Cantharidin-induced enterotoxicity: A molecular insight into intestinal barrier breakdown

Cantharidin (CTD), a terpenoid from Mylabris beetles, has been used in traditional Chinese medicine for cancer treatment ("using toxicity to combat toxicity"), but its clinical use is limited by unclear enterotoxicity mechanisms. This study integrates omics and traditional toxicology to decode its intestinal injury mechanisms in the context of traditional applications.

This study aimed to study the damage of CTD to the intestine and preliminarily explore its potential.

In this study, mice were exposed to CTD and the resulting colon injury was assessed by histology and western blotting. The effects of CTD on intestinal flora were analyzed using 16S ribosomal RNA sequencing technology. Integrated transcriptomics and network toxicology were used to explore the mechanism of CTD-induced enterotoxicity.

The results showed that CTD reduced body weight and the positive expression areas of acid proteins, shortened the colon and villi, and down-regulated the relative expression of occludin, claudin-1, and zonular occludens (ZO)-1. In addition, CTD decreased the relative abundance of probiotic Akkermansia muciniphila, and increased the relative abundance of enteric pathogens such as Helicobacter hepaticus and H. ganmani. After exposure to CTD, 687 differentially expressed genes were identified. These genes were mainly associated with cytokine and cytokine receptor interaction, and chemokine and Toll-like receptor signaling pathways were significantly enriched. Six potential core targets involved in intestinal injury induced by CTD were further screened, and the reliability of the targets was verified by molecular docking and quantitative polymerase chain reaction.

In conclusion, this study found that CTD disrupted the intestinal barrier in mice, damaged colon tissue, and disrupted intestinal microbiota homeostasis. The mechanism may involve up-regulation of mRNA expression levels of Ifng, Cxcl9, Cxcl 10, Ccl4, Il1a, and Il1b, and activation of related inflammatory pathways.