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Updated: Mar 28, 2026
Author Spotlight: Induced Microglia-Like Cell Technology to Shed Light on the Role of Microglial Dysfunction in Neuropsychiatric Disorders
Published on: September 6, 2024
Microbiota-Driven microglia reprogramming reverses depressive-like behaviors through Peripheral-to-Central immune
Jing Wu1,2, Xingyu Zhou1, Tiandong Luo1
1Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
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.
Insights
Gut microbiota interventions can reverse stress-induced depression-like behaviors by reprogramming brain microglia. This study identifies specific microglial subtypes and epigenetic changes involved in major depressive disorder (MDD) and their reversal through microbiota remodeling.
Area of Science:
- Neuroscience
- Immunology
- Microbiology
- Psychiatry
Background:
- Major depressive disorder (MDD) is linked to neuroimmune dysregulation, with microglia implicated.
- The specific microglial subpopulations and mechanisms involved in MDD remain unclear.
- Chronic unpredictable mild stress (CUMS) is a model for inducing depression-like phenotypes.
Purpose of the Study:
- To investigate the role of gut microbiota in modulating microglial responses in MDD.
- To identify specific microglial subtypes and their activation pathways affected by stress and microbiota intervention.
- To explore the epigenetic mechanisms underlying stress-induced immune cell alterations and their reversal.
Main Methods:
- Utilized chronic unpredictable mild stress (CUMS) model in mice.
- Administered gut microbiota intervention via bedding exchange from control mice.
- Employed CD45+ immune cell sorting, single-cell RNA sequencing (scRNA-seq), and ATAC-seq for comprehensive immune cell profiling and epigenetic analysis.
Main Results:
- Gut microbiota intervention reversed CUMS-induced behavioral deficits.
- CUMS altered transcriptional profiles primarily in microglia and monocytes; reversal was mainly observed in microglia (85%).
- Homeostatic microglia 2 (HM2) subtype responded to CUMS, initiating an activation trajectory reversed by microbiota intervention. Epigenetic dysregulation was partially restored, improving immune cell function.
Conclusions:
- Gut microbiota intervention ameliorates depressive phenotypes by dynamically reprogramming microglia through a periphery-CNS immune axis.
- This study highlights specific microglial subtypes (HM2) and epigenetic regulators (Klf2) in MDD pathogenesis.
- Findings offer novel targets for antidepressant strategies focusing on neuro-immune interactions and microbiota modulation.
