修回日期: 2008-03-15
接受日期: 2008-05-10
在线出版日期: 2008-05-18
肠易激综合征(irritable bowel syndrome, IBS)是一种以腹部不适和排便习惯改变为特征的胃肠功能性疾病. 其发病机制复杂, 尚未被人类充分认识, 可能与包括心理因素、胃肠道异常运动与分泌、内脏高敏感性在内的中枢和外周因素有关. 但有的因子既能够调节胃肠道的运动, 又能够调节内脏的敏感性, 使IBS患者的胃肠道对应激及食物的敏感性增强. 目前认为内脏敏感性增高是其特征性的病理生理基础, 但IBS内脏高敏感性确切的神经生物学机制尚不清楚, 脑-肠轴上有多种机制单独或共同作用形成内脏感觉的异常. 本文综述近年来有关IBS患者肠道神经丛、脊髓及中枢神经系统存在结构或功能的异常.
引文著录: 康明祥, 贾红. 肠易激综合征内脏高敏感性机制的研究进展. 世界华人消化杂志 2008; 16(14): 1554-1558
Revised: March 15, 2008
Accepted: May 10, 2008
Published online: May 18, 2008
AIM: Irritable bowel syndrome (IBS) is a functional bowel disorder characterized by abdominal discomfort and altered bowel habits. The mechanism of IBS is complex and remains unclear. Both central and peripheral factors, including psychosocial factors, abnormal gastrointestinal motility and secretion, and visceral hypersensitivity, are thought to contribute to the symptoms of IBS. Importantly, several external and internal factors can modulate visceral sensitivity, as well as gastrointestinal motility, and then lead to enhanced responses within the GI tract to, for instance, stress and nutrients. Visceral hypersensitivity is currently considered to be perhaps the most important pathophysiological factor in IBS, but the exact mechanism remains unknown. A variety of different mechanisms in brain-gut axis, alone or in combination, may be responsible for visceral hypersensitivity. In this article, we review the studies on the abnormal structure and/or function of enteric neuron system, spinal cord and cerebral system in IBS.
- Citation: Kang MX, Jia H. Progress in mechanisms of visceral hypersensitivity in irritable bowel syndrome. Shijie Huaren Xiaohua Zazhi 2008; 16(14): 1554-1558
- URL: https://www.wjgnet.com/1009-3079/full/v16/i14/1554.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v16.i14.1554
肠易激综合征(irritable bowel syndrome, IBS)是临床上常见的一种胃肠功能紊乱性疾病, 以腹部不适或腹痛伴排便异常为主要特征, 缺乏形态学和生物化学异常. 目前, 研究发现IBS的发生与胃肠动力学异常、内脏高敏感性、肠道感染、精神因素及遗传因素等均有关系, 但IBS的发病机制仍不清楚, 其中内脏感觉异常机制最为广泛接受. 内脏高敏感性的发生机制非常复杂, 脑-肠轴的各个水平均可参与其中, 近年相关的研究也取得较大进展.
神经系统对整个胃肠道运动的调控按三个层次相互协调. 第一层次是由肠道神经丛内在肌源性的自律性活动对其运动和分泌进行局部调控. 第二层次是调控位于椎前神经节, 其中含有外周交感神经的节后神经元胞体, 支配整个胃肠道器官, 接受和调节来自肠道神经丛和中枢神经系统两方面的信息. 第三层次是调控在中枢神经系统, 他接收脑的各级中枢和脊髓接受体内外环境变化时传入的各种信息, 经过整合后, 经由自主神经系统和神经内分泌系统将其调控信息传送到胃肠道的肠神经丛或直接作用到平滑肌, 调整胃肠道各段的活动.
由内脏感受器的传入冲动所产生的感觉称为内脏感觉. 内脏感受器感受人体内环境的变化, 按其适宜刺激性质的不同可分为化学的、机械的、温度的、痛觉的等类型. 内脏感觉神经纤维的数目比一般体表感觉神经纤维的数目少, 他混在交感和副交感神经中, 传入冲动沿这些神经从背根进入脊髓或沿脑神经进入脑干, 引起相应的反射活动. 内脏传入冲动还可以进一步经丘脑上行到大脑皮层及边缘叶, 再通过下丘脑等处, 调节内脏的活动. 消化道同一部位的感觉可由多个部位神经元调控. 而一个神经节又可参与消化道多部位神经调控[1]. 而内脏高敏感性是指内脏组织对刺激的感受性增强的现象, 一般是通过引起各种感觉的容量阈值或压力阈值对内脏敏感性进行评估的, 在胃肠道尤为常用的是腔内球囊扩张[2].
内脏高敏感性既可存在外周, 也可存在中枢. 胃肠道主要受肠神经系统、迷走神经、脊髓神经、交感神经及副交感神经控制, 其中肠神经系统(enteric nervous system, ENS)因其功能独立于中枢神经系统(central nervous system, CNS), 又被称为"肠小脑"[3-4]. 其中内在初级感觉神经元(intrinsic primary afferent neurones, IPANs)作为ENS的一部分参与内在感觉的调节, 而内脏感觉的上传主要通过外在初级感觉神经元(extrinsic primary afferent neurones, EPANs)完成. IPANs对低阈值的非伤害刺激即可产生反应, 激发肠神经反射, 但这种反应较弱, 不向上传导. IPANs亦可对伤害性刺激产生反应, 主要是激发胃肠道保护性反应. 当胃肠道内环境发生改变时, IPANs的功能可被修改, 此时IPANs同样可产生强烈的感觉信号, 并向上传导, 使机体产生不适感[5]. 肠道感受器参与了内脏敏感性的调控[6]. 内脏感觉研究证明[7-8], IBS患者对机械刺激具高敏感性, 提示其高敏感性的初级反应部位可能在肠壁的机械性受体. 并有学者尝试通过检测直肠压力作为肠易激综合征诊断指标的研究[9]. 一些研究[10-13]报道IBS患者自主神经功能异常, 与正常人相比, IBS患者交感神经活动增强和副交感神经活动减弱. 自主神经系统一方面可激活肥大细胞使之脱颗粒释放活性物质, 如5-羟色胺(5-HT)和组胺等, 导致内脏感觉阈值下降, 另一方面可通过作用于ENS引起平滑肌细胞紧张性改变, 使肠壁压力/容积之比发生改变, 导致内脏传入纤维的传入冲动增加. 此外, 胃肠黏膜可感受内脏机械和化学刺激, 并分泌感觉神经递质, 主要的初级感觉神经递质是5-HT. 5-HT在胃肠道的功能主要包括调节肠道的动力、调节胃肠道的分泌和协调肠道的感知功能[14], 他也是参与脑-肠轴的重要神经介质[15]. 大量研究[16-20]证实IBS患者肠动力反应过强、感觉阈值降低以及心理障碍或精神异常表现与5-HT浓度较高有关. 5-HT作用于不同的受体会有不同的表现, 其中与IBS发病机制关系最为密切的是5-HT3受体和5-HT4受体[21-23]. 临床上, 腹泻型和便秘型IBS患者有完全不同的肠道运动形式, 可能与机体内各种5-HT受体的功能相互不协调以及受体的分布和比例不同有关. 5-HT主要来自肥大细胞(mast cell, MC); 另外, 作为肠道最主要的内分泌细胞肠嗜铬细胞(enterochromaffin cell, EC), 其主要功能是合成和储存5-HT. 大量研究[24-28]表明, IBS患者结肠黏膜内的MC细胞和EC细胞明显增高, 其功能活跃. 目前, 也有学者[29]致力于IBS患者肥大细胞与神经相互作用的研究和动物模型的建立. 除5-HT分泌增加外, 近年来的研究发现IBS患者血中和结肠黏膜其他胃肠激素含量也发生了变化[30-31]. 而各种胃肠激素对MC活化具有调节作用, 如P物质(substance P, SP)和降钙素基因相关肽(CGRP)对Mc活化具有反向调节作用, 而肠血管活性肽(vasoactive intestinal peptide,VIP)和一氧化氮(NO)则具有正向调节作用[32].
背髓背角作为脑-肠轴的"中继站", 是内脏敏感性调节的关键部位. 粗的有髓初级传入纤维(Aα、β)与细的有髓或无髓初级传入纤维(Aδ与C)、背角投射神经元(T)和胶状质区抑制性中间神经元组成了脊髓节段性调制的神经网络. SG细胞起关键的闸门作用, 他可改变传入神经纤维的膜电位对感觉性输入具有突触前抑制效应. 对正常情况下, 脊髓后角感觉神经元存在活化和抑制的相互平衡, 这一平衡系统若出现很小波动就会影响脊髓对痛觉的处理而引起内脏高敏感性. 而Coffin et al[33]对IBS患者的伤害性屈曲反射研究表明, IBS患者脊髓存在着超兴奋性. 当外周有害刺激包括炎症介质和神经损伤引起一些静止性伤害性感受器转为敏感性时, 增加了脊髓水平可活化的伤害性感受器的数量, 从而降低了初级传入神经的感受阈值[34-36]. 致敏的初级传入神经纤维将信号传入脊髓背角, 通过神经活性物质(谷氨酸、SP、CGRP)释放增加, 作用于Ⅱ级神经元, 致Ⅱ级神经元兴奋性增加, 使脊髓高兴奋性持续存在, 即使刺激物质消失后, 仍存在痛觉过敏, 亦可引起机体随后的疼痛阈值降低, 延长持续时间[37]. 国内孙刚 et al[38]研究显示C-IBs大鼠模型存在对直肠球囊扩张的内脏敏感性异常, C-IBs模型组大鼠脊髓背角5-HT、c-fos表达的A值和面积均明显超过正常对照组, 同国外的文献报道一致[39-40]. 5-HT是脊髓内主要的抑制性神经递质, 对脊髓背角浅层神经元的活动有抑制作用. 而c-fos被认为是一种即刻早基因, 在神经元活动时c-fos蛋白表达增强, 其表达产物被认为是伤害性感受神经元兴奋的标志物[41]. 王亚雷 et al[42]研究IBS大鼠模型脊髓背根神经节的电压门控钠离子发现, 新生大鼠直肠内气囊扩张使电压门控钠离子通道发生改变, 后者可能参与模型大鼠内脏高敏感性的发生和发展. 通过直肠球囊扩张检测脊髓诱发电位(somatosensory evoked potentials, SEP), 发现IBS内脏感觉过敏大鼠与正常大鼠SEP有显著差异[43], 通过球囊扩张刺激IBS患者直肠检测SEP也得出类似结论[44-46]. 这些研究表明, IBS患者对内脏刺激的高敏感性可能是在脊髓这一水平介导的.
近年来, 通过对内脏的刺激, 采用大脑诱发电位(cerebral evoked potentials, CEP)、正电子发射体层摄影(positron emission tomography, PET)、脑磁波描记术(magnetoencephalograph, MEG)、功能性磁共振成像(functional magnetic resonance imaging, fMRI)等手段, 记录大脑的反应. 这些研究显示, 在IBS患者CNS存在夸大的异常的内脏感知[47]. 通过PET对内脏疼痛的研究发现, 对感觉起主要作用的中枢核团有扣带前回皮质(anterior cingulate cortex, ACC)、前额叶皮质(prefrontal cortex, PFC)、岛叶皮质(insular cortex, IC)和丘脑, 这4个区组成大脑痛觉处理系统[48-51]. 研究显示, 丘脑是作为脊髓丘脑束和脊髓网状束的传入信号至高级中枢的中继站[52], IC处理初级内脏感觉如直肠扩张刺激等, 岛叶皮质神经元是接受压力感受器、化学感受器、味觉和伤害性疼痛信息的汇聚处[53]. ACC被认为处理情感或情绪产生的内脏感觉信息, 而PFC则具有对疼痛的高级执行功能[54]. Wilder-Smith et al[55]采用刺激直肠和足部的冷刺激方式记录IBS女性患者的刺激强度显示, 异位性刺激在IBS患者直肠疼痛强度高于对照组. 其他研究[56-58]也说明在IBS患者可能存在着内源性疼痛的调节异常和躯体的超敏反应.
通过脑显像技术如fMRI和PET用于直肠扩张反射时大脑核团反应的定位检测, 发现IBS患者在ACC、丘脑、岛叶及PFC等区域存在着不同的活动过程. 而且结论尚不统一. Silverman et al[59]报道IBS患者通过PET在直肠扩张时ACC活动减少, 出现直肠痛觉时PFC活动增加, 提示对刺激过度敏感和内源性疼痛抑制系统失活, 然而, Mertz et al[60]通过fMRI研究发现ACC活动增加, 提示患者中枢活动正常, 只是脑-肠轴存在增强的敏感性. 有报道IBS患者在排便和内脏疼痛时, 带状前回的活动增强; 而Bonaz et al报道右侧岛叶、右侧杏仁核和右侧纹状体活动减弱[61]. 此外, 患者的心里状态也很重要, 因为情绪可以调节脑的活动形式. 研究表明, 通过对IBS患者心理干预, 可以缓解IBS症状, 改善患者的生活质量[62-63]. 中枢对精神压力的处理系统中有促肾上腺皮质激素释放激素(corticotropin releasing factor, CRF)参与. 下丘脑接受刺激后释放CRF, 进一步激活下丘脑-垂体-肾上腺产生皮质醇. CRF神经元激活脑干蓝斑. 后者对动物有唤醒和易化内脏感觉性的作用. 人体注射CRF可提高内脏敏感性, 诱发IBS样症状产生[64-65]. 因此, CRF可能成为FGIDs药物治疗的另一个靶点[66-67].
总之, 内脏高敏感广泛存在于IBS患者中, 其既可发生在外周, 又可存在于脊髓和中枢神经系统. 多种神经递质在外周、脊髓和中枢参与内脏高敏感的调控. 对其调节机制的研究亦为内脏高敏感的药物治疗提供新的靶点.
肠易激综合征(IBS)的发病机制较为复杂, 尚未被人类充分认识. 目前证明内脏敏感性增高是其特征性的病理生理基础. 但IBS内脏高敏感性确切的神经生物学机制尚不清楚, 可能包括肠道局部机械性受体和神经末梢的超敏感, 神经通路及中枢神经短暂或长期的功能异常.
李振华, 教授, 中国中医科学院西苑医院消化科
脑-肠轴、神经-内分泌调节功能失调及内脏敏感性增高是目前IBS发病机制的研究热点之一.
本文对脑-肠轴各个层面与内脏高敏感机制的关系进行了综述, 并阐述各个层面目前研究的热点和趋势.
本文着重阐述了脑-肠轴在内脏高敏感性的关系, 使临床医生更好的了解肠易激综合征的发病机制, 并用于指导临床治疗.
本文条理清楚, 层次分明, 内容简洁明了, 参考文献较全面, 基本反映了该领域国内外研究现状.
编辑:李军亮 电编:吴鹏朕
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