益生菌与益生元

1.1  历史与定义

一个世纪之前，Elie Metchnikoff（俄国科学家，诺贝尔奖获得者，法国巴黎巴斯德学院教授）提出了乳酸菌(lactic acid bacteria, LAB)可以促进健康，延长寿命的假设。他认为通过调控肠道菌群和用益生菌替代水解蛋白微生物（该微生物通过消化蛋白质产生毒素包括酚类、吲哚类及氨类），可抑制“肠道自体中毒”及肠道衰老的过程。他开发了一种“保加利亚杆菌”的细菌发酵牛奶饮品。

随后肠道益生菌的观念得到了进一步的拓展，人们常常用非致病性活菌改变或替换肠道微生态来治疗肠道疾病。1917年，在Alexander Fleming发现青霉素之前，德国科学家Alfred Nissle从一名第一次世界大战士兵的粪便中分离出一种非致病性大肠埃希菌菌株，该士兵在一次严重的志贺菌爆发中并未受到感染。因此，大肠埃希菌菌株Nissle1917是少有的非乳酸菌类益生菌的成员之一。

Henry Tissier (巴斯德学院)从一名母乳喂养的婴儿粪便中分离出双歧杆菌，并将该菌应用于腹泻的婴儿中。他推测该菌可以替换引起腹泻的水解蛋白类细菌。在日本，Minoru Shirota博士分离出干酪乳杆菌Shirota菌株以控制腹泻爆发。含有该菌株的益生菌产品自1935年始进入市场。

    这些早期先驱在科学领域的成果已得到了进一步发展。如今，在PubMed中搜索相关临床试验，结果显示，超过1500项关于益生菌及近350项关于益生元的临床试验已发表。虽然这些试验由于菌株、益生元及研究人群的不同而具有异质性，但从许多不同的结果中所累积的证据均支持益生菌和益生元对人类健康有益。

    益生菌是一类活的微生物，摄入适量的益生菌有益宿主健康[1] (表1)。乳杆菌及双歧杆菌(图1) 是最常用的益生菌，而鲍氏酵母菌及某些大肠埃希菌和杆菌菌种也同样被广泛应用。新发现的丁酸梭菌，最近在欧盟国家中被批准作为一种新型食物。乳酸菌，包括乳杆菌菌种，数千年来一直被用来通过发酵以保存食物。它不仅能作为食物发酵剂，而且还对健康有益。然而，从严格意义上讲，“益生菌”一词是指在对照临床研究中证实有益于健康的活的微生物。发酵被广泛应用于生鲜农产品的保存（包括谷类、根茎类、块茎类、水果和蔬菜、牛奶、肉类、鱼类等）。

 

 

1.2  益生元与合生元

“益生元”这一概念在1995å¹´ç”±Gibson å’ŒRoberfroid首次提出，迟于益生菌概念[2]。益生元的主要特点是不能被宿主所消化，通过对肠道固有益生菌的正性作用而促进宿主健康。益生元或益生菌的应用，在于影响寄生有万亿共生菌所构成的肠道环境，从而对人类健康有益。益生菌与益生元的有益影响已远不止于肠道，而本指南将关注于其对肠道的影响。

益生元是膳食成分（绝大多数包含非淀粉类多糖及寡糖）。多数益生元被作为食品添加剂，如用于饼干、谷类食品、巧克力、涂抹酱、乳制品中。常见已知的益生元：

• 低聚果糖
• 菊粉
• 低聚半乳糖
• 乳果糖
• 母乳低聚糖

乳果糖是一种合成的双糖，用于治疗便秘及肝性脑病。益生元性的低聚果糖存在于许多天然食物中，如小麦、洋葱、香蕉、蜂蜜、大蒜及韭菜。低聚果糖也能从菊苣中分离或从蔗糖中通过酶促合成。

低聚果糖在结肠中的发酵过程可产生大量的生理反应，包括：

• 增加结肠中双歧杆菌的数量
• 促进钙吸收
• 增加粪便重量
• 缩短胃肠道传输时间
• 可能降低血脂水平

结肠双歧杆菌数量的增加可产生一些抑制潜在致病菌生长的复合物，减少血氨水平，同时产生维生素和消化酶，从而对宿主产生有益作用。

合生元是益生元和益生菌的复合制剂。合生元同时具有益生元及益生菌的作用。

1.3  益生菌菌属、菌种及菌株

益生菌菌株是按菌属、菌种、亚菌种和字母数字排列来命名的。在科学界，对微生物有公认的命名法---如干酪乳杆菌DN-114-001（Lactobacillus casei DN-114 001）或鼠李糖乳杆菌GG（Lactobacillus rhamnosus GG）。但商品名则不受上述命名法的约束。根据WHO/FAO指南(http://www.fao.org/3/a-a0512e.pdf)，益生菌制造商应该向国际菌株贮存库登记其生产的相关菌株。菌株贮存库将会给予这些菌株额外的编号。表2示某些商品菌株及其名称。

对益生菌实行菌株编号是重要的，因为证实益生菌有益（例如本指南中所讨论的对消化道特异性作用）的最有力的证据是将获益与有效剂量的特定菌株或混合菌株联系起来。

关于益生菌的推荐，尤其在临床工作中，应当将特定菌株与其基于临床研究中明确的益处紧密联系起来。某些菌株具有独特的性质，可能具有一些神经性、免疫性及抗微生物活性。然而，在益生菌领域中有一种观念正逐渐被认识，即益生菌活性相关机制可能在不同菌株、菌种，甚至菌属中共享。许多益生菌可能以一种类似的方式作用于定植耐受、调节肠道传输或恢复肠道失衡的菌群。例如，许多不同益生菌就是通过增加短链脂肪酸产物或降低结肠肠腔pH来发挥重要的有益作用。因此，某些益生菌的有益作用是被一些经过充分研究的乳酸菌和双歧杆菌菌株所传递的。如果使用益生菌的目标是为了促进消化道健康，那么，许多不同的益生菌制剂，只要含有足量的经过充分研究的菌株可能就足够了。

在益生菌领域中，纳入多种菌株的系统性综述及荟萃分析很普遍。如果研究中不同菌株的共同作用机制均显示了有益的作用，那么这种研究方法是有效的。

1.4  体内定植微生物

益生菌和益生元的功能均与定植在人体中的微生物密切相关。益生元是有益共生微生物的食物来源，进而促进健康。益生菌与宿主细胞或益生菌与机体常驻菌群的相互作用是影响宿主健康的关键因素。

肠道中含有大量微生物，具有成百上千的菌种，主要分布在结肠（表3）。据估计，在成人结肠中寄居着超过40万亿的细菌细胞（包括小部分的古生菌＜1%），真菌及原生物也占有极小比例。而病毒/噬菌体的数目远超于细菌细胞。整体而言，每个人平均携有60万个肠道微生物基因。

在菌种及菌株水平上，个体之间的微生物多样性是显著的：每个个体具有自己独有的细菌组成，这是由宿主基因型、出生时通过垂直传播途径获得的初始定植和饮食习惯共同决定的。

在健康成年人中，随着时间的变化，粪便中菌群组成处于稳定状态。在人类肠道生态系统中，拟杆菌门与厚壁菌门是两种主要的细菌，占全部微生物的90%以上。剩下的则为放线菌门、变性菌门、疣微菌门和梭菌门。

正常情况下，肠道菌群与其宿主之间是一种共生关系。肠道菌群对于机体免疫功能的影响主要是体现在小肠和大肠粘膜中大量的淋巴组织结构（小肠：Peyer’s集合淋巴小结；大肠：孤立性淋巴滤泡）。覆盖在这些结构之上的肠上皮专门用于抗原的吸收和取样，同时它们含有诱导机体适应性免疫反应的淋巴生发中心。结肠微生物可通过发酵食物或者内源性分泌物实现自身增殖，并为宿主提供营养。

许多研究显示，健康人群与病人之间的定植微生物显著不同。尽管如此，研究者仍不能定义一个健康个体微生物的组成。某些共生细菌（如罗氏菌、Akkermansia、双歧杆菌和普拉梭菌）与健康更为相关，当前的研究热点是探索补充这些菌群是否可能促进健康或逆转疾病状态。

 

1.5  益生菌的作用机制

益生元通过增加肠道有益的厌氧菌和减少潜在病原微生物的数量来影响肠道菌群。益生菌则通过影响粘膜免疫机制、与肠道共生菌或潜在病原微生物的相互作用、产生代谢终产物（如短链脂肪酸）和通过化学信号传导与宿主细胞交流等方式来影响肠道生态系统（图2，表4）。这些作用机制可遏制潜在致病菌，改善肠道环境，增强肠道屏障功能，下调炎症及上调接触抗原后的免疫反应。以上过程可介导许多有益效应，包括减少腹泻发病率及减轻其严重程度。腹泻也是益生菌最为广泛应用的疾病之一。

 

 

2.1  了解市场信息

益生菌产品在世界各地广泛应用。产品无论是以传统食物还是以处方药的形式均有市售（表5）。

关于益生菌产品种类的相关健康声明可以依据每个地区的监管不同而不同。益生菌和益生元最常以食品或者膳食补充剂形式被销售。一般而言，该产品的健康声明具有普适性，允许其不注明针对某类疾病。益生菌产品主要是针对一般健康人群。“天然保健品”是一类仅针对加拿大的产品，因为这是经加拿大相关管理部门批准，并允许使用这些产品来治疗疾病。

从科学角度而言，需要在益生菌产品的标签上给予其一个合适的描述。

• 菌属和菌种，与目前科学识别名称相一致
• 菌株名称
• 保质期内的活菌数
• 推荐的贮存条件
• 推荐使用条件下的安全性
• 基于生理效应诱导条件的推荐剂量
• 在法律允许条件下，对生理效应进行准确描述
• 售后监督联系方式

根据2015年美国市场研究公司Grand View Research研究报告显示，2013年益生菌全球市场销售额为320.6亿美元。将大量益生菌食品、膳食补充剂和药品立足于市场上是一项相当艰巨的任务。表6所示相关指南文件。

 

2.2  产品：剂量与质量

益生菌产品质量优劣主要取决于制造商。由于大部分产品并不需要满足制药标准，因此，相关管理部门可能不会依据质量标准来监督产品。关于益生菌质量，尤为重要的指标包括：益生菌在保质期内的活菌数（以菌落为单位，CFU衡量）和应用目前命名法来识别产品中包含的菌属、菌种及菌株。

益生菌的剂量根据菌株和产品的不同而不同。尽管许多非处方益生菌产品中每剂含有1-100亿CFU，数据显示，某些产品在低水平CFU时就有效，而另一些产品实际上需要更高的CFU才有效。因此，益生菌的剂量无法统一，剂量的制定应该基于对人群有益的临床研究数据。

由于益生菌是活菌，在贮存过程中容易发生死亡。负责的制造商为了在产品到保质期前，益生菌数量不至于低于商标中所示的有效数，会在产品中灌输超量的益生菌。尽管对于其它菌株而言，产芽孢益生菌的研究还不很充分，但其在保质期内具有更强的抵抗环境的作用。然而，市场上所售的某些益生菌产品，无论是活菌数量及种类都不符合商标上所标注的内容。

注意：应该将益生菌产品中活菌CFU限定在特定允许范围内，以降低毒性，同时也减少在生产过程中和保质期内菌群有效性的流失 [3,4]。

2.3  产品安全性

目前大多数使用的益生菌是从发酵的食物或定植在健康人群的微生物中所提取，而且这些益生菌产品已被应用数十年。由于乳酸杆菌普遍存在于发酵食物中，同时也是人体的正常定植菌，很少会引起机体感染，因此，微生物领域专家认为乳酸杆菌的潜在致病性是相当低的。证据显示，双歧杆菌菌种也具有相似的安全性。由于大部分益生菌产品是针对一般健康人群，因此，对于免疫功能缺陷病人或者患有潜在严重疾病人群，益生菌产品使用应严格限制菌株种类，适应证应是已被证明有效的（如第4节所述）。如Sanders等所总结的，微生物质量标准应满足具有高危人群的需求[4]。如要在其他疾病中测试或应用一种新分离的益生菌，应在获得独立的伦理委员会审核批准后方可实行。传统的乳酸细菌与食物发酵相关，对于一般健康人群，常规摄入乳酸菌相关食品或膳食补充剂是安全的。

 

以下是有关不同益生菌或益生元在胃肠病领域中临床应用的最新观点。根据证据等级水平推荐不同适应证（总结见表8和9）。

3.1  预防结直肠癌

• 尽管认为饮食可以影响结直肠癌发生，且研究显示，益生菌和益生元可改善结直肠癌相关生物指标，但益生菌或益生元预防结直肠癌的数据仍是有限的。

3.2  æ²»ç–—和预防腹泻

3.2.1  治疗急性腹泻

• 某些益生菌菌株可以减少儿童急性感染性腹泻的程度和病程。口服益生菌可将儿童急性腹泻病程缩短近1天。多项临床对照研究荟萃分析一致认为益生菌可能是安全和有效的。然而，作用机制可能具有菌株特异性。

3.2.2  预防急性腹泻

• 在成人及儿童腹泻预防方面，证据显示，某些益生菌在特定情况下是有效的。

3.2.3  预防抗生素相关性腹泻

• 在抗生素相关性腹泻预防方面，已有足够证据显示，益生菌对接受抗生素治疗的成人及儿童发生的腹泻预防是有效的。

3.2.4  预防难辨梭状芽孢杆菌感染性腹泻

• 一项2016年荟萃分析[5]结果显示，益生菌可减少抗生素治疗的患者发生梭状芽胞杆菌相关性腹泻的风险。但是，益生菌的最佳菌株和剂量仍需进一步研究。

3.2.5  预防放射性腹泻

• 肠道菌群可能在放射引起的腹泻预防中具有重要作用，主要是通过增强肠粘膜屏障功能、促进固有免疫和刺激肠道修复机制。一项2013年荟萃分析[6]数据显示，益生菌对放射性腹泻预防是有益的，对治疗可能也有效。

3.3 æ ¹é™¤å¹½é—¨èžºæ†èŒ

• 2016年关于幽门螺杆菌感染治疗的Maastricht V/Florence共识报告指出，益生菌与益生元可有效减少幽门螺杆菌感染治疗过程中所发生的不良反应。然而，相关证据质量及推荐证据等级均较低。一项2014年临床随机对照研究的荟萃分析显示[7]，在抗幽门螺杆菌治疗中补充特定益生菌可能有助于提高根除率，另外，对于根除失败的患者可能也有帮助。没有证据显示，单用益生菌，而不联合应用抗生素对根除幽门螺杆菌是有效的。

3.4 é¢„防和治疗肝性脑病

• 益生元，如乳果糖，广泛用于肝性脑病的预防和治疗。证据显示，若联合应用一种益生菌可逆转轻度的肝性脑病。

3.5 å…ç–«ååº”

• 有证据显示，某些益生菌和益生元（低聚果糖）可以改善机体免疫反应。在预防急性感染性疾病（儿童院内感染性腹泻、冬季流感爆发）和针对疫苗的测试抗体反应相关性研究中，证据均显示益生菌和益生元可增强机体免疫反应。

3.6 ç‚Žç—‡æ€§è‚ ç—… (Inflammatory bowel disease, IBD)

3.6.1  贮袋炎

• 证据显示，某些益生菌在预防初发性贮袋炎及经抗生素诱导缓解后复发的贮袋炎中具有一定作用。推荐轻度贮袋炎患者应用益生菌或者可作为缓解期患者的维持治疗。

3.6.2  溃疡性结肠炎

• 研究发现，在成人和儿童轻-中度活动性溃疡性结肠炎治疗中，益生菌与传统治疗一样安全有效。

3.6.3  克罗恩病

没有证据显示，益生菌对克罗恩病缓解期的维持治疗是有效的。

3.7 è‚ æ˜“激综合征 (Irritable bowel syndrome, IBS)

• 目前研究均显示，益生菌治疗可以减轻腹胀和胀气。某些菌株可能会减轻腹痛且改善总体症状。文献显示，某些益生菌可能会减轻功能性腹痛患者的症状，改善他们的生活质量。

3.8 è‚ ç»žç—›

• 研究显示，某些益生菌可以缩短母乳喂养的婴儿因肠绞痛而哭闹的时间。

3.9 ä¹³ç³–吸收不良

• 大量饮用含有活菌酸奶的对照研究证实，嗜热链球菌和保加利亚乳杆菌可促进乳糖消化，减轻乳糖不耐受相关症状。

3.10 åæ­»æ€§å°è‚ ç»“è‚ ç‚Ž

• 补充益生菌可减少早产儿患坏死性小肠结肠炎风险。随机对照研究的荟萃分析显示，益生菌治疗组中死亡风险降低，尽管并不是所有益生菌制剂均有效。为预防1例因各种原因引起的死亡病例而需要用益生菌治疗的患者数目（NNT）为20。

3.11 éžé…’精性脂肪性肝病

• 大量成人和儿童的随机对照研究显示，某些益生菌可以减轻脂肪性肝炎。益生菌可以改善体内稳态模型评估（HOMA）评分、降低血胆固醇浓度、降低肿瘤坏死因子-α(TNF-α)水平及肝功能-谷丙转氨酶（ALT）与谷草转氨酶（AST）水平。但有关益生菌的长期疗效，仍需进一步研究。

3.12 é¢„防系统性感染

• 尚无足够证据支持益生菌和合生元在重症监护室的危重病人中的应用。

 

虽然已超出本指南的叙述范围，但对于读者而言，仍有兴趣了解益生菌和益生元对消化道疾病以外的影响。越来越多的证据表明，肠道菌群可能影响一些非消化道疾病，因此，可以确立这些疾病与消化道之间有关联。大量研究显示，益生菌可降低细菌性阴道炎的发生，预防婴儿变应性皮炎，减少口腔致病菌和龋齿，减少常见上呼吸道感染的发生率和疾病病程。根据益生菌可以预防围产期过敏性疾病发生的证据，世界变态反应组织（WAO）推荐具有过敏性疾病高风险家族成员在孕期、哺乳期及断奶期使用益生菌。益生菌和益生元也正被用于预防代谢综合征相关临床表现，包括超重、2型糖尿病和脂代谢异常。

 

表8和表9对益生菌治疗胃肠道疾病进行了总结，每个疾病证据中均有至少1项关于口服一种特异益生菌或益生元具有疗效的高质量临床试验。这些表格主要是为了传达给读者关于支持所列产品有效性和安全性的相关研究，而一些其他市场销售产品可能没有进行过临床试验。

由于一些新的研究正在进行中，列表所列信息可能并不全面。证据水平可能因适应证不同而不同。剂量是根据临床随机对照研究中应用剂量而定。益生菌产品所列顺序是随机的。

从对照研究中得出的证据不足以对产品的有效性进行排序。以下表格只提供了根据牛津循证医学中心的标准所定的证据等级，而并未提供推荐等级（表7）。表中同时列了医学会推荐建议。

 

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