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Acta Academiae Medicinae Sinicae

Abbreviation (ISO4): Acta Academiae Medicinae Sinicae      Editor in chief: Xuetao CAO

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Acta Academiae Medicinae Sinicae >

2025 , Vol. 47 >Issue 1: 95 - 101

DOI: https://doi.org/10.3881/j.issn.1000-503X.16046

Review Articles

Research Progress in Effects of Vermiform Appendix on the Occurrence and Development of Diseases Related to Gut-Brain Axis

  • MO Shuting 1 ,
  • TIAN Zhe 1 ,
  • LEI Xin 1 ,
  • HAN Chao 2 ,
  • CHEN Yuhua , 1
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  • 1Graduate School,Bengbu Medical University,Bengbu,Anhui 233030,China
  • 2Department of Neurology,The First Affiliated Hospital of University of Science and Technology of China,Hefei 230001,China
CHEN Yuhua Tel:0551-62284085,E-mail:

Received date: 2024-02-22

  Online published: 2025-03-12

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Abstract

The gut-brain axis is a bidirectional communication pathway connecting the central nervous system and gastrointestinal tract,playing a key role in the occurrence and development of diseases related to this axis.The vermiform appendix,as a part of the gut that is connected to the cecum,has a unique anatomical location,a rich microbiome,and abundant immune cells.Appendicitis and appendectomy have been found to be associated with the development of diseases related to the gut-brain axis.This review first introduces the anatomy and functions of the vermiform appendix and then expounds the associations of appendicitis and appendectomy with diseases related to the gut-brain axis.Furthermore,this review summarizes and prospects the mechanisms of the vermiform appendix in affecting the occurrence and development of diseases related to the gut-brain axis.

Key words： vermiform appendix; microbiota-gut-brain axis; inflammatory bowel disease; Parkinson’s disease; multiple sclerosis; Alzheimer’s disease

Cite this article

MO Shuting , TIAN Zhe , LEI Xin , HAN Chao , CHEN Yuhua . Research Progress in Effects of Vermiform Appendix on the Occurrence and Development of Diseases Related to Gut-Brain Axis[J]. Acta Academiae Medicinae Sinicae, 2025 , 47(1) : 95 -101 . DOI: 10.3881/j.issn.1000-503X.16046

肠-脑轴是连接中枢神经系统和胃肠道的双向通信通路。肠-脑轴与大脑的相互作用和串扰主要通过3种途径:免疫途径、神经传导途径和内分泌/全身途径[1]。在免疫途径中,肠道炎症激活局部免疫并释放炎性因子,这些因子进入血液循环,透过血脑屏障后侵袭中枢神经系统;在神经传导途径中,外周和中枢系统可能通过肠神经和迷走神经[2]或交感神经[3]产生双向交流;在内分泌/全身途径中,激活的肠内分泌细胞产生神经肽,作用于大脑产生效应[4]。肠-脑轴一直被视为是应激、焦虑或抑郁等发生胃肠道相关疾病的中介,然而,最近研究表明,肠-脑轴的作用范围还包括以肠道受累为主的炎症性肠病(inflammatory bowel disease,IBD)[5]以及以脑受累为主的神经退行性疾病,如帕金森病(Parkinson’s disease,PD)、阿尔茨海默病(Alzheimer’s disease,AD)和多发性硬化(multiple sclerosis,MS)等炎症性脑病[6-7]。这些疾病通过肠-脑轴的双向交流机制,使大脑和肠道同时受累,统称为肠-脑轴相关性疾病。
随着对肠道微生物研究不断深入,发现肠道微生物及其代谢物不仅具有保护肠黏膜、调节宿主免疫及代谢[8]、维持肠上皮屏障完整性、与病原体竞争阻止其定植、促进免疫系统发育和成熟[9-10]等功能,而且能够通过肠-脑轴使大脑和肠道交互作用,进而影响大脑和肠道健康,由此提出微生物-肠-脑轴的概念[11]。研究证实,肠道微生物紊乱与肠-脑轴相关性疾病的发生密切相关[12],纠正肠道微生物紊乱有助于改善或阻止肠-脑轴相关性疾病的进展[13⇓-15]。以肠道为靶点研究肠-脑轴相关性疾病,具有更易获取预测疾病的潜在标志物、尽早采取干预措施的优势。
阑尾位于盲肠的起始部,与肠道其他部位相比,阑尾富含免疫细胞,同时是肠道微生物的贮藏地[16]。其特殊的解剖位置和结构,使阑尾易于发生炎症。研究表明,阑尾炎症或阑尾切除与肠-脑轴相关性疾病的发生发展相关[17]。本文介绍了阑尾的解剖及功能,以及阑尾炎症及阑尾切除与肠-脑轴相关性疾病相关性的研究进展,以期为肠-脑轴相关性疾病的“脑病肠治”提供思路。

1 阑尾的解剖与功能

阑尾是一个细长的盲管状器官,与盲肠相连,近端开口于盲肠后内侧壁回盲瓣下方2~3 cm处,远端为盲端,平均长9 cm,这种独特的解剖结构使其易于发生炎症。
阑尾是类似胸腺的免疫器官,分布着大量的淋巴组织。淋巴组织是免疫细胞的主要来源和储存场所。出生后阑尾中的淋巴组织开始形成,12~20岁达到高峰,随后开始逐渐减少,55~65岁后逐渐消失[18]。阑尾比结肠富含自然杀伤T细胞、活化T细胞和产生免疫球蛋白的B细胞[19]。此外,阑尾中分泌IgA的细胞可迁移至大肠[20],在肠道免疫中发挥重要作用[18]。
阑尾参与维持肠道菌群的平衡[21],是肠道的菌群库。阑尾切除术后的肠道细菌种类较非手术对照组减少[22]。阑尾中的微生物种类也比结肠的更丰富[23],这可能是由于阑尾独特的解剖结构使其较少受结盲肠内粪便移动的影响,因此有学者认为阑尾可能是结肠正常菌群的“安全屋”[24],具有调节和重新补充结肠微生物的功能[25]。
阑尾的生物被膜在维持肠道菌群结构和功能稳定性以及宿主的免疫耐受性方面发挥着积极作用[26]。阑尾中的B淋巴细胞在微生物群刺激下,成熟后产生IgA,分泌型IgA促进肠道细菌凝集,黏蛋白捕获这些凝集的细菌,在黏液层形成生物被膜[27]。与结肠相比,阑尾中的生物被膜似乎更丰富[24]。阑尾中的微生物群可能通过生物被膜与结肠相互作用,进而影响宿主健康。例如,在机体服用抗生素、发生感染或慢性腹泻性疾病时,一方面生物被膜能促进抗生素或病原体从肠道清除;另一方面能在抗生素或病原体与肠道上皮细胞之间形成屏障,以避免对免疫系统的过度刺激[28]。

2 阑尾影响肠-脑轴相关性疾病的发生发展

2.1 IBD

IBD包括溃疡性结肠炎(ulcerative colitis,UC)和克罗恩病(Crohn’s disease,CD),发病率在全球呈上升趋势[29]。IBD是一种病因不明的慢性炎症性肠道疾病。目前认为IBD是宿主免疫系统、肠道微生物群异常、易感基因和环境之间的复杂相互作用的结果[30]。研究表明,IBD通过肠-脑轴参与了多种神经系统疾病的发生。例如,IBD常伴发焦虑、抑郁等精神疾病[31];IBD与MS有共同的生物学基础[32],IBD增加MS的患病率[33];IBD明显增加PD[34]及痴呆症[35]等神经退行性疾病的患病率[36]。阑尾与IBD的发生似乎也有一定的联系,大多数研究支持阑尾切除术对IBD的保护作用[37]。有关阑尾切除术和UC的研究表明,在UC发病前或病程早期行阑尾切除术,可降低患者在病程后期行结肠切除术以及UC相关住院治疗的风险[38],对难治性UC患者行阑尾切除术可能有益于稳定病情[39];而在确诊UC后,对阑尾炎患者行阑尾切除术似乎会加重病程并增加行结肠切除术的风险[40]。此外,Reijntjes等[41]研究显示与健康对照组相比,无论疾病处于何种活动度,UC患者的阑尾直径更大,黏膜下层更厚。有关阑尾切除术和CD的研究表明,阑尾切除术会增加患者术后5年内CD患病风险[42]。

2.2 PD

PD是一种病因不明的常见神经退行性疾病。研究表明,PD的发生发展与肠道、肠道细菌及肠-脑轴密切相关。PD运动症状出现的病理标志是路易小体形成,它是由折叠错误的α-突触核蛋白(α-synuclein,α-syn)异常沉积在黑质致密部(substantia nigra pars compacta,SNpc)形成的。路易小体导致SNpc多巴胺能神经元进行性丢失。近年研究显示,这种病理性α-syn不仅在大脑中异常聚集,而且在PD运动症状或相应的运动前期非运动症状(便秘)出现前数十年,就已存在于肠黏膜中[43]。α-syn是一种由140个氨基酸组成的小分子蛋白质[44]。在生理条件下,α-syn是一种可溶性蛋白质,在神经元中高表达;在病理条件下,它会发生错误折叠、磷酸化或乙酰化形成有毒的寡聚中间体和不溶性蛋白原纤维[45-46],聚集后形成具有神经毒性的包涵体[47]。引起α-syn聚集的具体机制不清,但这些毒性α-syn具有传播性,以类似朊蛋白的方式从一个细胞传递到另一个细胞[48]。病理性α-syn的可传播性提示其可能启动PD的发生。
病理性α-syn可能起源于肠道,并通过肠-脑轴在大脑和肠道之间传播。2003年,Braak等[49]对已故PD患者大脑的解剖证实,折叠错误的α-syn通过迷走神经从胃肠道扩散至中脑SNpc,导致多巴胺能神经元退变,Klinkenberg等[50]研究也验证了上述结果。之后,Horsager等[51]和Braak等[52]在一些PD患者的迷走神经与脑干连接的“切入点”(如脑干底部的迷走神经背侧运动核)并未发现病理性α-syn,这表明部分PD患者的病理性α-syn并非起源于肠道,也可能来源于大脑。直到2020年,Horsager等[53]借助特殊扫描技术,在PD患者体内观察到不同起源和传播方向折叠错误的α-syn,由此提出将PD分为脑优先型(brain-first)和身体优先型(body-first),其中身体优先型PD的病理性α-syn起源于肠道自主神经。
阑尾炎时局部产生的病理性α-syn可能是肠源性PD的病理基础。在正常阑尾黏膜组织中,α-syn主要富集在巨噬细胞的溶酶体内[54],裂解后的α-syn更易聚集和传播[17]。研究表明,阑尾切除术能改善PD症状,并推迟发病年龄[55]。一项纳入147万人的流行病学调查研究显示,与未切除阑尾的人群相比,阑尾切除术后人群的PD发病率降低19.7%,发病年龄推迟3.6年[17]。然而,Rubin等[56]研究数据显示阑尾切除术会增加PD的发病风险,他们认为一方面手术过程会促使α-syn从阑尾释放,通过迷走神经进入大脑,导致脑组织发生病理改变;另一方面阑尾炎症直接引起神经炎症。此外,Chen等[57]开展的一项研究显示,近50%的PD患者影像学检查阑尾组织出现慢性炎症样改变,HE染色显示阑尾组织黏膜和黏膜下层出现断裂脱落和炎症细胞浸润,免疫荧光染色显示阑尾内聚集大量类似路易小体的结构,广泛沉积于黏膜及黏膜下层。这些患者具有特征性的临床表现,包括便秘等运动前期症状,以及焦虑、抑郁、思睡和中轴型僵硬等症状。此外,除了病理性α-syn,肠道微生物可能也参与了肠源性PD的发生。阑尾处于肠道微生物、外周免疫系统和神经系统的交叉点。阑尾中微生物群可以改变肠道的炎症反应和免疫力,微生物代谢产物可直接影响免疫细胞[58-59]。当阑尾微生物群异常时,阑尾中高表达的α-syn可能发生生物转化,产生致病性和抗原性,这些α-syn被定植的免疫细胞识别、处理,并递呈给免疫细胞,触发炎症反应[60]。

2.3 AD

AD是最常见的神经系统退行性病变,其组织病理学表现为大脑中大量沉积两种蛋白质病变:β-淀粉样蛋白斑块和神经原纤维缠结。AD发病与肠道及肠道菌群相关。早期研究显示,AD患者的肠黏膜下层存在对β-淀粉样蛋白免疫反应的斑块[61],但目前结果仍存在争议[62]。越来越多的证据表明,肠道微生物菌群失调在AD的发病机制中起着重要作用[63],且菌群组成可在疾病进展中发生进行性改变[64]。阑尾作为肠道菌群的储存库,可能在AD发生发展过程中扮演重要角色。一项流行病学研究显示,阑尾炎患者和行阑尾切除术患者的AD发病率高于对照组,且AD发病年龄较早[65],这可能与肠道微生物失调相关。

2.4 MS

MS是一种中枢神经系统慢性炎性脱髓鞘病变,影响神经元功能,导致不可逆的神经功能障碍[66]。免疫系统的促炎性激活在MS的发病机制中起着重要作用,这种免疫激活可能源于肠道菌群紊乱[67]。因此,肠道菌群改变可能是MS的一种发病机制[68]。MS患者的肠道微生物与健康人群相比有明显差异[69]。此外,细菌丰度与疾病活动性呈正相关,在疾病治疗前后,肠道微生物组成也随之改变[70]。也有研究发现MS与阑尾切除术呈正相关[71],这可能与阑尾的免疫功能和作为肠道微生物储存库相关,但目前仍缺乏足够证据,未来可进一步探索。

3 总结与展望

阑尾是连接肠道微生物群、免疫功能和神经系统以维持机体健康的重要器官。阑尾炎症或功能异常与肠-脑轴相关性疾病的发生发展相关[72],但其具体机制尚不明确。阑尾因富含α-syn而备受PD研究者的关注。微生物异常引发阑尾局部免疫炎症,导致α-syn异常转化并沿肠-脑轴传播,可能在PD的发病机制中发挥重要作用。其他与PD具有相似临床表现的多系统萎缩、路易体痴呆等疾病是否与阑尾相关值得关注。AD、MS及IBD与阑尾的联系目前还主要基于一些临床发现,其中有关AD、MS与阑尾关系的报道较少,机制不清,可能与肠道菌群的改变相关,或通过IBD间接联系。脑卒中、焦虑和抑郁等其他神经系统疾病的发病也与肠道微生物群相关,是否与阑尾有关也有待进一步探讨。此外,阑尾保守治疗能否替代阑尾切除术,从而降低肠-脑轴相关性疾病的发病或改善其预后,也值得深入探究。
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