脑-肠轴与精神疾病肠道微生物的研究进展

李瑞盈 鄢明辉 游春苹

李瑞盈,鄢明辉,游春苹. 脑-肠轴与精神疾病肠道微生物的研究进展[J]. 食品工业科技,2021,42(18):427−434. doi:  10.13386/j.issn1002-0306.2020080250
引用本文: 李瑞盈,鄢明辉,游春苹. 脑-肠轴与精神疾病肠道微生物的研究进展[J]. 食品工业科技,2021,42(18):427−434. doi:  10.13386/j.issn1002-0306.2020080250
LI Ruiying, YAN Minghui, YOU Chunping. Advances in the Study of Brain-Gut Axis and Intestinal Microorganisms in Neuropsychiatric Diseases[J]. Science and Technology of Food Industry, 2021, 42(18): 427−434. (in Chinese with English abstract). doi:  10.13386/j.issn1002-0306.2020080250
Citation: LI Ruiying, YAN Minghui, YOU Chunping. Advances in the Study of Brain-Gut Axis and Intestinal Microorganisms in Neuropsychiatric Diseases[J]. Science and Technology of Food Industry, 2021, 42(18): 427−434. (in Chinese with English abstract). doi:  10.13386/j.issn1002-0306.2020080250

脑-肠轴与精神疾病肠道微生物的研究进展

doi: 10.13386/j.issn1002-0306.2020080250
基金项目: 上海市青年科技启明星计划(19QB1400300);上海市优秀技术带头人计划项目(20XD1430100)
详细信息
    作者简介:

    李瑞盈(1995−),女,硕士研究生,研究方向:食品微生物,E-mail:Liruiying@yeah.net

    通讯作者:

    游春苹(1982−),女,博士,正高级工程师,研究方向:益生菌和食品安全,E-mail:youchunping@brightdairy.com

  • 中图分类号: TS201.1

Advances in the Study of Brain-Gut Axis and Intestinal Microorganisms in Neuropsychiatric Diseases

  • 摘要: 人体肠道拥有大量且种类丰富的微生物群,在机体的多项生理过程中扮演着重要的角色。近年来越来越多的研究表明,肠道菌群可以通过脑-肠轴来调节机体大脑的发育和行为,从而对自闭症谱系障碍、精神分裂症、抑郁症、焦虑症等精神类疾病具有良好的防治作用。本文在阐述脑-肠轴的双向调控机制基础上,总结了与各种精神疾病直接相关因素的变化和可能机制,并进一步归纳了近年来国内外关于各类精神疾病中肠道微生物改变的研究进展,以期为上述精神类疾病患者通过早期益生菌干预治疗的研究提供新的思路和理论参考。
  • 图  1  肠道微生物群产生的信号会影响脑-肠轴[12]

    Figure  1.  Signals produced by the intestinal microbiota affect the brain-gut axis[12]

    图  2  微生物对神经炎症和HPA轴活性的调节示意图[19]

    Figure  2.  A schematic diagram of microbial regulation of neuroinflammation and HPA axis activity[19]

    表  1  精神疾病患者与健康者菌群差异

    Table  1.   Difference of microflora between neuropsychiatric diseases and healthy people

    精神疾病与健康者菌群差异研究对象实验方法
    重度抑郁症
    (MDD)[67]
    丰度增加:厌氧菌属(Anaerostipes)、布劳特氏菌属(Blautia)、梭菌属(Clostridium)、克雷伯氏菌属(Klebsiella)、副拟杆菌属(Parabacteroides)、毛螺旋菌属(Parasutterella)、考拉杆菌属(Phascolarctobacterium)、链球菌属(Streptococcus)丰度减少:双歧杆菌属(Bifidobacterium)、小类杆菌属(Dialister)、埃希氏杆菌属(Escherichia)、
    粪杆菌属(Faecalibacterium)、瘤胃球菌属(Ruminococcus
    35~62岁,纳入6项研究,204名MDD患者和188名对照组,接受抗抑郁药物治疗的MDD组患者的百分比从33%到100%不等,抑郁平均水平中度到高度严重临床评估抑郁程度;16S rRNA基因测序;对鉴定出的细菌蛋白进行元蛋白质组分析
    精神分裂症
    (SCZ)[68]
    丰度增加:放线菌属(Actinomyces)、罗氏菌属(Rothia)、斯卡多维亚氏菌属(Scardovia)、
    奇异菌属(Atopobium)、乳杆菌属(Lactobacillus
    MDD患者,33.63±8.04岁,男性7例,女性9例;对照组,27.60±7.07岁,男性 16 名,女性4名粪便样本,16S rRNA 高通量测序分析
    自闭症谱系
    障碍(ASD)[69]
    丰度增加:拟杆菌属(Bacteroides)、副拟杆菌属(Parabacteroides)、梭菌属(Clostridium)、
    粪杆菌属(Faecalibacterium)、考拉杆菌属(Phascolarcto- bacterium)丰度减少:粪球菌属(Coprococcus)、双歧杆菌属(Bifidobac- terium
    2~18岁,纳入18项研究,493名ASD儿童和404名对照组,50%的研究人员在评估微生物群时考虑了饮食和益生菌的使用微生物培养;聚合酶链反应(PCR);焦磷酸测序技术
    阿尔茨海默病
    (AD)[70]
    丰度增加:埃希氏杆菌属(Escherichia)、劳特氏菌属(Blautia)、双歧杆菌属(Bifidobacterium)、
    链球菌属(Streptococcus)、乳杆菌属(Lactobacillus)、多尔氏菌属(Dorea)丰度减少:另枝菌属(Alistipes)、拟杆菌属(Bacteroides)、副拟杆菌属(Parabacteroides)、萨特氏菌属(Sutterella)、帕拉普氏菌属(Paraprevotella
    63~66岁,30名AD患者和30名对照组,男性占15%,接受教育平均年限11年,便秘比例3%16S rRNA基因测序
    帕金森病

    (PD)[71]
    丰度增加:氨基酸球菌属(Acidaminococcus)、不动细菌属(Acinetobacter)、
    肠球菌属(Enterococcus)、志贺菌属(Shigella)、
    巨单胞菌属(Megamonas)、巨球型菌属(Megasphaera)、变形杆菌属(Proteus)、链球菌属(Strepto- coccus)丰度减少:布劳特菌属(Blautia)、粪便菌属(Faecalibacterium)、嗜血杆菌属(Haemophilus)、
    瘤胃球菌属(Ruminococcus
    病程0.5~22.0年,平均病程(6.3±5.4)年,统一帕金森病评定量表(the Unified Parkinson’s Disease Rating Scale, UPDRS)评分(33.8±3.5)分;24名PD组,男性16例,女性8例;14名对照组,男性6名,女性8名。16S rRNA高通量测序
    下载: 导出CSV
  • [1] Ley R E, Backhed F, Turnbaugh P, et al. Obesity alters gut microbial ecology[J]. Proceedings of the National Academy of Sciences of the United States of America,2005,102(31):11070−11075. doi:  10.1073/pnas.0504978102
    [2] Ron S, Shai F, Ron M. Revised estimates for the number of human and bacteria cells in the body[J]. PloS Biology,2016,14(8):e1002533. doi:  10.1371/journal.pbio.1002533
    [3] Gebbers J O, Laissue J A. Immunologic structures and functions of the gut[J]. Schweizer Archiv fur Tierheilkunde,1989,131(5):221−238.
    [4] Heiss C N, Olofsson L E. The role of the gut microbiota in development, function and disorders of the central nervous system and the enteric nervous system[J]. Journal of Neuroendocrinology,2019,31(5):e12684. doi:  10.1111/jne.12684
    [5] Schmidt T S B, Raes J, Bork P. The human gut microbiome: From association to modulation[J]. Cell,2018,172(6):1198−1215. doi:  10.1016/j.cell.2018.02.044
    [6] Grochowska M, Wojnar M, Radkowski M. The gut microbiota in neuropsychiatric disorders[J]. Acta Neurobiologiae Experimentalis,2018,78(2):69−81. doi:  10.21307/ane-2018-008
    [7] Gomes A C, Hoffmann C, Mota J F. The human gut microbiota: Metabolism and perspective in obesity[J]. Gut Microbes,2018,9(4):308−325.
    [8] Locey K J, Lennon J T. Scaling laws predict global microbial diversity[J]. Proceedings of the National Academy of Sciences of the United States of America,2016,113(21):5970−5975. doi:  10.1073/pnas.1521291113
    [9] Nelson K E, Weinstock G M, Highlander S K, et al. A catalog of reference genomes from the human microbiome[J]. Science,2010,328(5981):994−999. doi:  10.1126/science.1183605
    [10] Rowland I, Gibson G, Heinken A, et al. Gut microbiota functions: Metabolism of nutrients and other food components[J]. European Journal of Nutrition,2018,57(1):1−24. doi:  10.1007/s00394-017-1445-8
    [11] Daliri E B-M, Wei S, Oh D H, et al. The human microbiome and metabolomics: Current concepts and applications[J]. Critical Reviews in Food Science and Nutrition,2017,57(16):3565−3576. doi:  10.1080/10408398.2016.1220913
    [12] Eisenstein M. Bacterial broadband[J]. Nature,2016,533(7603):S104−S106. doi:  10.1038/533S104a
    [13] Borre Y E, O’keeffe G W, Clarke G, et al. Microbiota and neurodevelopmental windows: Implications for brain disorders[J]. Trends in Molecular Medicine,2014,20(9):509−518. doi:  10.1016/j.molmed.2014.05.002
    [14] Bercik P, Park A J, Sinclair D, et al. The anxiolytic effect of Bifidobacterium longum NCC3001 involves vagal pathways for gut-brain communication[J]. Neurogastroenterology and Motility,2011,23(12):1132−1139. doi:  10.1111/j.1365-2982.2011.01796.x
    [15] Han W F, Tellez L A, Perkins M H, et al. A neural circuit for gut-Induced reward[J]. Cell,2018,175(3):887−888. doi:  10.1016/j.cell.2018.10.018
    [16] Bonaz B, Sinniger V, Pellissier S. Vagus nerve stimulation: A new promising therapeutic tool in inflammatory bowel disease[J]. J Intern Med,2017,282(1):46−63. doi:  10.1111/joim.12611
    [17] Ghia J E, Blennerhassett P, Kumar-Ondiveeran H, et al. The vagus nerve: A tonic inhibitory influence associated with inflammatory bowel disease in a murine model[J]. Gastroenterology,2006,131(4):1122−1130. doi:  10.1053/j.gastro.2006.08.016
    [18] Heck A L, Handa R J. Sex differences in the hypothalamic-pituitary-adrenal axis’ response to stress: An important role for gonadal hormones[J]. Neuropsychopharmacology,2019,44(1):45−58. doi:  10.1038/s41386-018-0167-9
    [19] Rea K, Dinan T G, Cryan J F. The microbiome: A key regulator of stress and neuroinflammation[J]. Neurobiology of stress,2016,4:23−33. doi:  10.1016/j.ynstr.2016.03.001
    [20] Barouei J, Moussavi M, Hodgson D M. Effect of maternal probiotic intervention on HPA Axis, immunity and gut microbiota in a Rat model of irritable bowel syndrome[J]. PloS One,2012,7:e46051. doi:  10.1371/journal.pone.0046051
    [21] Filaretova L, Bagaeva T. The realization of the brain-gut interactions with corticotropin-releasing factor and glucocorticoids[J]. Curr Neuropharmacol,2016,14(8):876−881. doi:  10.2174/1570159X14666160614094234
    [22] Mayer E A, Tillisch K, Gupta A. Gut/brain axis and the microbiota[J]. The Journal of Clinical Investigation,2015,125(3):926−938. doi:  10.1172/JCI76304
    [23] Furusawa Y, Obata Y, Fukuda S, et al. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells[J]. Nature,2014,506(7487):446−450.
    [24] Kayama H, Okumura R, Takeda K. Interaction between the microbiota, epithelia, and immune cells in the intestine[J]. Annual Review of Immunology,2020,38(1):23−48. doi:  10.1146/annurev-immunol-070119-115104
    [25] Levy M, Kolodziejczyk A A, Thaiss C A, et al. Dysbiosis and the immune system[J]. Nature Reviews Immunology,2017,17(4):219−232. doi:  10.1038/nri.2017.7
    [26] Rogers G B, Keating D J, Young R L, et al. From gut dysbiosis to altered brain function and mental illness: Mechanisms and pathways[J]. Mol Psychiatr,2016,21(6):738−748. doi:  10.1038/mp.2016.50
    [27] Hlatky M A, Boothroyd D, Vittinghoff E, et al. Quality-of-life and depressive symptoms in postmenopausal women after receiving hormone therapy-results from the heart and estrogen/progestin replacement study (HERS) trial[J]. Jama-Journal of the American Medical Association,2002,287(5):591−597. doi:  10.1001/jama.287.5.591
    [28] Dinan T G, Cryan J F. Melancholic microbes: A link between gut microbiota and depression?[J]. Neurogastroenterology & Motility,2013,25(9):713−719.
    [29] 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):786−796. doi:  10.1038/mp.2016.44
    [30] Jiang H Y, Ling Z X, Zhang Y H, et al. Altered fecal microbiota composition in patients with major depressive disorder[J]. Brain Behav Immun,2015,48:186−194. doi:  10.1016/j.bbi.2015.03.016
    [31] 李宁. 肠道菌群紊乱与粪菌移植[J]. 肠外与肠内营养,2014,21(4):193−197. [Li Ning. Intestinal flora disorder and fecal bacteria transplantation[J]. Parenteral and Enteral Nutrition,2014,21(4):193−197.
    [32] Cheung S G, Goldenthal A R, Uhlemann A C, et al. Systematic review of gut microbiota and major depression[J]. Front Psychiatry,2019,10:17.
    [33] Guida F, Turco F, Iannotta M, et al. Antibiotic-induced microbiota perturbation causes gut endocannabinoidome changes, hippocampal neuroglial reorganization and depression in mice[J]. Brain Behav Immun,2018,67:230−245. doi:  10.1016/j.bbi.2017.09.001
    [34] Kelly J R, Borre Y, Brien C O, et al. Transferring the blues: Depression-associated gut microbiota induces neurobehavioural changes in the rat[J]. J Psychiatr Res,2016,82:109−118. doi:  10.1016/j.jpsychires.2016.07.019
    [35] Liang S, Wang T, Hu X, et al. Administration of Lactobacillus helveticus NS8 improves behavioral, cognitive, and biochemical aberrations caused by chronic restraint stress[J]. Neuroscience,2015,310:561−577. doi:  10.1016/j.neuroscience.2015.09.033
    [36] Park H, Lee J Y, Shin C M, et al. Characterization of gastrointestinal disorders in patients with parkinsonian syndromes[J]. Parkinsonism & Related Disorders,2015,21(5):455−460.
    [37] Luo Y, Zeng B, Zeng L, et al. Gut microbiota regulates mouse behaviors through glucocorticoid receptor pathway genes in the hippocampus[J]. Translational Psychiatry,2018,8:187. doi:  10.1038/s41398-018-0240-5
    [38] Abildgaard A, Elfving B, Hokland M, et al. Probiotic treatment reduces depressive-like behaviour in rats independently of diet[J]. Psychoneuroendocrinology,2017,79:40−48. doi:  10.1016/j.psyneuen.2017.02.014
    [39] Moya-Perez A, Perez-Villalba A, Benitez-Paez A, et al. Bifidobacterium CECT 7765 modulates early stress-induced immune, neuroendocrine and behavioral alterations in mice[J]. Brain Behavior and Immunity,2017,65:43−56. doi:  10.1016/j.bbi.2017.05.011
    [40] Rudzki L, Ostrowska L, Pawlak D, et al. Probiotic Lactobacillus plantarum 299v decreases kynurenine concentration and improves cognitive functions in patients with major depression: A double-blind, randomized, placebo controlled study[J]. Psychoneuroendocrinology,2019,100:213−222. doi:  10.1016/j.psyneuen.2018.10.010
    [41] Nemani K, Ghomi R H, Mccormick B, et al. Schizophrenia and the gut-brain axis[J]. Progress in Neuro-Psychopharmacology & Biological Psychiatry,2015,56:155−160.
    [42] Severance E G, Prandovszky E, Castiglione J, et al. Gastroenterology issues in schizophrenia: Why the gut matters[J]. Current Psychiatry Reports,2015,17(5):S25−S26.
    [43] Castronallar E, Bendall M L, Pérezlosada M, et al. Composition, taxonomy and functional diversity of the oropharynx microbiome in individuals with schizophrenia and controls[J]. 2015, 3(8): e1140.
    [44] Yolken R H, Severance E G, Sabunciyan S, et al. Metagenomic sequencing indicates that the oropharyngeal phageome of individuals with schizophrenia differs from that of controls[J]. Schizophrenia Bulletin,2015,41(5):1153−1161. doi:  10.1093/schbul/sbu197
    [45] Zhu F, Ju Y, Wang W, et al. Metagenome-wide association of gut microbiome features for schizophrenia[J]. Nature Communications,2020,11(1):1612. doi:  10.1038/s41467-020-15457-9
    [46] Zheng P, Zeng B H, Liu M L, et al. The gut microbiome from patients with schizophrenia modulates the glutamate-glutamine-GABA cycle and schizophrenia-relevant behaviors in mice[J]. Sci Adv,2019,5(2):11.
    [47] Shen Y, Xu J T, Li Z Y, et al. Analysis of gut microbiota diversity and auxiliary diagnosis as a biomarker in patients with schizophrenia: A cross-sectional study[J]. Schizophr Res,2018,197:470−477. doi:  10.1016/j.schres.2018.01.002
    [48] Agrawal R, Kalmady S V, Venkatasubramanian G. In silico model-driven assessment of the effects of brain-derived neurotrophic factor deficiency on glutamate and gamma-aminobutyric acid: Implications for understanding schizophrenia pathophysiology[J]. Clinical Psychopharmacology and Neuroscience,2017,15(2):115−125. doi:  10.9758/cpn.2017.15.2.115
    [49] Caso J R, Balanza-Martinez V, Palomo T, et al. The microbiota and gut-brain axis: Contributions to the immunopathogenesis of schizophrenia[J]. Current Pharmaceutical Design,2016,22(40):6122−6133. doi:  10.2174/1381612822666160906160911
    [50] Baio J, Wiggins L, Christensen D L, et al. Prevalence of autism spectrum disorder among children aged 8 years-autism and developmental disabilities monitoring network[J]. Mmwr-Morbidity and Mortality Weekly Report,2020,69(16):503−503. doi:  10.15585/mmwr.mm6916a4
    [51] Coretti L, Paparo L, Riccio M P, et al. Gut microbiota features in young children with autism spectrum disorders[J]. Front Microbiol,2018,9:12. doi:  10.3389/fmicb.2018.00012
    [52] Tabouy L, Getselter D, Ziv O, et al. Dysbiosis of microbiome and probiotic treatment in a genetic model of autism spectrum disorders[J]. Brain Behav Immun,2018,73:310−319. doi:  10.1016/j.bbi.2018.05.015
    [53] Sgritta M, Dooling S W, Buffington S A, et al. Mechanisms underlying microbial-mediated changes in social behavior in mouse models of autism spectrum disorder[J]. Neuron,2019,101(2):246−259. doi:  10.1016/j.neuron.2018.11.018
    [54] Hsiao E Y, Mcbride S W, Hsien S, et al. Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders[J]. Cell,2013,155(7):1451−1463. doi:  10.1016/j.cell.2013.11.024
    [55] Principi N, Esposito S. Gut microbiota and central nervous system development[J]. Journal of Infection,2016,73(6):536−546. doi:  10.1016/j.jinf.2016.09.010
    [56] Shaaban S Y, El Gendy Y G, Mehanna N S, et al. The role of probiotics in children with autism spectrum disorder: A prospective, open-label study[J]. Nutritional Neuroscience,2018,21(9):676−681. doi:  10.1080/1028415X.2017.1347746
    [57] Tomova A, Babinska K, Kubranska A, et al. The difference of gastrointestinal microbiota of children with and without autism in Slovakia[J]. Acta Physiologica,2017,221:150−150.
    [58] Mcelhanon B O, Mccracken C, Karpen S, et al. Gastrointestinal symptoms in autism spectrum disorder: A meta-analysis[J]. Pediatrics,2014,133(5):872−883. doi:  10.1542/peds.2013-3995
    [59] Meltzer A, Van De Water J. The role of the immune system in autism spectrum disorder[J]. Neuropsychopharmacology,2017,42(1):284−298. doi:  10.1038/npp.2016.158
    [60] Lee G R. The balance of Th17 versus Treg Cells in autoimmunity[J]. International Journal of Molecular Sciences,2018,19(3):730. doi:  10.3390/ijms19030730
    [61] Azhari A, Azizan F, Esposito G. A systematic review of gut-immune-brain mechanisms in autism spectrum disorder[J]. Developmental Psychobiology,2019,61(5):752−771. doi:  10.1002/dev.21803
    [62] Vogt N M, Kerby R L, Dill-Mcfarland K A, et al. Gut microbiome alterations in Alzheimer’s disease[J]. Scientific Reports,2017,7:13537. doi:  10.1038/s41598-017-13601-y
    [63] Mancuso C, Santangelo R. Alzheimer's disease and gut microbiota modifications: The long way between preclinical studies and clinical evidence[J]. Pharmacological Research,2018,129:329−336. doi:  10.1016/j.phrs.2017.12.009
    [64] 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):264−276. doi:  10.1016/j.cell.2015.02.047
    [65] Cirstea M S, Yu A C, Golz E, et al. Microbiota composition and metabolism are associated with gut function in Parkinson's disease[J]. Movement Disorders,2020,35(7):1208−1217. doi:  10.1002/mds.28052
    [66] Pietrucci D, Teofani A, Unida V, et al. Can gut microbiota be a good predictor for Parkinson's disease? A machine learning approach[J]. Brain ences,2020,10(4):242.
    [67] Cheung S G, Goldenthal A R, Uhlemann A-C, et al. Systematic review of gut microbiota and major depression[J]. Frontiers in Psychiatry,2019,10:34. doi:  10.3389/fpsyt.2019.00034
    [68] 黄霞, 卓敏, 李时佳, 等. 精神分裂症患者肠道菌群结构特征初步观察与分析[J]. 中国神经精神疾病杂志,2019,45(7):401−406. [Huang Xia, Zhuo min, Li Shijia, et al. Preliminary observation and analysis on the structural characteristics of intestinal flora in patients with schizophrenia[J]. Chinese Journal of Nervous and Mental Diseases,2019,45(7):401−406. doi:  10.3969/j.issn.1002-0152.2019.07.004
    [69] Iglesias-Vázquez L, Riba G V G, Arija V, et al. Composition of gut microbiota in children with autism spectrum disorder: A systematic review and meta-analysis[J]. Nutrients,2020,12(3):792. doi:  10.3390/nu12030792
    [70] Li B, He Y, Ma J, et al. Mild cognitive impairment has similar alterations as Alzheimer's disease in gut microbiota[J]. Alzheimers & Dementia,2019,15(10):1357−1366.
    [71] 赵程, 于会艳, 李微, 等. 帕金森病患者肠道菌群变化的研究[J]. 中华神经科杂志,2018,51(7):498−503. [Zhao Cheng, Yu Huiyan, Li Wei, et al. A study of intestinal flora changes in Parkinson disease patients[J]. Chinese Journal of Neurology,2018,51(7):498−503. doi:  10.3760/cma.j.issn.1006-7876.2018.07.004
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  • 收稿日期:  2020-08-26
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    重要通知

    《食品工业科技》编辑部携手万方数据开通学术不端专属检测通道,具体信息参见本刊动态。