Integrative transcriptome and microbiome analysis reveals ferroptosis-driven duodenal damage caused by Ochratoxin A...

Ochratoxin A (OTA), a prevalent mycotoxin produced by fungal contaminants, poses a significant threat to intestinal health. That can induce ferroptosis, a regulated iron-dependent cell death by disrupting duodenal epithelium and gut microbiota homeostasis. We exposed mice to OTA (2 mg/kg body weight/day) for seven days and assessed duodenal damage using histological analysis, transmission electron microscopy (TEM), transcriptomics, quantitative real-time PCR (qRT-PCR), Western blotting, immunofluorescence, biochemical assays, and 16S rRNA sequencing of cecal contents. OTA markedly reduced body weight from day 2 onwards and significantly elevated serum lipopolysaccharides (LPS) (P<0.05), duodenal malondialdehyde (MDA), and iron levels compared to the control group. OTA significantly diminished duodenal antioxidant defenses, including glutathione, SOD, CAT, and total antioxidant capacity (T-AOC), and caused villus atrophy, crypt hyperplasia, and mitochondrial shrinkage with cristae loss, which are the hallmarks of ferroptosis. Transcriptomic analysis revealed 769 differentially expressed genes (DEGs), including 134 upregulated and 635 downregulated genes, with 26 overlapping ferroptosis-regulating genes (FerroDb). Among these, four key genes SLC7A11, GSTM1, CP, and SLC40A1 were downregulated, which are major regulators of redox and iron homeostasis, and were enriched in ROS/lipid metabolism pathways. Microbiome profiling showed augmented diversification, altered Bacteroidota abundance and enrichment of pathogenic microbiota (e.g., Oscillibacter and Barnesiella), linking ferroptosis with dysbiosis. These findings demonstrate that OTA induces duodenal ferroptosis through dual microbiota-duodenum axis, where microbial dysbiosis amplifies redox imbalance and iron homeostasis. Ferroptotic inhibitors may preserve the gut health in animals and humans exposed to fungal contaminants.