Targeting the Spleen-Gut-Brain Axis in Depression: Immune-Microbiota Drivers of Neuroinflammation

Xinyu Wang; Yumiao Du; Jiale Han

doi:10.54097/fag08395

Authors

Xinyu Wang
Yumiao Du
Jiale Han

DOI:

https://doi.org/10.54097/fag08395

Keywords:

Depression, Spleen-Gut-Brain Axis, Neuroinflammation, Immunomodulation, Gut Microbiota

Abstract

Emerging evidence highlights the spleen-gut-brain axis as a pivotal therapeutic frontier in depression, orchestrating crosstalk among peripheral immunity, gut microbiota, and neuroinflammatory cascades. Chronic stress triggers splenic hypersecretion of pro-inflammatory cytokines (e.g., IL-1β, TNF-α) and gut barrier dysfunction, which synergistically activate hippocampal microglial NLRP3 inflammasome via α7 nicotinic acetylcholine receptor (α7nAChR)-mediated vagal signaling. This neuroimmune cascade exacerbates synaptic loss and depressive-like behaviors by amplifying oxidative stress and suppressing BDNF/TrkB-dependent neuroplasticity. Natural compounds (e.g., astragaloside IV and baicalin) exhibit multi-target efficacy through dual modulation of HMGB1/TLR4/NF-κB-driven neuroinflammation and restoration of gut microbiota homeostasis. This review highlights novel therapeutic strategies involving natural compounds with dual immunomodulatory and microbiota-restoring properties, which not only circumvent the limitations of monoamine-centric drugs but also offer safer adjunctive therapies. Focusing on systemic inflammation as a root cause—rather than merely symptom management—these strategies hold promise for patients unresponsive to conventional antidepressants, potentially reducing relapse rates through sustained immunomodulation. By bridging immunology, microbiology, and neuropharmacology, this work proposes a paradigm shift of precision psychiatry—one where depression is treated not as a chemical imbalance, but as a systemic network modulation.

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References

[1] MARX W, PENNINX B W J H, SOLMI M, et al. Major depressive disorder [J]. Nature Reviews Disease Primers, 2023, 9(1): 44.

[2] DISEASES G B D, INJURIES C. Global burden of 369 diseases and injuries in 204 countries and territories, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019 [J]. Lancet, 2020, 396(10258): 1204-22.

[3] KATO M, HORI H, INOUE T, et al. Discontinuation of antidepressants after remission with antidepressant medication in major depressive disorder: a systematic review and meta-analysis [J]. Molecular Psychiatry, 2021, 26(1): 118-33.

[4] CUI L, LI S, WANG S, et al. Major depressive disorder: hypothesis, mechanism, prevention and treatment [J]. Signal Transduction and Targeted Therapy, 2024, 9(1): 30.

[5] ZHANG J, CHANG L, PU Y, et al. Abnormal expression of colony stimulating factor 1 receptor (CSF1R) and transcription factor PU.1 (SPI1) in the spleen from patients with major psychiatric disorders: A role of brain–spleen axis [J]. Journal of Affective Disorders, 2020, 272: 110-5.

[6] NJENGA C, RAMANUJ P P, DE MAGALHãES F J C, et al. New and emerging treatments for major depressive disorder [J]. BMJ, 2024, 386: e073823.

[7] ZHANG W, XIAO D, MAO Q, et al. Role of neuroinflammation in neurodegeneration development [J]. Signal Transduction and Targeted Therapy, 2023, 8(1): 267.

[8] MILLER A H, RAISON C L. The role of inflammation in depression: from evolutionary imperative to modern treatment target [J]. Nature Reviews Immunology, 2016, 16(1): 22-34.

[9] VALLES-COLOMER M, FALONY G, DARZI Y, et al. The neuroactive potential of the human gut microbiota in quality of life and depression [J]. Nature Microbiology, 2019, 4(4): 623-32.

[10] GINHOUX F, GAREL S. The mysterious origins of microglia [J]. Nature Neuroscience, 2018, 21(7): 897-9.

[11] COLONNA M, BUTOVSKY O. Microglia Function in the Central Nervous System During Health and Neurodegeneration [J]. Annual Review of Immunology, 2017, 35(Volume 35, 2017): 441-68.

[12] HICKMAN S, IZZY S, SEN P, et al. Microglia in neurodegeneration [J]. Nature Neuroscience, 2018, 21(10): 1359-69.

[13] VALENTE L A, BEGG L R, FILIANO A J. Updating Neuroimmune Targets in Central Nervous System Dysfunction [J]. Trends in Pharmacological Sciences, 2019, 40(7): 482-94.

[14] KWON H S, KOH S-H. Neuroinflammation in neurodegenerative disorders: the roles of microglia and astrocytes [J]. Translational Neurodegeneration, 2020, 9(1): 42.

[15] LIDDELOW S A, GUTTENPLAN K A, CLARKE L E, et al. Neurotoxic reactive astrocytes are induced by activated microglia [J]. Nature, 2017, 541(7638): 481-7.

[16] ROTHHAMMER V, BORUCKI D M, TJON E C, et al. Microglial control of astrocytes in response to microbial metabolites [J]. Nature, 2018, 557(7707): 724-8.

[17] XIA C-Y, GUO Y-X, LIAN W-W, et al. The NLRP3 inflammasome in depression: Potential mechanisms and therapies [J]. Pharmacological Research, 2023, 187: 106625.

[18] SURNAR B, SHAH A S, PARK M, et al. Brain-Accumulating Nanoparticles for Assisting Astrocytes to Reduce Human Immunodeficiency Virus and Drug Abuse-Induced Neuroinflammation and Oxidative Stress [J]. ACS Nano, 2021, 15(10): 15741-53.

[19] DOWLATI Y, HERRMANN N, SWARDFAGER W, et al. A Meta-Analysis of Cytokines in Major Depression [J]. Biological Psychiatry, 2010, 67(5): 446-57.

[20] RéUS G Z, MANOSSO L M, QUEVEDO J, et al. Major depressive disorder as a neuro-immune disorder: Origin, mechanisms, and therapeutic opportunities [J]. Neuroscience & Biobehavioral Reviews, 2023, 155: 105425.

[21] BAI S, GUO W, FENG Y, et al. Efficacy and safety of anti-inflammatory agents for the treatment of major depressive disorder: a systematic review and meta-analysis of randomised controlled trials [J]. Journal of Neurology, Neurosurgery & Psychiatry, 2020, 91(1): 21.

[22] HUSAIN M I, CULLEN C, UMER M, et al. Minocycline as adjunctive treatment for treatment-resistant depression: study protocol for a double blind, placebo-controlled, randomized trial (MINDEP2) [J]. BMC Psychiatry, 2020, 20(1): 173.

[23] XU K, WANG M, WANG H, et al. HMGB1/STAT3/p65 axis drives microglial activation and autophagy exert a crucial role in chronic Stress-Induced major depressive disorder [J]. Journal of Advanced Research, 2024, 59: 79-96.

[24] LENG L, ZHUANG K, LIU Z, et al. Menin Deficiency Leads to Depressive-like Behaviors in Mice by Modulating Astrocyte-Mediated Neuroinflammation [J]. Neuron, 2018, 100(3): 551-63.e7.

[25] NAGY C, MAITRA M, TANTI A, et al. Single-nucleus transcriptomics of the prefrontal cortex in major depressive disorder implicates oligodendrocyte precursor cells and excitatory neurons [J]. Nature Neuroscience, 2020, 23(6): 771-81.

[26] MEBIUS R E, KRAAL G. Structure and function of the spleen [J]. Nature Reviews Immunology, 2005, 5(8): 606-16.

[27] LEWIS S M, WILLIAMS A, EISENBARTH S C. Structure and function of the immune system in the spleen [J]. Science Immunology, 2019, 4(33): eaau6085.

[28] ANDERSSON U, TRACEY K J. Reflex Principles of Immunological Homeostasis [J]. Annual Review of Immunology, 2012, 30(Volume 30, 2012): 313-35.

[29] ZHANG X, LEI B, YUAN Y, et al. Brain control of humoral immune responses amenable to behavioural modulation [J]. Nature, 2020, 581(7807): 204-8.

[30] HUSTON J M, OCHANI M, ROSAS-BALLINA M, et al. Splenectomy inactivates the cholinergic antiinflammatory pathway during lethal endotoxemia and polymicrobial sepsis [J]. Journal of Experimental Medicine, 2006, 203(7): 1623-8.

[31] PELLISSIER S, DANTZER C, MONDILLON L, et al. Tu2104 Uncoupling Between the Vagal Tone and HPA Axis in Inflammatory Bowel Disease and Irritable Bowel Syndrome: Relation to Stress and Inflammation [J]. Gastroenterology, 2013, 144(5, Supplement 1): S-930.

[32] ZHAN H, HUANG F, YAN F, et al. Alterations in splenic function and gene expression in mice with depressive-like behavior induced by exposure to corticosterone [J]. Int J Mol Med, 2017, 39(2): 327-36.

[33] ZHANG J, MA L, CHANG L, et al. A key role of the subdiaphragmatic vagus nerve in the depression-like phenotype and abnormal composition of gut microbiota in mice after lipopolysaccharide administration [J]. Translational Psychiatry, 2020, 10(1): 186.

[34] FINNELL J E, LOMBARD C M, MELSON M N, et al. The protective effects of resveratrol on social stress-induced cytokine release and depressive-like behavior [J]. Brain, Behavior, and Immunity, 2017, 59: 147-57.

[35] CHANG L, WEI Y, QU Y, et al. Role of oxidative phosphorylation in the antidepressant effects of arketamine via the vagus nerve-dependent spleen-brain axis [J]. Neurobiology of Disease, 2024, 199: 106573.

[36] MA L, WANG L, QU Y, et al. A role of splenic heme biosynthesis pathway in the persistent prophylactic actions of arketamine in lipopolysaccharide-treated mice [J]. Translational Psychiatry, 2023, 13(1): 269.

[37] CHEN W, CHEN Y, CHENG W, et al. Acupuncture exerts preventive effects in rats of chronic unpredictable mild stress: The involvement of inflammation in amygdala and brain-spleen axis [J]. Biochemical and Biophysical Research Communications, 2023, 646: 86-95.

[38] DU TOIT A. The gut microbiome and mental health [J]. Nature Reviews Microbiology, 2019, 17(4): 196-.

[39] DALILE B, VAN OUDENHOVE L, VERVLIET B, et al. The role of short-chain fatty acids in microbiota–gut–brain communication [J]. Nature Reviews Gastroenterology & Hepatology, 2019, 16(8): 461-78.

[40] DOROSZKIEWICZ J, GROBLEWSKA M, MROCZKO B. The Role of Gut Microbiota and Gut–Brain Interplay in Selected Diseases of the Central Nervous System [J]. International Journal of Molecular Sciences, 2021, 22(18): 10028.

[41] CARLONI S, RESCIGNO M. The gut-brain vascular axis in neuroinflammation [J]. Seminars in Immunology, 2023, 69: 101802.

[42] ADEBISI B T. Gut Microorganisms, Neuroinflammation and Behavioral Changes [J]. European Psychiatry, 2024, 67(S1): S625-S6.

[43] EICHER T P, MOHAJERI M H. Overlapping Mechanisms of Action of Brain-Active Bacteria and Bacterial Metabolites in the Pathogenesis of Common Brain Diseases [J]. Nutrients, 2022, 14(13): 2661.

[44] WESTFALL S, CARACCI F, ESTILL M, et al. Chronic Stress-Induced Depression and Anxiety Priming Modulated by Gut-Brain-Axis Immunity [J]. Frontiers in Immunology, 2021, 12.

[45] CHANG L, WANG C, PENG J, et al. Rattan Pepper Polysaccharide Regulates DSS-Induced Intestinal Inflammation and Depressive Behavior through Microbiota–Gut–Brain Axis [J]. Journal of Agricultural and Food Chemistry, 2024, 72(1): 437-48.

[46] LIU R. The Microbiome as a Novel Paradigm in Studying Stress and Mental Health [J]. American Psychologist, 2017, 72.

[47] FRAGA A, ESTEVES-SOUSA D, FACUCHO-OLIVEIRA J, et al. Mechanisms linking gut microbiota to depression [J]. European Psychiatry, 2021, 64(S1): S741-S.

[48] RIEDER R, WISNIEWSKI P J, ALDERMAN B L, et al. Microbes and mental health: A review [J]. Brain, Behavior, and Immunity, 2017, 66: 9-17.

[49] JUNZHE C, HONGKUN H, YUMENG J, et al. Gut microbiota-derived short-chain fatty acids and depression: deep insight into biological mechanisms and potential applications [J]. General Psychiatry, 2024, 37(1): e101374.

[50] LIU P, LIU Z, WANG J, et al. Immunoregulatory role of the gut microbiota in inflammatory depression [J]. Nature Communications, 2024, 15(1): 3003.

[51] CROSS C, DAVIES M, BATEMAN E, et al. Fibre-rich diet attenuates chemotherapy-related neuroinflammation in mice [J]. Brain, Behavior, and Immunity, 2024, 115: 13-25.

[52] RöSSLER W. Nutrition, sleep, physical exercise: Impact on mental health [J]. European Psychiatry, 2016, 33: S12.

[53] BI C, GUO S, HU S, et al. The microbiota–gut–brain axis and its modulation in the therapy of depression: Comparison of efficacy of conventional drugs and traditional Chinese medicine approaches [J]. Pharmacological Research, 2022, 183: 106372.

[54] ZHONG D, JIN K, WANG R, et al. Microalgae-Based Hydrogel for Inflammatory Bowel Disease and Its Associated Anxiety and Depression [J]. Advanced Materials, 2024, 36(24): 2312275.

[55] ZHAO B, WU J, LI J, et al. Lycopene Alleviates DSS-Induced Colitis and Behavioral Disorders via Mediating Microbes-Gut–Brain Axis Balance [J]. Journal of Agricultural and Food Chemistry, 2020, 68(13): 3963-75.

[56] LEE K-I, KIM M-S, YUK H J, et al. Alleviating depressive-like behavior in DSS-induced colitis mice: Exploring naringin and poncirin from Poncirus trifoliata extracts [J]. Biomedicine & Pharmacotherapy, 2024, 175: 116770.

[57] ZHAO H, CHEN X, ZHANG L, et al. Ingestion of Lacticaseibacillus rhamnosus Fmb14 prevents depression-like behavior and brain neural activity via the microbiota–gut–brain axis in colitis mice [J]. Food & Function, 2023, 14(4): 1909-28.

[58] DE SANTA F, STRIMPAKOS G, MARCHETTI N, et al. Effect of a multi-strain probiotic mixture consumption on anxiety and depression symptoms induced in adult mice by postnatal maternal separation [J]. Microbiome, 2024, 12(1): 29.

[59] MA J, WANG R, CHEN Y, et al. 5-HT attenuates chronic stress-induced cognitive impairment in mice through intestinal flora disruption [J]. Journal of Neuroinflammation, 2023, 20(1): 23.

[60] HUANG Y-Y, WU Y-P, JIA X-Z, et al. Lactiplantibacillus plantarum DMDL 9010 alleviates dextran sodium sulfate (DSS)-induced colitis and behavioral disorders by facilitating microbiota-gut-brain axis balance [J]. Food & Function, 2022, 13(1): 411-24.

[61] MAO Q, ZHANG H, ZHANG Z, et al. Co-decoction of Lilii bulbus and Radix Rehmannia Recens and its key bioactive ingredient verbascoside inhibit neuroinflammation and intestinal permeability associated with chronic stress-induced depression via the gut microbiota-brain axis [J]. Phytomedicine, 2024, 129: 155510.

[62] SHIN Y-J, LEE D-Y, KIM J Y, et al. Effect of fermented red ginseng on gut microbiota dysbiosis- or immobilization stress-induced anxiety, depression, and colitis in mice [J]. Journal of Ginseng Research, 2023, 47(2): 255-64.

[63] HAO W, GAN H, WANG L, et al. Polyphenols in edible herbal medicine: targeting gut-brain interactions in depression-associated neuroinflammation [J]. Critical Reviews in Food Science and Nutrition, 2022, 63: 12207-23.

[64] CARSETTI R, DI SABATINO A, ROSADO M M, et al. Lack of Gut Secretory Immunoglobulin A in Memory B-Cell Dysfunction-Associated Disorders: A Possible Gut-Spleen Axis [J]. Frontiers in Immunology, 2020, 10.

[65] BUCHMANN GODINHO D, DA SILVA FIORIN F, SCHNEIDER OLIVEIRA M, et al. The immunological influence of physical exercise on TBI-induced pathophysiology: Crosstalk between the spleen, gut, and brain [J]. Neuroscience & Biobehavioral Reviews, 2021, 130: 15-30.

[66] BOURHY L, MAZERAUD A, BOZZA F A, et al. Neuro-Inflammatory Response and Brain-Peripheral Crosstalk in Sepsis and Stroke [J]. Frontiers in Immunology, 2022, 13.

[67] FUNG T C, OLSON C A, HSIAO E Y. Interactions between the microbiota, immune and nervous systems in health and disease [J]. Nature Neuroscience, 2017, 20(2): 145-55.

[68] YANG Y, EGUCHI A, MORI C, et al. Splenic nerve denervation attenuates depression-like behaviors in Chrna7 knock-out mice via the spleen–gut–brain axis [J]. Journal of Affective Disorders, 2024, 362: 114-25.

[69] MA L, ZHANG J, FUJITA Y, et al. Effects of spleen nerve denervation on depression–like phenotype, systemic inflammation, and abnormal composition of gut microbiota in mice after administration of lipopolysaccharide: A role of brain–spleen axis [J]. Journal of Affective Disorders, 2022, 317: 156-65.

[70] MOK S W-F, WONG V K-W, LO H-H, et al. Natural products-based polypharmacological modulation of the peripheral immune system for the treatment of neuropsychiatric disorders [J]. Pharmacology & Therapeutics, 2020, 208: 107480.

[71] LIU X, WANG S, WU X, et al. Astragaloside IV Alleviates Depression in Rats by Modulating Intestinal Microbiota, T-Immune Balance, and Metabolome [J]. Journal of Agricultural and Food Chemistry, 2024, 72(1): 259-73.

[72] DUAN Y, HUANG J, SUN M, et al. Poria cocos polysaccharide improves intestinal barrier function and maintains intestinal homeostasis in mice [J]. International Journal of Biological Macromolecules, 2023, 249: 125953.

[73] LI Y, YANG L, LI J, et al. Antidepression of Xingpijieyu formula targets gut microbiota derived from depressive disorder [J]. CNS Neuroscience & Therapeutics, 2023, 29(2): 669-81.

[74] GU C, ZHOU W, WANG W, et al. ZiBuPiYin recipe improves cognitive decline by regulating gut microbiota in Zucker diabetic fatty rats [J]. Oncotarget, 2017, 8(17).

[75] LIU M, FAN G, LIU H. Integrated bioinformatics and network pharmacology identifying the mechanisms and molecular targets of Guipi Decoction for treatment of comorbidity with depression and gastrointestinal disorders [J]. Metabolic Brain Disease, 2024, 39(1): 183-97.

[76] LI J-J, LI Y-L, CHU W, et al. Astragaloside IV alleviates cytarabine-induced intestinal mucositis by remodeling macrophage polarization through AKT signaling [J]. Phytomedicine, 2023, 109: 154605.

[77] ZHANG X, ZHANG F, LI Y, et al. Blockade of PI3K/AKT signaling pathway by Astragaloside IV attenuates ulcerative colitis via improving the intestinal epithelial barrier [J]. Journal of Translational Medicine, 2024, 22(1): 406.

[78] WANG X, XIE L, LONG J, et al. Therapeutic effect of baicalin on inflammatory bowel disease: A review [J]. Journal of Ethnopharmacology, 2022, 283: 114749.

[79] ZHANG S, LV H, ZHONG R, et al. Baicalin promotes appetite by regulating gut microbiome and immunity? [J]. Journal of Functional Foods, 2023, 105: 105557.

[80] LIU L, DONG Y, SHAN X, et al. Anti-Depressive Effectiveness of Baicalin In Vitro and In Vivo [J]. Molecules, 2019, 24(2): 326.

[81] ZHAO L, ZHANG T, ZHANG K. Pharmacological effects of ginseng and ginsenosides on intestinal inflammation and the immune system [J]. Frontiers in Immunology, 2024, 15.

[82] NIU Z, LIU Y, SHEN R, et al. Ginsenosides from Panax ginseng as potential therapeutic candidates for the treatment of inflammatory bowel disease [J]. Phytomedicine, 2024, 127: 155474.

[83] SHAO J, MA X, QU L, et al. Ginsenoside Rh4 remodels the periphery microenvironment by targeting the brain-gut axis to alleviate depression-like behaviors [J]. Food Chemistry, 2023, 404: 134639.

[84] CUI J, LI Y, JIAO C, et al. Improvement of magnesium isoglycyrrhizinate on DSS-induced acute and chronic colitis [J]. International Immunopharmacology, 2021, 90: 107194.

[85] XIA Y, SHI H, QIAN C, et al. Modulation of Gut Microbiota by Magnesium Isoglycyrrhizinate Mediates Enhancement of Intestinal Barrier Function and Amelioration of Methotrexate-Induced Liver Injury [J]. Frontiers in Immunology, 2022, 13.

[86] JIANG W, CHEN Q, LI P, et al. Magnesium Isoglycyrrhizinate attenuates lipopolysaccharide-induced depressive-like behavior in mice [J]. Biomedicine & Pharmacotherapy, 2017, 86: 177-84.

[87] XU H, WANG S, JIANG Y, et al. Poria cocos Polysaccharide Ameliorated Antibiotic-Associated Diarrhea in Mice via Regulating the Homeostasis of the Gut Microbiota and Intestinal Mucosal Barrier [J]. International Journal of Molecular Sciences, 2023, 24(2): 1423.

[88] ZHANG W, CHEN L, LI P, et al. Antidepressant and immunosuppressive activities of two polysaccharides from Poria cocos (Schw.) Wolf [J]. International Journal of Biological Macromolecules, 2018, 120: 1696-704.

[89] SONG H-P, HOU X-Q, LI R-Y, et al. Atractylenolide I stimulates intestinal epithelial repair through polyamine-mediated Ca2+ signaling pathway [J]. Phytomedicine, 2017, 28: 27-35.

[90] XU H, VAN DER JEUGHT K, ZHOU Z, et al. Atractylenolide I enhances responsiveness to immune checkpoint blockade therapy by activating tumor antigen presentation [J]. The Journal of Clinical Investigation, 2021, 131(10).

[91] ZHAI L, SHENG Y, WANG J, et al. Atractylenolide I Suppresses A1 Astrocyte Activation to Improve Depression in Mice [J]. Molecular Neurobiology, 2024, 61(9): 7037-45.

[92] PU Z, LIU Y, LI C, et al. Using Network Pharmacology for Systematic Understanding of Geniposide in Ameliorating Inflammatory Responses in Colitis Through Suppression of NLRP3 Inflammasome in Macrophage by AMPK/Sirt1 Dependent Signaling [J]. The American Journal of Chinese Medicine, 2020, 48(07): 1693-713.

[93] YU Y, BIAN Y, SHI J-X, et al. Geniposide promotes splenic Treg differentiation to alleviate colonic inflammation and intestinal barrier injury in ulcerative colitis mice [J]. Bioengineered, 2022, 13(6): 14616-31.

[94] CAI L, LI R, TANG W-J, et al. Antidepressant-like effect of geniposide on chronic unpredictable mild stress-induced depressive rats by regulating the hypothalamus–pituitary–adrenal axis [J]. European Neuropsychopharmacology, 2015, 25(8): 1332-41.

[95] ZHAO M, XIE X, XU B, et al. Paeonol alleviates ulcerative colitis in mice by increasing short-chain fatty acids derived from Clostridium butyricum [J]. Phytomedicine, 2023, 120: 155056.

[96] CHEN B, NING M, YANG G. Effect of Paeonol on Antioxidant and Immune Regulatory Activity in Hepatocellular Carcinoma Rats [J]. Molecules, 2012, 17(4): 4672-83.

[97] TAO W, WANG H, SU Q, et al. Paeonol attenuates lipopolysaccharide-induced depressive-like behavior in mice [J]. Psychiatry Research, 2016, 238: 116-21.

[98] LV Z, SHAN X, TU Q, et al. Ginkgolide B treatment regulated intestinal flora to improve high-fat diet induced atherosclerosis in ApoE−/− mice [J]. Biomedicine & Pharmacotherapy, 2021, 134: 111100.

[99] LI C, LIU K, LIU S, et al. Role of Ginkgolides in the Inflammatory Immune Response of Neurological Diseases: A Review of Current Literatures [J]. Frontiers in Systems Neuroscience, 2020, 14.

[100] GE Y, XU W, ZHANG L, et al. Ginkgolide B attenuates myocardial infarction-induced depression-like behaviors via repressing IL-1β in central nervous system [J]. International Immunopharmacology, 2020, 85: 106652.

[101] LI J, JIA J, TENG Y, et al. Gastrodin Alleviates DSS-Induced Colitis in Mice through Strengthening Intestinal Barrier and Modulating Gut Microbiota [J]. Foods, 2024, 13(15): 2460.

[102] ZHOU L, HU Z, LIU F, et al. Electrospun Self-Pumping dressing with gastrodin for immunomodulation and rapid healing of diabetic wounds [J]. Chemical Engineering Journal, 2024, 495: 153424.

[103] ZHANG J, LI L, LIU Q, et al. Gastrodin programs an Arg-1+ microglial phenotype in hippocampus to ameliorate depression- and anxiety-like behaviors via the Nrf2 pathway in mice [J]. Phytomedicine, 2023, 113: 154725.

[104] NIU Y, DONG Q, LI R. Matrine regulates Th1/Th2 cytokine responses in rheumatoid arthritis by attenuating the NF-κB signaling [J]. Cell Biology International, 2017, 41(6): 611-21.

[105] NI L, JING S, ZHU L, et al. The Immune Change of the Lung and Bowel in an Ulcerative Colitis Rat Model and the Protective Effect of Sodium Houttuyfonate Combined With Matrine [J]. Frontiers in Immunology, 2022, 13.

[106] ZHANG M, LI A, YANG Q, et al. Matrine alleviates depressive-like behaviors via modulating microbiota–gut–brain axis in CUMS-induced mice [J]. Journal of Translational Medicine, 2023, 21(1): 145.

[107] CHUNG C H, JUNG W, KEUM H, et al. Nanoparticles Derived from the Natural Antioxidant Rosmarinic Acid Ameliorate Acute Inflammatory Bowel Disease [J]. ACS Nano, 2020, 14(6): 6887-96.

[108] WANG Y-L, NI W. Rosmarinic acid improves cyclophosphamide-induced immunosuppression in mice by immunomodulatory and antioxidant effects [J]. Food Bioscience, 2023, 56: 103152.

[109] ZENG J, XIE Z, CHEN L, et al. Rosmarinic acid alleviate CORT-induced depressive-like behavior by promoting neurogenesis and regulating BDNF/TrkB/PI3K signaling axis [J]. Biomedicine & Pharmacotherapy, 2024, 170: 115994.

[110] DOU Y, LUO J, WU X, et al. Curcumin attenuates collagen-induced inflammatory response through the “gut-brain axis” [J]. Journal of Neuroinflammation, 2018, 15(1): 6.

[111] RASHID K, CHOWDHURY S, GHOSH S, et al. Curcumin attenuates oxidative stress induced NFκB mediated inflammation and endoplasmic reticulum dependent apoptosis of splenocytes in diabetes [J]. Biochemical Pharmacology, 2017, 143: 140-55.

[112] FAN C, LI Y, LAN T, et al. Prophylactic treatment of curcumin in a rat model of depression by attenuating hippocampal synaptic loss [J]. Food & Function, 2021, 12(22): 11202-13.

[113] MUNROE M E, ARBISER J L, BISHOP G A. Honokiol, a Natural Plant Product, Inhibits Inflammatory Signals and Alleviates Inflammatory Arthritis1 [J]. The Journal of Immunology, 2007, 179(2): 753-63.

[114] NIU L, WANG S, XU Y, et al. Honokiol targeting ankyrin repeat domain of TRPV4 ameliorates endothelial permeability in mice inflammatory bowel disease induced by DSS [J]. Journal of Ethnopharmacology, 2024, 325: 117825.

[115] FAN X-X, SUN W-Y, LI Y, et al. Honokiol improves depression-like behaviors in rats by HIF-1α- VEGF signaling pathway activation [J]. Frontiers in Pharmacology, 2022, 13.

[116] JEON Y-D, LEE J-H, LEE Y-M, et al. Puerarin inhibits inflammation and oxidative stress in dextran sulfate sodium-induced colitis mice model [J]. Biomedicine & Pharmacotherapy, 2020, 124: 109847.

[117] CHANG Y, GUO A, JING Y-Y, et al. Immunomodulatory activity of puerarin in RAW264.7 macrophages and cyclophosphamide-induced immunosuppression mice [J]. Immunopharmacology and Immunotoxicology, 2021, 43: 223-9.

[118] SONG X, WANG W, DING S, et al. Exploring the potential antidepressant mechanisms of puerarin: Anti-inflammatory response via the gut-brain axis [J]. Journal of Affective Disorders, 2022, 310: 459-71.

[119] CHEN Z, GUO M, SONG G, et al. Schisandrin B inhibits Th1/Th17 differentiation and promotes regulatory T cell expansion in mouse lymphocytes [J]. International Immunopharmacology, 2016, 35: 257-64.

[120] SUN Y, YAN T, GONG G, et al. Antidepressant-like effects of Schisandrin on lipopolysaccharide-induced mice : Gut microbiota, short chain fatty acid and TLR4/NF-κB signaling pathway [J]. International Immunopharmacology, 2020, 89: 107029.

[121] LIU X, ZHOU M, DAI Z, et al. Salidroside alleviates ulcerative colitis via inhibiting macrophage pyroptosis and repairing the dysbacteriosis-associated Th17/Treg imbalance [J]. Phytotherapy Research, 2023, 37(2): 367-82.

[122] FAN Y, BI Y, CHEN H. Salidroside Improves Chronic Stress Induced Depressive Symptoms Through Microglial Activation Suppression [J]. Frontiers in Pharmacology, 2021, 12.

[123] HU A P, DU J M, LI J Y, et al. Oridonin promotes CD4+/CD25+ Treg differentiation, modulates Th1/Th2 balance and induces HO-1 in rat splenic lymphocytes [J]. Inflammation Research, 2008, 57(4): 163-70.

[124] LIANG L, WANG H, HU Y, et al. Oridonin relieves depressive-like behaviors by inhibiting neuroinflammation and autophagy impairment in rats subjected to chronic unpredictable mild stress [J]. Phytotherapy Research, 2022, 36(8): 3335-51.

[125] SUN Y, LIAN M, LIN Y, et al. Role of p-MKK7 in myricetin-induced protection against intestinal ischemia/reperfusion injury [J]. Pharmacological Research, 2018, 129: 432-42.

[126] BERKöZ M, YALıN S, ÖZKAN-YıLMAZ F, et al. Protective effect of myricetin, apigenin, and hesperidin pretreatments on cyclophosphamide-induced immunosuppression [J]. Immunopharmacol Immunotoxicol, 2021, 43(3): 353-69.

[127] MA Z, WANG G, CUI L, et al. Myricetin Attenuates Depressant-Like Behavior in Mice Subjected to Repeated Restraint Stress [J]. International Journal of Molecular Sciences, 2015, 16(12): 28377-85.

[128] DOU W, ZHANG J, REN G, et al. Mangiferin attenuates the symptoms of dextran sulfate sodium-induced colitis in mice via NF-κB and MAPK signaling inactivation [J]. International Immunopharmacology, 2014, 23(1): 170-8.

[129] LIM S-M, JEONG J-J, CHOI H S, et al. Mangiferin corrects the imbalance of Th17/Treg cells in mice with TNBS-induced colitis [J]. International Immunopharmacology, 2016, 34: 220-8.

[130] YAN M, BO X, ZHANG X, et al. Mangiferin Alleviates Postpartum Depression–Like Behaviors by Inhibiting MAPK Signaling in Microglia [J]. Frontiers in Pharmacology, 2022, 13.

[131] NIU Z, LI X, YANG X, et al. Protective effects of sinomenine against dextran sulfate sodium-induced ulcerative colitis in rats via alteration of HO-1/Nrf2 and inflammatory pathway [J]. Inflammopharmacology, 2024, 32(3): 2007-22.

[132] JUN W, PEI-GEN X, SHI-YING L, et al. The inhibitory effect of Sinomenine on immunological function in mice [J]. Phytotherapy Research, 1992, 6(3): 117-20.

[133] LI X, LIU C, JIANG B, et al. The antidepressant-like effects of sinomenine in mice: a behavioral and neurobiological characterization [J]. Behavioural Pharmacology, 2018, 29(4): 306-15.