肠道菌群基于色氨酸代谢通路调控抑郁障碍的机制

Mechanisms by which the gut microbiota regulates depressive disorder via the tryptophan metabolic pathway

摘要

肠道菌群与抑郁障碍的关联是近年研究热点。在微生物群-肠-脑轴中，肠道菌群通过色氨酸代谢途径影响抑郁障碍的发生和发展。色氨酸作为人体必需氨基酸，其代谢受肠道菌群双重调控：菌群可通过刺激炎症反应及产生代谢产物调节色氨酸代谢平衡。在抑郁障碍中，色氨酸代谢的犬尿氨酸途径过度激活，导致促炎及神经毒性代谢物蓄积，进而加剧脑内神经炎症。干预研究显示：益生菌及中药的抗抑郁样作用与其重塑肠道菌群、逆转色氨酸代谢失衡及改善神经炎症相关；靶向抑制犬尿氨酸3-单加氧酶可通过调节小胶质细胞功能减轻神经炎症，进而改善抑郁样行为。综上，代谢物-炎症轴是色氨酸代谢与微生物群-肠-脑轴交互调控的核心节点，为肠道菌群基于色氨酸代谢通路调节抑郁障碍的新型治疗策略提供了理论依据。

Abstract

The relationship between gut microbiota and depressive disorder has become a research focus in recent years. Within the microbiota-gut-brain axis, the gut microbiota influences the onset and progression of depressive disorder primarily through the tryptophan metabolic pathway. Tryptophan, an essential amino acid in humans, is subject to dual regulation by intestinal microorganisms, which modulate its metabolic balance via inflammatory stimulation and microbial metabolite production. In depression, excessive activation of the kynurenine branch of tryptophan metabolism leads to the accumulation of proinflammatory and neurotoxic metabolites, thereby exacerbating neuroinflammation in the brain. Intervention studies indicate that the antidepressant-like effects of probiotics and traditional Chinese medicine are associated with remodeling of the gut microbiota, restoration of tryptophan metabolic balance, and alleviation of neuroinflammation. Furthermore, targeted inhibition of kynurenine 3-monooxygenase can mitigate neuroinflammation by regulating microglial activity, thus improving depressive-like behaviors. In summary, the metabolite-inflammation axis represents a central node in the interaction regulation between tryptophan metabolism and the microbiota-gut-brain axis. This provides a theoretical foundation for developing novel therapeutic strategies targeting depression through modulation of gut microbiota-mediated tryptophan metabolism.

关键词

抑郁障碍 / 色氨酸代谢 / 肠道菌群 / 微生物群-肠-脑轴 / 炎症

Key words

depressive disorder / tryptophan metabolism / gut microbiota / microbiota-gut-brain axis / inflammation

抑郁障碍是全球范围内常见精神障碍性疾病之一，表现为抑郁情绪、兴趣减退、精力下降、注意力难以集中、无价值感、有反复自杀观念及自杀意图等症状^[1]。世界卫生组织估计全球约有2.8亿人患抑郁障碍^[2]。肠道微生物是指栖息在人体肠道内的微生物群落，包括细菌、真菌和原生动物等。其中细菌占据主导地位，主要包括厚壁菌门、拟杆菌门及放线菌门等。这些微生物与宿主之间形成了复杂的共生关系，对宿主的健康和疾病具有重要影响^[3]。

抑郁障碍患者的肠道菌群组成与健康人群存在显著差异，其体内厚壁菌门的比例较低，拟杆菌门的比例较高，而乳酸菌、双歧杆菌及普拉梭菌等特定菌群的丰度显著较少^[4]。研究发现：肠道菌群通过微生物群-肠-脑轴实现与大脑进行双向通信，进而调控神经递质释放、免疫反应和代谢途径^[5-6]；该轴系统由肠道菌群、免疫系统、迷走神经和肠道神经系统组成^[7]，对抑郁障碍的作用机制可能涉及神经(迷走神经和肠道神经系统)、内分泌(皮质醇和下丘脑-垂体-肾上腺轴)和免疫(细胞因子)途径^[8]。应激是抑郁障碍的主要影响因素之一^[7]，其潜在致病机制可能为：1)导致肠道上皮损伤、通透性增强，进而促使革兰氏阴性杆菌携带的脂多糖发生易位，进一步诱导机体产生促炎性细胞因子，引发全身炎症反应并激活免疫系统，最终通过神经递质代谢紊乱阻滞大脑情绪调节相关的信号转导^[8-10]；2)激活的下丘脑-垂体-肾上腺轴可通过双重机制加剧炎症反应，一方面过度激活会破坏下丘脑-垂体轴的负反馈调节，导致皮质醇水平升高；另一方面可改变肠道菌群的组成、破坏肠道屏障完整性，刺激促炎性细胞因子的释放。这2种作用共同激活免疫细胞，进一步放大炎症级联反应^{[8, 11]}。

色氨酸(tryptophan，Trp)是必需氨基酸，无法由人体自身合成，必须通过饮食摄取。Trp在人体和动物体内通过多种代谢途径发挥重要的生理功能，包括蛋白质合成、神经递质生成及免疫调节等^[12]。研究^[13-14]表明肠道菌群可通过调控Trp代谢参与抑郁障碍的发生和发展。Trp代谢作为肠道菌群与大脑之间信息传递的核心代谢途径，在中枢神经和肠道系统的稳态维持中发挥关键作用^[15]，其不仅通过调节5-羟色胺(5-hydroxytryptamine，5-HT)等神经递质水平影响抑郁障碍的病理进程^[16]，还可通过介导兴奋性毒性、氧化应激及神经炎症损伤脑功能，进而参与抑郁障碍的调控^[17]。然而，目前尚无系统性研究阐明肠道菌群通过Trp代谢介导抑郁障碍发生和发展的机制^[18-19]。本文将围绕5-HT与犬尿氨酸(kynurenine，KYN)等核心代谢通路，系统梳理并整合肠道菌群在抑郁障碍发生和发展中的多维度作用机制，为靶向微生物-代谢轴的治疗策略开发提供新思路。

1 <bold>Trp</bold>代谢物途径

Trp代谢主要通过KYN和5-HT途径进行^[20]。其中，95%以上的Trp通过KYN途径分解代谢^[21-22]。

1.1 <bold>KYN</bold>代谢途径

Trp向KYN的初始转化需要诱导色氨酸2,3-双加氧酶(tryptophan 2,3-dioxygenase，TDO)或吲哚胺2,3-双加氧酶(indoleamine 2,3-dioxygenase，IDO)。IDO遍布全身，可由干扰素等促炎性细胞因子及糖皮质激素激活，而TDO表达主要限于肝，在大脑中表达仅限于星形胶质细胞^[21]。

KYN有2条主要代谢途径：1)犬尿喹啉酸(kynurenic acid，KYNA)途径。KYN经犬尿氨酸氨基转移酶转化为KYNA，小胶质细胞和星形胶质细胞中表达的犬尿氨酸氨基转移酶负责大脑中KYNA的生成^{[21, 23-24]}。2)喹啉酸(quinolinic acid，QUIN)途径。KYN经犬尿氨酸3-单加氧酶(kynurenine monooxygenase，KMO)转化为3-羟基犬尿氨酸，3-羟基犬尿氨酸再经犬尿氨酸酶转化为3-羟基邻氨基苯甲酸，3-羟基邻氨基苯甲酸经3-羟基邻氨基苯甲酸3,4-双加氧酶转化为不稳定中间体，最终非酶促转化为N-甲基-D-天冬氨酸(N-methyl-D-aspartate，NMDA)受体激动剂和兴奋毒素QUIN，或酶促转化为吡啶可来酸^[21]。

NMDA是一种谷氨酸受体，对于突触可塑性的调节至关重要，但其过度激活会导致神经毒性。KYNA和QUIN是具有神经活性特性的主要KYN分解代谢物，在大脑中调节NMDA受体的活性，KYNA充当NMDA受体的拮抗剂并具有神经保护作用，而QUIN充当NMDA受体的激动剂并发挥神经毒性作用^[22-24]。

1.2 <bold>5-HT</bold>代谢途径

5-HT主要在远端胃肠道(占90%)合成，其次是中枢神经系统(10%)^[25]，Trp通过色氨酸羟化酶(tryptophan hydroxylase，TPH；有2种变体，TPH1和TPH2)催化为5-HT。肠道内肠嗜铬细胞表达TPH1，而5-HT能神经元在中枢神经系统和肠道神经系统中表达TPH2。TPH1和TPH2将TPH转化为中间体L-5-羟色氨酸(L-5-hydroxytryptophan，5-HTP)，L-氨基酸脱羧酶将5-HTP转化为5-HT。在5-HT代谢过程中，通过单胺氧化酶分解代谢为5-羟基吲哚乙醛，然后通过醛脱氢酶分解代谢为5-羟基吲哚乙酸，并随尿液排出^[6]。

2 肠道菌群与<bold>Trp</bold>代谢的关系

2.1 肠道菌群调节<bold>KYN</bold>代谢途径

Trp代谢途径在5个主要的肠道微生物门(及其相关属)中富集，包括放线菌门、厚壁菌门、拟杆菌门、变形菌门和梭杆菌门，其中，梭菌属、伯克霍尔德菌属等被认为具有更高的Trp代谢潜力^[26]。此外，双歧杆菌属、乳酸杆菌属等也被证实参与Trp代谢^[27]。肠道菌群参与调节肠黏膜内Trp向KYN的代谢途径^[28]。模型小鼠肠道菌群影响外周Trp代谢主要发生在肠道结肠细胞并通过肠道细菌-结肠细胞相互作用调节宿主外周血清Trp-KYN代谢功能^[26]。持续的高脂饮食的小鼠结肠代谢重编程促进变形菌门在结肠腔中的扩增，变形菌门衍生的脂多糖刺激结肠免疫反应，上调IDO1介导的KYN通路，导致Trp耗竭和KYN在循环中积累^[26]。肠道菌群也可通过菌群代谢产物调节Trp代谢，在葡聚糖硫酸钠诱导的结肠炎模型小鼠中发现：共生细菌通过产生短链脂肪酸(尤其是L-赖氨酸)，以芳基烃受体依赖性方式激活代谢酶IDO1来增强Trp对KYN途径的分解代谢^[27]。肠道菌群与Trp代谢有关，肠道菌群可通过刺激炎症反应和其自身代谢产物(脂多糖、短链脂肪酸)对Trp代谢进行调节[主要是通过调控代谢酶(IDO1)发挥作用]，为后续靶向酶治疗提供了方向。

2.2 肠道菌群调节<bold>5-HT</bold>代谢途径

肠道菌群的组成直接影响5-HT的水平。例如，瘤胃球菌和梭状芽孢杆菌与结肠中5-HT水平呈正相关，而乳酸菌可能降低5-HT水平^[29]。肠道菌群中的嗜黏蛋白阿克曼菌可通过促进肠道和大脑中5-HT的生成改善抑郁障碍^[30]。嗜黏蛋白阿克曼菌的丰度增加促使肠嗜铬细胞在肠道中分泌5-HTP，5-HTP通过血液进入大脑，促进大脑中5-HT的合成；5-HT通过 5-HT能受体进一步激活脑源性神经营养因子/酪氨酸激酶受体B通道，从而改善小鼠抑郁样行为^[31]。此外，嗜黏蛋白阿克曼菌及其细胞外囊泡还参与调节小鼠结肠和海马体的5-HT表达，涉及信号转导代谢相关基因[包括SLC6A4(参与血清素运输)、TPH1(与血清素的生物合成有关)、MAO、HTR2B、HTR3、HTR4和HTR7(血清素受体)]^[32]。肠道菌群可能通过代谢途径和基因调控双向调节5-HT系统，为抑郁障碍的干预提供潜在靶点。

3 抑郁障碍与<bold>Trp</bold>代谢的关系

3.1 抑郁障碍与<bold>Trp</bold>代谢异常相关

抑郁障碍患者中的Trp代谢从5-HT合成转向KYN通路，导致5-HT生成减少^[33]。并且脑脊液中KYN途径代谢物的不平衡，大脑神经毒性代谢物(QUIN)增加，神经保护性代谢物(KYNA)下降^[34-35]，抑郁障碍不仅与5-HT合成不足有关^[36]，而且与谷氨酸能途径的紊乱有关^[37-38]。在抑郁障碍中发现海马萎缩，其也可能与神经毒性/神经保护化合物的失衡有关^[39]。

3.2 <bold>Trp</bold>代谢<bold>-</bold>炎症相互作用

抑郁障碍相关Trp代谢可能与炎症密切相关。在慢性约束压力(chronic restraint stress，CRS)诱导抑郁样行为的模型小鼠中，海马、前额叶皮层及纹状体的白细胞介素-1β和肿瘤坏死因子-α表达均显著升高，而抗感染治疗不仅可降低炎症水平，还能调节肠道菌群丰度，提升单胺类神经递质水平^[40]。炎症通过激活Trp代谢关键酶调控Trp代谢流向：促炎性细胞因子及糖皮质激素可诱导TDO激活并刺激IDO活性，导致重度抑郁患者Trp代谢向KYN途径转移，引发代谢失衡^{[22, 32]}。小胶质细胞作为脑内主要免疫细胞，通过释放炎症介质参与神经炎症过程，与抑郁障碍、精神分裂症等精神疾病密切相关^[41]。炎症小体作为识别损伤相关分子模式的胞内传感器家族^[42]，其激活可促进促炎性细胞因子的成熟与分泌^[43]。CRS抑郁模型小鼠海马区KYN水平升高可通过核因子κB通路激活星形胶质细胞炎症小体，进而介导抑郁障碍的神经免疫信号转导^[44]。星形胶质细胞还可通过放大小胶质细胞的炎症反应，形成脑内神经炎症的级联放大效应^[45]。此外，炎症反应引发的氧化应激可直接损伤脑细胞，导致脑功能异常并促进抑郁障碍进展^[17]。综上，在抑郁样模型小鼠中，炎症与Trp-KYN代谢途径存在相互促进作用，共同加剧抑郁样行为的发展。

神经性疼痛神经损伤模型诱导小鼠抑郁样行为的核心机制涉及脑内白细胞介素-1信号通路的激活与KYN代谢通路中KMO的上调，提示KMO抑制可能是抑郁障碍治疗的潜在靶点^[46]。已有研究^[47]发现：KMO抑制剂可显著逆转嗅球切除抑郁模型小鼠的抑郁样行为，同时降低脑内炎症标志物(如白细胞介 素-1β)及KYN水平，并升高Trp、5-HT及其代谢物 5-羟基吲哚乙酸(5-hydroxyindole-3-acetic acid，5-HIAA)含量。此外，KMO抑制还可通过调节小胶质细胞功能减轻神经炎症，进而改善抑郁样行为^[48]。综上所述，KMO抑制的抗抑郁作用可能依赖于“代谢物-炎症”交互网络的调控，但其具体通过小胶质细胞介导Trp代谢重编程的分子机制仍不明确。

4 肠道微生物介导<bold>Trp</bold>代谢对抑郁样行为的影响

随着研究深入，肠道与大脑通过“微生物群-肠-脑轴”形成动态调控网络，肠道菌群作为该轴的核心功能单元，其对宿主神经精神状态的调控机制已成为抑郁障碍领域的研究焦点。肠道菌群可通过调控Trp代谢参与抑郁发生：益生菌干预可通过调节Trp代谢通路缓解抑郁样症状，中药也体现出能够靶向菌群衍生的Trp代谢产物，改善模型动物的抑郁样行为。

4.1 微生物群<bold>-</bold>肠<bold>-</bold>脑轴介导抑郁样行为的炎症<bold>-</bold>代谢

在微生物群-肠-脑轴调控抑郁障碍的病理过程中，肠道菌群结构失衡(如多样性降低、致病菌丰度增加)可破坏肠道屏障完整性，导致脂多糖等促炎物质入血，激活全身免疫炎症反应。炎症因子进一步诱导Trp代谢关键酶(IDO、TDO)表达，促使Trp代谢向KYN途径偏移，同时抑制5-HT合成，最终影响单胺类神经递质的释放与信号转导效能^[49]。此外，大肠黏膜免疫细胞释放的细胞因子可激活下丘脑-垂体-肾上腺轴，导致糖皮质激素(如皮质酮)过度分泌，后者通过中枢糖皮质激素受体放大神经炎症级联反应，形成“炎症-代谢-神经内分泌”恶性循环^[50]。值得注意的是，CRS大鼠抑郁模型的研究^[51]证实：这种病理过程具有显著的轴区域特异性，即海马与结肠作为脑肠信号整合的关键节点，其Trp-KYN代谢紊乱程度及炎症因子富集水平显著高于其他组织，提示靶向“海马-结肠轴”的区域特异性干预可能成为抑郁障碍治疗的新突破口。

4.2 益生菌通过肠道菌群<bold>-Trp</bold>代谢轴调控抑郁样行为

益生菌可通过调控肠道菌群介导的Trp代谢通路参与抑郁样行为的病理生理过程。这类益生菌主要包括乳酸菌属、双歧杆菌属，以及部分链球菌属和肠球菌属菌株^[52-53]；其核心作用机制体现为通过调节Trp代谢网络及肠道菌群结构，缓解慢性、不可预测、轻度应激诱导的小鼠抑郁样行为^[54]。罗伊氏乳杆菌可优先催化KYN向神经保护型代谢KYNA转化，减少神经毒性产物生成^[55]。鼠李糖乳杆菌KY16通过促进肠道5-HTP分泌及菌群结构优化，上调中枢 5-HT水平^[31]。粪球菌属细菌可驱动Trp代谢向5-HT途径偏移，恢复神经递质平衡^[56]。植物乳杆菌可同步升高结肠与脑内5-HT水平，并下调海马区促炎因子表达^[57]。乳球菌通过微生物群-肠-脑轴改善老年小鼠海马神经元损伤及5-HT代谢紊乱，减轻小胶质细胞过度激活所致神经炎症^[58]。地衣芽孢杆菌通过调节肠道菌群增加结肠短链脂肪酸(如丁酸)水平，间接调控脑内单胺类神经递质释放^[47]。混合益生菌(如鼠李糖乳杆菌与屎肠球菌联合制剂)可恢复模型猕猴的肠道内稳态、增强Trp代谢通量，从而降低中枢炎症与缓解抑郁样行为^[59]。总而言之，益生菌可通过调控Trp代谢与中枢炎症反应改善抑郁样行为，其核心机制可能依赖于微生物群-肠-脑轴的多系统信号转导。

4.3 中药通过肠道菌群<bold>-Trp</bold>代谢轴调控抑郁样行为

中药抗抑郁研究为解析肠道菌群-Trp代谢-抑郁障碍的交互机制提供了独特视角。中药可通过多靶点调控菌群衍生的Trp代谢，其具体机制体现为以下3方面：1)调节Trp代谢与肠道屏障功能。疏肝和胃汤可靶向菌群衍生的Trp代谢通路，通过激活结肠自噬相关信号通路增强肠道屏障功能，进而发挥抗抑郁作用^[60]；白头翁皂苷类成分则通过抑制Trp代谢限速酶IDO1活性，阻断慢性不可预测性轻度应激诱导的Trp/KYN代谢失衡，同时下调JAK激酶1(Janus kinase 1，JAK1)-信号转导及转录活化因子1(signal transducer and activator of transcription 1，STAT1)磷酸化通路及干扰素-γ水平，防止KYN途径过度激活，最终改善小鼠抑郁样行为^[61]。2)抑制神经炎症-Trp代谢交互紊乱。柴胡皂苷D通过双重机制调控，一方面抑制炎症小体激活以降低海马促炎因子水平；另一方面通过减少IDO蛋白表达，阻断Trp向KYN途径分流，从而恢复单胺类神经递质平衡，缓解大鼠抑郁样行为^[62]。另有研究^[58]证实：KYN可通过激活核因子κB通路促进海马白细胞介素-1β生成，而中药干预可通过打断“KYN蓄积-神经炎症放大”恶性循环改善抑郁样行为。3)菌群结构重塑与代谢物调控。贯叶金丝桃以肠道菌群依赖方式发挥作用，即通过富集嗜黏蛋白阿克曼菌等有益菌，恢复菌群多样性；同时下调菌群衍生KYN水平，促进5-HTP合成，通过调控KYN-KYNA通路及5-HT能系统缓解抑郁症状^[58]。综上所述，中药可通过“菌群结构调节-Trp代谢重编程-神经炎症抑制”的多维度协同作用，参与肠道菌群介导的抑郁障碍调控，为开发基于肠脑轴的多靶点抗抑郁药物提供了理论依据。

5 结语与展望

肠道菌群通过Trp代谢途径影响抑郁障碍发生和发展的潜在分子机制，本文着重解析了微生物群-肠-脑轴在该过程中的多维调控作用。肠道菌群介导Trp代谢对抑郁障碍的作用可能并非单一因果作用，而是通过微生物群-肠-脑轴实现免疫、内分泌多系统交互调控。然而，尽管“肠道菌群紊乱与抑郁障碍存在关联”已得到广泛认可，二者间的直接因果关系及关键驱动菌仍需进一步验证。

在Trp代谢的关键环节中，小胶质细胞作为中枢神经系统的核心免疫细胞，其通过KYN代谢途径参与神经炎症与神经毒性损伤的机制值得关注。现有研究表明靶向Trp代谢关键酶干预策略已在动物模型中展现出抗抑郁样效应，为抑郁障碍治疗提供方向。此类干预的效应与炎症调控密切相关——炎症既是微生物群-肠-脑轴的重要中介，又可通过激活Trp代谢分流加剧抑郁样行为，提示“微生物-炎症-Trp代谢”的级联网络可能是核心调控节点，其具体分子机制仍需深入解析并转化至临床研究。

当前研究主要依赖动物模型复刻抑郁样行为以探索肠道菌群的作用机制，但人体肠道微生物组的组成与功能受饮食、抗生素使用、生活方式等多种因素影响，存在显著个体特异性。未来研究需重点突破“动物模型-人体转化”的瓶颈，结合多组学技术揭示人群特异性菌群代谢特征，为靶向微生物-Trp代谢轴的个体化抗抑郁策略开发奠定基础。

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基金资助

“脑科学与类脑研究”国家科技重大专项(2021ZD0202000)

甘肃省自然科学基金(25JRRA618)

兰州大学第二医院(第二临床医学院)“翠英学子科研培育计划”(CYXZ2023-55)

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