CN115804798A - 含微生物的组合物增加丁酸、叶酸或烟酸的肠道生产和/或降低琥珀酸的肠道生产的应用 - Google Patents
含微生物的组合物增加丁酸、叶酸或烟酸的肠道生产和/或降低琥珀酸的肠道生产的应用 Download PDFInfo
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Abstract
本发明涉及使用含细菌的组合物来提高丁酸、叶酸或烟酸的肠道生产和/或降低琥珀酸的肠道生产。此外，本发明涉及使用所述组合物治疗和/或预防肠道丁酸盐依赖性和/或琥珀酸盐依赖性的病理状况。具体用于治疗和/或预防肠道炎症、腹泻、溃疡性结肠炎或肠道结肠病。
Description
本发明涉及使用含细菌的组合物从而提高丁酸、叶酸或烟酸的肠道生产和/或降低琥珀酸的肠道生产。此外，本发明涉及使用所述组合物治疗和/或预防肠道丁酸盐依赖性和/或琥珀酸盐依赖性的病理状况，具体用于治疗和/或预防肠道炎症、腹泻、溃疡性结肠炎或肠道结肠病。
肠道微生物群，旧称肠道菌丛，是肠道中居住的与宿主身体共生的微生物总和，主要由细菌组成。
肠道微生物群是一个高度复杂的生态系统，组成肠道的不同微生物之间的平衡是确保身体健康的基础，因为微生物群会显著地调节宿主个体的肠道黏膜的发育和稳态。
换言之，所述肠道微生物群相当于一个真实的器官。事实上，个体的肠道微生物群的定性和/或定量变化，或所谓失调或微生物失调(dismicrobism)，会导致肠道内稳态丧失，由此会决定大量病理学的发病机理。
为了治疗肠道腹泻的症状或在任何情况写维持肠道微生物群的稳态，常摄取称为益生菌的物质，或者，按照FAO/WHO的定义，益生菌是一组"活的微生物，当以适当的量给予这些微生物时，能为宿主提供健康益处"。类似地，副益生菌(paraprobiotics)对健康的有效性也已得到证明；其被称为“非活力微生物细胞(完整或破损)或原始细胞提取物，将其以足够量(口服或局部)给予时对宿主健康产生益处”(Taverniti和Guglielmetti,2011)。
很明显微生物的有益活性会基于其组合物而变化，事实上常存在株系特异性活性。
基于上述考虑，仍需要确定微生物的可能的新型促进健康和/或治疗的效果从而开拓应用，尤其是益生菌或副益生菌中所具有的那些。
例如，本领域仍特别需要鉴定能调控对身体特别有益和有治疗性的肠道物质(如丁酸、叶酸和烟酸)含量的微生物。
丁酸是短链脂肪酸，其于生理学上在人类的结肠中通过微生物群对膳食纤维的发酵而形成。
丁酸是结肠细胞(colonocytes)的主要能量来源，并且因此是对人体非常重要的营养物质。
在肠道水平，丁酸行使各种重要的功能，例如：其刺激结肠细胞的更新和生理成熟；其在维持黏膜完整性和修复肠道损伤过程中起关键作用；其刺激结肠中水和钠的再吸收；并且其对降低肠道pH、形成对致病菌的发展不利的环境均有贡献。
缺乏丁酸可导致人类的结肠炎。
琥珀酸同样是二羧基型的短链有机酸。考虑其具有溃疡性并且可会黏膜造成严重损伤。因此，琥珀酸(琥珀酸盐)含量的增加对人体健康有害。
叶酸(维生素B9、或M或叶酸(folacin))是对全部群体来说都很重要的维生素，尤其是50岁以上的成人和育龄女性，这是因为其介入(直接介入或在大多数情况中通过降低高半胱氨酸的血浆水平介入)许多至关重要的过程例如DNA合成、修复和甲基化。
缺乏叶酸可导致巨红细胞性贫血，其可伴随有白斑病和血小板减少症、皮肤和黏膜变质和胃肠道紊乱(吸收不良和腹泻)。烟酸(或维生素PP或维生素B3)即尼克酸或烟碱，其非常重要，因其是辅酶NAD和NADH的必要组分之一，它们的缺乏会导致糙皮病病理学。通常，该病理学起始于胃肠道系统的问题，然后其伴随有光敏性皮炎、具疲劳的精神紊乱、抑郁和记忆紊乱。
本发明响应上述的本领域需求，涉及包含微生物的组合物，所述微生物优选乳杆菌(Lactobacillus)属副干酪(paracasei)种的细菌，其能够(直接和/或间接)增加对其进行摄取的个体中丁酸、叶酸、烟酸和/或其盐的肠道生产。
此外，发明人意外发现包含微生物(优选乳杆菌属副干酪种的细菌)的组合物能够(直接和/或间接)降低琥珀酸和/或其盐的肠道生产。因此，本发明组合物对治疗和/或预防肠道丁酸盐依赖性和/或琥珀酸盐依赖性的病理状况尤其有效。
本发明的其它益处将根据下文的详细描述和实施例而更为显见，然而，其仅仅起说明而非限制作用。
为了能够更好地理解详细说明，本发明附有图1-4：
-图1.1显示统计学分析的结果，证明用本发明组合物处理之前和之后粪球菌(Coprococcus)属细菌群体的增加(A)，和用安慰剂处理之前和之后粪球菌属细菌群体的减少(B)；
-图1.2显示统计学分析的结果，证明用本发明组合物处理之前和之后布劳特氏菌(Blautia)属细菌群体的减少(A)，和用安慰剂处理之前和之后粪球菌属细菌群体的增加(B)；
-图2.1显示，在用本发明组合物处理之前和之后，粪球菌属的细菌群的增加(深灰)和布劳特氏菌属的细菌群的减少(浅灰)；
-图2.2显示，用本发明组合物处理之前和之后(A)，粪球菌属的细菌群的百分比增加(深灰)和布劳特氏菌属的细菌群的百分比减少(浅灰)，以及用安慰剂处理之前和之后(B)，粪球菌属的细菌群的百分比减少(深灰)和布劳特氏菌属的细菌群的百分比增加(浅灰)；
-图3显示统计学分析的结果，用于证明用本发明组合物处理之前和之后烟酸代谢的增加，和用安慰剂处理之前和之后烟酸代谢的减少；
-图4显示统计学分析的结果，用于证明用本发明组合物处理之前和之后，叶酸的生物合成的增加，和相反地用安慰剂处理之前和之后没有任何变化。
本发明涉及含微生物(优选至少一种乳杆菌属副干酪种的细菌)的组合物在增加丁酸和/或其盐、和/或叶酸和/或其盐、和/或烟酸和/或其盐的直接和/或间接肠道生产，和/或降低琥珀酸和/或其盐的直接和/或间接肠道生产中的用途。
本文中，肠道生产表示任何肠道微生物在肠道的任何区域通过初级或次级代谢产生的任何分子释放到环境中。
此外，本发明组合物还可用于减少致病微生物的肠道增殖、和/或用于提升肠道黏膜的完整性、和/或促进肠道损伤的修复过程，优选通过增加丁酸和/或其盐的直接和/或间接肠道生产和/或通过降低琥珀酸和/或其盐的直接和/或间接肠道生产发挥上述作用。
对本发明组合物特别敏感的一些致病微生物例如肠出血性大肠杆菌(Escherichia coli)、单核细胞增生利斯特菌(Listeria monocytogenes)、艰难梭状芽胞杆菌(Clostridium difficile)、铜绿假单胞菌(Pseudomonas aeruginosa)和沙门氏菌(Salmonella spp.)。
本发明的上述用途针对健康个体或有病理学肠道症状的个体。具体地，在健康个体的情况中，本发明组合物在摄取后的个体中产生维持微生物群的稳态的作用和/或预防其改变的作用，并因此其可称为益生菌组合物(或益生菌)。
本发明的其他方面涉及组合物的医药用途，所述组合物包含微生物，优选至少一种乳杆菌属副干酪种的细菌，用于治疗和/或预防肠道丁酸盐-依赖性和/或琥珀酸盐-依赖性病理状况。
本文中，肠道丁酸盐-依赖性和/或琥珀酸盐-依赖性病理状况表示对用丁酸和/或其盐治疗和/或用琥珀酸和/或其盐治疗敏感的病理状况。示例性的病理为：腹泻、肠道炎症、溃疡性结肠炎、胃萎缩、肠憩室、狭窄、阻塞和糖尿病神经病变。
本发明的优选实施方式中，组合物包含副干酪乳杆菌DG细菌株系。细菌菌株副干酪乳杆菌DG由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。最初，保藏菌株的名称为干酪乳杆菌DG干酪亚种(Lactobacillus casei DG sub.casei)。
本发明的其他实施方式中，丁酸和/或其盐、和/或叶酸和/或其盐、和/或烟酸和/或其盐的所述直接和/或间接肠道生产增加和/或琥珀酸的所述直接和/或间接肠道生产降低归因于肠道微生物群，优选归因于粪球菌属和/或布劳特氏菌属的细菌。
本发明的优选实施方式中，丁酸和/或其盐的所述直接和/或间接肠道生产增加归因于粪球菌属的细菌，和/或琥珀酸的所述直接和/或间接肠道生产降低归因于布劳特氏菌属的细菌。
因此，包含微生物(优选至少一种乳杆菌属副干酪种的细菌，更优选副干酪乳杆菌DG细菌株系)的组合物可用于改良肠道微生物群中粪球菌属和/或布劳特氏菌属的细菌群的密度，优选从而诱导粪球菌属细菌群的增加和/或布劳特氏菌属细菌群的降低。换句话说，摄入本发明组合物改良肠道微生物群中粪球菌属和/或布劳特氏菌属细菌的含量。具体地，给予所述组合物后粪球菌属细菌增加和/或布劳特氏菌属细菌降低。
本文所用组合物包含所述微生物，优选所述至少一种乳杆菌属副干酪种的细菌，其为活的或死的形式，作为裂解物或提取物。
在本发明的一个实施方式中，所述组合物包含约150亿至300亿个集落形成单位(CFU)的细菌，优选200至250亿个CFU的细菌。
优选所述组合物配置为口服给予。具体而言，所述组合物以固体形式配制，优选丸剂、胶囊剂、片剂、粒状粉末、硬胶囊、水溶性颗粒、囊剂或粒料。
或者，本发明的组合物被配制为液体形式，例如糖浆或饮品，或者被添加至食物，例如酸奶、乳酪，或果汁。
或者，本发明的组合物以能够发挥局部作用的形式配制，例如，灌肠剂。
在本发明的另一个实施方式中，所述组合物还包含一般经许可用于生产益生菌和/或药物产品的赋形剂。
在本发明的另一个实施方式中，本发明的组合物可富含维生素、微量元素例如锌和硒，酶，益生元物质，例如，低聚果糖(FOS)、低聚半乳糖(GOS)、菊粉，瓜尔豆胶或其组合。为了本发明的用途，所述组合物优选一天摄取一次，更优选醒来后摄取。
或者，其可在晚间摄取，优选晚餐后。
实施例
处理
对健康个体进行随机、双盲、安慰剂-对照的交叉饮食干预研究。
志愿者按照如下标准征募：
-入选标准：健康男性和女性，年龄在18和55岁之间，签署知情同意书；
-排除标准：在首次检测之前一个月内有过抗生素处理；在首次检测之前2个月内有病毒或细菌性肠炎事件；在首次检测前5年内有胃溃疡或十二指肠溃疡；妊娠或哺乳期；近期或疑似酒精中毒或药物摄取(吸毒)事件；与该研究方案不相容的其它状况。
该益生饮食干预根据交叉设计进行，如下表1所示。
表I
在预登记阶段(4周)，志愿者遵循其常规饮食，不消耗益生发酵的乳品(因此允许传统酸奶)、益生饮食补充剂，或益生元饮食补充剂。
在预登记阶段末期，每天随机给予志愿者益生菌或安慰剂的一种胶囊，持续4周。
举例而言，采用Enterolactis Plus作为待给予的益生菌；其由包含240亿CFU(集落形成单位)的副干酪乳杆菌DG菌株的420mg胶囊组成。
包含安慰剂的胶囊在外观上与包含益生菌的那些相同，其明确地缺乏益生菌。
所述活性物质(即益生菌)的味道和颜色与安慰剂相同。
该产品在早晨于早餐前至少十分钟空腹摄取，若忘记，则在夜间就寝之前且在任何情况下需于最后一餐之后至少两个小时摄取。
在第一个四周处理之后，志愿者经历四周清洗期，与预登记阶段相同。
在清洗期终末，志愿者按照上述交叉设计每天摄取Enterolactis Plus或安慰剂的一种胶囊，持续四周。
总之，该研究涉及4个阶段，其各自持续4周：
·预招募阶段：所述个体既不经历A处理，也不经历B处理。
处理1：所述个体经历A处理或B处理。
·清洗：所述个体既不经历A处理，也不经历B处理
处理2：所述个体经历B处理或A处理。处理A和B可为本发明组合物，具体示例中为Enterolactis plus或安慰剂。处理开始时，不知晓个体摄入的是何物，仅在处理终末期知晓摄取顺序(解除双盲)。
检测和样品收集。
初始时，指示各志愿者遵循整个过程，这包括与每位志愿者的总计5次会晤。
在第一次会晤期间，获得知情同意书以及志愿者的个人数据。并且，告知志愿者所述研究将如何开展的总体信息，并且指示志愿者在预登记的后续4周的饮食上的变化(禁止消耗先前指定的产品)。4周后，志愿者携带粪便样品(TO样品)前来进行第二次会晤，所述粪便样品在先前24小时时程之内收集于第一次会晤交于的特定容器中。
为了确保最优保存，将粪便样品贮存在室温，并在24小时之内递送至实验室。
此外，在第二次会晤过程中，给予志愿者所述益生产品(或安慰剂)，以供在接下来的4周期间摄取。
并且，指示志愿者如何摄取所述产品。
在摄取所述产品(或安慰剂)的这4周末期，志愿者携带另一份粪便样品(T1样品)前来进行第三次会晤，所述粪便样品在之前24小时之内收集。
在第三次会面过程中，志愿者就源自消耗所述产品的可能效果(积极和不希望的)完成问卷。
然后，指示志愿者有关接下来4周的操作，在这期间他或她依然不摄取先前所述的产品。
在这4周末期，志愿者携带粪便样品(T2样品)前来进行第四次会面，并且给予其所述益生产品(或安慰剂)以供在接下来4周期间摄取。
最后，在摄取所述产品(或安慰剂)4周后，志愿者前来进行第五次会面以递交最后一份粪便样品(T3样品)。
在这最后一次会面过程中，志愿者完成与第三次会面中接收到的问卷类似的问卷。
在分析微生物群之前，收集的全部粪便样品在-20℃贮存不超过7天。
粪便微生物群的分析
通过分析编码16S rRNA细菌核糖体亚基的基因的部分的核苷酸序列来评价粪便微生物群。更具体地，采用宏基因组学(metagenomic)策略；简言之，其由如下步骤组成：
1.从粪便样品提取宏基因组学DNA，并对其定量和标准化；
2.通过PCR扩增编码16S rRNA的细菌基因的V3高变区；
3.对PCR产物定量；
4.对扩增的产物测序；
5.对序列进行生物信息学分析。
步骤1和3的操作是本领域熟知的技术，因此，其采用本领域中常用的方案进行。例如，实验室手册中描述的方法，例如见述于Sambrook等.2001或Ausubel等.1994。扩增16S核糖体RNA基因的V3区域的步骤2通过称为PCR的DNA扩增技术进行，采用Probio_Uni 5'-CCTACGGGRSGCAGCAG-3'(SEQ ID NO:1)和Probio_Rev 5'-ATTACCGCGGCTGCT-3'(SEQ IDNO:2)作为寡核苷酸(引物)。
具体而言，SEQ ID NO:1和2引物对扩增16S rRNA基因的V3区域。
步骤4可采用本领域已知的用于该目的的技术进行，例如基于桑格测序法、焦磷酸测序法或离子激流融合引物测序法的技术，其根据Milani等.(2013)的学术论文的材料与方法部分描述的方案用于本发明的特定实施例中。
在离子激流技术的情况中，引物以如下方式设计并合成，以在5'端包括用于该特定DNA测序技术中的两个衔接子序列之一。在该情况中，所述衔接子序列是SEQ ID NO:1和2。
进行PCR的条件如下：
·95℃，5分钟；
·94℃，30秒；55℃，30秒；和72℃，90秒；进行35个循环；
·72℃，10分钟。
在PCR结束时，通过电泳来检验扩增物的完整性。
本方法的步骤5是表征微生物群落所需，可用大量先前已知用于该目的的技术进行。更具体地，利用：分级聚类、分类分析和采用热图构建系统树，按照Milani等.(2013)的学术论文的材料与方法部分中描述的方案；更具体地，序列数据的分析采用QIIME软件进行。
数据的统计学分析
所述统计学分析采用STATISTICA软件(史丹索特公司(Statsoft Inc.)，美国俄克拉菏马州塔尔萨)进行。
为了揭示显著差异，数据采用参数(多变量和单变量重复测试ANOVA)和非参数(沃尔德-沃尔福威茨与曼-惠特尼)统计学方法分析。
数据集的正态性(ANOVA的重要假设)通过夏皮洛-威尔克(Shapiro-Wilk)和柯莫果夫-斯米尔诺夫(Kolmogorov-Smirnov)检验评价。
处理的结果
该研究由总计22位个体(11位女性和11位男性)完成。
初始时登记了33位个体，但其中11位因下述原因在早期退出了：摄入抗生素(4)，拒绝继续该研究(1)，频发腹泻(1)，在该研究期间摄入其它益生菌(3)，饮食习惯大幅变化(1)，和，伴有穿插腹泻的季节性流感(1)。
在总结研究并完成两次处理的结果分析之后，揭示双盲结果，并且观察到：A处理是包含副干酪乳杆菌DG的活性处理；B处理是外表与活性处理相同的安慰剂，但缺乏乳杆菌。
当分析获自该研究的数据时，就分类学而言，观察到该研究参与者的肠道微生物群的高稳定性。
事实上，发现：
a)15种鉴定的细菌中的两种细菌分离物，即，拟杆菌(Bacteroidetes)和厚壁菌(Firmicutes)，占超过90％的序列；
b)131种鉴定的家族中的11种占超过90％的序列；和
c)262种鉴定的属中的20个属占超过90％的序列。
此外，该研究证实，处于较低分类水平(即，处于家族和属水平)的人类肠道微生物群在个体彼此之间高度可变。
因此，实验证据显示，对健康群体进行交叉干预试验的必要性，以防止显著的个体间变异性会隐藏益生菌处理的可能作用或导致统计学假阳性。当评价由两种处理诱导的肠道微生物群的变化时，仅在接受副干酪乳杆菌DG处理(活性处理)的组中出现了以属为单元的统计学显著差异。更具体地，观察到粪球菌属的增加。事实上，由图1.1、2.1和2.2可见，在用副干酪乳杆菌DG处理之前和之后，观察到粪球菌的统计学显著增加。相反，在接受安慰剂处理的组中观察到中度减少。
此外，用副干酪乳杆菌DG处理之后，观察到布劳特氏菌属的细菌的统计学显著减少。相反，在接受安慰剂处理的组中观察到其轻微增加(图1.2、2.1和2.2)。
粪球菌是肠道水平的主要丁酸盐生成者之一。
丁酸盐是肠道水平的基础化合物，因为，一方面，其有助于恢复肠道粘膜的功能完整性并随时间进展维持该状况，而在另一方面，其具有重要的抗炎作用，以至于其被用作肠道结肠病(例如慢性炎性肠道疾病)的饮食处理的佐剂。
此外，其基因组的分析揭示，这些细菌能够利用琥珀酸盐作为发酵底物。
以该信息为基础，考虑到布劳特氏菌属的成员产生乙酸盐和琥珀酸盐作为葡萄糖发酵的主要终产物。
考虑琥珀酸盐是产生溃疡的因素，因此，能够使患有溃疡性结肠炎的个体状况恶化，因为其在上述疾病的活跃期间很可能造成粘膜损伤。
因此，在采用益生菌处理之后，在该情况中，在给予副干酪乳杆菌DG之后，观察到属于粪球菌属的细菌的增加，以及进而的，肠道丁酸盐浓度的增加。
同时，观察到可能造成患有溃疡性结肠炎的个体的粘膜损伤的琥珀酸盐的浓度直接下降，因为在用益生菌处理之后(在本文中为给予了副干酪乳杆菌DG之后)属于布劳特氏菌属的细菌间接地有所减少，这是因为增加的粪球菌群还能够通过以琥珀酸盐作为其发酵加工的底物而降低琥珀酸盐浓度。
因此，在用益生菌处理之后，在具体实施例中为给予副干酪乳杆菌DG之后，个体粪便中的丁酸浓度增加，同时其它有机酸(例如琥珀酸)减少。
最后，在以基于细菌基因组的认知进行宏基因组学的虚拟重建为目的的生物信息学分析中，采用与粪便微生物群的组成相关的数据(Okuda S，Tsuchiya Y，Kiriyama C，Itoh M，Morisaki H.“16S rRNA基因序列的虚拟宏基因组重建(Virtual metagenomereconstruction from 16S rRNA gene sequences)”.Nat Commun.2012；3:1203)；换言之，其以电脑模拟方式建立存在何种可能的基因和给定微生物群的丰度如何。该分析使得检验供于叶酸的合成和烟酸的代谢(图3和4)的编码基因的推定增加成为可能。这两种分子是对于人宿主而言重要的维生素(分别称为维生素B9和B3)。具体而言，维生素B9代表首要的营养因子，缺乏它(尤其是在特殊生理状况，例如妊娠中)会导致严重的健康后果。因此，采用本研究所用益生菌进行处理能够促进肠道微生物群生成叶酸(维生素B9)的能力，这对人类宿主具有后续营养益处。
Claims (10)
1.含乳杆菌(Lactobacillus)属副干酪(paracasei)种的至少一种细菌的组合物用于制造增加丁酸和/或其盐、和/或叶酸和/或其盐、和/或烟酸和/或其盐的直接和/或间接肠道生产和/或降低琥珀酸和/或其盐的直接和/或间接肠道生产的药物的用途。
2.如权利要求1所述的用途，所述药物用于通过丁酸和/或其盐的所述直接和/或间接肠道生产的增加和/或通过琥珀酸和/或其盐的所述直接和/或间接肠道生产的降低，减少致病微生物的肠道增殖、和/或用于提升肠道黏膜的完整性、和/或促进肠道损伤的修复过程。
3.一种组合物，所述组合物包含乳杆菌属副干酪种的至少一种细菌，用于治疗和/或预防肠道丁酸盐-和/或琥珀酸盐-依赖性病理状况。
4.如权利要求3所述的组合物，其中所述肠道病理状况选自：腹泻、肠道炎症、溃疡性结肠炎、胃萎缩、肠憩室、狭窄、阻塞和糖尿病神经病变。
5.如权利要求1或2所述的用途或权利要求3或4所述的组合物，其中所述乳杆菌是副干酪乳杆菌DG株。
6.如权利要求1、2和5中任一项所述的用途，其中丁酸和/或其盐、和/或叶酸和/或其盐、和/或烟酸和/或其盐的所述直接和/或间接肠道生产的增加和/或琥珀酸的所述直接和/或间接肠道生产的降低归因于肠道微生物群，优选归因于粪球菌属和/或布劳特氏菌属的细菌。
7.如权利要求1、2、5和6中任一项所述的用途，其中丁酸和/或其盐的所述直接和/或间接肠道生产的增加归因于粪球菌属的细菌，和/或琥珀酸的所述直接和/或间接肠道生产的降低归因于布劳特氏菌属的细菌。
8.如权利要求1、2、5-7中任一项所述的用途或权利要求3或4所述的组合物，其中所述乳杆菌属副干酪种的至少一种细菌为活细菌或死细菌、或细菌裂解物或提取物。
9.如权利要求1、2、5-8中任一项所述的用途或权利要求3、4、8中任一项所述的组合物，其中所述组合物用于口服给予，优选为下述形式：丸剂、胶囊剂、片剂、粒状粉末、硬胶囊、水溶性颗粒、囊剂或粒料。
10.如权利要求1、2、5-9中任一项所述的用途或权利要求3、4、8、9中任一项所述的组合物，其中所述组合物还含有益生元活性的膳食纤维，优选FOS、菊粉、瓜尔豆胶，或者含有其他物质如维生素、微量元素和/或酶。
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| CN201480049296.4A CN105916513A (zh) | 2013-09-06 | 2014-09-05 | 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 |
| PCT/IB2014/064285 WO2015033305A1 (en) | 2013-09-06 | 2014-09-05 | Use of a composition comprising microorganisms to increase the intestinal production of butyric acid, folic acid or niacin and/or decrease the intestinal production of succinic acid |
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| 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 |
| MA41010B1 (fr) | 2015-06-15 | 2020-01-31 | 4D Pharma Res Ltd | Compositions comprenant des souches bactériennes |
| EP3206700B1 (en) | 2015-06-15 | 2019-06-05 | 4D Pharma Research Limited | Compositions comprising bacterial strains |
| GB201612191D0 (en) | 2016-07-13 | 2016-08-24 | 4D Pharma Plc | Compositions comprising bacterial strains |
| MA45327A (fr) | 2016-05-13 | 2019-03-20 | Sofar Spa | Utilisation de probiotiques pour améliorer l'absorption des protéines |
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| TWI802545B (zh) | 2016-07-13 | 2023-05-21 | 英商４Ｄ製藥有限公司 | 包含細菌菌株之組合物 |
| IT201600122724A1 (it) | 2016-12-02 | 2018-06-02 | Sofar Spa | Exopolysaccharides and uses thereof |
| GB201621123D0 (en) | 2016-12-12 | 2017-01-25 | 4D Pharma Plc | Compositions comprising bacterial strains |
| IT201600127498A1 (it) | 2016-12-16 | 2018-06-16 | Sofar Spa | Probiotici per uso nella diverticolosi e malattia diverticolare |
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| JP2020520911A (ja) * | 2017-05-22 | 2020-07-16 | フォーディー ファーマ リサーチ リミテッド４Ｄ Ｐｈａｒｍａ Ｒｅｓｅａｒｃｈ Ｌｉｍｉｔｅｄ | 細菌株を含む組成物 |
| TW201907931A (zh) | 2017-05-24 | 2019-03-01 | 英商4D製藥研究有限公司 | 包含細菌菌株之組合物 |
| PL3804737T3 (pl) | 2017-06-14 | 2022-09-12 | 4D Pharma Research Limited | Kompozycje zawierające szczepy bakteryjne |
| TW201919670A (zh) | 2017-06-14 | 2019-06-01 | 英商4D製藥研究有限公司 | 包含細菌品系之組成物 |
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| AU2019209821A1 (en) * | 2018-01-17 | 2020-08-27 | Consorcio Centro de Investigación Biomédica en Red, M.P. | Targeted interventions directed at reducing the levels of circulating succinate in a subject, and kits and method for determining effectiveness of said interventions |
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| CN110669697B (zh) * | 2019-10-31 | 2022-07-15 | 微康益生菌(苏州)股份有限公司 | 一种高产短链脂肪酸的干酪乳杆菌、培养方法及其应用 |
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