えば、経口投与や経管投与であってもよい。簡便かつ安全性の観点から、経口投与が好ましい。また剤型は、とくに限定されないが、投与経路に応じて適宜選択することができ、例えば、液剤、カプセル剤、顆粒剤、丸剤、懸濁剤、乳剤、散剤、錠剤、シロップ剤、注射剤、トローチ剤などが挙げられる。
When the gastrin production inhibitor of the present invention is used as a medicine, the administration route is not particularly limited as long as dead cells of the genus Lactobacillus as an active ingredient act on the stomach as a result. It suppresses the production of gastrin in the administered individual and has an improvement effect on gastric hyperacidity, gastritis, gastric ulcer, reflux esophagitis and the like.
Administration of the gastrin production inhibitor of the present invention includes oral or parenteral administration. For example, oral administration or tube administration may be used. Oral administration is preferred from the viewpoint of convenience and safety. The dosage form is not particularly limited, and can be appropriately selected depending on the administration route. For example, it is a liquid, capsule, granule, pill, suspension, emulsion, powder, tablet, syrup, injection. And lozenges.

経口投与製剤としては、周知の各種剤型とすることができ、例えば、顆粒剤、散剤、錠剤、丸剤、カプセル剤、液剤、シロップ剤、乳剤、懸濁剤、トローチ剤などの剤型とすることができる。
非経口的な投与としては、注射剤などの形での投与を挙げることができる。また、本発明のガストリン産生抑制剤を、処置を施したい領域に局所的に投与することもできる。例えば、手術中の局所注入、カテーテルの使用により投与することも可能である。
Oral preparations can be made into various known dosage forms, such as granules, powders, tablets, pills, capsules, solutions, syrups, emulsions, suspensions, lozenges, and the like. can do.
Examples of parenteral administration include administration in the form of injections. Moreover, the gastrin production inhibitor of this invention can also be locally administered to the area | region which wants to treat. For example, it can be administered by local injection during surgery or by use of a catheter.

本発明の医薬組成物に用い得る担体としては、界面活性剤、賦形剤、着色料、着香料、保存料、安定剤、緩衝剤、懸濁剤、等張化剤、結合剤、崩壊剤、滑沢剤、流動性促進剤、矯味剤などが医薬上許容される担体として挙げられるが、その他常用の担体を適宜使用することができる。具体的には、軽質無水ケイ酸、乳糖、結晶セルロース、マンニトール、デンプン、カルメロースカルシウム、カルメロースナトリウム、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、ポリビニルアセタールジエチルアミノアセテート、ポリビニルピロリドン、ゼラチン、中鎖脂肪酸トリグリセライド、ポリオキシエチレン硬化ヒマシ油60、白糖、カルボキシメチルセルロース、コーンスターチ、無機塩類などを挙げることができる。   Carriers that can be used in the pharmaceutical composition of the present invention include surfactants, excipients, coloring agents, flavoring agents, preservatives, stabilizers, buffers, suspending agents, isotonic agents, binders, and disintegrants. , Lubricants, fluidity promoters, flavoring agents and the like are listed as pharmaceutically acceptable carriers, and other commonly used carriers can be used as appropriate. Specifically, light anhydrous silicic acid, lactose, crystalline cellulose, mannitol, starch, carmellose calcium, carmellose sodium, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylacetal diethylaminoacetate, polyvinylpyrrolidone, gelatin, medium chain fatty acid triglyceride, Examples thereof include polyoxyethylene hydrogenated castor oil 60, sucrose, carboxymethyl cellulose, corn starch, and inorganic salts.

本発明のガストリン産生抑制剤を医薬に用いる場合、含有されるラクトバチルス属細菌の死菌体の菌体濃度はとくに限定されないが、濃縮液として利用する場合、2×1010個/g以上、乾燥物として利用する場合、1×1011個/g以上とするのが好ましい。
本発明のガストリン抑制剤を医薬として用いる場合において、ラクトバチルス属細菌の死菌体の配合量は、とくに限定されないが、剤型、症状、体重、用途などに応じて適宜調整することができる。
本発明の医薬の一日当たりの摂取量は、とくに限定されないが、年齢、症状、体重、用途などに応じて適宜調整することができる。典型的には、0.1〜10000mg/kg体重を摂取することができ、好ましくは1〜2000mg/kg体重、さらに好ましくは10〜500mg/kg体重を摂取することができる。また、摂取の仕方としては、とくに限定されないが、例えば、およそ1gの製剤を1日1本摂取することから、10gの製剤を一日3本摂取することなど、適宜変更することが可能である。1日の摂取例としては、例えば、体重60kgの人が1〜5×1011細菌/gの粉末製剤の6gスティックを1日1〜3回摂取し、1日当たり100〜300mg/kgとすることが例示できる。
When the gastrin production inhibitor of the present invention is used in medicine, the concentration of the dead cells of the genus Lactobacillus is not particularly limited, but when used as a concentrate, 2 × 10 10 cells / g or more, When used as a dried product, it is preferably 1 × 10 11 pieces / g or more.
In the case where the gastrin inhibitor of the present invention is used as a medicine, the amount of dead cells of the genus Lactobacillus is not particularly limited, but can be appropriately adjusted according to the dosage form, symptoms, body weight, use and the like.
The daily intake of the medicament of the present invention is not particularly limited, but can be appropriately adjusted according to age, symptoms, body weight, use and the like. Typically, 0.1 to 10,000 mg / kg body weight can be taken, preferably 1 to 2000 mg / kg body weight, more preferably 10 to 500 mg / kg body weight. The way of ingestion is not particularly limited, but can be appropriately changed, for example, from taking about 1 g of the preparation once a day to ingesting 10 g of the preparation 3 times a day. . As an example of daily intake, for example, a person with a body weight of 60 kg takes 1 to 5 × 10 11 bacteria / g of a 6 g stick of a powder preparation 1 to 3 times a day to make 100 to 300 mg / kg per day. Can be illustrated.

本発明の食品組成物は、本発明にかかるガストリン産生抑制剤を含有する。
本発明における食品組成物は、とくに限定されない。例えば、元来、乳酸菌を含有する食品であっても、含有しない食品であってもよい。また、流動食(患者等が噛まずに飲み込めるような流動性を有する液状の食品)であってもよい。
本発明にかかるガストリン産生抑制剤が、ラクトバチルス属細菌の死菌体を含有することから、
本発明の食品組成物は、ラクトバチルス属細菌から選択される1種または2種以上の細菌の死菌体を含む。かかる食品組成物は、摂取個体のガストリン産生を抑制し、胃酸過多、胃炎、胃潰瘍、逆流性食道炎などに対して改善効果を奏する。
本発明の食品組成物はさらに、糖質、タンパク質、脂質、ビタミン類、生体必須微量金属(硫酸マンガン、硫酸亜鉛、塩化マグネシウム、炭酸カリウムなど)、香料やその他の配合物を含むことができる。
The food composition of the present invention contains the gastrin production inhibitor according to the present invention.
The food composition in the present invention is not particularly limited. For example, the food may originally contain lactic acid bacteria or may not contain food. Further, it may be a liquid food (a liquid food having fluidity that can be swallowed by a patient or the like without chewing).
The gastrin production inhibitor according to the present invention contains dead cells of Lactobacillus bacteria,
The food composition of the present invention contains dead cells of one or more bacteria selected from Lactobacillus bacteria. Such a food composition suppresses gastrin production by an ingested individual and has an improvement effect on gastric hyperacidity, gastritis, gastric ulcer, reflux esophagitis and the like.
The food composition of the present invention may further contain carbohydrates, proteins, lipids, vitamins, biologically essential trace metals (such as manganese sulfate, zinc sulfate, magnesium chloride, and potassium carbonate), fragrances, and other blends.

糖質としては、糖類、加工澱粉(デキストリンのほか、可溶性澱粉、ブリティッシュスターチ、酸化澱粉、澱粉エステル、澱粉エーテルなど)、食物繊維などが挙げられる。
タンパク質としては、例えば全脂粉乳、脱脂粉乳、部分脱脂粉乳、カゼイン、ホエイ粉、ホエイタンパク質、ホエイタンパク質濃縮物、ホエイタンパク質分離物、α−カゼイン、β−カゼイン、κ−カゼイン、β−ラクトグロブリン、α−ラクトアルブミン、ラクトフェリン、大豆タンパク質、鶏卵タンパク質、肉タンパク質などの動植物性タンパク質、これら加水分解物;バター、乳性ミネラル、クリーム、ホエイ、非タンパク態窒素、シアル酸、リン脂質、乳糖などの各種乳由来成分などが挙げられる。
Examples of the saccharide include saccharides, processed starch (in addition to dextrin, soluble starch, British starch, oxidized starch, starch ester, starch ether, etc.), dietary fiber, and the like.
Examples of the protein include whole milk powder, skim milk powder, partially skimmed milk powder, casein, whey powder, whey protein, whey protein concentrate, whey protein isolate, α-casein, β-casein, κ-casein, β-lactoglobulin , Α-lactalbumin, lactoferrin, soy protein, chicken egg protein, meat protein and other animal and plant proteins, hydrolysates thereof; butter, milk minerals, cream, whey, non-protein nitrogen, sialic acid, phospholipid, lactose, etc. And various milk-derived components.

脂質としては、例えば、ラード、魚油など、これらの分別油、水素添加油、エステル交換油などの動物性油脂;パーム油、サフラワー油、コーン油、ナタネ油、ヤシ油、これらの分別油、水素添加油、エステル交換油などの植物性油脂などが挙げられる。
ビタミン類としては、例えば、ビタミンA、カロチン類、ビタミンB群、ビタミンC、ビタミンD群、ビタミンE、ビタミンK群、ビタミンP、ビタミンQ、ナイアシン、ニコチン酸、パントテン酸、ビオチン、イノシトール、コリン、葉酸などが挙げられ、ミネラル類としては、例えば、カルシウム、カリウム、マグネシウム、ナトリウム、銅、鉄、マンガン、亜鉛、セレンなどが挙げられる。
Examples of lipids include animal oils such as lard and fish oil, fractionated oils thereof, hydrogenated oils and transesterified oils; palm oil, safflower oil, corn oil, rapeseed oil, coconut oil, fractionated oils thereof, Examples include vegetable oils such as hydrogenated oils and transesterified oils.
Examples of vitamins include vitamin A, carotene, vitamin B group, vitamin C, vitamin D group, vitamin E, vitamin K group, vitamin P, vitamin Q, niacin, nicotinic acid, pantothenic acid, biotin, inositol, choline. Examples of minerals include calcium, potassium, magnesium, sodium, copper, iron, manganese, zinc, and selenium.

本発明の食品組成物のカテゴリーや種類に制限はなく、機能性食品、特定保健用食品、特定用途食品、栄養機能食品、健康食品、介護用食品でもよく、また、菓子、乳酸菌飲料、チーズやヨーグルトなどの乳製品、調味料などであってもよい。飲食品の形状についても制限はなく、固形、液状、流動食状、ゼリー状、タブレット状、顆粒状、カプセル状など、通常流通し得るあらゆる飲食品形状をとることができ、各種食品(牛乳、清涼飲料、発酵乳、ヨーグルト、チーズ、パン、ビスケット、クラッカー、ピッツァクラスト、調製粉乳、流動食、病者用食品、栄養食品、冷凍食品、加工食品その他の市販食品など)に添加してもよい。上記飲食品の製造は、当業者の常法によって行うことができる。   There are no restrictions on the category or type of the food composition of the present invention, and it may be a functional food, a food for specified health use, a food for specific use, a functional nutrition food, a health food, a food for nursing care, and a confectionery, lactic acid bacteria beverage, cheese, It may be a dairy product such as yogurt or a seasoning. There is no limitation on the shape of the food and drink, and it can take any form of food or drink that can be distributed normally, such as solid, liquid, liquid food, jelly, tablet, granule, capsule, and various foods (milk, Soft drinks, fermented milk, yogurt, cheese, bread, biscuits, crackers, pizza crusts, formula milk, liquid foods, food for the sick, nutritional foods, frozen foods, processed foods and other commercial foods) . Manufacture of the said food / beverage products can be performed by those skilled in the art.

本発明にかかるラクトバチルス属細菌の死菌体は、乳酸菌による発酵食品に添加して用いることができる。乳酸菌による発酵食品には、例えば、発酵乳、キムチ、ピクルスなどが挙げられる。とくに発酵乳が好ましく、なかでもヨーグルトが好ましい。乳酸菌による発酵食品においては、ラクトバチルス属細菌の生菌は、増殖曲線を描いて指数関数的に増殖するが、その好適な発酵程度から、前記発酵食品における生菌の数が自ずと決定されてしまうところ、本発明にかかる食品組成物においては、生菌体に加えて、死菌体を添加することによって、既存の乳酸菌による発酵食品に含まれる菌体数を超えた総量(生菌+死菌)を含有することにより、胃において効果的にガストリン産生を抑制することができる。例えば、ヨーグルトの場合、最終製品に含まれるラクトバチルス属細菌の菌体量は、100g当り1×1010程度であると推計されるところ、効果的にガストリン産生を抑制するためには、1×10から5×1013、好ましくは、1×10から5×1012、とくに好ましくは、5×1010から5×1011程度の死菌体を添加して、総量(生菌+死菌)で1×1010から5×1013程度、好ましくは、1×1010から5×1012、とくに好ましくは、1×1011程度含有させる。The dead cell of the Lactobacillus genus bacteria concerning this invention can be added and used for the fermented food by lactic acid bacteria. Examples of fermented foods produced by lactic acid bacteria include fermented milk, kimchi, and pickles. Fermented milk is particularly preferable, and yogurt is particularly preferable. In fermented foods produced by lactic acid bacteria, live bacteria of the genus Lactobacillus grow exponentially with a growth curve, but the number of viable bacteria in the fermented foods is naturally determined from its suitable degree of fermentation. However, in the food composition according to the present invention, by adding dead cells in addition to viable cells, the total amount exceeding the number of cells contained in the fermented food by existing lactic acid bacteria (live cells + dead cells) ) Can effectively suppress gastrin production in the stomach. For example, in the case of yogurt, the amount of Lactobacillus bacteria contained in the final product is estimated to be about 1 × 10 10 per 100 g. In order to effectively suppress gastrin production, 1 × Add about 10 8 to 5 × 10 13 , preferably 1 × 10 9 to 5 × 10 12 , particularly preferably about 5 × 10 10 to 5 × 10 11 dead cells, 1 × 10 10 to 5 × 10 13 , preferably 1 × 10 10 to 5 × 10 12 , particularly preferably about 1 × 10 11 .

本発明の食品組成物に含有されるラクトバチルス属細菌の死菌体の菌体濃度は、とくに限定されないが、濃縮液として利用する場合、2×1010個/g以上、乾燥物として利用する場合、3×1011個/g以上とするのが好ましい。
本発明の食品組成物において、ラクトバチルス属細菌の死菌体の配合量は、とくに限定されないが、剤型、症状、体重、用途などに応じて適宜調整することができる。
本発明の食品組成物の一日当たりの摂取量は、とくに限定されないが、年齢、症状、体重、用途などに応じて適宜調整することができる。典型的には、0.1〜30000mg/kg体重を摂取することができ、好ましくは0.1〜20000mg/kg体重、さらに好ましくは0.1〜4000mg/kg体重を摂取することができる。
The cell concentration of dead Lactobacillus bacteria contained in the food composition of the present invention is not particularly limited, but when used as a concentrate, 2 × 10 10 cells / g or more is used as a dried product. In this case, it is preferable to set it to 3 × 10 11 pieces / g or more.
In the food composition of the present invention, the blending amount of dead bacteria of the genus Lactobacillus is not particularly limited, but can be appropriately adjusted according to the dosage form, symptoms, body weight, use, and the like.
The daily intake of the food composition of the present invention is not particularly limited, but can be appropriately adjusted according to age, symptoms, body weight, use and the like. Typically, 0.1 to 30000 mg / kg body weight can be taken, preferably 0.1 to 20000 mg / kg body weight, more preferably 0.1 to 4000 mg / kg body weight.

以下に、本発明を実施例に基づいてさらに説明するが、かかる実施例は、本発明の例示であり、本発明を限定するものではない。   Hereinafter, the present invention will be further described based on examples, but these examples are illustrative of the present invention and do not limit the present invention.

試験例:ラクトバチルス属細菌の死菌体を用いたガストリン産生抑制
1.材料および方法
[細菌]
細菌は、Lactobacillus gasseri OLL2716(明治乳業株式会社)を用いた。
マウスに接種するために、ラクトバチルス属細菌は、Difco(商標)MRS broth(Becton Dickinson)において、1日間増殖させた。
ラクトバチルス属細菌の熱処理は、細菌懸濁液を100℃で10分間インキュベートして行った。
Test example: Gastrin production suppression using dead cells of Lactobacillus sp. Materials and Methods [Bacteria]
Lactobacillus gasseri OLL2716 (Meiji Dairies Co., Ltd.) was used as the bacterium.
To inoculate mice, Lactobacillus bacteria were grown for 1 day in Difco ™ MRS broth (Becton Dickinson).
Heat treatment of Lactobacillus bacteria was performed by incubating the bacterial suspension at 100 ° C. for 10 minutes.

[マウス]
無菌(germ-free、GF)のBALB/c雄マウスを日本クレア株式会社より入手した。同腹のGFマウスは、Trexler型可撓性フィルムプラスチックアイソレーターを用い、滅菌した飼料および水を与えて飼育した。
[mouse]
Aseptic (germ-free, GF) BALB / c male mice were obtained from CLEA Japan. Littermate GF mice were reared using Trexler-type flexible film plastic isolators and fed sterilized feed and water.

細菌をマウスに定着させるため、10CFUの生菌を、0.5mlのリン酸緩衝液(PBS)に懸濁し、8週齢のマウスに1度、胃ゾンデを用いて経口で接種した。
死菌による処置として、1010CFUの熱処理した細菌(死菌)を、0.5mlのリン酸緩衝液(PBS)に懸濁し、毎日10日間、経胃で接種した。
最後の接種から10日後、胃を切り取り、免疫組織化学分析に用いた。
In order to establish bacteria in mice, 10 9 CFU viable bacteria were suspended in 0.5 ml of phosphate buffer (PBS), and 8-week-old mice were orally inoculated once using a stomach tube.
As a treatment with dead bacteria, 10 10 CFU of heat-treated bacteria (dead bacteria) were suspended in 0.5 ml of phosphate buffer (PBS) and inoculated by the stomach every day for 10 days.
Ten days after the last inoculation, the stomach was excised and used for immunohistochemical analysis.

[組織分析]
胃の組織病理学的分析のため、大弯に沿って切除した胃の半分を4%緩衝ホルマリンで固定し、パラフィンワックスに包埋し、2μmの切片に切り出した。次いで、標準の方法に従い、切片をヘマトキシリンおよびエオシンで染色した。胃の筋肉層の厚さは、分析用ソフトウェア(Olympus BP2-BSW)を用いて、垂直軸に沿って顕微鏡(Olympus AX80)で測定した。全部で10箇所の異なるポイントを測定し、標本の各領域の平均厚さを得た。矩形(150×200μm)における核の数を、胃の各領域の筋肉層において計数した。
[Organizational analysis]
For histopathological analysis of the stomach, half of the stomach excised along the large curvature was fixed with 4% buffered formalin, embedded in paraffin wax, and cut into 2 μm sections. The sections were then stained with hematoxylin and eosin according to standard methods. Gastric muscle layer thickness was measured with a microscope (Olympus AX80) along the vertical axis using analytical software (Olympus BP2-BSW). A total of 10 different points were measured to obtain the average thickness of each region of the specimen. The number of nuclei in a rectangle (150 × 200 μm) was counted in the muscle layer of each region of the stomach.

免疫組織化学分析のため、組織切片を脱パラフィン化し、10mMクエン酸緩衝液(pH6.0)中、98℃で15分間、電子レンジでボイルし、室温で15分間、5%正常ヤギ血清含有PBSでブロッキングした。切片を、4℃で一晩、一次抗体とともにインキュベートし、次いで、室温で2時間、蛍光マーカーで標識した二次抗体とともにインキュベートした。最後に、サンプルをDAPI(4,6-diamidino-2-phenylindole)およびDABCO(1,4-diazobicyclo[2,2,2]octane)で処理した。スライドを蛍光画像化用に調整された顕微鏡(Keyence BZ-9000)で視覚化した。マウスの幽門洞から胃体部−幽門洞の軸に沿った1mm長の間隔のランダムフィールドにおけるガストリン陽性(産生)細胞を染色した切片に対して、AxioVission Rel.4.8(Zeiss)を用いた形態学的分析を行った。   For immunohistochemical analysis, tissue sections were deparaffinized, boiled in a microwave oven at 98 ° C. for 15 minutes in 10 mM citrate buffer (pH 6.0), and PBS containing 5% normal goat serum for 15 minutes at room temperature. Blocked with. Sections were incubated with the primary antibody overnight at 4 ° C. and then incubated with a secondary antibody labeled with a fluorescent marker for 2 hours at room temperature. Finally, the sample was treated with DAPI (4,6-diamidino-2-phenylindole) and DABCO (1,4-diazobicyclo [2,2,2] octane). Slides were visualized with a microscope (Keyence BZ-9000) tuned for fluorescence imaging. Morphology using AxioVission Rel. 4.8 (Zeiss) for sections stained with gastrin positive (producing) cells in a random field 1 mm long from the pyloric sinus to the stomach body-pyloric sinus axis Analysis was performed.

1:300に希釈した抗ガストリン抗体(ウサギポリクローナル抗体、Dako)、コントロールのウサギIgG(Dako)およびコントロールのマウスIgG(Dako)を一次抗体として用いた。ヤギ抗ウサギIgG Alexa 488(Molecular Probe)およびヤギ抗マウスAlexa 594(Molecular Probe)を二次抗体として用いた。   Anti-gastrin antibody (rabbit polyclonal antibody, Dako) diluted 1: 300, control rabbit IgG (Dako) and control mouse IgG (Dako) were used as primary antibodies. Goat anti-rabbit IgG Alexa 488 (Molecular Probe) and goat anti-mouse Alexa 594 (Molecular Probe) were used as secondary antibodies.

[統計的分析]
結果は、適切に、Student's t検定または一元分散分析(ANOVA)よって統計学的に評価した。SSPS version 16.0(SSPS)またはGraphPad Prism 5(GraphPad Software)のソフトウェアプログラムをデータ分析に用いた。
[Statistical analysis]
Results were assessed statistically by Student's t test or one-way analysis of variance (ANOVA) as appropriate. A software program of SSPS version 16.0 (SSPS) or GraphPad Prism 5 (GraphPad Software) was used for data analysis.

2.結果
無処置GFマウス、L. gasseri OLL2716定着ノトバイオートマウス、PBS処置GFマウス、熱処理したL. gasseri OLL2716の死菌体を投与したGFマウスの夫々について、胃幽門洞におけるガストリン産生細胞数を計測した。その結果は次表のとおりであった。
2. Results The number of gastrin-producing cells in the gastric antrum was measured for untreated GF mice, L. gasseri OLL2716 colonized gnotobiotic mice, PBS-treated GF mice, and heat-treated L. gasseri OLL2716 GF mice. did. The results are shown in the following table.

3.考察
熱処理したラクトバチルス属細菌(死菌体)を経口投与したGFマウスでは、生菌によって誘導されたのと同程度にガストリン産生細胞の数の減少が認められた。かかる有意な減少は、Lactobacillus gasseri OLL2716の場合も見られた。
3. Discussion In GF mice that were orally administered heat-treated Lactobacillus bacteria (dead cells), the number of gastrin-producing cells decreased as much as that induced by viable bacteria. Such a significant decrease was also observed with Lactobacillus gasseri OLL2716.

本発明のガストリン抑制剤によれば、ピロリ菌に対する除菌作用を利用せずに、胃組織を構成する細胞に直接働きかけ胃酸分泌を抑制することができるため、ピロリ菌に起因するものではない胃炎、胃潰瘍および逆流性食道炎の改善や、ピロリ菌除菌後の胃酸過多などを改善する医薬組成物として用いることができる。
さらに、例えば、乳酸菌による発酵食品などにおいては、その食品の性質上、一定量以上の生菌を含有せしめることができないが、本発明のガストリン抑制剤によれば、死菌体を用いることから、既存の食品にない菌体量(生菌および死菌)を含む食品組成物として用いることができる。
According to the gastrin inhibitor of the present invention, gastritis not caused by Helicobacter pylori can be achieved by directly acting on cells constituting the stomach tissue and suppressing gastric acid secretion without using the sterilizing action against Helicobacter pylori. In addition, it can be used as a pharmaceutical composition for improving gastric ulcer and reflux esophagitis, gastric hyperacidity after Helicobacter pylori eradication and the like.
Furthermore, for example, in fermented foods by lactic acid bacteria, due to the nature of the food, it is not possible to contain more than a certain amount of live bacteria, but according to the gastrin inhibitor of the present invention, from dead cells It can be used as a food composition containing the amount of bacterial cells (live and dead) that are not present in existing foods.

Claims (6)

ラクトバチルス・ガセリ(Lactobacillus gasseriの死菌体を含み、生菌体を含まない、ガストリン産生抑制剤であって、
食品組成物に添加し、該食品組成物中のラクトバチルス・ガセリの死菌体の菌体濃度を2×10 10 個/g以上にするために用いる、
前記ガストリン産生抑制剤
Lactobacillus gasseri ( Lactobacillus gasseri ) dead cells, including no live cells, gastrin production inhibitor ,
Added to the food composition, and used to make the concentration of Lactobacillus gasseri dead cells in the food composition 2 × 10 10 cells / g or more.
The gastrin production inhibitor .
ラクトバチルス・ガセリが、ラクトバチルス・ガセリ OLL2716 (受託番号:FERM BP-6999)である、請求項1に記載のガストリン産生抑制剤。 The gastrin production inhibitor of Claim 1 whose Lactobacillus gasseri is Lactobacillus gasseri OLL2716 (Accession number: FERM BP-6999). 請求項1または2に記載のガストリン産生抑制剤添加され、ラクトバチルス・ガセリの死菌体の菌体濃度が2×10 10 個/g以上である、食品組成物。 A food composition, wherein the gastrin production inhibitor according to claim 1 or 2 is added , and the concentration of dead cells of Lactobacillus gasseri is 2 × 10 10 cells / g or more . 乳酸菌による発酵食品である、請求項3に記載の食品組成物。   The food composition according to claim 3, which is a fermented food produced by lactic acid bacteria. 乳酸菌による発酵食品が、発酵乳である、請求項4に記載の食品組成物。   The food composition according to claim 4, wherein the fermented food by lactic acid bacteria is fermented milk. 発酵乳が、ヨーグルトである、請求項5に記載の食品組成物。   The food composition according to claim 5, wherein the fermented milk is yogurt.
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