Epidemiological evidence suggests that occupational or environmental exposure to Chlorpyrifos (CPF) is associated with Alzheimer's disease (AD)-like behaviors. However, the exact mechanisms remain elucidate. This study investigates the impact of environmentally relevant concentrations of CPF on AD progression in 5XFAD mice and explores potential intervention strategies. Our results demonstrate that CPF exposure exacerbates AD symptoms in 5XFAD mice, characterized by cognitive deficits, increased amyloid-β accumulation, neuroinflammation, and neuron loss. Mechanistically, CPF induces gut microbiota dysbiosis in 5XFAD mice, with significant decreases in beneficial taxa such as Muribaculaceae and Faecalibaculum, and a marked increase in pathogenic genus Tyzzerella. This dysbiosis leads to intestinal structural damage, compromised barrier function, and disruption of arginine biosynthesis pathway. Therefore, disruption of this pathway in gut microbiota metabolites results in a significant decrease in L-Citrulline (L-Cit) concentration, thereby causing a marked reduction in serum L-Arginine (L-Arg) levels. Importantly, these altered metabolites upregulate the transcription of hippocampal neuroinflammation-related pathway spectrum, particularly through significant upregulation of Casp1 and Ccl3, indicating the occurrence of neuroinflammation. L-Cit supplementation significantly increase serum L-Arg levels in CPF-exposed 5XFAD mice, thereby alleviating AD pathology and improving cognitive function. Collectively, these findings reveal a novel arginine metabolism-mediated mechanism along the microbiota-gut-brain axis in CPF-mediated AD pathogenesis and underscore the therapeutic potential of L-Cit for CPF-related neurodegenerative disorders.
