Microbiota-derived TMAO links PM _2.5 exposure to cognitive impairment: A gut–liver–brain axis

Although fine particulate matter (PM _2.5 ) is linked to cognitive impairment, the mechanistic links between pulmonary exposure and neurodegeneration remain poorly understood. This study investigates the role of the gut–liver–brain axis in mediating PM _2.5 -induced neurotoxicity. We demonstrate that three weeks of intratracheal PM _2.5 instillation in mice causes significant memory deficits, impaired hippocampal adult neurogenesis, and reduced synaptic plasticity in both sexes. Metagenomic analysis revealed that PM _2.5 alters gut microbiota composition, specifically by upregulating pathways involved in trimethylamine (TMA) synthesis. This microbial shift led to a systemic increase in the metabolite trimethylamine N-oxide (TMAO) and its accumulation in the hippocampus. Mechanistic experiments revealed that TMAO drives neurotoxicity by activating the hippocampal PERK-mediated endoplasmic reticulum (ER) stress pathway. Critically, these deficits were reversed by suppressing hepatic TMAO production via either pharmacological inhibitors or genetic knockdown. Additionally, hippocampal-specific PERK silencing or dietary resveratrol intervention attenuated hippocampal ER stress, thereby protecting against PM _2.5 -induced cognitive and hippocampal impairments. These results identify the microbial metabolite TMAO as a key mediator of air pollution-related neurotoxicity and highlight the gut–liver–brain axis as a promising therapeutic strategy to counteract the neurological impacts of air pollution.