修回日期: 2013-08-22
接受日期: 2013-12-04
在线出版日期: 2014-01-28
肝脏和肠道不仅解剖学上而且在生物学功能上存在密切联系, 即所谓"肠-肝轴"学说, 其对某些疾病的影响越来越受到关注, 其中肠道菌群在维持肠-肝轴的平衡方面起着重要作用. 肠道菌群紊乱、肠道黏膜通透性改变、肠源性内毒素血症, 这将破坏肝脏与肠道之间的正常关系进而导致多种肝脏疾病的发生, 进而调整肠微生物成为一种治疗或预防慢性肝病的新手段. 有研究表明其在非酒精性脂肪性肝病(nonalcoholic fatty liver disease, NAFLD)的发生发展中起到了重要作用, 这里就肠道微生物对NAFLD的作用做一综述.
核心提示: 肠道菌群紊乱、小肠细菌过度生长、肠黏膜屏障受损、细菌移位所形成肠源性内毒素血症, 通过介导肝脏炎症反应, 促进非酒精性脂肪性肝病(nonalcoholic fatty liver disease)的发生和发展.
引文著录: 卢伟娜, 冯丽英. 肠道微生物在非酒精性脂肪性肝病发病中的作用. 世界华人消化杂志 2014; 22(3): 340-344
Revised: August 22, 2013
Accepted: December 4, 2013
Published online: January 28, 2014
A close anatomical and functional interplay exists between the gut and liver, named "gut-liver axis", which has been associated with the pathogenesis of some diseases. Intestinal bacteria play a key role in the maintenance of gut-liver axis health. Altered intestinal bacterial flora, increased intestinal permeability and gut-associated endotoxemia will damage the normal relationship between the liver and intestine, which in turn leads to a variety of liver disease. Thus, modulation of the gut microbiota may represent a new way to treat or prevent chronic liver disease. Studies have showed that gut microflora plays a significant role in the development of nonalcoholic fatty liver disease. This review summarizes the recent studies highlighting the role of the intestinal microflora in the development of NAFLD.
- Citation: Lu WN, Feng LY. Role of gut microbiota in pathogenesis of nonalcoholic fatty liver disease. Shijie Huaren Xiaohua Zazhi 2014; 22(3): 340-344
- URL: https://www.wjgnet.com/1009-3079/full/v22/i3/340.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v22.i3.340
近年来, 随着生活方式及饮食结构改变, 非酒精性脂肪性肝病(nonalcoholic fatty liver disease, NAFLD)在世界范围内的诊断率不断上升, 同时也是我国越来越严重的慢性肝病问题, 且发病率不断升高并有低龄化趋势. 尽管提出了较为经典"二次打击"学说[1-3], 关于NAFLD的发病机理仍尚未完全阐明, 随着研究进展, 肠道微生物在NAFLD的发病中的作用越来越受到关注.
胃肠道尤其是大肠, 有着人体最大数量的细菌. 最近数据估计肠道微生物至少由500-1000种不同的种类组成, 含有1013-1014个细菌[4]. 肠微生物是种类迥异的细菌在质和量上不断变化的一种动态混合[5]. 饮食习惯、生活方式、年龄、宿主基因类型和抗生素的使用都可能影响肠微生物的组成[6]. 正常情况下, 宿主和肠道微生物在进化过程中形成了一种相适应的共生关系.
肠道微生物的主要功能包含保护宿主抵御外来微生物、维持肠黏膜免疫系统平衡、保护肠道屏障完整性、参与新陈代谢活动及营养促进[7-9]. 但是, 肠道菌群在很多疾病的发展中起到很大影响, 包括肝脏疾病. 大量的动物实验已证实, 肠道微生物、肠黏膜及免疫系统三者之间的失衡在NAFLD的发生发展中起着重要作用.
肠道菌群改变包括微生物的失衡、小肠细菌过度生长(small intestinal bacterial overgrowth, SIBO)及释放到循环当中的肠道来源的产物, 也被称为病原相关分子模式(pathogen-associated molecular patterns, PAMPs), 例如细菌脂多糖(lipopolysaccharide, LPS)、肽聚糖、脂蛋白类等; 肝脏通过特定的Toll样受体(Toll-like receptors, TLRs)识别PAMPS[10]. 健康肝脏包含低水平的TLRs mRNA以及相应的受体分子(例如: CD14、MD-2及MyD88), 表明肝脏低表达TLR信号分子将有助于对肠道来源的TLR配体的高耐受性[11]. 因此, TLRs是将肠道菌群失调、肠源性内毒素血症及肝脏损伤联系起来的重要纽带[12].
肝脏与肠道在解剖上与功能上有着紧密联系, 在胚胎发育过程中, 肝脏通过胚胎前肠与肠道建立了直接输入和输出关系即门静脉系统和胆道系统[13], 二者间共同的胚胎起源, 可以解释在若干炎症和感染性肠病中观察到的肝胆的改变, 例如炎症性肠病患者常合并原发性硬化性胆管炎或者自身免疫性肝炎的发生[14,15].
肝脏通过门静脉系统接收从肠道来源的大部分血液, 同时肠道静脉血液中富含的物质(包含细菌及细菌产物)会激活肝脏的功能, 反过来, 肝脏通过分泌胆汁和胆汁肝肠循环影响肠道的功能. 肠道微生物产生的乙醇、氨和乙醛等, 这些物质一般通过肝脏进行代谢, 可以调节枯否细胞活性和细胞因子的产生[16]. 肠道微生物在质和量上的变化导致肠道黏膜通透性的增加和细菌移位, 肠源性内毒素血症的发生, 而脂多糖是革兰氏阴性菌外膜的主要成分, 在多种慢性肝病的门静脉和/或体循环中均有所增加[17].
肝脏包含大量的免疫细胞发挥天然及适应性免疫应答, 通过引起耐受与炎症反应来应对细菌移位的影响. 细菌和细菌产物激活了肝脏内巨噬细胞-枯否细胞, 通过核因子kB(nuclear factor kappa B, NF-kB)调节机制, 激发细胞因子如肿瘤坏死因子-α(tumor necrosis factor α, TNF-α)的释放, 从而触发特定的细胞内信号转导通路[18]. 同时, 肝脏也随之发生形态和功能上变化, 诱发急性炎症反应, 释放活性氧代谢物、蛋白酶和其他酶类, 进一步加重肝脏损害[19].
NAFLD是目前全世界最常见的慢性肝病, 包括单纯脂肪肝和非酒精性脂肪肝炎(nonalcoholic steatohepatitis, NASH)以及随之发展的并发症. NASH可以分为两类: 原发NASH(与肥胖、2型糖尿病和高血脂相关的代谢综合征有关)和继发NASH(发生于空-回肠的旁路手术后, 迅速的体质量减轻, 完全的肠外营养、药物、严重的营养不良等)[20-22]. 最新理论表明, 因为单纯性脂肪肝在大多数患者身上是一种良性过程, 所以NASH可能是与之有着不同发病机制的一种独立的疾病. 众多因素中, 尤其是肠道来源和脂肪组织产生的物质, 共同作用最终导致肝脏的炎症[23].
NAFLD的发病与肥胖及胰岛素抵抗密切相关, 被认为是代谢综合征在肝脏上的表现. 肠道微生物已经被证明可以影响脂肪储存和能量代谢, 因而在胰岛素抵抗和相关代谢疾病的发展上起着直接作用[24-26], 肥胖人群比瘦人有更少的拟杆菌和更多的厚壁菌, 最近的证据显示肠微生物群直接影响从肠道吸收的卡路里的比例[27].
早在80多年前, 患有慢性肝病的患者身上首次发现肠微生物群的改变. 肠道菌群紊乱, 尤其是小肠细菌过度生长发生在很大比例的慢性肝病患者身上[2].
支持肠-肝轴在NASH发病机制中作用的证据在过去十年中慢慢积累[28]. 首先, NASH被认为是病态肥胖患者为了减轻体质量在行空肠-回肠旁路手术后一种常见并发症[29]; 其次, NASH还被报道发生在有着空肠憩室病和肠道细菌过度增长的人身上[30]; 另外, 各种表现为肠道细菌过度增长的老鼠实验都存在与NASH的相似的肝脏损坏. 无论在老鼠实验还是在全胃肠外营养, 进行肠道旁路手术后患者上, 口服抗生素后肝脏的脂肪变性程度均得到了改善, 这一发现也支持了肠道细菌在NASH发病机制中的作用[31].
肝脏和肠道不仅解剖学上而且在生物学功能上存在密切联系, 即所谓"肠-肝轴"学说, 肠-肝轴在NAFLD的发病中起着重要作用, 通过肠道微生物和宿主免疫系统的对话调节炎症、胰岛素抵抗和肠道通透性. 微生物菌群有助于维持肠上皮细胞正常的生物形学和功能. 肠道细菌通过以下机制参与了NASH的发生[32]: (1)增加肠腔内源性乙醇的产生; (2)调节食物胆碱的新陈代谢(用于极低密度脂蛋白合成和肝脏脂质输出); (3)调节胆汁酸的代谢; (4)通过影响食物能量促进肥胖发生; (5)调节肠道通透性、减轻炎症和免疫反应, LPS的产生.
肠道黏膜是免疫系统与外环境之间的主要界面, 宿主与肠道黏膜表面菌群的对话在免疫系统的良好发展上起重要作用. 肠上皮间的紧密连接在维持肠道屏障完整性起着重要作用. SIBO发现于患有NAFLD的患者身上, 并已发现与脂肪变性的严重程度有关[16,33]. 但是, SIBO和NASH之间发展发展的机制尚未被完全阐述, 肠道通透性在这个过程中似乎起了主要作用. Thuy等[34]近来发现, NAFLD的患者血液中内毒素和血浆纤溶酶原激活物抑制剂-1(plasminogen activator inhibitor 1, PAI-1)的水平, 以及TLR4和PAI-1 mRNA在肝脏表达与对照组相比高很多. 另外, Miele等[35]最新研究发现, 人类NAFLD的发生是与肠道通透性的增高和SIBO的发生有关. 这些均说明了菌群和宿主在肠上皮上的失衡不仅导致了肠道屏障的改变而且促进了细菌移位, 进入门静脉加重了肝损伤. 为了支持这一理论, 口服抗生素如多黏菌素B和甲硝唑, 在动物试验及人体已经被证实可以降低脂肪变性的程度[36,37].
由于特定的饮食条件, 肠微生物群的改变导致了肠道通透性的增加, 肠源性内毒素血症发生, 进而引发炎症和代谢紊乱. 在动物实验中, 高脂饲料影响细菌种类, 有利于革兰氏阴性菌和/或革兰氏阳性菌增长, 促发了内毒素血症. 内生的LPS通过依赖脂蛋白的机制从肠腔内运输到靶细胞, 当他结合到特定的TLRs时, 导致促炎症细胞因子的分泌. 已经表明TLR2、TLR4和TLR9在NASH的发展中起作用[38,39]. TLR4突变的老鼠给予蛋氨酸-胆碱缺乏的饮食会导致损害减少以及脂质堆积, 这是一个关于NASH众所周知的实验[40]. 相反的, 蛋氨酸-胆碱缺乏的饮食在TLR2缺乏的老鼠中诱发了NASH[41]. Miura等[42]最近证实在给予胆碱氨基酸缺乏饮食形成的NASH的鼠类实验上, TLR9能识别细菌未甲基化的CpG DNA, 也在NAFLD的发病中起着重要作用.
NAFLD缺乏有效的治疗手段. 肠道微生物在该疾病发病机制上的作用为预防和治疗NASH提供了新的方法.
益生菌是有活性的微生物, 口服适量的益生菌对宿主健康有益[43]. 市售的主要益生菌是乳酸杆菌、链球菌和双歧杆菌[44]. 益生菌可以通过抑制细菌黏附、侵袭肠上皮, 保护肠道通透性, 防止细菌移位; 产生抗菌肽类, 减轻炎症和刺激宿主免疫, 从而保护肝脏的健康[45,46]. 益生菌的生物活性依赖于抗炎介质调节NF-kB通路, 抑制促炎因子, 包括干扰素-γ(interferon-γ, IFN-γ)和TNF-α的产生[47]. 因此, 益生菌为治疗肝脏损伤提供了一个新的途径, 促进宿主健康. 若干动物实验已经证实补充益生菌可以减轻NASH的发生发展[48,49]. 在给予高脂饮食喂养的ob/ob小鼠, 服用VSL#3(经冷冻干燥、多种活菌制成的益生菌)后, 改善了肝脏病理学的表现及胰岛素抵抗, 减轻了肝脂肪变和炎症的程度, 降低了血清转氨酶水平. 我们最近发现饮食中添加乳酸菌F19, 可以通过恢复肠微生物群和肠屏障功能减少LPS水平、减轻氧化应激和代谢引起的肝脏损伤[50]. 最近针对经肝组织活检确诊为NAFLD的患者进行的临床研究表明补充保加利亚乳杆菌和嗜热链球菌能降低肝脏转氨酶水平[51], 这些研究均支持了益生菌在治疗NAFLD上的潜在价值.
微生物菌群有助于维持肠上皮细胞正常的生物形学和功能. 当免疫调节受损或肠屏障功能损坏, 肠道细菌可能会通过激活先天的和适应性的免疫应答导致各种急性或慢性肝病的发生. 因此调整肠微生物群成为了一种治疗或预防各类肝病的新手段. 但是, 若干问题仍然有待解决, (1)导致肝脏损坏的具体肠道细菌的有哪些？(2)这些细菌是否与肝脏疾病的进程有关？(3)不同的微生物菌群如何影响肠道正常的完整性？(4)由肠微生物群紊乱导致相关的肝脏疾病的具体免疫反应是什么？这些问题的解决, 将为更好的了解肠微生物菌群和肝脏疾病之间的联系提供有力的证据, 并将可能为预防和治疗肝脏疾病提供新方案.
伴随着全球范围内肥胖以及与胰岛素抵抗相关疾病的不断增加, 非酒精性脂肪性肝病(nonalcoholic fatty liver disease, NAFLD)成为越来越严重的慢性肝病, 其发病机制目前尚未完全明确, 并且尚无有效治疗.
高泽立, 副教授, 周浦医院消化科, 上海交大医学院九院周浦分院; 金山, 主任医师, 内蒙古医学院附属医院普通外科; 方今女, 教授, 延边大学医学院预防医学教研部
"肠-肝轴"学说在NAFLD发病过程中的作用越来越受到重视, 肠道菌群在维持其平衡方面起着重要作用.
Miele等发现在NAFLD患者中同时存在肠黏膜通透性增加和小肠细菌过度生长(small intestinal bacterial overgrowth, SIBO), 并且SIBO水平与脂肪变性的严重程度有关; Li报道在给高脂喂养的ob/ob小鼠补充益生菌后, 肝脏的脂肪变及炎症减轻.
本文应用肠-肝轴学说, 从肠道微生物、肠道黏膜及宿主的免疫系统3个方面阐述NAFLD可能的发病机制.
本文密切联系临床, 紧扣当前脂肪肝研究热点. 选题得当, 具有一定指导意义.
编辑:田滢 电编:鲁亚静
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