Between intestinal inflammation and renal disulfidptosis caused by carbendazim exposure in common carp: Insights into the potential gut-kidney axis

Carbendazim induces renal disulfidptosis in common carp. • Carbendazim triggers intestinal inflammation and gut microbiota dysbiosis. • Inflammatory cytokines are elevated in the intestine, serum, and kidney, may act as mediators of gut-kidney cross-talk. • IL-1β may drive disulfidptosis under carbendazim stress. Carbendazim is a widely used fungicide and a pervasive water contaminant detected in aquaculture systems worldwide, yet its chronic toxicity mechanisms in farmed fish remain poorly understood. Here, we exposed common carp ( Cyprinus carpio ), a globally significant aquacultural species, to environmentally relevant concentrations of carbendazim (10 and 20 μg/L) for 30 days. We found that carbendazim dose-dependently reduced weight gain (WG), weight gain ratio (WGR), and specific growth rate (SGR). Histology revealed both intestine and kidney damage. Intestinal transcriptomics showed significant up-regulation of genes in toll-like receptor, cytosolic DNA-sensing, RIG-I-like receptor, and NOD-like receptor pathways, meaning that carbendazim induced inflammation in intestines. Metagenomics revealed expansion of pro-inflammatory bacteria ( Aeromonas , Plesiomonas , Acinetobacter ) and enrichment of microbial immune-evasion genes, suggesting that the inflammatory response may be amplified by gut microbiota dysbiosis. In the kidney, carbendazim induced inflammation and altered disulfidptosis markers: SLC7A11 , GYS1 , abi2a , TLN1 , NDUFA11 , and NDUFB10 . The inflammatory cytokines IL-1β, TNF-α, and IL-6, which are elevated in the intestine, serum, and kidney, may serve as mediators of gut-kidney communication. Furthermore, in vitro epithelioma papulosum cyprini (EPC) cell experiments revealed that carbendazim increased both IL-1β and disulfidptosis markers. siRNA knockdown of IL-1β significantly attenuated the changes in all the disulfidptosis-related factors, demonstrating a potential mediator role of this cytokine. While our correlative in vivo data and mechanistic in vitro findings suggest cytokine-mediated cross-talk, we acknowledge that definitive proof of the renal IL-1β originating specifically from the gut awaits lineage-tracing or organ-specific neutralization studies. This is the first study to establish a link between pesticide exposure, gut-kidney axis perturbation, and disulfidptosis in an aquatic vertebrate, providing testable biomarkers and mechanistic hypotheses for future causality validation.