The neurotoxic potential of microplastics (MPs) is an emerging environmental health crisis. However, the majority of environmental MPs are unable to penetrate the blood-brain barrier (BBB), leaving their mechanism of neurotoxicity largely unknown. Here, we show that oral exposure to pristine polystyrene MPs (which do not translocate to the brain) induces hippocampal-dependent cognitive deficits, impaired neurogenesis, and synaptic loss in mice, without detectable brain particle accumulation. This neurotoxicity is mediated by gut-brain axis disruption, characterized by gut microbiota dysbiosis, altered tryptophan metabolism, and increased permeability of both the intestinal barrier and the BBB. Crucially, hippocampal microglia exhibited a sustained pro-inflammatory shift (M1↑/M2↓) accompanied by defective autophagy. Fecal microbiota transplantation from healthy donors rescued the cognitive impairments and microglial dysfunction, establishing a causal role for the gut microbiota. Integrated multi-omics and correlation analyses identified the commensal bacterium Alloprevotella and the tryptophan-kynurenine metabolite 3-hydroxyanthranilic acid (3-HAA) as key mediators. In vitro, treatment of microglia with fecal supernatant from MPs-exposed mice recapitulated the M1/M2 imbalance, suppressed autophagy, and impaired brain-derived neurotrophic factor (BDNF) maturation. Remarkably, supplementation with 3-HAA restored autophagy in microglia, which in turn rebalanced their phenotypic polarization and rescued BDNF maturation. Our findings delineate a complete pathway from oral non-BBB-penetrable MPs exposure to cognitive dysfunction, orchestrated through the disruption of gut microbiota-3-HAA-microglial autophagy axis. This work unveils a fundamental indirect mechanism for the neurotoxicity of non-brain-penetrant environmental pollutants and identifies novel microbiota- and metabolite-centric targets for intervention.
Gut-Brain Axis