色氨酸代谢对慢性疲劳综合征微生物-肠-脑通讯影响的研究进展

doi:10.3969/j.issn.1006-5725.2025.23.023

Abstract

Abstract:

The pathogenesis of chronic fatigue syndrome （CFS） remains poorly defined， and while the tryptophan metabolic pathway is closely associated with the development of CFS， the underlying mechanisms are not yet fully understood. This review examines the alterations in tryptophan metabolites and related enzymes in both peripheral and central systems of CFS patients， with a particular focus on the involvement of the tryptophan pathway in the gut-brain axis （GBA）. Furthermore， it provides a comprehensive analysis of the mechanistic roles of tryptophan metabolites in modulating the progression of CFS， aiming to elucidate the current evidence and potential driving mechanisms linking the tryptophan metabolic pathway to CFS， thereby promoting new insights and advancements in this research domain.

Key words: chronic fatigue syndrome, tryptophan, 5-HT, kynurenine, gut-brain axis

CLC Number:

R749

Ming JIN,Sitong FANG,Lingjun KONG,Qingguang ZHU,Min. FANG. The Role of tryptophan metabolism in modulating microbiota⁃gut⁃brain communication in chronic fatigue syndrome[J]. The Journal of Practical Medicine, 2025, 41(23): 3786-3793.

Figures/Tables 1

References 68

[1]	LIM E J， AHN Y C， JANG E S， et al. Systematic review and meta-analysis of the prevalence of chronic fatigue syndrome/myalgic encephalomyelitis （CFS/ME）［J］. J Transl Med， 2020， 18（1）： 100. doi:10.1186/s12967-020-02269-0 doi: 10.1186/s12967-020-02269-0
[2]	伍侨，高静，柏丁兮，等. 中国人群慢性疲劳综合征患病率的Meta分析［J］. 右江医学， 2020， 48（10）： 727-735.
[3]	ARRON H E， MARSH B D， KELL D B， et al. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome： The biology of a neglected disease［J］. Front Immunol， 2024， 15： 1386607. doi:10.3389/fimmu.2024.1386607 doi: 10.3389/fimmu.2024.1386607
[4]	LEE J S， KANG J Y， PARK S Y， et al. Central 5-HTergic hyperactivity induces myalgic encephalomyelitis/chronic fatigue syndrome （ME/CFS）-like pathophysiology［J］. J Transl Med， 2024， 22（1）： 34. doi:10.1186/s12967-023-04808-x doi: 10.1186/s12967-023-04808-x
[5]	AGUS A， PLANCHAIS J， SOKOL H. Gut Microbiota Regulation of Tryptophan Metabolism in Health and Disease［J］. Cell Host Microbe， 2018， 23（6）： 716-724. doi:10.1016/j.chom.2018.05.003 doi: 10.1016/j.chom.2018.05.003
[6]	HSU C Y， AHMAD I， MAYA R W， et al. The potential therapeutic approaches targeting gut health in myalgic encephalomyelitis/chronic fatigue syndrome （ME/CFS）： A narrative review［J］. J Transl Med， 2025， 23（1）： 530. doi:10.1186/s12967-025-06527-x doi: 10.1186/s12967-025-06527-x
[7]	MA N， HE T， JOHNSTON L J， et al. Host-microbiome interactions： The aryl hydrocarbon receptor as a critical node in tryptophan metabolites to brain signaling［J］. Gut Microbes， 2020， 11（5）： 1203-1219. doi:10.1080/19490976.2020.1758008 doi: 10.1080/19490976.2020.1758008
[8]	GAO K， MU C L， FARZI A， et al. Tryptophan Metabolism： A Link Between the Gut Microbiota and Brain［J］. Adv Nutr， 2020， 11（3）： 709-723. doi:10.1093/advances/nmz127 doi: 10.1093/advances/nmz127
[9]	AHMED H S. The Multifaceted Role of L-Type Amino Acid Transporter 1 at the Blood-Brain Barrier： Structural Implications and Therapeutic Potential［J］. Mol Neurobiol， 2025， 62（3）： 3813-3832. doi:10.1007/s12035-024-04506-9 doi: 10.1007/s12035-024-04506-9
[10]	SU X， GAO Y， YANG R. Gut Microbiota-Derived Tryptophan Metabolites Maintain Gut and Systemic Homeostasis［J］. Cells， 2022， 11（15）：2296. doi:10.3390/cells11152296 doi: 10.3390/cells11152296
[11]	LIU Y， HOU Y， WANG G， et al. Gut Microbial Metabolites of Aromatic Amino Acids as Signals in Host-Microbe Interplay［J］. Trends Endocrinol Metab， 2020， 31（11）： 818-834. doi:10.1016/j.tem.2020.02.012 doi: 10.1016/j.tem.2020.02.012
[12]	CERVENKA I， AGUDELO L Z， RUAS J L. Kynurenines： Tryptophan's metabolites in exercise， inflammation， and mental health［J］. Science， 2017， 357（6349）： eaaf9794. doi:10.1126/science.aaf9794 doi: 10.1126/science.aaf9794
[13]	SAVITZ J， DREVETS W C， WURFEL B E， et al. Reduction of kynurenic acid to quinolinic acid ratio in both the depressed and remitted phases of major depressive disorder［J］. Brain Behav Immun， 2015， 46： 55-59. doi:10.1016/j.bbi.2015.02.007 doi: 10.1016/j.bbi.2015.02.007
[14]	DEHHAGHI M， PANAHI H K S， KAVYANI B， et al. The Role of Kynurenine Pathway and NAD（+） Metabolism in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome［J］. Aging Dis， 2022， 13（3）： 698-711. doi:10.14336/ad.2021.0824 doi: 10.14336/ad.2021.0824
[15]	SATHYASAIKUMAR K V， PéREZ DE LA CRUZ V， PINEDA B， et al. Cellular Localization of Kynurenine 3-Monooxygenase in the Brain： Challenging the Dogma［J］. Antioxidants （Basel）， 2022， 11（2）：315. doi:10.3390/antiox11020315 doi: 10.3390/antiox11020315
[16]	BANSAL Y， SINGH R， SODHI R K， et al. Kynurenine monooxygenase inhibition and associated reduced quinolinic acid reverses depression-like behaviour by upregulating Nrf2/ARE pathway in mouse model of depression： In-vivo and In-silico studies［J］. Neuropharmacology， 2022， 215： 109169. doi:10.1016/j.neuropharm.2022.109169 doi: 10.1016/j.neuropharm.2022.109169
[17]	EL-MERAHBI R， LöFFLER M， MAYER A， et al. The roles of peripheral serotonin in metabolic homeostasis［J］. FEBS Lett， 2015， 589（15）： 1728-1734. doi:10.1016/j.febslet.2015.05.054 doi: 10.1016/j.febslet.2015.05.054
[18]	CHAVES-FILHO A J M， MACEDO D S， DE LUCENA D F， et al. Shared microglial mechanisms underpinning depression and chronic fatigue syndrome and their comorbidities［J］. Behav Brain Res， 2019， 372： 111975. doi:10.1016/j.bbr.2019.111975 doi: 10.1016/j.bbr.2019.111975
[19]	NOWAK D B， TABORDA-BEJARANO J P， CHAURE F J， et al. Understanding Microglia in Mesocorticolimbic Circuits： Implications for the Study of Chronic Stress and Substance Use Disorders［J］. Cells， 2025， 14（13）：1014. doi:10.3390/cells14131014 doi: 10.3390/cells14131014
[20]	FUNG C， VENNEMAN T， HOLLAND A M， et al. Nutrients activate distinct patterns of small-intestinal enteric neurons［J］. Nature， 2025， 644（8078）： 1069-1077. doi:10.1038/s41586-025-09228-z doi: 10.1038/s41586-025-09228-z
[21]	CHEN L， HUANG S， WU X， et al. Serotonin signalling in cancer： Emerging mechanisms and therapeutic opportunities［J］. Clin Transl Med， 2024， 14（7）： e1750. doi:10.1002/ctm2.1750 doi: 10.1002/ctm2.1750
[22]	CHEN Y， GAO T， BAI J， et al. Ren-Shen-Bu-Qi decoction alleviates exercise fatigue through activating PI3K/AKT/Nrf2 pathway in mice［J］. Chin Med， 2024， 19（1）： 154. doi:10.1186/s13020-024-01027-4 doi: 10.1186/s13020-024-01027-4
[23]	BAHAR M E， KIM H J， KIM D R. Targeting the RAS/RAF/MAPK pathway for cancer therapy： From mechanism to clinical studies［J］. Signal Transduct Target Ther， 2023， 8（1）： 455. doi:10.1038/s41392-023-01705-z doi: 10.1038/s41392-023-01705-z
[24]	LIU J， PEI C， JIA N， et al. Preconditioning with Ginsenoside Rg3 mitigates cardiac injury induced by high-altitude hypobaric hypoxia exposure in mice by suppressing ferroptosis through inhibition of the RhoA/ROCK signaling pathway［J］. J Ethnopharmacol， 2025， 337（Pt 2）： 118861. doi:10.1016/j.jep.2024.118861 doi: 10.1016/j.jep.2024.118861
[25]	SOTO C， ORIHUELA L P， APOSTOL G， et al. Running Reverses Chronic Stress-Induced Changes in Serotonergic Modulation of Hippocampal Granule Cells and Altered Behavioural Responses［J］. Eur J Neurosci， 2025， 61（7）： e70084. doi:10.1111/ejn.70084 doi: 10.1111/ejn.70084
[26]	NIKOUI V， JAVADI-PAYDAR M， SALEHI M， et al. Protective Effects of Lithium on Sumatriptan-Induced Memory Impairment in Mice［J］. Acta Med Iran， 2016， 54（4）： 226-232.
[27]	ROAGER H M， LICHT T R. Microbial tryptophan catabolites in health and disease［J］. Nat Commun， 2018， 9（1）： 3294. doi:10.1038/s41467-018-05470-4 doi: 10.1038/s41467-018-05470-4
[28]	LEE J H， WOOD T K， LEE J. Roles of indole as an interspecies and interkingdom signaling molecule［J］. Trends Microbiol， 2015， 23（11）： 707-718. doi:10.1016/j.tim.2015.08.001 doi: 10.1016/j.tim.2015.08.001
[29]	WEI W， LIU Y， HOU Y， et al. Psychological stress-induced microbial metabolite indole-3-acetate disrupts intestinal cell lineage commitment［J］. Cell Metab， 2024， 36（3）： 466-483.e7. doi:10.1016/j.cmet.2023.12.026 doi: 10.1016/j.cmet.2023.12.026
[30]	JIANG Y， YANG J， XIA L， et al. Gut Microbiota-Tryptophan Metabolism-GLP-1 Axis Participates in β-Cell Regeneration Induced by Dapagliflozin［J］. Diabetes， 2024， 73（6）： 926-940. doi:10.2337/db23-0553 doi: 10.2337/db23-0553
[31]	ROTHHAMMER V， MASCANFRONI I D， BUNSE L， et al. Type I interferons and microbial metabolites of tryptophan modulate astrocyte activity and central nervous system inflammation via the aryl hydrocarbon receptor［J］. Nat Med， 2016， 22（6）： 586-597. doi:10.1038/nm.4106 doi: 10.1038/nm.4106
[32]	SEO S-K， KWON B. Immune regulation through tryptophan metabolism［J］. Exp Mol Med， 2023， 55（7）： 1371-1379. doi:10.1038/s12276-023-01028-7 doi: 10.1038/s12276-023-01028-7
[33]	GONZALEZ-MERCADO V J， MARRERO S， PéREZ-SANTIAGO J， et al. Association of Radiotherapy-Related Intestinal Injury and Cancer-related Fatigue： A Brief Review and Commentary［J］. P R Health Sci J， 2021， 40（1）： 6-11.
[34]	MARTíN F， BLANCO-SUáREZ M， ZAMBRANO P， et al. Increased gut permeability and bacterial translocation are associated with fibromyalgia and myalgic encephalomyelitis/chronic fatigue syndrome： Implications for disease-related biomarker discovery［J］. Front Immunol， 2023， 14： 1253121. doi:10.3389/fimmu.2023.1253121 doi: 10.3389/fimmu.2023.1253121
[35]	NAGY-SZAKAL D， BARUPAL D K， LEE B， et al. Insights into myalgic encephalomyelitis/chronic fatigue syndrome phenotypes through comprehensive metabolomics［J］. Sci Rep， 2018，8（1）：10056. doi:10.1038/s41598-018-28477-9 doi: 10.1038/s41598-018-28477-9
[36]	MISHIMA Y， ISHIHARA S. Enteric Microbiota-Mediated Serotonergic Signaling in Pathogenesis of Irritable Bowel Syndrome［J］. Int J Mol Sci， 2021， 22（19）：10235. doi:10.3390/ijms221910235 doi: 10.3390/ijms221910235
[37]	AGIRMAN G， HSIAO E Y. SnapShot： The microbiota-gut-brain axis［J］. Cell， 2021， 184（9）：2524-2524. doi:10.1016/j.cell.2021.03.022 doi: 10.1016/j.cell.2021.03.022
[38]	DE VOS W M， TILG H， VAN HUL M， et al. Gut microbiome and health： Mechanistic insights［J］. Gut， 2022， 71（5）： 1020-1032. doi:10.1136/gutjnl-2021-326789 doi: 10.1136/gutjnl-2021-326789
[39]	KEARNS R. Gut-Brain Axis and Neuroinflammation： The Role of Gut Permeability and the Kynurenine Pathway in Neurological Disorders［J］. Cell Mol Neurobiol， 2024， 44（1）： 64. doi:10.1007/s10571-024-01496-z doi: 10.1007/s10571-024-01496-z
[40]	铁子慧，何培坤，李彦颐，等. 帕金森病轻度认知障碍患者脑结构网络改变与肠道菌群的关系［J］. 实用医学杂志， 2024， 40（24）： 3438-3445.
[41]	STALLMACH A， QUICKERT S， PUTA C， et al. The gastrointestinal microbiota in the development of ME/CFS： A critical view and potential perspectives［J］. Front Immunol， 2024， 15： 1352744. doi:10.3389/fimmu.2024.1352744 doi: 10.3389/fimmu.2024.1352744
[42]	张裕祥，玛依拉·艾尼瓦尔，玛依拉·阿不都克力木. 肠道菌群通过Treg/IDO信号通路参与动脉粥样硬化进展的实验研究［J］. 中西医结合心脑血管病杂志， 2024， 22（18）： 3316-3320.
[43]	GE X， ZHENG M， HU M， et al. Butyrate ameliorates quinolinic acid-induced cognitive decline in obesity models［J］. J Clin Invest， 2023， 133（4）：e154612. doi:10.1172/jci154612 doi: 10.1172/jci154612
[44]	SUN P， WANG M， LIU Y X， et al. High-fat diet-disturbed gut microbiota-colonocyte interactions contribute to dysregulating peripheral tryptophan-kynurenine metabolism［J］. Microbiome， 2023， 11（1）： 154. doi:10.1186/s40168-023-01606-x doi: 10.1186/s40168-023-01606-x
[45]	DEYAERT S， POPPE J， DAI VU L， et al. Functional Muffins Exert Bifidogenic Effects along with Highly Product-Specific Effects on the Human Gut Microbiota Ex Vivo［J］. Metabolites， 2024， 14（9）： 497. doi:10.3390/metabo14090497 doi: 10.3390/metabo14090497
[46]	FAN Y， SONG Q， LI S， et al. Protective Role of Indole-3-Acetic Acid Against Salmonella Typhimurium： Inflammation Moderation and Intestinal Microbiota Restoration［J］. Microorganisms， 2024， 12（11）： 2342. doi:10.3390/microorganisms12112342 doi: 10.3390/microorganisms12112342
[47]	PETRUT S M， BRAGARU A M， MUNTEANU A E， et al. Gut over Mind： Exploring the Powerful Gut-Brain Axis［J］. Nutrients， 2025， 17（5）： 842. doi:10.3390/nu17050842 doi: 10.3390/nu17050842
[48]	LI K， WEI W， XU C， et al. Prebiotic inulin alleviates anxiety and depression-like behavior in alcohol withdrawal mice by modulating the gut microbiota and 5-HT metabolism［J］. Phytomedicine， 2024， 135： 156181. doi:10.1016/j.phymed.2024.156181 doi: 10.1016/j.phymed.2024.156181
[49]	WALITT B， SINGH K， LAMUNION S R， et al. Deep phenotyping of post-infectious myalgic encephalomyelitis/chronic fatigue syndrome［J］. Nat Commun， 2024， 15（1）： 907.
[50]	LEONG K H， YIP H T， KUO C F， et al. Treatments of chronic fatigue syndrome and its debilitating comorbidities： A 12-year population-based study［J］. J Transl Med， 2022， 20（1）： 268. doi:10.1186/s12967-022-03461-0 doi: 10.1186/s12967-022-03461-0
[51]	顾元嘉，谢芳芳，管翀，等. 肠道菌群对慢性疲劳综合征中枢神经系统的调控机制［J］. 世界中医药， 2023， 18（21）： 3109-3112，3117.
[52]	GAO L， GAO T， ZENG T， et al. Blockade of Indoleamine 2， 3-dioxygenase 1 ameliorates hippocampal neurogenesis and BOLD-fMRI signals in chronic stress precipitated depression［J］. Aging （Albany NY）， 2021， 13（4）： 5875-5891. doi:10.18632/aging.202511 doi: 10.18632/aging.202511
[53]	YU F， BILBERG A， DALGAS U， et al. Fatigued patients with multiple sclerosis can be discriminated from healthy controls by the recordings of a newly developed measurement system （FAMOS）： A pilot study［J］. Disabil Rehabil Assist Technol， 2013， 8（1）： 77-83. doi:10.3109/17483107.2012.680941 doi: 10.3109/17483107.2012.680941
[54]	MA L， WANG H B， HASHIMOTO K. The vagus nerve： An old but new player in brain-body communication［J］. Brain Behav Immun， 2025， 124： 28-39. doi:10.1016/j.bbi.2024.11.023 doi: 10.1016/j.bbi.2024.11.023
[55]	ZHANG T， YUE Y， LI C， et al. Vagus Nerve Suppression in Ischemic Stroke by Carotid Artery Occlusion： Implications for Metabolic Regulation， Cognitive Function， and Gut Microbiome in a Gerbil Model［J］. Int J Mol Sci， 2024， 25（14）：7831. doi:10.3390/ijms25147831 doi: 10.3390/ijms25147831
[56]	STAMPER C E， HASSELL J E J R， KAPITZ A J， et al. Activation of 5-HT（1A） receptors in the rat dorsomedial hypothalamus inhibits stress-induced activation of the hypothalamic-pituitary-adrenal axis［J］. Stress， 2017， 20（2）： 223-230. doi:10.1080/10253890.2017.1301426 doi: 10.1080/10253890.2017.1301426
[57]	ZHANG Y D， WANG L N. Research progress in the treatment of chronic fatigue syndrome through interventions targeting the hypothalamus-pituitary-adrenal axis［J］. Front Endocrinol （Lausanne）， 2024， 15： 1373748. doi:10.3389/fendo.2024.1373748 doi: 10.3389/fendo.2024.1373748
[58]	SLACK J， NOH H I， LEDBETTER L， et al. The association between the gut microbiome and fatigue in individuals living with cancer： A systematic review［J］. Support Care Cancer， 2024， 32（4）： 267. doi:10.1007/s00520-024-08468-5 doi: 10.1007/s00520-024-08468-5
[59]	CRYAN J F， O'RIORDAN K J， SANDHU K， et al. The gut microbiome in neurological disorders［J］. Lancet Neurol， 2020， 19（2）： 179-194. doi:10.1016/s1474-4422(19)30356-4 doi: 10.1016/s1474-4422(19)30356-4
[60]	CASALI B T， REED-GEAGHAN E G. Microglial Function and Regulation during Development， Homeostasis and Alzheimer's Disease［J］. Cells， 2021， 10（4）： 957. doi:10.3390/cells10040957 doi: 10.3390/cells10040957
[61]	GROVEN N， REITAN S K， FORS E A， et al. Kynurenine metabolites and ratios differ between Chronic Fatigue Syndrome， Fibromyalgia， and healthy controls［J］. Psychoneuroendocrinology， 2021， 131： 105287. doi:10.1016/j.psyneuen.2021.105287 doi: 10.1016/j.psyneuen.2021.105287
[62]	Myalgic encephalomyelitis or encephalopathy）/chronic fatigue syndrome： Diagnosis and management［M/OL］//London： National Institute for Health and Care Excellence（NICE）； 2021： 11-13（2021-10-29. .
[63]	ZHANG T， GAO G， KWOK L Y， et al. Gut microbiome-targeted therapies for Alzheimer's disease［J］. Gut Microbes， 2023， 15（2）： 2271613. doi:10.1080/19490976.2023.2271613 doi: 10.1080/19490976.2023.2271613
[64]	CHOW R， BRUERA E， SANATANI M， et al. Cancer-related fatigue-pharmacological interventions： Systematic review and network meta-analysis［J］. BMJ Support Palliat Care， 2023， 13（3）： 274-280. doi:10.1136/bmjspcare-2021-003244 doi: 10.1136/bmjspcare-2021-003244
[65]	XIONG R， GUNTER C， FLEMING E， et al. Multi-'omics of gut microbiome-host interactions in short- and long-term myalgic encephalomyelitis/chronic fatigue syndrome patients［J］. Cell Host Microbe， 2023， 31（2）： 273-287. doi:10.1016/j.chom.2023.01.001 doi: 10.1016/j.chom.2023.01.001
[66]	WANG J H， CHOI Y， LEE J S， et al. Clinical evidence of the link between gut microbiome and myalgic encephalomyelitis/chronic fatigue syndrome： A retrospective review［J］. Eur J Med Res， 2024， 29（1）： 148. doi:10.1186/s40001-024-01747-1 doi: 10.1186/s40001-024-01747-1
[67]	GERMAIN A， GILOTEAUX L， MOORE G E， et al. Plasma metabolomics reveals disrupted response and recovery following maximal exercise in myalgic encephalomyelitis/chronic fatigue syndrome［J］. JCI Insight， 2022， 7（9）： e157621. doi:10.1172/jci.insight.157621 doi: 10.1172/jci.insight.157621
[68]	BARANIUK J N. Cerebrospinal fluid metabolomics， lipidomics and serine pathway dysfunction in myalgic encephalomyelitis/chronic fatigue syndroome （ME/CFS）［J］. Sci Rep， 2025， 15（1）： 7381. doi:10.1038/s41598-025-91324-1 doi: 10.1038/s41598-025-91324-1

The Role of tryptophan metabolism in modulating microbiota⁃gut⁃brain communication in chronic fatigue syndrome

RichHTML

PDF (PC)

Knowledge

Abstract

Cite this article

share this article

Figures/Tables 1

References 68

Related Articles 2

Recommended Articles

Metrics

Comments

[1]	Rui GUO,Tao LIU,Xi. SU. Establishment of a nomogram model for comorbid cardiovascular disease in schizophrenia based on electrocardiogram parameters and kynurenine metabolites [J]. The Journal of Practical Medicine, 2025, 41(8): 1205-1211.
[2]	Haojun ZHANG,Mei JING,Yufeng ZHU,Tianpeng XU,Xi CHEN,Rongyi SHI,Yi. SHAN. Impact of microbiota⁃gut⁃brain axis on neuroinflammation after post⁃cardiac arrest brain injury [J]. The Journal of Practical Medicine, 2025, 41(6): 911-915.