修回日期: 2014-12-23
接受日期: 2015-12-30
在线出版日期: 2015-02-28
肠道细菌移位(bacterial translocation, BT)在多种病理状态下均存在, 尤其是在危重患者, BT可以引发肠源性感染, 最终导致多器官功能障碍综合征(multiple organ dysfunction syndrome, MODS). 肠道菌群和内毒素移位所致的内源性感染和内毒素血症是激发炎症反应的起源地, 同时肠道也是MODS发生的始动器官, 又是MODS的靶器官. 越来越多的研究显示BT在肠道外疾病如肝脏疾病, 急性胰腺炎等的发生中起着重要的作用. 早期诊断、干扰或阻止BT可能成为多种疾病治疗的新方向或重要环节. 本文就BT与肠外疾病相互作用关系及发生机制、检测技术、防治作一综述.
核心提示: 肠道细菌移位(bacterial translocation, BT)常发生在多种病理情况下, 在大面积烧伤、重症胰腺炎、重症监护患者等重症疾病患者病情的发展与预后中起着重要的作用, 如何早期诊断, 预防和治疗是减少BT发生的关键之处, 同时也是内、外科急危重症治疗的重点.
引文著录: 黎源, 吴疆. 肠道细菌移位的研究进展. 世界华人消化杂志 2015; 23(6): 938-943
Revised: December 23, 2014
Accepted: December 30, 2015
Published online: February 28, 2015
Intestinal bacterial translocation occurs in a variety of pathological conditions, especially for patients with severe diseases. Intestinal bacterial translocation can cause enterogenic infection and end with multiple organ dysfunction syndrome (MODS). Inflammation often origins from endogenous infection and endotoxemia caused by intestinal bacteria and their endotoxins. In MODS, the intestine is not only the initiating organ but also the target one. More and more studies show that intestinal bacterial translocation plays an important role in the development of intestinal diseases such as liver disease and acute pancreatitis. Early diagnosis, interference and prevention of bacterial translocation can be a novel way or a crucial step in the treatment of a variety of diseases. This review aims to elucidate the association between intestinal bacterial translocation and parenteral diseases as well as their pathogenesis, prevention, and detection.
- Citation: Li Y, Wu J. Advances in research of intestinal bacterial translocation. Shijie Huaren Xiaohua Zazhi 2015; 23(6): 938-943
- URL: https://www.wjgnet.com/1009-3079/full/v23/i6/938.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v23.i6.938
肠道细菌移位(bacterial translocation, BT)指原存在于肠腔内的细菌和/或其内毒素[即脂多糖(lipopolysaccharides, LPS)], 通过某种途径越过肠黏膜屏障, 进入肠系膜淋巴结、门静脉系统, 继而进入体循环以及肝、脾、肺等远隔器官的过程[1]. 在大面积烧伤、重症胰腺炎、重症监护患者等重症患者中, 当其肠屏障功能受损, 原存在于肠腔内的细菌及其内毒素向肠淋巴结、门脉系统及外周血移位, 引起黏膜下层免疫细胞异常激活, 炎症介质释放, 进而引发系统性炎症反应综合征(systemic inflammatory response syndrome, SIRS), 甚至多脏器功能衰竭综合征(multiple organ dysfunction syndrome, MODS)[2-5]. 已有研究[6]表明细菌和内毒素移位通过肠淋巴通道进而感染组织器官, 同时肠淋巴液中存在着多种介导炎症反应的物质, 可对器官造成损伤. 最近, 国外一项随机对照试验[7]中, 研究者通过诱导MODS的动物模型发现, 139只♂小鼠分为4组, 分别输入不同剂量的LPS与酵母聚糖(zymosan)后成功制作了MODS模型, 同时在肠外组织中分离出肠球菌和肠杆菌, 结果表明在MODS的发生过程中BT可能是其病情发展乃至死亡的一个重要因素.
在1979年Berg等[8]通过将活微生物注入事先进行了灌胃处理的无菌小鼠体内, 最后发现活微生物及其产物通过肠道黏膜屏障进入固有层, 继而到达肠系膜淋巴结以及更远处器官的现象, 并提出了"bacterial translocation"这一术语描述这一现象. 在1995年Berg[9]首次提出BT的发生发展与肠道细菌过度繁殖、肠黏膜屏障损害和机体免疫防御功能低下有关. 目前肠黏膜屏障受损是大家认同的导致BT或内毒素移位的重要原因[10-12]. 肠黏膜屏障包括机械屏障、免疫屏障、化学屏障、生物屏障4部分, 任何导致其功能受损的因素均会导致BT或内毒素移位. Meng等[13]在研究剧烈疼痛时发生BT与感染的原因时, 发现敲除了肠道上皮细胞Toll样受体(Toll-like receptors, TLR)如TLR2和TLR4基因的野生型动物的移位到肠系膜淋巴结(mesenteric lymph nodes, MLN)和肝脏的肠道细菌显著减少, 而进一步的研究发现肌球蛋白轻链激酶(myosin light chain kinase, MLCK)抑制阻断吗啡和TLR配体的紧密连接, 表明吗啡引起的肠上皮屏障功能障碍和随后的BT是由TLR信号介导的, 因此TLR可以被利用作为吗啡使用或滥用人群减轻感染, 甚至败血症潜在的治疗靶点. 目前BT的发生机制还没有明确的结论.
总结已有的研究[1,14], BT的检测包括体内和体外两种检测方法, 前者包括直接和间接检测, 体内检测法较常用. 直接检测即直接在肠外找到原存在于肠道内的细菌, 最常用的是组织培养法, 取肠系膜淋巴结、肠外组织、肠壁浆膜或腹腔的拭子以及血液、淋巴液等进行细菌培养, 分离出活的细菌在光镜或电镜下加以计数和分类, 直接检测的意义最大, 但是易受到各种因素的干扰. 目前[15]基因组学检查法正逐渐替代传统检测方法, 聚合酶链反应(polymerase chain reaction, PCR)技术, 可迅速确定肠外组织中的细菌DNA来源, 具有高敏感性, 高特异性, 但很难同时检测多种细菌, 提供的有关微生物的数量和分布信息十分有限; 为改善这一缺点, 国内学者提出[16]实时定量PCR(real-time quantitative PCR, RQ-PCR)快速检测法, 其通过取15份模拟全血标本及26份外科发热患者全血标本, 检测全血中金黄色葡萄球菌DNA, 结论是RQ-PCR可用于定量检测全血标本中的金黄色葡萄球菌DNA含量, 具有快速、灵敏、特异性强、重复性好的优点. 国外学者[17]在研究食管癌术后切除肠系膜淋巴结后发生细菌移位与菌血症时, 通过反转录-定量PCR(reverse transcription PCR, RT-qPCR)成功检测到肠源性细菌移位, 找到了食管癌术后发生细菌移位的证据. 其他的检测技术[18]如荧光原位杂交(fluorescence in situ hy-bridization, FISH)技术、肠道特异性免疫系统免疫功能检测法, 可直观得到细菌种类与分布信息, 并对细菌进行定量检测.
人体胃肠道中拟杆菌及双歧杆菌占到其细菌总数的90%以上[19,20]. 胃肠道内的细菌正常情况下呈稳定共生的状态, 共同组建及维护胃肠道黏膜屏障, 以维持肠腔内环境的平衡稳定, 一旦这种平衡打破, 会使肠道内细菌及内毒素经过淋巴管、肠道上皮细胞间隙、门脉系统进入体循环, 可导致一系列并发症[21,22].
急性胰腺炎(acute pancreatitis, AP)是临床上常见的急症, 由于其极易发展为重症急性胰腺炎(severe acute pancreatitis, SAP), 而使患者由于BT、内毒素血症(end toxemia)、继发感染的"二次打击"和MODS引起的脏器功能衰竭而死亡[23,24]. 研究[25]显示多数SAP患者肠屏障功能的损伤或衰竭, 其感染多由肠源性革兰阴性菌引起, 提示BT在SAP中起着重要作用. 感染是SAP最主要也是最严重的并发症, 而肠源性细菌是AP时胰腺及胰周感染的主要细菌来源[26]. 国内研究者[27]提出肠道菌群、细菌和内毒素(endotoxin, ET)通过肠腔移位进入其他组织器官, 激活多种炎症介质的释放而引发炎症级联反应, 对机体构成"二次打击", 损伤组织器官肠淋巴液中含ET、肿瘤坏死因子α(tumor necrosis factor, TNF-α)、白介素-6(interleukin-6, IL-6)等炎症介质介导炎性反应; 肠免疫功能障碍, 致肠淋巴细胞失衡, 从而加重胰腺损伤. Tian等[28]研究显示, 在SAP中, 炎症因子如TNF-α的瀑布式释放导致肠黏膜缺血-再灌注损伤, 从而造成了严重的氧化应激和肠黏膜的严重凋亡.
正常情况下, 肝脏凭借其强大的先天免疫系统快速、有效地抵御经正常的肠肝循环转运的肠道细菌产物, 环境毒素和食物抗原等潜在的有毒物质而不引起有害的免疫反应[29]. 当各种原因引起肠道屏障功能受损, 肠道内的细菌及其内毒素大量进入门静脉系统, 激活肝脏内的枯否氏细胞(Kupffer cells, KC), 释放出炎性因子, 进而导致肝脏受损. Fowler等[30]通过诱导小鼠肠道屏障受损可以见到肠道菌群通过肠-肝轴显著下调核糖体蛋白L29(ribosomal protein L29, RPL29) 转录而与肝脏脂肪变性、胰岛素抵抗(insulin resistance, IR)的发生有关. 新近研究[31]认为在肝脏疾病代偿期及非硬化阶段, BT也显得极其重要, 其与肝脏疾病的进展如纤维化及可能的癌变密切相关. 一项随机对照试验[32]中, 研究者通过对66例肝硬化患者(48例腹水, 18例无腹水)和74名健康对照者的肠道通透性及肠道细菌产物等有毒物质吸收率的研究后发现, 肝硬化患者胃肠功能障碍可能有助于诸如营养不良和自发性细菌性腹膜炎并发症的发生. 大量动物实验[33-35]表明, 在非酒精性脂肪性肝病(nonalcoholic fatty liver disease, NAFLD)的治疗中, 通过控制肠道菌群失调后可以大大改善NAFLD和IR的临床症状. 一项随机对照试验研究[36]显示细菌和细菌产物移位进入血液循环后是导致小鼠酒精性肝硬化(alcoholic liver cirrhosis, ALC)的发生与发展的重要因素, 在ALC小鼠中常见小肠细菌过度生长.
BT的防治主要在于维护肠道黏膜屏障的完整性, 对原发疾病进行治疗是关键. 目前方法[45-47]包括选择性消化系去污(selective gastrointestinal decontamination, SGD)、营养支持、营养添加剂、细胞因子疗法、补充益生菌、精氨酸、谷氨酰胺等可以有效维护肠道微生态平衡, 保护肠道屏障黏膜的完整性. 肠道上皮相关受体与蛋白质, TNF-α抗体与BT的发生有着重要的联系, 阻断肠道上皮相关受体可以减少BT的发生[48,49]. 国外多项随机对照试验发现对肝移植术后患者早期予以含有活益生菌的肠内营养治疗后可以显著降低细菌移位和感染的发生[50,51].
BT在多种病理状态下均存在, 与肠外疾病的发生有着十分重要的联系, BT多发生在肠道黏膜屏障损伤后, 肠道细菌及其产物进入肠系膜淋巴结、门静脉系统, 继而进入体循环以及肝、脾、肺等远隔器官进而可以引发全身炎性反应和多器官功能障碍, 反过来MODS又可加重肠黏膜坏死和细菌移位, 造成恶性循环. 早期诊断, 预防和治疗BT有助于重症疾病的预后, BT作为目前研究的热点, 正吸引着越来越多的人前去探究. 随着对BT理论的深入研究, 肠源性感染学说有了极大的发展. 但我们可以发现, 目前对于BT的相关机制, 早期诊断及治疗的问题还未有统一的认识, 这些是我们必须重视, 也有待进一步研究的地方.
肠道是人体最大的细菌和内毒素贮存场所, 正常肠黏膜屏障及其黏膜分泌功能可有效防止细菌和内毒素移位, 阻止其进入体循环造成肠源性感染. 当某些病理状态下, 机体应激反应过度或失调, 可使肠黏膜屏障的完整性遭到破坏, 使原先寄生于肠道内的微生物及其毒素越过受损的肠黏膜屏障, 大量侵入在正常情况下是无菌状态的肠道以外的组织, 及其他远隔脏器或系统, 引起肠道细菌移位(bacterial translocation, BT), 其结果可触发全身炎性反应(systemic inflammatory response syndrome, SIRS)和多器官功能障碍(multiple organ dysfunction syndrome, MODS), 反过来MODS又可加重肠黏膜坏死和BT, 造成恶性循环.
庹必光, 教授, 遵义医学院附属医院消化科
BT在内外科急危重症的发生、发展中起着重要的作用. 早期诊断、干扰或阻止BT可能成为多种疾病治疗的新方向或重要环节. 国内外最新研究显示早期维护肠道黏膜屏障的完整, 预防BT的发生, 可明显降低和减轻大面积烧伤、重症胰腺炎、重症监护患者的继发感染的发生率和严重程度, 可大大增加患者存活率.
2014年Nishigaki等通过相关实验证明在食道癌术后发生感染与肠源性细菌移位有关, 对术后患者应加强管理, 预防感染的发生. 这一研究表明外科手术后应重视肠源性细菌感染的危害性, 早期防治BT的发生, 研究论文发表在Annals of Surgery.
本文引用了大量新近的国内外研究, 详细、全面阐述了BT与肠外疾病的相互关系及发生机制、检测技术、防治等方面的最新研究进展. 为内外科急危重症的临床诊治, 提供新思路, 寻求新突破.
本文引用了多篇权威性的文章, 特别阐明了BT与肠外疾病的相互作用关系, 加深了我们对BT与人体多系统相关性疾病关系理解, 使我们能在疾病诊疗过程中, 注意早期防治BT的发生, 利于疾病的预后.
选择性消化系去污(selective gastrointestinal decontamination, SGD): 即应用口服抗生素, 主要包括多黏菌素E两性霉素B和妥布霉素等, 选择性去除肠道内致病细菌, 包括革兰阴性肠杆菌及共生的厌氧菌, 研究表明, SGD可显著减少肠道致病菌(厌氧菌和真菌为主)数量, 防治内源性感染, 降低急性坏死性胰腺炎并发症发生率和病死率.
BT存在于多种病理情况下, 临床常见. 该文综述了近年来来在BT方面的研究进展, 尤其是与肠外疾病的相互关系. 该文对了解BT对疾病的影响有一定的参考价值.
编辑: 韦元涛 电编: 闫晋利
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