精神分裂症患者肠道菌群与认知功能的关系研究进展
Research Progress on the Relationship between Intestinal Flora and Cognitive Func-tion in Patients with Schizophrenia
DOI: 10.12677/ACM.2022.12121607, PDF,   
作者: 赵 君, 刘 玮:西安医学院,陕西 西安;吴 斌*:西安市精神卫生中心,陕西 西安
关键词: 精神分裂症肠道菌群认知功能Schizophrenia Intestinal Flora Cognitive Function
摘要: 精神分裂症(Schizophrenia, SCZ)是临床常见的精神疾病,认知缺陷是造成SCZ患者社会功能受损的重要因素。探索SCZ认知缺陷的发病原因及其病理机制,对改善患者认知功能,提高患者患病后的社会功能具有重要意义。近年来,“脑–肠轴”的发现表明肠道微生物与大脑存在双向调节的作用。肠道微生物的紊乱在SCZ的发病过程中发挥了重要的作用,且与SCZ患者的认知损害密切相关。肠道微生物或可成为干预SCZ认知缺陷的潜在治疗靶点。本文将对SCZ患者肠道微生物与认知功能关系的研究进行综述,详细介绍肠道微生物的特点,“脑–肠轴”的概念及作用,总结肠道微生物在SCZ的发病过程中发挥的作用,重点介绍SCZ患者肠道微生物与认知功能相关性的研究进展,为防治SCZ和改善SCZ患者认知功能提供新的思路。
Abstract: Schizophrenia (SCZ) is a common clinical mental illness, and cognitive deficits are important factors in impaired social functioning in SCZ patients. Exploring the pathogenesis and pathological mecha-nism of SCZ cognitive deficit is of great significance to improve patients’ cognitive function and im-prove their social function after illness. In recent years, the discovery of the “brain-gut axis” has shown that there is a two-way regulation between the gut microbiome and the brain. Disturbances of the Intestinal flora play an important role in the pathogenesis of SCZ and are closely related to cognitive impairment in SCZ patients. The gut microbiome may be a potential therapeutic target for SCZ cognitive deficits. This article will review the research on the relationship between Intestinal flora and cognitive function in SCZ patients, introduce in detail the characteristics of intestinal mi-crobes, the concept and role of “brain-gut axis”, summarize the role of intestinal microbes in the pathogenesis of SCZ, focus on the research progress of the correlation between intestinal microbes and cognitive function in SCZ patients, and provide new ideas for preventing SCZ and improving cognitive function in SCZ patients.
文章引用:赵君, 刘玮, 吴斌. 精神分裂症患者肠道菌群与认知功能的关系研究进展[J]. 临床医学进展, 2022, 12(12): 11145-11153. https://doi.org/10.12677/ACM.2022.12121607

参考文献

[1] Burton, S.C. (2005) Strategies for Improving Adherence to Second-Generation Antipsychotics in Patients with Schizo-phrenia by Increasing Ease of Use. Journal of Psychiatric Practice, 11, 369-378. [Google Scholar] [CrossRef] [PubMed]
[2] 徐逸, 陆峥. 精神分裂症患者认知功能障碍评估与治疗[J]. 世界临床药物, 2016, 37(1): 8-12.
[3] Gabanyi, I., Lepousez, G., Wheeler, R., et al. (2022) Bacterial Sensing via Neuronal Nod2 Regulates Appetite and Body Temperature. Science, 376, eabj3986. [Google Scholar] [CrossRef] [PubMed]
[4] Cervenka, I., Agudelo, L.Z. and Ruas, J.L. (2017) Kynurenines: Tryptophan’s Metabolites in Exercise, Inflammation, and Mental Health. Science, 357, eaaf9794. [Google Scholar] [CrossRef] [PubMed]
[5] Dave, M., Higgins, P.D., Middha, S., et al. (2012) The Human Gut Microbiome: Current Knowledge, Challenges, and Future Directions. Translational Research, 160, 246-257. [Google Scholar] [CrossRef] [PubMed]
[6] Jandhyala, S.M., Talukdar, R., Subramanyam, C., et al. (2015) Role of the Normal Gut Microbiota. World Journal of Gastroenterology, 21, 8787-8803. [Google Scholar] [CrossRef] [PubMed]
[7] Romijn, J.A., Corssmit, E.P., Havekes, L.M., et al. (2008) Gut-Brain Axis. Current Opinion in Clinical Nutrition & Metabolic Care, 11, 518-521. [Google Scholar] [CrossRef
[8] Mawe, G.M. and Hoffman, J.M. (2013) Serotonin Signal-ling in the Gut—Functions, Dysfunctions and Therapeutic Targets. Nature Reviews Gastroenterology & Hepatology, 10, 473-486. [Google Scholar] [CrossRef] [PubMed]
[9] Gao, L., Li, J., Zhou, Y., et al. (2018) Effects of Baicalein on Cortical Proinflammatory Cytokines and the Intestinal Microbiome in Senescence Accelerated Mouse Prone 8. ACS Chemical Neuroscience, 9, 1714-1724. [Google Scholar] [CrossRef] [PubMed]
[10] 李鑫, 赵雪, 卓恺明, 等. 首发精神分裂症肠道菌群特征及其与精神症状的关系[J]. 中国神经精神疾病杂志, 2022, 48(2): 90-95.
[11] Schwarz, E., Maukonen, J., Hyytiäinen, T., et al. (2018) Analysis of Microbiota in First Episode Psychosis Identifies Preliminary Associations with Symptom Severity and Treatment Response. Schizophrenia Research, 192, 398-403. [Google Scholar] [CrossRef] [PubMed]
[12] Nguyen, T.T., Kosciolek, T., Maldonado, Y., et al. (2019) Dif-ferences in Gut Microbiome Composition between Persons with Chronic Schizophrenia and Healthy Comparison Sub-jects. Schizophrenia Research, 204, 23-29. [Google Scholar] [CrossRef] [PubMed]
[13] 张言武, 白丽君, 程强, 等. 精神分裂症发作期与缓解期肠道菌群高通量测序分析[J]. 中国神经精神疾病杂志, 2018, 44(12): 705-709.
[14] Quidé, Y., Wilhelmi, C. and Green, M.J. (2020) Structural Brain Morphometry Associated with Theory of Mind in Bipolar Disorder and Schizophrenia. PsyCh Journal, 9, 234-246. [Google Scholar] [CrossRef] [PubMed]
[15] Saze, T., Hirao, K., Namiki, C., et al. (2007) In-sular Volume Reduction in Schizophrenia. European Archives of Psychiatry and Clinical Neuroscience, 257, 473-479. [Google Scholar] [CrossRef] [PubMed]
[16] 朱锡群, 易伟. 微生物群-脑-肠轴和中枢神经系统研究进展[J]. 疑难病杂志, 2018, 17(7): 748-752.
[17] Neufeld, K.M., Kang, N., Bienenstock, J., et al. (2011) Reduced Anxiety-Like Behavior and Central Neurochemical Change in Germ-Free Mice. Neurogastroenterology & Motility, 23, 255-264, e119. [Google Scholar] [CrossRef] [PubMed]
[18] Hoban, A.E., Stilling, R.M., Ryan, F.J., et al. (2016) Reg-ulation of Prefrontal Cortex Myelination by the Microbiota. Translational Psychiatry, 6, e774. [Google Scholar] [CrossRef] [PubMed]
[19] Gareau, M.G., Wine, E., Rodrigues, D.M., et al. (2011) Bacterial Infection Causes Stress-Induced Memory Dysfunction in Mice. Gut, 60, 307-317. [Google Scholar] [CrossRef] [PubMed]
[20] 甄莉丽, 汪艳, 彭广海. 伴发代谢综合征的精神分裂症患者认知功能及事件相关电位P300研究[J]. 中国现代医学杂志, 2013, 23(34): 76-79.
[21] 邹超杰, 程宇琪. 肠道微生物在精神分裂症中的研究进展[J]. 医学信息, 2018, 31(2): 29-32+6.
[22] Jiang, H., Ling, Z., Zhang, Y., et al. (2015) Altered Fecal Microbiota Composition in Patients with Major Depressive Disorder. Brain, Behavior, and Immunity, 48, 186-194. [Google Scholar] [CrossRef] [PubMed]
[23] Hennings, J.M., Kohli, M.A., Uhr, M., et al. (2019) Pol-ymorphisms in the BDNF and BDNFOS Genes Are Associated with Hypothalamus-Pituitary Axis Regulation in Major Depression. Progress in Neuro-Psychopharmacology & Biological Psychiatry, 95, Article ID: 109686. [Google Scholar] [CrossRef] [PubMed]
[24] Bonaz, B., Sinniger, V. and Pellissier, S. (2016) An-ti-Inflammatory Properties of the Vagus Nerve: Potential Therapeutic Implications of Vagus Nerve Stimulation. The Journal of Physiology, 594, 5781-5790. [Google Scholar] [CrossRef
[25] Dinan, T.G. and Cryan, J.F. (2020) Gut Microbiota: A Missing Link in Psychiatry. World Psychiatry, 19, 111-112. [Google Scholar] [CrossRef] [PubMed]
[26] Bravo, J.A., Forsythe, P., Chew, M.V., et al. (2011) Ingestion of Lactoba-cillus Strain Regulates Emotional Behavior and Central GABA Receptor Expression in a Mouse via the Vagus Nerve. Proceedings of the National Academy of Sciences of the United States of America, 108, 16050-16055. [Google Scholar] [CrossRef] [PubMed]
[27] Bercik, P., Park, A.J., Sinclair, D., et al. (2011) The Anxiolytic Ef-fect of Bifidobacterium longum NCC3001 Involves Vagal Pathways for Gut-Brain Communication. Neurogastroenter-ology & Motility, 23, 1132-1139. [Google Scholar] [CrossRef] [PubMed]
[28] Hansen, M.K., Daniels, S., Goehler, L.E., et al. (2000) Subdiaphragmatic Vagotomy Does Not Block Intraperitoneal Lipopolysaccharide-Induced Fever. Autonomic Neurosci-ence, 85, 83-87. [Google Scholar] [CrossRef
[29] Goehler, L.E., Gaykema, R.P., Opitz, N., et al. (2005) Acti-vation in Vagal Afferents and Central Autonomic Pathways: Early Responses to Intestinal Infection with Campylobacter jejuni. Brain, Behavior, and Immunity, 19, 334-344. [Google Scholar] [CrossRef] [PubMed]
[30] Chunchai, T., Samniang, B., Sripetchwandee, J., et al. (2016) Vagus Nerve Stimulation Exerts the Neuroprotective Effects in Obese-Insulin Resistant Rats, Leading to the Improvement of Cognitive Function. Scientific Reports, 6, Article No. 26866. [Google Scholar] [CrossRef] [PubMed]
[31] Li, Q., Han, Y., Dy, A.B.C., et al. (2017) The Gut Microbiota and Autism Spectrum Disorders. Frontiers in Cellular Neuroscience, 11, Article No. 120. [Google Scholar] [CrossRef] [PubMed]
[32] Jenkins, T.A., Nguyen, J.C., Polglaze, K.E., et al. (2016) Influence of Tryptophan and Serotonin on Mood and Cognition with a Possible Role of the Gut-Brain Axis. Nutrients, 8, 56. [Google Scholar] [CrossRef] [PubMed]
[33] Roth, B.L., Hanizavareh, S.M. and Blum, A.E. (2004) Serotonin Receptors Represent Highly Favorable Molecular Targets for Cognitive Enhancement in Schizophrenia and Other Disorders. Psychopharmacology (Berl), 174, 17-24. [Google Scholar] [CrossRef] [PubMed]
[34] Margolis, K.G., Cryan, J.F. and Mayer, E.A. (2021) The Micro-biota-Gut-Brain Axis: From Motility to Mood. Gastroenterology, 160, 1486-1501. [Google Scholar] [CrossRef] [PubMed]
[35] Martin, A.M., Sun, E.W., Rogers, G.B., et al. (2019) The Influ-ence of the Gut Microbiome on Host Metabolism through the Regulation of Gut Hormone Release. Frontiers in Physiol-ogy, 10, Article No. 428. [Google Scholar] [CrossRef] [PubMed]
[36] Szalardy, L., Zadori, D., Toldi, J., et al. (2012) Manipulating Kynurenic Acid Levels in the Brain—On the Edge between Neuroprotection and Cognitive Dysfunction. Current Topics in Medicinal Chemistry, 12, 1797-1806. [Google Scholar] [CrossRef] [PubMed]
[37] Campbell, B.M., Charych, E., Lee, A.W., et al. (2014) Kynurenines in CNS Disease: Regulation by Inflammatory Cytokines. Frontiers in Neuroscience, 8, Article No. 12. [Google Scholar] [CrossRef] [PubMed]
[38] Lyte, M. (2011) Probiotics Function Mechanistically as Delivery Vehicles for Neuroactive Compounds: Microbial Endocrinology in the Design and Use of Probiotics. Bioessays, 33, 574-581. [Google Scholar] [CrossRef] [PubMed]
[39] Barrett, E., Ross, R.P., O’toole, P.W., et al. (2012) γ-Aminobutyric Acid Production by Culturable Bacteria from the Human Intestine. Journal of Applied Microbiology, 113, 411-417. [Google Scholar] [CrossRef] [PubMed]
[40] Dantzer, R., O’Connor, J.C., Freund, G.G., et al. (2008) From Inflammation to Sickness and Depression: When the Immune System Subjugates the Brain. Nature Reviews Neuroscience, 9, 46-56. [Google Scholar] [CrossRef] [PubMed]
[41] Yudkin, J.S., Kumari, M., Humphries, S.E., et al. (2000) Inflammation, Obesity, Stress and Coronary Heart Disease: Is Interleukin-6 the Link? Atherosclerosis, 148, 209-214. [Google Scholar] [CrossRef
[42] Claesson, M.J., Jeffery, I.B., Conde, S., et al. (2012) Gut Microbiota Composition Correlates with Diet and Health in the Elderly. Nature, 488, 178-184. [Google Scholar] [CrossRef] [PubMed]
[43] Biagi, E., Nylund, L., Candela, M., et al. (2010) Through Ageing, and beyond: Gut Microbiota and Inflammatory Status in Seniors and Centenarians. PLOS ONE, 5, e10667. [Google Scholar] [CrossRef] [PubMed]
[44] Chen, X., Xun, K., Chen, L., et al. (2009) TNF-Alpha, a Potent Lipid Metabolism Regulator. Cell Biochemistry and Function, 27, 407-416. [Google Scholar] [CrossRef] [PubMed]
[45] Hotamisligil, G.S., Arner, P., Caro, J.F., et al. (1995) Increased Adipose Tissue Expression of Tumor Necrosis Factor-Alpha in Human Obesity and Insulin Resistance. Journal of Clinical Inves-tigation, 95, 2409-2415. [Google Scholar] [CrossRef
[46] Zhang, C., Fang, X., Yao, P., et al. (2017) Metabolic Adverse Effects of Olanzapine on Cognitive Dysfunction: A Possible Relationship between BDNF and TNF-Alpha. Psychoneuroendocri-nology, 81, 138-143. [Google Scholar] [CrossRef] [PubMed]
[47] Schirmer, M., Smeekens, S.P., Vlamakis, H., et al. (2016) Linking the Human Gut Microbiome to Inflammatory Cytokine Production Capacity. Cell, 167, 1125-1136.e8. [Google Scholar] [CrossRef] [PubMed]
[48] Orbe-Orihuela, Y.C., Lagunas-Martínez, A., Bahena-Román, M., et al. (2018) High Relative Abundance of Firmicutes and Increased TNF-α Levels Correlate with Obesity in Children. Salud Pública de México, 60, 5-11. [Google Scholar] [CrossRef] [PubMed]
[49] Lew, L.C., Hor, Y.Y., Yusoff, N.A.A., et al. (2019) Probiotic Lactobacillus plantarum P8 Alleviated Stress and Anxiety While Enhancing Memory and Cognition in Stressed Adults: A Randomised, Double-Blind, Placebo-Controlled Study. Clinical Nutrition, 38, 2053-2064. [Google Scholar] [CrossRef] [PubMed]
[50] Van den Munckhof, I.C.L., Kurilshikov, A., Ter Horst, R., et al. (2018) Role of Gut Microbiota in Chronic Low-Grade Inflammation as Potential Driver for Atherosclerotic Cardiovascu-lar Disease: A Systematic Review of Human Studies. Obesity Reviews, 19, 1719-1734. [Google Scholar] [CrossRef] [PubMed]
[51] Sweat, V., Starr, V., Bruehl, H., et al. (2008) C-reactive Protein Is Linked to Lower Cognitive Performance in Overweight and Obese Women. Inflammation, 31, 198-207. [Google Scholar] [CrossRef] [PubMed]
[52] Bengmark, S. (2013) Gut Microbiota, Immune Development and Function. Pharmacological Research, 69, 87-113. [Google Scholar] [CrossRef] [PubMed]
[53] Dinel, A.L. andré, C., Aubert, A., et al. (2014) Lipopolysaccha-ride-Induced Brain Activation of the Indoleamine 2,3-Dioxygenase and Depressive-Like Behavior Are Impaired in a Mouse Model of Metabolic Syndrome. Psychoneuroendocrinology, 40, 48-59. [Google Scholar] [CrossRef] [PubMed]
[54] Grigoleit, J.S., Kullmann, J.S., Wolf, O.T., et al. (2011) Dose-Dependent Effects of Endotoxin on Neurobehavioral Functions in Humans. PLOS ONE, 6, e28330. [Google Scholar] [CrossRef] [PubMed]
[55] Monroe, J.M., Buckley, P.F. and Miller, B.J. (2015) Me-ta-Analysis of Anti-Toxoplasma gondii IgM Antibodies in Acute Psychosis. Schizophrenia Bulletin, 41, 989-998. [Google Scholar] [CrossRef] [PubMed]
[56] Forsythe, P. and Kunze, W.A. (2013) Voices from Within: Gut Mi-crobes and the CNS. Cellular and Molecular Life Sciences, 70, 55-69. [Google Scholar] [CrossRef] [PubMed]
[57] Nonaka, N., Shioda, S., Niehoff, M.L., et al. (2003) Characteriza-tion of Blood-Brain Barrier Permeability to PYY3-36 in the Mouse. Journal of Pharmacology and Experimental Thera-peutics, 306, 948-953. [Google Scholar] [CrossRef] [PubMed]
[58] Fetissov, S.O., Hamze Sinno, M., Coëffier, M., et al. (2008) Autoan-tibodies against Appetite-Regulating Peptide Hormones and Neuropeptides: Putative Modulation by Gut Microflora. Nu-trition, 24, 348-359. [Google Scholar] [CrossRef] [PubMed]
[59] Braniste, V., Al-Asmakh, M., Kowal, C., et al. (2014) The Gut Mi-crobiota Influences Blood-Brain Barrier Permeability in Mice. Science Translational Medicine, 6, 263ra158. [Google Scholar] [CrossRef] [PubMed]
[60] Smith, O. (2014) The Gut Microbiota and the Blood-Brain Bar-rier. Science Signaling, 7, ec333-ec. [Google Scholar] [CrossRef
[61] Santocchi, E., Guiducci, L., Fulceri, F., et al. (2016) Gut to Brain Interaction in Autism Spectrum Disorders: A Randomized Controlled Trial on the Role of Probiotics on Clinical, Bio-chemical and Neurophysiological Parameters. BMC Psychiatry, 16, Article No. 183. [Google Scholar] [CrossRef] [PubMed]
[62] Akbari, E., Asemi, Z., Daneshvar Kakhaki, R., et al. (2016) Effect of Probiotic Supplementation on Cognitive Function and Metabolic Status in Alzheimer’s Disease: A Randomized, Dou-ble-Blind and Controlled Trial. Frontiers in Aging Neuroscience, 8, Article No. 256. [Google Scholar] [CrossRef] [PubMed]
[63] Steenbergen, L., Sellaro, R., Van Hemert, S., et al. (2015) A Ran-domized Controlled Trial to Test the Effect of Multispecies Probiotics on Cognitive Reactivity to Sad Mood. Brain, Be-havior, and Immunity, 48, 258-264. [Google Scholar] [CrossRef] [PubMed]
[64] Talbott, S. and Talbott, J. (2009) Effect of BETA 1,3/1,6 GLUCAN on Upper Respiratory Tract Infection Symptoms and Mood State in Marathon Athletes. Journal of Sports Science and Medicine, 8, 509-515.
[65] Lagier, J.C., Dubourg, G., Million, M., et al. (2018) Culturing the Human Microbiota and Culturomics. Nature Reviews Microbiology, 16, 540-550. [Google Scholar] [CrossRef] [PubMed]