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Oral exposure to non-brain-penetrable microplastics induces neurotoxicity via disrupting the gut microbiota-tryptophan metabolism-microglial autophagy cascade.
Summary
Mice that ate microplastics showed memory problems and brain inflammation, even though the tiny plastic particles never actually reached their brains. Instead, the plastics disrupted gut bacteria in a way that sent harmful signals to the brain, and restoring healthy gut bacteria (or adding back a specific gut-produced compound) reversed the damage. This suggests microplastics may harm our brains indirectly through our gut health, and points to potential ways to protect against this damage in the future.
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.