High-fat diet primes vulnerability to polyethylene terephthalate nanoplastic toxicity via the gut microbiota-metabolism axis.

This study investigated whether a high-fat diet (HFD) acts as a priming factor that increases intestinal susceptibility to polyethylene terephthalate nanoplastics (PET-NPs, 100 nm, 25 mg/kg/d). After a 12-week combined exposure in mice, HFD priming potentiated the deleterious effects of PET-NPs on intestinal structure and function. Compared to HFD alone, the combined exposure (HFD + PET-NPs) exacerbated intestinal barrier injury, as evidenced by reduced tight junction proteins (Claudin-1, Occludin, and ZO-1), increased permeability, and disrupted histoarchitecture. These mice also exhibited enhanced oxidative stress, elevated inflammation (IL-1β, IL-6, and TNF-α), and exacerbated gut microbiota dysbiosis, characterized by a Firmicutes-dominated structure with decreased Lactobacillus and increased pro-inflammatory genera (Faecalibaculum, Lachnoclostridium, Romboutsia, and norank_f__Desulfovibrionaceae). Metabolomic analysis identified glycerophospholipid metabolism as the primary perturbed pathway, with additional alterations in sphingolipid, galactose, pentose phosphate, and tryptophan metabolism. Together, these findings suggest that HFD primes the gut for enhanced PET-NPs induced injury through microbiota-metabolism interactions, offering correlative insights into combined dietary-environmental health risks.