修回日期: 2022-08-25
接受日期: 2022-10-20
在线出版日期: 2022-11-08
肠易激综合征(irritable bowel syndrome, IBS)是一种常见的慢性胃肠道功能障碍疾病. 脑-肠-微生物轴功能障碍作为IBS的一个重要致病因素, 其中的神经递质、肠道微生物都发挥着关键作用. 胃肠道(gastrointestinal, GI)含有大量的血清素5-羟色胺(5-hydroxytryptamine, 5-HT), 作为肠道中的一种神经递质, 其与IBS相关症状有着密切联系. 超过90%的血清素是由肠道嗜铬细胞(enterochromaffin, EC)在肠道中合成的, 肠道内的部分菌群可以通过调节5-HT及其代谢影响IBS的发生发展. 在本综述中, 我们将讨论肠道菌群通过调节5-HT在IBS中发挥的作用.
核心提要: 肠易激综合征(irritable bowel syndrome, IBS)是一种常见的肠道功能障碍疾病. 脑-肠-微生物轴功能紊乱是IBS的发病机制之一, 其中, 5-羟色胺作为一种神经递质, 其与IBS有着密切联系, 且肠道内的部分菌群也可以通过调节血清素5-羟色胺(5-hydroxytryptamine, 5-HT)及其代谢影响IBS的发生发展.
引文著录: 冯雅, 杭露, 周盐, 蒋风茹, 袁建业. 肠道菌群通过调节5-HT代谢在IBS中发挥作用. 世界华人消化杂志 2022; 30(21): 941-949
Revised: August 25, 2022
Accepted: October 20, 2022
Published online: November 8, 2022
Irritable bowel syndrome (IBS) is a common chronic functional gastrointestinal disorder. Brain-gut-microbiota axis dysfunction is an important pathogenic factor for IBS, in which neurotransmitters and gut microbes play key roles. The gastrointestinal tract contains large amounts of serotonin (5-hydroxytryptamine, 5-HT), a neurotransmitter that has been strongly linked to IBS-related symptoms. More than 90% of serotonin is synthesized in the gut by enterochromaffin cells (ECs), and certain intestinal flora can affect the occurrence and development of IBS by regulating 5-HT and its metabolism. In this review, we will discuss the role of gut microbiota in IBS by regulating 5-HT.
- Citation: Feng Y, Hang L, Zhou Y, Jiang FR, Yuan JY. Gut microbiota plays a role in irritable bowel syndrome by regulating 5-HT metabolism. Shijie Huaren Xiaohua Zazhi 2022; 30(21): 941-949
- URL: https://www.wjgnet.com/1009-3079/full/v30/i21/941.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v30.i21.941
肠易激综合征(irritable bowel syndrome, IBS)是一种慢性肠道疾病. 其主要临床表现为腹痛、间歇性或持续性排便异常、粪便质地和性状异常[1]. 由于IBS患者没有出现明显的器质性异常变化, 它被认为是一种功能性疾病. 根据排便习惯, 罗马Ⅲ和罗马Ⅳ标准将IBS分为四种亚型: 腹泻型(diarrhea predominant IBS, IBS-D), 便秘型(constipation predominant IBS, IBS-C), 混合型(mixed stool pattern IBS, IBS-M)和未确定型(unclassified IBS, IBS-U)[1,2]. 在全球, 大约每10人中就有1人受到影响. IBS的患病率在东南亚约为7%, 在北美约为11.8%-14%, 在非洲、南美地区约为15%-21%[3,4]. 在我国, 不同地区的患病率也存在差异, 总体患病率约为1.4%-11.5%[5,6], 其中, 以IBS-D最为高发, 占总发病率的66.3%[7]. IBS的患病率与性别、年龄等也有相关性. 一项针对IBS的临床Meta分析显示, IBS-C在女性中更为常见, 而IBS-D则男性更为常见[8]. 根据罗马Ⅲ标准, IBS的病理生理学涉及多种因素, 如脑-肠轴功能紊乱、肠道微生物群改变、胃肠道(gastrointestinal, GI)感染、内脏超敏反应、肠道通透性增加、精神和心理状况(如焦虑和抑郁)异常、胃肠运动异常、免疫功能障碍和宿主遗传易感性等[9,10].
"脑-肠-微生物轴"是在"脑-肠轴"的基础上增加了肠道菌群对大脑和胃肠道之间双向调节的内涵. 肠道菌群大约共有400种, 其中一些被认为是健康消化所必需的[11]. 人体肠道内主要有厚壁菌门、拟杆菌门定居, 其次是放线菌门、变形菌门、疣状杆菌门、梭杆菌门等, 它们产生酶和代谢物[12,13], 帮助身体吸收必要的营养和维生素, 同时, 它们的存在对于肠道免疫系统的正常发育和功能也非常重要. 越来越多的研究表明, 肠道菌群通过各种方式与中枢神经系统(central nervous system, CNS)和胃肠道保持沟通[14]. 在生命早期, 肠道微生物的扰动便会对中枢神经系统的发育产生长期的影响[15]. 一些神经退化、精神和代谢障碍疾病如帕金森病、精神分裂症、阿尔兹海默病、抑郁症等, 都与肠道微生物有关[16]. 微生物群落对CNS的自下而上的调节主要通过神经免疫和神经内分泌机制, 通常由多种微生物及其衍生分子介导, 包括短链脂肪酸(short chain fatty acids, SCFAs)、次级胆汁酸(secondary bile acids, SBAs)和色氨酸代谢物等[17-19], 其中有些与肠道菌群相关的化学信使[20]可以穿过血脑屏障激活迷走神经的传入纤维, 直接调节大脑功能[21,22]. SCFAs对中枢神经系统的小胶质细胞的成熟也有着重要意义, 无菌条件下, 缺乏SCFAs受体FFAR的小鼠小胶质细胞有所缺陷[23]. 肠道微生物的另一产物ClpB, 是一种α-黑素细胞刺激素的模拟物, 能直接作用于下丘脑阿片黑皮质激素原神经元, 增加神经元放电, 诱发饱腹感[24]. 肠道菌群对肠道的调节除了可以通过神经、免疫和内分泌等途径发挥以外, 还可以通过与肠细胞之间的串扰或改变肠道内环境来实现[25]. 多项研究证明IBS患者的肠道菌群组成不同于健康受试者[26,27]. 与健康对照组相比, IBS患者的疣微菌丰度较低, 且不同的IBS类型其肠道菌群多样性也存在差异, 如甲烷杆菌在IBS-C患者中含量较高, 而在IBS-D患者中就明显降低[28,29]. 此外, 肠道微生物还包括一定的真菌, 对于这一部分的研究知之甚少, 而这一部分在IBS的发病机制中也发挥着作用. 有研究证明, 粪便真菌生物群与IBS的内脏超敏反应有关[30], 念珠菌与IBS-D患者的腹胀和焦虑程度呈正相关[31]. 在一项针对IBS-D患者的临床研究中发现, 与健康对照组相比, IBS-D患者的粪便真菌与IBS症状显著性相关, 尤其是真菌球菌、曲霉菌属、孢子菌属和潘多拉菌, 而曲霉菌的减少可能导致机会病原体如大肠杆菌是的过度生长, 证明了细菌和真菌之前的相关性[32].
血清素5-羟色胺(5-hydroxytryptamine, 5-HT)是一种单胺类神经递质和激素, 也是一种重要的信号分子, 在大脑和肠道中产生, 具有调节人体中枢和外周一系列生理功能的作用. 其中, 中枢5-HT辅助神经元控制肠道运动和肠液分泌, 及参与调节情绪[33,34]. 体内超过90%的5-HT位于胃肠道中, 主要由肠道嗜铬细胞(enteric chromaffin cells, EC)合成. 5-HT的合成需要两种不同的色氨酸羟化酶(tryptophan hydroxylase, TPH): TPH1和TPH2[35,36]. 前者主要存在于EC和脑干的外围, 而后者则存在于脑干的中缝核等中枢和外周的神经元中[37,38]. 色氨酸被TPH羟基化为5-羟色氨酸(5-hydroxytryptophan, 5-HTP), 后者再被芳香族氨基酸脱羧酶(aromatic amino acid decarboxylase, AAAD)脱羧为5-HT[39,40]. 被释放到细胞外的5-HT通过位于肠细胞和神经元上的多种5-HT受体发挥作用, 调节肠道运动、感觉和肠道腺体分泌, 维持肠道稳态[41]. 细胞外游离的多余5-HT可被肠上皮细胞或神经元上的血清素转运体(serotonin transporter, SERT)摄取转运至细胞内灭活[42]. 还有一部分进入血液的5-HT被血小板上的SERT转运储存于血小板内的致密颗粒中, 随血小板进入血液循环, 在某些特定情况下被重新释放出来[43]. 血小板上也存在5-HT2受体[44].
肠道中的EC在响应化学和机械等刺激时产生和释放5-HT, 有些肠道共生微生物能够通过其代谢物和/或细胞成分促进5-HT在结肠EC中合成[45]. 已有研究表明, 将无特定病原体(specific pathogen free, SPF)小鼠的粪便微生物群移植到GF(germ-free)小鼠的肠腔中, 增加了肠道内5-HT的含量[46]. 进一步的研究明确证实, 小鼠和人类中的天然产芽孢细菌可以促进结肠嗜铬细胞合成5-HT, 并且可以通过增加GF小鼠中特定微生物代谢物的浓度来增加结肠和血液中5-HT的浓度[47]. Reigstad等人[48]发现, 肠道菌群的代谢产物SCFA是促进EC产生5-HT的重要介质之一. 最近的研究提示, 肠道菌群的代谢物反过来调节肠道微生物群以稳定肠道微环境[49], 也可能影响了肠道5-HT的合成. 此外, 棒状杆菌属、链球菌属和肠球菌属等部分肠道中的常驻细菌还可以利用肠腔中的色氨酸直接产生5-HT[50]. 还有一些细菌, 如乳球菌、链球菌、大肠杆菌和克雷伯菌通过表达色氨酸合成酶产生5-HT[51,52]. 也有研究表明[53], 大肠杆菌表达TPH并产生5-HT的前体-5-HTP.
体内5-HT的含量不仅取决于其合成(与色氨酸的可用性及TPH的表达和活性等有关), 还受其降解(与5-HT降解相关的酶的活性等有关)的影响[54-56]. Nzakizwanayo等人[57]用大肠杆菌Nissle1917(Escherichia coli Nissle 1917, EcN)处理离体小鼠回肠组织, 发现组织暴露于EcN中可增加5-HT表达水平; 然后分析5-HT代谢物, 发现EcN降低了5-HIAA的表达. Wang等人[58]发现鼠李糖乳杆菌GG上清液(Lactobacillus rhamnosus GG, LGG-s)可以上调肠道上皮细胞HT-29和Caco-2细胞以及小鼠肠道组织中SERT mRNA的表达.
脑-肠-微生物轴的紊乱, 特别是肠道微生物的紊乱, 被认为是IBS的一个重要致病因素[59]. 肠道微生物中既有维护宿主健康的"有益菌", 也存在危害宿主健康的致病菌和在特定条件下危害宿主健康的条件致病菌[60,61]. 在有些情况下, 致病菌数量过度增加或有益菌过度减少破坏了肠道微生物之间的平衡状态, 出现所谓的"肠道微生态失衡", 或者被称作"肠道菌群失调". 已有大量研究证实IBS患者或动物模型存在肠道菌群失调[62,63]. 肠道微生物的变化导致肠道运动障碍、内脏过敏、肠道屏障功能受损等, 这些异常在IBS中均有所表现, 且越来越多的证据表明, 肠道微生物不仅可以解释IBS的腹部症状, 还与IBS的肠道外症状有关. 有研究表明IBS患者体内肠道菌群的丰度与神经递质之间存在相关性[64]. 5-HT作为一种神经递质, 在参与IBS的病理生理过程中, 同样也受到肠道菌群的调节.
肠动力异常被认为是IBS两大病理生理基础之一, 也是引起IBS排便习惯改变的主要原因. 肠道微生物通过调节5-HT参与IBS肠动力异常已被大量研究所证实, 其内在机制也被广泛探讨. 研究发现[65], 小鼠经抗生素处理4 wk后, 其近端结肠平滑肌的时相性收缩受到抑制, 伴随5-HT、TPH1和次级胆汁酸水平的明显降低. 摄入的食物和5-HTP在色氨酸酶(tryptophanase, TnaA)作用下代谢为5-羟基吲哚(5-hydroxyindole, 5-HI)的过程受肠道菌群的调节, 而5-HI能通过激活结肠平滑肌细胞上的L型钙通道促进平滑肌收缩, 增强肠动力, 加速肠内容物的传输[66], 5-HI还可以刺激肠嗜铬细胞产生5-HT. 此外, Karaki等人[67]的研究证实肠道微生物的代谢产物SCFA通过作用于肥大细胞上的相关受体刺激 5-HT释放, 提高结肠运动的兴奋性.
内脏高敏感性是IBS的另一主要病理生理基础, 被认为是引发IBS关键症状腹痛的主要原因. 肠道微生物可以通过刺激背根神经节中的初级伤害性神经元直接提高内脏疼痛敏感性, 或者通过激活肠道中的炎症免疫反应间接提高内脏敏感性[68,69], 肠内有部分通过激活5-HT直接感受疼痛, 但也有通过刺激肠系膜感觉纤维、迷走神经等来诱发疼痛的[70-72]. Zhang等[73]通过使用LncRNA XIST沉默SERT基因, 提高胞外5-HT含量, 增强了小鼠的内脏超敏反应. 有学者将IBS患者的粪菌移植到正常无菌大鼠体内后发现其内脏敏感性升高[74]. 微生物通过5-HT介导的黏膜炎症也可能是引起疼痛的原因之一, 而5-HT3受体拮抗剂可以抑制炎症反应, 减轻疼痛[75].
肠上皮屏障(intestinal epithelial barrier, IEB)是外界环境和身体内部环境接触的界面之一[76], 一方面需限制有害微生物和抗原的通过, 另一方面需确保营养、水分等的吸收[77]. IBS的发病机制与IEB的失调有关[78]. 临床研究发现IBS患者5-HT水平升高且普遍存在肠黏膜屏障损伤, 表现为紧密连接蛋白部分减少[79,80]. 亦有研究发现IBS患者肠道菌群失调, 肠内SERT表达水平下降, 肠细胞再摄取5-HT的能力显著降低, 黏膜保护屏障遭到破坏[81]. 动物研究发现, 应激诱导的IBS小鼠中枢神经系统5-HT代谢紊乱, 肠道屏障功能出现障碍[80], 将这些小鼠的粪菌移植到幼鼠肠内可引起后者5-HT代谢异常, 肠道通透性增加[82]. 此外, 肠上皮屏障的功能依赖于肠道内5-HT通过5-HT3受体传导的信号, 敲除5-HT3受体后, 小鼠的肠通透性显著增加[83]. 在评估肠道IEB和IBS的关系中, 肠道通透性和腹痛之间的相关性常常被研究[84]. 肠道微生物可以透过损伤的IEB刺激到肠道的免疫系统, 导致免疫介质的释放, 其中包括5-HT, 进而引起疼痛感觉的传入[85]. 由此可见, 肠道菌群可直接或通过衍生的代谢产物间接影响5-HT信号破坏肠道屏障功能, 参与到IBS的发病过程中.
肠道黏膜炎症和免疫异常与IBS的发生密切相关, 5-HT在调节肠道黏膜炎症和免疫功能方面也发挥重要作用, 5-HT的合成和释放受到微生物和免疫细胞的控制[86], 因此肠道菌群可以通过调节5-HT浓度变化参与宿主免疫调节[87]. 临床研究发现, IBS患者免疫系统存在异常, 表现为黏膜免疫细胞浸润(以CD3+、CD4+、CD8+ T细胞和肥大细胞为主)和促炎细胞因子水平的增加[88]. 此外, IBS-D患者黏膜SERT水平的降低与黏膜上皮内淋巴细胞和肥大细胞数量的增加有关[89]. 某些肠道微生物可以合成各种氨基酸脱羧酶以固化氨基酸, 进而改变宿主肠道中5-HT和免疫细胞介质等代谢物的分布[90], 而普氏杆菌可以直接下调5-HT水平, 发挥抗炎作用[91]. 包括梭状芽孢杆菌在内的产孢微生物通过促进结肠中调节性T细胞的增殖, 发挥免疫调节作用[92]. 值得注意的是, 肠道菌群的代谢产物SCFA可能通过G蛋白偶联受体(G-protein receptor, GPR)43激活诱导ECs释放5-HT, 进而激活5-HT3受体, 造成IBS患者肠道免疫的异常[93].
胃肠内分泌细胞分散在管腔内的上皮细胞中, 这些内分泌细胞在经刺激释放不同的激素后, 通过内分泌信号、旁分泌或自分泌信号、突出信号等发挥作用[94]. 越来越多的证据表明, 肠内分泌细胞的改变是IBS的一个原因. 有研究显示IBS患者肠道内分泌细胞的密度存在异常, 这可能导致IBS的内脏超敏反应、动力障碍等IBS的典型特征[95-97]. 观察发现IBS患者在接受健康受试者粪菌移植后, 其内分泌细胞密度和内分泌细胞类型比例向健康受试者转移[98]. 分泌5-HT的EC是肠内分泌细胞中数量最多的一种, EC细胞形态上呈三角形, 顶端微绒毛深入肠腔捕捉肠腔刺激. 一项临床研究发现[63], IBS患者盲肠中EC细胞的数量高于健康受试者, 且TPH1在降结肠中的蛋白表达水平较高; 通过菌落组成分析及相关性分析, 发现瘤胃球菌与EC细胞数量成正相关. Mandić等[45]表明, 与GF小鼠相比, 使用梭状芽孢杆菌后的小鼠体内G蛋白偶联受体5(EC细胞标记物)的表达增加, 因而提出肠道微生物可以影响EC细胞的发育.
IBS目前被认为是一种"身心疾病", 除了肠道相关症状外, IBS患者往往还伴发多种肠外异常表现. 其中焦虑和/或抑郁是其最常见的精神心理并发症. 焦虑、抑郁患者大脑中存在5-HT信号异常[99]. 肠道微生物可能通过肠道内的迷走神经通路影响情绪处理的基本回路[100], 越来越多的证据表明, 肠道微生物及其代谢产物通过脑-肠-微生物轴改变中枢5-HT代谢导致大脑内环境紊乱[101,102]. 几项研究报告显示, IBS患者和抑郁症患者粪便微生物组具有相似性, 如高丰度的变形菌和低丰度的双歧杆菌[103,104]. 另有结果表明[64], 在患有情绪困扰的IBS患者体内, 肠道菌群的α多样性和5-HT水平之间存在相关性.
通过针对5-HT途径的治疗IBS的药物主要有5-HT3激动剂、5-HT4拮抗剂、选择性5-HT再摄取抑制剂(selective serotonin reuptake inhibitor, SSRI)等, 主要用于IBS-D, 在临床上已大量使用[105-107]. 在针对肠道菌群的治疗方法主要包括一些常见的益生菌、合生元等药物, 以及现有的粪菌移植技术[108]. 目前通过调节肠道菌群影响5-HT来治疗IBS的研究相对较少, 肠道菌群的复杂性为其具体的靶向治疗带来了难度.
IBS的发病受生物、心理、社会和其它因素的影响. 目前, 仍然缺乏有效的治疗方法. 5-HT作为脑-肠-微生物轴中重要的神经递质, 能调节胃肠的运动和分泌, 直接或间接改善腹痛、腹泻等症状, 是治疗IBS的重要靶标, 且对于IBS相关的情绪障碍也有影响. 肠道菌群作为人体中复杂而庞大的微生物系统, 在维护人体健康中也起着重要作用. 它们能调节消化道免疫、营养吸收、能量代谢和肠道生物屏障功能. 肠道微生物的平衡对于宿主的消化、吸收等生理活动来说是必不可少的. IBS的发病机制中也涉及了肠道微生物, 不管是肠道的运动功能、肠道黏膜屏障功能、还是内脏过敏反应、免疫应答等, 随处可见肠道菌群的身影. 脑-肠-微生物轴为人们提供了开发新治疗方法的研究方向. 针对IBS患者微生物群落的相关治疗也已有所研究, 例如临床已开展的粪菌移植技术. 肠道菌群容易受到外部因素的影响, 包括饮食、压力、生活方式和其它因素. 这些因素也与IBS的发生密切相关, 表明IBS也可以通过饮食和生活方式干预来治疗.
肠道菌群能够通过多种机制对5-HT的代谢进行调节, 且不仅影响肠源性的, 还能通过神经系统影响中枢5-HT的代谢. 肠道菌群及其代谢物对5-HT代谢的调节参与IBS的发生和发展. 专注肠道菌群对5-HT信号的调节可能有助于找到治疗IBS的新方法.
迄今为止, 对于肠道微生物群的研究多集中在细菌上, 作为微生物群的一部分, 真菌的研究甚少, 有证据证明真菌可以加重结肠炎的严重程度[109], 能够刺激肥大细胞释放组胺降低内脏疼痛阈值[30]. 关于真菌与5-HT之间是否存在联系也需要进一步探索.
肠道微生物对焦虑抑郁的预防作已用得到证实, 粪菌移植可以改善焦虑和抑郁等IBS的肠道外表现, 提示粪菌移植可用于治疗合并有焦虑和抑郁表现的IBS患者.
肠道微生物的代谢产物是肠道微生物研究中不容忽视的重要内容. 与正常人相比, IBS患者粪便中肠道菌群的代谢产物SCFA水平存在差异, 表现为IBS-C患者粪便中丙酸盐和丁酸盐明显减少, 而IBS-D患者粪便中丁酸盐明显增加[110]. Li等[111]的研究表明胆汁酸能够通过肠黏膜肥大细胞增强痛觉感受, 诱导内脏超敏反应. 此外, 一些细菌可以将未消化的碳水化合物酵解为二氧化碳、甲烷等气体, 这些也可能是引起IBS患者腹胀腹痛的物质, 值得研究者进一步关注.
学科分类: 胃肠病学和肝病学
手稿来源地: 上海市
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科学编辑:张砚梁 制作编辑:张砚梁
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