CN110114073A - 憩室形成和憩室病的治疗中使用的益生菌 - Google Patents
憩室形成和憩室病的治疗中使用的益生菌 Download PDFInfo
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- CN110114073A CN110114073A CN201780077730.3A CN201780077730A CN110114073A CN 110114073 A CN110114073 A CN 110114073A CN 201780077730 A CN201780077730 A CN 201780077730A CN 110114073 A CN110114073 A CN 110114073A
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Abstract
本发明涉及益生菌在结肠壁结构改变的对象中，优选在患有憩室形成的对象中，以及在受憩室病影响的对象中，控制结肠炎症进程的用途。
Description
技术领域
本发明涉及益生菌在结肠壁结构改变的对象中，优选在患有憩室形成的对象中，优选在受憩室病影响的对象中控制结肠炎症进程的用途。
现有技术
结肠憩室形成是结肠最常见的解剖学改变，通常在结肠镜检查中检测到。它指的是结肠壁的结构修改，其特征在于存在称为憩室的小袋。
虽然绝对多数患有结肠憩室形成的人无症状，但约有20％的患者出现症状。这种情况定义为憩室病。
在没有肉眼可见的结肠炎或憩室炎的情况下存在由憩室引起的持续性腹部症状的情况被定义为有症状无并发症的憩室病。
相反，憩室炎是憩室的急性肉眼可见的炎症，其可能存在或不存在并发症，这取决于在计算机断层扫描中是否观察到诸如脓肿，腹膜炎，阻塞，瘘管或出血等并发症的特征。
导致结肠憩室形成的病理机制仍不清楚。这些形成可能是饮食，肠道微生物群，遗传因素，结肠运动和微观炎症之间复杂相互作用的结果。所有这些因素也必须被视为憩室病治疗的潜在靶标。
其中，肠道微生物群的改变可能具有重要作用。最近，事实上，已经提供了关于憩室病患者微生物群体改变的影响的各种初步信息，这可能是导致失调过程的原因，例如有利于几种症状的发展，以及与此同时，它们可能会使他们容易发生憩室炎。
此外，近年来，许多发现表明炎症在确定症状和并发症的发展中具有重要作用。
事实上，已经观察到憩室病具有显著的微观炎性浸润。这种微观炎症，从较大的慢性淋巴细胞浸润到活跃的中性粒细胞浸润，似乎与疾病的严重程度有关。
此外，憩室疾病表现出促炎细胞因子如TNFα的更大表达。内窥镜和组织学确定的持续性炎症最近被确定为憩室炎复发的重要危险因素。
鉴于上述情况，非常需要鉴定能够控制结肠水平的炎症过程的产品，特别是预防/控制/治疗憩室病及其症状并防止其并发症的产品。
申请人已经发现基于细菌和/或酵母和/或其他微生物的益生菌作为上述需求的解决方案的用途。具体说，本发明提出使用属于乳杆菌属和/或双歧杆菌属的细菌，优选细菌菌种副干酪乳杆菌。
事实上，在给予益生菌之后，如下面详细描述的，在健康对象中，尤其是在受到肠道侵袭性诸如大肠杆菌等病原菌刺激/处理的各种形式的憩室形成患者中，观察到iNOS表达、促炎细胞因子和NO释放的下调。因此，给予益生菌，特别是基于属于乳杆菌属和/或双歧杆菌属的细菌，优选细菌菌种副干酪乳杆菌(Lactobacillus paracasei)，已经显示出有效治疗和/或预防各种形式的憩室病和/或与之相关的症状。
附图说明
下面将借助于以下附图并且具有不具有任何限制特征的实施例来详细描述本发明。
具体来说：
-图1显示了收集的样品中iNOS表达以及NO和S100B的释放的基础水平(对照，憩室形成，SUDD，SUDD+AD)。
-图2显示收集的样品中A)IL-1β，B)IL-6和C)IL-10的表达的基础水平(对照，憩室形成，SUDD，SUDD+AD)。
-图3显示了在所检查的样品中细菌刺激之前和之后的iNOS表达水平(A-对照，B-憩室形成，C-SUDD，D-SUDD+AD)。
-图4显示了在所检查的样品中细菌刺激和之后释放的NO水平(A-对照，B-憩室形成，C-SUDD，D-SUDD+AD)。
-图5显示了在所检查的样品中细菌刺激之前和之后蛋白质S100B的释放水平(A-对照，B-憩室形成，C-SUDD，D-SUDD+AD)。
具体实施方式
本发明的第一方面涉及益生菌用于治疗和/或预防和/或改善与憩室形成，特别是憩室病相关的症状的用途。憩室病优选是有症状无并发症的憩室病(SUDD)，或与憩室形成相关的节段性结肠炎(SCAD)。本发明一般参考的有症状或无症状憩室病相关的憩室形成伴有NO和/或iNOS和/或至少一种促炎细胞因子的过表达，优选选自TNFα、IL1β、IL-6b、IL-10及其组合。出于本发明的目的，益生菌可以作为任何旨在治疗或预防憩室形成和上述优选形式的疗法的辅助试剂，即服用益生菌，优选定期服用，如下面更详细描述的，显示有利于旨在治疗和/或预防不同形式的该病的目前可用的治疗方法的积极结果。因此，旨在治疗和/或预防和/或改善与憩室形成相关的症状，特别是无症状憩室形成和/或憩室病的益生菌的使用可与其他治疗方法相关联或联合，优选药理学或社会行为学类型，例如健康的生活方式或饮食。
本文中，“益生菌”的定义是由粮农组织(FAO)和世界卫生组织(WHO)于2001年联合召集的一组专家制定的：“活的微生物，其在足量给予时赋予宿主健康益处”。特别是在意大利，卫生部将益生菌定义为“一旦摄入足够量就能发挥有益于身体的功能的微生物”，基本上与上述两个组织的定义相呼应。
本发明涉及的益生菌基于细菌和/或酵母和/或其他微生物。
根据本发明的一个优选方面，细菌优选属于选自以下的属：乳杆菌属，双歧杆菌属，芽孢杆菌属，丙酸杆菌属，链球菌属，乳球菌属，气球菌属，肠球菌及其组合。对于本发明的目的而言优选的属是乳杆菌属和/或双歧杆菌属。
根据本发明的另一个优选方面，乳杆菌属的细菌属于以下菌种中的至少一种：副干酪乳杆菌(Lactobacillus paracasei)、嗜酸乳杆菌(Lactobacillus acidophilus)、鼠李糖乳杆菌(Lactobacillus rhamnosus)、解淀粉类乳杆菌(Lactobacillusamylolyticus)、嗜淀粉乳杆菌(Lactobacillus amylovorus)、食品乳杆菌(Lactobacillusalimentarius)、鸟乳杆菌(Lactobacillus aviaries)、短乳杆菌(Lactobacillusbrevis)、布氏乳杆菌(Lactobacillus buchneri)、干酪乳杆菌(Lactobacillus casei)、纤维二糖乳杆菌(Lactobacillus cellobiosus)、棒状乳杆菌(Lactobacilluscoryniformis)、卷曲乳杆菌(Lactobacillus crispatus)、弯曲乳杆菌(Lactobacilluscurvatus)、德氏乳杆菌(Lactobacillus delbrueckii)、香肠乳杆菌(Lactobacillusfarciminis)、发酵乳杆菌(Lactobacillus fermentum)、鸡乳杆菌(Lactobacillusgallinarum)、加氏乳杆菌(Lactobacillus gasseri)、瑞士乳杆菌(Lactobacillushelveticus)、希氏乳杆菌(Lactobacillus hilgardii)、约氏乳杆菌(Lactobacillusjohnsonii)、马乳样乳杆菌(Lactobacillus kefiranofaciens)、开菲尔乳杆菌(Lactobacillus kefiri)、粘膜乳杆菌(Lactobacillus mucosae)、面包乳杆菌(Lactobacillus panis)、丘状乳杆菌(Lactobacillus collinoides)、类植物乳杆菌(Lactobacillus paraplantarum)、戊糖乳杆菌(Lactobacillus pentosus)、植物乳杆菌(Lactobacillus plantarum)、蓬蒂乳杆菌(Lactobacillus pontis)、罗伊氏乳杆菌(Lactobacillus reuteri)、清酒乳杆菌(Lactobacillus sakei)、唾液乳杆菌(Lactobacillus salivarius)和旧金山乳杆菌(Lactobacillus sanfranciscensis)。
对于本发明的目的特别优选的是细菌菌种副干酪乳杆菌(Lactobacillusparacasei)，优选菌株(副干酪乳杆菌CNCM I-1572)。
副干酪乳杆菌细菌(Lactobacillus paracasei CNCM I1572)由索发股份公司(SOFAR S.p.A.)于05/05/1995在巴黎的巴斯德研究所的国家微生物保藏中心(CNCM)保藏，保藏号为CNCM I-1572。
根据本发明的另一个优选方面，双歧杆菌属的细菌属于以下菌种中的至少一种：B.动物双歧杆菌(B.animalis)、双歧双歧杆菌(B.bifidum)、短双歧杆菌(B.breve)、婴儿双歧杆菌(B.infantis)、长双歧杆菌(B.longum)、青春双歧杆菌(B.adolescentis)、链状双歧杆菌(B.catenulatum)、角双歧杆菌(B.angulatum)、小行星双歧杆菌(B.asteroids)、布氏双歧杆菌(B.boum)、豚双歧杆菌(B.choerinum)、棒状双岐杆菌(B.coryneforme)、串孔双歧杆菌(B.cuniculi)、齿垢双歧杆菌(B.denticolens)、齿双歧杆菌(B.dentium)、高卢双歧杆菌(B.gallicum)、加氏沙门氏菌(B.gallinarum)、印度双歧杆菌(B.indicum)、奇异双歧杆菌(B.inopinatum)、乳酸双歧杆菌(B.lactis)、大黑盘双歧杆菌(B.magnum)、瘤胃双歧杆菌(B.merycicum)、最小双歧杆菌(B.minimum)、假小链双歧杆菌(B.pseudocatenulatum)、伪长双歧杆菌(B.pseudolongum)、小鸡双歧杆菌(B.pullorum)、反刍月形双歧杆菌(B.ruminantium)、世纪双歧杆菌(B.saeculare)、细弱双歧杆菌(B.subtile)、嗜酸嗜热双歧杆菌(B.thermacidophilum)、嗜热双歧杆菌(B.thermophilum)和图氏双歧杆菌(B.tsurumiense)。
根据本发明的另一个优选方面，芽孢杆菌属的细菌属于以下菌种中的至少一种：克氏芽孢杆菌(Bacillus clausii)、枯草芽孢杆菌(Bacillus subtilis)、凝结芽孢杆菌(Bacillus coagulans)、巨大芽孢杆菌(Bacillus megaterium)、嗜碱芽孢杆菌(Bacillushalodurans)、苏云金芽孢杆菌(Bacillus thuringiensis)、无色芽孢杆菌(Bacillusinsolitus)和海洋芽孢杆菌(Bacillus marinus)。
根据本发明的另一个优选方面，丙酸杆菌属的细菌属于以下菌种中的至少一种：谢氏丙酸杆菌(P.shermanii)、疮疱丙酸杆菌(P.acnes)、太空丙酸杆菌(P.australiense)、贪婪丙酸杆菌(P.avidum)、环己丙酸杆菌(P.cyclohexanicum)、费氏丙酸杆菌(P.freudenreichii)、颗粒丙酸杆菌(P.granulosum)、詹氏丙酸杆菌(P.jensenii)、微需氧丙酸杆菌(P.microaerophilum)、丙酸丙酸杆菌(P.propionicum)和特氏丙酸杆菌(P.thoenii)。
根据本发明的另一个优选方面，链球菌属的细菌属于以下菌种中的至少一种：嗜热链球菌(Streptococcus thermophilus)、唾液链球菌(Streptococcus salivarius)、无乳链球菌(Streptococcus agalactiae)、咽峡炎链球菌(Streptococcus anginosus)、牛链球菌(Streptococcus bovis)、犬链球菌(Streptococcus canis)、星群链球菌(Streptococcus constellatus)、汗毛链球菌(Streptococcus downei)、停乳链球菌(Streptococcus dysgalactiae)、马肠链球菌(Streptococcus equinus)、野鼠链球菌(Streptococcus ferus)、婴儿链球菌(Streptococcus infantarius)、海豚链球菌(Streptococcus iniae)、中间链球菌(Streptococcus intermedius)、米勒链球菌(Streptococcus milleri)、轻型链球菌(Streptococcus mitis)、变异链球菌(Streptococcus mutans)、口腔链球菌(Streptococcus oralis)、鼠口腔链球菌(Streptococcus orisratti)、副血链球菌(Streptococcus parasanguinis)、泛口腔链球菌(Streptococcus peroris)、肺炎链球菌(Streptococcus pneumoniae)、假肺炎链球菌(Streptococcus pseudopneumoniae)、化脓性链球菌(Streptococcus pyogenes)、鼠链球菌(Streptococcus ratti)、替格涅斯链球菌(Streptococcus tigurinus)、血链球菌(Streptococcus sanguinis)、表兄链球菌(Streptococcus sobrinus)、猪链球菌(Streptococcus suis)、乳链球菌(Streptococcus uberis)、前庭链球菌(Streptococcusvestibularis)、草绿色链球菌(Streptococcus viridians)和兽疫链球菌(Streptococcuszooepidemicus)。
根据本发明的另一个优选方面，乳球菌属的细菌属于以下菌种中的至少一种：春氏乳球菌(L.chungangensis)、台湾桧木乳球菌(L.formosensis)、弗氏乳球菌(L.fujiensis)、格氏乳球菌(L.garvieae)、乳酸乳球菌(L.lactis)、雌蕊乳球菌(L.piscium)、植物乳球菌(L.plantarum)、棉籽糖乳球菌(L.raffinolactis)和台湾乳球菌(L.taiwanensis)。
根据本发明的另一个优选方面，气球菌属的细菌属于以下菌种中的至少一种：尿道气球菌(A.urinae)、血气球菌(A.sanguinicola)、柯氏气球菌(A.christensenii)、猪气球菌(A.suis)、马脲气球菌(A.urinaeequi)和人尿气球菌(A.urinaehominis)。
根据本发明的另一个优选方面，肠球菌属的细菌属于以下菌种中的至少一种：鸟肠球菌(Enterococcus avium)、坚韧肠球菌(Enterococcus durans)、粪肠球菌(Enterococcus faecalis)、屎肠球菌(Enterococcus faecium)、鹑鸡肠球菌(Enterococcus gallinarum)、溶过氧化肠球菌(Enterococcus haemoperoxidus)、海氏肠球菌(Enterococcus hirae)、病臭肠球菌(Enterococcus malodoratus)、莫拉氏肠球菌(Enterococcus moraviensis)、蒙氏肠球菌(Enterococcus mundtii)、假鸟肠球菌(Enterococcus pseudoavium)、棉子糖肠球菌(Enterococcus raffinosus)和孤立肠球菌(Enterococcus solitaries)。
根据本发明的另一个优选方面，酵母优选属于酵母属(Saccharomyces)，更优选属于酿酒酵母(Saccharomyces cerevisiae)和/或布拉酵母(Saccharomyces boulardii)。
本发明的另一个方面涉及包含如上所述的益生菌的组合物。
本发明组合物的微生物优选是活的，由此所述组合物也可被定义为益生剂。或者，可用微生物是死的或减活的(tyndallized)。
在另一实施方式中，微生物是裂解物或提取物的形式，因此组合物也可以定义为是间益生菌属性的(paraprobiotic)，或单一组分，或其几种组分，以细菌壁水平存在。
在本发明的另一实施方式中，组合物还包含称为后益生菌(postbiotics)的微生物产生的代谢生物产物和/或细菌衍生的各种其他产物。因此，本发明的组合物又称为或又被认为是益生菌或间益生菌或后益生菌或细菌壁组分。
一般而言，本发明组合物中包含的微生物是EFSA的QPS列表中包括的单一微生物或任何微生物物种的组合。
优选地，组合物中包含的细菌能够在胃肠道转运中存活，并因此能够活着到达结肠。
每次给予，本发明的微生物优选以10至1,000亿，更优选100至750亿，甚至更优选150至500亿，最优选200至300亿个细胞，优选细菌细胞的量施用。
根据一个优选的方面，微生物(优选细菌)的给予每天至少进行1-2次。
在本发明中设想了每种给予途径。优选地，组合物和/或益生菌(优选基于细菌)的施用是口服的，更优选以丸剂，胶囊，片剂，粒状粉末，硬壳胶囊，口服溶解颗粒，小药囊，锭剂或可饮用小瓶的形式。
或者，本发明的组合物和/或益生菌(优选基于细菌)被配制成液体，例如糖浆或饮料，或者它(它们)被添加到食物中，例如酸奶、奶酪或果汁中。或者，本发明的组合物和/或益生菌(优选基于细菌)以能够进行局部作用的形式配制，例如作为灌肠剂。
本发明涉及的组合物和/或益生菌的口服制剂(优选基于细菌)还包含通常可用于生产益生菌和/或药物产品的赋形剂。
根据本发明的一个优选方面，该组合物还包含抗结块剂，优选二氧化硅或硬脂酸镁。
根据本发明的一个优选方面，该组合物还包含包衣试剂，优选明胶。
在本发明的另一实施方案中，本发明的组合物包含维生素，微量元素，优选锌或硒，酶和/或益生元物质，优选低聚果糖(FOS)，低聚半乳糖(GOS)，菊粉，瓜尔胶或其组合。
实施例
本发明的实验研究基于从40名患者分离的活组织检查样品。因此，如下分配对象：
-10例患有无症状的憩室形成的患者，其中3例为女性；年龄：59-77；
-10例患有有症状性无并发症的憩室形成的(SUDD)患者，其中3例为女性；年龄：44-92；
-10例患有急性憩室炎然后是有症状无并发症的憩室病的患者，其中2例为女性；年龄：31-77；
-10例无胃肠道问题的患者，其中6例为女性；年龄：33-75。
从每位患者的乙状结肠获得6个活组织检查样品；在患有憩室的患者中，活组织检查在其附近被分离。
所有患者均获得知情同意，并获得了那不勒斯费德里科二世大学(University ofNaples Federico II)伦理委员会的批准。
将极化的活组织检查物置于无菌金属网格上，粘膜侧朝下，浆膜侧朝上。然后将金属网格置于器官培养皿的中心24小时，并在95％氧气和5％CO2存在下在37℃下保持在DMEM-F12中。然后用浆膜侧水平的致病菌和/或益生菌刺激活组织检查，如表I所示。
表I
实验中使用的致病菌是：肠侵袭性大肠杆菌(EIEC)；测试的益生菌是干酪乳杆菌(副干酪乳杆菌CNCM I-1572；LCDG)。选择前者是因为其对胃肠道的有害影响，选择后者是因为其益生菌作用。
随后回收上清液并用RIPA缓冲液处理活组织检查样品。两者均在-80℃下冷冻。
如Turco,F.等人(2015)所述，通过蛋白质印迹控制蛋白质提取。使用的抗体是：兔抗iNOS(1:500体积/体积)或小鼠抗α肌动蛋白(1:1000体积/体积)。
使用Turco,F.等人(2015)中描述的相同技术测量一氧化氮(NO)。
在用于测量S100B的ELISA测试(酶联免疫吸附测定)的情况下，遵循的方案是制造商手册中描述的方案。
统计分析包括方差分析和Bonferroni多重比较检验。提供的数据是实验的平均值±SD。统计学显著性水平固定在p<0.05。
iNOS表达以及NO、S100B和细胞因子的释放的基础水平
测量胃肠道中炎症介质的表达和释放的基础水平。
憩室形成患者的iNOS表达水平高于健康受试者(图1A)。
患有有症状无并发症的憩室病(SUDD)和先有急性憩室炎然后是有症状无并发症的憩室病(SUDD+AD)的患者与健康受试者相比iNOS表达显示出更大的差异(与对照相比，+2.04和+2.86倍-图1A)。
无症状憩室形成的患者和SUDD患者的NO释放量略高于健康受试者(图1B)。SUDD+AD患者显示出更显著的差异(与对照相比为+7.77倍-图1B)。
图1C中显示的数据表明蛋白质S100B的表达没有显著差异(之前与NO的释放相关)。
此外，与健康受试者相比，证实了细胞因子IL-1β释放的增加，尤其是在SUDD+AD患者中(图2A)。对于细胞因子IL-6也观察到相同的模式(图2B)。至于IL-10，特别是在SUDD+AD患者中观察到释放水平的增加(图2C)。
细菌刺激对iNOS表达的影响。
随后在健康受试者和具有各种类型憩室形成的对象中测试细菌刺激后对炎症介质表达的所述值的影响。
具体说，评估了粘膜活组织检查中的iNOS表达。
在健康(对照)受试者中，用EIEC刺激导致iNOS表达增加(与基础相比+2.11-图3A)。在EIEC之前或之后添加LCDG不改变iNOS表达，而当LCDG与EIEC一起添加时，观察到iNOS表达的显著降低(与仅用EIEC刺激相比，为-1.50倍-图3A)。
在患有憩室形成的患者中，EIEC的存在增加了iNOS表达(与基础相比增加2.86倍-图3B)。在这种情况下，与单独使用EIEC的刺激相比，添加LCDG导致iNOS表达水平降低，而不管细菌被添加到EIEC的时刻(图3B)。
在患有SUDD和SUDD+AD的患者中，用EIEC刺激导致iNOS表达增加(与基础相比+2.14-图3C)。在这种情况下，如果与EIEC一起使用，LCDG的作用更有效(图3C)。用LCDG刺激在任何情况下都不会导致iNOS表达水平的增加。
细菌刺激对NO释放的影响。
在健康受试者的样品中，在用EIEC刺激后NO的释放显著增加(图4A)。在EIEC之前，之后或与EIEC一起添加LCDG显著改变了NO的基础值。
在无症状憩室形成和SUDD患者中观察到相同的效果。事实上，EIEC的施用增加了NO的释放，并且LCDG的存在抵消了这种效应(图4B和4C)，而不管何时添加LCDG。
SUDD+AD患者显示出非常高的NO释放基础水平，因此EIEC的引入并未使这些对象显著增加。由于非常高的基础水平，LCDG的添加同样没有引起NO释放水平的任何变化(图4D)。
在对照中，用EIEC刺激引起S100B释放的增加(与基础相比约为+2.7倍，p<0.05-图5A)。在施用EIEC后，用LCDG和EIEC同时刺激引起S100B增加的减少(与EIEC相比为-2.90倍，p<0.05-图5A)。
上述结果表明炎症系统的激活依赖于NO(并且与iNOS表达相关)导致NO的释放，其从憩室形成到SUDD+AD患者逐渐增加。INOS表达遵循相同的趋势。特别是在憩室形成(相对于对照增加1.5)，SUDD(相对于对照增加2)和SUDD+AD(相对于对照增加3)中。此外，还证明了给予LCDG可以防止观察到的效果。特别是，LCDG能够抵抗病原菌的影响，特别是在患有SUDD+AD的对象中。
这些数据清楚地表明，LCDG可以有效地用作预防和/或治疗的益生菌，用于患有憩室形成的对象，特别是憩室病SUDD和SUDD+AD，和/或与之相关的症状。
PCT/RO/134表
Claims (13)
1.包含细菌和/或酵母和/或其他微生物的益生菌在治疗和/或预防和/或减轻与有症状和无症状的憩室形成，优选憩室病相关的症状中的用途，其中所述细菌属于选自以下的至少一种：乳杆菌(Lactobacillus)、双歧杆菌(Bifidobacterium)、芽孢杆菌(Bacillus)、丙酸杆菌(Propionibacterium)、链球菌(Streptococcus)、乳球菌(Lactococcus)、气球菌(Aerococcus)、肠球菌(Enterococcus)及其组合。
2.如权利要求1所述的用途，其中，所述憩室病是有症状无并发症的憩室病(SUDD)，或与憩室形成相关的节段性结肠炎(SCAD)。
3.如权利要求1或2所述的用途，其中，所述与有症状和无症状的憩室病相关的憩室形成与NO和/或iNOS和/或至少一种促炎细胞因子的过表达相关，所述促炎细胞因子优选选自TNFα，IL1β，IL-6b，IL-10及其组合。
4.如权利要求1-3中任一所述的用途，其中，所述细菌属选自：乳杆菌，双歧杆菌。
5.如权利要求1-4中任一项所述的用途，其中，所述乳杆菌属的细菌属于以下菌种中的至少一种：副干酪乳杆菌(Lactobacillus paracasei)、嗜酸乳杆菌(Lactobacillusacidophilus)、鼠李糖乳杆菌(Lactobacillus rhamnosus)、解淀粉类乳杆菌(Lactobacillus amylolyticus)、嗜淀粉乳杆菌(Lactobacillus amylovorus)、食品乳杆菌(Lactobacillus alimentarius)、鸟乳杆菌(Lactobacillus aviaries)、短乳杆菌(Lactobacillus brevis)、布氏乳杆菌(Lactobacillus buchneri)、干酪乳杆菌(Lactobacillus casei)、纤维二糖乳杆菌(Lactobacillus cellobiosus)、棒状乳杆菌(Lactobacillus coryniformis)、卷曲乳杆菌(Lactobacillus crispatus)、弯曲乳杆菌(Lactobacillus curvatus)、德氏乳杆菌(Lactobacillus delbrueckii)、香肠乳杆菌(Lactobacillus farciminis)、发酵乳杆菌(Lactobacillus fermentum)、鸡乳杆菌(Lactobacillus gallinarum)、加氏乳杆菌(Lactobacillus gasseri)、瑞士乳杆菌(Lactobacillus helveticus)、希氏乳杆菌(Lactobacillus hilgardii)、约氏乳杆菌(Lactobacillus johnsonii)、马乳样乳杆菌(Lactobacillus kefiranofaciens)、开菲尔乳杆菌(Lactobacillus kefiri)、粘膜乳杆菌(Lactobacillus mucosae)、面包乳杆菌(Lactobacillus panis)、丘状乳杆菌(Lactobacillus collinoides)、类植物乳杆菌(Lactobacillus paraplantarum)、戊糖乳杆菌(Lactobacillus pentosus)、植物乳杆菌(Lactobacillus plantarum)、蓬蒂乳杆菌(Lactobacillus pontis)、罗伊氏乳杆菌(Lactobacillus reuteri)、清酒乳杆菌(Lactobacillus sakei)、唾液乳杆菌(Lactobacillus salivarius)和旧金山乳杆菌(Lactobacillus sanfranciscensis)，优选的细菌菌种是副干酪乳杆菌，更优选的菌种是副干酪乳杆菌DG。
6.如权利要求1-5中任一项所述的用途，其中，所述双歧杆菌属的细菌属于以下菌种中的至少一种：动物双歧杆菌(B.animalis)、双歧双歧杆菌(B.bifidum)、短双歧杆菌(B.breve)、婴儿双歧杆菌(B.infantis)、长双歧杆菌(B.longum)、青春双歧杆菌(B.adolescentis)、链状双歧杆菌(B.catenulatum)、角双歧杆菌(B.angulatum)、小行星双歧杆菌(B.asteroids)、布氏双歧杆菌(B.boum)、豚双歧杆菌(B.choerinum)、棒状双岐杆菌(B.coryneforme)、串孔双歧杆菌(B.cuniculi)、齿垢双歧杆菌(B.denticolens)、齿双歧杆菌(B.dentium)、高卢双歧杆菌(B.gallicum)、加氏沙门氏菌(B.gallinarum)、印度双歧杆菌(B.indicum)、奇异双歧杆菌(B.inopinatum)、乳酸双歧杆菌(B.lactis)、大黑盘双歧杆菌(B.magnum)、瘤胃双歧杆菌(B.merycicum)、最小双歧杆菌(B.minimum)、假小链双歧杆菌(B.pseudocatenulatum)、伪长双歧杆菌(B.pseudolongum)、小鸡双歧杆菌(B.pullorum)、反刍月形双歧杆菌(B.ruminantium)、世纪双歧杆菌(B.saeculare)、细弱双歧杆菌(B.subtile)、嗜酸嗜热双歧杆菌(B.thermacidophilum)、嗜热双歧杆菌(B.thermophilum)和图氏双歧杆菌(B.tsurumiense)。
7.如权利要求1-6中任一项所述的用途，其中：1)所述芽孢杆菌属的细菌属于以下菌种中的至少一种：克氏芽孢杆菌(Bacillus clausii)、枯草芽孢杆菌(Bacillus subtilis)、凝结芽孢杆菌(Bacillus coagulans)、巨大芽孢杆菌(Bacillus megaterium)、嗜碱芽孢杆菌(Bacillus halodurans)、苏云金芽孢杆菌(Bacillus thuringiensis)、无色芽孢杆菌(Bacillus insolitus)和海洋芽孢杆菌(Bacillus marinus)；和/或2)所述丙酸杆菌属的细菌属于以下菌种中的至少一种：谢氏丙酸杆菌(P.shermanii)、疮疱丙酸杆菌(P.acnes)、太空丙酸杆菌(P.australiense)、贪婪丙酸杆菌(P.avidum)、环己丙酸杆菌(P.cyclohexanicum)、费氏丙酸杆菌(P.freudenreichii)、颗粒丙酸杆菌(P.granulosum)、詹氏丙酸杆菌(P.jensenii)、微需氧丙酸杆菌(P.microaerophilum)、丙酸丙酸杆菌(P.propionicum)和特氏丙酸杆菌(P.thoenii)；和/或3)所述链球菌属的细菌属于以下菌种中的至少一种：嗜热链球菌(Streptococcus thermophilus)、唾液链球菌(Streptococcus salivarius)、无乳链球菌(Streptococcus agalactiae)、咽峡炎链球菌(Streptococcus anginosus)、牛链球菌(Streptococcus bovis)、犬链球菌(Streptococcus canis)、星群链球菌(Streptococcus constellatus)、汗毛链球菌(Streptococcus downei)、停乳链球菌(Streptococcus dysgalactiae)、马肠链球菌(Streptococcus equinus)、野鼠链球菌(Streptococcus ferus)、婴儿链球菌(Streptococcus infantarius)、海豚链球菌(Streptococcus iniae)、中间链球菌(Streptococcus intermedius)、米勒链球菌(Streptococcus milleri)、轻型链球菌(Streptococcus mitis)、变异链球菌(Streptococcus mutans)、口腔链球菌(Streptococcus oralis)、鼠口腔链球菌(Streptococcus orisratti)、副血链球菌(Streptococcus parasanguinis)、泛口腔链球菌(Streptococcus peroris)、肺炎链球菌(Streptococcus pneumoniae)、假肺炎链球菌(Streptococcus pseudopneumoniae)、化脓性链球菌(Streptococcus pyogenes)、鼠链球菌(Streptococcus ratti)、替格涅斯链球菌(Streptococcus tigurinus)、血链球菌(Streptococcus sanguinis)、表兄链球菌(Streptococcus sobrinus)、猪链球菌(Streptococcus suis)、乳链球菌(Streptococcusuberis)、前庭链球菌(Streptococcus vestibularis)、草绿色链球菌(Streptococcusviridians)和兽疫链球菌(Streptococcus zooepidemicus)；和/或4)所述乳球菌属的细菌属于以下菌种中的至少一种：春氏乳球菌(L.chungangensis)、台湾桧木乳球菌(L.formosensis)、弗氏乳球菌(L.fujiensis)、格氏乳球菌(L.garvieae)、乳酸乳球菌(L.lactis)、雌蕊乳球菌(L.piscium)、植物乳球菌(L.plantarum)、棉籽糖乳球菌(L.raffinolactis)和台湾乳球菌(L.taiwanensis)；和/或5)所述气球菌属的细菌属于以下菌种中的至少一种：尿道气球菌(A.urinae)、血气球菌(A.sanguinicola)、柯氏气球菌(A.christensenii)、猪气球菌(A.suis)、马脲气球菌(A.urinaeequi)和人尿气球菌(A.urinaehominis)；和/或6)所述肠球菌属的细菌属于以下菌种中的至少一种：鸟肠球菌(Enterococcus avium)、坚韧肠球菌(Enterococcus durans)、粪肠球菌(Enterococcusfaecalis)、屎肠球菌(Enterococcus faecium)、鹑鸡肠球菌(Enterococcus gallinarum)、溶过氧化肠球菌(Enterococcus haemoperoxidus)、海氏肠球菌(Enterococcus hirae)、病臭肠球菌(Enterococcus malodoratus)、莫拉氏肠球菌(Enterococcus moraviensis)、蒙氏肠球菌(Enterococcus mundtii)、假鸟肠球菌(Enterococcus pseudoavium)、棉子糖肠球菌(Enterococcus raffinosus)和孤立肠球菌(Enterococcus solitaries)。
8.如权利要求1-7中任一项所述的用途，其中，所述酵母属于酵母属，优选酿酒酵母(Saccharomyces cerevisiae)和/或布拉氏酵母(Saccharomyces boulardii)。
9.如权利要求1-8中任一项所述的用途，其中，所述微生物是活的和/或死的和/或减活的和/或作为裂解物和/或提取物。
10.如权利要求1-9中任一项所述的用途，进一步包含由微生物产生的代谢产物和/或源自微生物的任何其他产物。
11.如权利要求1-10中任一项所述的用途，其中，所述微生物，优选细菌，摄取量为每剂量10亿至1000亿，优选100-750亿，更优选150-500亿，更优选200-300亿个细胞，优选所述剂量每天提供1-2次。
12.如权利要求1-11中任一项所述的用途，其中所述剂量，优选基于细菌，用于口服给予，优选作为丸剂，胶囊，片剂，粒状粉末，硬壳胶囊，口服溶解颗粒，小药囊，锭剂或可饮用小瓶的形式。
13.如权利要求1-11中任一项所述的用途，其中，所述益生菌，优选基于细菌，配制成液体，优选作为糖浆或作为饮料，或者将它们加入食物中，优选加入酸奶、干酪或果汁中；或者，优选基于细菌的益生菌被配制成作用于局部的制剂，优选作为灌肠剂。
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113862184A (zh) * | 2021-05-19 | 2021-12-31 | 湖南农业大学 | 一株粪肠球菌mg 2108及其应用 |
Families Citing this family (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ITMI20131467A1 (it) | 2013-09-06 | 2015-03-07 | Sofar Spa | Uso di una composizione comprendente microrganismi per aumentare la produzione intestinale di acido butirrico, di acido folico o di niacina e/o per diminuire la produzione intestinale di acido succinico |
| MA39710A (fr) | 2014-04-23 | 2015-10-29 | Sofar Spa | Composition topique destinée à être utilisée dans le traitement d'une maladie inflammatoire de l'intestin |
| MA45327A (fr) | 2016-05-13 | 2019-03-20 | Sofar Spa | Utilisation de probiotiques pour améliorer l'absorption des protéines |
| MA45288A (fr) | 2016-06-08 | 2019-04-17 | Sofar Spa | Nouvelle utilisation médicale de probiotiques |
| IT201600122724A1 (it) | 2016-12-02 | 2018-06-02 | Sofar Spa | Exopolysaccharides and uses thereof |
| IT201600127498A1 (it) | 2016-12-16 | 2018-06-16 | Sofar Spa | Probiotici per uso nella diverticolosi e malattia diverticolare |
| CN109576185B (zh) | 2018-12-26 | 2020-07-03 | 江南大学 | 一种具有抗流感能力的益生菌混合制剂及其应用 |
| US11751597B2 (en) | 2019-11-05 | 2023-09-12 | Alfasigma S.P.A. | Compositions comprising bacterial strains for use in increasing the bioavailability of amino acids derived from proteins, and related food product methods and systems |
| CN115551990A (zh) * | 2020-02-26 | 2022-12-30 | Gi生物群系公司 | 瑞士乳杆菌菌株及含有其的用于预防或治疗炎性疾病的组合物 |
| CN114874944B (zh) * | 2022-05-24 | 2023-04-18 | 西南大学 | 一株控制辣椒细菌性软腐病的香肠乳杆菌及其应用 |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1161795A (zh) * | 1996-04-08 | 1997-10-15 | 钟春燕 | 椰宝 |
| US20090098088A1 (en) * | 2007-10-10 | 2009-04-16 | The Procter & Gamble Company | Methods And Kits For The Treatment Of Diverticular Conditions |
| WO2014068338A1 (en) * | 2012-11-05 | 2014-05-08 | Multigerm Uk Enterprises Ltd | Diverticulitis treatment |
| CN105916513A (zh) * | 2013-09-06 | 2016-08-31 | 索发股份公司 | 含微生物的组合物在增加丁酸、叶酸或烟酸的肠道生产和/或降低琥珀酸的肠道生产中的应用 |
Family Cites Families (71)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0517363A (ja) | 1991-07-11 | 1993-01-26 | Yakult Honsha Co Ltd | 抗炎症剤及びそれを含有する化粧料 |
| US5716615A (en) | 1992-02-10 | 1998-02-10 | Renata Maria Anna Cavaliere Vesely | Dietary and pharmaceutical compositions containing lyophilized lactic bacteria, their preparation and use |
| US5531989A (en) | 1994-10-28 | 1996-07-02 | Metagenics, Inc. | Immunoglobulin and fiber-containing composition for human gastrointestinal health |
| US6461607B1 (en) | 1998-08-24 | 2002-10-08 | Ganeden Biotech, Inc. | Probiotic, lactic acid-producing bacteria and uses thereof |
| CZ9900769A3 (cs) | 1999-03-04 | 2000-10-11 | Petr Ing. Drsc. Hušek | Použití špičky s filtrem k vytvoření sloupce sorbentu s definovaným objemem v prostoru pod filtrem |
| US20020090416A1 (en) | 1999-03-09 | 2002-07-11 | Philip Connolly | Method of enhancing absorption and utilization of protein |
| IT1307850B1 (it) | 1999-03-15 | 2001-11-19 | Italmed Di Galli Giovanna E Pa | Composizione farmaceutica a base di fermenti lattici e carboidratinon assorbibili contenente un sale di calcio ed un sale di alluminio |
| EP1145643A1 (en) | 2000-04-10 | 2001-10-17 | Phillip Connolly | Improved milk protein concentrate |
| US20040170617A1 (en) | 2000-06-05 | 2004-09-02 | Finegold Sydney M. | Method of treating diseases associated with abnormal gastrointestinal flora |
| RU2182008C1 (ru) | 2000-10-20 | 2002-05-10 | Самойленко Игорь Иннокентьевич | Вводимая перорально, ректально или интравагинально композиция, содержащая живые бактерии |
| PE20030284A1 (es) | 2001-07-26 | 2003-05-01 | Alimentary Health Ltd | Cepas de bifidobacterium |
| FI20020078A (fi) | 2002-01-15 | 2003-07-16 | Danisco | Immuunijärjestelmän stimulointi polydextroosilla |
| US6881419B2 (en) | 2002-04-09 | 2005-04-19 | William E. Lovett | Vitamin formulation for enhancing bone strength |
| EP1539192A1 (en) | 2002-04-24 | 2005-06-15 | Medicarb AB | Composition and kit for the treatment of inflammatory bowel diseases |
| JP2005534315A (ja) | 2002-08-06 | 2005-11-17 | ダニスコ エイ／エス | 食品および薬学的組成物中に細胞外多糖類を産生する乳酸桿菌の使用 |
| AU2002951270A0 (en) | 2002-09-06 | 2002-09-19 | Vri Biomedical Ltd | Probiotic Bacterium and Methods of Use |
| WO2005001109A2 (en) | 2003-05-06 | 2005-01-06 | Government Of The United States Of America As Represented By The Sercretary Of The Department Of Health And Human Services National Institutes Of Health | Methods and compositions to detect microbes in fecal samples |
| US20100112088A1 (en) | 2003-08-29 | 2010-05-06 | Jay Pravda | Materials and methods for treatment of disorders associated with oxidative stress |
| EP1730302A2 (en) | 2004-02-27 | 2006-12-13 | Stichting Laboratorium voor Infectieziekten | Method for detecting a microorganism in a fecal specimen |
| EP1722804B1 (en) | 2004-03-04 | 2015-01-21 | E-L Management Corp. | Skin treatment method with lactobacillus extract |
| US20090197249A1 (en) | 2004-11-01 | 2009-08-06 | George Mason University | Compositions and methods for diagnosing colon disorders |
| EP2243383A3 (en) | 2005-04-06 | 2011-02-16 | Nestec S.A. | A method and composition for nutritionally improving glucose control and insulin action |
| FI20051319L (fi) | 2005-12-22 | 2007-06-23 | Cyflo Oy | Menetelmä eläimen ja/tai ihmisen ravitsemuksen ja hyvinvoinnin ja eläinten tuottavuuden seuraamiseksi ja kehittämiseksi |
| CN1840206A (zh) | 2006-01-19 | 2006-10-04 | 上海交通大学 | 人源菌群仔猪模型的构建及仔猪肠道中菌群分子检测方法 |
| WO2007097323A1 (ja) | 2006-02-21 | 2007-08-30 | National University Corporation University Of Toyama | 感染症起因菌の迅速同定方法 |
| KR101482800B1 (ko) | 2006-02-24 | 2015-01-14 | 큐피가부시키가이샤 | 신규한 저분자량 히알루론산 및/또는 이의 염, 및 이를 이용한 화장료, 의약 조성물 및 식품 조성물 |
| CA2689862A1 (en) | 2006-06-09 | 2007-12-13 | Nutravital Inc. | Probiotic compositions comprising propionibacterium and uses thereof |
| US20080069861A1 (en) | 2006-09-19 | 2008-03-20 | National Starch And Chemical Investment Holding Corporation | Probiotic/Non-Probiotic Combinations |
| US20080081035A1 (en) | 2006-10-03 | 2008-04-03 | National Enzyme Company | Therapeutic protease compositions |
| US8460726B2 (en) | 2006-12-18 | 2013-06-11 | Advanced Bionutrition Corporation | Dry food product containing live probiotic |
| EP1972208A1 (en) | 2007-03-16 | 2008-09-24 | Kirin Holdings Kabushiki Kaisha | Composition for improving intestinal microflora |
| CA2682763A1 (en) | 2007-03-27 | 2008-10-02 | The Procter & Gamble Company | Methods and kits for administering probiotics |
| EP2155167A2 (en) | 2007-06-04 | 2010-02-24 | Egalet A/S | Controlled release pharmaceutical compositions for prolonged effect |
| EP2173196B1 (en) | 2007-07-06 | 2011-02-16 | N.V. Nutricia | Use of probiotics and fibers for diarrhoea |
| US8193155B2 (en) | 2009-02-09 | 2012-06-05 | Elc Management, Llc | Method and compositions for treating skin |
| CN101240315A (zh) | 2008-02-21 | 2008-08-13 | 上海交通大学 | 检测药物防癌效果的非损伤性分子方法 |
| WO2010008272A1 (en) | 2008-07-15 | 2010-01-21 | N.V. Nutricia | Treatment of gut motility disorders |
| JP2010161944A (ja) | 2009-01-13 | 2010-07-29 | Syngen Biotech Co Ltd | 新型カゼイ菌の亜種（ｓｇ９６）及びこれを含有する菌抑制組成物及びその用途 |
| EP2403510B1 (en) | 2009-03-05 | 2020-02-26 | Probiotical S.p.A. | Bacteria strains having a high anti-inflammatory activity |
| WO2010103132A1 (es) | 2009-03-10 | 2010-09-16 | Hero España, S.A. | Aislamiento, identificación y caracterización de cepas con actividad probiótica a partir de heces de lactantes alimentados exclusivamente con leche materna |
| WO2011036539A1 (en) | 2009-09-23 | 2011-03-31 | Borody Thomas J | Therapy for enteric infections |
| EP2498626B1 (en) | 2009-11-12 | 2015-06-17 | Nestec S.A. | Nutritional composition for promoting gut microbiota balance and health |
| CA2784723C (en) | 2009-12-22 | 2021-01-12 | Probi Ab | Non-fermented compositions comprising a cereal based fraction and a probiotic and uses thereof |
| US8575130B2 (en) | 2010-01-04 | 2013-11-05 | Holy Stone Healthcare Co., Ltd. | Mixture of hyaluronic acid for treating and preventing inflammatory bowel disease |
| ITUD20100112A1 (it) | 2010-06-09 | 2011-12-10 | Farma Derma S R L | Preparazione per uso vaginale e rettale e relativo procedimento di produzione |
| WO2012135499A1 (en) | 2011-03-31 | 2012-10-04 | Ganeden Biotech, Inc. | Probiotic sports nutrition compositions |
| WO2012154738A1 (en) | 2011-05-09 | 2012-11-15 | The Cleveland Clinic Foundation | Composition and method to improve intestinal health |
| RU2630299C2 (ru) | 2011-06-20 | 2017-09-06 | Г.Дж. Хайнц Компани Брэндс ЛЛК | Композиции, способ и наборы для стимулирования мукозальной иммунной системы |
| CN102919922A (zh) | 2012-11-08 | 2013-02-13 | 黑龙江省轻工科学研究院 | 一种复合益生菌发酵蓝莓果汁粉的制备方法 |
| BR112015020819A2 (pt) | 2013-03-05 | 2017-07-18 | Academisch Ziekenhuis Groningen | uso de faecalibacterium prausnitzii htf-f (dsm 26943) para supressão de inflamação |
| EP3016511B1 (en) | 2013-07-02 | 2019-10-09 | Austrianova Singapore Pte Ltd. | A method of freeze-drying encapsulated cells, compositions suitable for freezing of encapsulated cells and use of such compositions |
| ITMI20131473A1 (it) | 2013-09-06 | 2015-03-07 | Sofar Spa | Metodo per valutare gli effetti di una composizione comprendente microrganismi sul microbiota intestinale |
| MA39710A (fr) | 2014-04-23 | 2015-10-29 | Sofar Spa | Composition topique destinée à être utilisée dans le traitement d'une maladie inflammatoire de l'intestin |
| WO2015172191A1 (en) | 2014-05-12 | 2015-11-19 | Medlab Ip Pty Ltd | Probiotic compositions and uses thereof for treatment of obesity-related disorders |
| DK2990045T3 (en) | 2014-08-26 | 2017-02-13 | Chr Hansen As | Bifidobacterium animalis subsp. lactis for use in reducing abdominal pain in a postmenopausal woman |
| WO2017195182A1 (en) | 2016-05-13 | 2017-11-16 | Sofar S.P.A. | Use of probiotics for improving protein absorption |
| MA45327A (fr) | 2016-05-13 | 2019-03-20 | Sofar Spa | Utilisation de probiotiques pour améliorer l'absorption des protéines |
| MA45288A (fr) | 2016-06-08 | 2019-04-17 | Sofar Spa | Nouvelle utilisation médicale de probiotiques |
| IT201600122724A1 (it) | 2016-12-02 | 2018-06-02 | Sofar Spa | Exopolysaccharides and uses thereof |
| IT201600127498A1 (it) | 2016-12-16 | 2018-06-16 | Sofar Spa | Probiotici per uso nella diverticolosi e malattia diverticolare |
| EP3554517B1 (en) | 2016-12-16 | 2023-09-13 | Compagnie Gervais Danone | Probiotic composition comprising lactobacillus rhamnosus and lactobacillus paracasei strains |
| WO2019019961A1 (zh) | 2017-07-26 | 2019-01-31 | 海思科医药集团股份有限公司 | 防治消化道和/或皮肤反应的菌群及其应用 |
| IT201700101704A1 (it) | 2017-09-12 | 2019-03-12 | Sofar Spa | Nuovo uso per trattamento delle infezioni da clostridium difficile |
| KR20200096807A (ko) | 2017-12-06 | 2020-08-13 | 락2바이오메 에스.알.엘. | 프로바이오틱스 조성물 및 그 용도 |
| CN108743851A (zh) | 2018-08-09 | 2018-11-06 | 深圳市博奥生物科技有限公司 | 一种复合益生菌粉的制备方法及复合益生菌粉 |
| IT201900016805A1 (it) | 2019-09-20 | 2021-03-20 | Sofar Spa | Ceppi batterici, loro composizioni e loro uso per il trattamento di disturbi gastrointestinali |
| IT201900016811A1 (it) | 2019-09-20 | 2021-03-20 | Sofar Spa | Ceppi batterici, loro composizioni e loro uso per il trattamento di disturbi gastrointestinali |
| IT201900016865A1 (it) | 2019-09-20 | 2021-03-20 | Sofar Spa | Composizioni a base di ceppi batterici e loro uso come antinfiammatori |
| IT201900016850A1 (it) | 2019-09-20 | 2021-03-20 | Sofar Spa | Composizioni a base di ceppi batterici e estratti di bacche e loro uso come antinfiammatori |
| US11751597B2 (en) | 2019-11-05 | 2023-09-12 | Alfasigma S.P.A. | Compositions comprising bacterial strains for use in increasing the bioavailability of amino acids derived from proteins, and related food product methods and systems |
| IT201900020422A1 (it) | 2019-11-05 | 2021-05-05 | Sofar Spa | Composizioni comprendenti ceppi di batteri per uso per aumentare la biodisponibilità degli amminoacidi derivanti da proteine |
-
2016
- 2016-12-16 IT IT102016000127498A patent/IT201600127498A1/it unknown
-
2017
- 2017-12-15 CN CN201780077730.3A patent/CN110114073A/zh active Pending
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- 2017-12-15 AU AU2017377139A patent/AU2017377139A1/en active Pending
- 2017-12-15 EP EP17829025.0A patent/EP3554522A1/en active Pending
- 2017-12-15 US US16/467,797 patent/US11896631B2/en active Active
- 2017-12-15 BR BR112019011817-9A patent/BR112019011817A2/pt unknown
- 2017-12-15 WO PCT/IB2017/057980 patent/WO2018109730A1/en unknown
-
2019
- 2019-06-14 CL CL2019001643A patent/CL2019001643A1/es unknown
- 2019-07-16 CO CONC2019/0006257A patent/CO2019006257A2/es unknown
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1161795A (zh) * | 1996-04-08 | 1997-10-15 | 钟春燕 | 椰宝 |
| US20090098088A1 (en) * | 2007-10-10 | 2009-04-16 | The Procter & Gamble Company | Methods And Kits For The Treatment Of Diverticular Conditions |
| WO2014068338A1 (en) * | 2012-11-05 | 2014-05-08 | Multigerm Uk Enterprises Ltd | Diverticulitis treatment |
| CN105916513A (zh) * | 2013-09-06 | 2016-08-31 | 索发股份公司 | 含微生物的组合物在增加丁酸、叶酸或烟酸的肠道生产和/或降低琥珀酸的肠道生产中的应用 |
Non-Patent Citations (7)
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113862184A (zh) * | 2021-05-19 | 2021-12-31 | 湖南农业大学 | 一株粪肠球菌mg 2108及其应用 |
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| CO2019006257A2 (es) | 2019-09-09 |
| CL2019001643A1 (es) | 2019-11-08 |
| EP3554522A1 (en) | 2019-10-23 |
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| US11896631B2 (en) | 2024-02-13 |
| BR112019011817A2 (pt) | 2019-10-29 |
| AU2017377139A1 (en) | 2019-07-04 |
| MX2019006948A (es) | 2019-08-14 |
| WO2018109730A1 (en) | 2018-06-21 |
| IT201600127498A1 (it) | 2018-06-16 |
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