Longitudinal multi-omics decipher chlorinated paraffin 52 disruption of gut-brain axis homeostasis in HFD-fed mice

The global rise in metabolic diseases linked to high-fat diet (HFD) patterns has coincided with the emergence of chlorinated paraffins (CPs) as persistent, toxic environmental contaminants detected across food systems, raising dual concerns for public health. While studies have demonstrated CPs-induced intestinal damage and neurotoxicity in bee and zebrafish models, their effects on gut-brain axis homeostasis in HFD-fed mice under metabolic disease conditions remain unexplored. Here, we found that CP52 disrupt intestinal homeostasis, impair barrier function, reduce tight junction protein expression, and induce mucosal damage and enterocyte apoptosis. Concurrently, CP52 exposure triggers neuronal damage, Tau protein accumulation, and activation of neurodegenerative signaling pathways under HFD condition. The observed changes in metabolites serve as a critical bridge, linking the pronounced association between gut dysbiosis and brain damage. Our findings reveal that CPs disrupt gut-brain axis homeostasis under HFD conditions, elucidating the complex toxicity mechanisms of CP52, which significantly impair intestinal physiology and the brain microenvironment, thereby emphasizing the urgent need to address CPs contamination in metabolic health.