CN102076361A - 益生菌、分泌型免疫球蛋白a和感染 - Google Patents
益生菌、分泌型免疫球蛋白a和感染 Download PDFInfo
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Abstract
本发明大体上涉及营养、健康和身心健康领域。具体来说,本发明涉及益生菌和增加其有效性的途径。本发明的一个实施方案涉及益生菌和分泌型IgA的组合以及此组合的可能用途。例如公开了包含分泌型SIgA和至少一种益生菌的组合物在制备用于治疗或预防感染的产品中的用途。
Description
本发明大体上涉及营养、健康(health)和身心健康(wellness)领域。具体来说,本发明涉及益生菌和增加其有效性的途径。本发明的一个实施方案涉及益生菌和分泌型免疫球蛋白A(IgA)的组合以及此组合的可能用途。
感染是外来物种在宿主生物中进行的有害建群。通常,感染生物试图用宿主的资源促进其自身增殖。由此感染生物(或称病原体)可以干扰宿主的正常功能,并导致更多感染相关的疾病,所述疾病可能具有不同的严重性,最严重的情况可以导致死亡。
如果感染生物和宿主之间存在协同作用,其中此关系对于感染生物是有利的,对后者则是有害的,则表征为寄生现象。
与感染相关联的疾病种类繁多,与治疗和预防感染相关的花费也很可观。
仅美国的抗菌剂市场就拥有约260亿美元。
如今可通过合适的药物治疗不需要的感染。然而,选择适当的药物需要定义待处理的感染类型。细菌感染通常使用抗菌抗生素治疗。误服错误的抗菌抗生素治疗特定的非病毒感染不但不能治疗感染,甚至可能是有害的。此外,此类药物通常可能导致不需要的副作用,并且经常需要医务人员的监督。
此外,广泛使用抗生素可能致使产生具有抗生素抗性的传染物种。福布斯杂志在2006年6月声称被药物抗性的感染杀死的美国人比AIDS和乳腺癌加起来还要多。
因此,研发能够降低社会对抗生素的需求的组合物是当今的研究重点。
因此,在本领域需要这样的非抗生素组合物,即可以不具副作用,优选每日施用,并可安全地用于治疗或预防感染,而无需事先定义致病因子的准确性质。
达到此目的的一种途径是施用包含益生菌的食物组合物。
已经知道益生菌微生物对宿主的健康和身心健康具有有益作用。在近几十年中,作为治疗例如胃肠疾病(Isolauri E,等人,Dig Dis Sci1994,39:2595-2600)的安全和易得形式,益生细菌的用途已经得到相当的关注。在此方面应用的典型益生细菌属于乳杆菌属(Lactobacillus)或双歧杆菌属(Bifidobacterium)。
益生菌的有效性部分取决于其抵抗消化道条件和粘附于肠上皮的能力。并且,决定其对宿主潜在益处的关键方面是益生菌和宿主环境的对话(cross-talk)和其对上皮屏障及其功能的影响。
尽管在胃肠道建群方面,一些益生菌已经取得了非常不错的结果,仍然期望获得一种工具以进一步改进益生菌微生物在肠中定居的有效性。
因此本发明的目的是为本领域提供一种组合物,所述组合物具有与对需要的受试者施用益生菌相同的益处,但是在治疗或预防感染方面比单独使用益生菌更有效。
本发明者已论述了此需要,并发现他们可以通过根据权利要求1的用途和根据权利要求13的食物组合物达到此目的。
因此本发明涉及包含抗体,特别是分泌型IgA和至少一种益生菌的组合物,并涉及其治疗、调节、减弱和/或预防感染的用途。
抗体通常为糖蛋白,其特异性识别抗原。已描述的5类脊椎动物免疫球蛋白类别(包括IgG、IgM、IgA、IgD和IgE)中,其在免疫系统中的功能均有不同。分泌型IgA(SIgA)是肠粘膜分泌物中占主要且较稳定的免疫球蛋白,对本发明的目的特别有效。
不希望受理论限制,发明者相信SIgA和益生菌可形成复合物以增强益生菌和宿主的相互作用及改进其健康益处。
所述组合和宿主肠粘膜的可能的相互作用机制展示于图1。
益生菌和宿主的首次相互作用发生在肠粘膜的水平。选择益生菌微生物的关键标准之一是其粘附于肠粘膜的能力。
此粘附似乎是阻断病原体进入所需要的,并且在例如调节保护性免疫功能中起作用。
在大多数哺乳动物中粘膜免疫系统最独特的特征之一是分泌型抗体的优势存在,特别是分泌型IgA(SIgA),其是粘膜中独有的抗体种类。
多聚IgA的生物合成在粘膜固有层中进行,通过隐窝和柱状上皮细胞表达的多聚Ig受体(pIgR)保证其穿过排列在粘膜表面的上皮的运输。
在分泌过程中,pIgR的大部分(称作分泌成分(SC))保持与多聚IgA的结合,同时释放SIgA。
SIgA至腔的释放取决于SC的产生,SC的表达在出生后上调。pIgR似乎在抗体的稳定性和粘膜锚定中起关键作用(Phalipon等人(2002)Secretory component:A new role in secretory IgA-mediatedimmune exclusion in vivo.Immunity 17:107-115)。
几乎检测不到SIgA抗体的新生儿依赖经胎盘转移的母体IgG和在母乳中充足的外源供应的SIgA。
这共同提供了在胃肠免疫系统成形和成熟期对保护宿主至关重要的肠中的被动免疫。
因此本发明的组合物对新生儿和婴儿(最大至2岁)特别有益,因为他们不产生足够量的SIgA而依赖于外部供应。
发明者现在相信正是SIgA和益生菌的关联增强了益生菌和宿主的相互作用,从而改善宿主的健康益处。
本发明者发现SIgA抗体能够与共生细菌菌株结合。
本发明者在体外使用了Caco-1上皮细胞单层以研究SIgA是如何利于非病原细菌和上皮表面的对话。作为原则证明,评估了2种主要菌种乳杆菌和双歧杆菌的2种益生菌代表菌株,即鼠李糖乳杆菌(Lactobacillusrhamnosus)NCC4007(LPR)和乳双歧杆菌(Bifidobacterium lactis)NCC2818(BL818)。
发现SIgA和/或SC当与益生菌结合时,促进益生菌和宿主的相互作用并调节涉及防御机制的下游过程。
这在增强益生菌的健康益处中起作用。通过与益生菌组合,SIgA和/或SC能够最佳的帮助触发有效的保护性宿主防御反应,包括对抗各种病原体的反应。考虑到其体内稳态作用,与益生菌组合的SIgA可帮助触发对抗感染的免疫加强作用,同时预防任何潜在的损害性炎症过程。
因此,本发明的一个实施方案是包含SIgA和至少一种益生菌的组合物,用于制备治疗或预防非病毒性感染的产品。
本发明还涉及包含SIgA和至少一种益生菌的组合物在制备用于治疗或预防非病毒性感染的产品中的用途。
本发明另外涉及包含SIgA和至少一种益生菌的组合物,用于治疗和/或预防非病毒性感染。
本发明扩展至包含SIgA和至少一种益生菌的组合物,用于治疗和/或预防非病毒性感染。
非病毒性感染的治疗包括非病毒性感染的减弱。
“益生菌”是指对宿主健康或身心健康具有益作用的微生物细胞制备物或微生物细胞组分。(Salminen S,Ouwehand A.Benno Y.等人“Probiotics:how should they be defined”Trends Food Sci.Technol.1999:10 107-10)。
根据本发明可使用所有益生菌微生物。优选的,它们可选自双歧杆菌属(Bifidobacterium)、乳杆菌属(Lactobacillus)、链球菌属(Streptococcus)和酵母属(Saccharomyces)或其混合物,特别选自长双歧杆菌(Bifidobacterium longum)、乳双歧杆菌(Bifidobacteriumlactis)、嗜酸乳杆菌(Lactobacillus acidophilus)、鼠李糖乳杆菌(Lactobacillus rhamnosus)、副干酪乳杆菌(Lactobacillus paracasei)、约氏乳杆菌(Lactobacillus johnsonii)、胚芽乳杆菌(Lactobacillusplantarum)、唾液乳杆菌(Lactobacillus salivarius)、屎肠球菌(Enterococcus faecium)、布拉酵母(Saccharomyces boulardii)和罗伊乳杆菌(Lactobacillus reuteri)或其混合物,优选的选自约氏乳杆菌(NCC533;CNCM I-1225)、长双歧杆菌(NCC490;CNCM I-2170)、长双歧杆菌(NCC2705;CNCM I-2618)、乳双歧杆菌(2818;CNCM I-3446)、副干酪乳杆菌(NCC2461;CNCM I-2116)、鼠李糖乳杆菌GG(ATCC53103)、鼠李糖乳杆菌(NCC4007;CGMCC 1.3724)、屎肠球菌SF 68(NCIMB101415),和其混合物。
本发明的组合物还可包含益生素。益生素的添加是有益的,因为当与益生菌组合时其可发挥在健康益处方面的协同作用。包含益生素和益生菌组合的组合物一般被称为共生组合物。
“益生素”是指在肠中促进益生菌生长的食物成分。它们不在消化其的人胃中和/或肠的上部被分解或在胃肠道中被吸收,但被胃肠微生物群和/或益生菌发酵。益生素例如定义于Glenn R.Gibson和Marcel B.Roberfroid,Dietary Modulation of the Human Colonic Microbiota:Introducing the Concept of Prebiotics,J.Nutr.1995125:1401-1412。
根据本发明可使用的益生素没有特别限制,包括所有在肠中促进有益细菌例如双歧杆菌或乳杆菌,和/或益生菌生长的食物成分。优选的,它们可选自寡糖,任选的包含果糖、半乳糖、甘露糖;膳食纤维,特别是可溶纤维、大豆纤维;菊粉;或其混合物。优选的益生素为寡聚果糖(FOS)、寡聚半乳糖(galacto-oligosaccharides,GOS)、寡聚异麦芽糖、寡聚木糖、大豆寡糖、糖基蔗糖(GS)、乳蔗糖(LS)、乳果糖(LA)、寡聚异麦芽酮糖(PAO)、寡聚麦芽糖、果胶和/或其水解产物。
本发明的非病毒性感染可以是细菌和/或寄生虫感染。也可是真菌感染。
非病毒性感染可以是细菌感染,选自大肠杆菌感染、霍乱弧菌(Vibriocholerae)感染、沙门氏菌感染、梭状芽胞杆菌感染、志贺菌属感染、寄生虫感染,包括兰伯贾第虫(Giardia lamblia)、溶组织内阿米巴(Entamoeba histolytica)和隐孢子虫属(Cryptosporidium spp)或其混合物。
可用本发明治疗或预防的典型细菌感染性疾病包括沙门氏菌病、细菌性痢疾、伤寒、细菌性脑膜炎、炭疽、食物中毒、普鲁斯病、弯曲菌病、猫抓病、霍乱、白喉、流行性斑疹伤寒、淋病、小脓疱疹、军团杆菌病、麻疯病(Hansen病)、细螺旋体病、利斯特菌病、莱姆病、类鼻疽、风湿热、MRSA感染、诺卡菌病、百日咳、瘟疫、肺炎球菌性肺炎、鹦鹉病、Q热、洛矶山斑疹热(RMSF)、猩红热、梅毒、伤风、沙眼、肺结核、土拉菌病、斑疹伤寒症、和/或尿道感染。
可用本发明治疗或预防的典型寄生虫传染性疾病包括非洲锥虫病、变形虫病、蛔虫病、巴贝西虫病、美洲锥虫病、华支睾吸虫病、隐孢子虫病、囊虫病、裂头绦虫病、龙线虫病、包虫病、蛲虫病、片形吸虫病、姜片虫病、丝虫病、自由生活阿米巴感染、贾第鞭毛虫病、腭口线虫病、膜壳绦虫病、等孢球虫病、黑热病、利什曼病、疟疾、后殖吸虫病、蝇蛆病、盘尾丝虫病、虱咬症、蛲虫感染、疥疮、血吸虫病、绦虫病、弓蛔虫病、弓形体病、旋毛虫病、旋毛虫病、鞭虫病、滴虫病、和/或锥虫病。
可用本发明治疗或预防的典型真菌感染性疾病包括曲霉菌病、芽生菌病、念珠菌病、球孢子菌病、隐球菌病、组织胞浆菌病、和/或脚癣。
使用本发明制备的产品可为食物产品、动物食物产品或药物组合物。例如,所述产品可为营养组合物、营养食品、饮料、食物添加剂或药物。
食物添加剂或药物可为例如片剂、胶囊、锭剂或液体形式。食物添加剂或药物优选以持续释放制剂提供,使SIgA和益生菌的持续供应维持更长的时间。
产品优选的选自基于奶粉的产品、方便饮料、可立即饮用的制剂、营养粉、营养液、基于奶的产品特别是酸乳酪或冰激凌、谷物产品、饮料、水、咖啡、热牛奶咖啡(cappucc ino)、麦芽饮料(malt drink)、巧克力口味饮料、烹饪产品、汤、片剂和/或糖浆。
奶可为任意可从动物或植物来源得到的奶,优选的为牛奶、人奶、绵羊奶、山羊奶、马奶、骆驼奶、米乳(rice milk)或豆奶。
除了奶以外,可使用来源于奶的蛋白质部分或初乳。
组合物可进一步包含保护性水状胶质(例如树胶、蛋白质、变性淀粉)、粘合物、成膜剂、成胶囊剂/材料、囊/外壳材料、基质化合物、涂料、乳化剂、表面活性剂、加溶剂(油、脂肪、蜡、卵磷脂等等)、吸附剂、载体、填料、共化合物(co-compound)、分散剂、湿润剂、加工助剂(溶剂)、流动剂、掩味剂、增重剂、胶凝剂(jellifying agents)、胶凝剂(gel formingagents)、抗氧化剂和抗菌剂。其还可包含传统药物添加剂和佐剂、赋形剂和稀释剂,包括但不局限于水、任意来源的明胶、植物胶、木素磺酸盐、滑石、糖、淀粉、阿拉伯树胶、植物油、聚亚烷基二醇、调味剂、防腐剂、稳定剂、乳化剂、缓冲液、润滑剂、着色剂、湿润剂、填料,等等。此外,其可包含适于口或肠施用的有机或无机载体材料及维生素、微量矿物质元素和符合政府机关推荐的例如美国推荐的日摄食量(USRDA)的其他微量营养素。
本发明的组合物可包含蛋白质来源、碳水化合物来源和/或脂来源。
可使用任意合适的膳食蛋白质,例如动物性蛋白质(例如奶蛋白、肉蛋白和卵蛋白);植物性蛋白质(例如大豆蛋白、小麦蛋白、大米蛋白和豌豆蛋白);游离氨基酸的混合物;或其组合。奶蛋白例如酪蛋白和乳清和大豆蛋白是特别优选的。
如果组合物包括脂肪来源,则脂肪来源更优选提供配方5%至40%的能量;例如20%至30%的能量。可添加DHA。可使用芥籽(canola)油、玉米油和高油酸向日葵油混合物得到合适的脂肪谱。
碳水化合物来源可更优选的提供组合物的40%至80%能量。可使用任意合适的碳水化合物,例如蔗糖、乳糖、葡萄糖、果糖、固体玉米糖浆、麦芽糊精和其混合物。
由本发明制备的产品可对人或动物施用,特别是伴侣动物、宠物或家畜。其对任何年龄群体均具有有益作用。优选的,产品计划供婴儿、青少年、成人或老年人使用。然而也可对怀孕期和哺乳期的母亲施用以治疗婴儿。
当益生菌和SIgA同时、一种紧接另一种施用时,在最大时间范围少于60分钟、优选的少于30分钟、更优选的少于15分钟和最优选的少于5分钟时,和/或二者在施用前已组合存在于食物产品中时,本发明的组合物有效。
然而,发现如果SIgA和益生菌在施用前组合为复合物,益生菌和SIgA的组合特别有效。其优势在于有益的复合物不需要在消耗产品后组成,而是已经存在于食物产品中。
因此,本发明的一个实施方案涉及包含SIgA和益生菌的组合物的用途,其中SIgA分子和至少一种益生菌在组合物中至少部分结合。
SIgA和至少一种益生菌优选的作为免疫复合物存在,例如至少90%、更优选的至少95%、甚至更优选的所有益生细菌均结合至少1个SIgA分子,例如至少5个SIgA分子以免疫复合物存在。
组合物还可包含至少另一种其他食品级细菌,优选的选自乳酸细菌、双歧杆菌、肠球菌或其组合。这些其他食品级细菌可利于得到健康的肠微生物群,因此利于更有效的实现本发明的目的。
本发明还涉及包含SIgA和至少一种益生菌微生物的食物组合物。SIgA和益生菌微生物可优选的在食物组合物中作为复合物组合。SIgA和益生菌微生物可优选的以至少10∶1、优选的至少100∶1、最优选的至少2000∶1至100000∶1的化学计量比率存在。SIgA饱和的上限由益生菌微生物的表面和可结合SIgA的结合位点数决定。
一般的,益生菌在大范围的量内有效。如果细菌活着到达肠,则单个细菌就足以通过在肠中延续并增殖达到有力的效果。然而一般而言,如果产品包含每日剂量102和1010之间的细胞益生菌则是优选的。
发挥作用所需要的SIgA量同样没有局限。原则上一个SIgA分子与一个益生菌微生物结合,优选以复合物形式,即对于本发明而言有效。然而一般而言,如果产品包含0.0001mg SIgA和10mg SIgA之间的每日剂量则是优选的。
本领域技术人员将理解在不背离公开的发明范围内,他们可自由组合此处描述的本发明的所有特征。具体来说,描述本发明用途的特征将应用于本发明的组合物,例如食物组合物,反之亦然。
通过以下实施例和图,本发明的其他优势和特征是显而易见的。
图1图解显示了SIgA是如何被认为改进共生细菌的作用的,当SIgA与其结合时增加了与宿主肠粘膜的相互作用。
图2显示了代表2种主要菌种乳杆菌和双歧杆菌的2种益生菌菌株鼠李糖乳杆菌NCC4007(LPR)和乳双歧杆菌NCC2818(BL818)与上皮细胞的结合性能的检测实验结果。数据以每100个Caco-2细胞的菌落形成单位(CFU)平均值±标准误(SEM)表示。
图3显示了代表2种主要菌种乳杆菌和双歧杆菌的2种益生菌菌株鼠李糖乳杆菌NCC4007(LPR)和乳双歧杆菌NCC2818(BL818)与上皮细胞的结合性能以及分泌型IgA(SIgA)或分泌成分(SC)的影响的检测实验结果。数据以每100个Caco-2细胞的CFU平均值±SEM表示。
图4显示了代表2种主要菌种乳杆菌和双歧杆菌的2种益生菌菌株鼠李糖乳杆菌NCC4007(LPR)和乳双歧杆菌NCC2818(BL818),单独或与SIgA或SC组合,对测量上皮渗透性的跨上皮电阻(TER)的影响的检测实验结果。数据以每平方厘米的欧姆平均值±SEM表示。
图5显示了LPR,与SIgA或SC组合或未组合,在Caco-2细胞单层中对NF-κB活化的影响的检测实验结果。NF-κB结合活性的降低指示Caco-2细胞内减弱的炎症途径。
图6显示了LPR,与SIgA或SC组合或未组合,对Caco-2细胞的福氏志贺菌(S.flexneri)入侵的影响的检测实验结果。使用了2种单克隆SIgA分子:识别沙门氏菌属表位的非特异性SIgA(SIgAnon特异性)和特异性抗福氏志贺菌SIgAC5。数据以每Transwell滤膜的CFU平均值±SEM表示。
图7显示了益生菌对Caco-2单层中多聚Ig受体(pIgR)表达的影响的检测实验结果。(A)在16小时检测不同的处理,包括益生菌和非特异性SIgA的组合,及福氏志贺菌和特异性抗福氏志贺菌SIgA的组合。用蛋白质印迹检测pIgR的存在,如同β-肌动蛋白。(B)pIgR表达水平的半定量分析,用β-肌动蛋白标准化,通过对A中凝胶鉴定条带的密度计分析。(C)与各种制剂孵育24小时的Caco-2细胞中的pIgR表达的动力学(酶联免疫吸附法(ELISA))。
实施例1:
与上皮细胞的结合
每平方厘米Transwell滤膜上接种约106Caco-2细胞。细胞和不同剂量的细菌(如图注中所示)在无抗生素或FCS下于37℃孵育16小时。使用LPR、BL818和大肠杆菌(E.coli)TG-1细菌的新鲜过夜培养物。之后在计数前清洗细胞。通过在MRS或LB平板上涂板计数结合的细菌。每个实验进行3次重复检测。数据以每100个Caco-2细胞结合的细菌的平均值±SEM表示。每个实验进行3次重复检测。在随后的实验中,在存在递增浓度的SIgA或SC下(如图3的图注中所示),细胞和2x107细菌于37℃孵育16小时。之后在计数前清洗细胞。通过在MRS或LB平板上涂板计数结合的细菌。每个实验进行3次重复检测。数据以每100个Caco-2细胞结合的细菌的平均值±SEM表示。每个实验进行3次重复检测。
与大肠杆菌TG-1相比,观察到LPR或BL818对极化Caco-2细胞的优先结合。益生菌对肠上皮细胞具有剂量依赖性的结合能力。可以观察到结合性能在2种菌株之间存在差异。
在随后的实验中使用2x107CFU的益生菌,因为此剂量一方面不会引起培养基的任何pH改变,另一方面显示了有效的结合比率。
提高单克隆SIgA的剂量促进了LPR和BL818二者结合极化Caco-2细胞单层的能力。与细菌结合时,分泌成分未展示这些性能(图3)。在随后的实验中选择1μg剂量的SIgA,此剂量可显著改进益生菌的结合能力。此剂量致使形成由约50’000至100’000单位SIgA对应1个细菌组成的最终复合物。
结果显示于图2和3。
实施例2:
极化Caco-2细胞单层的屏障功能
每平方厘米Transwell滤膜上接种约106Caco-2细胞。细胞和2x107CFU细菌在不存在抗生素或FCS下于37℃孵育24小时。检测单独的细菌,或与图4的图注中指示浓度的SIgA或SC组合的细菌。在3、6、9、15和24小时测量跨上皮电阻(TER)。对照包括和SIgA和SC单独的孵育。每个实验进行3次重复检测。
极化Caco-2细胞单层和LPR或BL818的单独孵育导致跨上皮电阻(TER)的20-25%的增加,提示益生菌增强了上皮的屏障功能。当细菌和SIgA或SC组合时仍然如此(图4)。SIgA或SC本身不引起任何TER变化。
结果显示于图4。
实施例3:
极化Caco-2细胞单层中的NF-kB活化
每平方厘米Tran8well滤膜上接种约106Caco-2细胞。细胞和2x107CFU LPR在不存在抗生素或FCS下于37℃孵育16小时。检测单独的细菌,或与图5的图注中指示浓度的SIgA或SC组合的细菌。使用福氏志贺菌、伤寒沙门菌(S.Typhi)和幽门螺杆菌(H.Pylori)(2x107CFU)在对照实验中作为前炎性病原体。制备细胞核提取物并进行电泳迁移位移分析(EMSA)以检测NF-κB与特异性DNA探针的结合。平行获得细胞质提取物,用蛋白质印迹检测IKBα的存在,使用针对该蛋白的抗IKBα特异性单克隆抗体。
与非病原菌相比,极化的Caco-2细胞单层暴露于病原菌导致明显更显著的细胞核NF-κB活化(图5)。
IκBα(下图)的消失表示导致NF-κB核转运的途径活化。因此,虽然单独的LPR对NF-κB活化具有轻微作用,LPR和SIgA或SC的组合降低了Caco-2细胞中的NF-κB活化(未检测BL818)。与预期中相同,上皮细胞和致病福氏志贺菌的孵育导致IκBα表达的完全消失。
结果显示于图5。
实施例4:
抗致病活性
每平方厘米Transwell滤膜上接种约106Caco-2细胞。细胞和2x107CFU LPR在不存在抗生素或FCS下于37℃孵育16小时。检测单独的LPR,或与0.2μg SC、1μg多克隆SIgA或1μg特异性抗福氏志贺菌LPS的SIgAC5组合的LPR。与LPR孵育后清洗细胞,之后与107福氏志贺菌孵育6小时,再次清洗细胞并与50mg/ml庆大霉素孵育45分钟。最后,裂解细胞并在LB琼脂平板上计数细胞内的福氏志贺菌。每个实验进行3次重复检测。
LPR的加入以剂量依赖的方式降低了福氏志贺菌对极化Caco-2细胞单层的感染。与SIgA组合后此作用大大增强了。当使用福氏志贺菌LPS特异性SIgAC5抗体时可得到对感染的完全保护(图6)。
结果显示于图6。
实施例5:
极化Caco-2细胞单层中的多聚Ig受体的表达
每平方厘米Transwell滤膜上接种约106Caco-2细胞。细胞和2x107CFU LPR或BL818在不存在抗生素或FCS下于37℃孵育16小时。检测单独的益生菌,或与0.2μg SC或1μg多克隆SIgA组合的益生菌。检测单独的对照福氏志贺菌,或与1μg特异性抗福氏志贺菌LPS的SIgAC5组合的对照福氏志贺菌。清洗后,从Transwell滤膜上直接收获Caco-2细胞并裂解。去除细胞核,通过蛋白质印迹分析细胞碎片和细胞质,使用抗pIgR抗体和人SC和β-肌动蛋白的抗血清作为对照。每个实验进行3次重复检测。
在随后的实验中,按照相同的程序孵育细胞,之后在孵育8、16和24小时后从transwell滤膜上收获细胞。通过ELISA在细胞碎片/细胞质组分中进行pIgR的定量分析。通过BCA蛋白质法测定总蛋白质。用蛋白质含量标准化数值,数据以ng pIgR/mg总蛋白的平均值±SEM表示。
pIgR在上皮细胞中的表达用β-肌动蛋白的表达标准化。蛋白质印迹(上图)和对各个(条带)信号的密度计分析(下图)显示,与单独益生菌相比,过夜暴露于LPR或BL818和SIgA或SC组合的极化Caco-2细胞单层中的pIgR水平增加(图7a)。特异性抗福氏志贺菌LPS的SIgAC5阻止了病原菌和Caco-2细胞极化单层的相互作用,因此解释了与福氏志贺菌单独处理相比pIgR表达的降低。
结果进一步显示了在极化Caco-2细胞单层暴露于益生菌和SIgA或SC的组合后,多聚Ig受体(pIgR)水平的时间依赖性增加(图7b)。
结果显示于图7。
Claims (14)
1.包含分泌型IgA和至少一种益生菌的组合物在制备用于治疗、减弱或预防非病毒性感染的产品中的用途。
2.根据权利要求1的用途,其中非病毒性感染为细菌感染、寄生虫感染或真菌感染。
3.根据前述权利要求之一的用途,其中非病毒性感染为细菌感染,选自大肠杆菌感染、霍乱弧菌(Vibrio cholerae)感染、沙门氏菌感染、梭状芽胞杆菌感染、志贺菌属感染,寄生虫感染,包括兰伯贾第虫(Giardialamblia)、溶组织内阿米巴(Entamoeba histolytica)和隐孢子虫属(Cryptosporidium spp)或其混合物。
4.根据前述权利要求之一的用途,其中益生菌选自双歧杆菌属(Bifidobacterium)、乳杆菌属(Lactobacillus)、链球菌属(Streptococcus)和酵母属(Saccharomyces)或其混合物,特别选自长双歧杆菌(Bifidobacterium longum)、乳双歧杆菌(Bifidobacteriumlactis)、嗜酸乳杆菌(Lactobacillus acidophilus)、鼠李糖乳杆菌(Lactobacillus rhamnosus)、副干酪乳杆菌(Lactobacillus paracasei)、约氏乳杆菌(Lactobacillus johnsonii)、胚芽乳杆菌(Lactobacillusplantarum)、唾液乳杆菌(Lactobacillus salivarius)、屎肠球菌(Enterococcus faecium)、布拉酵母(Saccharomyces boulardii)和罗伊乳杆菌(Lactobacillus reuteri)或其混合物,优选的选自约氏乳杆菌(NCC533;CNCM I-1225)、长双歧杆菌(NCC490;CNCM I-2170)、长双歧杆菌(NCC2705;CNCM I-2618)、乳双歧杆菌(2818;CNCM I-3446)、副干酪乳杆菌(NCC2461;CNCM I-2116)、鼠李糖乳杆菌GG(ATCC53103)、鼠李糖乳杆菌(NCC4007;CGMCC 1.3724)、屎肠球菌SF 68(NCIMB101415),和其混合物。
5.根据前述权利要求之一的用途,其中产品为食物产品或药物组合物。
6.根据前述权利要求之一的用途,其中产品计划供人,特别是婴儿、青少年、成人或老年人消耗。
7.根据前述权利要求之一的用途,其中分泌型IgA和至少一种益生菌在组合物中至少部分结合。
8.根据前述权利要求之一的用途,用于增强免疫功能。
9.根据前述权利要求之一的用途,其中组合物包含至少另一种其它食品级细菌,其优选的选自乳酸菌、双歧杆菌、肠球菌或其混合物。
10.根据前述权利要求之一的用途,其中产品还包含至少一种益生素,其优选的选自寡糖。
11.根据前述权利要求之一的用途,其中产品每日剂量包含102至1010个益生菌细胞。
12.根据前述权利要求之一的用途,其中产品每日剂量包含0.0001mg分泌型SIgA至10mg SIgA。
13.包含SIgA和至少一种益生菌微生物的食物组合物。
14.根据权利要求12的食物组合物,其中所述的至少一种益生菌微生物和SIgA相结合。
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Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104994910A (zh) * | 2013-01-04 | 2015-10-21 | 威斯康星校友研究基金会 | 分泌型IgA组合物、其制备方法和使用方法 |
CN104473292A (zh) * | 2014-12-22 | 2015-04-01 | 威海百合生物技术股份有限公司 | 一种婴幼儿益生菌固体饮料 |
CN110013490A (zh) * | 2018-01-09 | 2019-07-16 | 柯顺议 | 益生菌组合物及其用途 |
CN114502582A (zh) * | 2019-06-28 | 2022-05-13 | 雀巢产品有限公司 | 包含分泌型IgA和益生菌的组合物 |
WO2022180587A1 (zh) * | 2021-02-26 | 2022-09-01 | 丰华生物科技股份有限公司 | 提升口腔免疫球蛋白a含量及抑制病原菌的组合物及用途 |
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EP2700411A1 (en) | 2014-02-26 |
BRPI0914624B1 (pt) | 2021-11-09 |
JP2011525484A (ja) | 2011-09-22 |
PT2700411T (pt) | 2017-03-29 |
ES2477882T5 (es) | 2018-11-07 |
US20120014963A1 (en) | 2012-01-19 |
US9173937B2 (en) | 2015-11-03 |
ES2477882T3 (es) | 2014-07-18 |
EP2318047B1 (en) | 2014-05-14 |
PT2318047E (pt) | 2014-06-24 |
CN105816875A (zh) | 2016-08-03 |
EP2318047A1 (en) | 2011-05-11 |
US20170281757A1 (en) | 2017-10-05 |
EP2138187A1 (en) | 2009-12-30 |
WO2009156307A1 (en) | 2009-12-30 |
EP2318047B2 (en) | 2018-08-15 |
BRPI0914624A2 (pt) | 2015-10-20 |
CA2727303A1 (en) | 2009-12-30 |
AU2009264423A1 (en) | 2009-12-30 |
US9629908B2 (en) | 2017-04-25 |
EP2700411B1 (en) | 2016-12-28 |
US20160106834A1 (en) | 2016-04-21 |
ES2616334T3 (es) | 2017-06-12 |
PL2700411T3 (pl) | 2017-06-30 |
PL2318047T3 (pl) | 2014-10-31 |
AU2009264423B2 (en) | 2014-01-16 |
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