微生物学报

乳果糖调节肠道微生物并改善抑郁症状的研究进展

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李彦 ¹ , 黄彦玮 ¹ , 曾开泰 ¹ , 温子琪 ¹ , 陈容平 ²^,^*

微生物学报 | 综述 2024,64(9): 3105-3123

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微生物学报 | 综述 2024, 64(9): 3105-3123

乳果糖调节肠道微生物并改善抑郁症状的研究进展

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李彦¹, 黄彦玮¹, 曾开泰¹, 温子琪¹, 陈容平²^,^*

作者信息

1 南方医科大学, 广东广州 510515

2 南方医科大学珠江医院内分泌代谢科, 广东广州 510280

Research progress in the regulation of gut microbiota and mitigation of depressive symptoms by lactulose

Yan LI¹, Yanwei HUANG¹, Kaitai ZENG¹, Ziqi WEN¹, Rongping CHEN²^,^*

Affiliations

1 Southern Medical University, Guangzhou 510515, Guangdong, China

2 Department of Endocrinology and Metabolism, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, Guangdong, China

出版时间: 2024-05-06 doi: 10.13343/j.cnki.wsxb.20240108

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摘要

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抑郁是一种常见的情绪障碍，对个体的情绪和认知功能产生显著的负面影响，多见于其他疾病共患病中。随着抑郁年轻化趋势加重，抑郁对我国精神健康事业产生严重影响。近年来，随着肠道菌群研究的深入，抑郁症状与肠道菌群的关系愈发引起重视，而乳果糖作为一种用于促进肠道健康且对认知功能和情绪存在一定的改善作用的药物，引起了人们对其在改善抑郁症状方面的临床应用的关注。本文综述了乳果糖在改善抑郁症状方面的一些临床研究成果，并概述了一些乳果糖改善抑郁症状可能的机制，对通过肠-脑轴改善抑郁症状提出了展望。

关键词

乳果糖 / 抑郁症状 / 肠道菌群 / 肠-脑轴

Abstract

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Depression is a prevalent affective disorder exerting negative impacts on an individual's emotional and cognitive functions and is commonly complicated with other diseases. As depression is affecting increasingly younger populations, it poses a serious challenge to the mental health initiatives in China. In recent years, the relationship between depressive symptoms and gut microbiota has garnered increasing attention, fueled by the deepening research on gut microbiota. Lactulose, a medication aimed at promoting gut health and known for its potential benefits on emotional and cognitive functions, has sparked interests regarding its clinical application in ameliorating depressive symptoms. This article reviews the clinical research findings on the efficacy of lactulose in alleviating depressive symptoms and outlines the potential mechanisms through which lactulose may mitigate these symptoms. Furthermore, this article offers a perspective on the mitigation of depressive symptoms through the gut-brain axis.

Key words

lactulose / depressive symptoms / gut microbiota / gut-brain axis

引用本文

李彦, 黄彦玮, 曾开泰, 温子琪, 陈容平. 乳果糖调节肠道微生物并改善抑郁症状的研究进展. 微生物学报, 2024 , 64 (9) : 3105 -3123 . DOI: 10.13343/j.cnki.wsxb.20240108

Yan LI, Yanwei HUANG, Kaitai ZENG, Ziqi WEN, Rongping CHEN. Research progress in the regulation of gut microbiota and mitigation of depressive symptoms by lactulose[J]. Acta Microbiologica Sinica, 2024 , 64 (9) : 3105 -3123 . DOI: 10.13343/j.cnki.wsxb.20240108

正文

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抑郁作为一种常见的情绪障碍，在现代社会发病率逐年上升，在新型冠状病毒(corona virus disease 2019, COVID-19)大流行后更为显著^[1-2]。同时，抑郁症状作为共患病在多种疾病中被观察到，并与疾病进程和药物使用密切相关^[3]，因此引起了学界的广泛关注。在目前的研究中，认为抑郁症状的发生涉及多种因素，包括环境因素、遗传因素、大脑结构改变等^[4-7]。近年来，随着肠道菌群研究的进一步深入，脑-肠轴理论的提出，使得越来越多的研究聚焦于肠道微生态与抑郁症状的相互影响^[8-10]，如肠道中促炎细菌的富集和抗炎基因的衰竭^{[8, 11-12]}、短链脂肪酸和胆汁酸等代谢物水平变化^[13-16]等得到了较为深入的研究。

乳果糖作为一种已被证实的能够改善肠道微生态的药物^{[12, 17-19]}，其在改善抑郁症状方面的作用受到广泛关注。一项针对便秘患者的临床队列研究发现，与其他改善便秘的药物相比，乳果糖干预在改善便秘的同时，更为显著地改善了患者的抑郁症状^[20]，揭示了乳果糖干预在改善抑郁症状中的潜在作用。尽管乳果糖改善抑郁症状的机制尚不清楚，但本综述对现有机制进行了总结，以期为后续研究提供参考。

首先，短链脂肪酸等关键循环代谢物在大脑功能调节中占据重要地位，已有研究揭示其通过影响小胶质细胞发育进而影响大脑功能^[21-22]。在乳果糖干预后，与短链脂肪酸生成相关的细菌显著增多^[23]，同时观察到胆汁酸、N-乙酰神经氨酸和维生素D等代谢物水平的变化^{[12, 18, 24-26]}。其次，神经炎症在抑郁症状的研究中受到广泛关注^[27-29]，而且与肠道微生态密切相关^[30-31]。乳果糖作为常用的肠道微生态调节剂，能够增加抗炎和促认知功能的肠道菌群丰度^[12]，从而可能通过调节机体炎症水平对早期抑郁进行干预。此外，肠道细菌产生的神经递质和神经营养因子对抑郁等神经性疾病具有重要影响^[32-35]。乳果糖干预可改变神经递质水平，如降低γ-氨基丁酸(γ-aminobutyric acid, GABA)水平^[36]，这可能与改善抑郁症状相关。鉴于细胞自噬与抗抑郁作用的关联^[37]，乳果糖可能通过减少神经炎症并提升自噬相关通路水平，为抗抑郁治疗提供新的策略^[38]。

在目前的临床实践中，粪菌移植(fecal microbiota transplantation, FMT)治疗抑郁症患者已取得一定进展，但仍存在疗效维持时间较短等缺陷^[39-40]。目前有研究表明益生元或膳食纤维等有利于维持肠道微生态的稳定^[15]。乳果糖作为常见的能够改善肠道微生态的益生元，在联合粪菌移植方面具有广阔的研究前景。

本综述基于肠-脑轴(gut-brain axis)与抑郁症状相关性的基础讨论乳果糖改变肠道菌群和代谢途径来治疗抑郁症状的进展，以期为乳果糖在改善抑郁症状的研究提供参考。

1 抑郁症状与肠道菌群的关系

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1.1 抑郁的发生机制简述

抑郁是一种常见的情绪障碍，其常见的症状有疲劳和缺乏能量^[41]、悲观或无法集中注意力^[42]、食欲或体重发生显著变化^[43]和产生睡眠问题^[44]等。在目前的研究中，抑郁症状在多种疾病中被观察到，而且与疾病的进程和药物使用密切相关^[3]。根据美国国家精神卫生研究所(National Institute of Mental Health, NIMH)的数据，2021年美国成年人中至少有一次大型抑郁发作的人数估计为2 100万，占全部成年人口的8.3%^[1]。研究指出，COVID-19的大流行加重了全球抑郁的患病率^[2]。

抑郁是一种复杂的情绪障碍，可能涉及多种因素。遗传学上有研究发现，个体出现抑郁症状的风险受基因影响^[4]，并已发现一些与之相关的基因，如核因子κB (nuclear factor kappa-B, NF-κB)、cAMP反应元件结合蛋白(cyclic-AMP response binding protein, CREB)和糖皮质激素受体(glucocorticoid receptor, GR)基因等^[5]。此外，环境因素，包括压力事件，如失去亲人、工作压力等，均可增加出现抑郁症状的风险^[6]。也有研究发现，抑郁症患者的大脑结构可能与正常人存在差异，如情绪反应区的海马体体积越小，对悲伤面孔的反应越大，可以预测扫描时抑郁症状的增加，而杏仁核体积越大，脑岛体积越小和情绪反应区反应越大则可以预测情绪调节技能的下降^[7]。

1.2 抑郁症状与肠道菌群

1.2.1 肠道菌群组成改变

近年来，随着肠道菌群研究的进一步深入，抑郁症状与肠道菌群组成的关系愈发引起重视。研究表明，抑郁症患者中菌群多样性与正常人存在差异，如在β多样性中，抑郁状态下的肠道微生物与对照组存在明显差异^[8]，而且在使用抗生素后导致的菌群多样性下降增加了出现抑郁症状的风险^[9]；这些差异体现在抑郁症状的炎症假说中^[10]，即促炎细菌的富集和抗炎细菌的耗竭，如脱硫弧菌(Desulfovibrio)和埃希氏菌/志贺氏菌(Escherichia/Shigella)的富集、双歧杆菌(Bifidobacterium)和粪杆菌(Faecalibacterium)的耗竭^{[8, 11]}。此外，乳果糖干预也被证实可以使得轻度肝性脑病(mild hepatic encephalopathy, MHE)患者肠道中抗炎相关菌群的相对丰度增加^[12]。更为重要的是，Kelly等和Zheng等^[45-46]在啮齿动物中进行粪菌移植后发现肠道微生态失调先于抑郁症发生。

同时，抑郁症状存在的时间^[47-48]和不同样本的地域差异^[49]也均在肠道菌群组成差异上有所体现，进一步揭示了肠道菌群与抑郁症状之间的密切关系。除上述提及的肠道细菌之外，肠道病毒组^[50-51]和肠道真菌^[52]的研究也逐渐发展，肠道微生态在抑郁症状的产生和发展中愈发引起重视。

1.2.2 肠道菌群代谢物的改变

肠道菌群代谢物改变是肠道菌群组成改变影响抑郁症状的重要途径。目前研究发现，抑郁症状严重程度与胆汁酸水平成反比^[13]，而与氧化三甲胺水平则成正比^[53]。同时，在抑郁患者中发现了短链脂肪酸(short chain fatty acid, SCFAs)，尤其是丁酸的耗竭^[14-16]，在补充丁酸盐后，抑郁症状得到改善^[54]，研究证明，使用乳果糖治疗使得肠道菌群衍生的SCFAs增多^[55]。除此之外，脂多糖、乳酸盐和维生素等也被发现与抑郁症状相关^[55-57]，可见代谢物水平在抑郁症状的发生机制中发挥着重要作用。

1.2.3 肠道菌群和代谢物改变通过肠-脑轴影响抑郁症状

目前针对肠道菌群与神经性疾病的关系，提出了肠-脑轴的概念^[58]。肠道菌群和代谢物通过破坏肠道上皮，使得肠道屏障功能受损和局部炎症发生^[59]，而炎症因子透过受损的肠道屏障引起全身炎症^[60]，继而影响抑郁症状。同时肠神经系统也被认为在肠-脑轴中发挥重要作用，肠道中的微生物信号通过迷走神经途径进而对大脑产生影响^[61]。此外，部分可以通过血脑屏障的代谢物，如革兰氏阴性菌产生的脂多糖，透过血脑屏障引起神经炎症，进而加重抑郁症状^{[55, 60]}。

综上，肠道菌群与抑郁症状的发生密切相关。本综述将基于此，探索肠-脑轴介导的代谢因素对抑郁症状的影响^[62-63]，并综述乳果糖改变肠道菌群和代谢途径来治疗抑郁症状的进展。

2 乳果糖通过肠道微生态影响抑郁症状

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乳果糖是一种合成双糖，包含果糖和半乳糖^[64]。作为一种不被吸收的双糖，乳果糖已被广泛应用于肝性脑病的治疗。肝性脑病(hepatic encephalopathy, HE)是一种与神经系统并发症相关的脑功能障碍，其早期患者常伴有抑郁症状和情绪障碍，高氨血症、促炎细胞因子和特定神经递质的积累等被认为参与HE发展的因素^[65]，并且其发生与肠道微生态失调有密切联系^[66]。Yang等^[67]研究探讨了乳果糖促进神经可塑性，改善早期肝性脑病的认知功能，为乳果糖治疗抑郁这一神经系统性疾病提供了理论基础。Hudson等的综述文章回顾了乳果糖和/或利福昔明在长期管理肝性脑病中的应用，提到了乳果糖对认知功能和情绪改善的潜在作用，为改善抑郁症状提供了一定的基础^[68]。

据此不难推测乳果糖具有影响肠道微生态来改善抑郁症状的作用。具体而言，目前较为清晰的机制是乳果糖在肠-脑轴的介导下改善抑郁症状，其干预既能使肠道微生物衍生的短链脂肪酸、神经营养因子以及神经元分泌的神经递质等有益产物增多，又能下调炎症反应及氧化应激水平(图1)。

2.1 乳果糖治疗便秘同时改善抑郁症状

国内一项最新的队列研究表明，便秘患者更容易患有抑郁症状^[69]。传统上通常用乳果糖改善患者的便秘症状^[70]，而便秘患者常伴有抑郁焦虑等症状^[71]。通过综合大量相关研究发现，乳果糖具有改善抑郁症状的作用，这一发现为临床实践中关注及治疗便秘患者的心理健康提供了重要依据。乳果糖干预的机制在于其能发挥益生元作用，加强肠道屏障、加速肠道蠕动，抑制炎症反应，并改善肠道中的代谢^[72]。具体而言，乳酸杆菌对慢性功能性便秘患者的积极影响被证实^[73]，其在缓解压力诱导的焦虑和抑郁方面的作用也被揭示^[74]，而乳果糖作为益生元，其促进乳酸杆菌主导的微生物群落形成的特性也得到了验证^[75]。因此，乳果糖疗法可能通过促进肠道内益生菌定殖，在调节肠道微生态的同时对抑郁情绪产生积极影响，间接进行抑郁进程的早期干预，可以作为一种神经(退行)性疾病的试验性治疗药物。马后莲等通过乳果糖与莫沙必利治疗老年患者慢性功能性便秘及伴随症状的前瞻性随机对照研究，验证了乳果糖在改善便秘的同时降低便秘相关的焦虑、抑郁评分^[20]。潘姣等自拟缩泉润肠汤治疗阴虚肠燥型慢性便秘的临床研究中用到乳果糖口服液作为治疗慢性功能性便秘患者的干预对照组，与服用前相较，患者症状得到了显著改善^[76-77]。在帕金森患者中，便秘和抑郁是常见的共患病，大量研究表明^[78-79]在用乳果糖改善帕金森患者的便秘症状时发现同时改善了抑郁症状，这一发现不仅拓宽了乳果糖的临床应用范围，也为帕金森病患者提供了更为全面的治疗方案。

以上案例均表明，尽管目前关于乳果糖在改善抑郁的临床应用的研究仍然有限，但已有一些工作证实了乳果糖对认知功能和情绪改善的潜在作用。乳果糖作为一种传统的治疗便秘的药物，其潜力远不止于此。随着研究的深入，有望发现更多关于乳果糖在治疗抑郁症状方面的新应用。

2.2 短链脂肪酸和循环代谢物

在患有抑郁症状的群体中，由于肠道菌群的种类和数目不同^[8]，短链脂肪酸和循环代谢物水平存在显著差异^[14-16]，并在抑郁症状的发生和发展中起关键作用^[62-63]，因此肠道菌群代谢物的检测和干预可以初步对抑郁患者进行诊断和治疗。

这些短链脂肪酸通过神经、化学及免疫作用，并以肠-脑轴为中介调节肠道与大脑功能的相互作用^[21]。首先，SCFAs被证实有助于调节下丘脑中神经递质如谷氨酸、谷氨酰胺等的合成^[80]，进而调节迷走神经信号传导。另外，微生物群-肠道-免疫-神经胶质细胞轴被推测在抑郁症状中起作用^[81]。具体而言，小胶质细胞的成熟依赖于SCFAs的持续输入，肠道微生物损耗会导致小胶质细胞不成熟和功能障碍^[22]，从而可能加剧抑郁症状。最后，SCFAs可以通过血脑屏障直接向神经细胞提供能量^[82]并充当信号分子^[83]，也可以作为肠上皮细胞的重要能量来源^[84]，还可以增强肠道屏障功能、维持血脑屏障完整性、减少海马细胞凋亡和调节免疫稳态^[85-86]，这些功能共同维护了肠道与大脑之间的平衡状态。

乳果糖治疗可能使肠道菌群衍生的SCFAs增多，改善抑郁症状。研究表明，乳果糖可以逆转AOM/DSS处理诱导的毛螺菌科(Lachnospiraceae)丰度降低^[23]，而毛螺菌科是肠道微生物群的核心，其成员是短链脂肪酸的主要生产者。短链脂肪酸不仅影响肠道健康，还可能通过肠-脑轴影响大脑的功能和情绪状态。因此，毛螺菌科通过产生短链脂肪酸可能对抑郁症状有缓解作用，这提示了乳果糖逆转的毛螺菌科丰度下调在抑郁治疗中有潜在积极作用。值得注意的是，在一项鉴定重度抑郁症(major depressive disorder, MDD)患者的性别特异性肠道微生物群研究中，不同性别的MDD患者减少的肠道菌群均主要归入毛螺菌科^[87]，进一步说明了乳果糖诱导毛螺菌科丰度上调这一现象揭示了乳果糖治疗抑郁症状的潜力。Wang等^[18]采用气相色谱-质谱联用(gas chromatography-mass spectrometry, GC-MS)检测体内SCFAs含量，发现乳果糖干预后的短链脂肪酸水平显著升高并伴有毛螺菌属相对丰度增加，这一结果证实了上述观点。

除了衍生短链脂肪酸，肠道微生物还可以调节循环代谢物，包括氨基酸、胆汁酸和维生素等。肝性脑病的患者早期可能伴有抑郁症状及认知功能减退，早有研究表明，乳果糖能够使有毒的含氮产物如血氨和有机酸产物含量显著下降，降低肝性脑病相应并发症的发生且不具有一般药物的肝毒性^[88]，是肝性脑病的一线治疗药物^[89-90]，提示了乳果糖改善抑郁症状的潜力。一项前瞻性队列研究也显示，乳果糖疗法可以在改善慢性肝病时改善患者的认知障碍与睡眠障碍^[91]，进一步表明乳果糖可能参与抑郁症状的改善。另外，一些胆汁酸可以通过血脑屏障，作用于中央法尼醇X受体(farnesoid X receptor, FXRFXR)和G蛋白胆汁酸激活受体1 (G protein bile acid activates receptor 1, GPBAR-1)^[25]，进而加重抑郁症状的风险，而通过构建急性肝损伤大鼠模型，研究人员证实乳果糖干预可能通过调节肠道菌群，降低甘氨鹅脱氧胆酸，进而改善肝脏及肠道病情^[92]。以上证据均表明乳果糖有助于维持神经细胞的正常功能，降低抑郁发生的风险。除此之外，维生素也参与宿主微生物群的串扰并有利于抑郁症状的治疗。人类依靠肠道微生物群代谢来产生维生素^[93]，在人体中(包括大脑)的多种生理过程中发挥着作用^[94-95]。在中枢神经系统中，维生素在从能量稳态扩展到神经递质的产生中都发挥着作用，维生素缺乏会对神经功能产生显著的负面影响^[96]。例如，维生素D具有神经调节、抗炎和抗氧化特性^[97]，通过将血清素水平保持在正常水平来有效预防抑郁症状^[98]；叶酸和维生素B₁₂是一碳代谢的主要决定因素，其中形成的S-腺苷甲硫氨酸(S-adenosylmethionine, SAMe)可以提供对神经功能至关重要的甲基^[99]。值得注意的是，虽然目前尚无研究直接对乳果糖干预后的维生素水平做出评定，但乳果糖促进益生菌定殖^[12]及益生菌促进肠道微生物产生维生素的作用^[26]均已被证实。

综上所述，肠道微生物衍生的短链脂肪酸和循环代谢产物可以充当肠道微生物信使参与肠-脑轴的信息传递，可能是治疗抑郁症状的有效干预措施。未来的研究可结合乳果糖对肠道微生物和循环代谢物的具体作用机制，进一步探讨乳果糖在治疗抑郁中的临床效果和安全性。

2.3 炎症因子和氧化应激

抑郁经常作为一种共发症状，大量研究通过Meta分析证实其与炎症生物标志物的存在有关^[27-29]。与健康个体相比，抑郁患者在肠道菌群的相对丰度方面表现出显著变化，其中促炎细菌的增加和抗炎细菌的减少能较大程度地影响免疫反应和大脑功能(肠-脑轴)^[10]。肠道微生态受损时，外周炎症因子可以直接穿过血脑屏障激活小胶质细胞，也可以通过炎症因子的迁移激活下丘脑-垂体-肾上腺(hypothalamic-pituitary-adrenal, HPA)轴从而诱发抑郁症状^[100-102]。另外，抑郁患者的肠道菌群失调还会引起血浆脂多糖(lipopolysaccharide, LPS)的升高^[103]。LPS作为常见的内毒素，可诱导多种促炎细胞因子释放，从而引发炎症，诱导抑郁发生^[104]。

一项临床研究发现^[105]，肠易激综合征(irritable bowel syndrome, IBS)症状与心理障碍密切相关，在高症状患者中特定炎症因子升高。在抑郁小鼠的大脑中也观察到炎症因子，特别是肿瘤坏死因子-α (tumor necrosis factor-α, TNF-α)、白细胞介素-1β (interleukin-1β, IL-1β)、IL-6、IL8等水平上调以及星形胶质细胞和小胶质细胞的增加，这些因素可以激活NF-κB信号传导并诱发抑郁行为^[30-31]。相反，IL-6缺陷的小鼠对抑郁样症状的发展产生了抵抗力^[107-108]，表明抑制这些炎症因子可能有助于预防或治疗抑郁症状。

乳果糖干预可以减少炎症因子的产生，有利于抑郁症状的治疗。乳果糖治疗后的MHE患者肠道中与抗炎和良好认知功能相关的特定分类菌群的相对丰度增加^[12]。与之相反，在Wang等^[18]实验中，乳果糖抑制可使炎性细胞因子上调，显著提高TNF-α、IL-6和TGF-β1的转录水平表达。乳果糖通过抑制这些炎症因子可能抑制小胶质细胞形态转化，通过TGF-β/Smad等信号转导通路调节应激反应，进而发挥神经保护作用^[109]。基于上述细胞因子的外周血液循环水平被证实具有潜在的预测抑郁症状发展的临床价值，我们进一步认为乳果糖干预疗法有助于早期的抑郁干预和治疗。

除此之外，氧化应激也与神经功能障碍和情绪困扰密切相关^[110]。目前，越来越多证据表明肠道菌群可与HPA轴相互作用，即通过内分泌途径作用于肠-脑轴，调节机体对外界环境的应激反应，进而影响包括抑郁在内的精神性疾病^[111-112]。一项系统评价表明，运动员的抑郁行为增加与肠道微生物群的内分泌作用影响了HPA轴有关^[106]。因此，基于乳果糖对肠道微生物的调节作用，乳果糖治疗可能通过肠-脑轴对HPA轴功能产生影响进而干预抑郁症状。Zheng等^[113]发现乳果糖可以防止镰菌真菌毒素引起的氧化损伤，直接揭示了乳果糖减少氧化应激反应的潜力。因此推测，乳果糖干预可能同其他益生菌相似，能够使体内氧化应激减弱和抗氧化防御系统增强，如还原性物质谷胱甘肽(glutathione, GSH)的水平和过氧化氢酶活性升高^[114-116]等，但具体机制仍需大量实验进一步探究。

综上所述，肠道菌群变化引起的炎症和一些代谢性变化疾病能够作为抑郁患者的标志性疾病。尽管该反应不具有特异性，但通过乳果糖干预相应的炎症反应对患者而言有着积极作用。

2.4 神经递质和脑神经营养因子

神经递质和神经营养因子对抑郁症状与肠道菌群的串扰很重要，在调节肠-脑轴中起重要作用^[117]。肠道细菌所分泌的各种神经递质和神经营养因子可以通过神经作用影响脑，进行由肠道至脑的信息传递。神经细胞又反过来通过迷走神经改变神经递质和其他细胞因子水平对中枢和外周神经系统进行神经调节，维持稳定的双向肠-脑轴信号传导^[21]。

研究表明^[32-35]，肠道细菌可产生多种神经递质和神经营养因子，这些物质通过血液循环作用于脑，包括脑源性神经营养因子(brain derived neurotrophic factor, BDNF)、5-羟色胺(5-hydroxytryptamine, 5-HT)、γ-氨基丁酸(gamma-aminobutyric acid, GABA)、色氨酸和神经肽等，最终引起个体应激反应和认知水平的改变，进而影响抑郁等神经性疾病的发展。

色氨酸作为一种必需氨基酸，可产生具有既定情绪调节特性的神经活性分子，包括血清素、犬尿氨酸和吲哚，对肠道微生物群和肠-脑轴之间的相互作用有着深远影响^[118]。膳食中摄入色氨酸主要通过调节中枢神经系统的血清素水平影响抑郁症状的发展，而色氨酸的耗竭则会导致抑郁症状的加重^[119]。2项动物实验也均发现乳果糖饮食使色氨酸代谢水平显著增高^{[72, 120]}，在乳果糖发酵实验中色氨酸代谢物水平也显著上调^[121]，直接表明了乳果糖的治疗潜力。值得注意的是，“抑郁症的单胺理论”提出，抑郁的生物学机制之一是单胺水平的缺乏，即5-HT、去甲肾上腺素和多巴胺的缺乏。目前研究显示，许多抗抑郁药物如单胺氧化酶抑制剂和三环类抗抑郁药虽然可以通过增强5-HT和去甲肾上腺素活性来改善抑郁症状，但其增加单胺水平的作用几乎是瞬间的，而抗抑郁药治疗的临床效果通常需要数周才能观察到^[122]。乳果糖干预诱导的益生菌定殖增加被证明可以合成单胺类物质，其作为益生元有着较小的副作用且无成瘾性^[123-125]，因此认为乳果糖可以显著地改善目前已有的单胺靶向药物的治疗局限性，其对肠道微生物群的调节可能成为抑郁的一种新兴治疗方式，有利于为抗抑郁药物的研发和改进提供方向。

另外，徐婧等^[125]发现伊托必利联合乳果糖可以显著提高5-HT水平和更好改善便秘症状，乳果糖治疗的健康小鼠全身血清GABA水平也显著低于健康对照组^[36]，基于GABA作为一种重要的抑制性神经递质在中枢神经系统中发挥抑制作用，这一现象可能赋予了对抑郁样状态的保护^[126]。除了上述物质，神经肽Y (neuropeptide Y, NPY)表达异常也是抑郁症状的重要致病机制^[127-128]。肠脑肽(如甘丙肽、胆囊收缩素等)作为神经肽的一种，主要由内分泌系统产生并在调节抑郁症状方面有重要作用；一些神经肽作为信号分子从神经元中释放出来^[129]，可以影响兴奋细胞上的神经递质或调节剂，通过细胞信号传导实现脑对肠道的调节^[130]。Zhou等^[131]研究发现与观察组相比，对照组使用乳果糖治疗可以使NPY水平上升并降低焦虑、健康担忧及社会反应得分，表明乳果糖可以有效干预抑郁症状。

除神经递质以外，神经营养因子，尤其是BDNF，广泛分布于中枢和周围神经系统，由神经所支配的组织、星形胶质细胞或者神经元合成^[132]，与神经元的生长、发育和功能完整性以及抑郁症状的发生发展密切相关^{[127, 132-134]}。深入探究BDNF与抑郁之间的关联发现，临床证据明确指出了改变BDNF水平对应激诱导的抑郁病理有着显著的影响^[135]，这为理解抑郁的发病机制提供了新的视角，同时也为抑郁的治疗提供了新的潜在靶点。在动物模型的实验中，研究人员通过将BDNF直接输注到海马体或中脑中，成功观察到了持久的抗抑郁样作用^[136]，这进一步验证了BDNF在抗抑郁治疗中的潜力。最近一项随机双盲实验也表明^[137]，益生菌干预显著增加血清BDNF水平，促进健康老年人的心理健康，证实了益生元作用对抑郁症状的改善。然而，尽管已经对BDNF有了较为深入的了解，但目前对于乳果糖这种常用的治疗药物是否能够对神经营养因子产生调节作用，仍缺乏足够的研究和了解。因此，为了更全面地理解乳果糖在治疗抑郁等神经系统疾病中的作用机制，仍需要进行更为深入和系统的研究。

2.5 细胞自噬

最近，细胞自噬与抗抑郁作用之间的关联已被报道，提出自噬在抑郁症状的发生发展中至关重要。细胞自噬作为支持细胞在应激下存活的关键机制，在神经元的存活和突触可塑性中扮演着重要角色^[37]。通过维持神经元的功能、调节神经递质和神经肽的水平及参与神经再生和突触可塑性的调节，自噬被认为可以辅助抑郁的治疗^[138]。研究人员利用小鼠模型和体外实验确定了氟西汀作为一种典型的抗抑郁药物，其自噬原作用与抑郁症状患者中对星形胶质细胞保护之间有显著的相关性，确定了氟西汀以p53依赖性机制促进星形胶质细胞自噬从而有效减轻抑郁症状，肯定了自噬对于抑郁的改善作用^[139]。

综合已有文献，推测乳果糖可能可以作为一种抗抑郁药，触发自噬以对应激状况做出反应。近几年的研究显示，乳果糖改善抑郁症状的机制主要涉及2个方面：自噬和抗炎。首先，从病理学分析来看，乳果糖能够下调炎症因子水平，减少神经炎症并增加自噬通路的水平，这表明其通过抗炎和自噬可以实现神经保护作用。Lee等^[140]等通过检查阿尔茨海默病(Alzheimerʼs disease, AD)小鼠海马体中巨自噬标志物LC3和p62以及伴侣介导的自噬(chaperone-mediated autophagy, CMA)标记物Hsc70和Lamp-2a的水平证实，乳果糖干预使LC3 Ⅱ升高且P62同时降低，表明自噬流通畅；另外，免疫荧光分析显示乳果糖可以逆转Aβ处理导致的Lamp-2a降低和显著增加Hsc70水平，表明其在CMA中的促进作用，而自噬作用的促进最终导致AD小鼠认知障碍的改善。研究表明抑郁和认知障碍可能共享一些神经生物学机制，抑郁患者往往表现出动机下降和认知控制障碍，通过增强动机和认知控制，可能有助于同时改善抑郁和认知障碍^[141]。因此，乳果糖改善认知障碍的同时可能对改善抑郁症状有着极大的促进作用。除此之外，研究发现褪黑激素治疗抑郁小鼠依赖于逆转抑郁时的FOXO3a水平下调和p-FOXO3a水平升高^[142]。虽然仍未有实验探究乳果糖与FOXO3a的直接关系，但两歧双歧杆菌(Bifidobacterium bifidum)和副干酪乳杆菌(Lactobacillus paracasei)干预被证实可以激活FOXO3a信号通路^[38]，基于乳果糖诱导双歧杆菌等有益菌定殖增加的作用，推测乳果糖干预有利于通过上调FOXO3a信号通路，这可以为深入研究乳果糖治疗抑郁的分子作用机制提供方向。

总的来说，这些研究结果共同指向了乳果糖在改善抑郁方面的潜在机制，即通过促进自噬来发挥作用，提供了一种根据星形胶质细胞自噬治疗抑郁症状的新方法，并为除调节神经递质之外的抗抑郁药物如乳果糖等的利用，提供了一个有前途的分子靶点。

然而，神经炎症、自噬和抑郁症状之间的机制相互作用在很大程度上仍然存在争议。一项最新研究发现慢性皮质酮可诱导小鼠海马齿状回中过度活跃的神经元自噬，并导致神经元中BDNF的过度溶酶体降解，最终诱导抑郁样行为^[143]。因此，通过乳果糖温和的益生元作用以调节细胞自噬活性，维持BDNF的正常水平，可能是治疗抑郁的有效策略。

3 粪菌移植联合乳果糖在改善抑郁症状中的潜在应用

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粪菌移植是一种将健康供体的肠道微生物移植到患者肠道，直接改变受者肠道微生物群，使其组成正常化，从而获得治疗效果的方法。陈容平等^[144]基于将FMT应用于干预肥胖糖尿病形成了专家共识。肠道微生物组与中枢神经系统之间存在相互作用，特别是通过微生物-肠-脑轴的通信途径。张艺等^[62]综述了粪菌移植通过微生物-肠-脑轴改善抑郁症的研究进展，提及肠道微生物组与抑郁症之间存在关联，并且抑郁症患者的肠道微生物组与健康人存在差异。粪菌移植的应用已经为多种肠道疾病(如肠易激综合征^[145]、溃疡性肠炎^[146])或非肠道疾病(如抑郁症)的治疗或改善提供了新的治疗方向。Guo等^[147]的随机对照实验和Doll等^[148]的案例报告均表明，粪菌移植可调整肠道微生物群，改善胃肠道和抑郁症状。通过粪菌移植治疗，有益菌可以取代异常菌，细菌多样性上调，肠道微生物的组成丰度得到改善，肠道菌群平衡重新建立，胃肠道症状和抑郁症状得到改善。

目前粪菌移植治疗抑郁症状患者已取得一定的进展，但仍存在维持时间较短的缺陷^[39-40]，因为一段时间后一些有害菌群会重新达到较高的丰度，有益菌群丰度的变化趋势则相反，使得菌群移植的效果减弱。目前解决这种缺陷的办法主要为移植后患者口服益生元或膳食纤维等维持肠道微生态的稳定^[149]。乳果糖是一种不可吸收的合成双糖^[64]，也是一种益生元。研究表明，乳果糖可以通过调整肠道微生物群结构^[23]、调节SCFAs^[18]等肠道菌群代谢产物含量和改善肠道屏障^[150]等途径改善抑郁症状。这些研究和报告提示粪菌移植联合乳果糖对于抑郁症状的疗效值得进一步追踪，并且对于探索和确定粪菌移植在抑郁症治疗中的潜力具有重要意义。

虽然乳果糖作为益生元可能在抑郁症状的治疗及改善粪菌移植的疗效中起作用，而且在临床实验中报告显示研究对象对乳果糖无不良反应或症状较轻^{[151, 70]}，表明其安全性是可靠的。目前记录较多的用于抑郁症治疗的益生元是低聚果糖和低聚半乳糖，而将乳果糖用于抑郁症治疗或抑郁症状的改善的临床研究较少，因此，在联合粪菌移植方面，乳果糖相对于其他益生元的优势或不足仍需要进一步地探索。同时，由于乳果糖改善抑郁症状的具体分子机制尚未明晰，以及针对粪菌移植用于治疗抑郁症的研究数量有限，其长期的安全性和疗效有待进一步评估，因此乳果糖联合粪菌移植的治疗方法仍需要更多的临床试验。

4 总结与展望

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抑郁症状患者的肠道菌群多样性与正常人存在差异，肠道菌群代谢物的改变也影响抑郁症状的发生和发展。然而乳果糖作为一种调节肠道健康的合成双糖，其在改善抑郁症状方面的潜在作用引起了研究者的广泛关注。

乳果糖通过调节肠道微生态和菌群代谢产物，影响肠-脑轴功能，可能对改善抑郁症状有潜在作用。乳果糖可以平衡肠道微生物，增加有益菌、减少有害菌，从而积极影响抑郁症状。此外，乳果糖可能通过调节炎症因子和氧化应激水平等方式改善抑郁症状。

近年来，细胞自噬在抑郁症发生发展中的作用逐渐被揭示，乳果糖对细胞自噬的潜在调控作用可能成为未来研究的新方向。

尽管目前关于乳果糖调节肠道菌群以改善抑郁症状的研究已取得初步成果，但尚需更多严谨的动物实验和临床试验来验证其作用机制和疗效。粪菌移植(FMT)作为一种直接干预肠道微生物群的治疗方法，与乳果糖的联合应用可能成为抑郁症状的辅助治疗手段。进一步的研究可以深入探讨乳果糖对肠道菌群-肠-脑轴信号传导路径的具体影响，以及粪菌移植联合乳果糖在抑郁症状治疗中的协同效应，以期为抑郁症状的临床治疗提供更为精准和个性化的干预措施。

基金

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大学生创新创业训练计划(S202312121085)

参考文献

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文献

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参考文献引证文献

排序方式：

[1]

SIDERIDIS G, ALKHADIM G. A methodological note on the CYP-guides randomized controlled trial for the treatment of major depression[J]. Frontiers in Psychiatry, 2022, 13,888065.

https://doi.org/10.3389/fpsyt.2022.888065

[2]

SANTOMAURO DF, MANTILLA HERRERA AM, SHADID J, ZHENG P, ASHBAUGH C, PIGOTT DM, ABBAFATI C, ADOLPH C, AMLAG JO, ARAVKIN AY, BANG-JENSEN BL, BERTOLACCI GJ, BLOOM SS, CASTELLANO R, CASTRO E, CHAKRABARTI S, CHATTOPADHYAY J, COGEN RM, COLLINS JK, DAI XC, et al. Global prevalence and burden of depressive and anxiety disorders in 204 countries and territories in 2020 due to the COVID-19 pandemic[J]. The Lancet, 2021, 398 (10312):1700-1712.

https://doi.org/10.1016/S0140-6736(21)02143-7

[3]

PAIVA JA, de ARAUJO, BORGES D. Main and moderated effects of multimorbidity and depressive symptoms on cognition[J/OL][J]. Revista Brasileira De Psiquiatria (Sao Paulo, Brazil: 1999), 2022, 44 (6):644-649.

[4]

HAMANO T, LI XJ, LÖNN SL, NABIKA T, SUNDQUIST J, SUNDQUIST K. Is familial risk for depression confounded by individual and familial socioeconomic factors and neighborhood environmental factors? A 7-year follow-up study in Sweden[J]. Psychiatry Research, 2018, 266,30-35.

https://doi.org/10.1016/j.psychres.2018.05.041

[5]

CHO JHJ, IRWIN MR, EISENBERGER NI, LAMKIN DM, COLE SW. Transcriptomic predictors of inflammation-induced depressed mood[J]. Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology, 2019, 44 (5):923-929.

https://doi.org/10.1038/s41386-019-0316-9

[6]

YANG LF, ZHAO YH, WANG YC, LIU L, ZHANG XY, LI BJ, CUI RJ. The effects of psychological stress on depression[J]. Current Neuropharmacology, 2015, 13 (4):494-504.

https://doi.org/10.2174/1570159X1304150831150507

[7]

PAGLIACCIO D, LUBY JL, LUKING KR, BELDEN AC, BARCH DM.Brain-behavior relationships in the experience and regulation of negative emotion in healthy children: implications for risk for childhood depression[J].Development and Psychopathology,2014, 26 (4 Pt 2):1289-1303.

[8]

LIU LX, WANG HY, ZHANG HP, CHEN XY, ZHANG YD, WU J, ZHAO LB, WANG DF, PU JC, JI P, XIE P. Toward a deeper understanding of gut microbiome in depression: the promise of clinical applicability[J]. Advanced Science, 2022, 9 (35):e2203707.

https://doi.org/10.1002/advs.202203707

[9]

GUIDA F, TURCO F, IANNOTTA M, de GREGORIO D, PALUMBO I, SARNELLI G, FURIANO A, NAPOLITANO F, BOCCELLA S, LUONGO L, MAZZITELLI M, USIELLO A, de FILIPPIS F, IANNOTTI FA, PISCITELLI F, ERCOLINI D, de NOVELLIS V, Di MARZO V, CUOMO R, MAIONE S. Antibiotic-induced microbiota perturbation causes gut endocannabinoidome changes, hippocampal neuroglial reorganization and depression in mice[J]. Brain, Behavior, and Immunity, 2018, 67,230-245.

https://doi.org/10.1016/j.bbi.2017.09.001

[10]

BEUREL E, TOUPS M, NEMEROFF CB. The bidirectional relationship of depression and inflammation: double trouble[J]. Neuron, 2020, 107 (2):234-256.

https://doi.org/10.1016/j.neuron.2020.06.002

[11]

SIMPSON CA, DIAZ-ARTECHE C, ELIBY D, SCHWARTZ OS, SIMMONS JG, COWAN CSM. The gut microbiota in anxiety and depression-a systematic review[J]. Clinical Psychology Review, 2021, 83,101943.

https://doi.org/10.1016/j.cpr.2020.101943

[12]

WANG MW, MA WJ, WANG Y, MA XH, XUE YF, GUAN J, CHEN X. Comparison of the effects of probiotics, rifaximin, and lactulose in the treatment of minimal hepatic encephalopathy and gut microbiota[J]. Frontiers in Microbiology, 2023, 14,1091167.

https://doi.org/10.3389/fmicb.2023.1091167

[13]

SUN N, ZHANG J, WANG JZ, LIU ZF, WANG X, KANG PL, YANG CX, LIU PH, ZHANG KR. Abnormal gut microbiota and bile acids in patients with first-episode major depressive disorder and correlation analysis[J]. Psychiatry and Clinical Neurosciences, 2022, 76 (7):321-328.

https://doi.org/10.1111/pcn.13368

[14]

CASPANI G, KENNEDY S, FOSTER JA, SWANN J. Gut microbial metabolites in depression: understanding the biochemical mechanisms[J]. Microbial Cell, 2019, 6 (10):454-481.

https://doi.org/10.15698/mic2019.10.693

[15]

LIU LX, WANG HY, CHEN XY, ZHANG YD, ZHANG HP, XIE P. Gut microbiota and its metabolites in depression: from pathogenesis to treatment[J]. EBioMedicine, 2023, 90,104527.

https://doi.org/10.1016/j.ebiom.2023.104527

[16]

van de WOUW M, BOEHME M, LYTE JM, WILEY N, STRAIN C, O'SULLIVAN O, CLARKE G, STANTON C, DINAN TG, CRYAN JF. Short-chain fatty acids: microbial metabolites that alleviate stress-induced brain-gut axis alterations[J]. The Journal of Physiology, 2018, 596 (20):4923-4944.

https://doi.org/10.1113/JP276431

[17]

MA JX, MA HL, ZHENG SB, YU XF, WANG K, WANG J, PAN YR, YAO JF. Intestinal flora in the constipation patients before versus after lactulose intervention[J]. Medicine, 2023, 102 (32):e34703.

https://doi.org/10.1097/MD.0000000000034703

[18]

WANG JY, JIANG ML, HU Y, LEI YP, ZHU Y, XIONG HF, HE C. Lactulose regulates gut microbiota dysbiosis and promotes short-chain fatty acids production in acute pancreatitis patients with intestinal dysfunction[J]. Biomedicine & Pharmacotherapy, 2023, 163,114769.

[19]

BAI JY, WANG BT, TAN X, HUANG LH, XIONG SL. Regulatory effect of lactulose on intestinal flora and serum metabolites in colitis mice: in vitro and in vivo evaluation[J]. Food Chemistry: X, 2023, 19,100821.

https://doi.org/10.1016/j.fochx.2023.100821

[20]

马后莲, 马建霞, 郑松柏, 王珂, 王军, 姚健凤. 乳果糖与莫沙必利治疗老年患者慢性功能性便秘及伴随症状的前瞻性随机对照研究[J]. 中华老年多器官疾病杂志, 2022, 21 (6):424-427. https://www.cnki.com.cn/Article/CJFDTOTAL-ZLQG202206005.htm

MA HL, MA JX, ZHENG SB, WANG K, WANG J, YAO JF. Lactulose and mosapride in treatment of chronic functional constipation and its concomitant symptoms in the elderly: a prospective randomized controlled trial[J]. Chinese Journal of Multiple Organ Diseases in the Elderly, 2022, 21 (6):424-427 (in Chinese). https://www.cnki.com.cn/Article/CJFDTOTAL-ZLQG202206005.htm

[21]

CHANG LJ, WEI Y, HASHIMOTO K. Brain-gut-microbiota axis in depression: a historical overview and future directions[J]. Brain Research Bulletin, 2022, 182,44-56.

https://doi.org/10.1016/j.brainresbull.2022.02.004

[22]

MITCHELL RW, ON NH, del BIGIO MR, MILLER DW, HATCH GM. Fatty acid transport protein expression in human brain and potential role in fatty acid transport across human brain microvessel endothelial cells[J]. Journal of Neurochemistry, 2011, 117 (4):735-746.

[23]

HIRAISHI K, ZHAO FY, KURAHARA LH, LI XD, YAMASHITA T, HASHIMOTO T, MATSUDA Y, SUN ZH, ZHANG HP, HIRANO K. Lactulose modulates the structure of gut microbiota and alleviates colitis-associated tumorigenesis[J]. Nutrients, 2022, 14 (3):649.

https://doi.org/10.3390/nu14030649

[24]

BERGERON R, IMAMURA Y, FRANGIONI JV, GREENE RW, COYLE JT. Endogenous N-acetylaspartylglutamate reduced NMDA receptor-dependent current neurotransmission in the CA1 area of the hippocampus[J]. Journal of Neurochemistry, 2007, 100 (2):346-357.

https://doi.org/10.1111/j.1471-4159.2006.04253.x

[25]

REN ZL, LI CX, MA CY, CHEN D, CHEN JH, XU WX, CHEN CA, CHENG FF, WANG XQ. Linking nonalcoholic fatty liver disease and brain disease: focusing on bile acid signaling[J]. International Journal of Molecular Sciences, 2022, 23 (21):13045.

https://doi.org/10.3390/ijms232113045

[26]

KHAN S, MOORE RJ, STANLEY D, CHOUSALKAR KK. The gut microbiota of laying hens and its manipulation with prebiotics and probiotics to enhance gut health and food safety[J]. Applied and Environmental Microbiology, 2020, 86 (13):e00600-20.

[27]

OSIMO EF, PILLINGER T, RODRIGUEZ IM, KHANDAKER GM, PARIANTE CM, HOWES OD. Inflammatory markers in depression: a meta-analysis of mean differences and variability in 5 166 patients and 5 083 controls[J]. Brain, Behavior, and Immunity, 2020, 87,901-909.

https://doi.org/10.1016/j.bbi.2020.02.010

[28]

STRAWBRIDGE R, ARNONE D, DANESE A, PAPADOPOULOS A, HERANE VIVES A, CLEARE AJ. Inflammation and clinical response to treatment in depression: a meta-analysis[J]. European Neuropsychopharmacology, 2015, 25 (10):1532-1543.

https://doi.org/10.1016/j.euroneuro.2015.06.007

[29]

DOWLATI Y, HERRMANN N, SWARDFAGER W, LIU H, SHAM L, REIM EK, LANCTÔT KL. A meta-analysis of cytokines in major depression[J]. Biological Psychiatry, 2010, 67 (5):446-457.

https://doi.org/10.1016/j.biopsych.2009.09.033

[30]

WANG YH, XU JJ, LIU Y, LI ZY, LI XH. TLR4-NF-κB signal involved in depressive-like behaviors and cytokine expression of frontal cortex and hippocampus in stressed C57BL/6 and ob/ob mice[J]. Neural Plasticity, 2018, 2018,7254016.

[31]

YAMANISHI K, DOE N, MUKAI K, HASHIMOTO T, GAMACHI N, HATA M, WATANABE Y, YAMANISHI C, YAGI H, OKAMURA H, MATSUNAGA H. Acute stress induces severe neural inflammation and overactivation of glucocorticoid signaling in interleukin-18-deficient mice[J]. Translational Psychiatry, 2022, 12,404.

https://doi.org/10.1038/s41398-022-02175-7

[32]

CHEN YJ, XU JY, CHEN Y. Regulation of neurotransmitters by the gut microbiota and effects on cognition in neurological disorders[J]. Nutrients, 2021, 13 (6):2099.

https://doi.org/10.3390/nu13062099

[33]

DICKS LMT. Gut bacteria and neurotransmitters[J]. Microorganisms, 2022, 10 (9):1838.

https://doi.org/10.3390/microorganisms10091838

[34]

GAO K, PI Y, MU CL, FARZI A, LIU Z, ZHU WY. Increasing carbohydrate availability in the hindgut promotes hypothalamic neurotransmitter synthesis: aromatic amino acids linking the microbiota-brain axis[J]. Journal of Neurochemistry, 2019, 149 (5):641-659.

https://doi.org/10.1111/jnc.14709

[35]

GAO K, PI Y, MU CL, PENG Y, HUANG Z, ZHU WY. Antibiotics-induced modulation of large intestinal microbiota altered aromatic amino acid profile and expression of neurotransmitters in the hypothalamus of piglets[J]. Journal of Neurochemistry, 2018, 146 (3):219-234.

https://doi.org/10.1111/jnc.14333

[36]

MINUK GY, SARJEANT EJ. The effect of (a) neomycin and lactulose treatment on systemic and portal serum GABA levels in rats and (b) pH changes on [3H] GABA binding to isolated rat hepatocytes[J]. Clinical and Investigative Medicine Medecine Clinique et Experimentale, 1988, 11 (5):373-376.

[37]

NAM KH, ORDUREAU A. How does the neuronal proteostasis network react to cellular cues?[J]. Biochemical Society Transactions, 2024, 52 (2):581-592.

https://doi.org/10.1042/BST20230316

[38]

BAEK JS, SHIN YJ, MA XY, PARK HS, HWANG YH, KIM DH. Bifidobacterium bifidum and Lactobacillus paracasei alleviate sarcopenia and cognitive impairment in aged mice by regulating gut microbiota-mediated AKT, NF-κB, and FOXO3a signaling pathways[J]. Immunity & Ageing, 2023, 20 (1):56.

[39]

LI L, LI XF, ZHONG WL, YANG M, XU MQ, SUN Y, MA JH, LIU TY, SONG XL, DONG WX, LIU X, CHEN YG, LIU Y, ABLA Z, LIU WT, WANG BM, JIANG K, CAO HL. Gut microbiota from colorectal cancer patients enhances the progression of intestinal adenoma in Apc^min/+ mice[J]. EBioMedicine, 2019, 48,301-315.

https://doi.org/10.1016/j.ebiom.2019.09.021

[40]

ANDERSON EM, ROZOWSKY JM, FAZZONE BJ, SCHMIDT EA, STEVENS BR, O'MALLEY KA, SCALI ST, BERCELI SA. Temporal dynamics of the intestinal microbiome following short-term dietary restriction[J]. Nutrients, 2022, 14 (14):2785.

https://doi.org/10.3390/nu14142785

[41]

HSU YJ, HUANG WC, LIN JS, CHEN YM, HO ST, HUANG CC, TUNG YT. Kefir supplementation modifies gut microbiota composition, reduces physical fatigue, and improves exercise performance in mice[J]. Nutrients, 2018, 10 (7):862.

https://doi.org/10.3390/nu10070862

[42]

ZHU XX, MA QY, YANG FR, LI XJ, LIU YY, CHEN JB, LI L, CHEN M, ZOU XJ, YAN L, CHEN JX. Xiaoyaosan ameliorates chronic restraint stress-induced depression-like phenotype by suppressing A2AR signaling in the rat Striatum[J]. Frontiers in Pharmacology, 2022, 13,897436.

https://doi.org/10.3389/fphar.2022.897436

[43]

ZHU XF, LI T, HU E, DUAN LH, ZHANG CH, WANG Y, TANG T, YANG ZY, FAN R. Proteomics study reveals the anti-depressive mechanisms and the compatibility advantage of chaihu-shugan-san in a rat model of chronic unpredictable mild stress[J]. Frontiers in Pharmacology, 2022, 12,791097.

https://doi.org/10.3389/fphar.2021.791097

[44]

McDONALD K, SMITH T, BROADBENT M, PATEL R, GEDDES JR, SAUNDERS KEA. Prevalence and incidence of clinical outcomes in patients presenting to secondary mental health care with mood instability and sleep disturbance[J]. European Psychiatry, 2020, 63 (1):e59.

https://doi.org/10.1192/j.eurpsy.2020.39

[45]

KELLY JR, BORRE Y, O' BRIEN C, PATTERSON E, EL AIDY S, DEANE J, KENNEDY PJ, BEERS S, SCOTT K, MOLONEY G, HOBAN AE, SCOTT L, FITZGERALD P, ROSS P, STANTON C, CLARKE G, CRYAN JF, DINAN TG. Transferring the blues: depression-associated gut microbiota induces neurobehavioural changes in the rat[J]. Journal of Psychiatric Research, 2016, 82,109-118.

https://doi.org/10.1016/j.jpsychires.2016.07.019

[46]

ZHENG P, ZENG B, ZHOU C, LIU M, FANG Z, XU X, ZENG L, CHEN J, FAN S, DU X, ZHANG X, YANG D, YANG Y, MENG H, LI W, MELGIRI ND, LICINIO J, WEI H, XIE P. Gut microbiome remodeling induces depressive-like behaviors through a pathway mediated by the host's metabolism[J]. Molecular Psychiatry, 2016, 21 (6):786-796.

https://doi.org/10.1038/mp.2016.44

[47]

MARTINO C, DILMORE AH, BURCHAM ZM, METCALF JL, JESTE D, KNIGHT R. Microbiota succession throughout life from the cradle to the grave[J]. Nature Reviews Microbiology, 2022, 20,707-720.

https://doi.org/10.1038/s41579-022-00768-z

[48]

YANG Y, NGUYEN M, KHETRAPAL V, SONNERT ND, MARTIN AL, CHEN HW, KRIEGEL MA, PALM NW. Within-host evolution of a gut pathobiont facilitates liver translocation[J]. Nature, 2022, 607,563-570.

https://doi.org/10.1038/s41586-022-04949-x

[49]

CHEN JJ, HE SR, FANG L, WANG B, BAI SJ, XIE J, ZHOU CJ, WANG W, XIE P. Age-specific differential changes on gut microbiota composition in patients with major depressive disorder[J]. Aging, 2020, 12 (3):2764-2776.

https://doi.org/10.18632/aging.102775

[50]

YANG J, ZHENG P, LI YF, WU J, TAN XM, ZHOU JJ, SUN ZL, CHEN X, ZHANG GF, ZHANG HP, HUANG Y, CHAI TJ, DUAN JJ, LIANG WW, YIN BM, LAI JB, HUANG TT, DU YL, ZHANG PF, JIANG JJ, et al. Landscapes of bacterial and metabolic signatures and their interaction in major depressive disorders[J]. Science Advances, 2020, 6 (49):eaba8555.

https://doi.org/10.1126/sciadv.aba8555

[51]

SHKOPOROV AN, TURKINGTON CJ, HILL C. Mutualistic interplay between bacteriophages and bacteria in the human gut[J]. Nature Reviews Microbiology, 2022, 20,737-749.

https://doi.org/10.1038/s41579-022-00755-4

[52]

JIANG HY, PAN LY, ZHANG X, ZHANG Z, ZHOU YY, RUAN B. Altered gut bacterial-fungal inter kingdom networks in patients with current depressive episode[J]. Brain and Behavior, 2020, 10 (8):e01677.

https://doi.org/10.1002/brb3.1677

[53]

MUDIMELA S, VISHWANATH NK, PILLAI A, MORALES R, MARRELLI SP, BARICHELLO T, GIRIDHARAN VV. Clinical significance and potential role of trimethylamine N-oxide in neurological and neuropsychiatric disorders[J]. Drug Discovery Today, 2022, 27 (11):103334.

https://doi.org/10.1016/j.drudis.2022.08.002

[54]

SKONIECZNA-ŻYDECKA K, GROCHANS E, MACIEJEWSKA D, SZKUP M, SCHNEIDER-MATYKA D, JURCZAK A, ŁONIEWSKI I, KACZMARCZYK M, MARLICZ W, CZERWIŃSKA-ROGOWSKA M, PEŁKA-WYSIECKA J, DEC K, STACHOWSKA E. Faecal short chain fatty acids profile is changed in Polish depressive women[J]. Nutrients, 2018, 10 (12):1939.

https://doi.org/10.3390/nu10121939

[55]

ORTEGA MA, ALVAREZ-MON MA, GARCÍA-MONTERO C, FRAILE-MARTINEZ O, GUIJARRO LG, LAHERA G, MONSERRAT J, VALLS P, MORA F, RODRÍGUEZ-JIMÉNEZ R, QUINTERO J, ÁLVAREZ-MON M. Gut microbiota metabolites in major depressive disorder-deep insights into their pathophysiological role and potential translational applications[J]. Metabolites, 2022, 12 (1):50.

https://doi.org/10.3390/metabo12010050

[56]

LI T, ZHENG LN, HAN XH. Fenretinide attenuates lipopolysaccharide (LPS)-induced blood-brain barrier (BBB) and depressive-like behavior in mice by targeting Nrf-2 signaling[J]. Biomedicine & Pharmacotherapy, 2020, 125,109680.

[57]

RUDZKI L, STONE TW, MAES M, MISIAK B, SAMOCHOWIEC J, SZULC A. Gut microbiota-derived vitamins-underrated powers of a multipotent ally in psychiatric health and disease[J]. Progress in Neuro-Psychopharmacology & Biological Psychiatry, 2021, 107,110240.

[58]

CRYAN JF, O'RIORDAN KJ, COWAN CSM, SANDHU KV, BASTIAANSSEN TFS, BOEHME M, CODAGNONE MG, CUSSOTTO S, FULLING C, GOLUBEVA AV, GUZZETTA KE, JAGGAR M, LONG-SMITH CM, LYTE JM, MARTIN JA, MOLINERO-PEREZ A, MOLONEY G, MORELLI E, MORILLAS E, O'CONNOR R, et al. The microbiota-gut-brain axis[J]. Physiological Reviews, 2019, 99 (4):1877-2013.

https://doi.org/10.1152/physrev.00018.2018

[59]

KRONSTEN VT, TRANAH TH, PARIANTE C, SHAWCROSS DL. Gut-derived systemic inflammation as a driver of depression in chronic liver disease[J]. Journal of Hepatology, 2022, 76 (3):665-680.

https://doi.org/10.1016/j.jhep.2021.11.008

[60]

KIECOLT-GLASER JK, WILSON SJ, BAILEY ML, ANDRIDGE R, PENG J, JAREMKA LM, FAGUNDES CP, MALARKEY WB, LASKOWSKI B, BELURY MA. Marital distress, depression, and a leaky gut: translocation of bacterial endotoxin as a pathway to inflammation[J]. Psychoneuroendocrinology, 2018, 98,52-60.

https://doi.org/10.1016/j.psyneuen.2018.08.007

[61]

PU YY, TAN YF, QU YG, CHANG LJ, WANG SM, WEI Y, WANG XM, HASHIMOTO K. A role of the subdiaphragmatic vagus nerve in depression-like phenotypes in mice after fecal microbiota transplantation from Chrna7 knock-out mice with depression-like phenotypes[J]. Brain, Behavior, and Immunity, 2021, 94,318-326.

https://doi.org/10.1016/j.bbi.2020.12.032

[62]

张艺, 许宁宁, 彭子翀, 陈容平. 粪菌移植通过微生物-肠-脑轴改善抑郁症的研究进展[J]. 微生物学通报, 2022, 49 (2):756-768. https://www.cnki.com.cn/Article/CJFDTOTAL-WSWT202202029.htm

ZHANG Y, XU NN, PENG ZC, CHEN RP. Fecal microbiota transplantation to improve depression by modulating microbiota-gut-brain axis: a review[J]. Microbiology China, 2022, 49 (2):756-768 (in Chinese). https://www.cnki.com.cn/Article/CJFDTOTAL-WSWT202202029.htm

[63]

赵零, 武树奇, 许宁宁, 陈容平. 肠道上皮与肠道微生物相互作用的研究现状[J]. 微生物学通报, 2022, 49 (8):3508-3519. https://www.cnki.com.cn/Article/CJFDTOTAL-WSWT202208038.htm

ZHAO L, WU SQ, XU NN, CHEN RP. Interaction between intestinal epithelium and microbiome[J]. Microbiology China, 2022, 49 (8):3508-3519 (in Chinese). https://www.cnki.com.cn/Article/CJFDTOTAL-WSWT202208038.htm

[64]

LIN CH, WEI PC, CHEN CM, HUANG YT, LIN JL, LO YS, LIN JL, LIN CY, WU YR, CHANG KH, LEE-CHEN GJ. Lactulose and melibiose attenuate MPTP-induced Parkinson's disease in mice by inhibition of oxidative stress, reduction of neuroinflammation and up-regulation of autophagy[J]. Frontiers in Aging Neuroscience, 2020, 12,226.

https://doi.org/10.3389/fnagi.2020.00226

[65]

HIGUERA-DE-LA-TIJERA F, VELARDE-RUIZ VELASCO JA, RAÑA-GARIBAY RH, CASTRO-NARRO GE, ABDO-FRANCIS JM, MORENO-ALCÁNTAR R, PÉREZ-HERNÁNDEZ JL, TORRE A, CONTRERAS-OMAÑA R, CANO-CONTRERAS A, CASTILLO-BARRADAS M, PÉREZ-ESCOBAR J, ALDANA-LEDESMA JM, CERDA-REYES E, FERNÁNDEZ-PÉREZ NJ, MEZA-CARDONA J, FLORES-GARCÍA NC, REYES-BASTIDAS M, LIRA-VERA JE, GARCÍA-JIMÉNEZ ES, et al. Current vision on diagnosis and comprehensive care in hepatic encephalopathy[J]. Revista de Gastroenterologia de Mexico (English), 2023, 88 (2):155-174.

https://doi.org/10.1016/j.rgmx.2023.03.001

[66]

CHEN ZF, RUAN JS, LI DH, WANG M, HAN ZW, QIU WX, WU GB. The role of intestinal bacteria and gut-brain axis in hepatic encephalopathy[J]. Frontiers in Cellular and Infection Microbiology, 2021, 10,595759.

https://doi.org/10.3389/fcimb.2020.595759

[67]

YANG N, LIU H, JIANG Y, ZHENG J, LI DM, JI C, LIU YY, ZUO PP. Lactulose enhances neuroplasticity to improve cognitive function in early hepatic encephalopathy[J]. Neural Regeneration Research, 2015, 10 (9):1457-1462.

https://doi.org/10.4103/1673-5374.165516

[68]

HUDSON M, SCHUCHMANN M. Long-term management of hepatic encephalopathy with lactulose and/or rifaximin: a review of the evidence[J]. European Journal of Gastroenterology & Hepatology, 2019, 31 (4):434-450.

[69]

YUN QP, WANG SY, CHEN SQ, LUO H, LI BY, YIP P, YU X, YANG ZR, SHA F, TANG JL. Constipation preceding depression: a population-based cohort study[J]. EClinicalMedicine, 2024, 67,102371.

https://doi.org/10.1016/j.eclinm.2023.102371

[70]

KASUGAI K, IWAI H, KUBOYAMA N, YOSHIKAWA A, FUKUDO S. Efficacy and safety of a crystalline lactulose preparation (SK-1202) in Japanese patients with chronic constipation: a randomized, double-blind, placebo-controlled, dose-finding study[J]. Journal of Gastroenterology, 2019, 54 (6):530-540.

https://doi.org/10.1007/s00535-018-01545-7

[71]

SADLER K, ARNOLD F, DEAN S. Chronic constipation in adults[J]. American Family Physician, 2022, 106 (3):299-306.

[72]

ZHANG XY, ZHENG JP, JIANG N, SUN GJ, BAO XK, KONG MW, CHENG X, LIN AZ, LIU HT. Modulation of gut microbiota and intestinal metabolites by lactulose improves loperamide-induced constipation in mice[J]. European Journal of Pharmaceutical Sciences, 2021, 158,105676.

https://doi.org/10.1016/j.ejps.2020.105676

[73]

KUBOTA M, ITO K, TOMIMOTO K, KANAZAKI M, TSUKIYAMA K, KUBOTA A, KUROKI H, FUJITA M, VANDENPLAS Y. Lactobacillus reuteri DSM 17938 and magnesium oxide in children with functional chronic constipation: a double-blind and randomized clinical trial[J]. Nutrients, 2020, 12 (1):225.

https://doi.org/10.3390/nu12010225

[74]

JANG HM, LEE KE, KIM DH. The preventive and curative effects of Lactobacillus reuteri NK33 and Bifidobacterium adolescentis NK98 on immobilization stress-induced anxiety/depression and colitis in mice[J]. Nutrients, 2019, 11 (4):819.

https://doi.org/10.3390/nu11040819

[75]

COLLINS SL, McMILLAN A, SENEY S, van der VEER C, KORT R, SUMARAH MW, REID G. Promising prebiotic candidate established by evaluation of lactitol, lactulose, raffinose, and oligofructose for maintenance of a Lactobacillus-dominated vaginal microbiota[J]. Applied and Environmental Microbiology, 2018, 84 (5):e02200-17.

[76]

潘姣, 张晓雨, 孙光军, 林爱珍. 缩泉润肠方对便秘模型大鼠结肠组织中水通道蛋白的影响[J]. 中医学报, 2022, 37 (2):360-364. https://www.cnki.com.cn/Article/CJFDTOTAL-HNZK202202029.htm

PAN J, ZHANG XY, SUN GJ, LIN AZ. Effect of Suo Quan Run Chang formula on aquaporin in colon tissue of constipation model rats based on theory of facilitating urination to compacting stool[J]. Acta Chinese Medicine, 2022, 37 (2):360-364 (in Chinese). https://www.cnki.com.cn/Article/CJFDTOTAL-HNZK202202029.htm

[77]

潘姣, 孙光军, 林爱珍. 缩泉润肠方治疗脾肾阳虚型便秘临床观察[J]. 中西医结合研究, 2021, 13 (6):402-403,406.

https://doi.org/10.3969/j.issn.1674-4616.2021.06.011

PAN J, SUN GJ, LIN AZ. Clinical observation on treating constipation of spleen and kidney Yang deficiency type with Suoquan Runchang recipe[J]. Research of Integrated Traditional Chinese and Western Medicine, 2021, 13 (6):402-403,406 (in Chinese).

https://doi.org/10.3969/j.issn.1674-4616.2021.06.011

[78]

程永华, 靳楠楠, 田亚振. 补肾滋阴润肠方联合乳果糖治疗帕金森病便秘随机平行对照研究[J]. 江西中医药大学学报, 2021, 33 (2):50-52. https://www.cnki.com.cn/Article/CJFDTOTAL-XYXB202102015.htm

CHENG YH, JIN NN, TIAN YZ. A randomized parallel controlled study on the treatment of Parkinson's disease constipation with Bushen Ziyin Runchang prescription combined with lactofructose[J]. Journal of Jiangxi University of Traditional Chinese Medicine, 2021, 33 (2):50-52 (in Chinese). https://www.cnki.com.cn/Article/CJFDTOTAL-XYXB202102015.htm

[79]

万东炎. 乳果糖联用莫沙比利治疗帕金森症便秘临床疗效观察[J]. 临床合理用药杂志, 2015, 8 (11):12-13. https://www.cnki.com.cn/Article/CJFDTOTAL-PLHY201511007.htm

WAN DY. Effect observation of lactulose combined with mosapride in the treatment of Parkinsonism with constipation[J]. Chinese Journal of Clinical Rational Drug Use, 2015, 8 (11):12-13 (in Chinese). https://www.cnki.com.cn/Article/CJFDTOTAL-PLHY201511007.htm

[80]

SILVA YP, BERNARDI A, FROZZA RL. The role of short-chain fatty acids from gut microbiota in gut-brain communication[J]. Frontiers in Endocrinology, 2020, 11,25.

https://doi.org/10.3389/fendo.2020.00025

[81]

RUDZKI L, MAES M. The microbiota-gut-immune-Glia (MGIG) axis in major depression[J]. Molecular Neurobiology, 2020, 57 (10):4269-4295.

https://doi.org/10.1007/s12035-020-01961-y

[82]

LIU H, WANG J, HE T, BECKER S, ZHANG GL, LI DF, MA X. Butyrate: a double-edged sword for health?[J]. Advances in Nutrition, 2018, 9 (1):21-29.

https://doi.org/10.1093/advances/nmx009

[83]

IKEDA T, NISHIDA A, YAMANO M, KIMURA I. Short-chain fatty acid receptors and gut microbiota as therapeutic targets in metabolic, immune, and neurological diseases[J]. Pharmacology & Therapeutics, 2022, 239,108273.

[84]

BLAAK EE, CANFORA EE, THEIS S, FROST G, GROEN AK, MITHIEUX G, NAUTA A, SCOTT K, STAHL B, van HARSSELAAR J, van TOL R, VAUGHAN EE, VERBEKE K. Short chain fatty acids in human gut and metabolic health[J]. Beneficial Microbes, 2020, 11 (5):411-455.

https://doi.org/10.3920/BM2020.0057

[85]

MA QT, LI YQ, WANG JK, LI PF, DUAN YH, DAI HY, AN YC, CHENG L, WANG TS, WANG CG, WANG T, ZHAO BS. Investigation of gut microbiome changes in type 1 diabetic mellitus rats based on high-throughput sequencing[J]. Biomedicine & Pharmacotherapy, 2020, 124,109873.

[86]

HAO CY, GAO ZF, LIU XJ, RONG ZJ, JIA JJ, KANG KQ, GUO WW, LI JG. Intravenous administration of sodium propionate induces antidepressant or prodepressant effect in a dose dependent manner[J]. Scientific Reports, 2020, 10,19917.

https://doi.org/10.1038/s41598-020-77085-z

[87]

CHEN JJ, ZHENG P, LIU YY, ZHONG XG, WANG HY, GUO YJ, XIE P. Sex differences in gut microbiota in patients with major depressive disorder[J]. Neuropsychiatric Disease and Treatment, 2018, 14,647-655.

https://doi.org/10.2147/NDT.S159322

[88]

TELLES-CORREIA D, JOÃO FREIRE M, MEGA I, BARREIRAS D, CORTEZ PINTO H. Anxiety and depression symptoms in hepatic encephalopathy: are they psychiatric or organic?[J]. Transplantation Proceedings, 2015, 47 (4):1005-1007.

https://doi.org/10.1016/j.transproceed.2015.03.011

[89]

李文惠. 分析乳果糖预防肝硬化患者上消化道出血后诱发肝性脑病的疗效[J]. 医学食疗与健康, 2022, 20 (13):29-31,42. https://www.cnki.com.cn/Article/CJFDTOTAL-YXSL202213009.htm

LI WH. To analyze the effect of lactulose in preventing hepatic encephalopathy induced by upper gastrointestinal bleeding in patients with liver cirrhosis[J]. Medical Diet and Health, 2022, 20 (13):29-31,42 (in Chinese). https://www.cnki.com.cn/Article/CJFDTOTAL-YXSL202213009.htm

[90]

刘宁静, 于慧静, 曹晓春. 门冬氨酸鸟氨酸联合乳果糖对老年肝性脑病疗效和NSE的影响[J]. 中南医学科学杂志, 2023, 51 (4):579-581 https://www.cnki.com.cn/Article/CJFDTOTAL-HYYY202304026.htm

LIU NJ, YU HJ, CAO XC. Effect of ornithine aspartate combined with lactulose on curative effects and NSE in elderly patients with hepatic encephalopathy[J]. Medical Science Journal of Central South China, 2023, 51 (4):579-581 (in Chinese). https://www.cnki.com.cn/Article/CJFDTOTAL-HYYY202304026.htm

[91]

PLOTOGEA OM, DIACONU CC, GHEORGHE G, STAN-ILIE M, BADEA MA, PRELIPCEAN CC, CONSTANTINESCU G. The prevalence and association of cognitive impairment with sleep disturbances in patients with chronic liver disease[J]. Brain Sciences, 2022, 12 (4):444.

https://doi.org/10.3390/brainsci12040444

[92]

周志儒. 乳果糖对急性肝损伤大鼠肠道菌群及血清代谢物影响的实验研究[D]. 太原: 山西医科大学硕士学位论文, 2020.

ZHOU ZR. Effect of lactulose on the intestinal flora and serum metabolites in rats with acute liver injury[D]. Taiyuan: Master's Thesis of Shanxi Medical University, 2020 (in Chinese).

[93]

PHAM VT, DOLD S, REHMAN A, BIRD JK, STEINERT RE. Vitamins, the gut microbiome and gastrointestinal health in humans[J]. Nutrition Research, 2021, 95,35-53.

https://doi.org/10.1016/j.nutres.2021.09.001

[94]

HANNA M, JAQUA E, NGUYEN V, CLAY J. B vitamins: functions and uses in medicine[J]. The Permanente Journal, 2022, 26 (2):89-97.

https://doi.org/10.7812/TPP/21.204

[95]

CALDERÓN-OSPINA CA, NAVA-MESA MO. B vitamins in the nervous system: current knowledge of the biochemical modes of action and synergies of thiamine, pyridoxine, and cobalamin[J]. CNS Neuroscience & Therapeutics, 2020, 26 (1):5-13.

[96]

CHATTERJEE K, MAZUMDER PM, SARKAR SR, SAHA R, CHATTERJEE A, SARKAR B, BANERJEE S. Neuroprotective effect of vitamin K2 against gut dysbiosis associated cognitive decline[J]. Physiology & Behavior, 2023, 269,114252.

[97]

KOUBA BR, CAMARGO A, GIL-MOHAPEL J, RODRIGUES ALS. Molecular basis underlying the therapeutic potential of vitamin D for the treatment of depression and anxiety[J]. International Journal of Molecular Sciences, 2022, 23 (13):7077.

https://doi.org/10.3390/ijms23137077

[98]

EKINCI GN, SANLIER N. The relationship between nutrition and depression in the life process: a mini-review[J]. Experimental Gerontology, 2023, 172,112072.

https://doi.org/10.1016/j.exger.2022.112072

[99]

COPPEN A, BOLANDER-GOUAILLE C. Treatment of depression: time to consider folic acid and vitamin B₁₂[J]. Journal of Psychopharmacology, 2005, 19 (1):59-65.

https://doi.org/10.1177/0269881105048899

[100]

TING EYC, YANG AC, TSAI SJ. Role of interleukin-6 in depressive disorder[J]. International Journal of Molecular Sciences, 2020, 21 (6):2194.

https://doi.org/10.3390/ijms21062194

[101]

TROUBAT R, BARONE P, LEMAN S, DESMIDT T, CRESSANT A, ATANASOVA B, BRIZARD B, EL HAGE W, SURGET A, BELZUNG C, CAMUS V. Neuroinflammation and depression: a review[J]. The European Journal of Neuroscience, 2021, 53 (1):151-171.

https://doi.org/10.1111/ejn.14720

[102]

CUEVAS-GARCÍA CF, SEGURA-MÉNDEZ NH, HERRERA-SÁNCHEZ DA. Actualidades en la inmunopatología de la esclerosis múltiple[J]. Gaceta Medica de Mexico, 2018, 154 (5):588-597.

[103]

STEVENS BR, GOEL R, SEUNGBUM K, RICHARDS EM, HOLBERT RC, PEPINE CJ, RAIZADA MK. Increased human intestinal barrier permeability plasma biomarkers zonulin and FABP2 correlated with plasma LPS and altered gut microbiome in anxiety or depression[J]. Gut, 2018, 67 (8):1555-1557.

[104]

YANG YB, LI LL, XU CJ, WANG YK, WANG Z, CHEN MY, JIANG Z, PAN J, YANG CH, LI XQ, SONG K, YAN JF, XIE WL, WU XG, CHEN ZG, YUAN Y, ZHENG S, YAN J, HUANG J, QIU FM. Cross-talk between the gut microbiota and monocyte-like macrophages mediates an inflammatory response to promote colitis-associated tumourigenesis[J]. Gut, 2020, 70 (8):1495-1506.

[105]

PROSPERO L, RIEZZO G, LINSALATA M, ORLANDO A, D'ATTOMA B, Di MASI M, MARTULLI M, RUSSO F. Somatization in patients with predominant diarrhoea irritable bowel syndrome: the role of the intestinal barrier function and integrity[J]. BMC Gastroenterology, 2021, 21 (1):235.

https://doi.org/10.1186/s12876-021-01820-7

[106]

CLARK A, MACH N. Exercise-induced stress behavior, gut-microbiota-brain axis and diet: a systematic review for athletes[J]. Journal of the International Society of Sports Nutrition, 2016, 13,43.

https://doi.org/10.1186/s12970-016-0155-6

[107]

SUN LJ, MA LJ, ZHANG HH, CAO Y, WANG CC, HOU NN, HUANG N, von DENEEN KM, ZHAO CH, SHI YP, PAN Y, WANG MX, JI G, NIE YZ. Fto deficiency reduces anxiety- and depression-like behaviors in mice via alterations in gut microbiota[J]. Theranostics, 2019, 9 (3):721-733.

https://doi.org/10.7150/thno.31562

[108]

MONJE FJ, CABATIC M, DIVISCH I, KIM EJ, HERKNER KR, BINDER BR, POLLAK DD. Constant darkness induces IL-6-dependent depression-like behavior through the NF-κB signaling pathway[J]. The Journal of Neuroscience, 2011, 31 (25):9075-9083.

https://doi.org/10.1523/JNEUROSCI.1537-11.2011

[109]

李瑶, 陈旖, 朱丹妮, 宋小红, 张金龙, 张哲, 赵拯浩, 侯利华, 吴诗坡, 陈薇. 重组人神经生长因子通过抑制小胶质细胞炎症反应发挥神经保护作用[J]. 中国药理学与毒理学杂志, 2023, 37 (8):574-582.

https://doi.org/10.3867/j.issn.1000-3002.2023.08.002

LI Y, CHEN Y, ZHU DN, SONG XH, ZHANG JL, ZHANG Z, ZHAO ZH, HOU LH, WU SP, CHEN W. Neuroprotective effect of recombinant human nerve growth factors by inhibiting microglia inflammation[J]. Chinese Journal of Pharmacology and Toxicology, 2023, 37 (8):574-582 (in Chinese).

https://doi.org/10.3867/j.issn.1000-3002.2023.08.002

[110]

LIU ZZ, LI T, LI P, WEI NN, ZHAO ZQ, LIANG HM, JI XY, CHEN WW, XUE MZ, WEI JS. The ambiguous relationship of oxidative stress, tau hyperphosphorylation, and autophagy dysfunction in Alzheimer's disease[J]. Oxidative Medicine and Cellular Longevity, 2015, 2015,352723.

[111]

巩子汉, 王英, 杨婧雯, 梁文青, 孟丹华, 佘楷杰, 梁媛, 岳广欣. 二次打击致抑郁小鼠的证候属性及其机制[J]. 中国实验方剂学杂志, 2024, 30 (6):29-38 https://www.cnki.com.cn/Article/CJFDTOTAL-ZSFX202406004.htm

GONG ZH, WANG Y, YANG JW, LIANG WQ, MENG DH, SHE KJ, LIANG Y, YUE GX. Syndromes and mechanisms of depression induced by second hit in mice[J]. Chinese Journal of Experimental Traditional Medical Formulae, 2024, 30 (6):29-38 (in Chinese). https://www.cnki.com.cn/Article/CJFDTOTAL-ZSFX202406004.htm

[112]

PURICELLI C, ROLLA R, GIGLIOTTI L, BOGGIO E, BELTRAMI E, DIANZANI U, KELLER R. The gut-brain-immune axis in autism spectrum disorders: a state-of-art report[J]. Frontiers in Psychiatry, 2022, 12,755171.

https://doi.org/10.3389/fpsyt.2021.755171

[113]

ZHENG WJ, JI X, ZHANG Q, DU WC, WEI QW, YAO W. Hydrogen-rich water and lactulose protect against growth suppression and oxidative stress in female piglets fed Fusarium toxins contaminated diets[J]. Toxins, 2018, 10 (6):228.

https://doi.org/10.3390/toxins10060228

[114]

ILGIN S, CAN OD, ATLI O, UCEL UI, SENER E, GUVEN I. Ciprofloxacin-induced neurotoxicity: evaluation of possible underlying mechanisms[J]. Toxicology Mechanisms and Methods, 2015, 25 (5):374-381.

https://doi.org/10.3109/15376516.2015.1026008

[115]

ARJUNAN P, LIN XC, TANG ZS, DU YX, KUMAR A, LIU LX, YIN XK, HUANG LJ, CHEN W, CHEN QS, YE ZM, WANG SS, KUANG HQ, ZHOU LB, XU K, CHEN X, ZENG HT, LU WS, CAO YH, LIU YZ, et al. VEGF-B is a potent antioxidant[J]. Proceedings of the National Academy of Sciences of the United States of America, 2018, 115 (41):10351-10356.

[116]

LEE MH, LEE YC, KIM SS, HONG HD, KIM KT. Quality and antioxidant activity of ginseng seed processed by fermentation strains[J]. Journal of Ginseng Research, 2015, 39 (2):178-182.

https://doi.org/10.1016/j.jgr.2014.10.007

[117]

PENG GJ, TIAN JS, GAO XX, ZHOU YZ, QIN XM. Research on the pathological mechanism and drug treatment mechanism of depression[J]. Current Neuropharmacology, 2015, 13 (4):514-523.

https://doi.org/10.2174/1570159X1304150831120428

[118]

SAVITZ J, FORD BN, YEH HW, AKEMAN E, COSGROVE K, CLAUSEN AN, MARTELL C, KIRLIC N, SANTIAGO J, TEAGUE TK, IRWIN MR, PAULUS MP, AUPPERLE RL. Behavioral activation therapy for depression is associated with a reduction in the concentration of circulating quinolinic acid[J]. Psychological Medicine, 2022, 52 (13):2500-2509.

https://doi.org/10.1017/S0033291720004389

[119]

KLIMOVA B, NOVOTNY M, VALIS M. The impact of nutrition and intestinal microbiome on elderly depression-a systematic review[J]. Nutrients, 2020, 12 (3):710.

https://doi.org/10.3390/nu12030710

[120]

ZHANG Z, ZHAO JT, TIAN CY, CHEN X, LI H, WEI X, LIN WS, ZHENG NX, JIANG AM, FENG R, YUAN J, ZHAO XN. Targeting the gut microbiota to investigate the mechanism of lactulose in negating the effects of a high-salt diet on hypertension[J]. Molecular Nutrition & Food Research, 2019, 63 (11):e1800941.

[121]

HASHIKURA N, MURAKAMI R, SAKURAI T, HORIGOME A, TODA K, XIAO JZ, ODAMAKI T. Synbiotics of Bifidobacterium breve MCC1274 and lactulose enhances production of tryptophan metabolites in fermented human fecal communities[J]. Food Research International, 2023, 163,112308.

https://doi.org/10.1016/j.foodres.2022.112308

[122]

FRIES GR, SALDANA VA, FINNSTEIN J, REIN T. Molecular pathways of major depressive disorder converge on the synapse[J]. Molecular Psychiatry, 2023, 28,284-297.

https://doi.org/10.1038/s41380-022-01806-1

[123]

DOBIELSKA M, BARTOSIK NK, ZYZIK KA, KOWALCZYK E, KARBOWNIK MS. Mechanisms of cognitive impairment in depression. May probiotics help?[J]. Frontiers in Psychiatry, 2022, 13,904426.

https://doi.org/10.3389/fpsyt.2022.904426

[124]

GUARINO MPL, ALTOMARE A, EMERENZIANI S, di ROSA C, RIBOLSI M, BALESTRIERI P, IOVINO P, ROCCHI G, CICALA M. Mechanisms of action of prebiotics and their effects on gastro-intestinal disorders in adults[J]. Nutrients, 2020, 12 (4):1037.

https://doi.org/10.3390/nu12041037

[125]

徐婧, 武喜明. 伊托必利联合乳果糖治疗便秘的效果及对血清5-HT、MOT及VIP表达水平的影响[J]. 中国肛肠病杂志, 2021, 41 (9):44-45.

https://doi.org/10.3969/j.issn.1000-1174.2021.09.020

XU J, WU XM. Efficacy of itopride plus lactulose in the treatment of constipation, and their influence on the expression of serum 5-hydroxytryptamine, motilin and vasoactive intestinal peptide[J]. Chinese Journal of Coloproctology, 2021, 41 (9):44-45 (in Chinese).

https://doi.org/10.3969/j.issn.1000-1174.2021.09.020

[126]

MAYNERIS-PERXACHS J, CASTELLS-NOBAU A, ARNORIAGA-RODRÍGUEZ M, MARTIN M, deLa VEGA-CORREA L, ZAPATA C, BUROKAS A, BLASCO G, COLL C, ESCRICHS A, BIARNÉS C, MORENO-NAVARRETE JM, PUIG J, GARRE-OLMO J, RAMOS R, PEDRAZA S, BRUGADA R, VILANOVA JC, SERENA J, GICH J, RAMIÓ-TORRENTÀ L, et al. Microbiota alterations in proline metabolism impact depression[J]. Cell Metabolism, 2022, 34 (5):681-701.e10.

https://doi.org/10.1016/j.cmet.2022.04.001

[127]

FRÖHLICH EE, FARZI A, MAYERHOFER R, REICHMANN F, JAČAN A, WAGNER B, ZINSER E, BORDAG N, MAGNES C, FRÖHLICH E, KASHOFER K, GORKIEWICZ G, HOLZER P. Cognitive impairment by antibiotic-induced gut dysbiosis: analysis of gut microbiota-brain communication[J]. Brain, Behavior, and Immunity, 2016, 56,140-155.

https://doi.org/10.1016/j.bbi.2016.02.020

[128]

FARZI A, REICHMANN F, HOLZER P. The homeostatic role of neuropeptide Y in immune function and its impact on mood and behaviour[J]. Acta Physiologica, 2015, 213 (3):603-627.

https://doi.org/10.1111/apha.12445

[129]

SHAHBAZI F, HOLMGREN S, LARHAMMAR D, JENSEN J. Neuropeptide Y effects on vasorelaxation and intestinal contraction in the Atlantic cod Gadus morhua[J]. American Journal of Physiology Regulatory, Integrative and Comparative Physiology, 2002, 282 (5):R1414-R1421.

https://doi.org/10.1152/ajpregu.00434.2001

[130]

RANA T, BEHL T, SEHGAL A, SINGH S, SHARMA N, ABDEEN A, IBRAHIM SF, MANI V, IQBAL MS, BHATIA S, ABDEL DAIM MM, BUNGAU S. Exploring the role of neuropeptides in depression and anxiety[J]. Progress in Neuro-Psychopharmacology & Biological Psychiatry, 2022, 114,110478.

[131]

ZHOU YP, YANG DJ, GU WJ. Efficacy and mechanism of trimebutine maleate combined with lactulose in the treatment of constipation-predominant irritable bowel syndrome in the elderly[J]. Emergency Medicine International, 2022, 2022,6125120.

[132]

ZHANG JC, YAO W, HASHIMOTO K. Brain-derived neurotrophic factor (BDNF)-TrkB signaling in inflammation-related depression and potential therapeutic targets[J]. Current Neuropharmacology, 2016, 14 (7):721-731.

https://doi.org/10.2174/1570159X14666160119094646

[133]

ALTAR CA. Neurotrophins and depression[J]. Trends in Pharmacological Sciences, 1999, 20 (2):59-61.

https://doi.org/10.1016/S0165-6147(99)01309-7

[134]

BROOK N, BROOK E, DHARMARAJAN A, CHAN A, DASS CR. Pigment epithelium-derived factor regulation of neuronal and stem cell fate[J]. Experimental Cell Research, 2020, 389 (2):111891.

https://doi.org/10.1016/j.yexcr.2020.111891

[135]

PHILLIPS C. Brain-derived neurotrophic factor, depression, and physical activity: making the neuroplastic connection[J]. Neural Plasticity, 2017, 2017,7260130.

[136]

HOSHAW BA, MALBERG JE, LUCKI I. Central administration of IGF-I and BDNF leads to long-lasting antidepressant-like effects[J]. Brain Research, 2005, 1037 (1/2):204-208.

[137]

KIM CS, CHA LN, SIM M, JUNG S, CHUN WY, BAIK HW, SHIN DM. Probiotic supplementation improves cognitive function and mood with changes in gut microbiota in community-dwelling older adults: a randomized, double-blind, placebo-controlled, multicenter trial[J]. The Journals of Gerontology: Series A, 2021, 76 (1):32-40.

https://doi.org/10.1093/gerona/glaa090

[138]

GASSEN NC, REIN T. Is there a role of autophagy in depression and antidepressant action?[J]. Frontiers in Psychiatry, 2019, 10,337.

https://doi.org/10.3389/fpsyt.2019.00337

[139]

SHU XD, SUN YM, SUN XY, ZHOU YZ, BIAN YQ, SHU ZM, DING JH, LU M, HU G. The effect of fluoxetine on astrocyte autophagy flux and injured mitochondria clearance in a mouse model of depression[J]. Cell Death & Disease, 2019, 10,577.

[140]

LEE YS, LAI DM, HUANG HJ, LEE-CHEN GJ, CHANG CH, HSIEH-LI HM, LEE GC. Prebiotic lactulose ameliorates the cognitive deficit in Alzheimer's disease mouse model through macroautophagy and chaperone-mediated autophagy pathways[J]. Journal of Agricultural and Food Chemistry, 2021, 69 (8):2422-2437.

https://doi.org/10.1021/acs.jafc.0c07327

[141]

GRAHEK I, SHENHAV A, MUSSLICK S, KREBS RM, KOSTER EHW. Motivation and cognitive control in depression[J]. Neuroscience and Biobehavioral Reviews, 2019, 102,371-381.

https://doi.org/10.1016/j.neubiorev.2019.04.011

[142]

ALI T, RAHMAN SU, HAO Q, LI WF, LIU ZZ, ALI SHAH F, MURTAZA I, ZHANG ZJ, YANG XF, LIU GP, LI SP. Melatonin prevents neuroinflammation and relieves depression by attenuating autophagy impairment through FOXO3a regulation[J]. Journal of Pineal Research, 2020, 69 (2):e12667.

https://doi.org/10.1111/jpi.12667

[143]

ZHANG K, WANG F, ZHAI MY, HE MY, HU YX, FENG LJ, LI YT, YANG JY, WU CF. Hyperactive neuronal autophagy depletes BDNF and impairs adult hippocampal neurogenesis in a corticosterone-induced mouse model of depression[J]. Theranostics, 2023, 13 (3):1059-1075.

https://doi.org/10.7150/thno.81067

[144]

陈容平, 杨锐, 陈宏. 菌群移植干预肥胖糖尿病专家共识[J]. 华南预防医学, 2022, 48 (10):1165-1169. https://www.cnki.com.cn/Article/CJFDTOTAL-GDWF202210001.htm

CHEN RP, YANG R, CHEN H. Consensus, standards and guidelines expert consensus on intervention of obese diabetes by microbiota transplantation[J]. South China Journal of Preventive Medicine, 2022, 48 (10):1165-1169 (in Chinese). https://www.cnki.com.cn/Article/CJFDTOTAL-GDWF202210001.htm

[145]

EL-SALHY M, CASEN C, VALEUR J, HAUSKEN T, HATLEBAKK JG. Responses to faecal microbiota transplantation in female and male patients with irritable bowel syndrome[J]. World Journal of Gastroenterology, 2021, 27 (18):2219-2237.

https://doi.org/10.3748/wjg.v27.i18.2219

[146]

COSTELLO SP, HUGHES PA, WATERS O, BRYANT RV, VINCENT AD, BLATCHFORD P, KATSIKEROS R, MAKANYANGA J, CAMPANIELLO MA, MAVRANGELOS C, ROSEWARNE CP, BICKLEY C, PETERS C, SCHOEMAN MN, CONLON MA, ROBERTS-THOMSON IC, ANDREWS JM. Effect of fecal microbiota transplantation on 8-week remission in patients with ulcerative colitis: a randomized clinical trial[J]. JAMA, 2019, 321 (2):156-164.

https://doi.org/10.1001/jama.2018.20046

[147]

GUO QQ, LIN H, CHEN PC, TAN SL, WEN ZY, LIN LJ, HE JQ, WEN JB, LU SY. Dynamic changes of intestinal flora in patients with irritable bowel syndrome combined with anxiety and depression after oral administration of enterobacteria capsules[J]. Bioengineered, 2021, 12 (2):11885-11897.

https://doi.org/10.1080/21655979.2021.1999374

[148]

DOLL JPK, VÁZQUEZ-CASTELLANOS JF, SCHAUB AC, SCHWEINFURTH N, KETTELHACK C, SCHNEIDER E, YAMANBAEVA G, MÄHLMANN L, BRAND S, BEGLINGER C, BORGWARDT S, RAES J, SCHMIDT A, LANG UE. Fecal microbiota transplantation (FMT) as an adjunctive therapy for depression-case report[J]. Frontiers in Psychiatry, 2022, 13,815422.

https://doi.org/10.3389/fpsyt.2022.815422

[149]

LIU JK, ZHAO FF, XU YY, QIU J, QIAN YZ. Gut flora-mediated metabolic health, the risk produced by dietary exposure to acetamiprid and tebuconazole[J]. Foods, 2021, 10 (4):835.

https://doi.org/10.3390/foods10040835

[150]

WU JM, LIN ZS, WANG X, ZHAO Y, ZHAO JB, LIU H, JOHNSTON LJ, LU L, MA X. Limosilactobacillus reuteri SLZX19-12 protects the colon from infection by enhancing stability of the gut microbiota and barrier integrity and reducing inflammation[J]. Microbiology Spectrum, 2022, 10 (3):e0212421.

https://doi.org/10.1128/spectrum.02124-21

[151]

SAKAI Y, SEKI N, HAMANO K, OCHI H, ABE F, MASUDA K, IINO H. Prebiotic effect of two grams of lactulose in healthy Japanese women: a randomised, double-blind, placebo-controlled crossover trial[J]. Beneficial Microbes, 2019, 10 (6):629-639.

https://doi.org/10.3920/BM2018.0174

2024年第64卷第9期

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doi: 10.13343/j.cnki.wsxb.20240108

接收时间：2024-02-20
首发时间：2026-03-20
出版时间：2024-05-06

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收稿日期：2024-02-20
录用日期：2024-04-28

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College Student Innovation and Entrepreneurship Training Program Project(S202312121085)

大学生创新创业训练计划(S202312121085)

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1 南方医科大学, 广东广州 510515

2 南方医科大学珠江医院内分泌代谢科, 广东广州 510280

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2种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

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