由于其病因不明确,目前尚无特异性药物治疗复发性和无法治愈的炎症性肠病(IBD)。不健康的饮食习惯在不知不觉中导致了IBD的进展,例如,高盐饮食(HSD)是最被忽视和经常采用的习惯。然而,HSD如何加重IBD进展的分子机制尚未发现。在这里,我们关注的假设是,坏死途径可能参与了HSD加重的IBD过程。为此,在高渗培养条件下,人上皮的不同基因表达(DEGs)谱被用来筛选候选途径。更重要的是,基因表达操作,免疫微环境检测,RIPK3/MLKL基因敲除(KO),以野生型(WT)小鼠为研究对象,研究高盐摄入对IBD进展的促进作用。根据我们目前的结果,在盐或蔗糖诱导的高渗培养条件下,人正常结肠上皮细胞NCM460的基因表达谱发生了显着变化。RIPK3在两种条件下均显著上调。此外,通过额外的NaCl孵育,小鼠结肠上皮细胞CT26的生长受到时间和剂量依赖性的抑制。自噬,LPS预处理激活并增强了坏死途径。HSD以剂量依赖性方式在体内显著加剧DSS诱导的IBD症状。此外,RIPK3-/-和MLKL-/-小鼠在体内表现出严重的IBD症状。总的来说,结果表明,HSD通过坏死激活加重了IBD的进展,为IBD的临床治疗提供了新的策略和有希望的靶点。
Due to its unclear etiology, there is no specific medicine to cure the recurrent and incurable inflammatory bowel disease (IBD). Unhealthy dietary habits unconsciously contributed to the progression of IBD, for example a High-Salt-Diet (
HSD) is the most neglected and frequently adopted habit. However, the molecular mechanism of how
HSD aggravates the progression of IBD has yet to remain uncovered. Herein, we focus on the hypothesis that necroptosis pathway may be involved in the process of IBD exacerbated by
HSD. To this end, different gene expression (DEGs) profiles of human epithelia under hypertonic culture conditions were applied to screen candidate pathways. What\'s more, gene expression manipulation, immune microenvironment detection, RIPK3/MLKL gene knockout (KO), and wild-type (WT) mice were carried out to research the promotion of IBD progression under treatments of high salt intake. Based on our present results, gene expression profiles in human normal colon epithelia cell NCM460 were significantly changed under salt- or sucrose-induced hypertonic culture conditions. RIPK3 was significantly up-regulated under both conditions. Furthermore, mice colon epithelia cell CT26 growth was inhibited in a time- and dose-dependent manner by extra NaCl incubation. Autophagy, and Necroptosis pathways were activated and enhanced by LPS pretreatment.
HSD significantly exacerbated DSS-induced IBD symptoms in vivo in a dose-dependent manner. Moreover, RIPK3-/- and MLKL-/- mice presented severe IBD symptoms in vivo. Overall, the results demonstrated that
HSD aggravated the IBD progression via necroptosis activation, providing novel strategies and promising targets for the clinical treatment of IBD.