Abstract：
OBJECTIVE: Deoxynivalenol (DON), namely vomitoxin, is one of the most prevalent fungal toxins in cereal crops worldwide. However, the underlying toxic mechanisms of DON remain largely unknown.
METHODS: DON exposure-caused changes in the murine plasma metabolome and gut microbiome were investigated by an LC-MS/MS-based nontargeted metabolomics approach and sequencing of 16S rRNA in fecal samples, respectively. Cellular models were then used to validate the findings from the metabolomics study.
RESULTS: DON exposure increased intestinal barrier permeability evidenced by its-mediated decrease in colonic Claudin 5 and E-cadherin, as well as increases in colonic Ifn-γ, Cxcl9, Cxcl10, and Cxcr3. Furthermore, DON exposure resulted in a significant increase in murine plasma levels of deoxycholic acid (DCA). Also, DON exposure led to gut microbiota dysbiosis, which was associated with DON exposure-caused increase in plasma DCA. In addition, we found not only DON but also DCA dose-dependently caused a significant increase in the levels of IFN-γ, CXCL9, CXCL10, and/or CXCR3, as well as a significant decrease in the expression levels of Claudin 5 and/or E-cadherin in the human colonic epithelial cells (NCM460).
CONCLUSIONS: DON-mediated increase in DCA contributes to DON-caused intestinal injury. DCA may be a potential therapeutic target for DON enterotoxicity.
METHODS: DON exposure-caused changes in the murine plasma metabolome and gut microbiome were investigated by an LC-MS/MS-based nontargeted metabolomics approach and sequencing of 16S rRNA in fecal samples, respectively. Cellular models were then used to validate the findings from the metabolomics study.
RESULTS: DON exposure increased intestinal barrier permeability evidenced by its-mediated decrease in colonic Claudin 5 and E-cadherin, as well as increases in colonic Ifn-γ, Cxcl9, Cxcl10, and Cxcr3. Furthermore, DON exposure resulted in a significant increase in murine plasma levels of deoxycholic acid (DCA). Also, DON exposure led to gut microbiota dysbiosis, which was associated with DON exposure-caused increase in plasma DCA. In addition, we found not only DON but also DCA dose-dependently caused a significant increase in the levels of IFN-γ, CXCL9, CXCL10, and/or CXCR3, as well as a significant decrease in the expression levels of Claudin 5 and/or E-cadherin in the human colonic epithelial cells (NCM460).
CONCLUSIONS: DON-mediated increase in DCA contributes to DON-caused intestinal injury. DCA may be a potential therapeutic target for DON enterotoxicity.
摘要：
目标：脱氧雪腐镰刀菌烯醇（DON），即呕吐毒素,是全球谷类作物中最普遍的真菌毒素之一。然而,DON的潜在毒性机制仍然未知。
方法：通过基于LC-MS/MS的非靶向代谢组学方法和粪便样品中16SrRNA的测序，研究了DON暴露引起的鼠代谢组和肠道微生物组的变化，分别。然后使用细胞模型来验证代谢组学研究的发现。
结果：DON暴露可增加肠道屏障通透性，其介导的结肠claudin5和E-cadherin的减少证明，以及结肠Ifn-γ的增加，Cxcl9、Cxcl10和Cxcr3。此外，DON暴露导致小鼠血浆脱氧胆酸（DCA）水平显着增加。此外，DON暴露导致肠道微生物群生态失调，这与DON暴露引起的血浆DCA增加有关。此外,我们发现，不仅DON，而且DCA剂量依赖性地引起IFN-γ水平的显着增加，CXCL9、CXCL10和/或CXCR3,以及人结肠上皮细胞(NCM460)中紧密连接蛋白5和/或E-钙黏着蛋白的表达水平的显著降低。
结论：DON介导的DCA增加有助于DON引起的肠损伤。DCA可能是DON肠毒性的潜在治疗靶点。
方法：通过基于LC-MS/MS的非靶向代谢组学方法和粪便样品中16SrRNA的测序，研究了DON暴露引起的鼠代谢组和肠道微生物组的变化，分别。然后使用细胞模型来验证代谢组学研究的发现。
结果：DON暴露可增加肠道屏障通透性，其介导的结肠claudin5和E-cadherin的减少证明，以及结肠Ifn-γ的增加，Cxcl9、Cxcl10和Cxcr3。此外，DON暴露导致小鼠血浆脱氧胆酸（DCA）水平显着增加。此外，DON暴露导致肠道微生物群生态失调，这与DON暴露引起的血浆DCA增加有关。此外,我们发现，不仅DON，而且DCA剂量依赖性地引起IFN-γ水平的显着增加，CXCL9、CXCL10和/或CXCR3,以及人结肠上皮细胞(NCM460)中紧密连接蛋白5和/或E-钙黏着蛋白的表达水平的显著降低。
结论：DON介导的DCA增加有助于DON引起的肠损伤。DCA可能是DON肠毒性的潜在治疗靶点。
