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Microbiota-Driven microglia reprogramming reverses depressive-like behaviors through Peripheral-to-Central immune crosstalk

Molecular Psychiatry (2026)Cite this article

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Abstract

Major depressive disorder (MDD) is a major psychiatric condition associated with neuroimmune dysregulation. Microglia, the principal innate immune cells of the central nervous system, have been implicated in MDD. Nevertheless, the specific subpopulations involved and the mechanisms that govern their responses are still elusive. Here, we found that gut microbiota intervention using bedding from control non-stressed mice reverses chronic unpredictable mild stress (CUMS)-induced alterations in behavior. Using CD45+ immune cell sorting and single-cell RNA sequencing (scRNA-seq), we built an atlas of brain-resident microglia and non-microglial immune cells in the central and peripheral compartments. CUMS primarily induced transcriptional alterations in microglia and monocytes, while the reversed changes induced by bedding exchange mainly detected in microglia (85%). Among the microglial subtypes, homeostatic microglia 2 (HM2) primarily responded to CUMS. HM2 shaped microglial states through activation trajectory: the HM2→chemokine-related microglia 3→inflame microglia 1, which could be reversed by bedding exchange. Brain Mdcs served as the mainly immune cells interact with microglia. Furthermore, we systematically characterized alterations in the myeloid-derived cells across the brain, skull, and peripheral blood mononuclear cells (PBMC). Meanwhile, CUMS disrupted immune cell differentiation by suppressing chromatin openness in global accessibility sequencing analyses, and Krüppel-like factors Klf2 emerged as a master regulator expressed in monocytes and HM2 microglial subtype. Remarkably, microbiota remodeling partially reversed this epigenetic dysregulation, restoring immune cell migration and activation processes. In summary, this study revealed that gut microbiota intervention ameliorates depressive phenotypes by dynamically reprogramming microglia via the “periphery-CNS immune” axis, providing a novel entry for antidepressant strategies targeting neuro-immune interactions.

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Fig. 1: Bedding exchange (BDex) reverses depression-like behaviors and gut microbiota alteration in CUMS mice.
Fig. 2: CUMS induces distinct alterations in microglia subtype composition and gene expression.
Fig. 3: Microglial gene networks link to human psychiatric disorders and reveal disrupted cell-cell communication.
Fig. 4: CUMS alters microglial activation trajectories via KLF2 regulation, reversed by BDex intervention.
Fig. 5: Monocytes mediate peripheral-to-CNS immune communication disrupted by CUMS.
Fig. 6: Chromatin accessibility changes underlie CUMS-induced immune dysregulation.

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Acknowledgements

This work was supported by Chongqing medical scientific research project (Joint project of Chongqing Health Commission and Science and Technology Bureau, 2026DBXM002), the National Key R&D Program of China (STI2030-Major Projects2021ZD0200600), the National Natural Science Foundation Project of China(82571748, 82471545, 82401784, 32400850, 82401523, 82501836, 82501469, 82501837), National Reserve Talent Project in the Health and Wellness Sector of Chongqing (HBRC202410, HBRC202417), China Postdoctoral Science Foundation (2024MD754023, 2025MD774171, 2025T180580), the Key Project of the Natural Science Foundation of Chongqing (Chongqing Science and Technology Development Foundation) under Grant No. 2024NSCQ-KJFZZDX0005, the New Chongqing Youth Innovation Talent Project (Life and Health) under Grant No. 2024NSCQ-qncxX0029.

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  1. These authors contributed equally: Jing Wu, Xingyu Zhou.

Authors and Affiliations

  1. Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China

    Jing Wu, Xingyu Zhou, Tiandong Luo, Xin Wang, Hongzhou Zuo, Ruijing Yang, Ruimin Tian, Yiyuan Wu, Yang Wu, Wenxia Jiang, Jie Yang, Yu Huang, Jianping Zhang, Yifan Li, Ping Liu, Xunmin Tan, Minghao Yuan & Peng Zheng

  2. NHC Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, Chongqing Medical University, Chongqing, China

    Jing Wu, Yang Wu & Peng Zheng

  3. Department of Psychology, University of Oslo, Oslo, Norway

    Yunpeng Wang

  4. Department of Psychiatry, College of Medicine, SUNY Upstate Medical University, Syracuse, NY, USA

    Ma-Li Wong & Julio Licinio

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Contributions

PZ conceived, designed, and supervised the project; XW, RY and YW performed the animal experiments; RT, YYW and WJ processed the sequencing samples; YPW, JW and YH performed 16S rRNA analysis; JZ, YL and PL participated in flow cytometry sorting experiments; XT, MY and HZ participated in ATAC data analysis; JW and XZ performed Single-Cell RNA Sequencing analysis and wrote the manuscript; MLW, JL and PZ revised the manuscript and provided guidance for experiments and analysis. All the authors validated and approved the final manuscript.

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Correspondence to Peng Zheng.

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Wu, J., Zhou, X., Luo, T. et al. Microbiota-Driven microglia reprogramming reverses depressive-like behaviors through Peripheral-to-Central immune crosstalk. Mol Psychiatry (2026). https://doi.org/10.1038/s41380-026-03545-z

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