CN102325458A - 预防及治疗轮状病毒腹泻 - Google Patents
预防及治疗轮状病毒腹泻 Download PDFInfo
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- CN102325458A CN102325458A CN2009801571464A CN200980157146A CN102325458A CN 102325458 A CN102325458 A CN 102325458A CN 2009801571464 A CN2009801571464 A CN 2009801571464A CN 200980157146 A CN200980157146 A CN 200980157146A CN 102325458 A CN102325458 A CN 102325458A
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- rotavirus
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- bifidobacterium breve
- prevention
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Abstract
本发明涉及短双岐杆菌(Bifidobacterium breve)CNCM I-3865、包含短双岐杆菌CNCM I-3865的组合物，以及短双岐杆菌CNCM I-3865用于预防或治疗轮状病毒腹泻的用途。
Description
技术领域
本发明涉及轮状病毒腹泻(rotavirus diarrhoea)的预防及治疗，尤其涉及婴儿及幼儿轮状病毒腹泻的预防及治疗。
背景技术
腹泻疾病仍是婴儿及儿童生存的主要全球性威胁，且在发展中国家及工业化国家，轮状病毒感染是该群体罹患严重性脱水胃肠炎的主要原因。在西方国家，轮状病毒感染的管理成本(估计仅美国每年的成本就超过10亿美元)是负担日益增加的健保预算的主要开支。近期开发的两种新型轮状病毒疫苗带来希望，但即使可获得有效的疫苗，其使用也可能受发展中国家财政拮掘的限制。此外，其对具有营养不良及伴随免疫缺陷的儿童的功效仍值得怀疑。
在最近几十年内，益生菌作为治疗胃肠疾病的安全及可利用形式已受到极大关注。已被用于治疗(intervention)由病毒引起的腹泻的细菌属于乳杆菌属(Lactobacillus)及双歧杆菌属(Bifidobacterium)。已提出抵抗轮状病毒引起的胃肠炎的某种益生菌的治疗能力归因于其稳定及增强黏膜屏障、产生抗微生物物质及刺激局部抗原特异性与非特异性免疫应答的能力。也注意了与不同菌株有效性及作用模式相关的显著差异。
例如，在1990年代初期，Saavedra等人观察到：相比未接受任何益生菌者的26个儿童，施用乳双歧杆菌(Bifidobacterium lactis)与嗜热链球菌(Streptococcus thermophilus)的组合在美国医院慢性护理病房中降低29个儿童的腹泻发生率及轮状病毒释放18个月(Saavedra等人，The Lancet 344，1046：1994)。然而，在利用双歧杆菌的其他试验中并未获得明 确结果。例如，对1000名法国儿童的预防研究并未显示腹泻发生率或持续时间的降低(Thibault等人，J Ped Gastro Nutr 39，147：2004)。
最近，WO01/10453描述广泛筛选的260种不同细菌菌株的结果，其中仅4种显示基本抑制轮状病毒复制。已发现所有这四种菌株均属于本发明人推断的长双歧杆菌(B.longum)或青春双歧杆菌(B.adolescentis)物种，这些物种对预防及治疗轮状病毒腹泻特别有效。特别强调了青春双歧杆菌的一种特定菌株，青春双歧杆菌CNCM I-2168预防轮状病毒感染人类细胞的能力。然而，据称已从成人粪便中分离了该菌株，使其较不适合包含于为婴儿设计的产品中。
由上可见，仍然需要具有有效抗轮状病毒活性，且适合并入婴儿及幼儿消费产品中的其他益生菌。
发明内容
本发明人已出乎意料地发现，与先前推测相反的，益生菌双歧杆菌的抗轮状病毒活性并非根据该菌种可预测。更特定而言，本发明人已发现最初分离自人乳中的短双歧杆菌(Bifidobacterium breve)的特定菌株，短双歧杆菌CNCM I-3865，对于预防及治疗轮状病毒腹泻极为有效，且即使是非复制形式时，仍可保持该活性。
因此，在第一方面中，本发明提供短双歧杆菌CNCM I-3865，其于2007年11月15日保藏于法国微生物保藏中心。
在第二方面中，本发明提供适用于预防或治疗轮状病毒腹泻的组合物，其包含短双歧杆菌CNCM I-3865。
在第三方面中，本发明提供短双歧杆菌CNCM I-3865在制备用于预防或治疗轮状病毒腹泻的药物或治疗性营养组合物中的用途。
在第四方面中，本发明提供预防或治疗轮状病毒腹泻的方法，其包含对需要其的婴儿或幼儿施用治疗量的短双歧杆菌CNCM I-3865。
已知年龄为2至4周的健康、经阴道分娩、母乳喂养的婴儿的肠道小型生物群(可将其视为此年龄组的最佳小型生物群)主要为双歧杆菌属，而配方食品喂养的婴儿拥有较复杂的小型生物群，其通常同时存在双歧杆 菌属、拟杆菌属(Bacteroides)、梭菌属(Clostridia)及链球菌属(Streptococci)。已假设由于母乳哺育的婴儿比配方食品喂养的婴儿较少罹患腹泻感染，因此以双歧杆菌为主的小型生物群必定提供抗轮状病毒感染的保护作用。然而，由美国疾病控制中心(US Centers for Disease Control)在孟加拉国进行的一系列研究并未证实母乳哺育的婴儿比配方食品喂养的婴儿较少罹患轮状病毒感染(Glass等，Acta Paediatr.Scand.75，713-718；1986)。因此，流行病学数据并不支持双歧杆菌大体上抗轮状病毒腹泻的保护作用。本发明人已证实尽管已于数种双歧杆菌属中发现抗轮状病毒活性，但该活性并非物种特有特征。这表示尽管尚未阐明针对所观察到的作用的机制，但介导抗轮状病毒性质的基因可能不属于该物种的共享核心基因组部分。
附图简述
图1比较感染猿猴轮状病毒并接受不同益生菌治疗的四组小鼠随时间的腹泻症状的程度。
图2比较感染猿猴轮状病毒及接受呈未处理及经热处理形式的相同益生菌治疗的三组小鼠随时间的腹泻症状的程度。
发明详述
在本说明书中，以下术语具有以下含义：
“婴儿”意指年龄为12个月以下的儿童；
“益生菌，，意指对宿主的健康或康乐具有有益效果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)；
“幼儿”意指年龄为一至六岁的儿童。
除非另外说明，否则所有百分比是重量比。
益生菌短双歧杆菌CNCM I-3865可作为药物对婴儿或幼儿施用，例 如以相当于10e10 cfu的每日剂量溶解于水中并用匙施用。或者，其可方便地在婴儿配方食品、较大婴儿配方食品或成长乳中，以相当于10e3至10e12 cfu/g(基于干重)的量施用，更优选以相当于10e7至10e12 cfu/g的量施用。术语“相当于的量”包括下列可能性：细菌是活的、非复制的或死的或甚至以片段形式(如DNA或细胞壁物质)存在。换言之，细菌数量是以假如所有细菌均是活的时该数量的细菌的菌落形成能力表示，而不论其是否真正是活的、非复制的或死的、片段的或任何或所有这些状态的混合物。
根据本发明婴儿配方食品可包含蛋白质源，其含量不超过2.0g/100kcal，优选1.8至2.0g/kcal。虽然优选以乳清作为超过50wt％的蛋白质源，但只要能满足必需胺基酸的最小需求并可确保令人满意的生长，蛋白质的种类并不认为是本发明的关键。因此，可使用基于乳清、酪蛋白及其混合物的蛋白质源及基于大豆的蛋白质源。至于所关注的乳清蛋白，该蛋白质源基于酸乳清或甜乳清或其混合物，且可包括期望的任何比例的α-乳清蛋白及β-乳球蛋白。
蛋白质是完整或水解的蛋白质或完整蛋白质与水解蛋白质的混合物。希望提供部分水解的蛋白质(水解度是2至20％之间)，以例如用于据信具有发生牛奶过敏反应风险的婴儿。若需要水解蛋白，则水解过程可按期望的方式进行，且其是本领域中已知的。例如，乳清蛋白水解物可依一或多个步骤，用酶促水解乳清部分制得。若作为起始材料的乳清部分实质上不含乳糖，则发现在水解过程期间，该蛋白质较少受到赖氨酸阻断。这能使赖氨酸阻断的程度从约15wt％的总赖氨酸减少至低于约10wt％的赖氨酸；例如，约7wt％的赖氨酸可极大改善蛋白源的营养品质。
该婴儿配方食品可包含糖类来源。尽管优选糖类来源是乳糖，但仍可使用任何常见于婴儿配方食品中的常用糖类来源，例如乳糖、蔗糖、麦芽糖糊精、淀粉及其混合物。优选地，糖类来源提供该配方食品总能量的35至65％。
婴儿配方食品可包含脂质来源。脂质来源可以是适用于婴儿配方食品 的任何脂质或脂肪。优选的脂肪来源包括棕榈油精、高油酸向日葵油及高油酸红花油。亦可添加必需脂肪酸(亚油酸及α-亚麻酸)及少量含有大量预形成花生四烯酸及二十二碳六烯酸的油，例如鱼油或微生物油。总之，脂肪含量优选是提供配方食品总能量的30至55％的含量。脂肪来源中n-6对n-3脂肪酸的比例优选为约5∶1至约15∶1，例如约8∶1至约10∶1。
婴儿配方食品还可含有所有被认为是每天膳食所必需及营养上有效量的维生素及矿物质。已针对某些维生素及矿物质建立最低需求。矿物质、维生素及任选存在于婴儿配方食品中的其他营养素的实例包括维生素A、维生素B1、维生素B2、维生素B6、维生素B12、维生素E、维生素K、维生素C、维生素D、叶酸、肌醇、烟酸、生物素、泛酸、胆碱、钙、亚磷、碘、铁、镁、铜、锌、锰、氯、钾、钠、硒、铬、钼、牛磺酸、及L-肉碱。矿物质通常是以盐形式加入。特定矿物质及其他维生素的存在及量将依旨在施用的婴儿群而变化。
若须要，婴儿配方食品可含有乳化剂及稳定剂，如大豆卵磷脂、单-及二-柠檬酸甘油酯等。
婴儿配方食品可任选含有其他具有有益效果的物质，如纤维、乳铁蛋白(lactoferrin)、核苷酸、核苷等。
上述婴儿配方食品可以由任何合适的方法制备。例如，可由蛋白质、糖类来源和脂肪来源以合适比例混合在一起而制备。若使用乳化剂，则可在此时添加。维生素及矿物质可在此时添加，但通常是稍后添加，以避免热降解。可在混合之前，先将任何亲脂性维生素、乳化剂等溶解于脂肪来源中。然后可将水，优选是已接受反渗透处理的水混合至其中，形成液体混合物。水温宜约50℃至约80℃，以辅助这些成分分散。可使用市售的液化剂形成液体混合物。然后例如以两个阶段使该液体混合物均化。
然后可通过例如在约5秒至约5分钟内，将该液体混合物快速加热至约80℃至约150℃范围内的温度来热处理该液体混合物，以减少细菌量(load)。可通过蒸汽喷射、高压灭菌器或通过热交换器，例如，平板热交换器进行此过程。
然后可通过例如急骤冷却，将该液体混合物冷却至约60℃至约85℃。接着，可例如以两个阶段再次使该液体混合物均化，第一阶段是于约10MPa至约30MPa下，第二阶段于约2MPa至约10MPa下。然后，进一步冷却该均化混合物，以添加热敏组分，例如维生素及矿物质。此时，适宜调整该均化混合物的pH及固体含量。
将该均化混合物转移至合适的干燥装置(例如喷雾干燥器或冷冻干燥器)，并转化为粉末。该粉末应具有少于约5wt％的水分含量。
短双歧杆菌CNCM I-3865可根据任何合适方法培养并通过例如冷冻干燥器或喷雾干燥器制备，以添加至婴儿配方中。
现将参考以下实施例进一步阐述本发明：
实施例1
根据本发明婴儿配方的组合物实例如下所示。此组合物仅以举例方式给出。
实施例2
该实施例比较短双歧杆菌的三种不同菌株在小鼠中对抗轮状病毒感染的效力。基于三个原因选择特定小鼠模式。首先，在该模式中，猿猴轮状病毒不仅引起肠道轮状病毒感染，也引起轮状病毒腹泻。其次，轮状病毒对于鼠肠粘膜的影响的组织病理学类似于感染轮状病毒的幼儿。第三，该模式已再现不同益生菌菌株在临床试验中所获得的较大及较小作用。
怀孕14天BALB/c小鼠购自丹麦 
小鼠分别置于瑞典胡丁格市卡罗林斯卡大学医院(Karolinska University Hospital，Huddinge，Sweden)的动物设施。自由取用寝具及巢穴材料、标准颗粒膳食及水。保持12∶12小时的光∶暗循环。幼崽于怀孕19至20天后出生。同胎的幼崽先随机挑出后再重新分配至不同实验组，每组7至10只。4组4天大的幼崽用于研究(三组实验组及一组对照组)。从第一天开始每天一次对幼崽 施用10μL体积的细菌并持续至第3天。新鲜培养的细菌以10e10 cfu/ml的浓度重悬于PBS中(该PBS介质已事先于相同模式动物中测试，并未发现该介质影响腹泻结果)。三组实验组分别接受短双歧杆菌CNCMI-3865(亦指定为内参NCC 2950)、短双歧杆菌NCC 2791及短双歧杆菌NCC 458。对照组仅接受PBS介质。
第0天，经口使用2.10e7 FFU猿猴轮状病毒RRV引起感染。整个研究仅使用一批RRV。记录腹泻的发生率直到第4天。第4天时，经腹膜内使用戊巴比妥使幼崽安乐死。
根据粪便的稠度评估幼崽的腹泻。水泻得到2分，稀便得到1分，无粪便或普通粪便得到0分。通过费希尔精确测试(Fisher′s exact test)，每日比较处理组之间是否出现腹泻，并在图表中以腹泻％表示。严重度定义为实验过程期间针对各幼崽的腹泻分数的总和(严重度＝∑腹泻值(第一天+第二天+第三天+第四天))，持续时间定义为腹泻总天数。严重度及持续时间通过克-瓦二氏(Kruskal-Wallis)测试法及邓恩测试法(Dunn test)分析。用曼-惠特尼检验法(Mann-Whitney test)测试实时PCR，评估肠道病毒量的差异。
感染率、严重度及持续时间示于下表2中。
表2
| NCC 2950 | NCC 2791 | NCC 458 | 对照组 | |
| 数据数量 | 8 | 8 | 8 | 6 |
| 持续时间平均值 | 0.75 | 1.5 | 2.125 | 2.5 |
| 持续时间SE | 0.2500 | 0.2673 | 0.2266 | 0.5000 |
| 平均严重度 | 1 | 1.75 | 3 | 3.667 |
从表2及图1中可了解，对照动物中获得高感染率，其中在第3天，100％的实验对象产生腹泻，因此可进行可靠数据分析。短双歧杆菌CNCM I-3865显示在腹泻持续时间及腹泻症状得分方面都显著减少(图1)。反之，短双歧杆菌NCC 2791显示有限的保护作用，同时来自短双歧杆菌NCC458的结果类似于对照组中的结果。
实施例3
该实施例采用上述实施例2中描述的模式，在小鼠体内比较短双歧杆菌CNCM I-3865的两种不同制剂对抗轮状病毒感染的效果。在该实施例中，有两个实验组及一个对照组。一个实验组接受以10e10 cfu/ml(NCC2950L)重悬于PBS中的活细菌。另一实验组接受相似细菌制剂，但在施用之前，该制物于90℃加热处理30分钟(NCC 2950H)。对照组动物仅接受PBS介质。结果示于表3及图2中。从其中可见，对照组动物获得高感染率，其中第2天100％动物腹泻。相较于对照组动物，两个实验组均减少腹泻症状。
表3
| NCC 2950H | NCC 2950L | 对照组 | |
| 数据数量 | 7 | 7 | 6 |
| 持续时间平均值 | 1.429 | 1.143 | 2.167 |
| 持续时间SE | 0.2974 | 0.4592 | 0.3073 |
| 平均严重度 | 1.429 | 1.429 | 4 |
Claims (8)
1.短双歧杆菌CNCM I-3865。
2.适用于预防或治疗轮状病毒腹泻的组合物，其包含短双歧杆菌CNCM I-3865。
3.权利要求2的组合物，其是婴儿配方食品、较大婴儿配方食品或成长乳。
4.权利要求3的组合物，其包含基于干重，相当于10e3至10e12 cfu/g的量的短双歧杆菌CNCM I-3865。
5.权利要求3或4的组合物，其包含相当于10e7至10e12 cfu/g的量的短双歧杆菌CNCM I-3865。
6.权利要求3至5中任一项的组合物，其还包含至少一种益菌素，其量为该组合物的0.3至6wt％。
7.权利要求2的组合物，其是补充剂且每单位剂量包含104至1012 cfu的短双歧杆菌CNCM I-3865。
8.权利要求1至7中任一项的组合物的用途，其用于制备预防或治疗轮状病毒腹泻的药物或治疗性营养组合物。
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| ME02997B (me) | 2014-12-23 | 2018-10-20 | 4D Pharma Res Ltd | Soj bacteroides thetaiotaomicron i njegova upotreba u smanjenju inflamacije |
| WO2016102951A1 (en) | 2014-12-23 | 2016-06-30 | 4D Pharma Research Limited | Pirin polypeptide and immune modulation |
| MA41060B1 (fr) | 2015-06-15 | 2019-11-29 | 4D Pharma Res Ltd | Compositions comprenant des souches bactériennes |
| CN115364122A (zh) | 2015-06-15 | 2022-11-22 | 4D制药研究有限公司 | 包含细菌菌株的组合物 |
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