胃肠源性非正常免疫激活与精神疾病病理机制关系研究进展
2018-02-14和西波毛富强禚传君
和西波 毛富强 禚传君,3
胃肠道是产生70%~80%人体免疫细胞的最大免疫器官。因此,其功能异常可以导致精神病理学改变,并且导致个体出现精神病性症状。目前免疫系统和炎症反应在精神疾病发病机制中作用已经被证实[1]。其中,关于应激、肠道菌群异位、食源性抗原、肠道屏障的通透性是近几年来研究的热点,本文将2018年以前的部分研究进行综述,以期增加对此方面知识的理解。
1 应激-胃肠反应-诱发脑病理改变
炎症、病毒、细菌或寄生虫感染、损伤、暴露于各种毒素、辐射、氧化和硝化等应激因素可以导致心理和躯体的应激反应。应激反应激活下丘脑-垂体-肾上腺轴,增加抗炎性肾上腺皮质激素皮质醇的分泌,可以防止潜在破坏性炎症反应的过度激活。然而,最近的研究显示应激源可以直接或间接导致肠道屏障通透性增加,并介导多种不利的免疫反应,诱发精神病理学后果。血脑屏障的结构和机制在很多方面与胃肠道屏障相似[2],破环肠道屏障的免疫因素可以破环血脑屏障通透性,从而导致有害物质进入大脑,导致精神障碍发生。其中,导致上述异常反应的因素主要为:胃肠道细菌易位、食物来源性抗原、自身抗体和抗原共价结合。
1.1 胃肠道细菌易位 细菌脂多糖是在革兰氏阴性细菌外膜中发现的糖脂复合物,对免疫和脑功能具有影响,脂多糖激发可诱导短暂的、低级别炎症反应及其随后的动物行为改变和人类受试者的疾病行为[3]。肠道菌群从肠腔易位以及随后脂多糖诱导的炎症反应激活会导致肠道渗透性超过30倍,增加抗原蛋白辣根过氧化物酶(HRP)的通透性。并能诱导犬尿氨酸通路的酶异常,例如吲哚胺2,3双加氧酶(IDO),吲哚胺2,3双加氧酶将色氨酸分解为犬尿氨酸,增加具有神经毒性的犬尿氨酸的表达[4]。随后导致实验动物以及受试者的焦虑情绪增加、情绪低落以及言语和非言语记忆功能下降[5,6]。而且细菌脂多糖对认知功能具有负面影响,并呈剂量依赖性[7]。此外,细菌易位和脂多糖可诱导单核细胞活化,使其向中枢神经系统运输,这被认为是人类免疫缺陷病毒(HIV)相关性痴呆发病的关键机制[8]。
1.2 食物来源性抗原 食物来源的抗原和外啡肽有关。目前研究证实麸质蛋白、酪蛋白和外啡肽参与精神病、精神分裂症、双相情感障碍和孤独症谱系障碍(ASD)的病理过程。麸质蛋白、酪蛋白和乳清蛋白是外啡肽的来源,外啡肽是具有吗啡样活性的肽,有与阿片样μ-受体在中枢神经系统或胃肠道中一样的结合的能力[9]。这些食物源性抗原可刺激T细胞并诱导肽特异性T细胞应答,导致炎症反应的进一步激活,包括促炎细胞因子水平和自身免疫性增加[10],导致多种阿片受体配体的功能异常,从而影响神经免疫功能,参与精神病理过程。目前已有研究证实在精神分裂症患者中阳性和阴性综合征量表评分测量的阴性症状与α和β亚基酪蛋白抗体水平显著相关。
中枢神经系统内屏障系统的功能障碍可能是促使食物衍生抗原和神经活性多肽从肠腔进入脑的另一个促成因素[11,12]。有研究发现未用药精神分裂症患者中血清和脑脊液中IgG水平与麸质蛋白和牛奶酪蛋白之间有显著的相关性,说明这些抗原来源于外围并且需要穿越缺陷血脑屏障进入中枢神经系统[13]。
胃肠道炎症和肠道通透性增加在自杀症状中也起重要作用。一项最近的研究显示与健康对照组相比,重症抑郁症、双相情感障碍和精神分裂症患者中自杀未遂者抗酿酒酵母菌抗体IgA、麦胶蛋白抗体IgG和脂多糖IgA抗体水平增加[14]。
1.3 自身抗体和抗原共价结合 自身抗体可能在抑郁症的发病机制中起重要作用,并且自身免疫疾病和抑郁症可能拥有共同的致病因子[15]。脑室内注射人抗核糖体P蛋白抗体引起小鼠抑郁行为的发生[16]。而且在重症抑郁症和精神分裂症患者中,多种细胞蛋白自身抗体的浓度增加,如α7-烟碱型多巴胺受体、心磷脂、壁细胞(PCA)、平滑肌肌动蛋白,抗核抗体(ANA)和抗甲状腺抗体(TGA)[17]。患有分裂情感性精神病、慢性酒精中毒和类风湿性关节炎的患者中有血清素自身抗体的存在[18]。在精神分裂症和情感性精神障碍患者中都已证明有下丘脑、海马和小脑自身抗体以及抗核抗体水平的提高[19]。精神分裂症中还有其他各种自身抗体的存在[20]。此外,最近许多科学研究关注与神经和精神表现有关的各种细胞表面自身抗体,如 N-甲基-D-天冬氨酸受体(NMDAR)抗体、AMPA受体、电压门控钾通道(VGKC)、γ-氨基丁酸B受体(GABABR)、甘氨酸受体(GlyR)和代谢型谷氨酸受体5(mGluR5)自身抗体[21],这些抗体可能与肿瘤有关,但更常见的是非肿瘤性,这种自身免疫的来源还不清楚[22,23]。这些自身抗体的共同出现与各种精神症状相关,如精神异常、躁狂症、激动、情绪不稳、焦虑、攻击、强迫行为、性格改变、混乱、记忆障碍和遗忘症[24]。NMDA受体抗体和电压门控钾通道抗体在精神分裂症患者中已有描述[25]。Lennox BR等[26]的研究提出诊断为精神分裂症的亚组患者实际上可能患有未确诊的NMDAR脑炎。在实验室动物中已经证明,由弓形虫感染引起的胃肠道炎症和增加的肠道通透性是精神分裂症的已知风险因素,从而导致抗NMDA受体抗体的产生。这种感染还导致抗麸质蛋白和抗酪蛋白IgG抗体水平的增加以及补体因子浓度的增加,从而在神经发育和神经元修剪中发挥重要作用[27]。最近的一项研究显示胃肠道来源抗原与神经元自身免疫性有明确的相关性,Lambert FN等[28]证明对特异食物蛋白具有抗体反应性的患者与没有这种食物反应性的对照组相比,前者多种组织抗体共同出现的情况更高。更确切地说,35%的对照组(抗麸质蛋白IgG抗体阴性)和64%的患者(抗麸质蛋白IgG抗体阳性)对组织具有反应性;30%对照组受试者(乳蛋白抗体阴性)和73%的患者(乳蛋白抗体阳性)对组织具有反应性;22%的对照组受试者(抗麦胚凝集素抗体IgG阴性)和76%的患者(抗麦胚凝集素抗体IgG阳性)对组织具有反应性。
到目前为止,已经确定了两个参与对抗多种组织食物蛋白诱导的自身免疫的主要机制,即分子模拟(也称为交叉反应)和食物衍生的凝集素与人体组织的共价结合[29]。在分子模拟中,特定食物抗原与人体组织之间发生不幸的分子相似性,如麦胶蛋白或乳蛋白与人体组织的氨基酸同源性。然而由于各种原因(如肠通透性增加)可以产生对抗这些食物抗原的抗体,免疫系统可能会“错误”的认识宿主组织与这些模拟抗原,并对其进行对抗,例如已经报道麦胶蛋白和乳蛋白与小脑组织和髓磷脂之间的这种反应。
2 胃肠道微生物群在未来精神疾病研究和治疗中的潜在作用
确定肠道通透性和胃肠道、中枢神经系统免疫力的微生物-肠-脑轴的关键要素是肠道微生物群。理解这些菌群在大脑功能和行为中的作用方面具有重要意义,多项研究已经取得了突破性进展[30~34]。
微生物群通过各种作用在维持心理-神经-免疫平衡方面发挥重要作用,如免疫和神经内分泌系统(下丘脑-垂体肾上腺轴)调节、色氨酸(Trp)及其代谢产物犬尿氨酸(Kyn)和5-羟色胺的变化,多种神经活性物质(短链脂肪酸和神经递质)的生成和代谢。这些有益微生物还影响神经发生和中枢神经系统(CNS)中神经递质受体的表达[35]。它也被认为是神经炎症的关键调节剂,在感染、炎症和自身免疫过程中调节粘膜先天性和适应性免疫应答[33]。例如有研究证明健康的胃肠微生物群在小胶质细胞的成熟和免疫功能中起重要作用[34]。此外,正常胃肠道微生物群在维持和调节肠道屏障以及肠道相关淋巴组织(GALT)的多种功能方面具有关键作用[36],这些有益微生物的一些关键作用是由于它们降低促炎性细胞因子和核因子NF-κB的浓度,增加抗炎性细胞因子的浓度以及改变色氨酸和犬尿氨酸水平的能力[37~42]。越来越多的研究表明,微生物菌群和益生菌对焦虑症状、情绪低落和抑郁症状、慢性疲劳综合征(CFS)和认知功能有治疗效果[43~50]。在多种精神疾病,如慢性疲劳综合征、重症抑郁症[49~58]、孤独症谱系障碍[59~61]、精神分裂症和双相情感障碍和酒精中毒中肠道微生物组成发生变化。在重症抑郁症中,普氏菌属和克雷伯菌属的比例变化与汉密尔顿抑郁量表一致[62]。此外,将重度抑郁症患者粪便微生物移植到无菌小鼠中,可导致小鼠出现抑郁样行为[63]。小肠细菌过度生长(SIBO)是在孤独症谱系障碍和酒精中毒中观察到的肠道菌群的另一种异常形式[64],治疗期间患者体质量增加继发于肠道微生物群的改变[65]。此外,抗生素给药减弱了奥氮平诱导的大鼠代谢功能障碍。因此,提出了一种新的治疗靶点,即益生菌或益生元给药可以防止或逆转抗精神病药物治疗后的体质量增加[66]。
微生物群通过各种作用在维持心理-神经-免疫平衡方面发挥重要作用,如免疫和神经内分泌系统(下丘脑-垂体肾上腺轴)调节、色氨酸(Trp)及其代谢产物犬尿氨酸(Kyn)和5-羟色胺的变化,多种神经活性物质(短链脂肪酸和神经递质)的生成和代谢。这些有益微生物还影响神经发生和中枢神经系统(CNS)中神经递质受体的表达[30,31],是神经炎症的关键调节剂,在感染、炎症和自身免疫过程中调节粘膜先天性和适应性免疫应答。有研究表明微生物菌群和益生菌对焦虑症状、情绪低落和抑郁症状、慢性疲劳综合征(CFS)和认知功能有治疗效[53,54]。有研究发现益生菌或益生元给药可以防止或逆转抗精神病药物治疗后的体质量增加[55,56,67~70]。
3 小结
随着胃肠微生物-肠道通透增加-脑轴交互作用的研究深入,针对各种食物、微生物、病毒和寄生虫抗原的免疫球蛋白的检测以及肠道微生物群组成的评估在精神病诊断和治疗中将具有重要意义。同样,肠道微生物群的改变还可以预防与抗精神病药物治疗有关的代谢不良反应。补充益生菌或其他对肠道屏障有积极影响的干预手段也可作为暴露于应激及其产生的有害后果的预防措施。这些,将是我们未来研究的众多方向。
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