Gut-derived extracellular vesicle enriched miR-125a-5p mediates cadmium-induced intestinal injury through NF-κB pathway activation

Cadmium (Cd), as a prevalent environmental heavy metal pollutant, has an incompletely elucidated mechanism of intestinal toxicity following oral ingestion. This study aims to elucidate novel mechanisms underlying cadmium-induced intestinal injury. By establishing a murine model of cadmium exposure, it was found that cadmium not only directly disrupts the intestinal barrier structure but also induces intestinal microbiota dysbiosis. Fecal microbiota transplantation (FMT) experiments confirmed that the dysbiotic microbiota alone is sufficient to provoke intestinal injury, indicating that microbial dysregulation serves as a critical amplifier of cadmium toxicity. Further investigation revealed that cadmium exposure reshapes the intestinal microenvironment and alters the miRNA profile of gut-derived extracellular vesicles (EVs), with miR-125a-5p being significantly enriched in EVs from the cadmium-exposed group. Mechanistically, miR-125a-5p directly targets and suppresses TNFAIP3, a negative regulator of the NF-κB pathway, thereby relieving the inhibition of this signaling axis and driving sustained inflammation and barrier dysfunction, while inhibition of miR-125a-5p effectively blocks this toxic effect. This study is the first to delineate the axis of "cadmium exposure - intestinal microbiota dysbiosis - gut EV - miR-125a-5p - TNFAIP3 - NF-κB pathway activation - intestinal injury", providing new insights for the development of biomarkers and targeted interventions for cadmium-related intestinal disorders.