1.1 历史和定义

一个多世纪以前, Elie Metchnikoff （俄罗斯科学家、诺贝尔奖得主及巴黎巴斯德研究所教授）提出乳酸菌（LAB；表 1）具有促进长寿的健康益处。他认为通过调节肠道菌群，用糖水解菌株替代在消化蛋白质过程中产生苯酚、吲哚和氨等有毒物质的蛋白水解菌株，可以抑制“肠道自体中毒”和由此导致的衰老。他开发了一种饮食，里面包含了被他称为“保加利亚杆菌”发酵过后的牛奶。

这一概念的其他早期发展随之而来。具有活性的非致病性菌株开始被频繁用于治疗肠道疾病，以改变或替代肠道菌群。1917年，在Alexander Fleming爵士发现青霉素之前，德国教授Alfred Nissle从一名第一次世界大战士兵的粪便中分离出一株非致病性大肠杆菌，该士兵在严重的志贺氏菌感染暴发期间没有罹患小肠结肠炎。由此得到的大肠杆菌菌株Nissle 1917成为了非乳酸菌性益生菌的一个例子。

Henry Tissier（来自巴斯德研究所）从母乳喂养的婴儿中分离出一株双歧杆菌，目的是将其用于治疗患有腹泻的婴儿。他猜测它会取代导致腹泻的蛋白水解菌株。在日本，Minoru Shirota博士分离出副干酪乳杆菌（Lacticaseibacillus paracasei）菌株Shirota来对抗腹泻疫情。含有该菌株的益生菌产品已于1935年起在市场上售卖。

这些都是一个正在蓬勃发展的科学领域的早期先驱。如今，在PubMed中搜索人体临床试验显示，已经发表了超过1500项关于益生菌的研究。虽然这些研究在菌株和研究人群方面存在异质性，但许多不同的研究结果均显示了益生菌的益处，并得到了越来越多的证据支持。

益生菌是能够在摄入足够量时对宿主产生健康益处的活的微生物[1]（表1）。乳酸杆菌和双歧杆菌是历史上常见的益生菌。2020年，乳酸杆菌属进行了重大重组，以更好地处理该菌属广泛多样性的问题。23个新属被重新定义，其中包括一些已有深入研究的益生菌品种（表2）。

布拉氏酵母菌（Saccharomyces boulardii）和一些大肠杆菌（E. coli）和芽孢杆菌（Bacillus）也被使用。新加入益生菌行列的丁酸梭菌（Clostridium butyricum），最近已被欧盟批准为一种新食品。数千年来一直通过发酵被用于保存食物的乳酸菌（表1）也可能具有潜在的健康益处。然而，“益生菌”这个术语应该仅用于已在人体对照研究中证明具有健康益处的活的微生物。发酵在全球范围内被应用于保存一系列农业原料，如谷物、根茎、块茎、水果和蔬菜、牛奶、肉类和鱼类。

1.2 益生元和合生元

益生元的概念最初由Gibson和Roberfroid于1995年提出，是比益生菌更新的概念。益生元的关键特点是它无法被宿主消化，通过对常驻有益微生物的积极影响为食用者带来健康益处（表1）。益生元或益生菌的使用旨在影响有数万亿微生物居住的肠道环境，以促进人体健康。益生元和益生菌都已经被证明具有肠道以外的益处，但本指南将重点关注对肠道的影响。

益生元通常由非淀粉多糖和寡糖组成，尽管其他物质也被作为候选益生元在进行研究，如抗性淀粉、共轭亚油酸和多酚。大多数益生元被用作食品配料，用于饼干、谷物、巧克力、果酱和乳制品等食品中。常见的益生元有：

• 寡果糖（低聚果糖，FOS）
• 菊粉
• 低聚半乳糖（GOSs）
• 乳果糖
• 母乳寡糖（人乳寡糖或HMOs）

乳果糖是一种用于治疗便秘和肝性脑病的合成双糖。低聚果糖作为益生元在许多食物中自然存在，如小麦、洋葱、香蕉、蜂蜜、大蒜和韭菜。低聚果糖还可以从菊苣根中分离出来，或通过酶法从蔗糖中合成。

在结肠中发酵的低聚果糖可能会产生几种生理效应，包括：

• 增加结肠中双歧杆菌的数量
• 增加钙吸收
• 增加粪便重量
• 缩短胃肠传输时间
• 降低血脂水平

然而，食用者可能经历的这些生理效应的程度因许多因素而异，包括基础肠道菌群和饮食。

已经有假说认为，结肠中双歧杆菌的增加通过产生抑制潜在病原体的化合物、降低血氨水平以及产生维生素和消化酶对人类健康产生益处。

合生元最初被描述为益生元和益生菌的适当组合。最近，合生元的概念演变为包括互补型和协同型合生元（表1）。互补型合生元被简单地定义为益生菌和益生元的混合物，其中两种成分符合各自定义的标准，包括正确的特性，并使用能够提供健康效益的剂量。然而，协同型合生元为一种选定出来能够利用底物的活的微生物和该底物的混合物，两者一起产生明确的健康效益。协同型合生元的成分不需要单独满足益生菌或益生元的标准。

1.3 用作益生菌的属、种和菌株

益生菌菌株由属、种、亚种（如果适用）和识别特定菌株的字母数字名称来识别（表3）。在科学界，属、种和亚种名称有商定的命名规范。菌株名称、产品名称和商品名称不受科学界的控制。根据世界卫生组织（WHO）和粮食及农业组织（FAO）的指南（http://www.fao.org/3/a-a0512e.pdf），益生菌制造商应将其菌株存放在国际公认的培养菌种收藏中心。这样的储存库将会给菌株提供一个额外的名称。表3展示了一些商业菌株及其相关名称。

益生菌的菌株命名对于益生菌很重要，因为最可靠的益生菌研究证据是将益处（如本指南中讨论的特定胃肠道靶点）与有效剂量的特定菌株或菌株组合联系起来。

益生菌的推荐，特别是在临床中，应该将特定菌株与人体研究显示的益处联系起来。有些菌株会具有特性，可能可以解释其某些神经、免疫和抗菌活性。然而，益生菌领域一种新兴概念是认识到益生菌活性的一些机制可能在不同菌株、菌种甚至菌属之间共享。许多益生菌在促进定植抗力、调节肠道传输功能或使紊乱的微生物群正常化方面可能发挥类似的作用。例如，增加短链脂肪酸的产生或降低结肠肠腔pH可能是许多不同益生菌菌株的核心益处。因此，某些益生菌益处可能由某些经过充分研究的益生菌属的不同菌株提供。

现在在益生菌领域，系统评价和荟萃分析通常包括多个菌株。如果不同菌株之间共享的作用机制被证明是产生所评价益处的原因，那这种方法是合理的。否则，应该侧重于特定菌株的证据。

1.4 定植菌群

益生菌和益生元对胃肠道的功效与居住在人体肠道中的微生物交织在一起。益生元被共生微生物群落中的有益成员利用，从而促进健康。益生菌与宿主细胞或益生菌与宿主微生物之间的交互是影响宿主健康的重要机制。

肠道中含有大量微生物，主要分布于结肠，由数百种菌种组成（表4）。据估计，成年人的结肠中有超过40万亿个细菌细胞（包括一小部分古生菌，不到1%）。此外还存在真菌和原生生物，在细胞数量方面的贡献可以忽略不计，而病毒/噬菌体的细胞数量可能超过细菌细胞。肠道微生物平均为每个人增加了60万个基因[4]。

在菌种和菌株水平上，不同个体间的微生物多样性非常显著：每个人都具有其自身独特的细菌组成模式，部分由宿主基因型、出生时通过垂直传播进行的初始定植以及饮食习惯所决定。

在健康成年人中，粪便成分是稳定的。在人类肠道生态系统中，拟杆菌门（Bacteroidetes）和厚壁菌门（Firmicutes）这两种细菌分类占主导地位，超过90%的微生物属于这两个菌门。其余为放线菌门（Actinobacteria）、变形菌门（Proteobacteria）、疣微菌门（Verrucomicrobia）和梭杆菌门（Fusobacteria）。

肠道微生物与宿主之间的正常互动是一种共生关系。在小肠粘膜和大肠粘膜中存在大量淋巴组织（潘氏斑和孤立淋巴滤泡），提示肠道细菌对免疫功能的重要影响。这些结构上的上皮细胞专门用于抗原的摄取和采样，并包含淋巴样生发中心，用于诱导获得性免疫反应。在结肠中，微生物通过发酵从日常饮食或内源性分泌物中获得的底物来繁殖，并为宿主提供营养。

许多研究表明，健康个体和患有疾病或不健康的个体之间所定植微生物的数量存在差异。然而，研究人员目前无法确定健康人体的微生物群落构成。某些共生菌（如Roseburia、Akkermansia、Bifidobacterium、Faecalibacterium prausnitzii等）似乎更常与健康相关，但目前研究活跃的领域是确定补充这些细菌是否能够改善健康或逆转疾病。

1.5 益生菌和益生元的作用机制

益生元可以通过增加有益菌的数量或活性来影响肠道细菌。这可能会降低潜在致病微生物的数量或减少宿主微生物群落的潜在有害代谢活性。益生元还可能影响免疫功能。

益生菌菌株可以通过一种或多种机制介导健康效应。益生菌可能通过影响粘膜免疫机制、与共生或潜在致病微生物相互作用、产生代谢终产物如短链脂肪酸以及通过化学信号与宿主细胞进行相互作用来影响肠道的生态系统（图3；表5）。这些机制可以抵抗潜在病原体、改善肠道环境、增强肠道屏障、下调炎症反应，和上调对抗原挑战的免疫反应。这些现象被认为介导了大多数有益效应，包括减少腹泻的发生率和严重程度，这是益生菌被最广泛认可的用途之一。

 

2.1 市场理解

含有益生菌的产品已经在全球许多地区成功推广。从传统食品到处方药，一系列产品类型都可以在市场上买到（表6）。

根据地区的监管规定，对这些产品的声明可能有所不同。益生菌和益生元最常被作为食品或补充剂的形式销售。通常不允许提及疾病或病症，声明往往是一般性的，针对的是一般健康人群。在加拿大，天然保健品是一个特定的类别，管理当局政府批准声明并允许产品标签写明可用于治疗疾病。

从科学角度来看，标签上对益生菌产品的适当描述应包括：

• 按当前科学公认名称一致的命名方式鉴定的属、种（和亚种，如适用）
• 菌株标识

• 每个菌株在保质期结束时的活菌计数
• 推荐的储存条件
• 推荐的剂量，应基于可诱导出所声称的生理效应
• 根据法律规定允许的生理效应的准确描述
• 上市后监督的联系信息

2.2 产品：剂量和质量

根据2015年Grand View Research的报告，2013年全球益生菌市场价值为321亿美元。据预测，全球益生菌市场将以每年8.1%的增长率迅速发展，到2027年将达到854亿美元（来源：“Probiotics Market”，https://www.marketsandmarkets.com/）。在市面上搜寻大量的食品、补充剂和药品并不容易。医疗机构提供的大多数指导意见都是基于菌株而非产品名称，而产品名称可能因地域不同而有所不同。要将益生菌菌株与具体产品匹配起来并不容易，并非所有产品都标识恰当。加拿大和美国进行此类工作，由商业实体提供无限制的资金支持，能够将产品与现有的可用证据联系起来（详见http://www.probioticchart.ca/和http://usprobioticguide.com/）。

益生菌产品的质量取决于相关制造商。由于大多数产品不是按照药品标准制造的，监管机构可能不会监督其是否遵守质量标准。对益生菌质量特别重要的问题包括保证效力（维持活性，通常由到保质期结束时的菌落形成单位表示）、纯度（生产工艺，足以减少任何有关的病原体）和身份（目前的命名法则用于指定产品中每一个菌株的属、种和亚种（如果适用）以及菌株名称）。

益生菌所需的剂量因菌株和产品而异。尽管许多非处方药产品的剂量在1-10亿cfu/剂的范围内，但有些产品已被证明在较低水平下也有疗效，而有些则需要远高于此水平的剂量。例如，Bifidobacterium longum subsp. longum 35624在1亿cfu/天的剂量下有效地减轻了肠易激综合征的症状，而其他益生菌产品的有效剂量则为3000-4500亿cfu每日三次。要确定益生菌所需的一般剂量是不可能的，剂量的确定应基于那些显示对健康有益的人体研究。

由于益生菌是活体，因此容易在产品储存过程中死亡。制造商通常会加入超额数量的菌数，以便产品在保质期结束时不会低于其标签上声明的效力。负责任的制造商会标明使用日期时（而非生产时）的预期剂量。产芽孢益生菌菌株在保质期间具有较强的环境抗逆性。然而，有力的证据显示，产芽孢益生菌的有效性不及非芽孢益生菌。市场上的某些益生菌产品无法符合标签上所声明的产品中存在的活菌数和类型的要求。因此，向可靠的制造商购买产品至关重要。

2.3 产品安全性

今天使用的大多数益生菌要么来自发酵食品，要么来自健康人体内定植的微生物，并且已经在产品中使用了几十年。鉴于乳酸杆菌在发酵食品中普遍存在，并作为人体的正常定植菌，而且由其引起的感染率低，专家们认为其致病潜力相当低。双歧杆菌菌种也有类似的安全性。大多数产品是针对一般健康人群的，因此，在免疫功能缺陷或患有严重基础疾病的人群中使用，应限于已经证实对目标患者群体安全有效的菌株和适应证，详见下文第4节所述。如Sanders等人所述[5]，微生物质量标准应满足高危患者的需求。测试或使用新分离的益生菌或将已知的益生菌用于新的疾病适应证，只有经过独立伦理委员会的审查和批准后才能被接受。传统的乳酸菌，长期以来与食品发酵有关，通常被认为作为食品和补充剂按传统使用的水平口服，对于一般健康人群是安全的。

下文总结了目前有关益生菌和益生元在胃肠病学中的临床应用的最新见解（按字母顺序排列）。需要指出的是，本文提供的是临床疗效的总体概述。然而，益生菌的作用因菌株和剂量而异，而对于益生元，其效果取决于特定的配方。基于分级证据等级的不同适应证参考表8和表9。荟萃分析被认为是评估临床疗效的最高级别证据。然而，由于试验设计的异质性、所用益生菌干预措施的异质性、研究人群的异质性以及每个临床试验中包含相对较少的样本量，因此，使用荟萃分析评估益生菌的临床试验尚存在诸多问题。这些问题会影响任何实施干预措施的荟萃分析结果，但益生菌的荟萃分析需要仔细考虑菌株特异性的作用。在参考研究结果提出医学建议时，应避免将有相似作用机制的不同益生菌菌株的数据结合起来。因此，本节概述了益生菌在临床情况下的总体疗效，表8和表9详细介绍了各个益生菌制剂及其有效的临床表现。

3.1 结直肠癌的预防

• 虽然饮食被认为与结直肠癌的发病有关，在动物模型中，益生菌和益生元都被证明可以改善与结直肠癌相关的生物标志物，但在人类中，益生菌或益生元预防结直肠癌的数据有限。

3.2 腹泻的治疗与预防

3.2.1 急性腹泻的治疗

• 一些益生菌菌株有助于减轻儿童急性感染性腹泻的严重程度和持续时间。口服给药可使儿童急性腹泻的病程缩短约1天。已经发表的多篇关于其他益生菌菌株的临床对照试验的荟萃分析显示出一致的结果，表明益生菌可能是安全有效的。

3.2.2 急性腹泻的预防

• 在预防成人和儿童腹泻方面，有证据表明，某些益生菌在某些特定情况下是有效的。一项低偏倚风险的大型试验的Cochrane荟萃分析[6]得出结论，对于持续48小时或更长时间的腹泻，益生菌可能没有效果。因此，可能需要尽早给予益生菌治疗。

3.2.3 抗生素相关性腹泻的预防

• 在预防抗生素相关性腹泻方面，有证据表明，益生菌对正在接受抗生素治疗的成人或儿童是有效的。荟萃分析得出结论，在预防儿童[7]、成人[8]和老年人[9]的抗生素相关性腹泻方面，益生菌可能具有中等程度的效果。

3.2.4 难辨梭菌相关性腹泻的预防

• 2017年的一项荟萃分析以中等程度的确定性得出结论，对接受抗生素治疗的患者，益生菌可有效预防难辨梭菌相关性腹泻[10]。益生菌在非免疫缺陷或严重虚弱的患者中的使用似乎是安全的。作者虽然指出还需要进一步的研究，但得出的结论表明，那些有高风险发展为难辨梭菌相关性腹泻的患者会从了解益生菌的潜在益处和危害中受益。

3.2.5 放疗相关性腹泻的预防

• 肠道菌群可能通过增强肠道屏障功能、改善先天免疫和刺激肠道修复等机制，在放疗相关性腹泻中发挥着重要作用。2013年的一项荟萃分析得出结论，益生菌可能有助于预防和治疗放疗相关性腹泻[11]。

3.3 幽门螺杆菌的根除治疗

• 2022年马斯特里赫特VI/佛罗伦萨共识报告指出，某些益生菌已被证明在减轻幽门螺杆菌根除治疗引起的胃肠道副作用方面是有效的，然而，证据质量较弱，推荐等级为中等[12]。没有证据支持仅使用益生菌而不联合抗生素治疗会有效这一观点。益生菌似乎通过减少与根除治疗相关的副作用来增加H. pylori的根除率，而不是通过对H. pylori的直接作用。

3.4 肝性脑病的预防与治疗

• 乳果糖等益生元常被用来预防和治疗肝性脑病。有一种益生菌混合物的证据表明，其可以逆转轻度肝性脑病。2017年的一项Cochrane荟萃分析发现，三项关于益生菌对肝性脑病患者有益的研究证据质量较低[13]。虽然没有观察到死亡率的差异，但作者推断益生菌可能改善康复、生活质量和血氨浓度。

3.5 免疫反应

• 有证据表明，几种益生菌菌株和益生元低聚果糖可改善免疫应答。在预防急性传染病（儿童院内腹泻、冬季流感）和测试疫苗抗体反应的研究中，已经有证据表明有增强免疫反应作用。

3.6 炎症性肠病（IBD）

3.6.1 贮袋炎

• 有证据表明，益生菌混合物在预防初发贮袋炎和预防抗生素诱导缓解后的复发方面是有用的。建议将益生菌混合物用于成人和儿童的轻度活动性贮袋炎，或作为缓解期患者的维持治疗[14]。

3.6.2 溃疡性结肠炎

• 个别研究表明，某些益生菌在成人和儿童轻度至中度活动性溃疡性结肠炎的治疗反应和缓解率方面，可能与传统治疗一样安全有效。然而，2020年的一项Cochrane荟萃分析得出结论，关于轻度至中度溃疡性结肠炎的诱导缓解作用的证据确定性较低，并且没有证据表明益生菌对更严重的疾病状态是有效的[15]。

3.6.3 克罗恩病

• 克罗恩病中关于益生菌的研究表明，没有证据表明它们对诱导或维持克罗恩病的缓解有益。

3.7 肠易激综合征（IBS）

• 已发表的研究均显示，益生菌治疗可减少腹胀和胀气；一些菌株可能缓解疼痛和整体症状。文献表明，某些益生菌可能改善功能性腹痛患者的症状并改善其生活质量。某些益生菌对IBS症状的菌株特异性效应见表8和表9。

3.8 肠绞痛

• L. reuteri DSM17938和B. animalis ssp. lactis BB12已被证明可以减少母乳喂养的肠绞痛婴儿的哭闹时间（表格9）。

3.9 乳糖吸收不良

• Streptococcus thermophilus和Lactobacillus delbrueckii亚种bulgaricus可以促进乳糖消化，并减轻与乳糖不耐受相关的症状。这在多项以食用含活菌酸奶的人群为研究对象的对照研究中得到了证实[16]。

3.10 坏死性小肠结肠炎

• 补充益生菌可以降低早产儿坏死性小肠结肠炎的风险。随机对照试验的荟萃分析还显示，益生菌治疗组的死亡风险降低，尽管并非所有测试过的益生菌制剂都有效。使用益生菌治疗避免一例因各种原因导致的死亡所需要的治疗数为20。特别注意益生菌产品的质量对于这一弱势群体非常重要[17]。目前有中等程度的确定性认为益生菌可以减少死亡率和迟发性侵袭性感染，但没有观察到对严重神经发育障碍的影响[18]。

3.11 非酒精性脂肪肝

• 多项成人和儿童随机临床试验证实，某些益生菌可改善脂肪性肝炎。益生菌改善了稳态模型评估（HOMA）、血液胆固醇、TNF-α和肝功能（ALT和AST）的结果。需要进一步研究来证实其长期效益。

3.12 全身性感染的预防

• 目前尚缺乏足够的证据支持在重症监护室的危重成人患者中使用益生菌或合生元。

虽然这些不在本指南的范围之内，但读者可能会感兴趣的是，益生菌和益生元已被证明会影响多种与肠道疾病无关的临床结果。新出现的证据表明，肠道菌群可能会影响多种非胃肠疾病，从而建立起这些疾病与胃肠道之间的联系。大量研究表明，益生菌可以改善细菌性阴道炎、预防婴儿特应性皮炎、减少口腔病原体和龋齿、降低常见上呼吸道感染的发生率和持续时间。由于益生菌在围产期预防过敏性疾病方面的净效益，世界变态反应组织（World Allergy Organization）建议过敏性疾病高风险的家庭在怀孕、哺乳和断奶期间使用益生菌[19]。此外，益生菌和益生元也被用于预防代谢综合征的某些表现，包括超重、2型糖尿病和血脂异常。

 

我们综合评估了胃肠道疾病的证据。表7列出了用于确定证据等级的标准。

表格8和9总结了一些胃肠道疾病，这些疾病中至少有一个设计良好的临床试验表明口服特定益生菌菌株或益生元是有效的。这些表格的目的是向读者介绍存在支持所列产品的功效和安全性的研究，因为市场上销售的其他一些产品可能没有经过测试。“备注”专列包含了来自主要儿科胃肠病学学会的最新（2020-2022年）建议，例如欧洲儿科胃肠病、肝病学和营养学会以及美国胃肠病学会。

对于表格8和9，益生菌必须按照报告获益的研究中的属、种和菌株名称描述。如果未给出菌株，则不包括菌株名称。表格仅包含阳性研究（即主要结局具有统计学意义的研究），不包含阴性（无效）研究（即主要结局不具有统计学意义的研究）。对于每个疾病，具有益处的益生菌菌株或益生元均被列出。

然而，对于临床决策，只有与特定益生菌菌株和/或益生元有关的证据是有意义的。每项研究都应该在相关证据的整体背景下进行考虑。纳入试验的偏倚风险未被评估。

该列表可能不完整，因为新的研究还在发表中。在当地，经过随机对照试验（RCTs）评估的其他益生菌和/或益生元可能可用。不同适应证之间的证据等级可能会有所不同。所示剂量是RCTs中使用的剂量。产品列出的顺序是随机的。

没有比较研究的证据来对这些产品的功效进行排名。这些表格不提供推荐等级，只提供基于循证医学标准的证据等级。

 

 

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