TWI724099B - Composition for improving or preventing herpes virus infection - Google Patents

Composition for improving or preventing herpes virus infection Download PDF

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TWI724099B
TWI724099B TW106103340A TW106103340A TWI724099B TW I724099 B TWI724099 B TW I724099B TW 106103340 A TW106103340 A TW 106103340A TW 106103340 A TW106103340 A TW 106103340A TW I724099 B TWI724099 B TW I724099B
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herpes virus
composition
virus infection
bifidobacteria
bifidobacterium
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TW201729823A (en
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林京子
牧岡祐子
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日商康貝股份有限公司
學校法人中部大學
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    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
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    • A61K35/744—Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
    • A61K35/745—Bifidobacteria

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Abstract

本發明以提供一種用於改善或預防疱疹病毒感染症之組合物為目的，使疱疹病毒感染模型攝取雙歧桿菌。其結果可知其病毒量減少，又，其感染症狀之發展被抑制。進而發現，即便使疱疹病毒感染模型之免疫功能降低，對其抑制效果亦無影響，因此於預防宿主之免疫功能降低時產生之疱疹病毒感染症之復發之方面，雙歧桿菌亦有效。The purpose of the present invention is to provide a composition for improving or preventing herpes virus infection, so that the herpes virus infection model can ingest bifidobacteria. As a result, it can be seen that the amount of virus is reduced, and the development of infection symptoms is suppressed. Furthermore, it was found that even if the immune function of the herpes virus infection model is reduced, its inhibitory effect is not affected. Therefore, bifidobacteria are also effective in preventing the recurrence of herpes virus infection caused when the immune function of the host is reduced.

Description

用於改善或預防疱疹病毒感染症之組合物Composition for improving or preventing herpes virus infection

本發明係關於一種用於改善或預防疱疹病毒感染症之組合物。更詳細而言，係關於一種含有雙歧桿菌作為有效成分之用於改善或預防疱疹病毒感染症之組合物。The present invention relates to a composition for improving or preventing herpes virus infection. More specifically, it relates to a composition containing bifidobacteria as an effective ingredient for improving or preventing herpes virus infection.

疱疹病毒感染症係由疱疹病毒感染引起之疾病，可列舉由單純疱疹病毒1型(HSV-1)感染引起之口唇疱疹、由單純疱疹病毒2型(HSV-2)感染引起之生殖器疱疹等。 如上所述，該等疾病由於各種不同之疱疹病毒而發病，但於潛伏感染與復發之方面相同。即，已知疱疹病毒於體表初期感染後，潛伏於神經節，在因壓力等宿主之免疫功能降低時復發。 又，針對疱疹病毒感染症，將阿昔洛韋、伐昔洛韋等核酸類似物用於其治療(非專利文獻1～3)，進而，為了防止復發而對感染者繼續投予亦得到認同。但是，對於該等治療方法，亦報告有一些副作用，又，藥價較高，對患者於身體方面及經濟方面之負擔較大成為問題。進而，於藉由繼續投予而其治療長期進行之情形時，疱疹病毒很可能獲得耐藥性。因此，要求替代核酸類似物之代替醫療。 因此，要求探索、開發廉價且安全性較高之用於改善或預防疱疹病毒感染症之物質，但現狀為尚未獲得此種物質。 且說，近年來對於雙歧桿菌等腸道細菌驗證了疾病之預防效果或疾病症狀之改善效果等，嘗試用作安全性較高之藥物或飲食品。然而，目前為止，對於雙歧桿菌等雖報告有針對各種疾病之症狀改善效果，但尚未報告在疱疹病毒感染症之治療中應用之例。 [先前技術文獻] [非專利文獻] [非專利文獻1]S. E Straus、H等人，N. Engl. J. Med.，1984年，310卷，1545～1550頁 [非專利文獻2]J. M. Douglas等人，N. Engl. J. Med.，1984年，310卷，1551～1556頁 [非專利文獻3]L. G. Kaplowitz等人，JAMA，1991年，265卷，747～751頁Herpes virus infection is a disease caused by herpes virus infection, including herpes labialis caused by herpes simplex virus type 1 (HSV-1) infection, and genital herpes caused by herpes simplex virus type 2 (HSV-2) infection. As mentioned above, these diseases are caused by various herpes viruses, but they are the same in terms of latent infection and recurrence. That is, it is known that the herpes virus lurks in the ganglia after the initial infection of the body surface and recurs when the immune function of the host decreases due to stress or the like. In addition, nucleic acid analogues such as acyclovir and valacyclovir are used for the treatment of herpes virus infections (Non-Patent Documents 1 to 3), and furthermore, it has been approved to continue to administer the infection to the infected person in order to prevent recurrence . However, for these treatment methods, some side effects have been reported, and the high drug price has become a problem in terms of physical and economic burden on patients. Furthermore, when the treatment is continued for a long time by continuing the administration, the herpes virus is likely to acquire drug resistance. Therefore, it is required to replace the medical treatment of nucleic acid analogs. Therefore, it is required to explore and develop cheap and safe substances for improving or preventing herpes virus infections, but the current situation is that such substances have not yet been obtained. In addition, in recent years, intestinal bacteria such as bifidobacteria have verified the preventive effect of diseases or the effect of improving disease symptoms, etc., and tried to use them as safe drugs or foods. However, although there have been reports of symptom-improving effects for various diseases for bifidobacteria, etc., no examples of application in the treatment of herpes virus infections have been reported. [Prior Art Document] [Non-Patent Document] [Non-Patent Document 1] S. E Straus, H et al., N. Engl. J. Med., 1984, Volume 310, pages 1545-1550 [Non-Patent Document 2] JM Douglas et al., N. Engl. J. Med., 1984, volume 310, pages 1551 to 1556 [Non-Patent Document 3] LG Kaplowitz et al., JAMA, 1991, volume 265, pages 747 to 751

[發明所欲解決之問題] 本發明係鑒於上述先前技術所存在之課題而完成，目的在於發現一種對用於改善或預防疱疹病毒感染症有效且具有較高安全性之廉價物質。進而目的在於提供一種含有該物質作為有效成分之用於改善或預防疱疹病毒感染症之組合物。 [解決問題之技術手段] 本發明者等人為了解決上述課題，對雙歧桿菌於疱疹病毒感染動物模型中之有效性進行了研究。具體而言，使該模型小鼠經口攝取作為雙歧桿菌之一例之長雙歧桿菌(Bifidobacterium longum)(BR-108株)，評價該小鼠中之病毒量及其症狀之程度。其結果可知，藉由攝取雙歧桿菌，病毒量減少，又，其感染症狀之發展被抑制。又，亦可知該雙歧桿菌之抗病毒活性為持續性者。進而發現，即便使模型小鼠之免疫功能降低，對該抑制效果亦並無多少影響，因此，於預防宿主之免疫功能降低時產生之疱疹病毒感染症之復發之方面，雙歧桿菌亦有效，從而完成了本發明。 更詳細而言，本發明提供以下之發明。 (1)一種用於改善或預防疱疹病毒感染症之組合物，其含有雙歧桿菌作為有效成分。 (2)如(1)記載之組合物，其中上述雙歧桿菌為長雙歧桿菌。 (3)如(1)或(2)記載之組合物，其中上述疱疹病毒感染症係由單純疱疹病毒2型引起之感染症。 (4)如(1)至(3)中任一項記載之組合物，其為經口攝取用組合物。 再者，雙歧桿菌如後述之BR-108株般，係於正常嬰幼兒之菌群(糞便等)中優勢存在之菌，因此其安全性可謂確定。又，其培養方法亦確定，因此亦可廉價提供。 [發明之效果] 藉由攝取本發明之組合物，能夠實現改善或預防疱疹病毒感染症。又，本發明之組合物之有效成分為雙歧桿菌，廉價且安全性較高。進而，本發明之組合物能夠日常容易地攝取，進而亦能夠繼續長期容易地攝取。又，由雙歧桿菌產生之對疱疹病毒感染症之抑制效果持續，進而，即便於宿主之免疫功能降低時，由雙歧桿菌產生之對疱疹病毒感染症之抑制效果亦維持。因此，於抑制疱疹病毒感染症之復發上亦有用。[Problems to be Solved by the Invention] The present invention was completed in view of the above-mentioned problems in the prior art, and the purpose is to find an inexpensive substance that is effective for improving or preventing herpes virus infection and has high safety. A further object is to provide a composition for improving or preventing herpes virus infection containing the substance as an active ingredient. [Technical Means to Solve the Problem] In order to solve the above-mentioned problems, the inventors studied the effectiveness of bifidobacteria in animal models of herpes virus infection. Specifically, the model mouse was orally ingested Bifidobacterium longum (BR-108 strain), which is an example of Bifidobacterium, to evaluate the amount of virus in the mouse and the degree of symptoms. As a result, it can be seen that by ingesting bifidobacteria, the amount of virus is reduced, and the development of infection symptoms is suppressed. In addition, it is also known that the antiviral activity of the bifidobacteria is persistent. Furthermore, it was found that even if the immune function of the model mice is reduced, the inhibitory effect is not much affected. Therefore, bifidobacteria are also effective in preventing the recurrence of herpes virus infection caused when the immune function of the host is reduced. Thus, the present invention has been completed. In more detail, the present invention provides the following inventions. (1) A composition for improving or preventing herpes virus infection, which contains bifidobacteria as an active ingredient. (2) The composition according to (1), wherein the above-mentioned bifidobacterium is Bifidobacterium longum. (3) The composition according to (1) or (2), wherein the aforementioned herpes virus infection is an infection caused by herpes simplex virus type 2. (4) The composition according to any one of (1) to (3), which is a composition for oral ingestion. Furthermore, like the strain BR-108 described later, Bifidobacterium is a dominant bacteria in the flora (feces, etc.) of normal infants and young children, so its safety can be described as certain. In addition, the cultivation method is also determined, so it can also be provided at low cost. [Effects of the invention] By ingesting the composition of the present invention, it is possible to improve or prevent herpes virus infection. In addition, the active ingredient of the composition of the present invention is bifidobacteria, which is inexpensive and has high safety. Furthermore, the composition of the present invention can be easily ingested on a daily basis, and furthermore, can continue to be easily ingested for a long period of time. In addition, the inhibitory effect of bifidobacteria on herpes virus infection continues, and further, even when the host's immune function is reduced, the inhibitory effect of bifidobacteria on herpes virus infection is maintained. Therefore, it is also useful in inhibiting the recurrence of herpes virus infection.

本發明提供一種含有雙歧桿菌作為有效成分之用於改善或預防疱疹病毒感染症之組合物。 於本發明中，「疱疹病毒感染症」係指由屬於疱疹病毒科之病毒引起之病毒感染症，作為此種病毒，例如可列舉屬於α疱疹病毒亞科之疱疹病毒(單純疱疹病毒1型(HSV-1)、單純疱疹病毒2型(HSV-2)、人類疱疹病毒3(HHV-3，水痘/帶狀疱疹病毒，VZV))、屬於β疱疹病毒亞科之疱疹病毒(人類疱疹病毒5(HHV-5，巨細胞病毒，CMV)、人類疱疹病毒6(HHV-6)、人類疱疹病毒7(HHV-7))、屬於γ疱疹病毒亞科之疱疹病毒(人類疱疹病毒4(HHV-4，Epstein-Barr病毒，EBV)、人類疱疹病毒8(HHV-8，卡波西(Kaposi)肉瘤相關疱疹病毒))。 於本發明中，「改善」除包括完全治療疱疹病毒感染症之外，亦包括緩和症狀、以及抑制其發展。「預防」包括抑制或延遲疱疹病毒感染症之發病、以及抑制其復發。進而，改善或預防亦包括減少作為疱疹病毒感染症之原因之疱疹病毒之量。又，例如如後述之實施例所示，疱疹病毒感染症之改善或預防之作用能夠藉由利用噬斑分析進行病毒量測定或利用病變記分將症狀程度數值化而評價。 作為本發明之組合物之有效成分之「雙歧桿菌」為屬於雙歧桿菌屬之細菌即可，例如可列舉長雙歧桿菌(Bifidobacterium longum)、短雙歧桿菌(Bifidobacterium breve)、兩歧雙歧桿菌(Bifidobacterium bifidum)、嬰兒雙歧桿菌(Bifidobacterium infantis)、青春雙歧桿菌(Bifidobacterium adolescentis)、鏈狀雙歧桿菌(Bifidobacterium catenulatum)、假長雙歧桿菌(Bifidobacterium pseudolongum)、嗜熱雙歧桿菌(Bifidobacterium thermophilum)，只要具有疱疹病毒感染症之改善或預防作用，則並無特別限制。 本發明之組合物中使用之雙歧桿菌較佳為長雙歧桿菌，尤佳為長雙歧桿菌BR-108株。再者，BR-108株(BR-108)係自嬰幼兒糞便單離之長雙歧桿菌，且係於2012年4月13日寄存於獨立行政法人製品評價技術基盤機構(NITE、〒292-0818 千葉縣木更津市上總鎌足2-5-8 122號室)之菌(寄存編號：NITE P-1317)。又，該雙歧桿菌亦係具有序列編號1所示之核苷酸序列作為16SrRNA基因之序列之細菌。 又，上述雙歧桿菌可將僅一種用於本發明之組合物，亦可將兩種以上之菌種調配用於本發明之組合物。進而，於本發明之組合物中，雙歧桿菌能夠以活菌使用亦能夠以死菌體使用。死菌體就耐熱性優異而品質穩定、且無味無臭之方面而言，較佳作為本發明之組合物之有效成分。作為本發明之組合物中之死菌體，可使用經加熱殺菌之菌體。經加熱殺菌之菌體可藉由如下方式製備：自按照常規方法培養雙歧桿菌而得之培養物例如利用過濾、離心分離等方法回收菌體，水洗後懸浮於水等中，以120℃以下(較佳為80～120℃)、30分鐘以內(3秒～30分鐘)進行加熱處理，然後根據需要進行濃縮、乾燥(冷凍乾燥等)及粉碎處理。再者，長雙歧桿菌BR-108株之加熱殺菌菌體之微細粉末係以製品名「BR-108(註冊商標)」(康貝功能性食品事業部製造)市售。又，在本發明之組合物中作為有效成分含有之雙歧桿菌可為如前所述之菌體，亦可為該細菌所含有之物質、該細菌之分泌產物、由該細菌產生之代謝產物。 本發明之組合物可為用於改善或預防疱疹病毒感染症之醫藥組合物、飲食品(包括動物用飼料)、或用於模型動物實驗等之試劑之形態。 本發明中之組合物能夠藉由公知之製劑學方法進行製劑化。例如可製成膠囊劑、錠劑、丸劑、液劑、散劑、顆粒劑、細粒劑、薄膜包衣劑、粒劑、喉劑、舌下劑、咀嚼劑、口含劑、糊劑、糖漿劑、懸浮劑、酏劑、乳劑、塗敷劑、軟膏劑、硬膏劑、泥罨劑、經皮吸收型製劑、洗劑、吸入劑、氣霧劑、注射劑、栓劑等經口或非經口地使用。本發明係以作為腸道細菌之雙歧桿菌為有效成分之組合物，能夠藉由經口非侵入且簡便地攝取。即，本發明之組合物之較佳之攝取方法為藉由經口來攝取。 於該等製劑化中，能夠適當組合藥理學上或者作為飲食品容許之載體、具體為生理鹽水、滅菌水、植物油、溶劑、賦形劑、基劑、乳化劑、懸浮劑、界面活性劑、穩定劑、香味劑、芳香劑、媒劑、防腐劑、結合劑、稀釋劑、等張劑、舒緩劑、增量劑、崩解劑、緩衝劑、塗佈劑、潤滑劑、著色劑、甜味劑、增稠劑、矯味矯臭劑、溶解助劑或其他添加劑等。 於將本發明之組合物以醫藥組合物之形式使用之情形時，可與用於疱疹病毒感染症之改善或預防之公知之物質併用。作為該公知之物質，例如可列舉阿昔洛韋、伐昔洛韋、西多福韋、泛昔洛韋、福米韋生、膦甲酸、更昔洛韋、碘苷、噴昔洛韋、曲氟尿苷、纈更昔洛韋、及阿糖腺苷之類之核酸類似物、DNA(deoxyribonucleic acid，脫氧核糖核酸)合成抑制劑等。又，如後述之實施例中所示，於阿昔洛韋之抗病毒活性減少時，雙歧桿菌之抗病毒活性增強，因此，藉由與該用於疱疹病毒感染症之改善或預防之公知之物質併用，於本發明中能夠更有效率且有效果地改善及預防疱疹病毒感染症。 於將本發明之組合物以飲食品之形式使用之情形時，該飲食品例如可為健康食品、功能性食品、特定保健用食品、營養功能食品、功能性標示食品、營養輔助食品、患者用食品、或動物用飼料。本發明之飲食品能夠以如上所述之組合物形式攝取，亦能夠以各種飲食品之形式攝取。作為飲食品之具體例，可列舉酸乳酪、乳酸飲料等醱酵食品、醱酵飲料；食用油、沙拉醬、蛋黃醬、人造黃油等含有油分之製品；湯類、乳飲料、清涼飲料、茶飲料、酒精飲料、飲劑、果凍狀飲料、功能性飲料等液狀食品；米飯類、麵條類、麵包類等含碳水化物食品；火腿、香腸等畜產加工食品；魚糕、乾貨、鹹魚等水產加工食品；醃菜等蔬菜加工食品；果凍等半固體狀食品；味噌等醱酵食品；西點類、日本點心類、糖果類、口香糖類、軟糖、冰淇淋、冰棒等各種點心類；咖喱、澆汁、中式湯等軟罐頭製品；速食湯，速食味噌汁等速食食品或微波爐食品等。進而亦可列舉製備成粉末、顆粒、錠劑、膠囊劑、液狀、糊狀或果凍狀之健康飲食品。再者，本發明中之飲食品之製造能夠藉由該技術領域所公知之製造技術實施。在該飲食品中，亦可添加對疱疹病毒感染症之改善或預防有效之一種或兩種以上之成分(例如營養素等)。又，亦可藉由與發揮該改善等以外之功能之其他成分或其他功能性食品組合而製成多功能性之飲食品。 本發明之組合物能夠以包括人類在內之動物作為對象使用，作為除人類以外之動物，並無特別限制，能夠以各種家畜、家禽、寵物、實驗用動物等為對象。具體而言，可列舉豬、牛、馬、綿羊、山羊、雞、野鴨、鴕鳥、家鴨、狗、貓、兔、倉鼠、小鼠、大鼠、猴等，但不限制於該等。 又，作為本發明之組合物之對象，可不考慮其如何發病地列舉感染疱疹病毒之動物，又，就預防之觀點考慮，可對未感染疱疹病毒或疑似感染疱疹病毒之動物投予或使其攝取本發明之組合物。進而，就預防復發之觀點考慮，對於未出現其症狀之攜帶疱疹病毒之動物亦能夠較佳地使用本發明之組合物。 於投予或攝取本發明之組合物之情形時，其投予量或攝取量係根據對象之年齡、體重、疱疹病毒感染症之症狀、健康狀態、組合物之種類(藥品、飲食品等)等適當選擇。例如每1天雙歧桿菌之投予量或攝取量通常為0.5×109 個/kg體重～50×109 /kg體重，較佳為2×109 個/kg體重～50×109 個/kg體重。 又，本發明亦提供一種用於改善或預防對象之疱疹病毒感染症之方法，其特徵在於：如上所述對對象投予或使其攝取雙歧桿菌或含有雙歧桿菌作為有效成分之組合物。 再者，雙歧桿菌或含有雙歧桿菌作為有效成分之組合物之投予或攝取量如上所述，可每1天1次或分成複數次(例如2次)投予或攝取。又，投予或攝取期間亦可根據疱疹病毒感染症之改善程度而中止，但如上所述，就預防復發之觀點考慮，期望不中止地繼續投予或攝取。再者，關於「繼續」，可為每天繼續，亦可為空出間隔之繼續，就效果之方面考慮，較佳為每天繼續地投予或攝取雙歧桿菌或含有雙歧桿菌作為有效成分之組合物。 本發明之組合物之製品(藥品、飲食品、試劑)或其說明書可附上用於改善或預防疱疹病毒感染症之內容之標示。又，關於飲食品，為了於形態及對象者等方面與一般食品作區分，可作為保健功能食品(特定保健用食品、營養功能食品、功能性標示食品)於本發明之組合物之製品等附上健康功能之標示。此處「於製品或說明書附上標示」意指在製品本身、容器、包裝等附上標示，或者在揭示製品資訊之說明書、附加文書、宣傳物、其他印刷物等附上標示。 [實施例] 以下，基於實施例，對本發明更具體地進行說明，但本發明不限定於以下實施例。 為了瞭解雙歧桿菌對疱疹病毒及由其引起之感染症之有效性，進行如下之實驗。 (雙歧桿菌) 再者，使用之雙歧桿菌係自人類嬰幼兒糞便單離之長雙歧桿菌BR-108株(Bifidobacterium longum BR-108)，係2012年4月13日寄存於獨立行政法人製品評價技術基盤機構(NITE、〒292-0818 千葉縣木更津市上總鎌足2-5-8 122號室)之菌(寄存編號：NITE P-1317)。並且，將對該菌進行加熱殺菌、冷凍乾燥及粉碎處理而得之者(康貝功能性食品事業部製造、製品名：BR-108(註冊商標))如下所述使小鼠攝取。 (疱疹病毒) 又，使用之疱疹病毒係HSV-2 UW268株(富山縣衛生研究所提供)。使該病毒株以0.01 PFU/細胞感染Vero細胞，於20～24小時後移至-80℃，其後反覆3次冷凍融解。接著，將培養物加入至50 ml之離心管中，於4℃下進行1500轉/分鐘、10分鐘之離心，將其上清液各1 ml分注至1.5 ml微型管中，於-80℃下保存並維持。然後，取出其中1支，用Vero細胞進行噬斑分析，測定病毒量(PFU)，供於後述之感染。 然後，使用該等雙歧桿菌及HSV-2，進行如下實驗。即，首先，於後述之HSV-2接種7天前，將BALB/c小鼠(6週齡，雌)分成以下之組，每組10隻，開始雙歧桿菌(BR-108)之攝取。 A：陰性對照組(生理鹽水)(亦稱為「對照組」) B：BR-108(0.42×109 個/天)攝取組(亦稱為「BR4億個」) C：BR-108(2.1×109 個/天)攝取組(亦稱為「BR20億個」) D：BR-108(10.5×109 個/天)攝取組(亦稱為「BR100億個」)。 再者，以各組之每1天之攝取量分別成為上述量之方式，1天分2次(上午9點與下午6點)使小鼠經口攝取使BR-108懸浮於生理鹽水中所得者。又，對該等小鼠，為了使發情週期同期化，增加生殖器對HSV-2感染之敏感性，於HSV-2接種之6天前及1天前皮下注射醋酸甲羥孕酮(medroxyprogesterone 17-acetate，3 mg/個體)。 又，疱疹病毒感染症容易因免疫功能降低而產生發病、復發、重症化、長期化。因此，在該等各小鼠攝取組中，亦於HSV-2接種之7天前～該接種之13天後每隔1天皮下注射免疫抑制劑5-FU(5-氟尿嘧啶，每1次之攝取量：0.25 mg/0.1 ml/個體)而分別準備免疫降低組(各組各5隻)。 然後，對該等小鼠之生殖器局部接種HSV-2(1×104 PFU/20 μl/個體)。接著，在該接種3天後用冷PBS(phosphate buffer saline，磷酸鹽緩衝液)(100 μl)局部洗滌生殖器，藉由下述噬斑分析測定其病毒量。將得到之結果示於圖1。 ＜噬斑分析＞ 將回收之上述局部洗滌液先用PBS適當稀釋。將所得之稀釋液100 μl添加至在35 mm培養皿中以單層狀培養之Vero細胞中，於室溫下培育1小時，使其感染。接著，疊層加入有0.8%甲基纖維素及2%胎牛血清之MEM(minimum essential medium，最小必需培養基)培養基(2 ml/培養皿)，於37℃下培養2天。於該培養後，除去培養基，用結晶紫實施固定、染色。然後，於顯微鏡下測定噬斑數，由該測定數計算出噬斑形成單位(plaque-forming unit，PFU)。 ＜基於病變記分之評價＞ 又，HSV-2接種後，記錄疱疹症狀與死亡病例，基於下述病變記分(lesion score)進行評價。將得到之結果示於圖2。 0：無症狀 1：輕度發紅 2：中度發紅與腫脹 3：伴有滲液之發紅與腫脹 4：後肢麻痹 5：死亡。 如圖1所示，測定自接種HSV-2起3天後生殖器中之該病毒量，結果可知，藉由攝取雙歧桿菌(BR-108)，病毒量減少。進而，亦確認該減少有顯示用量依賴性之傾向。又，亦顯示因免疫抑制劑處理，該減少有所緩和。 進而，如圖2所示，亦可知藉由攝取雙歧桿菌，HSV-2接種後1週生殖器疱疹症狀之急速發展被抑制(延遲)。特別是於自接種HSV-2起六天後之時間點，儘管於未攝取雙歧桿菌之對照組中病變記分達到2.5以上，但於每1天攝取100億個雙歧桿菌之組中病變記分被抑制至「零」(無症狀之狀態)。又，關於其用量依賴性，確認了中、高用量(BR20億個，BR100億個)與低用量(BR4億個)相比有更強地抑制症狀發展之傾向。再者，關於生殖器疱疹症狀之抑制，未發現由免疫抑制劑處理帶來之明顯影響。又，最後(於對照組中為至HSV-2接種後9天，於雙歧桿菌攝取組中為至HSV-2接種後12天)，於任一投予組中死亡率均為100%。 再者，已知疱疹病毒之復發過程、即於自潛伏感染狀態至回歸發病之過程中，增殖之病毒量對於是否發病為較大之決定因素。並且預測藉由於此時投予雙歧桿菌，如圖1所示使體內病毒產生量降低，能夠不發病。因此，亦能夠期待預防復發。又，於圖2所示之模型動物實驗中，由於設定了對照組之小鼠全例死亡之條件，因此認為施加了與人類回歸發病時之病毒量相比大得多之負荷。 ＜抗HSV活性之檢測＞ 如上所述可明確，藉由經口攝取雙歧桿菌，可使疱疹病毒之量減少，又，抑制疱疹病毒感染症之發展。於是接著，為了明確該由雙歧桿菌帶來之病毒增殖抑制效果係以何種作用機制實現，進行了以下實驗。 即，本發明者等人假設源自雙歧桿菌之抗病毒活性成分被吸收並轉移至血中而有助於病毒增殖抑制之路徑參與該機制之可能性，基於該假設，於經口投予雙歧桿菌後經過0.5至8小時之時間點採取血清，評價其有無抗HSV活性。 更具體而言，利用以下程序進行抗HSV活性之檢測。 1)首先，對BALB/c小鼠(雌，6週齡)自病毒感染7天前至3天後1天2次(9點、18點)經口投予BR-108(1.0×1010 個/0.4 ml/天)或阿昔洛韋(ACV)(1 mg/0.4 ml/天)。再者，對於各投予組，進行n＝3×7次之取樣。又，亦準備未處理之3隻小鼠作為對照。 2)對上述各小鼠之生殖器局部接種HSV-2(2×104 PFU/20 μl/小鼠)。 3)於感染3天後之早晨亦投予BR-108或阿昔洛韋。然後，於投予30分鐘、1小時、2小時、3小時、4小時、6小時、8小時後，自各小鼠採取血液，自該等血液分離血清。 4)接著，將得到之各血清用培養基稀釋10倍，製成100 μl/ml。 5)又，於48-孔培養盤中培養Vero細胞，翌日添加HSV-2(0.1 PFU/ml)，於室溫下培育1小時，使其感染。 6)用PBS洗滌後，以200 μl/孔添加上述1)之血清稀釋液，於37℃下培育。 7)於開始該培育24小時後，回收培養物(細胞及培養基)，以-80℃冷凍保存。 8)進行3次冷凍融解，用PBS適當稀釋至101 ～105 倍。接著，將該稀釋液供至使用Vero細胞(35-mm培養皿)之噬斑分析。0小時區係使用在上述3)中之取樣當天於30分鐘之時間點自未處理之小鼠採取之血清。對照區係用PBS代替血清。 9)然後，以%求得以上述分析中對照區之噬斑數為100%時各血清之噬斑數，經時評價自經口投予了BR-108或ACV之小鼠分離之血清之抗HSV-2活性。將得到之結果示於下述表1及圖3。再者，表1中之數值表示各組3隻之血清中之噬斑數(%)之平均值±SD(標準偏差)。又，圖3係將表1中記載之該等數值製成圖表而得者。 [表1]

Figure 106103340-A0304-0001
由表1及圖3所示之結果可知，ACV經口投予組(#2)中，投予後於2小時內抗HSV-2活性增強，其後活性緩慢減弱，6小時後活性消失。與此相對，雙歧桿菌投予組(#1)中，投予6小時後抗病毒活性變高，8小時後以後亦持續。 根據該結果，認為源自雙歧桿菌及其代謝產物等之生理活性物質藉由轉移至血中而發揮其抗HSV活性。又，亦可知該抗HSV活性為持續之活性。特別是於作為疱疹病毒感染症之現有藥的ACV之抗病毒活性減少時，雙歧桿菌之抗病毒活性增強，因此，可藉由與該現有藥併用而更有效率且有效果地改善及預防疱疹病毒感染症。 [產業上之可利用性] 如以上說明，根據本發明，藉由經口攝取雙歧桿菌，可使疱疹病毒之量減少，又，抑制疱疹病毒感染症之發展。進而，該效果可並不太受到宿主之免疫功能降低之影響地發揮，又，為持續性。因此，攝取雙歧桿菌於疱疹病毒感染症之復發預防方面亦有效。再者，雙歧桿菌為安全性較高、可廉價提供之物質。 因此，以雙歧桿菌為有效成分之本發明之組合物於疱疹病毒感染症之改善或預防方面有用。The present invention provides a composition containing bifidobacteria as an effective ingredient for improving or preventing herpes virus infection. In the present invention, "herpes virus infection" refers to a viral infection caused by a virus belonging to the herpesvirus family. Examples of such a virus include herpes virus belonging to the alpha herpesvirus subfamily (herpes simplex virus type 1 ( HSV-1), herpes simplex virus type 2 (HSV-2), human herpes virus 3 (HHV-3, varicella/zoster virus, VZV)), herpes virus belonging to the beta herpes virus subfamily (human herpes virus 5) (HHV-5, cytomegalovirus, CMV), human herpes virus 6 (HHV-6), human herpes virus 7 (HHV-7)), a herpes virus belonging to the gamma herpesvirus subfamily (human herpes virus 4 (HHV- 4. Epstein-Barr virus, EBV), human herpes virus 8 (HHV-8, Kaposi sarcoma-associated herpes virus)). In the present invention, "improvement" includes not only the complete treatment of herpes virus infection, but also the alleviation of symptoms and the inhibition of its development. "Prevention" includes inhibiting or delaying the onset of herpes virus infection and inhibiting its recurrence. Furthermore, improving or preventing also includes reducing the amount of herpes virus that is the cause of herpes virus infection. In addition, as shown in the examples described later, the effect of improving or preventing herpes virus infection can be evaluated by measuring the amount of virus using plaque analysis or quantifying the degree of symptoms using lesion scores. The "Bifidobacterium" as the effective ingredient of the composition of the present invention may be a bacterium belonging to the genus Bifidobacterium. Examples include Bifidobacterium longum, Bifidobacterium breve, and Bifidobacterium breve. Bifidobacterium bifidum, Bifidobacterium infantis, Bifidobacterium adolescentis, Bifidobacterium catenulatum, Bifidobacterium pseudolongum, Bifidobacterium thermophilus (Bifidobacterium thermophilum), as long as it has the effect of improving or preventing herpes virus infection, there is no particular limitation. The bifidobacterium used in the composition of the present invention is preferably Bifidobacterium longum, and particularly preferably Bifidobacterium longum strain BR-108. Furthermore, BR-108 strain (BR-108) is a Bifidobacterium longum isolated from the stool of infants and young children, and it was deposited with the independent administrative legal person product evaluation technology base agency (NITE, 〒292-) on April 13, 2012. 0818 Room 122, Kamizukazuka 2-5-8, Kisarazu City, Chiba Prefecture (Deposit No.: NITE P-1317). In addition, the bifidobacterium is also a bacterium having the nucleotide sequence shown in SEQ ID NO:1 as the sequence of the 16SrRNA gene. In addition, only one kind of the above-mentioned bifidobacteria may be used in the composition of the present invention, or two or more species of bacteria may be used in the composition of the present invention. Furthermore, in the composition of the present invention, bifidobacteria can be used as live bacteria or as dead bacteria. Dead cells are preferable as the active ingredient of the composition of the present invention in terms of excellent heat resistance, stable quality, and tasteless and odorless. As dead bacteria in the composition of the present invention, heat sterilized bacteria can be used. Bacterial cells that have been heat-sterilized can be prepared by the following methods: cultures obtained by culturing bifidobacteria according to conventional methods, such as filtration, centrifugal separation, etc., to recover the cells, and then suspend them in water, etc., at a temperature below 120°C. (Preferably 80 to 120°C), heat treatment is performed within 30 minutes (3 seconds to 30 minutes), and then concentration, drying (freeze drying, etc.) and crushing treatment are performed as needed. Furthermore, the fine powder of the heat sterilized cells of Bifidobacterium longum BR-108 strain is commercially available under the product name "BR-108 (registered trademark)" (manufactured by Combi Functional Food Division). In addition, the bifidobacterium contained as an active ingredient in the composition of the present invention may be the bacteria as described above, or may be a substance contained in the bacteria, a secretion product of the bacteria, and a metabolite produced by the bacteria . The composition of the present invention can be in the form of a pharmaceutical composition for improving or preventing herpes virus infection, food and beverage (including animal feed), or a reagent for model animal experiments. The composition of the present invention can be formulated by a well-known pharmacological method. For example, it can be made into capsules, lozenges, pills, liquids, powders, granules, fine granules, film coatings, granules, throats, sublingual agents, chews, buccal preparations, pastes, syrups Oral or parenteral preparations, suspensions, elixirs, emulsions, coatings, ointments, plasters, pastes, transdermal absorption preparations, lotions, inhalants, aerosols, injections, suppositories, etc. To use. The present invention is a composition using Bifidobacterium as an intestinal bacterium as an active ingredient, which can be ingested non-invasively and simply by oral administration. That is, a preferred method of ingesting the composition of the present invention is by oral ingestion. In these formulations, it is possible to appropriately combine pharmacologically or as acceptable carriers for food and beverages, specifically physiological saline, sterilized water, vegetable oils, solvents, excipients, bases, emulsifiers, suspending agents, surfactants, Stabilizers, fragrances, fragrances, vehicles, preservatives, binders, diluents, isotonic agents, soothing agents, extenders, disintegrants, buffers, coating agents, lubricants, colorants, sweeteners Flavoring agents, thickeners, flavoring agents, dissolution aids or other additives, etc. When the composition of the present invention is used in the form of a pharmaceutical composition, it can be used in combination with known substances for the improvement or prevention of herpes virus infection. As the known substance, for example, acyclovir, valacyclovir, cidofovir, famciclovir, fomivir, foscarnet, ganciclovir, iodoside, penciclovir, and triflurure can be cited Nucleic acid analogs such as glycosides, valganciclovir, and arabinosine, DNA (deoxyribonucleic acid, deoxyribonucleic acid) synthesis inhibitors, etc. In addition, as shown in the following examples, when the antiviral activity of acyclovir decreases, the antiviral activity of bifidobacteria is enhanced. Therefore, it is combined with the known use for the improvement or prevention of herpes virus infections. The combined use of these substances can improve and prevent herpes virus infections more efficiently and effectively in the present invention. When the composition of the present invention is used in the form of a food or drink, the food or drink may be, for example, a health food, a functional food, a specific health food, a nutritional functional food, a functional labeled food, a nutritional supplement, and a patient's use. Food or animal feed. The food and drink of the present invention can be taken in the form of the composition as described above, and can also be taken in the form of various food and drink products. Specific examples of food and beverage products include fermented foods such as yogurt and lactic acid beverages, fermented beverages; edible oils, salad dressings, mayonnaise, margarine, and other oil-containing products; soups, milk drinks, soft drinks, teas Liquid foods such as beverages, alcoholic beverages, beverages, jelly-like beverages, and functional beverages; carbohydrate-containing foods such as rice, noodles, and bread; processed livestock foods such as ham and sausage; fish cakes, dried foods, salted fish, etc. Processed aquatic foods; processed vegetable foods such as pickles; semi-solid foods such as jelly; fermented foods such as miso; pastry, Japanese confectionery, candy, chewing gum, soft candy, ice cream, popsicles and other confectionery; curry, Soft canned products such as pouring juice and Chinese soup; instant soup, instant miso juice and other instant food or microwave oven food, etc. Furthermore, health food and drink prepared into powder, granule, lozenge, capsule, liquid, paste or jelly can also be mentioned. Furthermore, the manufacturing of the food and beverage in the present invention can be implemented by manufacturing techniques known in this technical field. One or two or more ingredients (for example, nutrients, etc.) that are effective for improving or preventing herpes virus infection may be added to the food and drink. Moreover, it can also be made into a multifunctional food and drink by combining it with other ingredients or other functional foods that exert functions other than the improvement. The composition of the present invention can be used for animals including humans, and there are no particular restrictions on animals other than humans, and can be used for various domestic animals, poultry, pets, experimental animals, and the like. Specifically, pigs, cows, horses, sheep, goats, chickens, wild ducks, ostriches, domestic ducks, dogs, cats, rabbits, hamsters, mice, rats, monkeys, etc. can be cited, but are not limited to these. In addition, as the object of the composition of the present invention, animals infected with herpes virus can be listed regardless of how it develops, and from the viewpoint of prevention, it can be administered or made to animals that are not infected with herpes virus or are suspected of being infected with herpes virus. Ingest the composition of the present invention. Furthermore, from the viewpoint of preventing recurrence, the composition of the present invention can be preferably used for animals carrying herpes viruses that have not shown symptoms. In the case of administering or ingesting the composition of the present invention, the dosage or intake is based on the subject’s age, weight, symptoms of herpes virus infection, health status, and type of composition (drugs, food and drink, etc.) Wait for the appropriate selection. For example, the dosage or intake of bifidobacteria per day is usually 0.5×10 9 pieces/kg body weight～50×10 9 /kg body weight, preferably 2×10 9 pieces/kg body weight～50×10 9 pieces /kg body weight. In addition, the present invention also provides a method for improving or preventing herpes virus infection in a subject, which is characterized by administering or ingesting a bifidobacterium or a composition containing bifidobacterium as an active ingredient to the subject as described above . Furthermore, the dosage or intake of the bifidobacterium or the composition containing the bifidobacterium as an active ingredient is as described above, and can be administered or ingested once per day or divided into multiple times (for example, twice). In addition, the administration or ingestion period may be stopped depending on the degree of improvement of herpes virus infection. However, as described above, it is desirable to continue the administration or ingestion without stopping from the viewpoint of preventing recurrence. Furthermore, regarding "continuation", it can be continuation every day or continuation with an interval. In terms of effect, it is better to continue to administer or ingest bifidobacteria or contain bifidobacteria as active ingredients. combination. The product (medicine, food and drink, reagent) of the composition of the present invention or its instructions can be attached with a label for improving or preventing herpes virus infection. In addition, regarding food and beverages, in order to distinguish them from general foods in terms of form and targets, they can be used as supplements for products of the composition of the present invention as health functional foods (specified health foods, nutritional functional foods, and functionally labeled foods). On the label of health function. "Attaching a label to a product or manual" here means attaching a label to the product itself, container, packaging, etc., or attaching a label to manuals, additional documents, promotional materials, and other printed materials that reveal product information. [Examples] Hereinafter, the present invention will be described more specifically based on examples, but the present invention is not limited to the following examples. In order to understand the effectiveness of bifidobacteria against herpes viruses and the infections caused by them, the following experiments were carried out. (Bifidobacterium) In addition, the Bifidobacterium used is a strain of Bifidobacterium longum BR-108 (Bifidobacterium longum BR-108) isolated from human feces of infants and young children, and was deposited with an independent administrative legal person on April 13, 2012 Bacteria from the Product Evaluation Technology Foundation Agency (NITE, 〒292-0818 Room 122, Kamizokazu 2-5-8, Kisarazu City, Chiba Prefecture) (Deposit No.: NITE P-1317). In addition, the bacteria (manufactured by Combi Functional Food Division, product name: BR-108 (registered trademark)) obtained by heat-sterilizing, freeze-drying, and pulverizing the bacteria were ingested in mice as follows. (Herpes virus) In addition, the herpes virus used is HSV-2 UW268 strain (provided by Toyama Prefectural Institute of Health). The virus strain was infected with Vero cells at 0.01 PFU/cell, moved to -80°C after 20-24 hours, and then repeatedly frozen and thawed three times. Next, the culture was added to a 50 ml centrifuge tube, centrifuged at 1500 rpm for 10 minutes at 4°C, and 1 ml of the supernatant was dispensed into 1.5 ml microtubes at -80°C Save and maintain under. Then, one of them was taken out, and plaque analysis was performed with Vero cells to determine the amount of virus (PFU), which was used for the infection described later. Then, using these bifidobacteria and HSV-2, the following experiment was performed. That is, first, 7 days before HSV-2 inoculation described later, BALB/c mice (6 weeks old, female) were divided into the following groups, each with 10 mice, and the intake of Bifidobacterium (BR-108) was started. A: Negative control group (physiological saline) (also called "control group") B: BR-108 (0.42×10 9 pcs/day) intake group (also called "BR 400 million pcs") C: BR-108 ( 2.1×10 9 pieces/day) ingestion group (also called "BR 2 billion pieces") D: BR-108 (10.5×10 9 pieces/day) ingestion group (also called “BR 10 billion pieces”). Furthermore, in such a way that the daily intake of each group was the above-mentioned amount, the mice were orally ingested twice a day (9 am and 6 pm) and BR-108 was suspended in physiological saline. By. In addition, for these mice, in order to synchronize the estrus cycle and increase the sensitivity of the genitals to HSV-2 infection, medroxyprogesterone acetate (medroxyprogesterone 17- acetate, 3 mg/individual). In addition, herpes virus infections are likely to cause onset, recurrence, severe, and prolonged periods due to decreased immune function. Therefore, in each of these mice ingestion groups, the immunosuppressant 5-FU (5-fluorouracil) was injected subcutaneously every other day from 7 days before HSV-2 vaccination to 13 days after the vaccination. Intake: 0.25 mg/0.1 ml/individual) and prepare immune-reduced groups (5 in each group). Then, HSV-2 (1×10 4 PFU/20 μl/individual) was locally inoculated to the genitals of these mice. Then, 3 days after the inoculation, the genitals were washed locally with cold PBS (phosphate buffer saline) (100 μl), and the virus amount was determined by the following plaque analysis. The results obtained are shown in Figure 1. <Plaque analysis> The recovered local washing solution was first diluted appropriately with PBS. 100 μl of the obtained dilution was added to Vero cells cultured in a monolayer in a 35 mm petri dish, and incubated at room temperature for 1 hour to infect them. Then, the laminate was added with 0.8% methylcellulose and 2% fetal bovine serum MEM (minimum essential medium) medium (2 ml/culture dish), and cultured at 37°C for 2 days. After the cultivation, the medium was removed, and fixation and staining were performed with crystal violet. Then, the number of plaques is measured under a microscope, and the plaque-forming unit (PFU) is calculated from the measured number. <Evaluation based on lesion score> In addition, after HSV-2 inoculation, herpes symptoms and deaths were recorded, and evaluation was based on the following lesion score (lesion score). The results obtained are shown in Figure 2. 0: Asymptomatic 1: Mild redness 2: Moderate redness and swelling 3: Redness and swelling with exudate 4: Hind limb paralysis 5: Death. As shown in Fig. 1, the amount of the virus in the genitals was measured 3 days after inoculation with HSV-2. As a result, it was found that the amount of virus was reduced by ingesting Bifidobacterium (BR-108). Furthermore, it was also confirmed that the decrease tends to show a dose-dependence. In addition, it was also shown that the reduction was alleviated due to immunosuppressant treatment. Furthermore, as shown in Fig. 2, it can also be seen that by ingesting bifidobacteria, the rapid development of genital herpes symptoms one week after HSV-2 inoculation is suppressed (delayed). Especially at the time point six days after HSV-2 inoculation, although the lesion score reached 2.5 or more in the control group that did not ingest bifidobacteria, the lesions in the group that ingested 10 billion bifidobacteria every day The score is suppressed to "zero" (asymptomatic state). In addition, regarding its dosage dependence, it was confirmed that medium and high dosages (BR 2 billion and BR 10 billion) have a stronger tendency to inhibit the development of symptoms than low dosages (BR 400 million). Furthermore, with regard to the suppression of genital herpes symptoms, no significant effects caused by immunosuppressant treatment were found. Furthermore, at the end (in the control group, up to 9 days after HSV-2 inoculation, in the bifidobacteria ingestion group, up to 12 days after HSV-2 inoculation), the mortality rate was 100% in either administration group. Furthermore, it is known that during the recurrence process of herpes virus, that is, from the latent infection state to the relapse of the disease, the amount of the proliferated virus is a major determinant of whether the disease is onset. It is also predicted that by administering bifidobacteria at this time, the amount of virus production in the body is reduced as shown in Fig. 1, and the disease can be prevented. Therefore, prevention of recurrence can also be expected. In addition, in the model animal experiment shown in Fig. 2, because the conditions for the death of all mice in the control group were set, it is thought that a much larger load was applied than the amount of virus at the time of relapse in humans. <Detection of anti-HSV activity> As described above, it is clear that oral intake of bifidobacteria can reduce the amount of herpes virus and inhibit the development of herpes virus infection. Then, in order to clarify the mechanism by which the virus growth inhibition effect by bifidobacteria is achieved, the following experiment was performed. That is, the inventors hypothesized that the antiviral active ingredients derived from bifidobacteria are absorbed and transferred to the blood to contribute to the possibility of the path of viral proliferation inhibition participating in the mechanism. Based on this hypothesis, they were administered orally After the bifidobacteria, the serum was collected at a time point of 0.5 to 8 hours to evaluate its anti-HSV activity. More specifically, the following procedures were used to detect anti-HSV activity. 1) First, BALB/c mice (female, 6 weeks old) were orally administered BR-108 (1.0×10 10 Pcs/0.4 ml/day) or acyclovir (ACV) (1 mg/0.4 ml/day). Furthermore, for each administration group, n=3×7 sampling is performed. In addition, 3 untreated mice were also prepared as controls. 2) HSV-2 (2×10 4 PFU/20 μl/mouse) was locally inoculated to the genitals of the above-mentioned mice. 3) BR-108 or Acyclovir was also administered in the morning 3 days after infection. Then, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, and 8 hours after the administration, blood was collected from each mouse, and serum was separated from the blood. 4) Next, each obtained serum was diluted 10-fold with the culture medium to make 100 μl/ml. 5) In addition, Vero cells were cultured in a 48-well culture dish, HSV-2 (0.1 PFU/ml) was added the next day, and incubated at room temperature for 1 hour to infect them. 6) After washing with PBS, add the serum diluent of 1) above at 200 μl/well, and incubate at 37°C. 7) After 24 hours of incubation, the culture (cells and culture medium) was recovered and stored frozen at -80°C. 8) Perform freezing and thawing three times, and appropriately dilute with PBS to 10 1 to 10 5 times. Next, the diluted solution was used for plaque analysis using Vero cells (35-mm petri dishes). The 0 hour zone uses serum collected from untreated mice at 30 minutes on the day of sampling in 3) above. Serum was replaced by PBS in the control area. 9) Then, calculate the number of plaques in each serum when the number of plaques in the control area in the above analysis is 100%, and evaluate the anti-sera of the serum isolated from mice that were orally administered BR-108 or ACV over time. HSV-2 activity. The obtained results are shown in Table 1 and FIG. 3 below. Furthermore, the values in Table 1 represent the mean ± SD (standard deviation) of the number of plaques (%) in the serum of 3 animals in each group. In addition, Fig. 3 is a graph obtained by drawing the values described in Table 1 into a graph. [Table 1]
Figure 106103340-A0304-0001
 From the results shown in Table 1 and Figure 3, it can be seen that in the ACV oral administration group (#2), the anti-HSV-2 activity increased within 2 hours after the administration, then the activity gradually weakened, and the activity disappeared after 6 hours. In contrast, in the bifidobacteria administration group (#1), the antiviral activity increased 6 hours after the administration, and continued after 8 hours. Based on this result, it is considered that physiologically active substances derived from bifidobacteria and their metabolites are transferred into the blood to exert their anti-HSV activity. In addition, it is also known that the anti-HSV activity is a continuous activity. Especially when the antiviral activity of ACV, which is an existing drug for herpes virus infection, is reduced, the antiviral activity of bifidobacteria is enhanced. Therefore, it can be more efficiently and effectively improved and prevented by combining with the existing drug Herpes virus infection. [Industrial Applicability] As explained above, according to the present invention, by orally ingesting bifidobacteria, the amount of herpes virus can be reduced and the development of herpes virus infection can be suppressed. Furthermore, the effect can be exerted without being affected by the decrease in the immune function of the host, and again, it is continuous. Therefore, ingestion of bifidobacteria is also effective in preventing the recurrence of herpes virus infection. Furthermore, Bifidobacterium is a substance with high safety and low cost. Therefore, the composition of the present invention using bifidobacteria as an active ingredient is useful for improving or preventing herpes virus infection.

圖1係表示對接種有單純疱疹病毒2型(HSV-2)之小鼠生殖器中之自接種起3天後之該病毒量進行測定之結果的圖表。「BR4億個」、「BR20億個」及「BR100億個」表示使上述HSV-2接種小鼠每1天分別攝取雙歧桿菌(BR-108株)4億個、20億個及100億個之結果。又，「對照組」表示未攝取雙歧桿菌之上述HSV-2接種小鼠之結果。進而，「+」表示經免疫抑制劑處理之上述HSV-2接種小鼠之結果，「-」表示未經免疫抑制劑處理之上述HSV-2接種小鼠之結果。又，柱狀圖及其上所附之條表示平均值±SD(平均值±標準偏差)。進而，「*」表示與未經免疫抑制劑處理之對照組相比確認到統計上之有意義差(P＜0.05)，「#」表示與經免疫抑制劑處理之對照組相比確認到統計上之有意義差(P＜0.05)。再者，統計上之有意義差係藉由Dunnet檢驗及Mann-Whitney U檢驗進行評價。 圖2係表示接種有HSV-2之小鼠中之病變記分(平均值)之經時變化之圖表。再者，圖表中之標記與圖1之標記相同。 圖3係表示攝取雙歧桿菌或阿昔洛韋(ACV)後之接種有HSV-2之小鼠血中之病毒量(抗病毒活性)之經時變化之圖表。縱軸表示以對照區之血中病毒量為100%時各小鼠之血中病毒量之比率(%)。橫軸之時間表示使小鼠攝取雙歧桿菌或ACV後之時間。又，柱狀圖及其上所附之條表示平均值±SD。Fig. 1 is a graph showing the results of measuring the amount of the virus in the genitals of mice inoculated with herpes simplex virus type 2 (HSV-2) 3 days after the inoculation. "BR 400 million", "BR 2 billion" and "BR 10 billion" indicate that the HSV-2 vaccinated mice ingested 400 million, 2 billion and 10 billion Bifidobacterium (BR-108 strain) every day. The result. In addition, the "control group" refers to the result of the aforementioned HSV-2 inoculated mice that did not ingest the bifidobacterium. Furthermore, "+" indicates the result of the above-mentioned HSV-2 inoculated mice treated with immunosuppressive agents, and "-" indicates the result of the above-mentioned HSV-2 inoculated mice that have not been treated with immunosuppressive agents. In addition, the histogram and the bars attached to it indicate the mean ± SD (mean ± standard deviation). Furthermore, "*" means that a statistically significant difference is confirmed compared with the control group without immunosuppressant treatment (P<0.05), and "#" means that it is statistically confirmed compared with the control group treated with immunosuppressant The significant difference (P<0.05). Furthermore, statistically significant differences are evaluated by Dunnet test and Mann-Whitney U test. Figure 2 is a graph showing changes over time in lesion scores (average values) in mice vaccinated with HSV-2. Furthermore, the labels in the diagram are the same as those in Figure 1. Fig. 3 is a graph showing the time-dependent changes in the amount of virus (antiviral activity) in the blood of mice inoculated with HSV-2 after ingesting bifidobacteria or acyclovir (ACV). The vertical axis represents the ratio (%) of the amount of virus in the blood of each mouse when the amount of virus in the blood in the control area is 100%. The time on the horizontal axis represents the time after the mice ingested Bifidobacterium or ACV. In addition, the histogram and the bars attached to it represent the mean ± SD.

[寄存國家] JP日本 [寄存機構] National Institute of Technology and Evaluation Patent Microorganisms Depositary (NPMD) 獨立行政法人製品評價技術基盤機構特許微生物寄託中心 [寄存日期] 2012/04/13 [寄存號碼] NITE BP-01317[Deposit Country] JP Japan [Deposit Organization] National Institute of Technology and Evaluation Patent Microorganisms Depositary (NPMD) Independent Administrative Legal Person Product Evaluation Technology Foundation Agency Licensed Microorganism Depositary [Deposit Date] 2012/04/13 [Deposit Number] NITE BP- 01317

<110> 康貝股份有限公司(Combi Corporation) 學校法人中部大學(CHUBUUNIVERSITY EDUCATIONAL FOUNDATION) <110> Combi Corporation Chubu University (CHUBUUNIVERSITY EDUCATIONAL FOUNDATION)

<120> 用於改善或預防疱疹病毒感染症之組合物 <120> Composition for improving or preventing herpes virus infection

<150> JP2016-014817 <150> JP2016-014817

<151> 2016-01-28 <151> 2016-01-28

<160> 1 <160> 1

<170> PatentIn版本3.5 <170> PatentIn version 3.5

<210> 1 <210> 1

<211> 1508 <211> 1508

<212> DNA <212> DNA

<213> 長雙歧桿菌 <213> Bifidobacterium longum

<400> 1

Figure 106103340-A0305-02-0017-1
<400> 1
Figure 106103340-A0305-02-0017-1

Claims (3)

一種用於改善或預防疱疹病毒感染症之組合物，其含有雙歧桿菌作為有效成分，上述雙歧桿菌為以寄存編號：NITE BP-1317進行寄存之長雙歧桿菌BR-108株。 A composition for improving or preventing herpes virus infection, which contains Bifidobacterium as an effective ingredient. The above-mentioned Bifidobacterium is the Bifidobacterium longum strain BR-108 deposited under the deposit number: NITE BP-1317. 如請求項1之組合物，其中上述疱疹病毒感染症係由單純疱疹病毒2型引起之感染症。 The composition of claim 1, wherein the aforementioned herpes virus infection is an infection caused by herpes simplex virus type 2. 如請求項1或2之組合物，其為經口攝取用組合物。 The composition of claim 1 or 2, which is a composition for oral ingestion.
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