万字强文深度分析益生菌与肥壮（下）

原标题：万字强文：深度剖析益生菌与肥胖（下）

这是《肠道产业》第 161 篇文章

编者按：

我们昨天的文章分享了发表在 Microorganism 杂志上关于益生菌与肥胖综述的上半部分，主要以微生物组为核心，阐述了胖代谢机制的研究： 万字强文：深度剖析益生菌与肥胖（上）

今天，我们继续分享该综述的下半部分：主要阐述了不同饮食模式对肥胖人群的影响，以及益生菌治疗肥胖的未来方向等。

以下为下半部分的编译内容：

其它因素引起的肥胖

（1）益生菌对肥胖相关性肾病患者的影响

肥胖增加了患慢性肾脏疾病（CKD）的可能性，还提高了发展为末期肾病（ESRD）的可能性，而益生菌能够大大减少某些尿毒症毒素的产生。

由 Niwa 提出的蛋白代谢假说中，肾小管中的有机阴离子转运体可以吸收由肠道微生物产生的毒素 109。

比如，鼠乳杆菌（ Lactobacillus murinus ）可以阻止高盐饮食小鼠的高血压症状的发展 113,114。

Ichii 等人发现在小鼠足细胞中的脂多糖可以引起促炎症现象、降低足细胞特异性的基因表达并且降低细胞活性 115。

在末期肾病患者中大约有 190 种微生物操作分类单元（OUT），与健康状态时相比要更为丰富 116；在慢性肾脏疾病患者中，发现了普雷沃氏菌科和乳杆菌科（均为天然结肠微生物）降低，而肠球菌和肠杆菌增长了 100 倍 116。

同时给患有自发性狼疮肾炎的混合淋巴细胞反应（MLR）的小鼠添加口服补冲剂，能够更好的降低肠道通透性，减少系统性炎症反应，从而增强肾脏功能和提高整体存活率。

另一项研究发现，在使用嗜酸乳杆菌治疗自发性 5/6 高血压肾切除大鼠（典型的 CKD 模型）时会减轻肾脏损伤，并且会加强胃肠道屏障功能、减缓内部肿胀并且积累尿毒症毒素 117。

当用多种细菌治疗乙酰氨基酚诱导的尿毒症大鼠和铬诱导的氧化应激大鼠时，研究发现，脂质过氧化作用减弱，而抗氧化相关的酶类（过氧化物歧化酶和水解酶）的活性发生了提高 118-120；另外，减缓氧胁迫可以减缓肾坏死 119,121,122。

益生菌可以保护肾脏，避免其被损伤，具体也就是可以通过减少肿胀、凋亡和氧化应激来减少功能障碍。

某些实验现象可能会出现不一致的结果，这可能是由于实验过程中所用到的细菌不同、患者群体不同以及动物模型的不同所造成的。

肥胖通过改变菌群组成而引起肠道环境变化，这可能是造成肾脏损伤的原因之一。

实验发现，特定的个人和微生物群特征可以预测特定的葡萄糖反应，这在某种程度上预示着人们有可能能够最终靠饮食、益生元和益生菌干预进行个性化的微生物组调控 123。

用益生菌调节肠道菌群平衡可能是肥胖患者改善肾功能的一种较为合适的选择。

（2）益生元和膳食纤维在肥胖治疗中的作用

FAO 和 WHO 将益生元定义为：不可消化的食物，它可以促进特定的肠道菌的活性进而对宿主产生有益的影响 124。

益生元主要为不可消化和水解的碳水化合物，比如果糖寡糖（FOSs）、半乳糖寡糖（GOSs）、大豆寡糖、环糊精、菊粉、葡萄糖寡糖、木糖寡糖、乳果糖、乳蔗糖和异麦芽寡糖等，这些碳水化合物具有到达人体肠道远端的能力 125。

已有实验证明，益生元可以对肠道菌群有促进作用，它可以促进肥胖动物肠道内的乳杆菌和双歧杆菌的生长 126。

母乳是牛奶低聚糖（可能是益生元）的丰富来源，它能促进有益菌（拟杆菌和双歧杆菌）的生长，并抑制大肠杆菌、空肠弯曲杆菌和幽门螺杆菌等病原体的粘附 127。

多项试验都发现，低聚果糖在治疗肥胖和糖尿病小鼠时会引起变化，该变化与肠内分泌细胞生长加速、葡萄糖稳态和瘦素敏感性有关 128,129。

这些变化还与细胞内胰高血糖素样肽-2（GLP-2）的高产量有关，GLP-2 与肠道通透性相关，能够大大减少肥胖相关性胃炎和心血管疾病。

基于此， Everard 等在用低聚果糖治疗动物时发现了非肥胖代谢表型，具体表现为降低甘油三酯浓度、脂肪组织和肌肉脂质浸润 128。

关于鼠李糖乳杆菌 GG 治疗儿童肥胖相关的非酒精性脂肪肝的积极影响，现在已有大量的研究支持。

在多数临床研究中，益生元能够大大减少肝脏组织中甘油三酯和/或胆固醇的积累，即减少脂肪变性。这一研究现象是很有意义的，因为 25%至 75%的肥胖者患有非酒精性脂肪肝。

尽管能量摄入功能是一个问题，但研究并未发现长期补充益生元，如餐前菊粉和低聚半乳糖或短期果糖低聚糖，有任何影响 130。

其它研究表明，非肥胖和肥胖个体的寡果糖或菊粉补充至少在 2 周内，能够大大减少他们的总能量摄入量 130-133。

对益生元的实验发现，益生元可以对体重、腰围、BMI、脂质分布、脂肪沉积和慢性炎症状态具有明显的有益调控作用，这可能成为肥胖和相关代谢紊乱的替代治疗方法 123。

肥胖与免疫系统的关系及母婴传递

（1）肥胖患者高脂饮食对相关免疫衰老的影响

胃肠道黏膜吸收的增加（如肠漏综合征），特别是与免疫变化相关的，可以引起对肠道的重大伤害。具体来讲，会造成细菌、毒素、营养物质和代谢垃圾从肠道中渗漏到血液中，当这些毒素进入肝脏中时会引起严重的自身免疫反应 134。

Moya-Pérez 等人在鼠模型中发现，具有假链状双歧杆菌 CECT7765 的肠道生态系统调节了高脂饮食（HFD）诱导的免疫细胞浸润以及肠道和外周炎症，并改善了肥胖相关的代谢功能障碍 135。

研究还发现，双歧杆菌的抗炎症效应与 B 淋巴细胞相关的先天免疫功能和适应性免疫功能相关。

Zhang 等人发现，通过为仔猪接种两个洛德乳杆菌菌株 ZJ617 和 ZJ615，发现 ZJ617 具有较强的黏附作用，而 ZJ615 的黏附作用较弱 136。他们还进一步研究了不同粘附能力菌株的免疫调节作用。

Kowalska 等人首先在大鼠中概述了高脂饮食对瘦素水平的研究，并通过实验进行了验证 137-140。

研究发现，与对照组大鼠相比，高脂饮食能够引起的瘦素水平升高 141，且在大鼠中，不论体重是否增加，高脂饮食均能升高瘦素水平 142。这一现象的原因还未被阐明。

除此之外，还有一些其它因素共同起作用，如身体脂肪含量，可以影响免疫应答，但在不同年龄段的人群中存在显着差异，身体脂肪含量的升高在老人和年轻人群中产生的不良反应是不相同的。

研究表明，当 BMI 达到 25（通常被认定为肥胖）的 65 岁以上老年人群生存获益 143,144。

除了脂肪组织和免疫细胞之外，其它的脂肪细胞或者参与炎症的促炎因子也会参与到免疫功能中 144,146。

由于益生菌在肥胖治疗中的免疫调节作用，研究者认为在饮食中添加益生菌是对健康有益的。

（2）孕妇肥胖对新生儿的影响

在近几十年中，产前和产后变化（例如早产和低出生体重，妊娠糖尿病，妊娠期体重增加过多和配方奶喂养）与儿童肥胖的发生率上升息息相关 147-150。而且这些患病风险因素在发展中国家急剧增高 151-153。

妊娠期糖尿病（Gestational diabetes mellitus，GDM）增加了婴儿肥胖和巨婴的风险。长期妊娠期糖尿病与儿童肥胖和婴儿代谢相关 154,155。

Boyle 等人发现父母肥胖会增加脐带间充质的分化能力，造成婴儿肥胖 156。儿童肥胖会增加其成人时肥胖的风险，并且会增加多种代谢疾病、糖尿病和心血管疾病的风险 157。

肠道微生物组是悉生小鼠（一种用已知菌培养的小鼠）测序技术中的新环境因素。肠道微生物组可以通过影响能量平衡、必需和非必需食物摄取、炎症和肠道阻滞功能的调节信号影响整个机体的代谢，从而刺激体重的增加。

肠道微生物是人体中的一个特殊的实体，它具有比宿主更加庞大的基因组和基因池。

在肥胖和糖尿病之间发现存有新联系，即肠道微生物在肠道组织外（如脂肪组织中）的广泛的生理功能 158,159。因此肠道菌群在肥胖和糖尿病的病理中发挥及其重要的作用。

利用无菌小鼠发现，微生物组可能通过调控宿主代谢使小鼠免于饮食诱导肥胖 154,157,159。

动物研究表明，怀孕和哺乳期的益生菌能够大大减少母体高脂饮食诱导的与母体肥胖相关的饮食程序，说明改变双亲的肠道微生物组可能加强父母与婴儿之间的代谢联系 160。

Vähämiko 等人在对人体的实验中发现，在怀孕期间补充益生菌可能影响母婴的与肥胖相关的启动子和基因的 DNA 甲基化程度 161。

Everard 等人的实验表明，L. rhamnosus GG 对婴儿的影响可以从出生前一个月开始并持续到 6 个月大，具体为通过减少婴儿非正常的体重增加从而改变儿童的发育模式。

使用益生菌可能是对妊娠期糖尿病的一个很有前景的预防或治疗方法。益生菌可以治疗微生物组失调，且使用益生菌慢慢的变成了一种提高早产儿健康的有效的干预方式。

基于饮食的肠道菌群控制

饮食在预防肥胖中是一个重要的健康因素，并且与调节肠道菌群密切相关。众多研究表明遗传性肥胖的易感性与肥胖环境（饮食重大变化影响肠道微生物、不运动、久坐的生活方式）相关 163。

目前有许多常见的饮食方法，包括标准饮食和西式饮食。益生菌对人体健康的影响、新的益生菌菌株的研究是目前较为流行的研究课题。后续的内容将展示益生菌补充剂如何帮助肥胖病人降低体重并改善肠道菌群。

（1）基于正常饮食的肠道微生物组

饮食在肠道菌群的组成方面和肠型的决定方面有着重要的作用 164,165。Arumugam 等人称，肠型大致上可以分为 3 类，分别以普雷沃菌属，拟杆菌属和胃瘤球菌属为优势种，肠型的分类不完全依据地域起源 165。

特定饮食对肠型改变的影响有：拟杆菌属的改变与高蛋白和动物脂肪饮食相关，而普雷沃菌属的变化与高碳水化合物饮食的摄取相关（图 3）。

Zimmer 等认为，杂食者的肠道菌群丰富度要比素食者的肠道菌群丰富度高 166。

实验结果显示，在素食者的肠道微生物中，肠杆菌属，拟杆菌属，双歧杆菌属这些微生物所占的比例要比杂食者的占比少。科水平上肠杆菌科，属水平上克雷伯氏菌属、肠杆菌属、柠檬酸杆菌属和梭菌属，这些菌在二者之间并没有差别。

图 3. 正常饮食的调节肠道菌群示意图。

正常饮食、营养、能量摄入和微生物组调节之间的相关作用。条形图代表了宏基因组门水平上的结果。饼图表示了正常饮食代谢影响的百分比。红色箭头表示活性增强。

（2）基于西式饮食的肠道微生物组

在许多国家，西方化、城市化和工业化的进程导致了久坐的生活方式、高脂肪高热量的饮食上的习惯 100,167,168。脂肪是饮食的重要部分，是肠道菌群生长和产生短链脂肪酸的底物 169,170。

脂肪含量高的食物比如鱼油（ω-3 多不饱和脂肪酸）和猪脂肪（猪油、主要为饱和脂肪酸）对肠道菌群的调控有重要的影响，猪脂肪对拟干菌门和变形菌门有促进增强作用，而鱼油可以促进放线菌门 171,172。

大量研究报道肥胖影响特定的菌门，能影响人体和啮齿动物的硬壁菌门和拟杆菌门的比率。

在消瘦人群中，微生物组的差异与粪便的能量损失相关 173。当 150 kcal 的收集能量增加 20%时，相应的拟杆菌的数量会降低。据报道，肥胖人群的拟杆菌的相对比例要低于消瘦人群 174。

肥胖患者肠道微生物组中硬壁菌门数量的增加，有助于从西式饮食中的热量获取，从而促进更好的卡路里的吸收和体重增加 170。

此外，在遗传或饮食诱导的肥胖小鼠和大鼠中，已报道了在 HFD 的对照组中硬壁菌门和拟杆菌门的比例增加 107,175。

近期的实验证明西式饮食中急剧增加的脂肪会影响肠道反应信号的调控，导致能量摄入，脂肪积累和炎症 176。西式饮食会增加硬壁菌门的数量和脂肪并减少肠道菌群多样性（图 4）。

图 4. 西式饮食的调节肠道菌群示意图。

西式饮食、营养、能量摄入和微生物组调节之间的相关作用。条形图代表了宏基因组门水平的结果。饼图表示了西式饮食代谢影响的百分比。红色箭头表示活性增强。

（3）基于添加益生菌饮食的肠道微生物组

之前许多研究发现，益生菌能够大大减少脂肪生成、缓解炎症反应并降低体重（图 5）。

特别的，鼠李糖乳杆菌 GG 菌株已经用于肥胖的研究中 177,178，鼠李糖乳杆菌 GG 代替 HFD 治疗通过增强脂联素的分泌来抑制高脂饮食小鼠的肥胖。脂联素可以使动物免受胰岛素抗性并缓解脂肪肝 179。

另外，在 HFD 小鼠中鼠李糖乳杆菌 GG 产生的胞外多糖能够大大减少脂肪和脂肪垫的形成，同时通过表达 Toll 样受体 2 缓解炎症 178。

当使用含有 14 种（包含双歧杆菌、乳球菌和丙酸杆菌）混合益生菌制剂短期治疗 Wistar 大鼠后，其全身和内脏脂肪组织明显减少，并增强了对胰岛素的敏感性 180。

一项涉及 49 个超重和肥胖成人的临床健康研究结果证明了艾克曼菌的丰度与代谢健康具有一定的联系。拥有更高的基因多样性和艾克曼菌的人确实处于更为健康的代谢状况，比如空腹血浆、甘油三酯和身体脂肪分布表现更好 181。

通过使用巴氏灭菌失活的艾克曼菌治疗，发现其可以抑制脂肪量增加，胰岛素抗性和血脂异常 182,183。这种现象可能是由于 Toll 样受体 2 和巴氏杀菌过程均与艾克曼菌细胞壁上的某种蛋白之间具有相关作用 182。

图 5. 益生菌补充的调节肠道菌群示意图。

条形图代表了宏基因组门水平的结果。饼图表示了补充益生菌的西式饮食代谢影响的百分比。红色箭头表示活性增强，绿色表示活性减弱。

艾克曼菌对内毒素血症和流化脂肪的缓解作用表明了益生菌在治疗肥胖方面的应用价值百科 160,162,181。

对肠道微生物宏基因组分析发现，与脂肪、蛋白代谢、碳水化合物代谢相关的 67 条代谢通路均受到了饮食干预的影响，表明了饮食对肠道微生物组代谢的影响。

未来治疗肥胖的方向

（1）粪便菌群移植

粪便菌群移植（Fecal microbiota transplantation，FMT）是将粪便微生物组从特定的供体转移到受体中，是调控肠道菌群较为简单的方法。在多种尖端的研究中，粪菌移植中的受体一般是无菌小鼠。

粪菌移植作为一种创新有效安全的方法，经常在临床中作为治疗艰难梭菌感染的手段 184。由于其菌群组成的未知性和复杂性，粪菌移植需要完全按照国际益生菌与益生元科学协会（ISAPP）的指导进行 181。

近期，有研究粪菌移植调节肠道菌群并治疗肥胖和代谢紊乱有效性的相关报道发布。Gough 等人发现在 27 项研究中，粪菌移植可以对艰难梭菌感染患者产生积极影响 185。粪菌移植可以消除 92%的艰难梭菌感染病例 181。

目前有 8 项使用粪菌移植治疗肥胖的注册实验 186。

（2）合生元调节饮食的综合作用

合生元对肠道和宿主的健康要比单独服用益生元或者益生菌更有效果，因为合生元可以给益生菌提供益生元，促进益生菌在肠道内的存活和生长 187。合生元已经证明在改善肠道微生物组组成方面是有效的 188。

在一个 12 周的研究中，Roller 等人发现使用富含低聚果糖的菊粉、鼠李糖乳杆菌 GG 和动物双歧杆菌 Bb12 后分别能够大大减少 16%、18%和 31%的产气荚膜梭状芽胞杆菌（Clostridium perfringens）的死亡 189。体外研究表明，合生元在调节肠道菌群方面要比益生元和益生菌更有效 190。

（3）肥胖症治疗的基因组学和代谢组学方法的相关性

对肠道微生物代谢组的研究，毫无疑问能够在一定程度上帮助探索肠道微生物、微生物-宿主互作的代谢途径 176, 191。但是在研究人员想要研究肠道微生物在代谢组方面的代谢调控和与之相关的特定细菌时，面临了许多困难。

宏转录组和宏基因组分析是肠道微生物组方面有效的分析手段 192。近期 Sridharan 等人使用基于质谱（MS）的代谢组学开发了基于基因组注释数据的代谢网络模型，用于检测 26 种宏基因组的代谢物 193。

目前代谢产物研究最常见的方法是质谱和质子核磁共振（1HNMR）光谱 80-82。1HNMR 可以产生生物液体样本（血液、细胞、尿液）的可重复且可靠的代谢组数据，而且需要的样本量较少。

相反，质谱更加灵敏可以检测到浓度显著减少的代谢产物。为了增强分辨率，质谱经常同色谱和气相色谱联用 83。

将代谢组学同其它组学结合，比如宏蛋白组、宏基因组和宏转录组，可以加深我们对肠道微生物复杂的生物合成的理解。这样的结合研究可以给肥胖的诊断、优化私人订制医疗和提高单个饮食补充剂有效性等方面带来贡献。在未来，仍有众多肠道微生物的代谢问题等待解决。

结论

本篇综述的目的在于汇总调查使用益生菌治疗肥胖的文献资料。益生菌在动物和人体的研究中发挥了降低体重的作用，并且也发现一些抗肥胖的机制。

早前，微生物群落对代谢调控、疾病和遗传紊乱方面的作用还是一个未知的领域。目前微生物在胆盐、SCFAs、代谢性内毒素血症和肥胖等的调控作用已经在多种分子测序手段如宏基因组、宏代谢组下逐渐被阐明。

然而益生菌的特异性使得确定益生菌作用机制的特定方式变得困难。对人体的研究需要利用宏基因组和宏代谢组来发现更加微小的差异，并探索益生菌用于治疗肥胖和代谢疾病的潜能。

预临床模型有望引导独特且性价比高的益生菌菌株的开发，这将需要在未来几年内完成大量临床研究，以确定它们是否适合人类食用。

使用益生菌、益生元或合生元甚至于粪菌移植来恢复或者调节肠道菌群的组成是预防或治疗肥胖的一种潜在的方法。

然而目前存在的一个问题是用于治疗的益生菌的剂量还没有确定。尽管有大量的实验动物模型，但是不同的给药方法可能会影响到先前研究的结果和结论。

我们大家都认为，按照目前的方向一直前行，可能关于管理肥胖及其相关的代谢缺陷方面的策略将会迎来光明的前景。

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原文链接：https:///2076-2607/7/10/456/htm#B66-microorganisms-07-00456

作者｜Kaliyan Barathikannan 等人

翻译｜gemiu

审校｜617

编辑｜崔心伟

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