CN100502888C - 来自乳酸菌的脂磷壁酸及其调节革兰氏阴性菌、可能致病的革兰氏阳性菌介导的免疫应答的用途 - Google Patents
来自乳酸菌的脂磷壁酸及其调节革兰氏阴性菌、可能致病的革兰氏阳性菌介导的免疫应答的用途 Download PDFInfo
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Abstract
本发明涉及调节免疫应答的组合物,所述免疫应答由革兰氏阴性菌、可能致病的革兰氏阳性菌和/或它们的衍生物诱导,所述组合物包含来自乳酸菌的脂磷壁酸作为活性成分。本发明也涉及作为活性成分的来自乳酸菌的脂磷壁酸和/或产生它的乳酸菌和/或其培养物上清,在制备用于美容、皮肤或眼部应用的药物、口部或局部产品,用于在胃肠道、骨、皮肤、眼、耳、肺和口腔中调节细菌定殖、免疫应答、降低与细菌介导的疾病和感染有关的炎症过程的食品或宠物食品中的用途。本发明也涉及特定的脂磷壁酸。
Description
技术领域
本发明涉及调节免疫应答的组合物,所述免疫应答由革兰氏阴性菌、可能致病的革兰氏阳性菌和/或它们的衍生物诱导,所述组合物包含来自乳酸菌的脂磷壁酸作为活性成分。本发明也涉及作为活性成分的来自乳酸菌的脂磷壁酸和/或产生它的乳酸菌和/或其培养物上清,在制备用于美容、皮肤或眼部应用的药物、口部或局部产品,用于在胃肠道、骨、皮肤、眼、耳、肺和口腔中调节细菌定殖、免疫应答、降低与细菌介导的疾病和感染有关的炎症过程的食品或宠物食品中的用途。本发明也涉及特定的脂磷壁酸。
背景技术
在分娩时,先前无菌的胎肠被大量的微生物接种体定殖(colonisation)。在胃肠道的特定区域中建立起稳定的种群之前,肠微生物区(microflora)的建立在生命的第一天是非常活跃的过程。存在相继的定殖,首先是大肠杆菌和链球菌(Mata,L.J.和J.J.Urrutia,1971,Ann N Y Acad Sci 176:93-108),随后是bifidogenic微生物区,这在喂奶的婴儿中是非常明显的,提供了对潜在病原体的某些保护(Gibson,G.R.和X.Wang,1994,J Appl Bacteriol,77:412-420)。
乳酸菌(LAB)如乳杆菌和双歧杆菌是成人胃肠道的正常习居菌。这些菌属的特定菌株(称为益生菌(probiotics))在口服给宿主后对健康有益(Brassart,D.和E.J.Schiffrin,1997,Trends Food Sci Technol9:321-326)。如共生的LAB那样,益生菌拮抗病原生物体,并刺激免疫防御机制。虽然产生这些生物作用的准确机制很少为人所知,但广泛接受的是最有利于健康的菌株是那些可能通过细胞壁中的脂磷壁酸(LTA)而与肠上皮短暂粘附的菌株。
LTA是一种与疏水的脂部分连接的复合甘油-磷脂聚合物(Fischer,W.1990,细菌磷糖脂和脂磷壁酸,糖脂,磷糖脂和硫糖脂,M.Kates,编辑Hanahan,D.J.,纽约和伦敦,123-234)。它是大多数革兰氏阳性菌的细胞壁成分。虽然不同细菌的LTA差别很大,但它的结构与革兰氏阴性生物体的细胞壁中发现的LPS类似。
虽然革兰氏阴性菌的LPS以其对免疫细胞的前炎性效应为人们所知,但用革兰氏阳性生物体的LTA进行的工作很少。似乎只有特定细菌的LTA才具有这样的效应(Suda,Y.等,1995,FEMS ImmunolMed Microbiol 12:97-112;Arakaki,R.等,1998,FEMS Immunol MedMicrobiol 22:283-291)。
虽然革兰氏阳性菌的LTA随细菌菌株的不同而呈现极大的差异,它与革兰氏阴性生物体的细胞壁中存在的LPS有结构上的相似性。模式识别受体(Pattern Recognition Receptor,PRR)识别细菌结构的保守区和细菌接种体存在的宿主信号。CD14(一种骨髓细胞中存在的糖基磷脂酰肌醇(GPI)固着性糖蛋白)是一种这样的受体。现已知道它能结合LTA和LPS。实际上,由革兰氏阴性生物体引起的败血症是通过与单核细胞-巨噬细胞膜上的CD14结合的LPS产生的。越来越多的证据表明CD14受体的可溶形式介导LPS与CD14阴性细胞的结合。然而,该分子也识别其他细菌成分,例如肽聚糖、脂***甘露聚糖和manuronic酸聚合物(Dziarski,R.等,2000,Chem Immunol.74:83-107)。我们已报道了在用非致病性的大肠杆菌或其LPS攻击之后,人乳中存在的CD14的可溶形式(sCD14)刺激人肠上皮细胞(IECs)释放细胞因子(Labeta,M.O.等,2000,J Exp Med 191:1807-1812),但在用***或其细胞壁成分攻击之后不行。
本发明的目的是提供一种组合物,它能在人或动物的胃肠道、骨、皮肤、眼、肺、耳和口腔中调节与细菌定殖或感染有关的免疫应答、防止或减少由此产生的炎症反应。
发明概述
相应地,本发明的第一方面提供一种组合物,其含有来自乳酸菌的脂磷壁酸作为活性成分,用于调节由革兰氏阴性菌、可能致病的革兰氏阳性菌和/或它们的衍生物诱导的免疫应答。
含有来自乳酸菌的脂磷壁酸的组合物能够维持免疫内环境稳定,防止或降低由革兰氏阴性菌诱导的炎症过程和/或LPS介导的失调。它也可用于抗致病或可能致病的革兰氏阳性菌和/或LTA介导的失调。
实际上,已发现来自乳酸菌菌株(例如约氏乳杆菌La1菌株和嗜酸乳杆菌La10菌株)的LTA对用LPS或完整的大肠杆菌攻击的IECs的响应有拮抗作用,其中所述LPS纯化自大肠杆菌和肠炎沙门氏菌。此外,当来自两种乳杆菌菌株中任一种的LTA与LPS同时存在于人乳中时,LPS-sCD14介导的IL-8的产生被抑制。
所述组合物可以是药物、口部或局部美容用品、皮肤或眼部产品、食品或宠物食品组合物。它对胃肠道、骨、皮肤、眼、肺、耳和口腔中与细菌介导的疾病或LPS介导的失调有关的炎症过程有作用,可用于调节细菌在上述组织中定殖和免疫应答。
本发明的另一方面提供来自乳酸菌的脂磷壁酸。通过它们结合CD14的能力以及它们不能诱导从IECs中前炎性细胞因子(例如IL-8或TNF-α)的释放来筛选它们。
当口服时,本发明的脂磷壁酸不仅可在胃肠道中,而且也可在骨、皮肤、眼、耳、肺和口腔中维持免疫内环境稳定,调节细菌定殖,或定靶(target)细菌介导的疾病和感染或LTA/LPS介导的疾病。
相应地,本发明的另一方面提供至少一种来自乳酸菌的脂磷壁酸在制备用于调节由革兰氏阴性菌和/或它们的衍生物诱导的免疫应答的组合物中的用途。脂磷壁酸可用于制备用于在人或动物中降低与细菌介导的疾病或LTA/LPS介导的失调有关的炎症过程的药物、局部产品(例如乳膏或洗剂)、食品或宠物食品组合物。
本发明的另一方面提供在人或动物中调节上述应答的方法,其包括施用有效量的来自乳酸菌的脂磷壁酸或含有它的组合物。
另一方面,本发明提供在宠物动物中调节由革兰氏阴性细菌、可能致病的***和/或它们的衍生物诱导的免疫应答的方法。该方法包括给宠物动物施用一种组合物,所述组合物含有能够调节所述应答的益生菌菌株的一部分。
所述方法可包括给宠物动物施用一种组合物,所述组合物含有益生菌、其培养物上清或其代谢物,所述益生菌能够至少暂时粘附至宠物动物的肠上皮。
在一个实施方案中,所述方法包括施用作为营养平衡食品的组分的组合物。在优选的实施方案中,该组分包含在湿或干的宠物食品制备物中。
本发明的最后一个方面涉及宠物食品制备物,它包含营养平衡食品和一种活性成分,所述活性成分具有调节在宠物动物中由革兰氏阴性菌菌株、可能致病的革兰氏阳性菌菌株和/或其衍生物诱导的免疫应答的能力。
在一个实施方案中,活性成分包含具有LTA的微生物。LTA优选地存在于所述微生物的细胞壁中。
所述微生物优选地是能够暂时粘附到摄食了该微生物的宠物的肠上皮的益生菌。在优选的实施方案中,微生物是乳酸菌。
本发明的一个优点是提供了调节针对革兰氏阴性生物体、致病或可能致病的革兰氏阳性生物体或它们的衍生物LPS或LTA的免疫应答的手段,特别是降低炎症过程的手段,所述炎症过程例如IEC产生前炎性细胞因子,例如IL-8、TNF-α和来源于上皮细胞的嗜中性粒细胞激活蛋白(ENA)。
本发明的另一优点是提供一种通过例如降低前炎性细胞因子(例如IL-8和TNF-α)的释放而下调(down-regulate)巨噬细胞炎症应答的手段。
本发明的另一优点是通过单纯食用本发明的食品组合物,可以提高哺乳动物中的保护性免疫过程,降低有害的炎症和感染的风险。应意识到静脉或皮下施用药物需要专业技能,而且与口服相比不安全、不方便、更难被患者接受。因此,本发明的可以口服的营养和/或治疗产品具有明显的优点。
此外,本发明使用来自食品级细菌的LTA,具有GRAS(GenerallyRegarded As Safe,一般认为是安全的)状况,提供了一些归因于益生菌的优点。因此,本发明可用于无菌药品(sterile medicaments)、用于临床失调的肠内和局部组合物和不能使用活的益生菌的感染。
发明详述
在下面的描述中使用了以下缩写:ENA-78:来源于上皮细胞的嗜中性粒细胞激活蛋白-78;HM:人乳;IECs:肠上皮细胞;IL:白介素;LPS:脂多糖;LTA:脂磷壁酸;mAb:单克隆抗体;PBMC:外周血单核细胞;PRR:模式识别受体;TNF:肿瘤坏死因子。
最后,“NCC”表示雀巢培养物保藏机构(雀巢研究中心,Vers-chez-les-Blanc,洛桑,瑞士)。
本发明的第一方面涉及一种组合物,其含有来自乳酸菌的脂磷壁酸,用于调节由革兰氏阴性菌、可能致病的革兰氏阳性菌和/或它们的衍生物诱导的免疫应答,特别是炎症过程。
所述炎症过程可被革兰氏阴性菌(例如埃希氏菌、螺杆菌、沙门氏菌)和/或其LPS诱导;它们也可被致病或可能致病(即在某些条件下致病)的革兰氏阳性菌诱导。
优选地,来自乳酸菌的脂磷壁酸具有结合CD14的能力,不具有诱导IECs释放前炎性因子(例如IL-8或TNF-α)的能力。脂磷壁酸应含有其脂质部分。
优选地,脂磷壁酸分离自乳杆菌、双歧杆菌或链球菌属细菌,例如嗜酸乳杆菌、加氏乳杆菌、约氏乳杆菌、瑞士乳杆菌、酪乳杆菌、植物乳杆菌、双歧双歧杆菌、长双歧杆菌、婴儿双歧杆菌、动物双歧杆菌、嗜热链球菌;最优选约氏乳杆菌La1菌株(NCC 533)、嗜酸乳杆菌La10菌株(NCC 90)和加氏乳杆菌(NCC 2493)。
约氏乳杆菌NCC 533菌株、嗜酸乳杆菌NCC90菌株已分别于92年6月30日和99年10月12日保藏于巴斯德研究所(23 rue du DocteurRoux,F-75024 Paris cédex 15,FRANCE),保藏号分别为CNCM I-1225和CNCM I-2332。
在最优选的实施方案中,来自乳酸菌的LTA可与例如sCD14的分子结合使用。
脂磷壁酸和/或产生它的乳酸菌和/或其培养物上清可被掺入干的或液态的食品组合物或肠饲(enteral feeds),用于婴儿营养、宠物营养和动物饲料,用于临床营养和药物应用。
它也可以以局部(乳膏和药膏)或口腔制备物形式用于美容或皮肤应用、眼部应用(洗眼液)或口腔应用(漱口液、牙膏)。LTA可用于预防耳部感染。此外,产品中的LTA可用于预防LPS介导的骨失调。
相应地,所述组合物可以是药物、口部或局部化妆品、皮肤或眼部制备物、食品或宠物食品组合物。
脂磷壁酸的使用量可以变化,但相应于食品组合物中的细菌水平,可从105cfu/g至大约1011cfu/g,最优选从大约107cfu/g至109cfu/g。对于药物制备物而言,LTA的量可以变化并相应于细菌的量,可从105cfu/g至1016cfu/g,优选从大约107cfu/g至1010cfu/g。
它对胃肠道、骨、皮肤、眼、耳、肺或口腔中与细菌介导的疾病或LTA/LPS介导的失调有关的炎症过程有作用。
最特别地,这些产品能改变细菌定殖和新生儿感染,以及婴儿的免疫能力(competence),用于临床营养,用于治疗败血症、细菌移位(translocation)、炎症、感染和疾病以及细菌过度生长。
在优选的实施方案中,所述组合物可以是完全的、营养平衡的食品或宠物食品。它也可以是例如食品添加物。
如果制得的食品组合物是用于人的,它可以是营养完全的婴儿食品(formula)、奶制品、冷藏的或货架稳定的饮料、汤、食品添加物、膳食替代品、营养条棒(bar)或糖果。
除了脂磷壁酸和/或产生它的乳酸菌和/或其培养物上清之外,根据本发明,营养婴儿食品可包含蛋白源。优选地用食品蛋白(dietaryproteins)作为蛋白源。食品蛋白可以是任何适合的食品蛋白,例如动物蛋白(如乳蛋白、肉蛋白和卵蛋白)、植物蛋白(例如大豆蛋白、小麦蛋白、稻米蛋白和豌豆蛋白)、游离氨基酸的混合物、或它们的组合。乳蛋白例如酪蛋白、乳清蛋白和大豆蛋白是特别优选的。所述组合物也可含有碳水化合物源和脂肪源。
如果营养婴儿食品包括脂肪源,该脂肪源优选提供营养婴儿食品的大约5%至大约55%的能量,例如大约20%至大约50%的能量。组成脂肪源的液体可以是任何适当的脂肪或脂肪组合物。植物脂肪是特别优选的,例如豆油、棕榈油、椰子油、红花油、葵花油、玉米油、canola油、卵磷脂等。如果需要的话可以添加动物脂肪例如奶类脂肪。
可向营养婴儿食品中添加碳水化合物源。它优选地提供营养组合物的大约40%至大约80%的能量。可以使用任何适当的碳水化合物,例如蔗糖、乳糖、葡萄糖、果糖、玉米糖浆固体、麦芽糖糊精和它们的混合物。如果需要的话可以加入食用纤维。如果使用了食用纤维,它优选地构成营养婴儿食品的至多大约5%的能量。食用纤维可以是任何适当来源的,包括例如大豆、豌豆、燕麦、果胶、瓜尔胶、***树胶、果糖寡糖(fructooligosaccharides)。
可以在营养婴儿食品中加入适当的维生素和矿物质,加入的量合乎适当的指引。
如果需要,可以在营养婴儿食品中加入一种或几种食品级乳化剂,例如二乙酰酒石酸一或二甘油酯、卵磷脂以及一和二甘油酯。类似地,可以加入适当的盐和稳定剂。
营养婴儿食品优选地肠内施用,例如以粉末、片剂、胶囊、液体浓缩物、固体产品和即饮型饮料。如果需要生产粉末状的营养婴儿食品,将均匀化的混合物转移到适当的干燥装置(例如喷雾干燥器、冷冻干燥器)中,转变成粉末。
在另一实施方案中,可在普通食品中富集至少一种本发明的来自乳酸菌的脂磷壁酸。例如发酵的奶、酸乳酪、新鲜干酪、凝乳(rennetedmilk)、甜食(例如甜的或增甜的饮料)、糖果条棒、早餐谷类薄片或条棒、饮料、奶粉、豆制品、非奶类发酵产品或临床营养品的营养添加物。
在另一实施方案中,可以制备营养完全的宠物食品。营养完全的宠物食品可以是任何适当的形式,例如干的、半湿的或湿的形式。它可以是冷藏的或货架稳定的宠物食品。这些宠物食品可以用常规的方法制备。除本发明的脂磷壁酸之外,这些宠物食品可以包含任何一种或几种碳水化合物源、蛋白源和脂质源。
可以使用任何适当的碳水化合物源。优选地,碳水化合物源以谷物、面粉和淀粉的形式提供。例如,碳水化合物源可以是稻米、大麦、高梁、粟、燕麦、玉米粗粉(meal)和小麦粉。也可以使用简单的糖例如蔗糖、葡萄糖和玉米糖浆。碳水化合物源提供的碳水化合物的量可以根据需要选择。例如,宠物食品可含有高达大约60重量%的碳水化合物。
合适的蛋白源可选自任何合适的动物或植物蛋白源,例如,肌肉或骨骼肉类、肉和骨膳食、禽肉、鱼肉、奶蛋白、玉米面筋(gluten)、小麦面筋、大豆粉、大豆蛋白浓缩物、大豆蛋白分离物、卵蛋白、乳清、酪蛋白、面筋等。蛋白源提供的蛋白的量可以根据需要选择。例如,以干重计,宠物食品可含有大约12重量%至大约70重量%的蛋白。
宠物食品可含有脂肪源。可以使用任何合适的动物脂肪和植物脂肪的脂肪源。优选地,脂肪源是动物脂肪源,例如动物脂(tallow)。也可使用植物油,例如玉米油、葵花油、红花油、菜籽油、大豆油、橄榄油和其他富含单不饱和和多不饱和脂肪酸的油。除必需脂肪酸(亚油酸和α亚油酸)外,脂肪源可包含长链脂肪酸。脂肪源提供的脂肪的量可以根据需要选择。例如,以干重计,宠物食品可含有大约5%至40重量%的脂肪。优选地,宠物食品具有相对少量的脂肪。
宠物食品可含有其他活性因子,例如长链脂肪酸。合适的长链脂肪酸包括α亚油酸、γ亚油酸、亚油酸、二十碳五烯酸和二十二碳六烯酸。鱼油是二十碳五烯酸和二十二碳六烯酸的适当来源。琉璃苣油、黑加仑籽油和月见草油是γ亚油酸的合适来源。红花油、葵花油、玉米油和大豆油是亚油酸的合适来源。
碳水化合物、蛋白和脂类来源的选择不是关键性的,可根据动物的营养需要、适口性要求和产品的类型来选择。此外,不同的其他成分,例如糖、盐、香料、调味品、维生素、矿物质、香味剂、树胶、前生菌(prebiotics)和益生菌也可根据需要掺入宠物食品中。
相应地,益生菌可选自适用于动物的一种或几种微生物,其能提高肠内的微生物平衡。益生菌可以是粉末状、干燥的形式,特别是形成孢子的微生物的孢子的形式。此外,如果需要,益生菌可装入胶囊以进一步提高其生存能力,例如,在糖基质、脂肪基质或多糖基质中。
对干的宠物食品来说,适当的加工方法是挤压烹制,虽然也可以使用烘焙或其他适当的加工方法。当挤压烹制后,干的宠物食品通常是粗粉(kibble)形式。如果使用了前生菌,它可以在加工之前与干的宠物食品的其他成分混合。欧洲专利申请No 0850569描述了一种适当的加工方法。如果使用了益生菌,该微生物最好包被在干的宠物食品上或填入干的宠物食品中。欧洲专利申请No 0862863描述了一种适当的加工方法。
对湿的宠物食品来说,可以使用美国专利4,781,939和5,132,137描述的方法以产生仿制的肉类产品。也可使用生产大块(chunk)产品的其他方法,例如在蒸气炉中烹制。或者,通过以下方法来生产条块(loaf)产品:乳化适当的肉以产生肉浆,加入适当的胶凝剂,在装入罐头或其他容器之前加热肉浆。
以下实施例仅是示例性的,不构成对本发明主题的限制。除非另外指出,百分比和份数以重量计。实施例之前是附图简述。
图1.来自约氏乳杆菌La1菌株和嗜酸乳杆菌La10菌株的LTA对HT29细胞释放IL-8的作用,所述HT29细胞受到纯化自大肠杆菌的LPS的攻击。在10ng/ml(●)或100ng/ml(■)的大肠杆菌LPS以及不同量的来自La1(A)或La10(B)的LTA的存在下,通过ELISA测量在补充了2%人乳(HM)的培养基中温育24小时的HT29细胞的上清液中产生的IL-8。单独用LPS-HM对HT29细胞的激活用虚线表示。误差(Error bars)表示SD。结果由三个独立的实验表示。
图2.来自乳杆菌La1的LTA对HT29细胞释放IL-8的作用,所述HT29细胞受到来自肠炎沙门氏菌的LPS或完整大肠杆菌的攻击。在不同量的来自La1的LTA的存在下,通过ELISA测量在补充了2%人乳(HM)和10ng/ml(●)或100ng/ml(■)的肠炎沙门氏菌LPS(A)或2.5×105/ml完整大肠杆菌(B)的培养基中温育24小时的HT29细胞的上清液中产生的IL-8。在没有LTA的条件下的HT29细胞的激活用虚线表示。误差表示SD。
图3.来自乳杆菌La1和La10的LTA对HT29细胞释放TNF-α的作用,所述HT29细胞受到大肠杆菌LPS的攻击。在100ng/ml的大肠杆菌LPS和不同量的来自La1(■)或La10(●)的LTA的存在下,通过ELISA测量在补充了2%人乳(HM)的培养基中温育24小时的HT29细胞的上清液中产生的TNF-α。在没有LTA的条件下的HT29细胞的激活用虚线表示。误差表示SD。
图4.来自乳杆菌La1的LTA对HT29细胞中LPS诱导的ENA-78mRNA表达的作用。通过RT-PCR测定在HT29细胞的完整RNA上的ENA-78表达,所述HT29细胞受到100ng/ml大肠杆菌LPS的攻击,条件分别为不存在(泳道1)或存在2%人乳(泳道2至6),添加MY4抗CD14mAb(泳道3),同型匹配(isotype-matched)抗体对照(泳道4),或1μg/ml(泳道5)或50μg/ml(泳道6)来自La1的LTA。ENA-78转录物的预期PCR产物大小为220bp。作为内标,β肌动蛋白(460bp)的扩增带被用作管家基因。
图5.来自乳杆菌La1和La10的LTA对分化的HT29细胞释放IL-8的作用,所述HT29细胞受到大肠杆菌LPS的攻击。在100ng/ml的大肠杆菌LPS和标明量的来自乳杆菌La1(■)或La10(●)的LTA的存在下,通过ELISA测量在补充了2%人乳(HM)的培养基中温育24小时的分化的HT29细胞的上清液中产生的IL-8。
图6.来自乳杆菌La1的LTA对人PBMC活化的作用。(A)在不同量的大肠杆菌LPS(·)或来自La1的LTA(●)存在下,在补充了1%人血清的RPMI中温育刚分离的人PBMC(2×105细胞/孔)。(B)和(C)在加入大肠杆菌LPS(1ng/ml)之前,在不存在(虚线)或存在(实线)不同量的来自La1的LTA的条件下,在37℃下将PBMC温育30分钟。在24小时温育之后,收集培养物上清,通过特异性ELISA分析IL-8(A)和(B),或TNF-α(C)的存在。误差表示SD。
图7.LTA的脱酰基作用对它们的拮抗活性的作用。在不存在(虚线)或存在(实线)纯化自La1(A)或La10(B)的不同量的天然LTA(■)或脱酰基LTA(●)的条件下,在补充了2%人乳(HM)的培养基中,用大肠杆菌LPS(100ng/ml)攻击HT29细胞。24小时之后,用ELISA测量培养物上清中的IL-8的释放。
图8.将细胞用LTA和sCD14或LTA和LPS预温育对拮抗作用的影响。(A)在存在2%的人乳(HM)的条件下,用La1 LTA(50和100μg/ml)预温育HT29细胞4小时,用无血清培养基清洗两次,然后在不存在和存在HM的条件下用大肠杆菌LPS(100ng/ml)攻击20小时。(B)在加入大肠杆菌LPS(100ng/ml)之前,在存在人乳(HM)的条件下,用La1 LTA(1、10和50μg/ml)温育HT29细胞4小时。(C)在加入2%人乳(HM)之前,在存在大肠杆菌LPS(100ng/ml)的条件下,用La1LTA(1、10和50μg/ml)温育HT29细胞4小时。(D)在加入La1LTA(1、10和50μg/ml)之前,在存在2%人乳(HM)的条件下,用大肠杆菌LPS(100ng/ml)攻击HT29细胞4小时。在总共24小时之后,用ELISA测量培养物上清中IL-8的释放。误差表示SD。
实施例1:来自约氏乳杆菌NCC 533菌株和嗜酸乳杆菌NCC 90菌株的脂磷壁酸拮抗人肠上皮细胞对LPS或革兰氏阴性菌的反应
材料和方法
细胞、培养基和试剂
人结肠腺癌细胞系HT29得自美国典型培养物保藏中心(ATCC,Manassas,VA.ATCC:HTB-38)。在5% CO2/空气的恒温箱中,在37℃下,将未分化的细胞维持在补充了10%胎牛血清(FCS;AmimedBjoConcept,Allschwill,瑞士)的含葡萄糖的DMEM中,而分化的细胞在无葡萄糖的培养基中生长。每两天更换培养基,直至细胞单层达到90%汇合。人外周血单核细胞(PBMC)用Ficoll-Isopaque(Pharmacia)密度梯度离心分离自肝素化的成人供血者的血。分离的PBMC清洗3次,重悬于补充了1% FCS的RPMI 1640培养基(Life Technologies,address)中。来自大肠杆菌和肠炎沙门氏菌菌株的LPS购自Sigma化学品公司(St Louis,MO)。鼠抗CD14单克隆抗体MY4(IgG2b)购自Coulter(Instrumentation Laboratory AG,瑞士)。同型匹配的对照mAb是小鼠IgG2b(kappa),来源于MOPC 141(Sigma)。人乳得自健康的母亲。样品用乳泵挤压法在最多产后70天收集到无菌的离心管中,在收集后2小时之内进行处理。在200×g离心30分钟后,无非细胞液体的级分在-80℃下冷冻备用。
LTAs的分离和纯化
约氏乳杆菌La1 NCC 533和嗜酸乳杆菌La10 NCC 90的LTAs用Fischer等的方法(Fischer,W.等,1983,Eur.J.Biochem 133:523-530)分离。简单地说,细菌在MRS肉汤中培养过夜,收集,以800毫克湿重/毫升缓冲液重悬于0.1M乙酸钠(pH4.5)中。然后将它们与2体积的甲醇和1体积的氯仿在室温下混合过夜而脱脂。过滤回收脱脂的细菌,用2体积的甲醇清洗,重悬于0.1M乙酸钠(pH4.7)中,浓度为每毫升缓冲液500毫克细菌。悬浮液与等体积的热的80%(w/v)含水苯酚混合,在65℃水浴中匀速搅拌45分钟。冷却后,将形成的乳液在4℃以5000×g离心30分钟。将上面的水层用0.1M乙酸钠(pH5)充分透析(截止分子量6-8kDa)。用溶于5mM MgSO4、40mM EDTA二钠和0.2mM NaN3的30U/ml DNAse I(Sigma)、9U/ml核糖核酸酶消化核酸(室温下24小时),加入1毫升甲苯防止微生物污染。将消化物用0.1M乙酸钠(pH4.7)再次透析,用1-丙醇调到15%。将它加样到用0.1M乙酸钠加15% 1-丙醇平衡的Octyl-琼脂糖柱上,流速为0.1毫升/分钟。收集5毫升的级分。在相同的缓冲液中用15-80%梯度的1-丙醇洗脱LTA,流速为0.5毫升/分钟。收集3毫升的级分。通过测量折射率来监测1-丙醇浓度。分析每个级分的总中性糖含量(Dubois,M.A.等,确定糖和相关物质的比色方法,AnalChem 28:350-356),磷含量(Chen,P.S.等,1956,磷的微量测定,Anal Chem 28:1756-1758),核酸含量和折射率。用旋转蒸发器(rotavap)浓缩样品峰,以除去丙醇,然后用水彻底透析。浓缩之后,加入0.1M乙酸钠(pH4.7)、1mM CaCl2和MgCl2,将等分试样在-20℃下冷冻。用最近描述的ELISA法确认La1 LTA的抗原活性(Granato,D.等,1999,Appl Environ Microbiol 65:1071-1077)。用Teti等描述的方法脱(Teti,G.等,1987,Infect Immun 55:3057-3064)。
鲎变形细胞裂解物测试
对所有将与细胞接触的试剂用比浊动力学鲎变形细胞裂解物凝块测试(E-Toxate测试)来检测内毒素污染。检测的灵敏度为每毫升0.05-0.1内毒素单位(大肠杆菌0.55:B5 LPS)。发现在本研究中所用的不同培养基是无活性的或含有<50pg/ml的内毒素。
细胞处理
将HT29细胞以104细胞/孔加入96孔平底平板。在温育5天之后,在加入溶于200μl的DMEM中的人乳、LPS和/或LTA之前,用无血清培养基清洗HT29细胞两次。在某些孔中,加入终浓度为20μg/ml的抗CD14单克隆抗体。在其他实验中,将PBMC悬浮于含1%FCS的RPMI 1640培养基中,然后以2×105细胞/孔的浓度加入96孔平底平板中。然后将细胞与LTA在37℃下温育30分钟,再用LPS刺激。在37℃下温育24小时之后,收集上清,在-20℃下贮存,用于进一步测量细胞因子含量。用细胞毒性检测试剂盒(RocheDiagnostics)检测细胞的生存能力,该方法检测从受损细胞的细胞溶质释放到上清中的乳酸脱氢酶(LDH)的活性。
IL-8和TNF-α在培养物上清中的浓度
通过ELISA测量细胞培养物上清中生成的IL-8的量。简单地说,通过4℃下温育过夜将抗IL-8单克隆抗体(2μg/ml,ImmunoKontakt,Bioggio,瑞士)包被在96孔平板(Nunc)上。用溶于PBS的0.05%Tween-20清洗平板2次。通过用溶于PBS的10% FCS在室温下温育平板2个小时来封闭非特异性结合。加入样品或标准浓度的溶于FCS-PBS的重组细胞因子(15.625至2000pg/ml,ImmunoKontakt),室温下3个小时。在加入生物素标记的抗人IL-8单克隆抗体(1μg/ml,ImmunoKontakt)之前,用PBS-Tween清洗平板4次,室温下1小时。4次清洗之后,加入链霉抗生物素-过氧化物酶(0.5μg/ml,KPL,Bioreba,Reinach,瑞士),室温下1小时。再次清洗平板,加入底物(TMB-peroxydase,KPL)10-30分钟。通过加入1N HCl中断酶促反应。在ELISA读数器(Dynex Technologies)中读取450nm的吸收值。检测范围是大约30pg/ml。通过市售的ELISA试剂盒(R&D systems)测量释放到细胞培养物上清的TNF-α的量。
上皮嗜中性粒细胞激活因子(ENA)-78的逆转录和聚合酶链式反应(RT-PCR)
用Trizol法(GIBCO-BRL)从组织培养皿中的HT29细胞中提取总细胞RNA。用Moloney鼠白血病病毒逆转录酶(Perkin-Elmer,address)逆转录分离自肠上皮细胞的RNA。简单地说,将RNA样品(0.5μg的总RNA)、0.5单位的RNase抑制剂、1mM的各dNTP、0.5nmol/ml的特异性3’引物、5mM MgCl2和1.25单位的逆转录酶以总体积10μl的反应混合物进行温育,所述反应混合物含有制造商提供的酶缓冲液。反应混合物在42℃下温育30分钟,然后在95℃下加热。用GoldDNA聚合酶(Perkin Elmer)在热循环仪(B iolabo,Scientific Instruments,Chatel St Denis,瑞士)上扩增逆转录产物。PCR以50μl总体积进行,使用10μl溶于PCR缓冲液的逆转录产物,2mM MgCl2,5μM各dNTP,0.2nmol/ml ENA-78-特异性3’反义和5’有义引物(分别为CGTTCTCAGGGAGGCTC和TCCTTCGAGCTCCTTGTG,Keates等,1997Am.J.Physiol 273 G75-G82)和1.25单位的DNA聚合酶。在95℃下起始变性10分钟后,对样品进行35个循环的扩增:94℃变性45秒,60℃退火1分钟,72℃延伸1分30秒,然后进行在72℃下进行7分钟的延伸。对所有样品进行RT-PCR,以β肌动蛋白作为阳性对照。将RT-PCR产物的样品加样到溶于TAE缓冲液的1.2%琼脂糖凝胶(含溴乙锭)中,在150V下电泳1小时进行分离。在紫外光下RT-PCR产物为可见的。通过与DNA分子量标记物(BoehringerMannheim)进行比较确定条带的正确大小。
结果
来自乳杆菌的LTA抑制HT29细胞由大肠杆菌或LPS诱导的IL-
8、TNF-α和ENA-78释放
我们检查了革兰氏阳性菌或它们的衍生物是否也能刺激人肠上皮细胞HT29细胞。不同的革兰氏阳性生物体在存在或不存在作为sCD14来源的人乳的条件下与HT29细胞温育。与大肠杆菌相反,革兰氏阳性菌L.sakei、酪乳杆菌、嗜酸乳杆菌La10菌株和约氏乳杆菌La1菌株,以及金黄色葡萄球菌和表皮葡萄球菌即使在sCD14存在下也不能刺激HT29细胞释放IL-8。此外,当以至多100μg/ml的浓度加入来自La1、La10或金黄色葡萄球菌的LTA时,没有观察到IL-8的分泌。
由于已知sCD14识别革兰氏阴性菌和革兰氏阳性菌二者的组分,我们检测了革兰氏阳性生物体的组分(例如LTA)是否拮抗革兰氏阴性菌对HT29细胞的作用。为此,在存在或不存在作为sCD14源的人乳,以及不同量的来自La1(图1A)或La10(图1B)的LTA的条件下,用LPS(10和100ng/ml)攻击HT29细胞。如预期的那样,在存在sCD14的条件下暴露于10或100ng/ml大肠杆菌LPS的HT29细胞释放大量的IL-8(图1,虚线)。加入来自La1(图1A,实线)或La10(图1B,实线)的LTA引起LPS诱导的IL-8分泌显著减少(marked decrease)。这种抑制活性是剂量依赖性的,使用100至1000倍过量的LTA观察到完全抑制。为了确定LTA的抑制活性是一种普遍现象,检测了LTA对HT29细胞应答另一LPS源的拮抗活性。如图2A所示,来自La1的LTA抑制HT29细胞分泌IL-8,所述HT29细胞受到10或100ng/ml的来自肠炎沙门氏菌的LPS的攻击。此外,来自La1的LTA拮抗全大肠杆菌sCD14对HT29细胞的作用(图2B)。
如图3所示,来自La1和La10的LTA都抑制大肠杆菌LPS诱导的由HT29细胞释放TNF-α。此外,来自La1的LTA也显著地抑制LPS诱导的ENA-78mRNA的表达(图4)。值得注意的是,观察到的乳杆菌LTA抑制活性并不归因于LTA制备物对HT29细胞的细胞毒作用,因为在培养物上清中不能检测到LDH的明显释放(数据未显示)。
来自La1和La10的LTA抑制LPS诱导分化的HT29细胞释放IL-8
如图5所示,在存在人乳的条件下,用10ng/ml的大肠杆菌LPS攻击的分化的HT29细胞释放大量的IL-8(虚线)。如上所述,来自La1或La10(实线)的LTA以剂量依赖方式引起分泌减少。用5000倍过量的LTA观察到完全抑制。
来自La1的LTA抑制LPS刺激人单核细胞
一些LTA与血单核细胞和巨噬细胞上的与膜结合的CD14相互作用,刺激不同细胞因子的分泌。我们因此分析了暴露于乳杆菌LTA的PBMC分泌的IL-8和TNF-α。在存在增加量的乳杆菌LTA(100至10000ng/ml)的条件下将PBMC温育30分钟,然后加入浓度为1ng/ml的大肠杆菌LPS。如图6所示,当单独给出时,La1 LTA在浓度为5μg/ml或更高时刺激IL-8分泌(图6A),然而,在任何受试浓度下都没有观察到刺激TNF-α释放。此外,虽然来自La1的LTA对由LPS诱导的PBMC分泌IL-8仅有弱的拮抗作用(图6B),但它以剂量依赖形式对LPS诱导的TNF-α的分泌有更明显的抑制(图6C)。来自La10的LTA,单独或与LPS结合,对IL-8或TNF-α的产生没有明显的作用。
脱酰基LTA的生物活性
LTA的脱酰基化导致细胞生物活性的损失。这意味着LTA的脂部分对免疫调节活性是关键性的。我们因此在我们的细胞模型中检测了LTA的脱酰基化对它们的LPS拮抗性的影响。如图7所示,来自La1(图7A)和La10(图7B)的LTA对LPS-sCD14诱导HT29细胞产生IL-8的拮抗活性,在脱酰基之后明显减弱。因此,在我们的细胞***中,乳杆菌LTA的拮抗活性也由脂部分所介导。
sCD14-LTA相互作用在抑制LPS-sCD14作用中的角色
为了理解LTA如何对革兰氏阴性菌产生拮抗作用,进行不同的处理方法,其中HT29细胞与来自La1的LTA以及人乳sCD14或大肠杆菌LPS预温育。将HT29细胞与La1 LTA(50和100μg/ml)(含有或不含人乳)预温育4小时,用无血清培养基清洗2次,然后在存在乳液的条件下用LPS(100ng/ml)攻击20小时,IL-8的分泌没有消除(图8A)。然而,将细胞在存在sCD14的条件下与La1 LTA(1至50μg/ml)预温育4小时,不经过清洗,用LPS(100ng/ml)攻击24小时,产生的IL-8的水平与HT29细胞和LTA、LPS和sCD14共同温育24小时后得到的水平是相似的(图8B)。图8C显示在向细胞加入sCD14源24小时之后产生的IL-8的水平,所述细胞与La1LTA(1-50μg/ml)和LPS(100ng/ml)预温育4小时。这一水平与HT29细胞和LTA、LPS和sCD14的混合物温育24小时所获得的量相似。当细胞在加入LTA之前与LPS(100ng/ml)和CD14源预温育4小时时,得到相似的结果(图8D)。
IEC不表达膜CD14,并要求以可溶形式来体外应答LPS(Pugin,J.等,1993 PNAS 90:2744-2748)。我们先前显示了革兰氏阴性菌和LPS在IEC中通过人乳sCD14的作用介导前炎性细胞因子产生(Labeta,M.O.等,2000,J Exp Med 191:1807-1812)。然而,IEC不应答不同的LTA源,即使存在sCD14。由于其他研究表明LTA与真核细胞膜的结合需要脂肪酸部分,并且结合脂肪酸的蛋白只在肠绒毛上部的分化的IEC上表达,我们也检测了LTA-乳对分化的HT29的作用。有趣的是,LTA仍没有引起任何应答,而来自约氏乳杆菌La1菌株和嗜酸乳杆菌La10菌株的LTA能够刺激血单核细胞释放IL-8。这些结果进一步支持了约氏乳杆菌La1菌株和嗜酸乳杆菌La10菌株的前生命期(probiotic)状态,并暗示了它们的LTA在对抗由革兰氏阴性菌或它们的衍生物引起的疾病中的治疗用途。
实施例2:婴儿食品
为了获得婴儿食品(infant formula),我们制备了在100ml中含有下列成分的混合物:0.5-5%,优选2%的肽;0.2-10%,优选4%的脂肪;1-25%,优选8%的非果聚糖碳水化合物(包括65%乳糖、20%麦芽糖糊精、15%淀粉);至少106cfu/ml的下列菌株:嗜酸乳杆菌NCC90(CNCM I-2332)或约氏乳杆菌NCC533(CNCM I-1225);痕量的维生素和日常所需的少量元素;0.01-2%,优选0.3%的矿物质;以及50-90%,优选75%的水。
实施例3:奶制品中的用途
根据本发明,嗜酸乳杆菌NCC 90(CNCM I-2332)或约氏乳杆菌NCC 533(CNCM I-1225)中的一种或几种菌株可用于制备发酵的酸奶样奶制品。
为此,制备了含有2.8%脂肪并补充了2%的脱脂奶粉和6%蔗糖的1升奶制品。将它在96℃下巴氏消毒30分钟,然后降温至42℃。嗜热链球菌的非增稠(non-thickening)菌株和保加利亚乳杆菌的非粘性菌株的预培养物,在含有10%的重建奶粉和0.1%市售酵母提取物的无菌的MSK培养基中重新活化。
一种或几种菌株的预培养物也在含有10%的重建奶粉和0.1%市售酵母提取物以及1%蔗糖的培养基中重新活化。用1%的各种重新活化的预培养物接种巴氏消毒的奶制品,然后将奶制品在32℃下发酵直至pH达到4.5。用这种方法产生发酵的酸奶样产物,在4℃下保存。
实施例4:干的宠物食品
饲料组合物由以下成分组成:大约58重量%玉米、大约6重量%的玉米面筋、大约23重量%的鸡肉,其余为盐、维生素和矿物质。
将饲料混合物送入预处理器(preconditioner)并弄湿。湿润的饲料被送入挤出机-烹制机(cooker)中并凝胶化。离开挤出机的凝胶化物质通过一个模具(die)并被挤出。将挤出物切成适于饲喂给猫的小块,在大约110℃下干燥大约20分钟,冷却形成小团块(pellet)。在此时,将约氏乳杆菌NCC533(CNCM I-1225)或嗜酸乳杆菌NCC 90(CNCMI-2332)中的一种或几种菌株的冻干粉末施加到小团块上。如此提供足够的粉末使得宠物摄入的量为大约1.0E+07-1.0E+9cfu/天。将一些粉末与第一份小团块混合并装袋。称出第二份量的粉末,混入液态载体中,然后喷洒在第二份小团块上。在50-60℃下若干分钟,待涂层充分干燥后将小团块装袋。
这种干的狗食品特别适用于降低与细菌定殖有关的炎症过程。
Claims (14)
1.一种用于调节免疫应答的营养组合物,所述免疫应答由革兰氏阴性菌、可能致病的革兰氏阳性菌和/或它们的衍生物诱导,所述组合物包含来自乳酸菌的脂磷壁酸作为活性成分。
2.权利要求1的组合物,其中来自乳酸菌的脂磷壁酸具有结合CD14的能力,不具有诱导由肠上皮细胞释放前炎性细胞因子的能力。
3.权利要求2的组合物,其中所述前炎性细胞因子为IL-8或TNF-α。
4.权利要求1或2的组合物,其中脂磷壁酸来自乳杆菌、双歧杆菌或链球菌属的乳酸菌。
5.权利要求4的组合物,其中脂磷壁酸来自嗜酸乳杆菌、加氏乳杆菌、约氏乳杆菌、瑞士乳杆菌、酪乳杆菌、植物乳杆菌、双歧双歧杆菌、长双歧杆菌、婴儿双歧杆菌、动物双歧杆菌、嗜热链球菌。
6.权利要求1-3中任一权项的组合物,其中乳酸菌是约氏乳杆菌CNCM I-1225、嗜酸乳杆菌CNCM I-2332。
7.权利要求1-3中任一权项的组合物,其含有产生所述脂磷壁酸的乳酸菌或其培养物上清。
8.权利要求1-3中任一权项的组合物,其中脂磷壁酸存在的量相应于细菌的量,在食品组合物中为105cfu/g至1011cfu/g,在药物制剂中为105cfu/g至1016cfu/g。
9.来自乳酸菌的脂磷壁酸,它能结合CD14,不能诱导由肠上皮细胞释放前炎性细胞因子。
10.权利要求9的来自乳酸菌的脂磷壁酸,所述前炎性细胞因子为IL-8或TNF-α。
11.至少一种来自乳酸菌的脂磷壁酸和/或产生它的乳酸菌和/或它的培养物上清在制备用于在人或动物中调节免疫应答的组合物中的用途,所述免疫应答由革兰氏阴性菌、可能致病的革兰氏阳性菌和/或它们的衍生物诱导。
12.权利要求11的用途,所述组合物用于在人或动物的胃肠道、骨、皮肤、眼、耳、肺和口腔中降低或预防与细菌介导的疾病或LTA/LPS介导的失调有关的炎症过程。
13.权利要求11或12的用途,所述组合物用于食品组合物或肠饲,用于婴儿营养、宠物营养和动物饲料,用于临床营养或药物应用。
14.权利要求11或12的用途,所述组合物以局部或口部制剂形式用于美容或皮肤应用、眼部应用或口部应用。
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103929979A (zh) * | 2011-10-11 | 2014-07-16 | Mjn美国控股有限责任公司 | 包含麦芽三糖的组合物,和使用该组合物抑制脱水过程所造成的损伤的方法 |
Families Citing this family (64)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB2408573A (en) * | 2003-11-25 | 2005-06-01 | Univ Leicester | Assay for the interaction of L-Ficolin with lipoteichoic acid |
BRPI0417307A2 (pt) * | 2003-12-04 | 2008-12-30 | Biofilms Strategies Inc | mÉtodos e composiÇÕes para impedir as formaÇÕes de biofilme, reduzindo os biofilmes existentes, e para reduzir os biofilmes existentes, e para reduzir as populaÇÕes de bactÉria |
AU2003289209A1 (en) * | 2003-12-05 | 2005-06-24 | Japan Allergy Applied Institute Co., Ltd. | Antiallergic agent containing ground lotus and/or extract thereof together with lactic acid bacterium |
US20050158294A1 (en) | 2003-12-19 | 2005-07-21 | The Procter & Gamble Company | Canine probiotic Bifidobacteria pseudolongum |
US8877178B2 (en) | 2003-12-19 | 2014-11-04 | The Iams Company | Methods of use of probiotic bifidobacteria for companion animals |
EP2514427A1 (en) | 2004-03-04 | 2012-10-24 | E-L Management Corp. | Skin treatment method with lactobacillus extract |
US7862808B2 (en) * | 2004-07-01 | 2011-01-04 | Mead Johnson Nutrition Company | Method for preventing or treating respiratory infections and acute otitis media in infants using Lactobacillus rhamnosus LGG and Bifidobacterium lactis Bb-12 |
JP4726109B2 (ja) * | 2005-02-10 | 2011-07-20 | 昭和電工株式会社 | 皮膚外用剤、それを用いる皮膚有害微生物の付着予防方法及び増殖防止方法 |
US7303745B2 (en) * | 2005-04-15 | 2007-12-04 | Bristol-Myers Squibb Company | Method for preventing or treating the development of respiratory allergies |
WO2006130188A1 (en) | 2005-05-31 | 2006-12-07 | The Iams Company | Feline probiotic bifidobacteria |
DK1880001T3 (da) | 2005-05-31 | 2011-09-12 | Iams Company | Feline probiotiske lactobacilli |
JP5799299B2 (ja) | 2007-02-01 | 2015-10-21 | ザ・アイムス・カンパニーThe Iams Company | ブドウ糖代謝拮抗物質、アボカド又はアボカド抽出物を使用する、哺乳動物における炎症及びストレスの低下方法 |
US8920814B2 (en) * | 2007-03-08 | 2014-12-30 | The Governors Of The University Of Alberta | Bacterial endotoxin for the prevention of metabolic disorders and bacterial infections |
WO2008134450A2 (en) * | 2007-04-24 | 2008-11-06 | Kemin Industries, Inc. | Broad-spectrum antibacterial and antifungal activity of lactobacillus johnsonii d115 |
JP5225652B2 (ja) * | 2007-10-29 | 2013-07-03 | 雪印メグミルク株式会社 | アディポネクチン分泌促進及び/又は減少抑制剤 |
US9771199B2 (en) | 2008-07-07 | 2017-09-26 | Mars, Incorporated | Probiotic supplement, process for making, and packaging |
EP2140772A1 (en) * | 2008-07-03 | 2010-01-06 | Nestec S.A. | Temperature-induced delivery of nutrients by micro-organisms in the gastrointestinal tract |
US9232813B2 (en) * | 2008-07-07 | 2016-01-12 | The Iams Company | Probiotic supplement, process for making, and packaging |
MX2011006488A (es) * | 2008-12-16 | 2011-07-13 | Nestec Sa | Composiciones y metodos para la salud oral mejorada. |
WO2010130663A1 (en) * | 2009-05-11 | 2010-11-18 | Nestec S.A. | Bifidobacterium longum ncc2705 (cncm i-2618) and immune disorders |
US10104903B2 (en) | 2009-07-31 | 2018-10-23 | Mars, Incorporated | Animal food and its appearance |
JP2013502456A (ja) * | 2009-08-26 | 2013-01-24 | アールエヌエー アイエヌシー | リポタイコ酸由来の糖脂質及びこれを含む組成物 |
JP2014506923A (ja) | 2011-03-01 | 2014-03-20 | クオラム イノベーションズ リミテッド ライアビリティ カンパニー | 病原性バイオフィルムと関連した状態を治療するための物質および方法 |
AU2012222827A1 (en) | 2011-03-03 | 2013-10-03 | The Governors Of The University Of Alberta | Use of bacterial endotoxins and lipoteichoic acids to improve postpartal health and productivity of dairy cows and their newborns |
GB201112091D0 (en) | 2011-07-14 | 2011-08-31 | Gt Biolog Ltd | Bacterial strains isolated from pigs |
GB201117313D0 (en) | 2011-10-07 | 2011-11-16 | Gt Biolog Ltd | Bacterium for use in medicine |
EP2589387A1 (en) * | 2011-11-04 | 2013-05-08 | Lunamed AG | Use of a teichoic acid for the treatment of malignant liquor cerebrospinalis in the brain |
CN102399733B (zh) * | 2011-12-14 | 2014-07-09 | 北京大北农科技集团股份有限公司 | 约氏乳杆菌及其菌剂、应用和预混料 |
GB201306536D0 (en) | 2013-04-10 | 2013-05-22 | Gt Biolog Ltd | Polypeptide and immune modulation |
US9399048B2 (en) * | 2014-03-05 | 2016-07-26 | Asian Probiotics And Prebiotics Ltd | Lactic acid bacteria and its applications in immunomodulation and anti-inflammation |
CN104161776A (zh) * | 2014-05-29 | 2014-11-26 | 浙江大学宁波理工学院 | 来自丁酸梭菌的脂磷壁酸及其调节畜禽免疫应答的用途 |
CN104161775A (zh) * | 2014-05-29 | 2014-11-26 | 浙江大学宁波理工学院 | 来自丁酸梭菌的脂磷壁酸在调节水产动物免疫应答中的用途 |
LT3065748T (lt) | 2014-12-23 | 2018-03-12 | 4D Pharma Research Limited | Bacteroides thetaiotaomicron padermė ir jos panaudojimas uždegimo sumažinimui |
SI3193901T1 (en) | 2014-12-23 | 2018-06-29 | 4D Pharma Research Limited | Pirin polypeptide and immune modulation |
AU2016219070B2 (en) | 2015-02-13 | 2020-06-11 | Mars, Incorporated | Pet food feeding system |
MA41060B1 (fr) | 2015-06-15 | 2019-11-29 | 4D Pharma Res Ltd | Compositions comprenant des souches bactériennes |
MA51639A (fr) | 2015-06-15 | 2020-04-15 | 4D Pharma Res Ltd | Compositions comprenant des souches bactériennes |
DK3307288T3 (da) | 2015-06-15 | 2019-10-07 | 4D Pharma Res Ltd | Sammensætninger omfattende bakteriestammer |
PE20180242A1 (es) | 2015-06-15 | 2018-01-31 | 4D Pharma Res Ltd | Composiciones que comprenden cepas bacterianas |
MA41010B1 (fr) | 2015-06-15 | 2020-01-31 | 4D Pharma Res Ltd | Compositions comprenant des souches bactériennes |
GB201520497D0 (en) | 2015-11-20 | 2016-01-06 | 4D Pharma Res Ltd | Compositions comprising bacterial strains |
DK3209310T3 (en) | 2015-11-20 | 2018-04-16 | 4D Pharma Res Ltd | COMPOSITIONS COMPREHENSIVE BAKERY STUES |
GB201520638D0 (en) | 2015-11-23 | 2016-01-06 | 4D Pharma Res Ltd | Compositions comprising bacterial strains |
GB201520631D0 (en) | 2015-11-23 | 2016-01-06 | 4D Pharma Res Ltd | Compositions comprising bacterial strains |
GB201612191D0 (en) | 2016-07-13 | 2016-08-24 | 4D Pharma Plc | Compositions comprising bacterial strains |
AU2017226831B2 (en) | 2016-03-04 | 2018-10-04 | 4D Pharma Plc | Compositions comprising bacterial Blautia strains for treating visceral hypersensitivity |
JP2019510037A (ja) | 2016-03-31 | 2019-04-11 | ゴジョ・インダストリーズ・インコーポレイテッド | 抗菌ペプチド刺激性洗浄組成物 |
US10874700B2 (en) | 2016-03-31 | 2020-12-29 | Gojo Industries, Inc. | Sanitizer composition with probiotic/prebiotic active ingredient |
TW201821093A (zh) | 2016-07-13 | 2018-06-16 | 英商4D製藥有限公司 | 包含細菌菌株之組合物 |
CN106236826A (zh) * | 2016-08-12 | 2016-12-21 | 福建万亿店中店电子商务有限责任公司 | 一种用于***疾病辅助治疗的乳酸菌磷壁酸凝胶 |
AU2017365019A1 (en) | 2016-11-23 | 2019-07-11 | Gojo Industries, Inc. | Sanitizer composition with probiotic/prebiotic active ingredient |
GB201621123D0 (en) | 2016-12-12 | 2017-01-25 | 4D Pharma Plc | Compositions comprising bacterial strains |
PT3630136T (pt) | 2017-05-22 | 2021-06-11 | 4D Pharma Res Ltd | Composições que compreendem estirpes bacterianas |
EP3630942B1 (en) | 2017-05-24 | 2022-11-30 | 4D Pharma Research Limited | Compositions comprising bacterial strain |
EP3638271B1 (en) | 2017-06-14 | 2020-10-14 | 4D Pharma Research Limited | Compositions comprising bacterial strains |
BR112019026677A2 (pt) | 2017-06-14 | 2020-06-30 | 4D Pharma Research Limited | composições compreendendo cepas bacterianas |
KR102205829B1 (ko) * | 2017-06-14 | 2021-01-21 | 기초과학연구원 | 신규한 비피도박테리움 비피덤 균주 및 균주 유래 다당체 |
US11197917B2 (en) | 2017-12-01 | 2021-12-14 | ByHeart, Inc. | Formulations for nutritional support in subjects in need thereof |
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Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4678773A (en) * | 1983-08-26 | 1987-07-07 | Chugai Seiyaku Kabushiki Kaisha | Antitumor agent |
EP0343544A2 (de) * | 1988-05-26 | 1989-11-29 | SANUM-KEHLBECK GmbH & Co. KG | Immunstimulierendes Mittel aus Propionibakterien sowie Verfahren zur Herstellung desselben |
US6180100B1 (en) * | 1994-09-30 | 2001-01-30 | Urex Biotech., Inc. | Lactobacillus compositions and methods for treating urinary tract infections |
Family Cites Families (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS6048928A (ja) * | 1983-08-26 | 1985-03-16 | Chugai Pharmaceut Co Ltd | Tνf誘起剤 |
JPS6048929A (ja) * | 1983-08-26 | 1985-03-16 | Chugai Pharmaceut Co Ltd | 抗腫瘍剤 |
JPS61275217A (ja) * | 1985-05-29 | 1986-12-05 | Yakult Honsha Co Ltd | グラム陰性桿菌感染症防御剤 |
US5804179A (en) * | 1985-12-31 | 1998-09-08 | Research Corporation Technologies, Inc. | Lactobacillus compositions and methods for treating urinary tract infections |
DE69223615T2 (de) * | 1992-07-06 | 1998-04-09 | Nestle Sa | Lactobacillus Acidophilus enthaltende Antigastritis-Mittel |
AU6362594A (en) * | 1993-03-10 | 1994-09-26 | Miles Inc. | Hyaluronic acid used as a cancer treatment |
JP3489930B2 (ja) * | 1996-03-08 | 2004-01-26 | 株式会社ヤクルト本社 | がん予防食品 |
DK0818529T3 (da) * | 1996-07-09 | 2005-10-17 | Nestle Sa | Fremgangsmåde til spraytörring |
ATE206873T1 (de) * | 1997-01-09 | 2001-11-15 | Nestle Sa | Probiotik enthaltendes getreideprodukt |
US5998482A (en) * | 1997-11-10 | 1999-12-07 | David; Sunil A. | Use of synthetic polycationic amphiphilic substances with fatty acid or hydrocarbon substituents as anti-sepsis agents |
JP3046303B1 (ja) * | 1999-06-24 | 2000-05-29 | 明治乳業株式会社 | Helicobacterpylori除菌性飲食品 |
DE19963420A1 (de) * | 1999-12-28 | 2001-07-12 | Sebo Gmbh | Gewinnung von biologischen Komponenten aus Körperflüssigkeiten |
-
2001
- 2001-05-23 EP EP01201958A patent/EP1260227A1/en not_active Withdrawn
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2002
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- 2003-11-21 NO NO20035187A patent/NO20035187L/no not_active Application Discontinuation
- 2003-12-18 ZA ZA200309821A patent/ZA200309821B/xx unknown
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- 2008-10-07 US US12/246,991 patent/US8329190B2/en not_active Expired - Fee Related
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2013
- 2013-08-15 US US13/967,936 patent/US20140056927A1/en not_active Abandoned
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4678773A (en) * | 1983-08-26 | 1987-07-07 | Chugai Seiyaku Kabushiki Kaisha | Antitumor agent |
EP0343544A2 (de) * | 1988-05-26 | 1989-11-29 | SANUM-KEHLBECK GmbH & Co. KG | Immunstimulierendes Mittel aus Propionibakterien sowie Verfahren zur Herstellung desselben |
US6180100B1 (en) * | 1994-09-30 | 2001-01-30 | Urex Biotech., Inc. | Lactobacillus compositions and methods for treating urinary tract infections |
Non-Patent Citations (2)
Title |
---|
Protective Effect of Lipoteichoic-acid from Lactobacillus-caseiand Lactobacillus-fermentum againstPseudomonas-aeruginosa in Mice. Setoyama et al.Journal of General Microbiology,Vol.131 No.9. 1985 |
Protective Effect of Lipoteichoic-acid from Lactobacillus-caseiand Lactobacillus-fermentum againstPseudomonas-aeruginosa in Mice. Setoyama et al.Journal of General Microbiology,Vol.131 No.9. 1985 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103929979A (zh) * | 2011-10-11 | 2014-07-16 | Mjn美国控股有限责任公司 | 包含麦芽三糖的组合物,和使用该组合物抑制脱水过程所造成的损伤的方法 |
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DK1395269T3 (da) | 2008-08-04 |
RU2003136828A (ru) | 2005-03-10 |
NO20035187L (no) | 2004-01-05 |
KR20040018375A (ko) | 2004-03-03 |
AU2002338873B2 (en) | 2008-04-10 |
SG101083A1 (en) | 2006-02-28 |
US20140056927A1 (en) | 2014-02-27 |
EP1395269A1 (en) | 2004-03-10 |
PL366455A1 (en) | 2005-02-07 |
US20040147010A1 (en) | 2004-07-29 |
ZA200309821B (en) | 2005-03-18 |
EP1395269B1 (en) | 2008-05-07 |
US8329190B2 (en) | 2012-12-11 |
NO20035187D0 (no) | 2003-11-21 |
MX260807B (es) | 2008-09-25 |
PT1395269E (pt) | 2008-06-16 |
MXPA03010598A (es) | 2004-03-09 |
JP2005500267A (ja) | 2005-01-06 |
ES2305256T3 (es) | 2008-11-01 |
BR0209975A (pt) | 2004-04-06 |
AU2002338873B8 (en) | 2008-05-08 |
AU2002338873A1 (en) | 2002-12-03 |
DE60226436D1 (de) | 2008-06-19 |
EP1260227A1 (en) | 2002-11-27 |
US20090142375A1 (en) | 2009-06-04 |
JP4738717B2 (ja) | 2011-08-03 |
RU2320356C2 (ru) | 2008-03-27 |
ATE394111T1 (de) | 2008-05-15 |
WO2002094296A1 (en) | 2002-11-28 |
CA2449403C (en) | 2011-11-15 |
IN2003DE02242A (en) | 2006-01-20 |
CA2449403A1 (en) | 2002-11-28 |
CN1525863A (zh) | 2004-09-01 |
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