Exposure to triclocarban (TCC), a commonly used antibacterial agent, has been shown to induce significant intestine injuries and colonic inflammation in mice. However, the detailed mechanisms by which TCC exposure triggered enterotoxicity remain largely unclear. Herein, intestinal toxicity effects of long-term and chronic TCC exposure were investigated using a combination of histopathological assessments, metagenomics, targeted metabolomics, and biological assays. Mechanically, TCC exposure caused induction of intestinal aryl hydrocarbon receptor (AhR) and its transcriptional target cytochrome P4501A1 (Cyp1a1) leading to dysfunction of the gut barrier and disruption of the gut microbial community. A large number of lipopolysaccharides (LPS) are released from the gut lumen into blood circulation owing to the markedly increased permeability and gut leakage. Consequently, toll-like receptor-4 (TLR4) and NF-κB signaling pathways were activated by high levels of LPS. Simultaneously, classic macrophage phenotypes were switched by TCC, shown with marked upregulation of macrophage M1 and downregulation of macrophage M2 that was accompanied by striking upregulation of proinflammatory factors such as Il-1β, Il-6, Il-17, and Tnf-α in the intestinal lamina propria. These findings provide new evidence for the TCC-induced enterotoxicity.

中文翻译：

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长期接触三氯卡班通过触发 AhR 介导的肠道炎症并破坏小鼠微生物群落而引起肠毒性

接触三氯卡班 (TCC)（一种常用的抗菌剂）已被证明会引起小鼠严重的肠道损伤和结肠炎症。然而，TCC 暴露引发肠毒性的详细机制仍不清楚。在此，结合组织病理学评估、宏基因组学、靶向代谢组学和生物测定，研究了长期和慢性 TCC 暴露的肠道毒性影响。从机械角度来看，TCC 暴露会诱导肠道芳基碳氢化合物受体 (AhR) 及其转录靶标细胞色素 P4501A1 ( Cyp1a1 )，从而导致肠道屏障功能障碍和肠道微生物群落破坏。由于通透性和肠渗漏显着增加，大量脂多糖（LPS）从肠腔释放到血液循环中。因此，高水平的 LPS 会激活 Toll 样受体 4 (TLR4) 和 NF-κB 信号通路。同时，TCC 改变了经典的巨噬细胞表型，表现为巨噬细胞 M1 显着上调，巨噬细胞 M2 下调，同时伴随着促炎因子（如Il-1β、Il-6、Il-17和Tnf - α）的显着上调。肠固有层。这些发现为 TCC 诱导的肠毒性提供了新的证据。