摘要抑郁障碍是以显著而持久的情绪低落为特征的常见精神障碍疾病,具有高患病率、高致残率和高自杀率等特点。“微生物-肠-脑轴”（MGBA）可能是抑郁障碍的潜在机制之一,肠道菌群代谢产物作为MGBA信号传递的重要介质通过多种途径在抑郁障碍中发挥作用,包括短链脂肪酸调控迷走神经传导、炎症反应和5-羟色胺合成,次级胆汁酸激活法尼醇X受体与G蛋白偶联受体5,以及胆碱调控DNA甲基化、三甲胺-N-氧化物生成等。本文通过检索中国知网、PubMed和Web of Science数据库2010—2025年发表有关短链脂肪酸、次级胆汁酸和胆碱等肠道菌群代谢产物在抑郁障碍中潜在作用的文献,为抑郁障碍防治提供理论依据。
Abstract：Depressive disorders are common mental illnesses characterized by significant and persistent low mood, with features such as high prevalence, high disability rate, and high suicide rate. The microbiota-gut-brain axis may be one of the potential mechanisms underlying depressive disorders. Gut microbiota metabolites, as important mediators of MGBA signaling, play roles in depressive disorders through multiple pathways. These include short-chain fatty acids, which can regulate the transmission of the vagus nerve, inflammatory responses, and 5-hydroxytryptamine synthesis; secondary bile acids, which can activate farnesoid X receptor and Takeda G protein-compled receptor 5; and choline, which can regulate DNA methylation and trimethylamine N-oxide production. This article reviews the literature on the potential mechanisms of action of gut microbiota metabolites, such as short-chain fatty acids, secondary bile acids, and choline, in depressive disorders. The literature was retrieved from CNKI, PubMed, and Web of Science databases from 2010 to 2025. It aims to provide a theoretical basis for the prevention and treatment of depressive disorders.
何靖恺, 胡洁琼, 张加玏, 季蕴辛. 肠道菌群代谢产物与抑郁障碍研究进展[J]. 预防医学, 2025, 37(6): 583-587.
HE Jingkai, HU Jieqiong, ZHANG Jiale, JI Yunxin. Research progress on gut microbiome metabolites and depressive disorders. Preventive Medicine, 2025, 37(6): 583-587.
[1] HUANG Y Q,WANG Y,WANG H,et al.Prevalence of mental disorders in China:a cross-sectional epidemiological study[J].Lancet Psychiatry,2019,6(3):211-224. [2] WANG D F,GUI S W,PU J C,et al.PsycGM:a comprehensive database for associations between gut microbiota and psychiatric disorders[J/OL].Mol Psychiatry,2025[2025-05-18].https://doi.org/10.1038/s41380-025-03000-5. [3] MEDINA-RODRIGUEZ E M,WATSON J,REYES J,et al.Th17 cells sense microbiome to promote depressive-like behaviors[J/OL].Microbiome,2023,11(1)[2025-05-18].https://doi.org/10.1186/s40168-022-01428-3. [4] JIANG Y B,WANG X M,CHEN J W,et al.Repeated(S)-ketamine administration ameliorates the spatial working memory impairment in mice with chronic pain:role of the gut microbiota-brain axis[J/OL].Gut microbes,2024,16(1)[2025-05-18].https://doi.org/10.1080/19490976.2024.2310603. [5] HU X,LI Y F,WU J,et al.Changes of gut microbiota reflect the severity of major depressive disorder:a cross sectional study[J/OL].Transl Psychiatry,2023,13(1)[2025-05-18].https://doi.org/10.1038/s41398-023-02436-z. [6] COOK T M,GAVINI C K,JESSE J,et al.Vagal neuron expression of the microbiota-derived metabolite receptor,free fatty acid receptor (FFAR3),is necessary for normal feeding behavior[J/OL].Mol Metab,2021,54[2025-05-18].https://doi.org/10.1016/j.molmet.2021.101350. [7] SU Q,TUN H M,LIU Q,et al.Gut microbiome signatures reflect different subtypes of irritable bowel syndrome[J/OL].Gut Microbes,2023,15(1)[2025-05-18].https://doi.org/10.1080/19490976.2022.2157697. [8] XIAO W P,SU J B,GAO X J,et al.The microbiota-gut-brain axis participates in chronic cerebral hypoperfusion by disrupting the metabolism of short-chain fatty acids[J/OL].Microbiome,2022,10(1)[2025-05-18].https://doi.org/10.1186/s40168-022-01255-6. [9] BUCKLEY M M,O'BRIEN R,BROSNAN E,et al.Glucagon-like peptide-1 secreting L-cells coupled to sensory nerves translate microbial signals to the host rat nervous system[J/OL].Front Cell Neurosci,2020,14[2025-05-18].https://doi.org/10.3389/ fncel.2020.00095. [10] GOLDSMITH D R,RAPAPORT M H,MILLER B J.A meta-analysis of blood cytokine network alterations in psychiatric patients:comparisons between schizophrenia,bipolar disorder and depression[J].Mol Psychiatry,2016,21(12):1696-1709. [11] LI G F,LIN J,ZHANG C,et al.Microbiota metabolite butyrate constrains neutrophil functions and ameliorates mucosal inflammation in inflammatory bowel disease[J/OL].Gut Microbes,2021,13(1)[2025-05-18].https://doi.org/10.1080/19490976.2021.1968257. [12] 贾雪冰,周芝兰,张博枰,等.适宜浓度短链脂肪酸混合物对小胶质细胞炎症抑制及机制研究[J].生物化学与生物物理进展,2019,46(5):504-512. JIA X B,ZHOU Z L,ZHANG B P,et al.Anti-inflammation effect and the mechanism of suitable concentration of short-chain fatty acids mixture on microglia[J].Prog Biochem Biophys,2019,46(5):504-512.(in Chinese) [13] TU A B,WANG X C,CHEN H W,et al.Ovomucin ameliorates intestinal barrier and intestinal bacteria to attenuate DSS-induced colitis in mice[J].J Agric Food Chem,2021,69(21):5887-5896. [14] 徐燕,刘冬光,宁停波,等.基于BDNF/TrkB/CREB通路探讨参苓开心颗粒的抗抑郁作用机制[J].中国中药杂志,2023,48(8):2184-2192. XU Y,LIU D G,NING T B,et al.Antidepressant mechanism of Shenling Kaixin Granules based on BDNF/TrkB/CREB pathway[J].China J Chin Mater Med,2023,48(8):2184-2192.(in Chinese) [15] GUO C P,LIU Y,FANG M S,et al.ω-3PUFAs improve cognitive impairments through Ser133 phosphorylation of CREB upregulating BDNF/TrkB signal in schizophrenia[J].Neurotherapeutics,2020,17(3):1271-1286. [16] ZHAO T T,LYU J,PENG M Y,et al.Fecal microbiota transplantation and short-chain fatty acids improve learning and memory in fluorosis mice by BDNF-PI3K/AKT pathway[J/OL].Chem Biol Interact,2023[2025-05-18].https://doi.org/10.1016/j.cbi.2023.110786. [17] ESSIEN B E,GRASBERGER H,ROMAIN R D,et al.ZBP-89 regulates expression of tryptophan hydroxylase I and mucosal defense against Salmonella typhimurium in mice[J].Gastroenterology,2013,144(7):1466-1477. [18] WILLIANS E K,CHANG R B,STROCHLIC D E,et al.Sensory neurons that detect stretch and nutrients in the digestive system[J].Cell,2016,166(1):209-221. [19] QIAO C M,ZHOU Y,QUAN W,et al.Fecal microbiota transplantation from aged mice render recipient mice resistant to MPTP-induced nigrostriatal degeneration via a neurogenesis-dependent but inflammation-independent manner[J].Neurotherapeutics,2023,20(5):1405-1426. [20] 姚娇,杨岩涛,艾启迪,等.神经递质功能与抑郁症发病的研究进展[J].中国药理学通报,2023,39(7):1217-1221. YAO J,YANG Y T,AI Q D,et al.Review of research progress on neurotransmitter function and depression[J].Chin Pharmacol Bull,2023,39(7):1217-1221.(in Chinese) [21] JIA M,FAN Y J,MA Q Y,et al.Gut microbiota dysbiosis promotes cognitive impairment via bile acid metabolism in major depressive disorder[J/OL].Transl Psychiatry,2024,14(1)[2025-05-18].https://doi.org/10.1038/s41398-024-03211-4. [22] SUN N,ZHANG J,WANG J Z,et al.Abnormal gut microbiota and bile acids in patients with first-episode major depressive disorder and correlation analysis[J].Psychiatry Clin Neurosci,2022,76(7):321-328. [23] 徐荣漪,李小丝,马建国,等.溃结康调控肠道法尼醇X受体影响胆汁酸代谢治疗小鼠溃疡性结肠炎[J].中国药理学通报,2025,41(2):383-391. XU R Y,LI X S,MA J G,et al.Kui Jie Kang regulates intestinal FXR and affects bile acid metabolism in treatment of ulcerative colitis in mice[J].Chin Pharmacol Bull,2025,41(2):383-391.(in Chinese) [24] CHEN W G,ZHENG J X,XU X,et al.Hippocampal FXR plays a role in the pathogenesis of depression:a preliminary study based on lentiviral gene modulation[J].Psychiatry Res,2018,264:374-379. [25] SEOK S,FU T,CHOI S E,et al.Transcriptional regulation of autophagy by an FXR-CREB axis[J].Nature,2014,516(7529):108-111. [26] 何慧,郭明亮,冉立成,等.基于海马FXR调控CREB-BDNF信号通路影响抑郁症的研究进展[J].中国临床药理学与治疗学,2025,30(2):265-271. HE H,GUO M L,RAN L C,et al.Research progress on the effect of hippocampal FXR regulation of CREB-BDNF signaling pathway on depression[J].Chin J Clin Pharmacol Ther,2025,30(2):265-271.(in Chinese) [27] HUANG F,WANG T T,LAN Y Y,et al.Deletion of mouse FXR gene disturbs multiple neurotransmitter systems and alters neurobehavior[J/OL].Front Behav Neurosci,2015,9[2025-05-18].https://doi.org/10.3389/fnbeh.2015.00070. [28] 王妙然,李月,张芸绮,等.基于网络药理学牛磺石胆酸抗炎作用及机制[J].中国药理学通报,2021,37(11):1614-1619. WANG M R,LI Y,ZHANG Y Q,et al.Study on anti-inflammatory effect of taurolithocholic acid based on network pharmacology and its mechanism[J].Chin Pharmacol Bull,2021,37(11):1614-1619.(in Chinese) [29] QIANG X,WANG X Y,LIANG S M,et al.Long-term effects of Nε-carboxymethyllysine intake on intestinal barrier permeability:Associations with gut microbiota and bile acids[J/OL].Food Res Int,2025,201[2025-05-18].https://doi.org/10.1016/j.foodres.2024.115543. [30] XU Y Y,WANG J F,WU X B,et al.Gut microbiota alteration after cholecystectomy contributes to post-cholecystectomy diarrhea via bile acids stimulating colonic serotonin[J/OL].Gut microbes,2023,15(1)[2025-05-18].https://doi.org/10.1080/19490976.2023.2168101. [31] LI X Y,ZHANG S Y,HONG Y Z,et al.TGR5-mediated lateral hypothalamus-dCA3-dorsolateral septum circuit regulates depressive-like behavior in male mice[J].Neuron,2024,112(11):1795-1814. [32] ROMANO K A,MARTINEZ-DEL CAMPO A,KASAHARA K,et al.Metabolic,epigenetic,and transgenerational effects of gut bacterial choline consumption[J].Cell Host Microbe,2017,22(3):279-290. [33] LI J X,KANG X,ZHANG L M,et al.Dietary choline is inversely associated with depressive symptoms:a cross-sectional study of the National Health and Nutrition Examination Survey(NHANES)2011 to 2018[J].J Affect Disord,2022,301:23-29. [34] STORY JOVANOVA O,NEDELJKOVIC I,SPIELER D,et al.DNA methylation signatures of depressive symptoms in middle-aged and elderly persons:meta-analysis of multiethnic epigenome-wide studies[J].JAMA Psychiatry,2018,75(9):949-958. [35] CHAU D T,RADA P V,KIM K,et al.Fluoxetine alleviates behavioral depression while decreasing acetylcholine release in the nucleus accumbens shell[J].Neuropsychopharmacology,2011,36(8):1729-1737. [36] MUDIMELA S,VISHWANATH N K,PILLAI A,et al.Clinical significance and potential role of trimethylamine N-oxide in neurological and neuropsychiatric disorders[J/OL].Drug Discov Today,2022,27(11)[2025-05-18].https://doi.org/10.1016/j.drudis.2022.08.002. [37] LIU C C,WU Y F,FENG G M,et al.Plasma-metabolite-biomarkers for the therapeutic response in depressed patients by the traditional Chinese medicine formula Xiaoyaosan:a 1H NMR-based metabolomics approach[J].J Affect Disord,2015,185:156-163. [38] WU W K,PANYOD S,LIU P Y,et al.Characterization of TMAO productivity from carnitine challenge facilitates personalized nutrition and microbiome signatures discovery[J/OL].Microbiome,2020,8(1)[2025-05-18].https://doi.org/10.1186/s40168-020-00912-y. [39] BRUNT V E,LAROCCA T J,BAZZONI A E,et al.The gut microbiome-derived metabolite trimethylamine N-oxide modulates neuroinflammation and cognitive function with aging[J].Geroscience,2021,43(1):377-394.
