色氨酸及其代谢产物与微生物–肠–脑轴的研究进展
Research Progress of Tryptophan and Its Metabolites in the Microbial-Gut-Brain Axis
摘要: 色氨酸是人体必需氨基酸之一,其可在体内通过三条途径代谢,生成多种生物活性分子,通过神经–内分泌、免疫和迷走神经途径参与中枢神经信号传递和宿主肠道内生理功能的调节。胃肠道与肠神经系统、中枢神经系统之间的双向交流被称为肠–脑轴。目前,肠道菌群基于“微生物–肠–脑轴”这一理论,通过影响色氨酸代谢从而对宿主的认知功能和行为产生影响得到广泛关注。本文就色氨酸及其代谢产物通过“微生物–肠–脑轴”途径影响宿主大脑发育的作用机制、内在联系作一综述,以期为临床改善认知功能提示新思路、新靶点。
Abstract: Tryptophan is one of the essential amino acids in the human body. It can be metabolized in the body through three pathways to produce a variety of bioactive molecules. The bidirectional communication between the GI tract and the enteric nervous system as well as the central nervous system is referred to as the gut-brain axis. At present, based on the theory of “microbiota-gut-brain axis”, gut microbiota has been widely concerned to affect the host's cognitive function and behavior by affecting tryptophan metabolism. This article reviews the mechanism and internal relationship of tryptophan and its metabolites on host brain development through the “microbiota-gut-brain axis” pathway, in order to suggest new ideas and new targets for clinical improvement of cognitive function.
文章引用:唐婕, 高进. 色氨酸及其代谢产物与微生物–肠–脑轴的研究进展[J]. 临床医学进展, 2024, 14(6): 1225-1232. https://doi.org/10.12677/acm.2024.1461901

参考文献

[1] Kałużna-Czaplińska, J., Gątarek, P., Chirumbolo, S., Chartrand, M.S. and Bjørklund, G. (2017) How Important Is Tryptophan in Human Health? Critical Reviews in Food Science and Nutrition, 59, 72-88. [Google Scholar] [CrossRef] [PubMed]
[2] Davidson, M., Rashidi, N., Hossain, M.K., Raza, A., Nurgali, K. and Apostolopoulos, V. (2023) Tryptophan and Substance Abuse: Mechanisms and Impact. International Journal of Molecular Sciences, 24, Article 2737. [Google Scholar] [CrossRef] [PubMed]
[3] Cryan, J.F., O’Riordan, K.J., Cowan, C.S.M., Sandhu, K.V., Bastiaanssen, T.F.S., Boehme, M., et al. (2019) The Microbiota-Gut-Brain Axis. Physiological Reviews, 99, 1877-2013. [Google Scholar] [CrossRef] [PubMed]
[4] Lukić, I., Getselter, D., Koren, O. and Elliott, E. (2019) Role of Tryptophan in Microbiota-Induced Depressive-Like Behavior: Evidence from Tryptophan Depletion Study. Frontiers in Behavioral Neuroscience, 13, Article 123. [Google Scholar] [CrossRef] [PubMed]
[5] Lindseth, G., Helland, B. and Caspers, J. (2015) The Effects of Dietary Tryptophan on Affective Disorders. Archives of Psychiatric Nursing, 29, 102-107. [Google Scholar] [CrossRef] [PubMed]
[6] Roth, W., Zadeh, K., Vekariya, R., Ge, Y. and Mohamadzadeh, M. (2021) Tryptophan Metabolism and Gut-Brain Homeostasis. International Journal of Molecular Sciences, 22, Article 2973. [Google Scholar] [CrossRef] [PubMed]
[7] 郭子涵, 赵娜, 王彬, 等. 色氨酸及其代谢产物在动物肠-脑轴中的作用研究进展[J]. 中国畜牧杂志, 2021, 57(9): 15-21.
[8] Margolis, K.G., Cryan, J.F. and Mayer, E.A. (2021) The Microbiota-Gut-Brain Axis: From Motility to Mood. Gastroenterology, 160, 1486-1501. [Google Scholar] [CrossRef] [PubMed]
[9] Park, L.T., Kadriu, B., Gould, T.D., Zanos, P., Greenstein, D., Evans, J.W., et al. (2020) A Randomized Trial of the N-Methyl-D-Aspartate Receptor Glycine Site Antagonist Prodrug 4-Chlorokynurenine in Treatment-Resistant Depression. International Journal of Neuropsychopharmacology, 23, 417-425. [Google Scholar] [CrossRef] [PubMed]
[10] Lee, J. and Lee, J. (2010) Indole as an Intercellular Signal in Microbial Communities. FEMS Microbiology Reviews, 34, 426-444. [Google Scholar] [CrossRef] [PubMed]
[11] Bader, M. (2020) Inhibition of Serotonin Synthesis: A Novel Therapeutic Paradigm. Pharmacology & Therapeutics, 205, Article ID: 107423. [Google Scholar] [CrossRef] [PubMed]
[12] Minich, D.M., Henning, M., Darley, C., Fahoum, M., Schuler, C.B. and Frame, J. (2022) Is Melatonin the “Next Vitamin D”?: A Review of Emerging Science, Clinical Uses, Safety, and Dietary Supplements. Nutrients, 14, Article 3934. [Google Scholar] [CrossRef] [PubMed]
[13] O’Mahony, S.M., Clarke, G., Borre, Y.E., Dinan, T.G. and Cryan, J.F. (2015) Serotonin, Tryptophan Metabolism and the Brain-Gut-Microbiome Axis. Behavioural Brain Research, 277, 32-48. [Google Scholar] [CrossRef] [PubMed]
[14] Ge, X., Ding, C., Zhao, W., Xu, L., Tian, H., Gong, J., et al. (2017) Antibiotics-induced Depletion of Mice Microbiota Induces Changes in Host Serotonin Biosynthesis and Intestinal Motility. Journal of Translational Medicine, 15, Article No. 13. [Google Scholar] [CrossRef] [PubMed]
[15] Reigstad, C.S., Salmonson, C.E., III, J.F.R., Szurszewski, J.H., Linden, D.R., Sonnenburg, J.L., et al. (2014) Gut Microbes Promote Colonic Serotonin Production through an Effect of Short‐Chain Fatty Acids on Enterochromaffin Cells. The FASEB Journal, 29, 1395-1403. [Google Scholar] [CrossRef] [PubMed]
[16] Xue, C., Li, G., Zheng, Q., Gu, X., Shi, Q., Su, Y., et al. (2023) Tryptophan Metabolism in Health and Disease. Cell Metabolism, 35, 1304-1326. [Google Scholar] [CrossRef] [PubMed]
[17] 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]
[18] Too, L.K., Li, K.M., Suarna, C., Maghzal, G.J., Stocker, R., McGregor, I.S., et al. (2016) Deletion of TDO2, IDO-1 and IDO-2 Differentially Affects Mouse Behavior and Cognitive Function. Behavioural Brain Research, 312, 102-117. [Google Scholar] [CrossRef] [PubMed]
[19] Salminen, A. (2023) Activation of Aryl Hydrocarbon Receptor (AhR) in Alzheimer’s Disease: Role of Tryptophan Metabolites Generated by Gut Host-Microbiota. Journal of Molecular Medicine, 101, 201-222. [Google Scholar] [CrossRef] [PubMed]
[20] Gao, K., Mu, C., Farzi, A. and Zhu, W. (2020) Tryptophan Metabolism: A Link between the Gut Microbiota and Brain. Advances in Nutrition, 11, 709-723. [Google Scholar] [CrossRef] [PubMed]
[21] Agudelo, L.Z., Ferreira, D.M.S., Cervenka, I., Bryzgalova, G., Dadvar, S., Jannig, P.R., et al. (2018) Kynurenic Acid and Gpr35 Regulate Adipose Tissue Energy Homeostasis and Inflammation. Cell Metabolism, 27, 378-392.E5. [Google Scholar] [CrossRef] [PubMed]
[22] Lin, C., Chou, C., Lee, Y. and Hung, C. (2022) Curcumin Facilitates Aryl Hydrocarbon Receptor Activation to Ameliorate Inflammatory Astrogliosis. Molecules, 27, Article 2507. [Google Scholar] [CrossRef] [PubMed]
[23] Hestad, K., Alexander, J., Rootwelt, H. and Aaseth, J.O. (2022) The Role of Tryptophan Dysmetabolism and Quinolinic Acid in Depressive and Neurodegenerative Diseases. Biomolecules, 12, Article 998. [Google Scholar] [CrossRef] [PubMed]
[24] Guillemin, G.J. (2012) Quinolinic Acid, the Inescapable Neurotoxin. The FEBS Journal, 279, 1356-1365. [Google Scholar] [CrossRef] [PubMed]
[25] Lovelace, M.D., Varney, B., Sundaram, G., Lennon, M.J., Lim, C.K., Jacobs, K., et al. (2017) Recent Evidence for an Expanded Role of the Kynurenine Pathway of Tryptophan Metabolism in Neurological Diseases. Neuropharmacology, 112, 373-388. [Google Scholar] [CrossRef] [PubMed]
[26] Müller, N. and Schwarz, M.J. (2007) The Immune-Mediated Alteration of Serotonin and Glutamate: Towards an Integrated View of Depression. Molecular Psychiatry, 12, 988-1000. [Google Scholar] [CrossRef] [PubMed]
[27] McDew-White, M., Lee, E., Premadasa, L.S., Alvarez, X., Okeoma, C.M. and Mohan, M. (2023) Cannabinoids Modulate the Microbiota–gut–brain Axis in HIV/SIV Infection by Reducing Neuroinflammation and Dysbiosis While Concurrently Elevating Endocannabinoid and Indole-3-Propionate Levels. Journal of Neuroinflammation, 20, Article No. 62. [Google Scholar] [CrossRef] [PubMed]
[28] Poeggeler, B., Sambamurti, K., Siedlak, S.L., Perry, G., Smith, M.A. and Pappolla, M.A. (2010) A Novel Endogenous Indole Protects Rodent Mitochondria and Extends Rotifer Lifespan. PLOS ONE, 5, e10206. [Google Scholar] [CrossRef] [PubMed]
[29] Yin, J., Zhang, Y., Liu, X., Li, W., Hu, Y., Zhang, B., et al. (2023) Gut Microbiota‐Derived Indole Derivatives Alleviate Neurodegeneration in Aging through Activating GPR30/AMPK/SIRT1 Pathway. Molecular Nutrition & Food Research, 67, e2200739. [Google Scholar] [CrossRef] [PubMed]
[30] Joseph, T.A. and Pe’er, I. (2021) An Introduction to Whole-Metagenome Shotgun Sequencing Studies. Methods in Molecular Biology, 2243, 107-122. [Google Scholar] [CrossRef] [PubMed]
[31] Gareau, M.G., Wine, E., Rodrigues, D.M., Cho, J.H., Whary, M.T., Philpott, D.J., et al. (2010) Bacterial Infection Causes Stress-Induced Memory Dysfunction in Mice. Gut, 60, 307-317. [Google Scholar] [CrossRef] [PubMed]
[32] Zhu, F., Guo, R., Wang, W., Ju, Y., Wang, Q., Ma, Q., et al. (2019) Transplantation of Microbiota from Drug-Free Patients with Schizophrenia Causes Schizophrenia-Like Abnormal Behaviors and Dysregulated Kynurenine Metabolism in Mice. Molecular Psychiatry, 25, 2905-2918. [Google Scholar] [CrossRef] [PubMed]
[33] Gao, K., Pi, Y., Mu, C., Farzi, A., Liu, Z. and Zhu, W. (2019) Increasing Carbohydrate Availability in the Hindgut Promotes Hypothalamic Neurotransmitter Synthesis: Aromatic Amino Acids Linking the Microbiota-Brain Axis. Journal of Neurochemistry, 149, 641-659. [Google Scholar] [CrossRef] [PubMed]
[34] Gao, K., Pi, Y., Mu, C., Peng, Y., Huang, Z. and Zhu, W. (2018) Antibiotics‐induced Modulation of Large Intestinal Microbiota Altered Aromatic Amino Acid Profile and Expression of Neurotransmitters in the Hypothalamus of Piglets. Journal of Neurochemistry, 146, 219-234. [Google Scholar] [CrossRef] [PubMed]
[35] Bombardi, C., Grandis, A., Pivac, N., et al. (2021) Serotonin Modulation of Hippocampal Functions: From Anatomy to Neurotherapeutics. Progress in Brain Research, 261, 83-158.
[36] Ogbonnaya, E.S., Clarke, G., Shanahan, F., Dinan, T.G., Cryan, J.F. and O’Leary, O.F. (2015) Adult Hippocampal Neurogenesis Is Regulated by the Microbiome. Biological Psychiatry, 78, e7-e9. [Google Scholar] [CrossRef] [PubMed]
[37] Jameson, K.G. and Hsiao, E.Y. (2018) Linking the Gut Microbiota to a Brain Neurotransmitter. Trends in Neurosciences, 41, 413-414. [Google Scholar] [CrossRef] [PubMed]
[38] Romo-Araiza, A., Gutiérrez-Salmeán, G., Galván, E.J., Hernández-Frausto, M., Herrera-López, G., Romo-Parra, H., et al. (2018) Probiotics and Prebiotics as a Therapeutic Strategy to Improve Memory in a Model of Middle-Aged Rats. Frontiers in Aging Neuroscience, 10, Article 416. [Google Scholar] [CrossRef] [PubMed]
[39] Wu, L., Han, Y., Zheng, Z., Peng, G., Liu, P., Yue, S., et al. (2021) Altered Gut Microbial Metabolites in Amnestic Mild Cognitive Impairment and Alzheimer’s Disease: Signals in Host-Microbe Interplay. Nutrients, 13, Article 228. [Google Scholar] [CrossRef] [PubMed]
[40] Deng, Y., Zhou, M., Wang, J., Yao, J., Yu, J., Liu, W., et al. (2021) Involvement of the Microbiota-Gut-Brain Axis in Chronic Restraint Stress: Disturbances of the Kynurenine Metabolic Pathway in Both the Gut and Brain. Gut Microbes, 13, Article ID: 1869501. [Google Scholar] [CrossRef] [PubMed]
[41] Marcantoni, A., Cerullo, M.S., Buxeda, P., Tomagra, G., Giustetto, M., Chiantia, G., et al. (2020) Amyloid β42 Oligomers Up‐Regulate the Excitatory Synapses by Potentiating Presynaptic Release While Impairing Postsynaptic NMDA Receptors. The Journal of Physiology, 598, 2183-2197. [Google Scholar] [CrossRef] [PubMed]
[42] Nakaizumi, K., Ouchi, Y., Terada, T., Yoshikawa, E., Kakimoto, A., Isobe, T., et al. (2018) In Vivo Depiction of Α7 Nicotinic Receptor Loss for Cognitive Decline in Alzheimer’s Disease. Journal of Alzheimers Disease, 61, 1355-1365. [Google Scholar] [CrossRef] [PubMed]
[43] Domin, H. (2022) Group III Metabotropic Glutamate Receptors as Promising Targets for Neuroprotective Therapy: Particular Emphasis on the Role of mGlu4 and mGlu7 Receptors. Pharmacology Biochemistry and Behavior, 219, 173452. [Google Scholar] [CrossRef] [PubMed]
[44] Barroso, A., Mahler, J.V., Fonseca-Castro, P.H. and Quintana, F.J. (2021) The Aryl Hydrocarbon Receptor and the Gut-Brain Axis. Cellular & Molecular Immunology, 18, 259-268. [Google Scholar] [CrossRef] [PubMed]
[45] Silva-Parra, J., Sandu, C., Felder-Schmittbuhl, M., Hernández-Kelly, L.C. and Ortega, A. (2023) Aryl Hydrocarbon Receptor in Glia Cells: A Plausible Glutamatergic Neurotransmission Orchestrator. Neurotoxicity Research, 41, 103-117. [Google Scholar] [CrossRef] [PubMed]
[46] Yu, D., Tao, B., Yang, Y., Du, L., Yang, S., He, X., et al. (2014) The IDO Inhibitor Coptisine Ameliorates Cognitive Impairment in a Mouse Model of Alzheimer’s Disease. Journal of Alzheimers Disease, 43, 291-302. [Google Scholar] [CrossRef] [PubMed]
[47] 郭丽. 菊粉通过肠道菌群调节色氨酸代谢干预精神分裂症小鼠神经炎症的作用及机制研究[D]: [博士学位论文]. 银川: 宁夏医科大学, 2023.
[48] Ye, J., Qiu, J., Bostick, J.W., Ueda, A., Schjerven, H., Li, S., et al. (2017) The Aryl Hydrocarbon Receptor Preferentially Marks and Promotes Gut Regulatory T Cells. Cell Reports, 21, 2277-2290. [Google Scholar] [CrossRef] [PubMed]
[49] Martin-Gallausiaux, C., Larraufie, P., Jarry, A., Béguet-Crespel, F., Marinelli, L., Ledue, F., et al. (2018) Butyrate Produced by Commensal Bacteria Down-Regulates Indolamine 2, 3-Dioxygenase 1 (IDO-1) Expression via a Dual Mechanism in Human Intestinal Epithelial Cells. Frontiers in Immunology, 9, Article 2838. [Google Scholar] [CrossRef] [PubMed]
[50] Israelyan, N. and Margolis, K.G. (2018) Serotonin as a Link between the Gut-Brain-Microbiome Axis in Autism Spectrum Disorders. Pharmacological Research, 132, 1-6. [Google Scholar] [CrossRef] [PubMed]
[51] Brushett, S., Gacesa, R., Vich Vila, A., Brandao Gois, M.F., Andreu-Sánchez, S., Swarte, J.C., et al. (2023) Gut Feelings: The Relations between Depression, Anxiety, Psychotropic Drugs and the Gut Microbiome. Gut Microbes, 15, Article ID: 2281360. [Google Scholar] [CrossRef] [PubMed]
[52] Liu, Z., Dai, X., Zhang, H., Shi, R., Hui, Y., Jin, X., et al. (2020) Gut Microbiota Mediates Intermittent-Fasting Alleviation of Diabetes-Induced Cognitive Impairment. Nature Communications, 11, Article No. 855. [Google Scholar] [CrossRef] [PubMed]
[53] Rothhammer, V., Mascanfroni, I.D., Bunse, L., Takenaka, M.C., Kenison, J.E., Mayo, L., et al. (2016) Type I Interferons and Microbial Metabolites of Tryptophan Modulate Astrocyte Activity and Central Nervous System Inflammation via the Aryl Hydrocarbon Receptor. Nature Medicine, 22, 586-597. [Google Scholar] [CrossRef] [PubMed]