修回日期: 2015-04-03
接受日期: 2015-04-10
在线出版日期: 2015-05-28
非酒精性脂肪性肝病(non-alcoholic fatty liver disease, NAFLD)俗称脂肪肝, 临床常见, 患病率持续上升, 发病机制未完全明确, 尚无有效防治方法. 近年, 随着高通量测序的应用, 胃肠道微生态研究取得进展, 已证实微生态失调(包括胃肠道菌群改变, 细菌移位和小肠细菌过度生长等)和NAFLD发病相关, 肠道微生态失调除了破坏肠黏膜屏障外, 更主要是通过"肠-肝轴"令细菌及其毒性产物进入肝脏, 经Toll样受体和NOD样受体通路激活肝脏免疫系统, 炎症因子(如肿瘤坏死因子、白介素等)诱发肝脏炎症, 导致NAFLD. 应用微生态制剂、抗生素及粪菌移植等方法取得一定疗效, 为NAFLD防治开辟新的途径.
核心提示: 肠道微生态失调与非酒精性脂肪性肝病(non-alcoholic fatty liver disease)发病相关, 近年高通量测序技术从基因水平获得有价值资料, 菌群失调除了导致肠黏膜屏障破坏和能量摄取增加外, 更重要的是通过"肠-肝轴", 激活免疫系统, 恢复胃肠道微生态的平衡是防治的新方法.
引文著录: 李瑜元. 肠道微生态失调与非酒精性脂肪性肝病关系研究进展. 世界华人消化杂志 2015; 23(15): 2355-2362
Revised: April 3, 2015
Accepted: April 10, 2015
Published online: May 28, 2015
Non-alcoholic fatty liver disease (NAFLD), also called fatty liver, is the most common chronic liver disease. Although the prevalence of NAFLD is increasing, the mechanisms underlying its pathogenesis are incompletely understood. So far, there has been no effective approach for its prevention and treatment. With the development of next generation sequencing technology, recent studies have shown that gut microbiota alterations including changes in the composition of gut flora, bacterial translocation and small intestinal bacterial overgrowth, play roles in the development of NAFLD. Besides destruction of the intestinal barrier, the most important pathogenic mechanism of gut microbiota distrubance is the facilitation of bacteria and their toxic products to reach the liver through the gut liver-axis. The hepatic immune system is activated through pattern recognition receptors, such as Toll-like and NOD-like receptor signaling pathways. The release of pro-inflammatory cytokines including tumor necrosis factor and interleukins results in liver injury, which progresses to NAFLD. Application of probiotics, antibiotics and fecal microbiota transplantation has shown efficiency, which provides new targets for the prevention and treatment of NAFLD.
- Citation: Li YY. Gut microbiota disturbance and non-alcoholic fatty liver disease. Shijie Huaren Xiaohua Zazhi 2015; 23(15): 2355-2362
- URL: https://www.wjgnet.com/1009-3079/full/v23/i15/2355.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v23.i15.2355
非酒精性脂肪性肝病(non-alcoholic fatty liver disease, NAFLD)俗称脂肪肝, 是指以肝实质细胞脂肪变性为病理特征, 而无过量饮酒史, 又除外其他肝病的临床综合征, 其病理类型包括单纯性脂肪肝(non-alcoholic fatty liver, NAFL)、脂肪性肝炎(nonalcoholic steatohepatitis, NASH)及NASH相关肝硬化, 后者可发展为肝癌[1]. NAFLD常与代谢综合征(MetS)即肥胖、2型糖尿病、血脂紊乱、高血压等症状并存, NAFLD可视为MetS的肝脏表现, 胰岛素抵抗(insulin resistance, IR)是重要的发病机制. NAFLD在全球广泛分布, 现已成为发达国家第1位肝病, 普通成人患病率为20%-33%, 其中NASH占10%-20%, 相关肝硬化2%-3%. 肥胖症患者NAFLD患病率达60%-90%, 糖尿病患者28%-55%, 高脂血症患者27%-92%. 随着肥胖症和MetS在全球流行, 亚洲国家近年患病率迅速上升且呈低龄化起病趋势. 我们在广东省健康人群调查显示NAFLD患病率15%, 与上海和香港等发达地区相近[2,3].
NAFLD的发病机制涉及遗传和环境等因素. 遗传方面包括基因变异及表观遗传学(epigenetics)的改变(如微小RNA、DNA甲基化、组蛋白修饰、染色质重塑、遗传印记和泛化作用等), 是发病的内因; 环境方面包括高脂肪、高热量的膳食结构、多坐少动的生活方式, 是发病的外因[4,5].
近年研究发现胃肠道微生态失调与NAFLD发病相关, 胃肠道含有人体最大的细菌库, 正常人肠道菌种达500多种, 总量达到100万亿, 质量1-2 kg, 菌群主要分布在大肠和远端回肠, 而胃、十二指肠、空肠及近端回肠仅有少量细菌(主要为需氧的革兰阳性球菌). 过去用细菌培养和聚合酶链式反应(polymerase chain reaction, PCR)等方法获得了许多有价值的资料, 但耗时耗力, 信息量少. 近年随着高通量和宏基因组测序的应用, 从基因组水平分析胃肠道菌群的构成, 完成了人类肠道细菌"基因普查", 获得更多资料. 胃肠道细菌基因组是人体细胞的150多倍, 粪便和定植于肠黏膜表面的细菌种类和数量并不完全一致. 胃肠道微生态失调通过多种机制扰乱机体稳态, 诱发包括NAFLD在内的许多疾病[6-9].
NAFLD患者存在肠道微生态失调, 正常人胃肠道细菌分六大门(phylum), 即硬壁菌门(含瘤胃球菌属、梭菌属、乳杆菌属、真细菌属、粪菌属、罗氏菌属等)、类杆菌门(含类杆菌属、普雷沃菌属、Xylanibacte菌属等)、放线菌门(含柯林斯菌属、二裂菌属等)、蛋白菌门(含埃希氏菌属、脱硫弧菌属等)、疣微菌门(含阿克曼菌属等)及阔古菌门(甲烷短杆菌属等), 以硬壁菌和类杆菌两门最为常见, 共占全部细菌的90%[10-12]. NAFLD和肥胖者肠道微生态失调, 包括胃肠道菌群改变, 细菌移位(bacterial translocation, BT)和小肠细菌过度生长(small intestinal bacterial overgrowth, SIBO)等[10,11,13]. 研究[13,14]显示, NAFLD和肥胖者胃肠道类杆菌减少, 硬壁菌增加, 至硬壁菌/类杆菌比率明显升高. 菌群改变是体质量增加和脂肪积聚的独立危险因素. 儿童胃肠道二裂菌属和金黄色葡萄球菌属的比例失衡, 是肥胖和NAFLD的危险因素[15]. NASH患者肠道双歧杆菌、类杆菌等专性厌氧菌显著减少, 而金黄色葡萄球菌和肠杆菌、肠球菌、酵母菌等兼性厌氧菌显著增加[15]. 长期高脂饮食人群胃肠道真菌, 梭菌属, 二裂菌属减少, 革兰阴性菌增加[16]. BT指胃肠道内细菌移位到胃肠道外脏器(如进入门静脉到达肝脏, 甚至达体循环). SIBO指上段小肠需氧细菌数目超过105/mL. 发生BT和SIBO时, 肠道内细菌(如革兰阴性菌)增加, 其DNA及细胞壁中的内毒素如脂多糖(lipopolysaccharide, LPS)通过门静脉进入肝脏, 引起肠源性内毒素血症, 通过肠-肝轴, 诱发肝脏炎症, 导致NAFLD. NAFLD患者常发生BT和SIBO已被多项14C-D-木糖和乳果糖呼气试验研究证实[10].
具体发病机制目前尚未完全明确, 可能涉及下述几方面, 这些病理改变彼此关联, 共同诱发NAFLD发病.
随着解剖学和生理学的发展, 我们知道胃肠道解剖和功能关系密切. 门静脉收集肠道血流, 首先到达肝脏, 肝脏对肠源性物质和肠道菌群产物进行首过作用. 1987年Volta等[17]发现肝硬化患者胃肠道菌群改变及免疫球蛋白A(immunoglobulin A, IgA)抗体分泌量相应改变. 随后"肠-肝轴"概念得到重视并逐步完善, 肝脏与胃肠道共同组成消化系统整体, 肠道是肝脏这个生化加工厂的初级原料库, 肝脏通过精细的生化反应, 加工来自肠源性物质, 包括肠道菌群产生的有益及有毒产物, 使之向有利人体健康的方向转化. 在病理状态下, 如肠道菌群改变, BT和SIBO, 肠道内的细菌及其产物(如LPS等内毒素)通过门静脉系统进入肝脏, 引起肝免疫应答异常, 导致肝损害. 反之, 肝脏疾病患者的消化系症状(如恶心、呕吐、胃纳下降等)导致肠道菌群营养底物不足, 胆汁分泌减少, 肠道内胆盐缺乏, 门静脉回流受阻, 引起胃肠道淤血以及肝脏固有免疫系统(如枯否细胞)释放一系列炎性因子, 造成肠道黏膜损伤和肠道功能失调[6,18-21].
肝脏Toll样受体(Toll-like receptors, TLRs)在肠-肝轴中起重要作用. TLRs是细胞膜上受体家族, 在肝脏的肝细胞, 枯否细胞和星状细胞均表达, TLRs通过病原体相关分子模式(pathogen-associated molecular patterns, PAMPs)识别微生物分子. 在正常人群, TLRs信号通路处于关闭状态, 肠道微生态失调时, 有害细菌的DNA及其产生的毒素(如LPS、肽多糖、鞭毛蛋白等)激活TLRs的表达, 上调肿瘤坏死因子-α(tumor necrosis factor, TNF-α)、白介素(interleukin, IL)-1β、IL-6、IL-8、IL-12和单核细胞趋化蛋白等炎症细胞因子的转录, 引起下游通路起瀑布样抗炎效应. 但长时间TLRs过度激活会诱发免疫失调、氧应激、IR、肝星状细胞活化, 进而促进肝脏炎症反应, 导致肝损害和NAFLD[22-24]. 在TLRs家族13个受体中, TLR2、TLR4、TLR5、TLR9和NAFLD发病相关性已得到证实, 其中LPS-TLR4信号通路最为重要. 肠道内革兰氏阴性细菌的外毒素LPS, 通过门静脉和体循环激活肝脏TLR4, 经CD14和MD2辅助, 构成TLR4-MD2-LPS复合体, 通过骨髓分化因子88(MyD88)依赖和非依赖两信号轴, 进一步激活IL-β、IL-6、IL-8、IL-12、TNF-α、转化生长因子(transforming growth factor, TGF)-β等炎症因子和干扰素-β的表达, 导致IR和肝脏炎症, 诱发NAFLD, 并同时促进肝星状细胞活化, 导致肝纤维化. 动物试验显示TLR4基因变异的小鼠可抵抗NAFLD的发生和发展, 进一步证实LPS-TLR4通路的重要性[25]. TLR2被革兰氏阳性细菌(如硬壁菌)壁成分(如肽多糖、脂磷等)激活, 通过TNF-α、IL-1β等炎症因子诱发NAFLD. TLR5是肠黏膜细胞防御感染的一种固有免疫成分, 由鞭毛蛋白激活, 引起IR, 诱发NAFLD. TLR9由细菌DNA激活, 介导枯否细胞产生IL-1, 促进肝脏炎症和纤维化[24]. 除TLRs外, 核苷酸结合寡聚化结构域受体(NOD-like receptors, NLRs)家族也可识别PAMPs, 诱发免疫失调和炎症激活, 是胃肠道菌群失调导致的NAFLD的另一关键受体. 其家族中NLR-P1、NLR-P3、NLR-P6和NLR-C4等被称为炎性蛋白复合物(inflammasomes), 促进炎性细胞因子(如TNF-α、IL-1β、IL-18等)的激活和分泌, 诱发IR和NAFLD[10].
肠黏膜屏障由生物、机械、免疫和化学等屏障组成, 是保证机体吸收能量, 储存能量的重要环境因素. 正常情况下, 完整的肠黏膜屏障可阻止肠道细菌及毒素等物质通过. 肠屏障功能受损时肠道通透性增高, 肠道内细菌DNA及其内毒素, 特别是革兰阴性菌细胞壁中的LPS大量涌入门静脉, 在超过肝脏清除能力时, 可进入体循环形成肠源性内毒素血症. 肠源性内毒素结合脂多糖绑定蛋白(lipopolysaccharide binding protein, LBP), 通过膜表面受体CD14, 激活肝脏Kupffer细胞, 活化核因子(nuclear factor, NF)-κB、TNF-α、IL-6、IL-8等促炎因子, 进而引起肝脏炎症损伤[26]. 生物屏障由寄居在肠腔内或定植于肠黏膜表面的肠道常驻菌群形成, 有益菌与致病菌相互制约, 互相依存, 在质和量上形成一定的生态平衡, 调节肠上皮细胞的增生和凋亡, 诱导肠上皮细胞产生多种抗菌肽, 控制炎症因子的表达, 维护肠道内环境的稳定. 如果肠道微生态失调, 有害细菌定植和繁殖呈优势, 通过产生蛋白酶及毒素抑制肠上皮细胞蛋白质合成, 使肠黏膜屏障损伤, 从而发生BT和SIBO. 肠道微生态失调不单直接破坏生物屏障, 影响肠道功能, 扰乱机体能量稳态, 还导致机械, 化学和免疫等屏障损害[18-20]. 机械屏障由肠道黏液层、肠黏膜上皮细胞、细胞间紧密连接等构成, 肠道微生态失调时, 肠道来源的毒物(如辣根过氧化物酶、聚乙烯吡、乙醇等)增加, 肠上皮细胞间紧密连接蛋白减少, 肠道黏膜机械屏障完整性受损, 肠黏膜及肠血管通透性增高[19,27,28]. 免疫屏障由肠道免疫系统细胞群构成, 包括肠道相关淋巴细胞和弥散免疫细胞. 淋巴细胞分布于肠道的集合淋巴小结内, 是免疫应答的诱导和活化的主要部位; 弥散免疫细胞是肠黏膜免疫的效应部位, 分泌型IgA(secretory IgA, sIgA)是主要体液免疫成分和效应分子. sIgA可包裹革兰阴性杆菌从而发挥保护效应, BT和SIBO时, 肠液中sIgA降低, 肠道脂质过氧化增强, 易于被吸收, 破坏肠黏膜免疫屏障[20]. 化学屏障由胆汁、胃酸和消化酶等组成, 肠道微生态失调通过促进胆汁的肠-肝循环, 引起胆汁失衡, 破坏主要由胆汁酸构成的肠黏膜化学屏障, 抑制肝细胞低密度及极低密度脂蛋白的合成和甘油三酯排泄的能力, 导致脂质在肝脏沉积. 肠道几个屏障之间相互联系, 任何一个屏障功能受损, 必然相应地引起其他屏障功能的损害[6,18-20,29].
NAFLD为MetS的重要组分, 治疗NAFLD首要目标是改善IR, 防止NAFL向NASH进展, 防止NASH相关肝硬化、肝癌及其并发症发生. 目前NAFLD防治尚无特效药物, 治疗对策为纠正IR, 减肥是成功的基石, 具体措施包括节制饮食和体育锻炼, 改变不良饮食和生活方式[33]. 鉴于NAFLD患者常有不同程度的肠道微生态失调, 后者又可通过多种机制引起IR, 加重肝脏损伤, 肠-肝损害互为因果, 并可形成恶性循环, 有效纠正肠道微生态失调, 阻断恶性循环是综合防治中不可缺少的措施.
包括益生菌、益生元和合生元等3类. 益生菌(probiotics)由对宿主有益无害的正常菌群制成, 主要包括双歧杆菌和乳酸杆菌等. 补充益生菌可抑制潜在致病菌(如葡萄球菌、变形杆菌、假单孢菌)的过度生长, 恢复肠道微生态平衡, 修复肠道菌膜屏障. 益生元(prebiotics)是一类非消化性化学物质, 多为低聚糖(乳果糖、乳梨醇、果聚糖、菊糖等), 能选择性地刺激结肠内有益细菌的生长. 乳果糖是临床最常用的益生元, 经肠道细菌分解, 产生乳酸和醋酸, 乳酸可促进肠道固有益生菌的生长, 乳酸和醋酸均可降低肠道酸度, 增加肠道渗透压, 促进肠蠕动, 加快肠道细菌及毒素从粪便排出. 合生元(synbiotics)是益生菌和益生元选择性组合的合剂, 旨在起到协同作用. Paolella等[6]综合分析10项使用益生菌治疗NAFLD的临床研究, 疗程2-6 mo, 益生菌的降低患者血清转氨酶疗效最为确切, 降低体质量, 血脂, 炎性因子等作用也达到显著性, 而影像学改变各文献有差异, 5个研究显示肝脂肪变改善, 1个研究肝脂肪变反而加重, 这6个研究均无金标准"组织学"结果. Ma等[34]从475文献中筛选4个质量好的随机对照研究(randomized controlled trials, RCTs)进行Meta分析, 疗程2-6 mo, 益生菌可显著降低NAFLD患者的血清转氨酶, 总胆固醇和TNF-α水平, 并改善IR, 而其他指标(组织学和影像学等)治疗前后的差异无统计学意义. 应用乳果糖治疗NAFLD的临床文献尚欠缺, Fan等[35]用乳果糖口服治疗高脂饮食诱导的NASH大鼠, 发现乳果糖显著降低血清转氨酶和肝组织炎症程度, 机制为乳果糖在肠道细菌分解下产生乳酸等物质, 降低肠道酸碱度, 抑制氨类物质生成, 并促进肠道固有益生菌的生长. 总体说来, 微生态调节剂为NAFLD治疗提供了全新的方向[36,37].
口服肠道吸收率低的抗生素, 进行肠道去污治疗, 有助于抑制潜在致病菌生长, 恢复肠道微生态平衡, 减少肠源性内毒素血症发生, 改善炎症状态, 调节宿主免疫反应, 理论上有助于NAFLD的防治. 应用吸收率和毒性低的抗菌中药黄连素(盐酸小檗碱)治疗NAFLD的研究[38]已起步. 动物研究[39]显示, 黄连素可调节高脂饮食喂养的脂肪肝小鼠的肠道菌群, 令模型鼠粪便中乳酸菌和双歧杆菌等益生菌数量显著增加, 脂肪肝的组织学显著改善. 临床研究[40,41]显示, 黄连素显著降低2型糖尿病患者的转氨酶水平, 显著改善丙型肝炎合并NAFLD患者的肝组织坏死[42], 显著改善NAFLD患者的血脂紊乱[43]. 由于NAFLD是慢性疾病, 合成抗生素使用的必要性和可行性尚无统一意见, 以治疗NAFLD为目标的临床研究尚欠缺, 但几项间接观察的研究支持抗生素的疗效. 接受全胃肠外营养的患者, 由于没有经口饮食, 肠道处于淤滞状态, 微生态失调发生率很高, 部分患者还并发其他器官感染, 需抗生素治疗. 临床研究[44]显示, 对这类患者使用多黏菌素, 在肠道微生态失衡得到纠正的同时, 肠道和血清LPS水平降低, NASH得到改善. 用多黏菌素喂养全胃肠外营养的大鼠, 取得同样结果, 大鼠肠道有害细菌数量减少, 血清TNF-α水平降低, 肝脂肪变改善[45]. 因重度肥胖症接受空回肠旁路手术的患者, 术后应用灭滴灵预防感染, 也观察到肝脂肪变得到显著改善, 疗效和患者进食的热量/蛋白等营养失衡无关[46].
粪菌移植(fecal microbiota transplantation, FMT), 前称粪便移植, 是将健康人粪便中的功能菌群移植到菌群分布异常患者的胃肠道内, 重建健康的菌群分布和结构的方法[47]. 1958年Eiseman等[48]报道FMT治疗严重伪膜性肠炎(与艰难梭菌感染有关)4例成功, 引起了全世界广泛的关注. 近年, 已有不少FMT治疗肠道艰难梭菌感染、炎症性肠病、肠易激综合征等成功的报告[49]. FMT治疗代谢性疾病和NAFLD在动物试验已有报告, 临床研究正于起步阶段. 一项小样本临床随机对照实验显示, 将体形偏瘦人群的粪便移植到患MetS人群的肠道中, 有助于恢复肠道微生态平衡, 改善患者血脂水平和IR, 改善NAFLD[50].
因胆汁可抑制肠道内许多致病细菌的生长, 使用利胆剂, 如熊去氧胆酸(ursodeoxycholic acid, UDCA)有助于调整肠道微生态平衡. 文献显示UDCA对NAFLD有一定的治疗作用, 一项纳入的8项临床文献的综述显示, 肝功能改善在全部研究均达显著性, 其中6项有肝穿刺活检结果, 均显示组织学显著改善[51].
胃肠道菌群失调和NAFLD发病相关, 随着高通量测序和宏基因组学的应用, 失调的菌种已逐步查明. 发病机制除了菌群失调直接导致肠黏膜屏障破坏和能量摄取增加外, 近年确定"肠-肝轴"的重要性, 经TLRs和NLRs受体通路, 激活肝脏免疫系统, 诱发下游炎症因子瀑布样效应是NAFLD发病的主要原因. 恢复胃肠道微生态的平衡可望成为NAFLD防治的新方法. 目前, 使用微生态制剂、抗生素及FMT等方法疗效刚起步, 干扰TLRs和NLRs受体通路尚在摸索中. 肠道菌群研究将为NAFLD的防治带来全新的方法.
非酒精性脂肪性肝病(non-alcoholic fatty liver disease, NAFLD)俗称脂肪肝, 临床常见, 发病机制未完全明确, 尚无有效防治方法. 近年, 胃肠道微生态研究取得进展, 已证实微生态失调和NAFLD发病相关, 本领域成果为NAFLD防治开辟新的途径.
姜春萌, 教授, 大连医科大学附属第二医院消化科
NAFLD的防治有困难与其发病机制未明确相关, 胃肠道微生态失调是近年热门课题, 从基因水平探讨发病机制和防治方法, 发现肠-肝轴、Toll样受体(Toll-like receptors, TLRs)和核苷酸结合寡聚化结构域受体(NOD-like receptors, NLRs)等概论, 令NAFLD研究取得突破性进展.
20世纪80年代已有肠道微生态失调与NAFLD和其他疾病相关报告. 近年用高通量测序从基因组水平分析胃肠道菌群构成, 完成了人类肠道细菌"基因普查". 临床使用微生态制剂、抗生素及粪菌移植等新疗法相继报道.
胃肠道微生态失调诱发NAFLD, 机制是除了导致肠黏膜屏障破坏和能量摄取增加外, 更重要的是通过肠-肝轴, 经TLRs和NLRs受体通路, 激活免疫系统, 诱发下游炎症因子瀑布样效应. 恢复胃肠道微生态的平衡是防治的新方法.
肠道菌群研究将为NAFLD的防治带来全新的方法. 目前, 微生态制剂、抗生素及粪菌移植等方法初见成效, 干扰TLRs和NLRs受体通路的药物正在研制中.
胃肠道微生态: 正常人有500多菌种, 总量100万亿, 质量1-2 kg, 微生态失调扰乱机体稳态, 诱发NAFLD和多种疾病; 肠-肝轴: 肝脏与胃肠道共同组成消化系统整体, 两者功能联系, 疾病相关.
本文内容新, 视角独特, 初步显示了最新关于肠道微生态与脂肪肝的关系和可能的机制, 论文书写规范, 引文权威、新, 对脂肪肝研究有重要引导价值.
编辑:韦元涛 电编:都珍珍
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