【摘要】抑郁症是全球范围内致残率最高的精神疾病之一，目前的一线抗抑郁药物存在起效延迟、疗效有限和副作用明显等问题。近年来，肠道微生物-肠-脑轴的发现为抑郁症的发病机制和治疗提供了新视角。产丁酸菌及其代谢产物丁酸在维持肠道屏障完整性、调节免疫反应和影响中枢神经系统功能方面发挥着关键作用。酪酸梭菌作为一种产丁酸肠道基石菌，在抑郁症干预中展现出巨大潜力。本文系统综述了抑郁症患者肠道菌群中产丁酸菌丰度降低特征，并从修复肠道屏障与抑制全身性低度炎症、抑制小胶质细胞介导的中枢神经炎症、提升脑源性神经营养因子并调控中枢神经可塑性、调节下丘脑-垂体-肾上腺轴功能与应激反应以及调控迷走神经与肠道神经递质通路五个方面，阐述了酪酸梭菌及其代谢产物丁酸改善抑郁症的分子机制。此外，本文还总结了酪酸梭菌在动物实验和临床研究中的干预效果。

【关键词】肠道基石菌；酪酸梭菌；丁酸；抑郁症；肠-脑轴；炎症

1 引言

抑郁症是最常见的精神障碍之一，以持续的情绪低落、兴趣丧失、认知功能障碍和植物神经症状（如睡眠和食欲紊乱）为主要临床特征[1]。抑郁症是一种严重疾病，已成为全球范围内重要的公共卫生问题，也是导致全球残疾的主要原因之一，全球约有3.5亿人受到其影响，且仍在持续稳步上升[2, 3]。尽管目前临床上使用的抗抑郁药物（如选择性5-羟色胺再摄取抑制剂SSRIs和5-羟色胺-去甲肾上腺素再摄取抑制剂SNRIs）在一定程度上能够缓解症状，但约30%的患者对初始治疗无反应，且药物起效延迟、副作用明显等问题严重影响患者的治疗依从性和预后[4]。

近年来，肠道微生物-肠-脑轴的发现为抑郁症的发病机制和治疗开辟了新方向[5]。肠道菌群不仅参与消化吸收和免疫调节，还能通过神经、内分泌和免疫途径与中枢神经系统进行双向通讯[6]。短链脂肪酸（特别是丁酸）是肠道菌群发酵膳食纤维产生的主要代谢产物，在维持肠道屏障完整性、调节免疫反应和影响中枢神经系统功能方面发挥关键作用[7, 8]。丁酸（又称酪酸）能通过抑制组蛋白去乙酰化酶（HDAC）调节基因表达、激活G蛋白偶联受体（如FFAR2/FFAR3）以及调节免疫细胞功能等多种途径发挥抗炎和神经保护作用[9, 10]。肠道基石菌酪酸梭菌（又称丁酸梭菌）作为一种重要的产丁酸厌氧芽孢杆菌，已被广泛应用于胃肠道疾病的治疗[11]。近年来，越来越多的研究表明酪酸梭菌在抑郁症干预中展现出巨大潜力。本文将从多维度系统阐述酪酸梭菌及其代谢产物丁酸改善抑郁症的分子机制。

2 抑郁症的治疗现状与困境

抑郁症的临床治疗主要包括药物治疗、心理治疗和物理治疗三大类[12]。以SSRIs和SNRIs为代表的抗抑郁药物通过抑制突触间隙单胺类神经递质的再摄取发挥抗抑郁作用[13]。然而，现有治疗存在以下困境：

起效延迟：尽管药物对单胺转运体的抑制在服药后数小时内即发生，但临床疗效通常需要2-4周才能显现，提示单胺假说不能完全解释抗抑郁作用机制[14]。疗效有限：大规模临床试验显示，仅约50-60%的患者对一线抗抑郁药物有反应，约30-35%的患者能达到临床缓解[15]。治疗抵抗：约30%的抑郁症患者对两种或以上不同作用机制的药物均无反应，被定义为难治性抑郁症（TRD）[16]。副作用明显：SSRIs常导致恶心、失眠、性功能障碍等副作用，严重影响用药依从性[17]。这些困境提示，迫切需要从新视角探索抑郁症的病理生理机制并开发新的治疗策略。

3 抑郁症患者肠道中的产丁酸菌及丁酸匮乏

大量临床研究证实，抑郁症患者存在显著的肠道菌群紊乱。一项系统性综述纳入26项研究，发现抑郁症患者肠道菌群的共同特征是促炎菌群丰度升高，产丁酸菌丰度降低[18]。Valles-Colomer等[19]对1054例样本分析发现，粪杆菌属和粪球菌属等产丁酸菌丰度与抑郁症状严重程度呈负相关。Zheng等[20]证实重性抑郁障碍（MDD）患者存在肠道菌群紊乱，进一步将该患者粪便菌群移植给无菌小鼠，受体小鼠出现抑郁样行为，证实了肠道菌群紊乱在抑郁症发病中的作用。

丁酸主要由厚壁菌门中的特定菌群（如酪酸梭菌等）代谢产生[21]。多项研究一致表明抑郁症患者粪便和血浆中丁酸水平显著降低[22-24]。Sun等[24]在CUMS小鼠模型中也观察到产丁酸菌丰度降低和丁酸水平下降。因此，抑郁症患者肠道中产丁酸菌的缺乏和丁酸水平的下降，是导致肠屏障功能障碍、系统性炎症、神经炎症以及神经可塑性受损重要环节。

图 1丁酸在肠-脑轴通讯中的作用

丁酸在肠-脑轴通讯中占据重要地位[7]。首先，丁酸是肠道上皮细胞的主要能量来源，能增强肠道屏障功能，减少脂多糖（LPS）等细菌产物易位[25]。其次，丁酸作为HDAC抑制剂调节基因表达，促进脑源性神经营养因子（BDNF）转录[26]。第三，丁酸是游离脂肪酸受体2/3（FFAR2/FFAR3）的内源性配体，能调节炎症反应和肠道激素分泌[27]。第四，丁酸能通过单羧酸转运体穿过血脑屏障直接影响中枢神经系统[28, 29]。这为补充酪酸梭菌等产丁酸菌干预抑郁症提供了理论基础。

4 酪酸梭菌改善抑郁症的分子机制

4.1 修复肠道屏障与抑制全身性低度炎症

肠道屏障功能障碍是抑郁症的重要病理特征，慢性应激能导致紧密连接蛋白表达下调，肠通透性增加，使LPS等细菌产物易位进入血液循环引发全身性低度炎症[30, 31]。酪酸梭菌及其代谢产物丁酸在维护肠道屏障完整性方面发挥重要作用。丁酸增强肠道屏障的机制包括：激活AMPK促进紧密连接蛋白的组装和表达[25]，抑制HDAC上调粘蛋白（MUC2）表达[32]，以及通过激活G蛋白偶联受体109A（GPR109A）受体调节肠道免疫[33]。通过修复肠道屏障，酪酸梭菌能减少LPS从肠腔向循环系统的易位，从而从源头抑制全身性炎症反应[31]。

4.2 抑制小胶质细胞介导的中枢神经炎症

神经炎症是抑郁症发病机制的核心环节之一。小胶质细胞作为中枢神经系统的固有免疫细胞，在受到炎症刺激后活化，释放IL-1β、IL-6、TNF-α等促炎细胞因子，导致神经元损伤和突触可塑性受损[34]。抑郁症患者和动物模型均表现出小胶质细胞过度活化的特征[35]。Tian等[36] 在CSDS小鼠模型中发现，在应激过程中同时给予酪酸梭菌预处理，能够阻止抑郁样行为的发生，降低海马IL-1β、IL-6和TNF-α水平，并抑制小胶质细胞过度活化。Erny等[29]在无菌小鼠中发现丁酸通过FFAR2受体维持小胶质细胞稳态。在LPS诱导的抑郁模型中，丁酸预处理能抑制小胶质细胞活化[37]。上述丁酸的抗炎作用主要通过两条分子途径实现：其一，丁酸作为HDAC抑制剂，能抑制NF-κB通路活化，减少促炎细胞因子转录[38]；其二，丁酸作为FFAR2/FFAR3的外源性配体，能直接调节小胶质细胞代谢和免疫功能[29]。

4.3 提升BDNF并直接调控中枢神经可塑性

BDNF是调控神经可塑性的关键分子，在神经发生和突触可塑性中发挥重要作用，而抑郁症患者脑内BDNF水平显著降低[39]。Sun等[24]在CUMS小鼠中发现酪酸梭菌能增加海马BDNF表达，并上调胰高血糖素样肽-1 （GLP-1）和GLP-1受体水平。丁酸提升BDNF表达的机制主要涉及其HDAC抑制活性。作为I类和IIa类HDAC抑制剂，丁酸能增加染色质组蛋白乙酰化水平，促进BDNF基因的转录[40]。Wei等[41]发现丁酸钠能增加TET1的表达，促进BDNF基因启动子区域的去甲基化，从而激活BDNF转录。丁酸还能促进神经生长因子（NGF）、胶质细胞源性神经营养因子（GDNF）等其他神经营养因子表达，协同增强神经可塑性[42]。

4.4 调节下丘脑-垂体-肾上腺（HPA）轴功能与应激反应

抑郁症患者常表现为HPA轴功能亢进、皮质醇水平升高、负反馈调节受损[43]。这种HPA轴功能异常与肠道菌群紊乱密切相关[44]。Sun等[24]在CUMS小鼠中发现酪酸梭菌干预能降低应激诱导的皮质酮水平，与抑郁样行为改善相关。丁酸调节HPA轴的机制包括：通过FFAR3调节交感神经活性[45]；影响下丘脑CRH神经元活性来调节HPA轴的应激反应[10]；以及通过抗炎作用间接改善HPA轴的负反馈调节[46]。

4.5 调控迷走神经与肠道神经递质通路

迷走神经是肠-脑轴通讯的主要通路，以传入纤维为主，能将肠道信息传递至情绪调节相关脑区[47]。Lal等[48]发现空肠内灌注丁酸能诱发大鼠迷走神经传入放电，该效应能被膈下迷走神经切断术消除。肠道菌群还能通过影响肠道中的5-羟色胺（5-HT）、γ-氨基丁酸（GABA）、多巴胺等神经递质来调节情绪和行为[49]。大部分的5-HT在肠道嗜铬细胞中合成，而丁酸能促进色氨酸羟化酶1（TPH1）的表达，从而增强肠道5-HT的合成[50]。5-HT能通过激活迷走神经传入纤维上的5-HT3受体向中枢传递信号[51]。

5 酪酸梭菌及丁酸对抑郁症的干预效果

5.1 动物实验证据

酪酸梭菌在抑郁症动物模型中显示出稳定的抗抑郁效果。Sun等[24]在CUMS小鼠中发现酪酸梭菌能显著缩短悬尾和强迫游泳试验不动时间，增加糖水偏好率，同时增加海马5-HT和BDNF水平。Tian等[36]发现，酪酸梭菌预处理28天不仅能通过调节肠道菌群（增加厚壁菌门丰度）和改善肠道屏障来减轻外周炎症，还能抑制小胶质细胞活化及相关促炎因子（IL-1β、IL-6、TNF-α）的表达，从而预防抑郁样行为的发生。Zhang等[52]发现酪酸梭菌能降低促肾上腺皮质激素（ACTH）和皮质酮水平，升高BDNF水平，并改善强迫游泳试验中的行为表现。

5.2 临床研究证据

酪酸梭菌在抑郁症患者中的临床应用已取得初步成效。Miyaoka等[16]开展8周前瞻性开放标签试验，纳入40例TRD患者，在抗抑郁药物基础上联合酪酸梭菌治疗。结果显示酪酸梭菌联合抗抑郁药物能显著改善抑郁症状，所有患者均完成试验，其中70%的患者对治疗有反应，缓解率为35%，未发生明显不良反应，表明酪酸梭菌联合抗抑郁药治疗TRD具有良好的疗效和耐受性。其他产丁酸菌相关临床研究也支持其应用前景。Kazemi等[53]报道8周益生菌和/或益生元干预能改善MDD患者的贝克抑郁量表（BDI）评分和炎症标志物。

6 总结与展望

酪酸梭菌作为一种重要的产丁酸肠道基石菌，通过多种途径发挥抗抑郁作用，其主要分子机制为：（1）修复肠道屏障，抑制全身性低度炎症；（2）抑制小胶质细胞活化，抑制中枢神经炎症；（3）促进BDNF表达，增强神经可塑性；（4）调节HPA轴功能，降低过度应激反应；（5）调控迷走神经与肠道神经递质通路，影响中枢功能。综上，酪酸梭菌及其代谢产物丁酸在抑郁症治疗中展现出广阔的应用前景，阐明其作用机制为开发基于肠道基石菌的新型抗抑郁策略提供了理论依据。

我国在酪酸梭菌的基础研究与产业化应用方面已取得重要进展。其中，酪酸梭菌菌株CGMCC0313-1具有自主知识产权，相关技术已获得中美两国发明专利授权（ZL 200610086642.3，US 7785581）。基于该菌株开发的酪酸梭菌活菌制剂展现出良好的安全性与应用前景，酪酸梭菌活菌胶囊与酪酸梭菌活菌散等微生态制剂已实现规模化生产，并经国家药品监督管理局批准为绿标OTC药品[54-55]。我国的上述研发成果为进一步阐明其抗抑郁症的作用机制及推动临床转化提供了可靠的菌株资源与制剂保障。

参考文献

[1] Malhi G S, Mann J J. Depression [J]. The lancet, 2018, 392(10161): 2299-312.

[2] Friedrich M J. Depression is the leading cause of disability around the world [Z]. 2017

[3] Yin Y, Ju T, Zeng D, et al. “Inflamed” depression: A review of the interactions between depression and inflammation and current anti-inflammatory strategies for depression [J]. Pharmacological Research, 2024, 207: 107322.

[4] Rush A J, Trivedi M H, Wisniewski S R, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR* D report [J]. American Journal of Psychiatry, 2006, 163(11): 1905-17.

[5] Cryan J F, O'Riordan K J, Cowan C S, et al. The microbiota-gut-brain axis [J]. Physiological reviews, 2019, 99(4): 1877-2013.

[6] Morais L H, Schreiber IV H L, Mazmanian S K. The gut microbiota–brain axis in behaviour and brain disorders [J]. Nature Reviews Microbiology, 2021, 19(4): 241-55.

[7] Dalile B, Van Oudenhove L, Vervliet B, et al. The role of short-chain fatty acids in microbiota–gut–brain communication [J]. Nature reviews Gastroenterology hepatology, 2019, 16(8): 461-78.

[8] Stilling R M, Van De Wouw M, Clarke G, et al. The neuropharmacology of butyrate: the bread and butter of the microbiota-gut-brain axis? [J]. Neurochemistry international, 2016, 99: 110-32.

[9] Silva Y P, Bernardi A, Frozza R L. The role of short-chain fatty acids from gut microbiota in gut-brain communication [J]. Frontiers in endocrinology, 2020, 11: 508738.

[10] Van de Wouw M, Boehme M, Lyte J M, et al. Short‐chain fatty acids: microbial metabolites that alleviate stress‐induced brain–gut axis alterations [J]. The Journal of physiology, 2018, 596(20): 4923-44.

[11] Hagihara M, Yamashita R, Matsumoto A, et al. The impact of probiotic Clostridium butyricum MIYAIRI 588 on murine gut metabolic alterations [J]. Journal of Infection Chemotherapy, 2019, 25(8): 571-7.

[12] Marx W, Penninx B W, Solmi M, et al. Major depressive disorder [J]. Nature Reviews Disease Primers, 2023, 9(1): 44.

[13] Cipriani A, Furukawa T A, Salanti G, et al. Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis [J]. The Lancet, 2018, 391(10128): 1357-66.

[14] Boku S, Nakagawa S, Toda H, et al. Neural basis of major depressive disorder: Beyond monoamine hypothesis [J]. Psychiatry clinical neurosciences, 2018, 72(1): 3-12.

[15] Trivedi M H, Rush A J, Wisniewski S R, et al. Evaluation of outcomes with citalopram for depression using measurement-based care in STAR* D: implications for clinical practice [J]. American journal of Psychiatry, 2006, 163(1): 28-40.

[16] Miyaoka T, Kanayama M, Wake R, et al. Clostridium butyricum MIYAIRI 588 as adjunctive therapy for treatment-resistant major depressive disorder: a prospective open-label trial [J]. Clinical neuropharmacology, 2018, 41(5): 151-5.

[17] Ferguson J M. SSRI antidepressant medications: adverse effects and tolerability [J]. Primary care companion to the Journal of clinical psychiatry, 2001, 3(1): 22.

[18] Simpson C A, Diaz-Arteche C, Eliby D, et al. The gut microbiota in anxiety and depression–a systematic review [J]. Clinical psychology review, 2021, 83: 101943.

[19] Valles-Colomer M, Falony G, Darzi Y, et al. The neuroactive potential of the human gut microbiota in quality of life and depression [J]. Nature microbiology, 2019, 4(4): 623-32.

[20] Zheng P, Zeng B, Zhou C, et al. Gut microbiome remodeling induces depressive-like behaviors through a pathway mediated by the host’s metabolism [J]. Molecular psychiatry, 2016, 21(6): 786-96.

[21] Louis P, Flint H J. Diversity, metabolism and microbial ecology of butyrate-producing bacteria from the human large intestine [J]. FEMS microbiology letters, 2009, 294(1): 1-8.

[22] Skonieczna-Żydecka K, Grochans E, Maciejewska D, et al. Faecal short chain fatty acids profile is changed in Polish depressive women [J]. Nutrients, 2018, 10(12): 1939.

[23] Liu R T, Rowan-Nash A D, Sheehan A E, et al. Reductions in anti-inflammatory gut bacteria are associated with depression in a sample of young adults [J]. Brain, behavior, immunity, 2020, 88: 308-24.

[24] Sun J, Wang F, Hu X, et al. Clostridium butyricum attenuates chronic unpredictable mild stress-induced depressive-like behavior in mice via the gut-brain axis [J]. Journal of agricultural food chemistry, 2018, 66(31): 8415-21.

[25] Peng L, Li Z-R, Green R S, et al. Butyrate enhances the intestinal barrier by facilitating tight junction assembly via activation of AMP-activated protein kinase in Caco-2 cell monolayers [J]. The Journal of nutrition, 2009, 139(9): 1619-25.

[26] Schroeder F A, Lin C L, Crusio W E, et al. Antidepressant-like effects of the histone deacetylase inhibitor, sodium butyrate, in the mouse [J]. Biological psychiatry, 2007, 62(1): 55-64.

[27] Kimura I, Inoue D, Maeda T, et al. Short-chain fatty acids and ketones directly regulate sympathetic nervous system via G protein-coupled receptor 41 (GPR41) [J]. Proceedings of the national academy of sciences, 2011, 108(19): 8030-5.

[28] Mitchell R W, On N H, Del Bigio M R, et al. 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): 735-46.

[29] Erny D, Hrabě de Angelis A L, Jaitin D, et al. Host microbiota constantly control maturation and function of microglia in the CNS [J]. Nature neuroscience, 2015, 18(7): 965-77.

[30] Kelly J R, Kennedy P J, Cryan J F, et al. Breaking down the barriers: the gut microbiome, intestinal permeability and stress-related psychiatric disorders [J]. Frontiers in cellular neuroscience, 2015, 9: 392.

[31] Stevens B R, Goel R, Seungbum K, et al. 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): 1555-7.

[32] Burger-van Paassen N, Vincent A, Puiman P J, et al. The regulation of intestinal mucin MUC2 expression by short-chain fatty acids: implications for epithelial protection [J]. Biochemical Journal, 2009, 420(2): 211-9.

[33] Singh N, Gurav A, Sivaprakasam S, et al. Activation of Gpr109a, receptor for niacin and the commensal metabolite butyrate, suppresses colonic inflammation and carcinogenesis [J]. Immunity, 2014, 40(1): 128-39.

[34] Singhal G, Baune B T. Microglia: an interface between the loss of neuroplasticity and depression [J]. Frontiers in cellular neuroscience, 2017, 11: 270.

[35] Setiawan E, Wilson A A, Mizrahi R, et al. Role of translocator protein density, a marker of neuroinflammation, in the brain during major depressive episodes [J]. JAMA psychiatry, 2015, 72(3): 268-75.

[36] Tian T, Xu B, Qin Y, et al. Clostridium butyricum miyairi 588 has preventive effects on chronic social defeat stress-induced depressive-like behaviour and modulates microglial activation in mice [J]. Biochemical biophysical research communications, 2019, 516(2): 430-6.

[37] Yamawaki Y, Yoshioka N, Nozaki K, et al. Sodium butyrate abolishes lipopolysaccharide-induced depression-like behaviors and hippocampal microglial activation in mice [J]. Brain research, 2018, 1680: 13-38.

[38] JP S. Butyrate inhibits inflammatory responses through NFkappaB inhibition. implications for Crohn's disease [J]. Gut, 2000, 47: 397-403.

[39] Molendijk M, Spinhoven P, Polak M, et al. Serum BDNF concentrations as peripheral manifestations of depression: evidence from a systematic review and meta-analyses on 179 associations (N= 9484) [J]. Molecular psychiatry, 2014, 19(7): 791-800.

[40] Ferrante R J, Kubilus J K, Lee J, et al. Histone deacetylase inhibition by sodium butyrate chemotherapy ameliorates the neurodegenerative phenotype in Huntington's disease mice [J]. Journal of Neuroscience, 2003, 23(28): 9418-27.

[41] Wei Y B, Melas P A, Wegener G, et al. Antidepressant-like effect of sodium butyrate is associated with an increase in TET1 and in 5-hydroxymethylation levels in the Bdnf gene [J]. International Journal of Neuropsychopharmacology, 2015, 18(2): pyu032.

[42] Varela R B, Valvassori S S, Lopes-Borges J, et al. Sodium butyrate and mood stabilizers block ouabain-induced hyperlocomotion and increase BDNF, NGF and GDNF levels in brain of Wistar rats [J]. Journal of Psychiatric Research, 2015, 61: 114-21.

[43] Pariante C M, Lightman S L. The HPA axis in major depression: classical theories and new developments [J]. Trends in neurosciences, 2008, 31(9): 464-8.

[44] Sudo N, Chida Y, Aiba Y, et al. Postnatal microbial colonization programs the hypothalamic–pituitary–adrenal system for stress response in mice [J]. The Journal of physiology, 2004, 558(1): 263-75.

[45] Kimura I, Ichimura A, Ohue-Kitano R, et al. Free fatty acid receptors in health and disease [J]. Physiological reviews, 2019.

[46] Miller A H, Raison C L. The role of inflammation in depression: from evolutionary imperative to modern treatment target [J]. Nature reviews immunology, 2016, 16(1): 22-34.

[47] Bonaz B, Bazin T, Pellissier S. The vagus nerve at the interface of the microbiota-gut-brain axis [J]. Frontiers in neuroscience, 2018, 12: 336468.

[48] Lal S, Kirkup A J, Brunsden A M, et al. Vagal afferent responses to fatty acids of different chain length in the rat [J]. American Journal of Physiology-Gastrointestinal Liver Physiology, 2001, 281(4): G907-G15.

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

[50] Yano J M, Yu K, Donaldson G P, et al. Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis [J]. Cell, 2015, 161(2): 264-76.

[51] Browning K N. Role of central vagal 5-HT3 receptors in gastrointestinal physiology and pathophysiology [J]. Frontiers in neuroscience, 2015, 9: 413.

[52] Zhang W, Ding T, Zhang H, et al. Clostridium butyricum RH2 alleviates chronic foot shock stress-induced behavioral deficits in rats via PAI-1 [J]. Frontiers in pharmacology, 2022, 13: 845221.

[53] Kazemi A, Noorbala A A, Azam K, et al. Effect of probiotic and prebiotic vs placebo on psychological outcomes in patients with major depressive disorder: A randomized clinical trial [J]. Clinical Nutrition, 2019, 38(2): 522-8.

[54] 国家药品监督管理局. 境内生产药品——国药准字S20040084[Z]. 2004.

[55] 国家药品监督管理局. 境内生产药品——国药准字S20040088[Z]. 2004.