CN102802648A - 约氏乳杆菌La1 NCC533(CNCM I-1225)和免疫病症 - Google Patents

约氏乳杆菌La1 NCC533(CNCM I-1225)和免疫病症 Download PDF

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Publication number
CN102802648A
CN102802648A CN2010800289628A CN201080028962A CN102802648A CN 102802648 A CN102802648 A CN 102802648A CN 2010800289628 A CN2010800289628 A CN 2010800289628A CN 201080028962 A CN201080028962 A CN 201080028962A CN 102802648 A CN102802648 A CN 102802648A
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China
Prior art keywords
compositions
lactobacillus johnsonii
preserving number
number cncm
disease
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CN2010800289628A
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Inventor
V·珀蒂
C·加西亚-罗德纳斯
M·尤莉塔
G·普里乌特
A·梅赛尼尔
S·努特恩
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Nestec SA
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Societe dAssistance Technique pour Produits Nestle SA
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First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=42646295&utm_source=***_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=CN102802648(A) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority claimed from EP09159929A external-priority patent/EP2251022A1/en
Priority claimed from EP09159925A external-priority patent/EP2251020A1/en
Application filed by Societe dAssistance Technique pour Produits Nestle SA filed Critical Societe dAssistance Technique pour Produits Nestle SA
Publication of CN102802648A publication Critical patent/CN102802648A/zh
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Abstract

本发明一般涉及预防和/或治疗炎症和感染病症领域，特别地通过加强内源的抗微生物防御来预防和/或治疗炎症和感染病症。本发明的一个实施方案是非复制的约氏乳杆菌(L.johnsonii)La1 NCC533(保藏号CNCM I-1225)在治疗或者预防涉及免疫***的病症(包括感染)中的用途。

Description

约氏乳杆菌La1 NCC533(CNCM I-1225)和免疫病症
本发明一般涉及预防和/或治疗炎症和感染病症领域，特别地通过加强内源的抗微生物防御来预防和/或治疗炎症和感染病症。本发明的一个实施方案是非复制的约氏乳杆菌(L.johnsonii)La1 NCC533(保藏号CNCMI-1225)在治疗或者预防涉及免疫***的病症(包括感染)中的用途。
我们的环境被大量潜在的致病微生物污染。皮肤角质形成细胞、内衬于胃肠道、呼吸道、泌尿生殖道的上皮细胞都提供了物理屏障，其保护机体免于微生物的侵入。
另外，这些上皮通过产生和分泌抗微生物剂以限制细菌和其他微生物的进入来帮助宿主防御。这些抗微生物分子组成天然免疫的基本防御线的关键组分。
防卫素是人体中抗微生物肽的最重要类型中的一种。防卫素由肺、皮肤、口腔、泌尿生殖道、呼吸道和胃肠道的上皮细胞产生。其中，有包括防卫素1(hBD1)和防卫素2(hBD2)的β-防卫素家族。
HBD1在多种黏膜表面如口腔黏膜、唾液腺、胃、小肠、结肠、肝和胰的表面表达。HBD2也存在于上皮细胞内的多种黏膜表面，包括胃肠道的黏膜表面。此外，这两种防卫素也存在于唾液和呼吸道表面液体中(Cunliffe，R.N.和Mahida，Y.R.2004，J Leukoc.Biol.75：49-58)。
HBD1组成型地表达并且从没有显示被细菌或者炎症一致地上调(Ou，G.，等人.，2009，Scand.J Immunol 69：150-161)。
公知益生菌能增强肠防御的多种体系：免疫排斥、免疫清除和免疫调节。已知益生菌也刺激针对微生物病原体的非特异的宿主抗性，并且因此帮助它们的清除。
然而，尽管如此，已经报道了组成型hBD1的表达不受益生细菌影响(O′Neil，D.A.等，J Immunol 163：6718-6724)，被共生(大肠杆菌)和致病(鼠伤寒杆菌)菌株轻微上调(Ou，G.，等人，2009，Scand.J Immunol 69：150-161)。
如今益生菌的应用在于减少与肠屏障功能异常相关的疾病的风险(E.Isolauri，等人，2002，Gut 2002；50：iii 54-iii 59)。益生菌通过在肠内存活，在酸和胆汁中的稳定性，以及在肠道中黏膜表面的暂时建群而被认为有效。
因此，大量出版文献涉及活的益生菌。然而，一些研究调查了非复制细菌传递的健康益处并且它们的大部分表明如通过热处理引起的益生菌的灭活导致它们据说的健康益处的丧失(Rachmilewitz，D.，等人.，2004，Gastroenterology 126：520-528；Castagliuolo，等人.，2005，FEMSImmunol.Med.Microbiol.43：197-204；Gill，H.S.和K.J.Rutherfurd，2001，Br.J.Nutr.86：285-289；Kaila，M.，等人.，1995，Arch.Dis.Child72：51-53.)。
今天在食品中运用存活细菌具有几个缺点。存活细菌通常不是非常抗胁迫的，并且因此难以以工业规模处理而保持活力。此外，由安全考虑，对于一些产品类别，将存活微生物加入到制剂中可能不是最优化的。因此，需要生物活性的非存活的微生物。
有利地，非复制的益生菌微生物的提供允许如粉末化的营养组合物的热重构同时保持对消费患者的健康益处。基于此，运用非复制的细菌代替它们活的对应物是所希望的，但是在这方面可得到的研究不是令人鼓舞的。
使用活的益生菌作为治疗或者预防炎性肠病的策略已经在文献中报道并且近来被Dotan等人综述(Dotan，I.和D.Rachmilewitz.2005；Curr.Opin.Gastroenterol.21：426-430)。例如，八种活的益生菌的高浓度混合物(VSL#3)已经显示在人体中复发的或者难治的隐窝炎的预防(Gionchetti，P.，等人.，2003，Gastroenterology 124：1202-1209)和治疗(Gionchetti，P.，等人.，2000，Gastroenterology 119：305-309；Mimura，T.，等人.，2004，Gut 53：108-114)中有效。有趣地，使用DSS诱导的结肠炎鼠模型，Rachmilewitz等人(Rachmilewitz，D.，等人，2004，Gastroenterology126：520-528)报道用存活的并且经γ-照射的VSL#3而非热灭活的VSL#3治疗保护抵抗结肠炎。相似地，热灭活的弯曲乳杆菌(L.crispatus)不能保护抵抗DSS诱导的结肠炎而它的存活的对应物明显地降低体重的减轻和肠中MPO的活性(Castagliuolo，等人，2005，FEMS Immunol.Med.Microbiol.43：197-204)。这些研究暗示在肠炎症的情况下活的益生菌比它们的非复制的对应物更有效。
发现灭活的弯曲乳杆菌(热灭活的和经γ-照射的)不能减少T84细胞的TNFα-诱导的IL-8产生，然而它的活的对应物展示了明显有益的效果(Ma，D.，等人，2004，Infect.Immun.72：5308-5314)。
因此，本领域需要在工业条件下易于处理的天然组合物，所述天然组合物对于施用是安全和容易的，并且所述天然组合物允许预防和/或治疗炎症和感染病症，特别是通过加强内源的抗微生物防御来预防和/或治疗炎症和感染病症。
理想地，天然组合物应该由益生菌培养物制备，特别地从现在广泛接受的并且被消费者认识用于传递健康益处的益生菌微生物来制备。有利地，组合物应该包含非复制的细菌，并且应该比包含了它们活的对应物更有效。
本发明人已经处理了该需要。
因此，本发明的目的是改进本领域现状并且提供天然组合物，所述组合物允许预防和/或治疗炎症和感染病症，特别地通过加强内源的抗微生物防御来预防和/或治疗炎症和感染病症，并且所述组合物满足上文列出的需要。
发明人惊奇地看到通过独立权利要求的主题，他们能实现本发明的目的。从属权利要求进一步地限定了本发明优选的实施方案。
本发明的主题通过施用包含微生物如非复制的微生物，例如热处理的微生物的产品加强了哺乳动物内源的抗微生物防御。
发明人描述了约氏乳杆菌(La1，NCC 533，保藏号CNCM I-1225)，特别是非复制的约氏乳杆菌(La1，NCC 533，保藏号CNCM I-1225)，例如热处理的约氏乳杆菌(La1，NCC 533，保藏号CNCM I-1225)在抗微生物肽表达的诱导上比文献中以前鉴定和描述的那些细菌具有更好的效果。
发现，例如：
-约氏乳杆菌(La1，NCC 533，保藏号CNCM I-1225)强烈地诱导组成型hBD1的表达，并且
-热处理的约氏乳杆菌(La1，NCC 533，保藏号CNCM I-1225)比它的活的对应物更强的上调hBD1。
hBD1展示对广谱细菌包括大肠杆菌和绿脓杆菌、幽门螺杆菌(H.pylori)的抗菌活性(Nuding，S.，等人.，2009，Microbes.Infect.11：384-393)，同时也展示对酵母如白假丝酵母(O′Neil，D.A.2003，Mol.Immunol40：445-450)的抗菌活性和对病毒(人免疫缺陷病毒)(Kota，S.Et al.，2008，J.Biol.Chem 283：22417-22429)的抗病毒活性。因此，这些抗微生物多肽可增强黏膜屏障并且因此限制细菌的黏附和侵入。
越来越多的证据表明在一些病理生理情况下防卫素的水平减少，并且在感染性和炎症疾病的发病机制和并发症中所述防卫素水平的减少是危险因素，如(Doss，M.et al.，2010，J Leukoc.Biol.87：79-92)；Rivas-Santiago，B.et al.，2009，Infect.Immun.77：4690-4695)所描述：
-在呼吸道中：
囊性纤维化、反应性呼吸道病、肺感染和吸烟、哮喘、肺炎、鼻炎、耳炎、窦炎、肺结核，
-在胃肠道中：
克隆病(结肠和回肠)、溃疡性结肠炎、幽门螺杆菌感染诱导的胃炎和胃溃疡、感染性腹泻、坏死性小肠结肠炎、抗生素相关的腹泻、乳糜泻、肠不成熟
-在泌尿生殖道中：
细菌性***病、HIV(人免疫缺陷病毒)、单纯疱疹病毒、***
-在皮肤中：
特应性皮炎、慢性溃疡、癌、特应性湿疹、烧伤
-在口腔中：
HIV患者、扁桃体炎、牙龈炎、龋齿
-眼中的角膜炎
本文列出的结果表明约氏乳杆菌La1(NCC 533，保藏号CNCMI-1225)比以前鉴定出的益生细菌具有更强的增强内源的抗微生物防御能力，并且因此在SIBO(小肠细菌的过度生长)、炎症和感染病症的预防和治疗中更有效。
另外，本发明数据表明-与文献中预期相反-热处理没有降低反而进一步增加了约氏乳杆菌La1(NCC 533，保藏号CNCM I-1225)的强抗微生物效果。
本发明的一个实施方案是包含约氏乳杆菌La1(NCC 533，保藏号CNCM I-1225)的组合物，其用于治疗和预防与免疫***相关的病症，包括感染。
根据本发明可以通过增加内源的hBD1表达来治疗或者预防与免疫***相关的病症。
本发明也涉及包含约氏乳杆菌La1(NCC 533，保藏号CNCM I-1225)的组合物用于病症的治疗或者预防，所述病症与降低的hBD1的表达联系，例如微生物感染。
本发明也涉及约氏乳杆菌La1(NCC 533，保藏号CNCM I-1225)在组合物的制备中的用途，所述组合物用于与免疫***相关的病症的治疗或者预防。
非复制的约氏乳杆菌La1(NCC 533，保藏号CNCM I-1225)至少可以部分地使用。非复制的，特别是热处理的约氏乳杆菌La1(NCC 533，保藏号CNCM I-1225)具有比它们活的对应物更有效的优点。
使用非复制的微生物如热处理的约氏乳杆菌La1(NCC 533，保藏号CNCM I-1225)代替它们活的对应物，具其他的优点：
-在敏感的目标群体中减少活的益生菌相关的脓毒的潜在风险，
-代表给免疫受损患者的安全备选，并且
-减少加工障碍，所述非复制的微生物可以整合到有长的货架期的货架稳定的液体产品中。
因此，在本发明的一个实施方案中，约氏乳杆菌La1(NCC 533，保藏号CNCM I-1225)至少90％，例如至少95％优选地至少98％，最优选的至少99％，理想的至少99.9％或者全部是非复制的。
本发明也涉及包含约氏乳杆菌La1(NCC 533，保藏号CNCM I-1225)的组合物，其中所述约氏乳杆菌La1(NCC 533，保藏号CNCM I-1225)至少95％，优选地至少98％，最优选的至少99％，理想的至少99.9％或者100％是非复制的。
因此，本发明也涉及生物活性的、非复制的例如热处理的约氏乳杆菌La1(NCC 533，保藏号CNCM I-1225)。
“非复制”的约氏乳杆菌La1(NCC 533，保藏号CNCM I-1225)包括已经经过热处理的约氏乳杆菌La1。该约氏乳杆菌La1包括灭活的、死的、无生活力的和/或以片段如DNA、代谢物、胞质化合物、和/或细胞壁物质存在的约氏乳杆菌La1(NCC 533，保藏号CNCM I-1225)。
“非复制”指的是通过经典的平板接种方法可以检测的无生活力的细胞和/或菌落形成单位。在微生物教科书中概述了这些经典的平板接种方法：James Monroe Jay，Martin J.Loessner，David A.Golden.2005.Modernfood microbiology.7th edition，Springer Science，New York，N.Y.790p。通常地，存活细胞的缺失可以如下显示：用不同浓度的细菌制备物(“非复制”的样品)接种并且在适合的条件(有氧和/或厌氧空气中持续至少24小时)下温育后，在琼脂平板上没有存活的菌落或者在液体生长培养基中没有增加的浊度。
约氏乳杆菌La1(NCC 533，保藏号CNCM I-1225)可以通过热灭活成为非复制的。热灭活可以在至少约70℃下发生。
任何热处理可用于灭活益生菌，只要它进行足够长的时间以便实现灭活。例如，该热处理可以进行至少10秒。
通常，高温需要短的加热时间，而更低的温度需要更长的加热时间。
例如，约氏乳杆菌La1(NCC 533，保藏号CNCM I-1225)在110°至140°持续1-30秒，例如10-20秒成为非复制的约氏乳杆菌La1。
该给定的时间范围指的是约氏乳杆菌La1在给定的温度下进行处理的时间。注意到取决于提供约氏乳杆菌La1的组合物的性质和量并且取决于使用的加热设备的结构，加热应用的时间可以不同。该温度处理可以在正常大气压下进行但也可以在高压力下进行。通常的压力范围是从1至50巴，优选地从1至10巴，更优选地从2至5巴。应用的理想压力将取决于提供了微生物的组合物的性质和使用的温度。
如果提供了约氏乳杆菌La1(NCC 533，保藏号CNCM I-1225)的组合物例如在进行包装和分配之前以任何方式进行热处理，可以优选地使用该热处理步骤来灭活La1 NCC 533。
通常，包含La1(NCC 533，保藏号CNCM I-1225)的组合物可以通过高温短时间(HTST)处理、巴氏瞬间灭菌法或者超高温(UHT)处理进行处理。
UHT处理是超高温加工或者超热处理(都缩写为UHT)，所述UHT处理涉及在超过135℃(275°F)的温度下通过短时间约1-10秒加热组合物进行至少部分灭菌，135℃是杀死奶中细菌孢子需要的温度。例如，用超过135℃的温度以这种方式加工奶允许在必要的保持时间(2-5秒)内降低细菌符合，使得能够进行连续流动操作。
有两种主要类型的UHT***：直接和间接***。在直接***中，通过蒸汽注射或者蒸汽注入处理产品，然而在间接***中，使用板式热交换器、管式热交换器或者刮面式换热器对产品进行热处理。在产品制备的方法中在任何步骤或者多个步骤应用UHT***的组合。
HTST处理定义如下(高温/短时间)：设计巴氏消毒法以实现奶中存活微生物5个数量级的减少，杀死99.9999％的存活微生物。认为该处理足够破坏几乎全部的酵母、霉菌和常见的腐败细菌并且也保证充分地破坏了常见致病的热抗性的生物。在HTST方法中，奶被加热到71.7℃(161°F)持续15-20秒。
巴氏瞬间灭菌法是易腐饮料如水果和蔬菜汁、啤酒和乳制品的热巴氏消毒法。巴氏瞬间灭菌法在产品装入容器之前进行以灭活腐败微生物，使产品更安全并且延长它们的货架期。当液体在71.5℃(160°F)至74℃(165°F)的温度下进行约15至30秒的处理时，在可控的持续流中移动。
为了本发明的目的，术语“短时间高温处理”也包括例如高温短时间(HTST)处理、UHT处理、和巴氏瞬间灭菌法。
本发明的组合物可以包含足够至少部分地治疗与免疫***相关的感染和病症和/或它们的并发症的量的La1。足够实现该治疗目的量被定义为“治疗有效剂量”。用于该目的的有效量将取决于本领域技术人员已知的很多因素如疾病的严重程度和消费者的体重和一般健康状况以及食品基质的效应。
在预防应用中，根据本发明的组合物以足够的量施用给易感染与免疫***相关的病症或者处在该病症的风险中的消费者，所述足够的量至少部分地降低患上此类病症的风险。这种量被定义为“预防有效剂量”。并且，该精确量取决于很多患者特异的因素，如患者的健康和体重状态以及食品基质的效应。
本领域技术人员将能适当地调节治疗有效剂量和/或预防有效剂量。
一般，本发明的组合物含有治疗有效剂量和/或预防有效剂量的La1(NCC 533，保藏号CNCM I-1225)。
通常，治疗有效剂量和/或预防有效剂量在每日剂量约0.005mg-1000mg La1范围内。
在数值的量方面，La1(NCC 533，保藏号CNCM I-1225)可以在组合物中以相应于每克干组合物104至1012当量cfu的量存在。显然，非复制的微生物不形成菌落，因此，该术语理解为从104至1012cfu/g复制细菌得到的非复制的微生物的量。该非复制的微生物包括灭活的、无生活力的、死的或以片段如DNA或细胞壁或胞质化合物存在的微生物。换句话说，组合物包含的微生物的数量按照该数量微生物的菌落形成能力(cfu)表述，就好像全部微生物是存活的一样，不考虑事实上它们是非复制的，如灭活的或者死的、碎片化的或者这些状态的任何或者全部的混合物。
例如，根据本发明组合物可以含有相应于每天剂量约104至1012cfu的量的约氏乳杆菌La1(NCC 533，保藏号CNCM I-1225)。
本发明组合物可以含有每日剂量约0.005mg-1000mg约氏乳杆菌La1(NCC 533，保藏号CNCM I-1225)。
本发明的组合物可以是任何类型的组合物。组合物可以经口、肠内、肠胃外(皮下或者肌内)、局部或者眼或者通过吸入例如直肠内和***施用。
因此，本发明的组合物可选自食物组合物、食品，包括宠物食品、饮料、用于完全营养的配方食品、营养补剂、营养药品、食品添加剂、药物组合物、化妆品组合物、药物和局部组合物。
可以添加益生元。在益生菌成为非复制的细菌之前益生元可以支持益生菌的生长。益生元也可以与组合物中存在的或者可被添加的存活的益生菌协同作用。
与免疫***相关的病症可以选自感染、特别地细菌、病毒、真菌和/或寄生虫的感染；炎症；吞噬细胞缺失；上皮屏障缺陷；免疫***不成熟，SIBO和它们的组合。
在本发明的一个实施方案中，包含约氏乳杆菌La1(NCC 533，保藏号CNCM I-1225)的组合物可用于微生物感染如病毒、真菌和/或寄生虫感染的治疗或预防。
与免疫***相关的病症也可以选自与防卫素特别是hBD1降低的水平相关的病症。这些病症可以选自囊性纤维化、反应性呼吸道病、吸烟引起的肺感染、哮喘、肺炎、鼻炎、耳炎、窦炎、肺结核、克隆病(结肠和回肠)、溃疡性结肠炎、乳糜泻、肠不成熟、幽门螺杆菌感染诱导的胃炎和胃溃疡、感染性腹泻、坏死性小肠结肠炎、抗生素相关的腹泻、细菌性***病、HIV、单纯疱疹病毒、***、特应性皮炎、慢性溃疡、癌、特应性湿疹、烧伤、扁桃体炎、牙龈炎、龋齿、眼中的角膜炎和所述病症的组合。
本发明的组合物可以用于加强内源的抗微生物防御。
例如通过加强内源的hBD1表达可以实现该目的。
本发明人已经发现约氏乳杆菌La1(NCC 533，保藏号CNCM I-1225)强烈地诱导组成型hBD1的表达，并且非复制的例如热处理的约氏乳杆菌La1(NCC 533，保藏号CNCM I-1225)比它的活的对应物更强地上调了hBD1的表达。
因此，本发明的主题也包含在与免疫***相关病症的治疗或预防中增加约氏乳杆菌La1(NCC 533，保藏号CNCM I-1225)有效性的方法，所述方法包括例如通过热处理使约氏乳杆菌La1(NCC 533，保藏号CNCMI-1225)成为非复制细菌的步骤。
与免疫***相关的病症例如可以是上文列出的病症之一。
在本发明的一个实施方案中，本方法包括在至少约70℃持续至少10秒的热处理步骤。
本领域的技术人员将理解他们可以自由的组合本文描述的本发明的所有特征，而不背离公开的本发明范围。特别地，用于描述本发明组合物的特征可以应用于本发明的用途和/或方法，反之亦然。
本发明其他的优点和特征从以下的实施例和附图中看是明显的。
图1显示与其他经热处理的菌株相比，在120℃-15秒热处理的La1(NCC 533，保藏号CNCM I-1225)强烈地诱导了体外肠上皮细胞中的hBD1 mRNA。T84细胞与经热处理的菌株一起培养4小时。用实时PCR分析hBD1的基因表达。条形代表对未刺激的细胞的基本表达归一化的平均值±sem。
图2显示La1(NCC 533，保藏号CNCM I-1225)的高温和短时间处理倾向于最好地诱导hBD1mRNA的表达。T84细胞用活的以及在120℃-15秒或在85℃-20分钟经热处理的La1(NCC 533，保藏号CNCM I-1225)刺激4小时。用实时PCR分析hBD1的基因表达。条形代表对未刺激的细胞的基本表达归一化的平均值±sem。
实施例
实验方案
使用传代30-40代的T84细胞并且在包含5％的胎牛血清(FCS)(Amined BioConcept)和2mM谷氨酰胺的Dulbecco改良的必需培养基/F-12(Sigma D 6421)中培养该T84细胞。以2×106细胞/每孔的浓度将细胞接种于6孔培养板，并且在5％CO2-95％空气37℃下该细胞生长成单细胞层。汇集后生长1周的细胞用血清和无抗生素的培养基培养至少12小时。该步骤对于消除血清诱导的防卫素的表达以及防止抗生素对益生菌和细胞免疫反应的任何影响是必需的。细胞进一步地与益生菌或者热处理的菌株培养4小时。在培养时间结束时，用PBS洗涤并且按照供应商的方案用TriPureTM分离试剂收获细胞。在如此处理的细胞中人hBD1和hBD2的基因表达用定量PCR评估。
在该实验中使用的细菌菌株是长双歧杆菌(B.longum)(NCC 2705，保藏号CNCM I-2618)，乳双歧杆菌(B.lactis)(NCC 2818，保藏号CNCMI-3446)，约氏乳杆菌(La1，NCC 533，保藏号CNCM I-1225)，类干酪乳杆菌(L.paracasei)(ST11，NCC 2461，保藏号CNCM I-2116)。这些菌株经检测是活的或者在120℃-15秒或者85℃-20分钟下进行热处理。
结果
与其他检测的热处理菌株比较，在120℃-15秒热处理的La1(NCC533，保藏号CNCM I-1225)在培养4小时后诱导了强烈的hBD1mRNA的表达(图1)。这些数据是独特的，因为hBD1的表达(组成型表达的)被如今科学界认为几乎不能被微生物、微生物产物或者炎症调节。
活的和热处理的La1(NCC 533，保藏号CNCM I-1225)都强烈地诱导hBD1 mRNA的表达，然而热处理的La1(高温和短时间处理)引发hBD1最高的诱导(图2)
打印输出
(该页不作为国际申请的一部分并且不认为是国际申请页)
Figure BDA0000125813520000121
Figure BDA0000125813520000131
仅供接受局使用
Figure BDA0000125813520000132
仅供国际局使用
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Claims (15)

1.包含约氏乳杆菌La1(NCC533，保藏号CNCM I-1225)的组合物，其用于治疗或预防与免疫***相关的病症，包括感染。
2.根据权利要求1的组合物，其中所述约氏乳杆菌La1(NCC533，保藏号CNCM I-1225)的至少90％，例如至少95％或者全部是非复制的。
3.根据权利要求2的组合物，其中所述非复制的约氏乳杆菌La1(NCC533，保藏号CNCM I-1225)是热灭活的，优选地通过至少约70℃下的处理进行热灭活。
4.根据权利要求3的组合物，其中所述热处理进行至少10秒。
5.根据权利要求2-4中一项的组合物，其中所述约氏乳杆菌La1(NCC533，保藏号CNCM I-1225)在110°至140°持续5-30秒成为非复制的细菌。
6.根据前面权利要求中一项的组合物，其中所述组合物包含每日剂量相应于约104至1012cfu的约氏乳杆菌La1(NCC533，保藏号CNCMI-1225)的量。
7.根据前面权利要求中一项的组合物，其中所述组合物包含每日剂量约0.005mg-1000mg的约氏乳杆菌La1(NCC533，保藏号CNCMI-1225)。
8.根据前面权利要求中一项的组合物，其中所述组合物选自食物组合物、食品，包括宠物食品、饮料、用于完全营养的配方食品、营养补剂、营养药品、食品添加剂、药物组合物、化妆品组合物、局部组合物和药物。
9.根据前面权利要求中一项的组合物，其中所述与免疫***相关的病症选自感染、特别是细菌、病毒、真菌和/或寄生虫的感染；炎症；吞噬细胞缺失；上皮屏障缺陷；免疫***不成熟；小肠细菌的过度生长(SIBO)和它们的组合。
10.根据前面权利要求中一项的组合物，其中所述与免疫***相关的病症选自与防卫素、特别是hBD1降低的水平相关的病症。
11.根据前面权利要求中一项的组合物，其中所述与hBD1降低的水平相关的病症选自囊性纤维化、反应性呼吸道病、吸烟引起的肺感染、哮喘、肺炎、鼻炎、耳炎、窦炎、肺结核、克隆病(结肠和回肠)、溃疡性结肠炎、乳糜泻、肠不成熟、幽门螺杆菌感染诱导的胃炎和胃溃疡、感染性腹泻、坏死性小肠结肠炎、抗生素相关的腹泻、细菌性***病、HIV、单纯疱疹病毒、***、特应性皮炎、慢性溃疡、癌、特应性湿疹、烧伤、扁桃体炎、牙龈炎、龋齿、眼中的角膜炎。
12.根据前面权利要求中一项的组合物，其用于增强内源的抗微生物防御和/或内源的hBD1表达。
13.在涉及免疫***的感染和病症的治疗或预防中增加约氏乳杆菌La1(NCC 533，保藏号CNCM I-1225)有效性的方法，所述方法包括使约氏乳杆菌La1成为非复制性的步骤。
14.根据权利要求13的方法，其中所述约氏乳杆菌La1(NCC 533，保藏号CNCM I-1225)通过在至少约70℃下至少约10秒的热处理步骤成为非复制细菌。
15.包含约氏乳杆菌La1(NCC 533，保藏号CNCM I-1225)的组合物，其中所述约氏乳杆菌La1(NCC 533，保藏号CNCM I-1225)的至少95％，优选地至少98％，最优选的至少99％，理想的至少99.9％或者100％是非复制的。
CN2010800289628A 2009-05-11 2010-05-07 约氏乳杆菌La1 NCC533(CNCM I-1225)和免疫病症 Pending CN102802648A (zh)

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