微生物代谢产物在肠-脑轴中作用机制研究进展

2022年6月23日18:08:52微生物代谢产物在肠-脑轴中作用机制研究进展已关闭评论
摘要

石媛嫄 侯琳 张丽 曹奕[摘要] 肠道微生物群具有丰富的生物转化能力,从而使宿主能接触到一系列具有生物活性的代谢产物。这些代谢产物参与了胃肠道和中枢神经系统之间的信号传递,并具有调节中枢神经系统

    石媛嫄 侯琳 张丽 曹奕

    [摘要] 肠道微生物群具有丰富的生物转化能力,从而使宿主能接触到一系列具有生物活性的代谢产物。这些代谢产物参与了胃肠道和中枢神经系统之间的信号传递,并具有调节中枢神经系统生理和病理过程的潜力。这种双向交流可以通过各种直接和间接机制发生,包括与宿主脑中的受体结合、刺激肠道中的迷走神经、改变中枢神经传递以及调节神经炎症。本文综述了短链脂肪酸、胆汁酸、神经递质等微生物代谢产物在肠-脑轴中的作用机制,从调控肠道微生物的角度为相关神经系统疾病的治疗提供新思路。

    [关键词] 微生物群;代谢;肠-脑轴;脂肪酸类;胆汁酸类和盐类;神经递质;综述

    [中图分类号] R329.35

    [文献标志码] A

    [文章编号] 2096-5532(2021)03-0470-05

    doi:10.11712/jms.2096-5532.2021.57.066

    [开放科学(资源服务)标识码(OSID)]

    [网络出版] https://kns.cnki.net/kcms/detail/37.1517.R.20210201.1055.005.html;2021-02-01 16:02:16

    RESEARCH ADVANCES IN THE MECHANISM OF ACTION OF MICROBIAL METABOLITES IN THE GUT-BRAIN AXIS

    SHI Yuanyuan, HOU Lin, ZHANG Li, CAO Yi

    (Organization and Personnel Office, Medical Department of Qingdao University, Qingdao 266071, China)

    [ABSTRACT]Intestinal microflora has rich biotransformation abilities, which enables the host to come into contact with a series of bioactive metabolites. Such metabolites participate in the signal transduction between the gastrointestinal tract and the central nervous system and have the potential to regulate the physiological and pathological processes of the central nervous system. Such two-way communication can take place through a variety of direct and indirect mechanisms, which include binding to receptors in the host brain, stimulating the vagus nerve in the intestinal tract, altering central neurotransmission, and regulating neuroinflammation. This article reviews the mechanism of action of microbial metabolites, including short-chain fatty acids, bile acids, and neurotransmitters, in the gut-brain axis, in order to provide new ideas for the treatment of nervous system diseases from the perspective of the regulation of intestinal microflora.

    [KEY WORDS]microbiota; metabolism; gut-brain axis; fatty acids; bile acids and salts; neurotransmitters; review

    人的腸道微生物群包含500~1 000种细菌,共有约 200万个基因,超过了人类基因总量的100倍[1],其中许多基因编码执行代谢功能并产生微生物专有代谢物的蛋白质。微生物群的这种作用扩大了宿主生物转化的利用范围,以及可以处理的化合物的多样性。这种广泛的代谢潜力使得微生物群与进入肠道的一系列底物相结合,产生了大量的代谢产物,其中许多代谢产物对宿主来说是重要的分子前体。肠-脑轴(GBA)是胃肠道和中枢神经系统(CNS)之间的双向信号网络。该轴有几种不同的信号途径,包括自主神经系统(ANS)、下丘脑垂体肾上腺轴(HPA轴)和免疫系统。微生物相关的代谢产物通过这些不同途径发生作用,调节CNS的功能和行为。先前研究已经观察到,在自闭症谱系障碍(ASD)、焦虑和抑郁等一系列CNS疾病中,肠道微生物群落结构发生显著变化[2]。虽然微生物变化和神经疾病之间的因果关系仍未完全阐明,但啮齿类动物的研究表明,微生物群的变化可以改变精神心理和行为[3]。本文主要综述短链脂肪酸(SCFA)、胆汁酸(BA)、神经递质等微生物来源的生物活性分子在肠道到大脑信号传导中的作用及机制。

    1 SCFA

    SCFA是盲肠和结肠中微生物对膳食中碳水化合物厌氧发酵产生的小分子有机酸,其可以通过各种机制影响CNS。乙酸、丙酸和丁酸是主要的SCFA,而异丁酸、戊酸和异戊酸的生成量较小。研究发现,高生活质量人群的粪便具有高丰度粪杆菌属(Faecalibacterium)和粪球菌属(Coprococcus),这两个菌属是革兰阳性厌氧细菌,可以发酵膳食纤维产生SCFA[4]。相反,与非抑郁对照相比,重度抑郁障碍(MDD)病人的粪便、尿液和血浆中的SCFA含量较低[5]。研究证实,益生元诱导的SCFA增加可以改善小鼠的抑郁和焦虑行为,并且能减轻痴呆模型小鼠的认知损害[6-7]。SCFA也被证明在亨廷顿症、阿尔茨海默病、帕金森病和卒中等神经退行性疾病和脑血管疾病中起着重要作用[8-9]。

    SCFA可以通过与细胞表达的受体结合以及改变宿主基因表达来实现与GBA的相互作用[10-12]。SCFA能够结合并激活游离脂肪酸受体2(GPR43或FFAR2)、游离脂肪酸受体3(GPR41或FFAR3)和羟基羧酸受体2(GPR109A或HCAR2)[13]。这些受体在人体内的多种细胞中普遍表达,包括肠内分泌细胞、脂肪细胞、免疫细胞和神经元等。宿主对SCFA和GPR43的依赖效应可延伸到CNS,小胶质细胞是CNS的常驻巨噬细胞,其成熟和功能依赖于肠道菌群,维持小胶质细胞的稳态需要SCFA和GPR43[14]。此外,SCFA可以通过调节组蛋白乙酰化和甲基化来对基因表达施加表观遗传控制[15-16]。

    SCFA可以通过刺激肠内分泌细胞释放肠道激素和肽类来间接调节GBA。SCFA还可通过刺激胰高血糖素样肽-1(GLP-1)、肽YY(PYY)和瘦素等厌食激素的分泌来调节摄食行为[11,17-19]。这些食欲激素除了可以作用于大脑中的受体,还可以作用于迷走神经。GOSWAMI等[20]研究证明了迷走神经在肠道微生物控制食欲中的作用,其中SCFA的厌食效应在迷走神经切断的小鼠中明显降低。SCFA也可以通过中枢机制参与食欲调节。肠源性乙酸盐可以穿过血-脑脊液屏障,通过改变神经肽的表达对下丘脑控制食欲有直接影响[21]。

    SCFA影响GBA的另一种机制是通过维持肠道和血-脑脊液屏障功能[22-23]。丁酸可以增强紧密连接蛋白的表达,稳定肠黏膜屏障功能,以限制细菌和其他微生物从肠道转移到血液中[24-26]。当肠道屏障通透性增加时,宿主与细菌脂多糖(LPS)的接触增加,从而导致慢性炎症反应。慢性炎症在包括抑郁症和焦虑症在内的一系列神经精神障碍中起着重要作用,促炎细胞因子能够影响神经传递并改变行为。与它们在肠道中的作用一致,SCFA可以通过增加紧密连接表达来促进血-脑脊液屏障的完整性[8]。尽管已经发现SCFA通过各种直接和间接的途径影响着CNS,但支持SCFA具有改善神经疾病潜力的结果仍不够一致,故而还需更深入地了解其潜在机制。

    2 BA

    BA是膽固醇衍生的类固醇,可通过直接和间接途径影响CNS。两种主要的BA,胆酸(CA)和鹅去氧胆酸(CDCA)在肝脏中合成,并与甘氨酸或牛磺酸结合,然后分泌到胆汁中。进食刺激后,BA被释放到肠道中,其中有95%被重新吸收。一小部分BA被运输到结肠,在肠道菌群的7α-脱羟基作用下转化为次级BA,即脱氧胆酸(DCA)和熊去氧胆酸(UDCA)。

    与SCFA一样,BA也可以作为信号分子激活法尼醇X受体(FXR)、G蛋白偶联胆汁酸受体5(TGR5)、孕烷X受体(PXR)及维生素D受体(VDR)等。通过激活这些受体,BA控制葡萄糖稳态、脂质代谢和能量消耗等,对宿主新陈代谢有显著影响。微生物群功能的变化可以改变BA池的组成,并改变其整体信号传导能力[27]。已经在人类和啮齿类动物的大脑中检测到BA,并且它们的受体和转运蛋白在CNS的细胞中表达[28-29]。这表明BA可能在CNS中起信号传导作用。虽然目前对这种信号传导潜能的了解有限,但在小鼠中发现FXR缺失扰乱了多种神经递质系统,并改变了情感、认知和运动功能等[30]。

    BA可以通过破坏紧密连接直接调节肠道和血-脑脊液屏障的通透性,从而直接影响脑功能[31]。DCA和CDCA可以增加血-脑脊液屏障的通透性,而UDCA可以通过减少脑内皮细胞的凋亡发挥保护作用[32]。BA也可以影响免疫反应,因为UDCA已被发现可以通过结合小胶质细胞上表达的TGR5来减轻小鼠的神经炎症[33]。另外,BA也可以通过激活肠道中的FXR来向CNS发出信号,以促进中间分子如GLP-1和成纤维细胞生长因子19(FGF19)的释放。GLP-1可以进入血液并激活脑中的受体,也可以通过激活迷走神经传入纤维向CNS发出信号[34-35]。FGF19可以通过与下丘脑弓状核(ARC)表达的受体结合来抑制刺鼠基因相关蛋白(AGRP)、神经肽Y(NPY)神经元,从而引发厌食效应[36]。

    3 神经递质

    中枢神经递质也存在于胃肠道中,在调节肠运动、肠细胞分泌以及细胞信号传导中起着重要作用[37-38]。肠道微生物群可以合成多种神经递质:乳酸杆菌和双歧杆菌产生γ-氨基丁酸(GABA),大肠杆菌产生5-羟色胺(5-HT)和多巴胺(DA),乳酸杆菌产生乙酰胆碱,以及更多的微生物群合成和释放具有神经活性的其他分子[39-41]。微生物群影响神经递质水平已在啮齿动物模型中被证明,微生物缺乏可显著降低DA和GABA等神经递质水平[42-43]。目前尚不清楚循环神经递质是直接来自微生物群还是来自宿主,因为微生物代谢物(例如次级BA、SCFA)可以刺激肠嗜铬细胞产生神经递质并进入血液循环[42]。

    调节神经递质前体是微生物群影响宿主神经传递的另一种途径。酪氨酸是左旋多巴胺(L-DOPA)前体,L-DOPA可以脱羧形成DA。反过来,DA可以代谢成其他儿茶酚胺,如去甲肾上腺素和肾上腺素。酪氨酸可以从饮食中获得,也可以从苯丙氨酸中获得,这两种氨基酸都可以被肠道中的微生物分解成一系列分子,从而改变宿主对它们的利用度。L-DOPA转化为DA也受微生物群的控制,肠球菌和乳酸杆菌通过表达酪氨酸脱羧酶参与L-DOPA的脱羧[44-45]。这对于帕金森病的治疗具有重要意义,因为抑制外周L-DOPA代谢可以最大化提高大脑中的L-DOPA浓度。

    微生物代谢产物还可以通过激活迷走神经来影响中枢神经传递。BRAVO等[46]研究证明,迷走神经参与了GBA交流,应用鼠李糖乳酸杆菌可改变中枢GABA受体的表达,同时减轻焦虑和抑郁症样症状,而在迷走神经切除小鼠中则没有观察到这种变化。肠道中产生的神经递质还能通过调节免疫系统来影响大脑功能,已经发现5-HT能激活免疫细胞,以及GABA可减轻肠道炎症[47-48]。这些研究表明,肠道微生物群直接或间接产生的神经递质通过结合CNS中的特定受体或外周细胞上的受体而影响宿主心理和行为。可能存在更多的类似神经递质的活性分子,有待于进一步发现和研究。肠道微生物群与宿主之间这种神经递质代谢交流本质上是双向的:除了合成能够改变宿主生理的神经递质外,肠道微生物还对宿主产生的神经递质做出反应,从而影响微生物群的生长和丰富度[49]。

    4 其他腸道微生物群代谢产物

    来自肠道微生物群的其他几种代谢产物也可以参与GBA通讯。胆碱是一种必需营养素,主要从饮食中的卵磷脂和肉碱中获取,但是在人体内,肝脏中也可以合成少量胆碱[50]。胆碱具有参与生物膜构成、表观遗传和细胞信号传导的功能。它参与乙酰胆碱的合成,并且是细胞膜成分磷脂酰胆碱和鞘磷脂的前体。尽管胆碱本身不是细菌产物,但肠道微生物可以将胆碱分解成一系列代谢产物,包括甜菜碱和三甲胺等。由于肠道微生物对胆碱的代谢会耗尽宿主体内可利用的胆碱,因此,利用胆碱的细菌过多将会导致胆碱的缺乏,这将增加代谢疾病的发生,增加心血管疾病的风险,改变宿主的神经精神行为。此外,胆碱是甲基的重要来源,它可以有效调节DNA甲基化。ROMANO等[51]在小鼠中发现,胆碱的细菌消耗降低了甲基供应,并减少了包括大脑在内的多个组织中的DNA甲基化。

    乳酸是一种有机酸,产生于宿主代谢过程以及乳酸杆菌、双歧杆菌和变形杆菌对膳食纤维的发酵[52]。尽管乳酸在肠道中水平很低,但它可以被吸收到血液中并穿过血-脑脊液屏障。乳酸在大脑信号传导中起着确定的作用,它可以作为神经元的能量底物,有助于突触可塑性,并在记忆形成过程中起重要作用[53-54]。乳酸调节情绪行为的潜在机制是通过直接激活海马、新皮质和小脑中表达的G-蛋白偶联受体81(GPR81),通过GPR81激活,乳酸可调节脂质和葡萄糖的代谢,发挥抗炎作用,并抑制GABA能神经传递[55-57]。尽管微生物对中枢乳酸浓度的影响已在无菌大鼠中得到证实,但其对乳酸和情绪中枢影响水平仍然难以评估[58]。

    微生物群可以在肠道内合成维生素,人类的维生素代谢在很大程度上依赖于微生物的供应。在CNS功能中具有重要作用的B族维生素,如核黄素(B2)、叶酸(B9)和钴胺(B12)等,作为中枢代谢反应的辅酶,其缺乏可以表现为各种神经系统症状,包括异常运动功能、睡眠记忆障碍以及精神情绪症状等[59]。据估计,微生物群可以为人类提供31%参考摄入量的B12,而B12缺乏与一系列精神和神经疾病有关,包括精神发育迟缓、记忆障碍、注意力缺陷和痴呆等[60]。

    5 小结

    在微生物群和哺乳动物宿主之间发生的双向通信是这两个互补系统协同进化的结果,这种信息交流可以通过各种机制来介导。微生物代谢产物可以通过直接和(或)间接方式调节CNS,最终影响宿主行为和认知功能。随着微生物代谢产物与CNS疾病之间的多因素相互作用的深入探究,人们对GBA病理机制的认识将进一步增加。在未来,具有参与关键作用潜力的微生物代谢产物可能被用于治疗和预防CNS疾病。

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    (本文編辑 马伟平)