TWI595090B - 益生菌劑 - Google Patents
益生菌劑 Download PDFInfo
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- TWI595090B TWI595090B TW099130665A TW99130665A TWI595090B TW I595090 B TWI595090 B TW I595090B TW 099130665 A TW099130665 A TW 099130665A TW 99130665 A TW99130665 A TW 99130665A TW I595090 B TWI595090 B TW I595090B
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Description
本發明關於自益生菌株鼠李糖乳桿菌Goldin Gorbach(LGG)獲取非存活之生物活性物質的方法。特別是,本發明關於用於製備可藉由該獲取方法獲得之抗過敏益生菌劑的方法,且關於包含該益生菌劑之飲食或營養產品。
乳桿菌GG(乳桿菌G.G.,菌株ATCC 53103)為天然出現於人體消化道中之細菌。此為研究頗多之具有一般健康效益的細菌。其被公認為是益生菌,因此被併入許多營養產品中,諸如乳製品、營養補充劑、嬰兒配方,等。
益生菌目前在本技藝中係定義為活微生物,當適量投服時可賦予宿主健康效益。然而,當將益生菌併入營養產品中時,其生命本質會帶來挑戰。尤其是,根據所使用之益生菌株類型、接受產品之個人的健康狀況或此二種因素,這些挑戰之程度可能會有所不同。再從處理技術之觀點來看,將活微生物併入產品中也有相當大的障礙需要克服。若個人想將益生菌納入長期產品(例如:粉狀產品,諸如嬰兒配方)中時,此點尤其有所影響。此外,隨著營養產品基質之複雜性增加,挑戰亦增加。
尤其在孕婦、嬰兒和兒童的營養產品方面,益生菌之使用有待進一步評估安全性和有效性。具體之安全問題係關於對養分利用率之可能影響、抗生素耐藥性轉移之排除及對腸道菌群之短期和長期影響、免疫反應和感染。雖然這並不意味著益生菌不能用於這類產品中,但其增加使用活菌或可存活細菌之實際複雜性。
另一方面,在用於嬰兒及兒童之飲食產品項目方面特別存有提供益生菌之助益效果的重要需求。此外,確保透過零售或醫院通路販售及暴露於周圍溫度之營養產品中的活菌之穩定性和活力特別具有挑戰性。透過將(加工)培養上清液應用在這方面將使細菌產品弓提供相當多的益處。
已知嬰兒之腸道菌群的發展遠不如成年人。雖然成年人之菌群係由超過1013個,接近500種之微生物所組成,但有些是有害,有些是有益的,嬰兒之菌群僅包含那些微生物之一部分(無論是絕對數量或品種之多樣性)。嬰兒出生時腸道無菌,但從產道(其初始環境)及其所攝入者獲得腸道菌群。由於新生兒早期生命中腸道微生物群非常不穩定,嬰兒的腸道要保持有害和有益細菌間之微妙平衡往往有困難,因而也降低免疫系統正常運作之能力。
由於餵食配方奶和餵食母乳之嬰兒的腸道菌種間之差別,餵食配方奶之嬰兒要維持這種平衡特別困難。餵食母乳之嬰兒的糞便中主要含有雙歧桿菌,鏈球菌和乳桿菌為較不常見的組成分。相反地,餵食配方奶之嬰兒的腸道微生物較多樣化,包含雙歧桿菌和擬桿菌屬,以及較具致病性之菌種,葡萄球菌、大腸桿菌及梭狀芽胞桿菌。餵食母乳和餵食配方奶之嬰兒糞便中的多種雙歧桿菌物種亦不同。已提出之造成餵食母乳和餵食配方奶之嬰兒糞便中菌群不同的因素有多種,包括母乳中蛋白質含量較低且組成不同、母乳中之磷含量較低、母乳中的寡糖種類繁多,以及母乳中有多種體液和細胞性免疫功能調節劑。Agostoni,et al.,Probiotic Bacteria in Dietetic Products for Infants: A Commentary by the ESPGHAN Committee on Nutrition,J. Pediatr. Gastro. Nutr. 38: 365-374(April 2004)。
建立正常之腸道菌群對健康和疾病具有重要的影響。從宿主的觀點來看,腸道菌群之主要功能為防止致病有機體在腸道定居並抑制潛在的致病微生物增殖,增加對腸道傳染病的自然抗性。益生菌藉由產生抗微生物化合物直接防止或透過合成短鏈揮發性脂肪酸來改變腸腔之pH值而間接防止致病菌與腸細胞結合以發揮此作用。
此外,正常菌群可能刺激胃腸免疫力、增強黏膜IgA之產製、刺激局部產製抗發炎細胞因子及減少具過敏性炎症特性之前炎性細胞因子的生成。關於益生菌在食品過敏、異位性皮膚炎和遺傳性過敏症之初級預防中的用途的最相關研究調查顯示出益生菌療法可緩解過敏性炎症(此點由臨床症狀獲得控制及局部和全身炎症標記減少得到證明)(Miraglia del Giudice M,De Luca MG. The role of probiotics in the clinical management of food allergy and atopic dermatitis. J Clin Gastroenterol 2004;38(6 Suppl): S84-5;Prescott S,Bjorksten B,Probiotics for the prevention or treatment of allergic disease. J. Allergy Clin. Immunol. 2007;120: 255-262)。
鑑於前述將可理解通常有需要提供具有益生菌之營養產品、飲食產品,尤其是嬰兒配方是。“嬰兒配方”一詞係指藉由作為母乳之替代品來滿足嬰兒營養需求的組成物。
同樣可理解的是在嬰兒配方奶中尤其需要併入益生菌,但不一定要併入活細菌或可存活之細菌。事實上,這需要“非存活益生菌。”
對這類非存活益生菌的研究正在進行中。然而,如Tao,等人(Am J. Physiol Cell Physiol. 290: C1018-C1030(2006)在一篇論文中所陳述者,雖然益生菌似乎改善許多疾病之進程,其作用機制仍不太了解。僅最近嘗試了解其作用背後之機制以及與宿主細胞之交互作用。現已提出許多不同之可能機制,包括正調節黏液生產、改善上皮屏障功能、增加IgA之生產及增加對小腸上皮細胞之黏附位置的競爭,以及抑制致病菌生長之各種有機酸、氨、過氧化氫和細菌素的產製。在這方面,Tao,等人提出對某些來自LGG之可溶性因子作用的研究。某些生物活性可歸結出係存在於LGG-CM超濾液之低分子量分液(分子量<10 kDa)中。類似之教示為US 2007/123460。此處係使用自益生菌衍生之無菌化合物,尤其是低分子量分液(分子量<10 kDa)取代活菌來治療,尤其是,發炎性腸病(IBDs)。其他談到非存活益生菌之參考資料係,如:US 2004/208863(其大致上係關於細菌之抗發炎作用及由細菌分泌之產物)和US 7052896(其內容關於由鼠李糖乳桿菌物種產生之肽類的抗發炎和抗過敏性質)。
US 6,506,389描述可自非致病性微生物獲得之蛋白質(該蛋白質具有黏膜結合活性且分子量為20-40 kD(較佳地20~30 kD))或其同等多肽。該揭示內容之要旨為提供用於識別能夠特異結合黏膜之蛋白質和多肽的篩選方法。
先前技藝之參考資料無一提出能適當地自LGG收穫可支持抗過敏活性之非存活益生菌劑的簡單方法。
此外,收獲分泌出之細菌產品則帶來培養基無法輕易去除不想要之組成分的問題。此點特別與用於相對弱勢之對象的營養產品(諸如嬰兒配方或臨床營養)有關。若先自培養上清液分離、純化出特定組成分,再將其施用於營養產品中則此問題將不會發生。然而,使用更完整的培養上清液是有需要的。此可用於提供更適當地反映益生菌(即LGG)之天然作用的組成物。然而,目前不能僅使用培養上清液本身作為專門用於嬰幼兒配方,等之非存活益生菌劑的基礎。因此,更需要提供解決這個問題的方法。
為了更適當地解決前述之一或多個需要,本發明之一觀點中提出用於治療或預防過敏性疾病之包含自LGG批式培養法指數生長後期之培養上清液獲得的蛋白質混合物的組成物。
於另一觀點中,本發明關於自LGG培養基收穫具有抗過敏活性之組成物的方法,其包含在合適之培養基中生長LGG,測定LGG群在指數生長後期之生長並在該指數生長後期自細菌培養中分離出培養上清液。
於其他觀點中,本發明提供一種飲食產品,其包含自LGG批式培養法指數生長後期之培養上清液中獲得之非存活益生菌組成物並提供前述組成物作為營養產品中之添加劑的用途。
再於另一觀點中,本發明提供治療或預防個體中過敏性疾病之方法,該方法包含投予該個體有效量之包含非存活益生菌的組成物,該非存活益生菌係自LGG批式培養法指數生長後期之培養上清液中獲得。
廣義上來說,本發明係基於深入了解自LGG之批式培養中可收穫具有抗過敏活性之培養上清液(其亦可稱為“耗盡之基質”)。本發明中,“抗過敏”一詞包括“過敏預防性活性以及抗過敏治療性活性”。
不欲受限於理論,本發明者相信此活性可歸因於所發現之在LGG批式培養法指數(或“對數”)生長末期釋入培養基中的組成分之混合物(包括蛋白質物質,並可能包括(胞外)多糖)。此組成物在下文中稱為“本發明之培養上清液”。
LGG為自健康之人體腸道菌分離的益生菌株。此揭示於授讓與Gorbach,等人之美國專利編號5,032,399(本文參考此篇並將其全部內容納為此文之參考資料)中。LGG對大部分抗生素具抗藥性,在酸和膽汁之存在下穩定,並强力黏附於人腸道之黏膜細胞。其在大部分個體中可生存1-3天,且在30%之個體中可生存長達7天。除了其定居之能力外,LGG亦有利地影響黏膜免疫反應。LGG存放於美國菌種保藏中心保管機關中,編號ATCC 53103。
熟習本技藝之人士已知細菌之批式培養法中所認定之各階段。這些階段為“遲滯期”、“對數期”(“對數”或“指數”)、“靜止期”和“死亡期”(或“對數遞減”)。在活菌存在之所有階段中,細菌代謝來自基質之營養並分泌(施加,釋出)物質到培養基中。在生長階段之指定時間點所分泌之物質的組成物大致上無法預測。
本發明中係自指數生長後期收穫分泌之物質。指數生長後期係在指數生長中期(其為指數期間之一半時間,因此稱指數生長後期為介於遲滯期與靜止期之間的後半段時間)後之時間發生。尤其是,此處所使用之“指數生長後期”一詞係指LGG批式培養法之介於遲滯期與靜止期之間的後四分之一時間。較佳地,根據本發明,該培養上清液係在指數生長期間之75%至85%的時間點收穫,最佳地為在指數期之時間過去約5/6收穫。
“培養(cultivation或culturing)”一詞係指微生物(本案例中為LGG)在合適之基質上或合適之基質中增殖。這類培養基可有多種,尤其是本技藝中常用之液態基質。例如:較佳之基質為一般用於培養乳桿菌之MRS基質。MRS基質通常包含已知可作為乳桿菌之特殊生長因子的聚山梨醇酯、醋酸酯、鎂及錳,以及富含營養之基底。典型之組成物包含(含量以克/升計):來自酪蛋白之腖10.0;肉類萃取物8.0;酵母萃取物4.0;D(+)-葡萄糖20.0;磷酸氫二鉀2.0;Tween801.0;檸檬酸三銨2.0;醋酸鈉5.0;硫酸鎂0.2;硫酸錳0.04。
本發明之培養上清液的較佳用途為用於嬰兒配方中。為了使本發明充分用於此處,需要確保在這類配方中,自LGG培養收穫之組成物不包含不需要或非法律所允許之組成分(如那些可能存在於培養基中者)。參考MRS基質中常出現之聚山梨醇酯,用於培養細菌之基質可包含乳化非離子表面活性劑,如:以聚氧乙烯化山梨醇酐和油酸為基礎(通常可以Tween聚山梨醇酯之形式獲得,諸如Tween80)。雖然這些表面活性劑經常在食品(如:冰淇淋)中發現且通常被視為安全的,其並非在所有管轄範圍內均被認為有需要,或甚至可以被接受用於相對弱勢之對象的營養產品(諸如嬰兒配方或臨床營養)中。
因此,於一較佳體系中,本發明亦關於使用其中可避免上述之聚山梨醇酯的培養基。為此,本發明之較佳培養基不含Tween 80並可包含選自油酸、亞麻子油、橄欖油、菜籽油、葵花子油或其混合物之油成分。可理解的,若可實質上或完全避免聚山梨醇酯表面活性劑存在則可取得油性成分之充分利益。
最佳地,MRS培養基中不含Tween 80且除了上述之一或多種油外還包含蛋白胰(通常為10克/升)、肉類萃取物(通常為8克/升)、酵母萃取物(通常為4克/升)、D(+)葡萄糖(通常為20克/升)、磷酸氫二鉀(通常為2克/升)、醋酸鈉三水合物(通常為5克/升)、檸檬酸三銨(通常為2克/升)、硫酸鎂七水合物(通常為0.2克/升)和硫酸錳四水合物(通常為0.05克/升)。
培養通常係在20℃至45℃之溫度下進行,較佳地在35℃至40℃進行,最佳為在37℃進行。
培養期間收穫該培養上清液之較佳時間點(即在上述指數生長後期)可根據,例如OD600nm和葡萄糖濃度測定。OD600係指600 nm處之光密度(此為已知之與培養基中之細菌濃度直接相關的光密度測量值)。
除了前述內容外,需注意的是,乳桿菌(包括LGG)之批式培養法為熟習本技藝之人士可取得之常見的一般知識。因此,本文中不需要進一步闡明這些方法。
較佳地,本發明之組成物係藉由大規模發酵法製造(例如:在超過100升的發酵器中,較佳地在200升或更大之發酵器中製造)。
本發明之組成物可藉由任何已知之用於自細菌培養中分離培養上清液的技術收穫。這類技術為本技藝眾所周知的,包括,例如:離心、過濾、沉澱,等。
該上清液可立即使用,或儲存以供未來使用。在後一種情況下,通常係將上清液冷藏、冷凍或凍乾。上清液可依需要而被濃縮或稀釋。
咸信,根據本發明收穫之組成物為蛋白質組成物。熟習本技藝之人士已知“似蛋白質的”一詞且其係指該組成物包含一或多種肽類、蛋白質或其他包含胺基酸殘基之化合物。
在化學物質方面,咸信本發明之培養上清液的組成物為具有各種分子量之多種胺基酸、寡-和多肽,以及蛋白質之混合物。
要強調的是,與本技藝不同之處為本發明宜關於全部,即未分餾之培養上清液。咸信,在上述之指數生長後期進行收穫及幾乎保留全部上清液組成分的明智選擇可有助於取得令人驚喜之結果,尤其是在抗過敏活性部分,更特別的是在嬰兒和新生兒中之這類活性,以及當分別投予圍產期之懷孕婦女及哺乳婦女時。
更具體地,完整之培養上清液之特點為大致上不含低分子量(通常係低於6 kDa)之組成分。這涉及到一個事實,該組成物較佳地不包含乳酸及/或乳酸鹽。因此,本發明之較佳上清液具有大於6kDa之分子量,因為此為去除乳酸及乳酸鹽類時獲得之典型的上清液。此通常涉及過濾或管柱層析法。事實上,此過濾保留物代表分子量大於6 kDa(換句話說,低於6 kDa之成分被過濾掉)。
一般而言,本發明之上清液組成物將不僅為蛋白質性,亦包含多糖類,尤其是胞外多糖類(由糖殘質所組成之高分子量聚合物,如:由LGG所產製者)。不欲受限於學理,本發明者相信與從其他階段(如:指數生長中期或遲滯期)收穫之組成物相比較,依上述自指數生長後期收穫之蛋白質物質的量與碳水化合物物質量之間的比例有助於抗過敏性質。
根據本發明收穫之培養上清液可以多種方式使用,以受益於所發現之抗過敏活性。這類用途一般涉及將本發明組成物投予有此需要之個體的某些形式。在這方面,該培養上清液可以,如:併入膠囊中口服或在液態營養組成物(如:飲料)中之形式使用,或者,其可先處理後再繼續使用。後者為較佳方式。
這類處理通常涉及將蛋白質組成物與上清液之大體上液態連續相分離。此宜藉由乾燥法完成,諸如噴霧乾燥法或冷凍乾燥法(凍乾法)。噴霧乾燥法為較佳者。於噴霧乾燥法之較佳體系中係在噴霧乾燥前先添加載體物質(如:麥芽糊精DE29)。咸信,在其中乳酸(此係由LGG所製造且存在於耗盡之培養基中)為液體之條件下製造乾燥粉末亦被認為是有利的。
本發明之組成物已被發現具有抗過敏(預防性及/或治療性)活性。抗過敏活性可在,如新發展之新生小鼠過敏及肺部發炎模型中測定。實際上,該模型為稱為OVA模型(其廣泛用於研究過敏疾病和氣喘之免疫病理,以及用於鑑定具有抗過敏活性之化合物)之修改體。過敏性疾病包括,但不限於氣喘(其可能係植基於過敏)、異位性濕疹(其亦可能係植基於過敏)、食物過敏及過敏性鼻炎/結膜炎。
為了使本發明之組成物發揮其益處(抗過敏作用),它係由個體(較佳地人類個體)消化。尤其是,於一較佳體系中,該個體為懷孕婦女、哺乳期婦女、新生兒、嬰兒或小孩。如上述所提及者,使用可被視為“非存活益生菌”之物質的優點將主要受惠於嬰兒營養產品。“嬰兒”一詞係指小於1歲左右之出生後的人類。
可理解的是,由個體消化將需要口服本發明的組成物。根據本發明之組成物的投服形式不是關鍵。於一些體系中,該組成物係經由錠劑、藥丸、包囊、囊片、膠帽、膠囊、油滴或藥囊投予個體。於另一體系中,該組成物係包囊在糖、脂肪或多糖中。
再於另一體系中,該組成物係添加到食品或飲品中再食入。該食品或飲品可能是兒童營養產品,諸如較大嬰兒配方、成長奶粉、飲料、牛奶、優格、果汁、以水果為主之飲料、咀嚼片劑、餅乾、薄脆餅乾或奶粉。於其他體系中,該產品可能為嬰兒營養產品,諸如嬰兒配方或母乳強化劑。
本發明之組成物(無論是否添加在分別之劑型中或係經由營養產品)通常係以可有效治療或預防過敏之量投服。較佳地,該有效量等於每天每公斤體重1×104至約1×1012細胞當量之活益生菌,更佳為108-109。細胞當量之回推計算係充分在熟習本技藝之人士的知識範圍內。
若本發明之組成物係經由嬰兒配方投服,該嬰兒配方可能為營養完整且包含合適之類型和數量的脂肪、碳水化合物、蛋白質、維生素和礦物質。脂質或脂肪之量通常可在約3至約7克/100千卡變化。脂質來源可為任何本技藝所已知或使用者,例如:蔬菜油,諸如棕櫚油、大豆油、棕櫚液油、椰子油、中鏈三酸甘油脂油、高油酸葵花油、高油酸紅花油,等。蛋白質的量通常係在約1至約5克/100千卡變化。蛋白質來源可為任何本技藝所已知或使用者,例如:脫脂奶粉、乳清蛋白、酪蛋白、大豆蛋白、(部分或大規模)水解蛋白、胺基酸,等。碳水化合物之量通常係在約8至約12克/100千卡變化。碳水化合物的來源可為任何本技藝所已知或使用者,例如:乳糖、葡萄糖、玉米糖漿固形物、麥芽糊精、蔗糖、澱粉、稻米糖漿固體,等。
較方便地,可使用市售之產前、早產、嬰兒和兒童的營養產品。例如:可在下列產品中補充適當量之本發明組成物,且使用這些配方來實行本發明之方法:Expecta、Enfamil、Enfamil早產兒配方、Lactofree、Nutramigen、Gentlease、Pregestimil、ProSobee、Enfakid、Enfaschool、Enfagrow、Kindercal(可從美國印第安納州Evansville美強生及公司(Mead Johnson & Company)取得)。
於一體系中,本發明之組成物可與一或多種活益生菌合併。本技藝中已知之任何活益生菌均為本技藝可接受者惟其此體系達到預期之結果。
若將活益生菌與本發明之組成物一起投服,活益生菌的數量可能相當於約1*104至1*1012株落形成單位(cfu)/公斤體重/天。於另一體系中,該活益生菌可包含約1*106至1*1012 cfu/公斤體重/天。再於另一體系中,該活益生菌可包含約1*109 cfu/公斤體重/天。再於另一體系中,該活益生菌的數量可包含約1*1010 cfu/公斤體重/天。
於另一體系中,本發明之組成物可與一或多種益菌生組合。“益菌生”意指刺激益生菌之生長及/或活性的不易消化之食品成分。任何本技藝已知之益菌生均可被本體系接受,只要其達到所需之結果。可用於本發明之益菌生可包括乳果糖、葡萄寡聚糖、菊糖、聚右旋糖、半乳寡聚糖、果寡聚糖、異麥芽寡聚糖、大豆寡聚糖、乳果寡聚糖、木寡聚糖及龍膽寡聚糖。
再於本發明之另一體系中,該嬰兒配方可能含有其它活性劑,諸如LCPUFA。合適之LCPUFA包括,但不限於:[α]-亞麻油酸、[γ]亞麻油酸、亞油酸、亞麻酸、二十碳五烯酸(EPA)、花生四烯酸(ARA)及/或二十二碳六烯酸(DHA)。於一體系中,本發明之組成物係與DHA一起投服。於另一體系中,本發明之組成物係與ARA一起投服。再於另一體系中,本發明之組成物係與DHA和ARA一起投服。包含DHA、ARA或彼等之組合的市售嬰兒配方可補充以本發明之組成物並用於本發明中。例如:包含有效量之DHA和ARA的Enfamil LIPIL可從市面上購得且可補充以本發明之組成物並用於本發明中。若包含彼等,本發明之體系中的ARA有效量通常係從約5毫克/公斤體重/天至約150毫克/公斤體重/天。於本發明之一體系中,該量係在約10毫克/公斤體重/天至約120毫克/公斤體重/天間變化。於另一體系中,該量係在約15毫克/公斤體重/天至約90毫克/公斤體重/天間變化。再於另一體系中,該量係在約20毫克/公斤體重/天至約60毫克/公斤體重/天間變化。若係使用嬰兒配方,該嬰兒配方中之DHA的量可在約5毫克/100千卡至約80毫克/100千卡間變化。於本發明之一體系中,DHA係在約10毫克/100千卡至約50毫克/100千卡間變化;再於另一體系中,DHA係在約15毫克/100千卡至約20毫克/100千卡間變化。於本發明之一特殊體系中,該DHA的量為約17毫克/100千卡。若係使用嬰兒配方,該嬰兒配方中之ARA的量可在約10毫克/100千卡至約100毫克/100千卡間變化。於本發明之一體系中,該ARA之量係在約15毫克/100千卡至約70毫克/100千卡間變化。再於另一體系中,該ARA之量係在約20毫克/100千卡至約40毫克/100千卡間變化。於本發明之一特殊體系中,該ARA之量為約34毫克/100千卡。若使用嬰兒配方,可使用本技藝中已知之標準技術在該嬰兒配方中補充含有DHA和ARA的油。例如:可經由取代等量之油(諸如通常存在於配方中之高油酸葵花油)來將DHA和ARA添加到配方中。另一實例為,該含有DHA和ARA之油可經由取代等量之通常存在於不含DHA和ARA之配方中的總體脂肪混合物的其餘部分來添加。若使用DHA和ARA,該DHA和ARA之來源可為本技藝中已知之任何來源,諸如海洋生物油、魚油、單細胞油、蛋黃脂質、腦血脂,等。於一些體系中,DHA和ARA係源自單細胞馬泰克油(Martek oil),DHASCO或其變體。該DHA和ARA可為天然形式,只要LCPUFA來源之其餘部分對嬰兒不會產生任何重大之有害影響。另外,DHA和ARA可以精製形式使用。於本發明之一體系中,DHA和ARA之來源為美國專利編號5374567;5550156;和5397591中所教示之單細胞油(其全部揭示內容納為此文之參考資料)。然而,本發明不僅限於這類油。於一體系中,包含EPA之LCPUFA來源係與至少一種本發明之組成物組合使用。於另一體系中係將實質上不含EPA之LCPUFA來源與至少一種本發明之組成物組合使用。例如:於本發明之一體系中係在含有少於約16毫克EPA/100千卡之嬰兒配方中補充本發明之組成物。再於另一體系中係在含有少於約10毫克EPA/100千卡之嬰兒配方中補充本發明之組成物。再於另一體系中係在含有少於約5毫克EPA/100千卡之嬰兒配方中補充本發明之組成物。
本發明之另一體系包括輔以本發明組成物之甚至不含微量EPA的嬰兒配方。咸信,提供本發明之組成物與DHA及/或ARA之組合物可對含有這些作用劑之調製劑的抗過敏性質提供互補或協同效果。
於另一較佳體系中,本發明之飲食產品包含一或多種通常存在於人母乳中之生物活性物質,諸如蛋白質或多糖。
較佳地,使用本發明之組成物來預防、減輕、緩和或治療過敏及/或其症狀。
過敏係定義為“對正常可容忍且一般認為是無害的物質異常過敏”。過敏之症狀範圍可從流鼻涕至過敏性休克。接近5000萬美國人患有過敏性疾病且這些疾病的發病率正在增加。
有兩個基本階段參與過敏性反應。第一階段涉及對過敏原之立即型過敏反應的早期階段之發展。過敏原第一次遇到免疫系統時並無過敏反應發生。而是,免疫系統本身為日後遇到過敏原做準備。巨噬細胞(其為清道夫細胞)和所謂的樹突狀細胞包圍並打破入侵的過敏原。然後,這些細胞在其細胞壁上對T淋巴細胞(此為身體免疫反應之主要安全管理者)展示過敏原片段。此種認知信號再加上一些非認知信號(如:細胞因子)激活初始型T細胞並指導T-細胞分化成T細胞效應子亞群。過敏串聯反應中之關鍵角色為具Th-2表型(TH-2)之T-細胞。Th-2型T-細胞之特點為分泌數種細胞因子,包括介白素-4(IL-4)、IL-5及IL-13。然後,細胞因子IL-4和IL-13激活B淋巴細胞以產生針對特定過敏原之子類E的抗體(IgE)。在效應子細胞(肥大細胞和嗜鹼性粒細胞)表面上之特異性IgE抗體與過敏原的交互作用觸發立即型過敏反應的早期階段。
此肥大細胞激活作用通常係在第二次或額外接觸過敏原後之數分鐘內發生。在敏感化階段建構之肥大細胞上的IgE抗體可辦認過敏原並結合該入侵者。一旦過敏原與受體結合,該肥大細胞中之顆粒釋出其內含物。這些內含物或傳介子為前發炎物質,諸如組織胺、血小板活化因子、前列腺素、細胞因子和白三烯。這些傳介子確實觸發過敏攻擊。組織胺刺激黏液產生並導致發紅、腫脹和發炎。前列腺素使氣道收縮並擴大血管。
過敏性免疫反應之第二階段的的特點為接觸過敏原後炎性細胞(諸如嗜酸性粒細胞)浸潤進入氣道。敏感化和發炎之間的重要聯繫代表為T細胞(其能分泌不僅參與IgE之合成,亦負責嗜酸性粒細胞之招募、激活和生存的傳介子)。該組織肥大細胞和鄰近細胞製造能傳遞嗜鹼性粒細胞、嗜酸性粒細胞和其他細胞移行進入組織循環之信號並協助對抗外來物質的化學傳訊子。嗜酸性粒細胞本身分泌能維持發炎、引起組織損傷並招募更多之免疫細胞的化學物質。此階段可在接觸過敏原後之數小時至數天的任何時間發生且可持續數小時甚至數天。
呼吸道過敏為一種影響呼吸道之特殊類型的過敏。從鼻子到肺之氣道的內襯結構相似,且被過敏過程影響之方式通常很類似。因此,影響鼻子或鼻竇之過敏原亦可能影響肺部。
例如,過敏性鼻炎(又稱花粉症)係由鼻子和呼吸道黏膜對空氣中之過敏原的過敏性反應造成。過敏性鼻炎之症狀通常包括鼻子、喉嚨和眼睛癢,以及過度打噴嚏。鼻塞或流鼻涕往往隨之而來。
由於呼吸道之一個區域中的過敏原可能會影響呼吸道之其他區域,鼻道中之鼻炎可導致氣喘(此較出現在肺部下方氣道者更加嚴重)。氣喘的特點為發展出呼吸道過度反應性、呼吸困難、呼氣時喘息、乾咳和胸口感到氣悶。反復接觸過敏原可能持續呼吸道中之炎症免疫反應,造成氣道重塑(俗稱慢性氣喘)。並非每位患有過敏性鼻炎的人都將發展出氣喘症狀,但有相當數量,特別是那些患有反復發生,未治療之過敏的人會出現肺部發炎的變化。百分之四十患有過敏性鼻炎的人將實際發展出典型之氣喘。
若伴隨過敏性鼻炎之鼻腔發炎到達鼻竇,結果可能是其中鼻竇無法自行清空細菌之稱為竇炎或鼻竇炎之不舒服的感染。症狀包括鼻塞、流鼻涕、喉嚨痛、發燒、頭痛、疲倦和咳嗽,以及額頭、臉頰後面疼痛,甚至是牙齒和下巴疼痛。
呼吸道過敏為兒童時期最常見的病痛之一。如同成人,兒童之呼吸道過敏最可能以過敏性鼻炎和氣喘之形式出現。
呼吸道過敏的預防在嬰兒和幼兒中尤其重要,因為對過敏原之早期敏感化顯示出與正常免疫反應延遲成熟有關。此外,過敏性敏感化通常被認為是發展過敏性疾病的第一步。Baena-Cagnani,Role of Food Allergy in Asthma in Childhood,Allergy. Clin. Immun. 1(2): 145-149(2001)。通常,早年開始之氣喘與特異反應性有關,因此,早期之過敏性敏感化似乎在亦持續性氣喘中扮演重要的角色。Martinez,F.,Development of Wheezing Disorders and Asthma in Preschool Children,Pediatr. 109: 362-367(2002)。
過敏性敏感化與氣喘間不僅有很強的相關性,且此相關性似乎與年齡有關。雖然很少兒童在生命之最初數年間即對過敏原過敏,絕大部分在此時期變敏感之個體在以後的生活中發展出似氣喘之症狀。Martinez,F.,Viruses and Atopic Sensitization in the Rirst Years of Life,Am. J. Respir. Crit. Care Med.,162: S99(2002)。因此,找到預防早期過敏原敏感化並預防以後生活中之呼吸道過敏是重要的。
越來越多的證據顯示健康和疾病之多種面向不僅係在嬰兒期,亦在懷孕期間被決定。尤其是在過敏性疾病方面更是如此,其中出生時之免疫反應涉及作為初始敏感化情況之子宮內接觸。例如:過敏原特異性T細胞在出生時已經存在且對食物過敏原之早期敏感被認為是往後發展出呼吸道過敏的預測。IHi,et al.,The Natural Course of Atopic Dermatitis from Birth to Age 7 Years and the Association with Asthma,Clin. Exp. Allergy 27: 28-35(1997)。此外,肺部發育在受精後很早就開始並在出生後至少持續兩年或三年。因此,產前和產後之呼吸道發展在嬰兒和兒童之呼吸道過敏的發病機制中是重要的。
人類胎兒顯示出在妊娠早期即發展製造IgE25之B細胞且可以類似於廣為人知之在各種產前感染所觀察到之IgM反應的方式在回應合適之抗原刺激時產生IgE抗體。Weil,G.,et al.,Prenatal Allergic Sensitization to Helminth Antigens in Offspring of Parasite-Infected Mothers,J. Clin. Invest. 71: 1124-1129(1983)。此亦說明產前和產後預防對呼吸道過敏原之過敏性敏感化的重要性。
呼吸道過敏之傳統藥物包括:抗組織胺、局部鼻腔類固醇、減充血劑和色胺酸(cromolyn)溶液。作為傳統藥物之替代,益生菌已成為某些類型過敏之可能治療劑。參考上述使用活或可存活之益生菌的缺點,本發明在取代用於預防、減輕、緩和或治療過敏性疾病及/或其症狀之產品中的這類益生菌上特別有利。為此,本組成物較宜經由飲食或營養產品投服,更佳地經由產前、嬰兒或兒童配方或營養組成物、醫療食品或用於特定醫療目的之食品(即標示用於界定之醫療目的的食品)投服,最佳地經由嬰兒配方,或懷孕或哺乳期婦女之圍產期營養(如上文大幅討論者)投服。
本發明將參考下列非限制性實例和所附圖形說明於下。
在批式發酵過程中,令LGG在生理條件下生長。經由加入33% NaOH將pH值保持在pH6不變,溫度則維持在37℃。攪拌器之速度為50rpm,將頂空注滿N2。提供下列培養基(一種經改造之MRS基質)(見表1)。
細菌之生長描繪於第1(a)和(b)圖中。
第1a圖顯示LGG發酵期間pH值、滴定之氫氧化鈉(33%)的量(DM鹼=劑量監測鹼)和OD600之演變。參考圖形中之說明。pH值及OD600測量值允許測定發酵器中之細菌生長;此處,將pH值保持在6時所需加入之NaOH與製造之乳酸化物有關(即細菌代謝活性之測量值)且OD 600為與發酵器中之細菌數量有關的密度測量值。
第1b圖中,縱軸表示在培養基中之以對數尺度表示之細菌計數。橫軸表示時間。
在三個時間點採取培養上清液之樣本(圖形中以MJ1、MJ2和MJ3指示)。
類似於實例1,在經改質之培養基的基礎上進行LGG培養。此處末加入Tween,依下述加入油:
(a)油酸,濃度為1克/公斤、2克/公斤和4克/公斤。
(b)亞麻籽油,濃度為1克/公斤、2克/公斤和4克/公斤。
(c)橄欖油,濃度為1克/公斤、2克/公斤和4克/公斤。
(d)菜籽油,濃度為1克/公斤、2克/公斤和4克/公斤。
(e)向日葵油,濃度為1克/公斤、2克/公斤和4克/公斤。
在(a)-(e)之所有這些測試中均可觀察到LGG生長成功,與含有Tween之介質中的生長相當。除此外,令人驚訝地,不加入Tween或任何油時亦可成功培養LGG。
此實例中,在本技藝所接受之體外模型中,使用RAW 264細胞(小鼠巨噬細胞株)篩選依實例1所獲得之上清液的抗過敏和抗炎活性。與其他上清液樣本收穫物相比較,RAW細胞培養顯示出與LGG培養之MJ2上清液樣本收穫物一起培育期間,調節性細胞因子IL-10之製造大幅增加。見第2圖。
在卵白蛋白(OVA)敏感化模型中比較實例1中所獲得之培養上清液MJ2與活LGG細菌。此廣為本技藝接受之活體內模型通常適用於青少年或成年老鼠。此實例中係調整傳統模型以容許進行生命早期過敏之研究。
因此,令新生Balb/C小鼠透過胃內投服隔天接受LGG或全LGG培養上清液,共六週。在第42和56天以卵白蛋白(OVA)將動物敏感化兩次,接著,進行挑戰並在第61、62和63天接觸OVA-氣溶膠。此時間表顯示在第3圖中。藉由肺功能分析、組織學和支氣管肺泡灌洗(BAL)來評估實驗性支氣管氣喘。藉由抗體量和細胞因子反應來評估全身過敏反應性。在支氣管肺泡灌洗液(BAL)及經重新刺激之引流淋巴結細胞培養中測量後者。
與活LGG以及LGG上清液二者接觸時發現可減少呼吸道炎症和杯狀細胞增生。肺組織切片之組織學染色(見第4圖)顯示出OVA過敏動物體內炎症細胞浸潤增加且杯狀細胞增生,而經LGG或LGG上清液治療之動物顯示出幾乎正常之肺結構和組織學。第4圖中“陰性對照組”係指:未經歷挑戰,亦未接受LGG或LGG上清液;“陽性對照”係指:經歷OVA挑戰,但未接受LGG或LGG上清液;“活LGG”係指:經歷挑戰且接受活LGG;“LGG上清液”係指:經歷挑戰並接受本發明之LGG上清液治療。
此外,測定發生炎症細胞浸潤(嗜酸性粒細胞)。第5圖顯示以活LGG或LGG上清液治療可大大減輕OVA過敏性動物肺部之嗜酸性粒細胞浸潤增加情況。第5圖中,縱軸代表過敏性細胞增加之比例。橫軸上呈現以下樣本:“陰性對照”:無OVA挑戰;未治療;“陽性對照”:OVA挑戰;未治療;“全LGG”:OVA挑戰後再以活LGG治療;“LGG上清液”:OVA挑戰後再以本發明之LGG上清液治療。
本實例反映自淋巴結分離細胞之體外培養的測定方法(以已知方式進行)。來自OVA過敏性小鼠之經重新刺激的淋巴結細胞培養中的典型Th2細胞因子變化形廓顯示出增加之IL-5和低IL-10及IFN-γ反應。由這些培養中IL-5反應減少和強IFN-γ刺激,以及IL-10之製造揭露出以全(活)LGG或本發明之LGG上清液治療可顯現抗過敏作用。此點描繪於第6圖中。
此實例陳述在Balb/C小鼠之卵白蛋白(OVA)過敏模型中於圍產期投服本發明之LGG培養上清液。令孕婦和哺乳期的母鼠接受隔天經胃內投服LGG上清液。以OVA將其後代敏感化並進行挑戰。第7圖中說明此測試之計劃。
藉由肺功能分析、組織學和支氣管肺泡灌洗(BAL)評估實驗性支氣管氣喘的參數。藉由抗體量和細胞因子反應來評估全身過敏性反應。後者同時在BAL及引流淋巴結培養中測量。第8圖指出該結果(可從圖形本身清楚明白)揭露以LGG上清液治療之動物的炎症細胞(嗜酸性粒細胞、巨噬細胞)浸潤減少。
第1圖顯示代表LGG群在培養時隨著時間推移而增加的圖形;此處,第1a圖藉由參考培養基之光密度(OD600值)以及pH值之變化來描述此圖形,第1b圖呈現藉由平皿接種技術測定之細菌數量。
第2圖顯示不同階段(MJ1、MJ2、MJ3)之LGG培養收穫物的細胞因子IL-10的產量;
第3圖描繪活體內卵白蛋白(OVA)敏感化之時間進程;測試本發明組成物的模型;
第4圖描繪OVA模型中,以包含活LGG和LGG上清液的不同組成物口服治療的小鼠之染色的肺組織之顯微鏡圖像;
第5圖顯示出代表OVA過敏性動物肺部中之過敏性細胞浸潤的圖表;
第6圖(a-c)顯示代表三種與過敏性疾病中發炎過程有關之不同細胞因子的體外反應之圖表;
第7圖代表活體內調查在圍產期投服本發明之LGG培養上清液的計劃;
第8圖顯示在圍產期投服本發明之LGG培養上清液時過敏性反應之結果。
Claims (10)
- 一種包含分子量高於6kDa之成分的蛋白質混合物於製備用於治療或預防過敏性疾病之非存活益生菌物質之用途,其特徵在於:自於中性pH和生理溫度下且於包含油成分但缺少Tween 80之培養基中進行之鼠李糖乳桿菌(Lactobacillus rhamnosus)GG(LGG)批式培養法之指數生長期的後段0.75至0.85期間之培養上清液獲得該蛋白質混合物,且該蛋白質混合物能有效刺激巨噬細胞產製IL-10。
- 如申請專利範圍第1項之用途,其中該油成分選自:油酸、亞麻籽油、橄欖油、油菜籽油、葵花油及彼等之混合物。
- 如申請專利範圍第1項之用途,其中該中性pH為pH 6且該生理溫度為37℃。
- 如申請專利範圍第1項之用途,其中該蛋白質混合物係經噴霧乾燥或冷凍乾燥。
- 如申請專利範圍第1項之用途,其中該益生菌物質進一步包含麥芽糊精DE29。
- 如申請專利範圍第1或2項之用途,其中該益生菌物質係用於製備營養產品。
- 如申請專利範圍第6項之用途,其中該營養產品進一步包含一或多種多不飽和脂肪酸(PUFA)。
- 如申請專利範圍第6項之用途,其中該營養產品進一步包含一或多種通常存在於人母乳中之生物活性成 分。
- 如申請專利範圍第6項之用途,其中該營養產品進一步包含一或多種益菌生(prebiotics),該益菌生係選自如下群體:不易消化之寡糖類、不易消化之多糖類及彼等之混合物。
- 如申請專利範圍第6項之用途,其中該營養產品為一種產前、嬰兒或兒童配方或營養組成物、醫療食品或用於特定醫療目的之食物。
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US20100233312A9 (en) * | 2005-04-11 | 2010-09-16 | The Procter & Gamble Company | Compositions comprising probiotic and sweetener components |
US20060233772A1 (en) * | 2005-04-15 | 2006-10-19 | Udo Herz | Method for preventing or treating the development of respiratory allergies |
US7303745B2 (en) * | 2005-04-15 | 2007-12-04 | Bristol-Myers Squibb Company | Method for preventing or treating the development of respiratory allergies |
WO2008052035A1 (en) * | 2006-10-24 | 2008-05-02 | Vanderbilt University | Compositions and methods for the treatment of disorders involving epithelial cell apoptosis |
WO2009137159A2 (en) * | 2008-04-17 | 2009-11-12 | Trustees Of Dartmouth College | Bioactive molecules produced by probiotic bacteria and methods for isolating and using the same |
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2009
- 2009-09-11 EP EP09170124A patent/EP2295535A1/en not_active Ceased
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2010
- 2010-09-10 AU AU2010293145A patent/AU2010293145B2/en not_active Ceased
- 2010-09-10 RU RU2012114190/10A patent/RU2012114190A/ru not_active Application Discontinuation
- 2010-09-10 PL PL10757324T patent/PL2475764T3/pl unknown
- 2010-09-10 CA CA2772593A patent/CA2772593C/en not_active Expired - Fee Related
- 2010-09-10 CN CN201080040659XA patent/CN102575224A/zh active Pending
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- 2010-09-10 BR BR112012005533A patent/BR112012005533A2/pt not_active Application Discontinuation
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- 2010-09-10 WO PCT/NL2010/050576 patent/WO2011031149A1/en active Application Filing
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Also Published As
Publication number | Publication date |
---|---|
CA2772593C (en) | 2018-11-27 |
KR20120061836A (ko) | 2012-06-13 |
PL2475764T3 (pl) | 2017-06-30 |
EP2295535A1 (en) | 2011-03-16 |
BR112012005533A2 (pt) | 2016-04-26 |
RU2012114190A (ru) | 2013-10-20 |
US20110217402A1 (en) | 2011-09-08 |
IN2012DN00951A (zh) | 2015-04-10 |
PE20121557A1 (es) | 2012-11-21 |
AU2010293145A1 (en) | 2012-03-08 |
MX2012002716A (es) | 2012-04-19 |
CA2772593A1 (en) | 2011-03-17 |
CN102575224A (zh) | 2012-07-11 |
WO2011031149A1 (en) | 2011-03-17 |
EP2475764B1 (en) | 2016-12-14 |
MX345077B (es) | 2017-01-16 |
JP2013504321A (ja) | 2013-02-07 |
NZ597818A (en) | 2014-01-31 |
MY160646A (en) | 2017-03-15 |
ES2614929T3 (es) | 2017-06-02 |
ECSP12011786A (es) | 2012-07-31 |
EP2475764A1 (en) | 2012-07-18 |
AU2010293145B2 (en) | 2016-04-14 |
SG178230A1 (en) | 2012-03-29 |
TW201124529A (en) | 2011-07-16 |
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