{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T13:58:12Z","timestamp":1790776692003,"version":"4.1.0"},"reference-count":46,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T00:00:00Z","timestamp":1790726400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T00:00:00Z","timestamp":1790726400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Developmental Neurobiology"],"published-print":{"date-parts":[[2026,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Bidirectional communication among the gut microbiota, immune system, and central nervous system shapes microglial maturation and responsiveness. This review evaluates microglia as context\u2010dependent neuroimmune integrators rather than fixed M1\/M2 populations. It organizes the literature into three linked layers: gut\u2010derived signals and barrier physiology, microglial state transitions, and therapeutic modulation by Traditional Chinese Medicine (TCM). Experimental depletion, colonization, and metabolite studies provide causal evidence that the microbiota can modify microglial biology in animals; however, human evidence remains predominantly associative. Herbal formulations, isolated constituents, and acupuncture may alter microbial ecology, intestinal permeability, metabolite production, systemic inflammation, and microglial signaling. Yet most intervention studies measure only selected links in this chain and rely on rodent behavior, bulk cytokines, or limited polarization markers rather than direct, state\u2010resolved microglial profiling. Therefore, improvements in cognition or inflammatory markers cannot by themselves, establish microbiota\u2010mediated microglial reprogramming. We critically distinguish direct from indirect evidence, replace binary polarization language with state\u2010specific terminology, and evaluate formulation standardization, bioavailability, safety, experimental confounding, and clinical generalizability. A credible translational program will require chemically defined interventions, causal perturbation of candidate microbes or metabolites, microglia\u2010resolved multi\u2010omics, preregistered clinical trials, and mediation analyses that connect target engagement to patient\u2010relevant outcomes. TCM is thus best regarded as a testable source of multicomponent interventions, not yet a validated systems\u2010level therapy for the gut\u2013brain\u2013immune axis.<\/jats:p>","DOI":"10.1002\/dneu.70060","type":"journal-article","created":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T13:18:11Z","timestamp":1790774291000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Microglial State Reprogramming Across the Gut\u2013Brain\u2013Immune Axis: Limitations and Therapeutic Prospects of Traditional Chinese Medicine"],"prefix":"10.1002","volume":"86","author":[{"given":"Muhammad Wasim","family":"Usmani","sequence":"first","affiliation":[{"name":"Institute of Drug Discovery Technology\/Zhejiang\u2010Pakistan Joint Laboratory on R&amp;D of Herbal Medicine Ningbo University  Ningbo China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muhammad Zulqarnain","family":"Shakir","sequence":"additional","affiliation":[{"name":"Institute of Drug Discovery Technology\/Zhejiang\u2010Pakistan Joint Laboratory on R&amp;D of Herbal Medicine Ningbo University  Ningbo China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muneeb Ahmad","family":"Khan","sequence":"additional","affiliation":[{"name":"University College of Medicine and Dentistry (UCMD)  Lahore Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muhammad","family":"Usman","sequence":"additional","affiliation":[{"name":"Department of Basic Sciences (Histology) University of Veterinary and Animal Sciences  Lahore Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Inam","family":"Ullah","sequence":"additional","affiliation":[{"name":"Institute of Drug Discovery Technology\/Zhejiang\u2010Pakistan Joint Laboratory on R&amp;D of Herbal Medicine Ningbo University  Ningbo China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Mengjie","sequence":"additional","affiliation":[{"name":"Laboratory Animal Center Ningbo University  Ningbo China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ning","family":"Wang","sequence":"additional","affiliation":[{"name":"Institute of Drug Discovery Technology\/Zhejiang\u2010Pakistan Joint Laboratory on R&amp;D of Herbal Medicine Ningbo University  Ningbo China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinmin","family":"Liu","sequence":"additional","affiliation":[{"name":"Institute of Drug Discovery Technology\/Zhejiang\u2010Pakistan Joint Laboratory on R&amp;D of Herbal Medicine Ningbo University  Ningbo China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,30]]},"reference":[{"key":"e_1_2_18_2_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3389\/fmolb.2025.1607330","article-title":"Phytonutrients and Their Neuroprotective Role in Brain Disorders","volume":"12","author":"Adhikary K.","year":"2025","journal-title":"Frontiers in Molecular Biosciences"},{"key":"e_1_2_18_3_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1515\/bmc-2022-0042","article-title":"\u03b2\u2010Amyloid Peptide Modulates Peripheral Immune Responses and Neuroinflammation in Rats","volume":"15","author":"Adhikary K.","year":"2024","journal-title":"Biomolecular Concepts"},{"key":"e_1_2_18_4_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.heliyon.2024.e34092","article-title":"Gut\u2010Brain Axis: A Cutting\u2010edge Approach to Target Neurological Disorders and Potential Synbiotic Application","volume":"10","author":"Ashique S.","year":"2024","journal-title":"Heliyon"},{"key":"e_1_2_18_5_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3389\/fnins.2018.00049","article-title":"The Vagus Nerve at the Interface of the Microbiota\u2013Gut\u2013Brain Axis","volume":"12","author":"Bonaz B.","year":"2018","journal-title":"Frontiers in Neuroscience"},{"key":"e_1_2_18_6_1","doi-asserted-by":"crossref","first-page":"44","DOI":"10.3389\/fpsyt.2018.00044","article-title":"Vagus Nerve as Modulator of the Brain\u2013Gut Axis in Psychiatric and Inflammatory Disorders","volume":"9","author":"Breit S.","year":"2018","journal-title":"Frontiers in Psychiatry"},{"key":"e_1_2_18_7_1","doi-asserted-by":"crossref","DOI":"10.3389\/fphar.2022.925514","article-title":"Research Progress on Classical Traditional Chinese Medicine Formula Xiaoyaosan in the Treatment of Depression","volume":"13","author":"Chen J.","year":"2022","journal-title":"Frontiers in pharmacology"},{"key":"e_1_2_18_8_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.phymed.2021.153883","article-title":"Ginsenoside Rd: A Promising Natural Neuroprotective Agent","volume":"95","author":"Chen Y.\u2010Y.","year":"2022","journal-title":"Phytomedicine"},{"key":"e_1_2_18_9_1","first-page":"1","article-title":"A Review on Traditional Chinese Medicine Natural Products and Acupuncture Intervention for Alzheimer's Disease Based on the Neuroinflammatory","volume":"19","author":"Chen Z.","year":"2024","journal-title":"Chinese Medicine (United Kingdom)"},{"key":"e_1_2_18_10_1","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1016\/j.bbamcr.2016.12.002","article-title":"Iron Mediated Toxicity and Programmed Cell Death: A Review and a Re\u2010Examination of Existing Paradigms","volume":"1864","author":"Eid R.","year":"2017","journal-title":"Biochimica et Biophysica Acta (BBA)\u2014Molecular Cell Research"},{"key":"e_1_2_18_11_1","doi-asserted-by":"crossref","first-page":"965","DOI":"10.1038\/nn.4030","article-title":"Host Microbiota Constantly Control Maturation and Function of Microglia in the CNS","volume":"18","author":"Erny D.","year":"2015","journal-title":"Nature Neuroscience"},{"key":"e_1_2_18_12_1","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2023.1193053","article-title":"Roles of Microglia in Adult Hippocampal Neurogenesis in Depression and Their Therapeutics","volume":"14","author":"Fang S.","year":"2023","journal-title":"Frontiers in Immunology"},{"key":"e_1_2_18_13_1","first-page":"1","article-title":"Immunological Dimensions of Neuroinflammation and Microglial Activation: Exploring Innovative Immunomodulatory Approaches to Mitigate Neuroinflammatory Progression","volume":"14","author":"Fornari Laurindo L.","year":"2023","journal-title":"Frontiers in Immunology"},{"key":"e_1_2_18_14_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.ijbiomac.2024.135967","article-title":"Biological Significance and Pathophysiological Role of Matrix Metalloproteinases in the Central Nervous System","volume":"280","author":"Ganguly K.","year":"2024","journal-title":"International Journal of Biological Macromolecules"},{"key":"e_1_2_18_15_1","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1007\/s12264-023-01039-4","article-title":"Novel Insight Into Glial Biology and Diseases","volume":"39","author":"He C.","year":"2023","journal-title":"Neuroscience Bulletin"},{"key":"e_1_2_18_16_1","doi-asserted-by":"crossref","DOI":"10.3390\/app131910795","article-title":"Chemical Composition Analysis of Lilium brownii var. Viridulum Baker and the Effect of Postharvest Primary Processing on Its Quality","volume":"13","author":"Hu M.","year":"2023","journal-title":"Applied Sciences"},{"key":"e_1_2_18_17_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3389\/fncel.2017.00024","article-title":"Glial Cells and Their Function in the Adult Brain: A Journey Through the History of Their Ablation","volume":"11","author":"J\u00e4kel S.","year":"2017","journal-title":"Frontiers in Cellular Neuroscience"},{"key":"e_1_2_18_18_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3389\/fpsyt.2021.596017","article-title":"The Cognitive\u2010Enhancing Effects of Dendrobium Nobile Lindl Extract in Sleep Deprivation\u2010Induced Amnesic Mice","volume":"12","author":"Jiang N.","year":"2022","journal-title":"Frontiers in Psychiatry"},{"key":"e_1_2_18_19_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3389\/fonc.2017.00159","article-title":"The Mitochondrial Unfolded Protein Response as a Non\u2010Oncogene Addiction to Support Adaptation to Stress During Transformation in Cancer and Beyond","volume":"7","author":"Kenny T. C.","year":"2017","journal-title":"Frontiers in Oncology"},{"key":"e_1_2_18_20_1","doi-asserted-by":"crossref","first-page":"1276","DOI":"10.1016\/j.cell.2017.05.018","article-title":"A Unique Microglia Type Associated With Restricting Development of Alzheimer's Disease","volume":"169","author":"Keren\u2010Shaul H.","year":"2017","journal-title":"Cell"},{"key":"e_1_2_18_21_1","doi-asserted-by":"crossref","first-page":"12","DOI":"10.4103\/REGENMED.REGENMED-D-24-00004","article-title":"The Role of Gut Microbiota Metabolites in the Regeneration and Protection of Nervous Tissue: A Narrative Review","volume":"1","author":"Kostiuchenko O.","year":"2024","journal-title":"Regenerative Medicine Reports"},{"key":"e_1_2_18_22_1","doi-asserted-by":"crossref","first-page":"2065","DOI":"10.1007\/s11011-023-01223-5","article-title":"Inulin\u2010Type Oligosaccharides of Morinda officinalis Exerted Antidepressant Effects by Reducing Hippocampal Inflammation","volume":"38","author":"Lai Z. K.","year":"2023","journal-title":"Metabolic Brain Disease"},{"key":"e_1_2_18_23_1","doi-asserted-by":"crossref","first-page":"1540","DOI":"10.3390\/pathogens11121540","article-title":"The History of the Intestinal Microbiota and the Gut\u2013Brain Axis","volume":"11","author":"Lewandowska\u2010Pietruszka Z.","year":"2022","journal-title":"Pathogens"},{"key":"e_1_2_18_24_1","first-page":"1","article-title":"New Tools for Investigating Astrocyte\u2010to\u2010Neuron Communication","volume":"7","author":"Li D.","year":"2013","journal-title":"Frontiers in Cellular Neuroscience"},{"key":"e_1_2_18_25_1","first-page":"1","article-title":"Mechanism of Neural Regeneration Induced by Natural Product LY01 in the 5\u00d7FAD Mouse Model of Alzheimer's Disease","volume":"13","author":"Li X. W.","year":"2022","journal-title":"Frontiers in Pharmacology"},{"key":"e_1_2_18_26_1","first-page":"1","article-title":"Kuijieyuan Decoction Improved Intestinal Barrier Injury of Ulcerative Colitis by Affecting TLR4\u2010Dependent PI3K\/AKT\/NF\u2010\u03baB Oxidative and Inflammatory Signaling and Gut Microbiota","volume":"11","author":"Liu B.","year":"2020","journal-title":"Frontiers in Pharmacology"},{"key":"e_1_2_18_27_1","doi-asserted-by":"crossref","first-page":"846","DOI":"10.1002\/ptr.6567","article-title":"Protective Effects of Genistein on the Cognitive Deficits Induced by Chronic Sleep Deprivation","volume":"34","author":"Lu C.","year":"2020","journal-title":"Phytotherapy Research"},{"key":"e_1_2_18_28_1","doi-asserted-by":"crossref","first-page":"1560","DOI":"10.3390\/ijms26041560","article-title":"Multi\u2010Omics Analysis of the Gut\u2013Brain Axis Elucidates Therapeutic Mechanisms of Guhong Injection in the Treatment of Ischemic Stroke","volume":"26","author":"Mao P.","year":"2025","journal-title":"International Journal of Molecular Sciences"},{"key":"e_1_2_18_29_1","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1038\/s41586-019-0924-x","article-title":"Spatial and Temporal Heterogeneity of Mouse and Human Microglia at Single\u2010Cell Resolution","volume":"566","author":"Masuda T.","year":"2019","journal-title":"Nature"},{"key":"e_1_2_18_30_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3389\/fnagi.2023.1201982","article-title":"Microglia in Alzheimer's Disease: Pathogenesis, Mechanisms, and Therapeutic Potentials","volume":"15","author":"Miao J.","year":"2023","journal-title":"Frontiers in Aging Neuroscience"},{"key":"e_1_2_18_31_1","doi-asserted-by":"crossref","DOI":"10.3389\/fnins.2021.742065","article-title":"Microglia in Neuroinflammation and Neurodegeneration: From Understanding to Therapy","volume":"15","author":"Muzio L.","year":"2021","journal-title":"Frontiers in Neuroscience"},{"key":"e_1_2_18_32_1","doi-asserted-by":"crossref","first-page":"3458","DOI":"10.1016\/j.neuron.2022.10.020","article-title":"Microglia States and Nomenclature: A Field at Its Crossroads","volume":"110","author":"Paolicelli R. C.","year":"2022","journal-title":"Neuron"},{"key":"e_1_2_18_33_1","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.jep.2018.12.043","article-title":"The Ethanol Extract of Zizyphus jujuba var. Spinosa Seeds Ameliorates the Memory Deficits in Alzheimer's Disease Model Mice","volume":"233","author":"Park H. J.","year":"2019","journal-title":"Journal of Ethnopharmacology"},{"key":"e_1_2_18_34_1","doi-asserted-by":"crossref","first-page":"987","DOI":"10.1038\/nn.4338","article-title":"A Polarizing Question: Do M1 and M2 Microglia Exist?","volume":"19","author":"Ransohoff R. M.","year":"2016","journal-title":"Nature Neuroscience"},{"key":"e_1_2_18_35_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.bbii.2023.100013","article-title":"Mental Health Benefits of Traditional Chinese Medicine\u2014An Umbrella Review of Meta\u2010Analyses","volume":"2","author":"Rodrigues J. M.","year":"2023","journal-title":"Brain Behavior and Immunity Integrative"},{"key":"e_1_2_18_36_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3389\/fimmu.2020.604179","article-title":"The Gut\u2013Brain Axis: How Microbiota and Host Inflammasome Influence Brain Physiology and Pathology","volume":"11","author":"Rutsch A.","year":"2020","journal-title":"Frontiers in Immunology"},{"key":"e_1_2_18_37_1","first-page":"3512","article-title":"Immunity Impacts Cognitive Deficits Across Neurological Disorders","volume":"168","author":"Shaw B. C.","year":"2023","journal-title":"Journal of Neurochemistry"},{"key":"e_1_2_18_38_1","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1016\/j.cell.2017.11.042","article-title":"Microbiome Influences Prenatal and Adult Microglia in a Sex\u2010Specific Manner","volume":"172","author":"Thion M. S.","year":"2018","journal-title":"Cell"},{"key":"e_1_2_18_39_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12974-022-02492-0","article-title":"Microglia in Depression: An Overview of Microglia in the Pathogenesis and Treatment of Depression","volume":"19","author":"Wang H.","year":"2022","journal-title":"Journal of Neuroinflammation"},{"key":"e_1_2_18_40_1","first-page":"1","article-title":"Phytochemistry, Pharmacology and Quality Control of Xiasangju: A Traditional Chinese Medicine Formula","volume":"13","author":"Wu S.","year":"2022","journal-title":"Frontiers in Pharmacology"},{"key":"e_1_2_18_41_1","first-page":"1","article-title":"Clec7a Signaling in Microglia Promotes Synapse Loss Associated With Tauopathy","volume":"26","author":"Yang S.","year":"2025","journal-title":"International Journal of Molecular Sciences"},{"key":"e_1_2_18_42_1","first-page":"1","article-title":"Effects of Inulin\u2010Type Oligosaccharides (JSO) From Cichorium intybus L. on Behavioral Deficits Induced by Chronic Restraint Stress in Mice and Associated Molecular Alterations","volume":"15","author":"Yao C.","year":"2024","journal-title":"Frontiers in Pharmacology"},{"key":"e_1_2_18_43_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12974-020-02065-z","article-title":"Microglial Activation Contributes to Cognitive Impairments in Rotenone\u2010Induced Mouse Parkinson's Disease Model","volume":"18","author":"Zhang D.","year":"2021","journal-title":"Journal of Neuroinflammation"},{"key":"e_1_2_18_44_1","doi-asserted-by":"crossref","DOI":"10.3389\/fphar.2024.1339148","article-title":"Mechanism of Traditional Chinese Medicine in Elderly Diabetes Mellitus and a Systematic Review of Its Clinical Application","volume":"15","author":"Zhang Q.","year":"2024","journal-title":"Frontiers in Pharmacology"},{"key":"e_1_2_18_45_1","first-page":"1","article-title":"Traditional Chinese Medicine and Gut Microbiome: Their Respective and Concert Effects on Healthcare","volume":"11","author":"Zhang R.","year":"2020","journal-title":"Frontiers in Pharmacology"},{"key":"e_1_2_18_46_1","doi-asserted-by":"crossref","DOI":"10.1111\/cpr.13295","article-title":"Brain\u2013Immune Interaction Mechanisms: Implications for Cognitive Dysfunction in Psychiatric Disorders","volume":"55","author":"Zhao F.","year":"2022","journal-title":"Cell Proliferation"},{"key":"e_1_2_18_47_1","first-page":"1","article-title":"Jie\u2010Yu Pill, a Proprietary Herbal Medicine, Ameliorates Mood Disorder\u2010Like Behavior and Cognitive Impairment in Estrogen\u2010Deprived Mice Exposed to Chronic Unpredictable Mild Stress: Implication for a Potential Therapy of Menopause Syndrome","volume":"11","author":"Zhou X. D.","year":"2020","journal-title":"Frontiers in Psychiatry"}],"container-title":["Developmental Neurobiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/dneu.70060","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/dneu.70060","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/dneu.70060","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T13:18:32Z","timestamp":1790774312000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/dneu.70060"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,30]]},"references-count":46,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2026,10]]}},"alternative-id":["10.1002\/dneu.70060"],"URL":"https:\/\/doi.org\/10.1002\/dneu.70060","archive":["Portico"],"relation":{},"ISSN":["1932-8451","1932-846X"],"issn-type":[{"value":"1932-8451","type":"print"},{"value":"1932-846X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,30]]},"assertion":[{"value":"2026-05-22","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-08-21","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-30","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70060"}}