Ochratoxin A induces abnormal tryptophan metabolism in the intestine and liver to activate AMPK signaling pathway

Background Ochratoxin A (OTA) is a mycotoxin widely present in raw food and feed materials and is mainly produced by Aspergillus ochraceus and Penicillium verrucosum. Our previous study showed that OTA principally induces liver inflammation by causing intestinal flora disorder, especially Bacteroide...
Ausführliche Beschreibung

Background Ochratoxin A (OTA) is a mycotoxin widely present in raw food and feed materials and is mainly produced by Aspergillus ochraceus and Penicillium verrucosum. Our previous study showed that OTA principally induces liver inflammation by causing intestinal flora disorder, especially Bacteroides plebeius (B. plebeius) overgrowth. However, whether OTA or B. plebeius alteration leads to abnormal tryptophan-related metabolism in the intestine and liver is largely unknown. This study aimed to elucidate the metabolic changes in the intestine and liver induced by OTA and the tryptophan-related metabolic pathway in the liver. Materials and methods A total of 30 healthy 1-day-old male Cherry Valley ducks were randomly divided into 2 groups. The control group was given 0.1 mol/L $ NaHCO_{3} $ solution, and the OTA group was given 235 μg/kg body weight OTA for 14 consecutive days. Tryptophan metabolites were determined by intestinal chyme metabolomics and liver tryptophan-targeted metabolomics. AMPK-related signaling pathway factors were analyzed by Western blotting and mRNA expression. Results Metabolomic analysis of the intestinal chyme showed that OTA treatment resulted in a decrease in intestinal nicotinuric acid levels, the downstream product of tryptophan metabolism, which were significantly negatively correlated with B. plebeius abundance. In contrast, OTA induced a significant increase in indole-3-acetamide levels, which were positively correlated with B. plebeius abundance. Simultaneously, OTA decreased the levels of ATP, $ NAD^{+} $ and dipeptidase in the liver. Liver tryptophan metabolomics analysis showed that OTA inhibited the kynurenine metabolic pathway and reduced the levels of kynurenine, anthranilic acid and nicotinic acid. Moreover, OTA increased the phosphorylation of AMPK protein and decreased the phosphorylation of mTOR protein. Conclusion OTA decreased the level of nicotinuric acid in the intestinal tract, which was negatively correlated with B. plebeius abundance. The abnormal metabolism of tryptophan led to a deficiency of $ NAD^{+} $ and ATP in the liver, which in turn activated the AMPK signaling pathway. Our results provide new insights into the toxic mechanism of OTA, and tryptophan metabolism might be a target for prevention and treatment. Graphical Abstract Ausführliche Beschreibung