PUFAs add fuel to Crohn’s disease-associated AIEC-induced enteritis by exacerbating intestinal epithelial lipid peroxidation

作者：Weiwei Wen, Yihan Xu, Wenwei Qian, Liangyu Huang, Jianfeng Gong, Yi Li, Weiming Zhu, Zhen Guo · 发表于：Gut Microbes · 年份：2023 · DOI：10.1080/19490976.2023.2265578 · 被引用次数：39 · 研究领域：Hormonal Regulation and Hypertension、Vitamin C and Antioxidants Research、Helicobacter pylori-related gastroenterology studies

Polyunsaturated fatty acids (PUFAs) have been shown to exacerbate Crohn’s disease (CD) by promoting lipid peroxidation (LPO) of intestinal epithelial cells (IECs). Dysbiosis of the gut microbiota may play a crucial role in this process. CD patients often exhibit an increased abundance of Escherichia coli (E. coli) in the gut, and the colonization of adherent-invasive E. coli (AIEC) is implicated in the initiation of intestinal inflammation in CD. However, the impact of AIEC on LPO remains unclear. In this study, we observed that AIEC colonization in the terminal ileum of CD patients was associated with decreased levels of glutathione peroxidase 4 (GPX4) and ferritin heavy chain (FTH) in the intestinal epithelium, along with elevated levels of 4-Hydroxynonenal (4-HNE). In vitro experiments demonstrated that AIEC infection reduced the levels of GPX4 and FTH, increased LPO, and induced ferroptosis in IECs. Furthermore, arachidonic acid (AA) and docosahexaenoic acid (DHA) supplementation in AIEC-infected IECs significantly aggravated LPO and ferroptosis. However, overexpression of GPX4 rescued AIEC-induced LPO and ferroptosis in IECs. Our results further confirmed that AIEC with AA supplementation, associated with excessive LPO and cell death in IECs, worsened colitis in the DSS mouse model and induced enteritis in the antibiotic cocktail pre-treatment mouse model in vivo. Moreover, treatment with ferrostatin-1, a ferroptosis inhibitor, alleviated AIEC with AA supplementation-ind...