Microglial State Reprogramming Across the Gut–Brain–Immune Axis: Limitations and Therapeutic Prospects of Traditional Chinese Medicine

Abstract

Bidirectional communication among the gut microbiota, immune system, and central nervous system shapes microglial maturation and responsiveness. This review evaluates microglia as context-dependent neuroimmune integrators rather than fixed M1/M2 populations. It organizes the literature into three linked layers: gut-derived 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-resolved microglial profiling. Therefore, improvements in cognition or inflammatory markers cannot by themselves, establish microbiota-mediated microglial reprogramming. We critically distinguish direct from indirect evidence, replace binary polarization language with state-specific 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-resolved multi-omics, preregistered clinical trials, and mediation analyses that connect target engagement to patient-relevant outcomes. TCM is thus best regarded as a testable source of multicomponent interventions, not yet a validated systems-level therapy for the gut–brain–immune axis.